Electrolyte and water balance


Electrolyte and water balance


Electrolyte and water balance


Electrolyte and water balance

8.1 Water balance and fluid compartments

Lothar Thomas

8.1.1 Water and electrolyte balance

The term water metabolism describes the balance between the intake and the excretion of water. The cell membrane separates the intracellular fluid compartment (ICF) from the extracellular fluid compartment (ECF). It is freely permeable to water, but not to electrolytes. Based upon the free movement of water between the ICF and the ECF, the osmolality, which is defined as the relationship of electrolytes to free water, is maintained uniform and constant.

Changes in the organism’s water homeostasis are classified as hypo osmolar or hyper osmolar disturbances, depending upon whether an excess or a deficiency of water, relative to the dissolved substances (solutes), is present. Water comprises 55–65% of body weight, depending upon gender, age and body fat, and its distribution between the ICF and the ECF is 2 : 1. In the ECF 80% of the water is found in the interstitial space, and 20% in the intravascular space (circulating blood volume).

Na+ is the predominant cation in the ECF, and its concentration in the plasma reflects the osmolality. In the ICF, K+ is the most important cation. The different pattern of distribution of the cations is maintained by the energy and oxygen-dependent Na+-K+ pump of the cell membrane. If there is a deficiency in energy or oxygen, the Na+-K+ pump becomes insufficient, the ion gradients collapse, mainly intracellularly, and the result is cellular edema /1/.

In order to preserve osmotic equilibrium and volume homeostasis of the fluid compartments, the organism maintains an even balance between the uptake and loss of water and electrolytes. This is regulated by:

  • The kidneys, which maintain plasma osmolality within the narrow range of 275–290 mmol/kg through the excretion or the reabsorption of free water solutes. The regulating hormone is arginine vasopressin.
  • The thirst mechanism, which is stimulated by intravascular hypovolemia and hyper osmolality. Thirst is the primary defense mechanism against severe fluid loss.

Water and electrolyte homeostasis is regulated by sensors and neurohumoral mechanisms with effector hormones, which function via negative feedback mechanisms (Tab. 8.1-1 – Neurohormonal mechanisms with regulatory effects on volume homeostasis).

8.1.2 Diagnosis of water and electrolyte disorders

Complex processes underlie the electrolyte and water balance disorders. An integrative analysis is, therefore, necessary. It is made up of the medical history, the medical examination and the laboratory test results.

Important biomarkers and their diagnostic value are listed in Tab. 8.1-2 – Examinations for the diagnosis of disorders of the electrolyte and water balance.

Examinations and findings with regard to two clinical issues are shown in an exemplary manner in Tab. 8.1-3 – Cases of disorders in electrolyte and water balance.

8.1.3 Osmotic equilibrium

Total body water is the determining factor with regard to the osmolality of the fluid compartments of the organism.

The maintenance of osmotic homeostasis is regulated by a change in the renal excretion of free, that is to say osmotically unbound water /2/. The antidiuretic hormone (ADH) arginine vasopressin plays a central role in the regulation of free water. Important stimuli of ADH release are:

  • Increase in plasma osmolality; even fluctuations of less than 2% are registered by the osmoreceptors of the anterolateral hypothalamus, leading to changes in plasma ADH concentrations. The stimulation of ADH secretion begins at a plasma osmolality of 280 mmol/kg, and is maximal at 290 mmol/kg. ADH acts on the kidneys to increase the reabsorption of water (anti- diuresis). Mediated by the osmoreceptors, an increase in plasma osmolality to ≥ 295 mmol/kg results in the sensation of thirst.
  • Changes in the effective arterial blood volume, which are transmitted to the anterolateral hypothalamus by the baroreceptors located in the right atrium. Total body water

Body water derives from dietary intake, retained by the kidneys, and produced by carbohydrate, fat and protein metabolism. Most body water derives from consumption, which is evolutionary programmed by thirst. Urinary water excretion varies to match intake and metabolic generation, less insensible losses. Metabolic water production is directly proportional to energy expenditure and averages 250 to 350 ml per day, a value that can rise after exercise /3/. Daily fluid consumption from all sources in adults in Europe is about 3 liters, even when salt intake is low.

The body water is up to 94% of body weight in the fetus, 75% in the newborn and falls to 60% in children 1 year of age. One transient increase in total body water is between the first and the second years of life, the second one at puberty. Thereafter total body water gradually falls with advancing age to about 60% in males and 50% in females, respectively /2/. Females after puberty have 10% more fat than men, accounting for women’s 10% lower body water.

In temperate climate zones water homeostasis is maintained by the drinking of 1.5 L of water per day. Additionally, the metabolism of foodstuffs and oxidation provide some 600 mL and 300 mL of water, respectively. Regulated water excretion consists of approximately 1 L per day via the kidneys. Daily unregulated (insensible) water loss includes pulmonary loss as humified air (0.3 L), loss in stools (0.1 L) and sweat (0.1 L). Urinary water excretion is regulated by the kidneys, to contain plasma osmolality constant within narrow limits.

8.1.4 Fluid compartments

Total body water is distributed between the extracellular (ECF) and the intracellular fluid compartment (ICF).


The tonicity of a solution, also called effective osmolality, is the concentration of a dissolved substance (e.g., urea) that exerts an osmotic force on the cells in this solution. In hypertonic solution the substance causes a shift of water outside the cell and the cell shrinks to reach a new steady state. In hypotonic solution the cell swells to reach a new steady state. Low-molecular organic substances such as urea, ethanol, methanol or ethylene glycol permeate the cell membrane freely like water, and therefore exert no osmotic force or displacement of water. Non-free permeable substances are Na+, K+ or glucose. Extracellular fluid compartment (ECF)

The ECF consists of all body water outside the cells and represents 45% of the total body water. The ECF includes plasma, interstitial fluid, lymphatic fluid, fluid of dense tissues such as connective tissue and bone, and trans cellular fluid are included in the ECF /2/.


Plasma contains water (93%) and solid constituents (7%), mainly proteins and lipids. The significant cation is Na+, while the significant anions are Cl and HCO3. Since plasma proteins do not permeate intact endothelium, they are critical with regard to the osmotic pressure at the capillary membranes. Plasma colloid osmotic pressure, up to 80% of which is due to albumin, is 28 mmHg. Plasma comprises 7.5% of the total body water.

Interstitial fluid

Interstitial fluid is formed as a result of filtration across the capillary vessel wall which is highly permeable to water, electrolytes and low-molecular organic substances. Approximately 25–50% of circulating proteins are filtered daily into the interstitium; approximately 80% of the fibrinogen remain intravascular. The level and the direction of plasma capillary flow is determined by Starling’s forces. In certain diseases, for example heart failure or liver cirrhosis, changes in Starling’s forces can lead to the formation of edema. Interstitial fluid comprises 20% of the total body water.

Trans cellular fluid

Trans cellular fluids that are secreted from organs such as saliva, pancreatic juice, bile, and intestinal secretions. The sum of trans cellular fluids is approximately 2.5% of the total body water.

Water in connective tissue and bone

This inaccessible water is bound in the dense connective tissue matrix of bone and cartilage. It comprises 15% of total body water. Intracellular fluid compartment (ICF)

In adults, the ICF contains 55% of the total body water. The ionic polarity between extracellular and intracellular fluid compartment is maintained by the Na+-K+ ATPase, which pumps intracellular Na+ out of cells and extracellular K+ into cells in a ratio of 3: 2. The intracellular and extracellular Na+ concentrations are 10 mmol/L and 140 mmol/L, respectively. The intracellular magnesium concentration is approximately 13 mmol/L, while its extracellular concentrations are only 1.5 mmol/L. The intracellular concentrations of Cl and HCO3 are lower than their extracellular levels, while the concentrations of phosphate and sulfate are higher intracellularly /2/.

The tendency of the cells to swell as the intracellular colloidal osmotic pressure rises due to the constant metabolic accumulation of anionic macromolecules is counteracted by the ion pumps of the plasma membrane, which transport equivalent quantities of anions out of the cells. Changes in fluid volume

In order to understand disorders of Na+ and water balance, the knowledge of the interrelationships described below is important /3/.

Changes in extracellular fluid volume (ECFV)

The ECFV is directly dependent upon total body Na+ since Na+ and its anions are restricted to the extracellular fluid and are the most relevant solutes. Expansion or contraction of the ECFV activates regulatory systems with the goal of establishing an equilibrium between intake and excretion of Na+. On a constant intake of Na+, excretion matches intake. If Na+ intake is inadequate low or high, the kidneys perform the task of regulating the extracellular Na+ content. The rate of excretion occurs in response to numerous physiological controls (e.g., hormonal paracrine, nervous) which act to prevent large variations in total body Na+.

Changes in Na+ concentration of the ECFV

The Na+ concentration, and thereby the osmolality, of the ECFV is regulated by the circulating blood volume. Volume sensors, localized in the carotid sinus, the atria of the heart and the afferent renal arterioles, respond via negative feedback (Fig. 8.1-1 – Physiology of the water and volume homeostasis in cases of dehydration). The kidney prevents deleterious changes in electrolyte balance, ECFV, and blood pressure. It is widely accepted that small changes in the ECFV, which correlates directly with Na+ intake, signals adjustments in the kidney to maintain Na+ excretion equal to Na+ dietary intake. Approximately 80% of exchangeable Na+ are present in intestinal and connective tissues, and about 15% of exchangeable Na+ is in plasma /3/.

The Na+ concentration in the phases differ in dependence of the ECF compartment /3/:

  • The thirst reflex, vasopressin and the kidney, maintain a relatively constant Na+ concentration in plasma
  • ECF compartments (cartilage) with high concentrations of negative charged glycosaminoglycan attract Na+ and generate local osmotic pressure favoring swelling.

The measured marker of the concerted activity of the systems is the plasma osmolality. For the maintenance of normal osmolality, the mechanisms mentioned adapt the intra- and extracellular water volumes to the solutes. In order that the osmolality of the ECFV and, in consequence, the tonicity, are held constant within a narrow range the organism can, if thirst develops, imbibe an unlimited quantity of water or, under water load, excrete 15–20 liters/24 hours of free water.

Changes in total body Na+

The ECFV is regulated by the content of body Na+ rather than its concentration. Thus, an excess or deficit in total body water alters the osmolality and Na+ concentration, but contributes little to the ECFV. In fact, the tonicity of the body fluids may vary independently of ECFV. Thus, either hyponatremia or hypernatremia may occur with increased, decreased, or normal ECFV.

Salt sensitivity

One useful definition of salt sensitivity is a difference in mean arterial pressure that is 10 mmHg or greater when salt balance is altered by a combination of diet or loop diuretics /17/. Reduction of the extracellular fluid volume (ECFV)

When salt intake restricts the ECFV a decrease of greater than 5% causes a reversible reduction in renal blood flow. and Na+ excretion. This leads to following mechanisms /3/:

  • Decrease in glomerular filtration rate (GFR)
  • Increase in angiotensin II, aldosterone, norepinephrine epinephrine. The neurohormones contribute to Na+ retention
  • The neurohormones link the ECFV with cardiovascular and sympathetic effects.

A reduction in the GFR causes the rise in the filtration fraction resulting in:

  • Reduced urine volume and high urine osmolality
  • Na+ excretions of greater than 20 mmol/L, and K+ excretions of over 40 mmol/L in the urine
  • A disproportionate rise in serum urea relative to creatinine. Normally the ratio of urea-N (mg/dL)/creatinine (mg/dL) = 10. In volume reduction, it is greater than 20 (conversion: urea × 0.357 = urea-N).
  • An increase in HCO3 in the urine to more than 20 mmol/L due to the exchange of H+ for Na+
  • An increase in serum uric acid because of decreased urinary excretion
  • An increase in serum calcium if, for example, hyperparathyroidism or bone metastases are present
  • The intensification of hyperkalemia in a poorly controlled diabetic, because less glucose is eliminated renally. Increase of the ECFV

When dietary Na+ intake increases, urinary Na+ excretion increases but does not match intake immediately and thus creates a positive Na+ balance. Increasing NaCl intake also increases body water. A volume overload of more than 5% may result in edema, anasarca, pleural effusion and ascites, and occurs frequently in the critically ill. This leads to an increase in body weight, cardiac frequency and arterial blood pressure.

The counter-regulatory mechanisms lead to:

  • An increase in urine volume and in Na+ excretion (over 20 mmol/L)
  • The rise in renal K+ excretion (greater than 40 mmol/L), and hypokalemia in spite of suppression of the renin-angiotensin-aldosterone system, contingent upon volume expansion
  • Hypouricemia; less uric acid is reabsorbed in the proximal tubule and more is secreted distally.

In chronic kidney disease, the time to reach a steady state after a dietary Na+ change is prolonged, making blood pressure more salt sensitive.

8.1.5 Volume homeostasis

Volume homeostasis is determined to a significant degree by the filling of the arterial circulation. The effective arterial blood volume is registered by the baroreceptors in the right atrium of the heart, in the lungs and in the aortic arch. It depends upon the balance between vasoconstrictor and vasodilator substances (Tab. 8.1-1 – Neurohormonal mechanisms with regulatory effects on volume homeostasis).

If the volume homeostasis is disturbed, the result is a change in the water and electrolyte distribution that relies on several factors /2/:

  • In consequence of a reduced filling of the arterial circulation (e.g., due to vasodilation or cardiac insufficiency) compensatory vasoconstriction with the retention of Na+ and water results. The reasons are activation of the sympathetic nervous system, the renin-angiotensin-aldosterone system, and the increased release of ADH.
  • Related to an overfilling of the arterial circulation (e.g., due to volume expansion or tachycardia) vasodilation with augmented water and Na+ excretion results. This is induced by atrial natriuretic peptide, by the kallikrein-kinin system, and by endothelial factors such as prostaglandins and NO. Regulators of electrolyte and water homeostasis

Relevant regulators of electrolyte and water homeostasis are:

  • The renin-angiotensin-aldosterone system
  • The atrial natriuretic peptides
  • The ADH thirst mechanism.

Renin-angiotensin-aldosterone system (RAAS)

A change in renin secretion occurs as a function of water and Na+ intake. Renin secretion is inhibited by table salt intake and stimulated by water intake. It thereby preserves the blood volume during salt and water loss, which may be modified by perspiration, diarrhea or vomiting. The concentration of aldosterone rises rapidly following a decrease in blood volume or a reduction in renal perfusion.

A similarly powerful stimulator of aldosterone synthesis is a rise in plasma K+, the result of which is augmented aldosterone-induced renal K+ excretion. In this way the RAAS prevents hyperkalemia with increased K+ dietary intake or following K+ release due to extreme muscular activity.

In chronic heart failure and liver cirrhosis, hyperaldosteronism with Na+ and water retention, as well as volume expansion, occur. In chronic heart failure, the hyperaldosteronism is based upon decreased renal perfusion, and in liver cirrhosis, on reduced hepatogenous metabolism of aldosterone. See also Chapter 31 – Renin-angiotensin-aldosterone system (RAAS).

Natriuretic peptides

This family consists of three structurally similar peptides (i.e., the atrial natriuretic peptide (ANP), the brain natriuretic peptide (BNP), and the C-type natriuretic peptide (CNP)). ANP and BNP are released during the stretching of cardiac muscle cells, while CNP is formed in numerous organs. The primary functions of ANP and BNP are the regulation of blood volume and blood pressure. They are released into the circulation in situations of high volume or elevated pressure. They activate the natriuretic peptide receptor A (NPR-A) in their target organs, namely, the kidneys and peripheral arteries and, as a result, intracellular concentrations of cyclic guanosine mono phosphate are increased. The consequences are natriuresis, diuresis, vasodilation and the decline of blood pressure. The effect on the kidneys is as follows: ANP and BNP cause dilation of the afferent glomerular arterioles and vasoconstriction of the efferent vessels. In this way, the GFR is increased. In the collecting ducts, ANP and BNP lead to reduced reabsorption of Na+ and, thereby, the excretion of Na+ is augmented. The natriuretic effect of ANP and BNP has two effects.

The Na+ excretion is increased as a result of:

  • A transient increase of the GFR, coupled with an antagonistic effect on RAAS-mediated Na+ reabsorption in the proximal tubule
  • Longer-term inhibition of Na+ reabsorption in the ascending limb of the loop of Henle and the collecting ducts.

ANP and BNP also suppress the release of renin and endothelin, and this represents an additional regulatory effect with regard to vascular tone.

Fluid consumption

The molecular basis of fluid consumption are:

  • The thirst sensors in the brain: neurons in the lamina terminalis centrumventricular organs that are unprotected by the blood-brain barrier. These excitatory neurons drive fluid consumption rapidly as a corrective behavior.
  • Extracellular volume depletion (salt loss) stimulates sets of neurons which respond to angiotensin II and aldosterone. Aldosterone-sensitive neurons express 11β-hydroxysteroid dehydrogenase type 2 (11β HSD2), conferring aldosterone selectivity. Neuronal deletion of 11β HSD2 causes persistent activation of mineralocorticoid receptors by glucocorticoids, increasing salt appetite /3/.

Only rarely is the hyponatremia based upon polydipsia, contingent upon an augmented sensation of thirst. In patients with chronic heart failure and hyponatremia, plasma hypoosmolality can be expected to suppress the secretion of arginine vasopressin. This is, however, not the case; on the contrary, persistently elevated concentrations of arginine vasopressin are found (see also Section 8.5 – Osmolality).

8.1.6 Renal regulation of water and sodium excretion

The kidney filters some 150 liters of isotonic glomerular filtrate (GFR) daily. In order to maintain the water equilibrium, the kidney can form maximally diluted as well as maximally concentrated urine.

Conceptually, renal water regulation is subdivided into the following steps /5/:

  • In the proximal tubule two thirds of the GFR is reabsorbed isotonically. In situations of arterial volume depletion, an increase to 80% is possible.
  • In the descending limb of the loop of Henle water is reabsorbed, while salts remain in the tubule and the osmolality can rise to 1,200 mmol/kg.
  • The ascending limb of the loop of Henle and the distal tubule are relatively impermeable to water. Only salts are reabsorbed, and this is why these parts of the nephron are also called diluting segments. The osmolality of the tubular fluid can fall to below 50 mmol/kg.
  • Water reabsorption is modulated by the antidiuretic hormone arginine vasopressin in the collecting ducts. If the tonicity in the ECF is inappropriately low, the secretion of vasopressin is inhibited and diluted urine is excreted. If the tonicity is high, the secretion of vasopressin is increased, the permeability to water of the collecting ducts is augmented, and the excreted urine is more concentrated. Because water reabsorption is a function of the secretion of arginine vasopressin, urine osmolality can fluctuate from less than 100 up to 1200 mmol/kg.

Refer to Fig. 8.1-2 – Renal-tubular handling of water and electrolytes. Determinants of maximal concentration and dilution of the urine

The delivery of GFR to the diluting segments is dependent upon the volume and the composition of the GFR, and on the function of the proximal tubule. Thus, decreased formation of free water results from:

  • A reduction of the GFR due to volume depletion, heart failure, the nephrotic syndrome and liver cirrhosis
  • The reduction of salt transport in the diluting segments. In this way minimal osmolality is not achieved and the formation of free water is limited; this is the case in interstitial kidney disease or during treatment with loop diuretics and thiazides
  • The maintenance of a corticomedullary concentration gradient in the renal interstitium. The concentration gradient begins with isotonicity at the corticomedullary junction and increases to up to 1,200 mmol/kg at the papilla. This interstitial osmotic gradient is responsible for the reabsorption of water from the collecting ducts into the blood. The development of the gradient is dependent upon effect of vasopressin on the collecting ducts. The development of a normal interstitial osmotic gradient is impaired in interstitial kidney disease, during treatment with loop diuretics, in deficient protein nutrition (reduced urea accumulation), in osmotic diuresis, and in all situations of increased urine flow.

The kidney regulates water excretion as a response to changes in osmolality and in the effective arterial blood volume. Due to the previously described regulatory mechanisms, urine volume can vary from 0.5–20 liter/24 hours. Nonetheless, neither gastrointestinal nor insensible water loss are recognized by the kidneys. Even with maximal renal reabsorption of water, daily renal and extrarenal water loss is of the order of 1 liter per day. The kidneys cannot prevent dehydration and ECF hypertonicity by themselves. Ultimate protection is provided by the thirst mechanism.

Disturbances of the acid-base balance influence the excretion of Na+ and K+. Thus, metabolic acidosis leads to natriuresis due to the inhibition of Na+ reabsorption in the proximal and distal tubules. The natriuresis induces an ECF volume restriction, and this leads to secondary hyperaldosteronism. Glomerulotubular balance (GTB)

The role of the kidney in maintaining Na+ homeostasis is determined by the relationship between the amount of Na+ filtered and the quantity reabsorbed into the peritubular capillaries, which is thereby returned to the systemic circulation /6/. For any alteration in GFR, a proportional change in Na+ reabsorption occurs, so that a fractional reabsorption (GFR × Na+ serum concentration) remains constant. This is owing to the property of the kidneys termed GTB, which maintains a close coupling between GFR and tubular Na+ reabsorption. By this coupling wide variations in distal tubular Na+ delivery are kept within reasonably narrow limits.

A disturbance in the GTB, with an alteration of water and Na+ excretion, can be contingent upon:

  • A change in kidney hemodynamics, for (e.g., in congestive heart failure) or in aortic stenosis above the renal arteries
  • Intraluminal factors such as elevated concentrations of solutes like glucose, amino acids, bicarbonate and chloride
  • Chronic renal insufficiency with a reduction in the number of functional nephrons. If the GFR falls, the Na+ excretion rate of individual nephrons increases. This adaptive mechanism is dependent upon ANP and BNP. But in spite of the elevated concentrations of these peptides, the extracellular fluid volume increases and furthermore, exogenous administration of ANP does not lead to augmented Na+ excretion /7/.

Patients with a GFR below 20 [mL × min–1 × (1.73 m2)–1] have only a low remaining capacity to concentrate urine; on the other hand, they remain sufficiently capable of diluting urine. As chronic renal insufficiency progresses, significant ECF volume expansion develops, with hypertension as a consequence. Free water clearance

The formation and excretion of free water, also called free water clearance, is an important variable in the understanding of renal water regulation /5/.

Urine volume for the excretion of solutes is subdivided conceptually into two compartments:

  • One compartment which is necessary to excrete solutes isoosmotically to the serum
  • A second compartment which describes the quantity of excreted or reabsorbed electrolyte-free water.

Since urea, the substance that is excreted in the urine in the greatest quantity, does not contribute to tonicity, the sum of the Na+ and the K+ concentrations is determined as the measured variable of solutes in the urine. Electrolyte-free water and electrolyte-free urine is the remaining volume after the volume that is required for the generation of an isotonic (to plasma) volume has been subtracted. Positive and negative values represent, respectively, the excretion and the reabsorption of free water.

Sample calculation: excretion of 300 mmol/L Na+ + K+ in 2 liters of urine. Serum osmolality 280 mmol/kg. Excretion of 300/280 = 1.07 liters of isotonic (to serum) urine and 0.93 liters of electrolyte-free urine (free water). Refer to Fig. 8.1-3 – Formation of electrolyte-free water by the kidneys. Acute renal failure (ARF)

Specific changes occur in ARF, depending upon whether pre renal, renal or post renal failure is the reason.

Pre renal acute renal failure

Diagnostic biomarkers:

The oliguria that results is associated with a urine that is very highly concentrated and has a very low Na+ content /6/.

Renal acute renal failure

The renal form of ARF includes diverse entities. The clinical course is divided into four phases, in which different disorders of water and Na+ balance occur:

  • Initiating phase: the initiating phase is dependent upon the extent of renal impairment. It can last, for example, for days if there is acute tubular necrosis due to damage caused by antibiotics, or only for hours in ischemic tubular necrosis. The GFR is normal, and the biochemical findings in urine correspond to those obtained in pre renal acute renal failure. The urinary Na+ excretion is below 20 mmol/L, the fractional Na+ excretion is below 1%.
  • Oliguric phase: if, due to the damage, the kidneys are no longer capable of concentrating the urine, a urinary Na+ excretion of greater than 40 mmol/L ensues and the fractional Na+ excretion is over 2%. A decrease in the GFR follows, and oliguria develops. The urine osmolality corresponds to that of the plasma; it is seldom above 320 mmol/kg.
  • Diuretic phase: the daily urine volume is doubled, the quantity increasing to 2–3 liters. The urine is similar to the plasma filtrate with Na+ and urea excretions are comparable to plasma. The latter does not decrease at the onset of the diuretic phase.
  • Recovery phase: the initial recovery of GFR to about 60% of normal within days or weeks, is followed by a lower rate of recovery to full normal values over several months. Tubular function and concentrating ability are present if the fractional Na+ excretion is below 1%. The urine osmolality rises to greater than 600 mmol/kg, and the Na+ excretion in the urine is below 20 mmol/L.

Post renal acute renal failure

In bilateral obstruction of the ureters a hemodynamic disturbance develops, causing a reduction in the tubular flow rate with enhanced resorption of Na+ and water. The result is reduced urine volume with elevated osmolality and a urinary Na+ excretion below 20 mmol/L, thus, a clinical picture similar to that or pre renal acute renal failure.

8.1.7 Potassium balance

Potassium is the most abundant intracellular cation. Total body potassium is 3500 mmol, corresponding to 50 mmol/kg body weight. 90% of the potassium is found in the intracellular fluid compartment (ICF), 2% in the extracellular fluid compartment (ECF), and 8% in bone and cartilage. The ECF concentration is regulated by the K+ exchange between the ECF and the ICF (internal potassium homeostasis). The loss of only 1% of total body K+ leads to a marked disturbance of the K+ balance, with massive physiological changes.

The daily potassium requirement is 40–50 mmol (1.6–2.0 g; 1 mmol = 40 mg). However, the daily intake of potassium varies considerably. Thus, elderly persons often ingest too little potassium, while persons who eat a lot of fruits and vegetables have a daily intake of 200–250 mmol (8–10 g). The urban population ingests some 62.5 mmol (2.5 g) per day. The minimal requirement is estimated at 40–50 mmol (1.6–2.0 g) /9/. Prospective population studies have shown that stroke-associated mortality increases with low potassium intake /9/, and that an increase in potassium intake exerts an anti-hypertensive effect. This is based upon augmented natriuresis, improved sensitivity of the baroreceptors, direct vasodilation and reduced cardiac responsiveness to noradrenaline and angiotensin-II /10/.

The regulation of potassium that is ingested with the diet (external potassium balance) is carried out to an extent of 80% by renal excretion of K+, to 15% via the gastrointestinal tract and to 5% via perspiration. Renal potassium homeostasis

Renal K+ excretion is dependent upon /11/:

  • Potassium intake with the diet and the serum concentration of K+
  • The delivery of Na+ and water to the distal tubules and the content of non absorbable anions
  • The acid-base status
  • The mineralocorticoid concentration.

Delivery of Na+ and water

In Fig. 8.1-4 – Renal-tubular K+ treatment, renal management of K+ is shown. In healthy fasting individuals the renal response to acute potassium loading is prompt, occurring within 3 hours. The K+ ions are secreted via the distal renal tubules and the collecting ducts. The secretion occurs via a direct stimulation of the Na+-K+-ATPase.

Variables relevant to the urinary K+ excretion are /12/:

  • The Na+ content in the distal tubules. Through increased Na+ delivery, the shift of K+ to extracellular is augmented due to the increasing electronegativity of the tubular cells, if more Na+ is reabsorbed.
  • Chloride anions which accompany Na+ during tubular reabsorption. The distal tubules are relatively impermeable to bicarbonate, phosphate, and sulfate. Elevated concentrations of these anions increase tubular electronegativity and, in consequence, K+ secretion.
  • The tubular flow of water /13/: increased water delivery to the distal tubules augments the K+ excretion. It is also responsible for the loss of K+ if renal tubular sodium chloride reabsorption caused by diuretics such as thiazide and furosemide in Henle’s loop and the initial portion of the distal tubule is inhibited (Fig. 8.1-5 – Mechanism of thiazide diuretics/14/. In contrast, in situations of more marked proximal K+ reabsorption, sodium chloride and bicarbonate are delivered to a lesser degree to the distal tubule, thereby resulting in decreased K+ secretion in exchange for Na+. Hence, in situations like pre renal acute renal failure, volume depletion, and congestive heart failure, which cause increased proximal tubular sodium chloride reabsorption via a reduction in the GFR, a tendency for hyperkalemia follows. Medication-dependent causes which lead to hyperkalemia are presented in
  • Fig. 8.1-6 – The effect of medicines on the tubule cell of the distal nephron
  • Fig. 8.1-7 – Mechanism of the aldosterone-dependent K+ secretion and its suppression.

Acidosis and alkalosis

In systemic acidosis the intracellular H+ content is increased and buffered within the cell. In order to preserve electroneutrality, K+ is shifted from the intracellular to the extracellular fluid compartment. In cases with decreased distal tubular K+ , the K+ shift is reduced. Thus, diminished tubular K+ contributes to the development of hyperkalemia in systemic acidosis.

In systemic alkalosis K+ is shifted from the tubular urine into the tubular cells and in this way, K+ secretion is enhanced. This effect, combined with increased water loading of the distal tubules in metabolic alkalosis, elevates the excretion of K+ and the tendency for hypokalemia.


Aldosterone is the essential mineralocorticoid responsible for potassium homeostasis. K+ act on the distal tubule and the collecting ducts and stimulate the reabsorption of Na+ and the secretion of K+. The effect of K+ is based upon an increase in the number of Na+ channels in the tubular luminal cell membrane and in the Na+-K+-ATPase of the basolateral membrane (Fig. 8.1-7 – Mechanism of the aldosterone-dependent K+ secretion and its suppression).

Adrenal secretion of aldosterone is stimulated by the renin-angiotensin-aldosterone system. Renin is increasingly synthesized in volume depletion and with reduced perfusion of the renal juxtaglomerular apparatus. The secretion of aldosterone is also directly stimulated by an elevation in intracellular K+ and is suppressed by certain medications /13/. Extrarenal potassium homeostasis

The maintenance of the extracellular K+ concentrations depends, apart from renal excretion, on the following factors /11/:

  • Acid-base balance
  • Insulin secretion
  • Mineralocorticoids
  • The sympathetic nervous system.

Acid-base balance

Augmented loading caused by inorganic acids such as HCl, NH4Cl or organic acids like lactate or ketone bodies lead to the shift of K+ from the intracellular to the extracellular fluid compartment, and to hyperkalemia. The situation is reversed in systemic alkalosis.


Insulin increases the cellular uptake of K+ and a high K+ loading of the organism stimulates the secretion of insulin. The effect is, however, minimal, as long as the K+ loading does not coincide with a glucose load. The effect of insulin on the Na+-K+-ATPase is believed to be based upon a cyclic AMP-independent mechanism.

Insulin-stimulated K+ cellular uptake is independent of glucose uptake. This independent effect has to be taken into consideration in the treatment of hyperkalemia with glucose and insulin. Glucose should not be administered alone, because if the secretion of insulin is suppressed, the increased osmolality that results from the glucose administration causes a K+ efflux of the cells, and the hyperkalemia increases further.


Aldosterone also acts on non-renal tissue and can affect K+ homeostasis in this way. Thus, through activation of the Na+-K+-ATPase of the colon mucous membrane, the stool content of K+ is increased, while that of Na+ is reduced. The concentrations of K+ in the saliva and the perspiration are also increased. These mechanisms play an important role with regard to K+ excretion in chronic renal insufficiency.

Sympathetic nervous system

The β-adrenergic stimulation shifts K+ from the ECF to the ICF. Thereby, renal K+ excretion is decreased. β-receptor blockers have an opposing effect. The effect of β-adrenergic stimulation is independent of changes in the concentrations of aldosterone and insulin.

The effect of β-adrenergic stimulation is based, in particular, upon activation of the β2-receptors. β2-agonists bind to these receptors and activate, via cyclic AMP, the Na+-K+-ATPase. α-adrenergic substances mediate a contrary effect. Thus, hyperkalemia that is caused by extreme physical effort is augmented by β-blockade with propranolol, while α-blockade with phentolamine results in an attenuated elevation of K+.


1. Martin PY, Schrier RW. Renal sodium excretion and edematous disorders. In: Dluhy RG (ed). Clinical disorders of fluid and electrolyte metabolism. Endocr Metab Clin North Am 1995; 24: 459–79.

2. Knepper MA, Kwon T.H. Nielsen S. Molecular physiology of water balance. N Engl J Med 2015; 372: 1349–58.

3. Ellison DH, Welling P. Insights into salt handling and blood pressure. N Engl J Med 2021; 385: 1981–93.

4. Khaw KT, Barrett-Konner E. Dietary potassium and stroke associated mortality: a twelve year prospective study. N Engl J Med 1987; 316: 235–40.

5. Fried LF, Palevsky PM. Hyponatriemia and hypernatriemia. Med Clin North Am 1997; 81: 585–609.

6. Méndez RE, Brenner BM. Glomerulotubular balance and the regulation of sodium excretion by intrarenal hemodynamics. In: Seldin DW, Giebisch G (eds). The regulation of sodium and chloride balance. New York: Raven, 1990: 105–31.

7. Shemin D, Dworkin LD. Sodium balance in renal failure. Current Op Nephrol Hypertens 1997; 6: 128–32.

8. Subramanian S, Ziedalski TM. Oliguria, volume overload, Na balance, and diuretics. Crit Care Clin 2005; 21: 291–303.

9. Cohn JN, Kowey PR, Whelton PK, Prisant LM. New guidelines for potassium replacement in clinical practice. Arch Intern Med 2000; 160: 2429–36.

10. Krishna GG, Kapoor SC. Potassium depletion exacerbates essential hypertension. Ann Intern Med 1991; 115: 77–83.

11. Clark BA, Brown RS. Potassium homeostasis and hyperkalemic syndromes. Endocrinol Metab North Am 1995; 24: 573–91.

12. Rasteger A, DeFronzo RA. Disorders of potassium metabolism associated with renal disease. In: Schrier RW, Gottschalk CW (eds). Diseases of the kidney. Boston; Little, Brown 1993: 2649.

13. Krapf R. Drei gefährliche Elektrolytentgleisungen: Hyponatriämie, Hyperkaliämie und Hypomagnesiämie. Schweiz Med Wschr 1993; 123: 739–48.

14. Perazella MA. Drug-induced hyperkalemia: old culprits and new offenders. Am J Med 2000; 109: 307–14.

15. Krapf R. Iatrogene Hyperkaliämie. Schweiz Med Wschr 1996; 126: 626–31.

16. Halperin ML, Bohn D. Clinical approach to disorders of salt and water balance. Emphasis on integrative physiology. Crit Care Clin 2002; 18: 249–72.

17. Elijovich F, Weinberger MH, Anderson CA, Appel LJ, Bursztyn M, Cook NR, et al. Salt sensitivity of blood pressure: a scientific statement form the American Heart Association. Hypertension 2016; 68 (3): e7–e46.

8.2 Sodium

Lothar Thomas

Sodium is the most abundant cation (Na+) of the extracellular fluid. It is critical for the maintenance of tonicity, also known as the effective osmolality, and thereby for water distribution between the extracellular fluid compartment (ECF) and the intracellular fluid compartment (ICF). Hyponatremia and hypernatremia occur if the ratio of the amounts of water and sodium in the ECF is shifted in favor of one or the other.

A frequent cause is an increase or decrease in total body water with no change in the electrolyte. Since sodium salts make up the major portion of the solutes in the ECF, hyponatremia and hypernatremia are often associated with hypo osmolality or hyperosmolality. Dysnatremia is also a frequent finding in patients who are not critically ill. Thus in outpatients, the prevalence of hypernatremia is up to 1%, and that of hyponatremia up to 6%. The latter is associated with elevated morbidity and mortality.

8.2.1 Indication

  • Disorders of fluid and electrolyte balance
  • Critically ill patients
  • Intra- and post-operatively
  • Persistent diarrhea or vomiting
  • Intake of diuretics
  • Deviations of other serum electrolytes from the reference range
  • Poly uric polydipsic syndrome and disorders of the thirst sensation
  • Disturbances of acid-base balance
  • Kidney disease, hypertension, edema
  • Certain endocrine diseases(e.g., hypothyroidism, hyper mineralocorticoid syndromes, mineralocorticoid deficiency syndromes)
  • High salt intake.

8.2.2 Method of determination

Direct and indirect potentiometric methods are used for the determination of Na+. With the direct methods the measurement is performed in undiluted blood, plasma or serum, while with the indirect potentiometric (ISE) methods and flame photometry, the samples are diluted. ISE is adapted to clinical chemistry analyzers, direct potentiometric measurement is used by blood-gas analyzers.

Flame photometer measures the concentration of the substance, while potentiometric methods determine ion activity.

Flame photometry

Principle: the emitted light intensity is measured when Na+ or K+ are excited in the flame. The light intensity is directly proportional to the number of atoms, and these in turn are directly proportional to the level of the corresponding ions in the sample. The flame photometer consists of a nebulizer, a burner and a photocell. The previously diluted sample is vaporized in the instrument and dispersed into the burner, whose flame is fed by propane or acetylene gas and compressed air /1/.

In the hot, non-luminous flame, Na+ emits a characteristic spectrum. Via a monochromator, the sodium-typical wavelength to be measured is selected and directed onto a photomultiplier. This creates an electric signal which, following intensification, guides the reading unit. The light emission as displayed by this unit is directly proportional to the Na+ concentration of the sample.

Some flame photometers function according to an internal standard principle. A lithium-containing solution is used for the dilution of calibrators, controls and patient samples; the flame emission is then measured using separate photocells for the wavelengths typical for lithium and sodium. Lithium is considered to be the internal standard and the voltage of the lithium photocell is considered as the reference voltage for the Na+ photocell. If the constant reference voltage changes, (e.g., due to instrument-dependent instability) the voltage of the Na+ photocell is compensated by this amount, and thus also the impact of potential instabilities on the analysis result.

Ion-selective electrode (ISE)

The ISE technology is employed for the determination of electrolytes (Na+, K+, Cl, Ca2+, Li+, Mg2+), of pH and of metabolites like glucose, urea, uric acid and lactate /234/.

Principle: the ISE measurement is a potentiometric method. The ISE comprises an ion-selective membrane in a measuring cell, which selectively permits the ion to be measured to shift into the inner electrolyte of the measurement electrode. If the ion activity of the sample is greater than that of the inner electrolyte, a positive membrane potential is generated. This is recorded by an electrode which is submerged in the inner electrolyte and measured against the constant potential of the outer reference electrode. Polymeric membranes, selected according to the ionophore that they contain, are employed. Ionophores are synthetic molecules that act as ion exchangers (e.g., for Na+ ETH 157, 227 or 2120 are used).

The measurement takes place within the ISE cell. An example, is illustrated in Fig. 8.2-1 – ISE unit for the determination of, for example, sodium. The cells contain the ISE electrode, which is in contact with the external reference electrode via the sample and the bridging solution.

Ion-selective electrode: the electrode consists of a flow cell in which the sample is separated from the inner electrolyte by a membrane. The inner electrode, which is made of, for example, Ag/AgCl, is submerged in the inner electrolyte.

External reference electrode: the external reference electrode is submerged in the bridging solution and is composed of an inner element, using usually Hg/HgCl2, a filling solution, usually concentrated KCl, and a device that provides a liquid junction.

Enzymatic spectrometric determination

Principle: Na+ activates the enzyme β-galactosidase (EC, which catalyzes the conversion of o-nitrophenyl-β-D-galactopyranoside (ONPG) to galactose and o-nitrophenol. The o-nitrophenol is measured kinetically at 405 nm, according to the following reaction:

ONPG Na + o-nitrophenol + galactose β-galactosidase

Because the Km of Na+ for β-galactosidase is 0.1 mol/L, and since a linear relationship between the Na+ concentration and kinetic activity exists only at low concentrations, the sample must be pre diluted. A further possibility is, with a cryptand such as Cryptofix 221, to trap a constant fraction of the Na+ and thereby to obtain a good test signal for the clinically important measurement range /5/.

8.2.3 Specimen

Serum, plasma (lithium and ammonium-heparinate): 1 mL

8.2.4 Reference range

Refer to Tab. 8.2-1 – Reference intervals for sodium.

8.2.5 Clinical significance Basic principles for interpreting the serum sodium concentration

Na+ is the most important electrolyte in the extracellular fluid (ECF) and K+ in the intracellular fluid (ICF). This asymmetrical distribution of electrolytes across the cell membrane requires the active exchange of both cations through Na+-K+-ATPase. Since the cell membrane is freely permeable to water, bodily fluids are in osmotic equilibrium.

The volume of the ECF is determined by the total body Na+. The concentrations of Na+ in the serum and in the interstitial fluid are identical. Na+ and its anions are responsible for more than 95% of the plasma osmotic activity. Because Na+ is the primary electrolyte in the ECF, it determines, based upon the flow of free water across the cell membrane, not only the osmolality of the ECF but also that of the ICF.

The distribution of water between the ICF and ECF is normally constant, with fluctuations of merely 1–2%. Acute changes in plasma Na+ that are not accompanied by qualitatively similar alterations in intracellular K+ (e.g., hyponatremia) lead to the movement of water from the ECF into the ICF. The result is cellular edema.

The organism regulates plasma Na+ concentrations by adjusting the water content of the ECF and by keeping total body sodium and the concentration of Na+ in the plasma constant within a narrow range. This takes place through drinking and by the renal excretion of free water. The intraindividual variation of serum Na+ level is 0.7% (e.g., approximately 1 mmol/L). It is therefore important, in order to recognize a disturbance of free water excretion, to be able to reliably detect a decrease in serum Na+ level of 3–4 mmol/L.

Changes in total body sodium and body water often occur together and are the most frequent cause of isotonic disturbances in Na+ and water balance /8/.

The ratio of serum Na+ to total body water is reflected in the osmolality. As a rule, changes in plasma Na+ concentrations go hand in hand with a comparable change in osmolality. There are, however, exceptions. While hypo osmolality is always associated with hyponatremia, hyponatremia can be associated with elevated, normal or low plasma osmolality.

The combined assessment of serum Na+ level and osmolality allows statements to be made regarding the distribution of water between the ECF and the ICF /9/:

  • If both behave in the same manner, no increase or decrease in solutes other than Na+ is present. The Na+ concentration provides information about the distribution of water.
  • The concentration of Na+ also determines the water distribution in the presence of freely permeable substances such as ethanol, ethylene glycol and urea. These substances can be distributed freely in the total body water, and they can elevate intracellular and extracellular osmolality. The result is a hypotonic status with a relative excess of water. In this case serum osmolality is elevated in hyponatremia.
  • Osmolality alone provides information concerning the distribution of water if solutes such as glucose and mannitol, which are distributed only in the ESC, are present. Water is shifted from the ICF to the ECF. In consequence, hyponatremia is the outcome, in spite of the fact that total body Na+, K+ and water content remains unchanged. In this case serum osmolality is increased.
  • Neither the Na+ concentration nor the osmolality provides information about the distribution of water. This is the case in situations of combined excess of a substance that is distributed only in the total body water, such as urea, and of another substance, the distribution of which is limited to the ECF, such as glucose. A situation such as this occurs in diabetics with hyperglycemia, in end stage renal failure. Disorders of sodium and water balance with normal serum sodium

All abnormalities of the extracellular fluid volume (ECFV) that are not associated with a change in serum osmolality are included in this group of disorders. They are also known as isotonic disorders. No fluid shift between the ICF and the ECF occurs, and Na+ levels in the serum remain within the reference interval. The serum Na+ concentration is tightly controlled by thirst and arginine vasopressin.

A distinction is made between /10/:

  • Isoosmolar (isotonic) dehydration. The ECFV is decreased, due to the isotonic loss of water and Na+. Isotonic losses occur in vomiting, diarrhea, poly uric renal failure, with enteral fistula and with the sequestration of fluid in the third space (e.g., peritonitis, pancreatitis). Clinical signs of dehydration are: orthostatic hypotension, tachycardia, thirst, dry skin and dry mucous membranes, deficient filling of the neck veins, low urine volume, and a high urinary urea/creatinine ratio.
  • Isoosmolar (isotonic) hyper hydration. The ECFV is increased by the isotonic excess of Na+ and water. Isotonic edema is present, since the renal excretion of Na+ is disturbed due to cardiac insufficiency, the malabsorption syndrome, the nephrotic syndrome, decompensated liver cirrhosis, or renal insufficiency. The serum level of Na+ is normal. Clinical symptoms are weight increase and edema. Hyponatremia

Hyponatremia is generally defined as Na+ concentration below 135 (136) mmol/L. Hyponatremia is classified as follows:

  • Mild; 135 (136)–126 mmol/L
  • Moderate; 125–121 mmol/L
  • Severe; below 121 mmol/L.

In hospitalized patients, the prevalence of hyponatremia is 20% with a threshold value of ≤ 136 mmol/L, 6–10% with a threshold value of ≤ 135 mmol/L, 1–4% with a threshold value of ≤ 130 mmol/L, and about 3% at a threshold of ≤ 125 mmol/L /1112/.

It is important to establish if hyponatremia is acute or chronic (see also Tab. 8.1-3– Cases of disorders in electrolyte and water balance).

  • Acute hyponatremia develops within 48 hours and is associated with neurological manifestations due to brain swelling, elevated intracellular pressure, and cerebral hypoxia. The symptoms may be mild (headache, nausea, vomiting) or severe (confusion, cramps, coma). The symptoms are the result of a water shift from the hypotonic fluid of the ECF into the more hypertonic brain cells.
  • Chronic hyponatremia develops slowly (longer than 48 hours). Due to adaptive mechanisms, the effects on the brain are more moderate. It is less urgent to clarify chronic hyponatremia, but a thorough clinical and laboratory evaluation is necessary.

Hyponatremia occurs if the normal ratio of electrolytes to total body water is disturbed due to a parallel decrease in plasma Na+ concentrations and osmolality. In hyponatremia there is often no Na+ deficiency in the organism but rather, primarily, a relative water excess due to decreased renal excretion, polydipsia or the infusion of Na+-poor solutions. Normally the capacity of the kidneys to excrete water is greater than the possible water intake.

Hyponatremia is generally dependent upon /13/:

  • Intrarenal factors that lead to a reduction in the diluting capacity in Henle’s loop, resulting in augmented free water excretion (see Fig. 8.1-2 – Renal-tubular handling of water and electrolytes).
  • Due to osmotically-independent release of arginine vasopressin (AVP). Normally the secretion of AVP is very low with an osmolality of 280 mmol/L or less, and water diuresis ceases. There are, in consequence, potent stimulators which assure a continuing basic secretion of AVP and anti diuresis. In spite of the fact that serum osmolality is the most important stimulus to AVP release, this can also occur non-osmotically via the baroreceptor stimulation. Differentiation of hyponatremia

Decreased osmolality of the ECFV is always associated with hyponatremia. Hyponatremia is, however, also seen in situations of normal or elevated osmolality of the ECFV /14/. Therefore, from the pathophysiological point of view, hyponatremia is classified according to the dependence on serum osmolality as normo-osmolar (normotonic), hyper osmolar (hypertonic) and hypo osmolar (hypotonic) forms (Fig. 8.2-2 – Differential diagnosis of hyponatremia).

From the clinical perspective the hyponatremia results from dilution or loss of Na+. Dilutional hyponatremia

Dilutional hyponatremia, the most common form of hyponatremia, is a hypotonic disorder and caused by water retention. Total body water is in excess in comparison with the total body Na+, which can be low, normal, or elevated. The excessive renal water retention is the most important cause. Dilutional hyponatremia can be classified according to the state of ECFV in hyper volemic and euvolemic disorders.

Hyper volemic hyponatremia

This form occurs if free water and Na+ are present in excess, but the free water is more markedly increased than the Na+ level and, in consequence, edema develops. The three primary causes are chronic cardiac insufficiency, liver cirrhosis, and kidney disease. Acute oliguric renal failure and chronic renal insufficiency, particularly chronic glomerulonephritis, lead to hypotonic hyper hydration. The Na+ excretion in random urine samples are above 20 mmol/L.

Euvolemic hyponatremia

Euvolemic hyponatremia is characterized by normal or nearly normal total body Na+ content and increased total body water, without symptoms of volume depletion or hypervolemia (edema, ascites). Often, a persistent or intermittent increase in AVP, in response to volume stimuli or osmotic stimuli that normally suppress the secretion of AVP, occurs. The following may be present /1516/:

  • An excess of free water due to exogenous intake, like that which occurs in the TURP syndrome following absorption of hypotonic irrigation fluids during transurethral prostatectomy. Other causes are glucocorticoid deficiency, severe hypothyroidism, thiazide diuresis-induced hyponatremia and polydipsia. Na+ excretion in random urine samples is above 20 mmol/L.
  • Increased secretion of AVP with retention of free water. Most frequently, the syndrome of inadequate ADH secretion (SIADH or Schwartz-Bartter syndrome) is present. Urine osmolality is higher than that of the serum, and the urine Na+ excretions are above 20 mmol/L. Pseudo hyponatremia

Hyponatremia may occur in the presence of normal plasma osmolality (pseudo hyponatremia). Na+ is measured by ion-selective-electrodes using either indirect potentiometry (ISE) on diluted samples on automated chemistry analyzers or by direct potentiometry on undiluted samples on blood-gas analyzers. During a hospital stay a patient may have several Na+ determinations measured by either of these methods and results may be assessed interchangeably, because discrepancies between direct and indirect potentiometry exist /45/. The causes can be:

  • Severe hyperlipidemia (turbid serum). For every mg of triglycerides/dL the concentration of Na+ decreases by 0.002 mmol/L /16/.
  • Hyperproteinemia, i.e. if multiple myeloma or Waldenström’s macroglobulinemia are known to exist. For every gram of total protein per liter above 80 g/L, the concentration of Na+ decreases by 0.25 mmol/L /17/.
  • High concentrations of solutes like glucose /45/, mannitol, sorbitol, glycerin, maltose, glycine and contrast media, which shift water from the intracellular fluid into the extracellular fluid. This is the case in transurethral resection of the prostate (TURP) and in endoscopic extirpation of the uterus, where 1.5% glycine (2006 mmol/L) is employed as a rinse solution in a volume of 3–5 liters. This is partially reabsorbed and can lead to hyponatremia and cerebral edema in the presence of normal osmolality, in the early phase (2 hours) following the start of the operation. Osmolality is normal, while the osmotic gap is large.
  • In a study /45/ increasing glucose levels caused a difference of of Na+ concentration between direct and indirect Na+ measurement. A glucose concentration of 131.2 mmol/L caused a difference in Na+ concentration by 2.15% between direct and indirect potentiometric measurements. Hyponatremia due to loss of Na+

These forms of hyponatremia are hypovolemic, with an absolute water deficiency, but even so a relative excess of water in comparison with Na+ /14/.

Pathophysiologically, the following can be present /1518/:

  • Extrarenal water loss, as is usually the case in vomiting, burns, edema and diarrhea. Additionally, third space loss in ascites or ileus plays a role. The drinking of a large amount of water following extreme sweating and the administration of plasma expanders following bleeding likewise lead to hypotonic dehydration /16/. Na+ excretion in random urine samples is below 20 mmol/L.
  • Renal Na+ and water loss. Following the exclusion of diuretic ingestion, the following less common diseases should be taken into consideration: Addison’s disease, hypophyseal anterior lobe insufficiency (mineralocorticoid deficiency), chronic kidney disease (renal salt loss), metabolic alkalosis and renal-tubular acidosis. The cerebral salt wasting syndrome should also be considered. The Na+ concentrations in random samples are above 20 mmol/L. Hyper osmolar (hypertonic) hyponatremia

The accumulation of solutes in the ECF shifts water from the intracellular to the extracellular fluid compartment, where it dilutes the Na+ concentration. The most common cause is hyperglycemia. For every increase of the glucose level of 100 mg/dL (5.6 mmol/L), serum Na+ concentration falls by 1.6 mmol/L. In acute renal insufficiency, high urea values also cause hyponatremia. Hospital-acquired hyponatremia

Hyponatremia is commonly acquired in hospitals. It results from the administration of hypotonic solutions, particularly to children, in special situations (e.g., post-operatively or in gastroenteritis). The cause is water retention which is contingent upon increased secretion of AVP. Situations which disrupt the close coordination between plasma osmolality and AVP secretion are non-osmotic stimuli such as stress, nausea, pain, vomiting, and intravascular volume depletion. The accumulation of free water can lead to cerebral edema which, often in the early phase and especially in children and in patients who cannot communicate, is not recognized clinically.

The rate of the Na+ decrease is as critical as is its absolute level. Thus, cerebral edema developed in an 8-week-old infant with a decrease in serum Na+ of 6 mmol/L within 9 hours and, likewise, in a 13-month-old baby with a decrease from 137 mmol/L to 120 mmol/L within 12 hours. Differential diagnostic examinations in hyponatremia

If hyponatremia is diagnosed, the findings from the following evaluations are relevant to the differential diagnosis.

Na+ excretion in urine

Useful for the differentiation between hyper- and euvolemic hyponatremia.

  • With euvolemia and Na+ excretion of greater than 20 mmol/L, water intoxication within the framework of the SIADH is usually present
  • If hypervolemia and hyponatremia are present, renal insufficiency (urine Na+ over 20 mmol/L) must be differentiated from hepatic insufficiency (urine Na+ below 20 mmol/L).
  • If hyponatremia and hypovolemia (exsiccosis patient) are found, then either extrarenal Na+ loss (urine Na+ below 10 mmol/L) or renal loss (urine Na+ greater than 20 mmol/L) are present.

Serum and urine osmolality

These investigations are used to determine whether the water excretion is reduced or increased. Polydipsia can be distinguished from pseudo hyponatremia. In the former case, the urine osmolality is lower than the serum osmolality.

Lipids and total protein

Confirmation of pseudo hyponatremia. Clinical significant pseudo hyponatremia is a consideration only with triglyceride levels greater than 1,500 mg/dL (17 mmol/L).

Calculation of serum osmolality: if hyperglycemia is present, in order to confirm this as a cause of hyper osmolality (see Section 8.5 – Osmolality). If the measured serum osmolality is higher than the calculated value by more than 10 mmol/kg, then there are additional solutes, such as urea or ethanol, present in the ECF.

Determination of the free water clearance

The amount of actual excess free water (i.e., water free from solutes) is determined. See also Section – Osmolality in the urine.

Further examinations

  • AVP in suspected SIADH
  • Creatinine: suspected renal insufficiency
  • Cortisol: suspected Addison’s disease
  • TSH: suspected hypothyroidism
  • ALT, cholinesterase: suspected hepatopathy.

Diseases and disorders with hyponatremia are listed in Tab. 8.2-2 – Diseases and causes that can lead to hyponatremia. Hypernatremia

The term hypernatremia refers to hyper osmolar (hypertonic) disorders of electrolyte and water balance. They almost always result from a deficiency in water relative to total body sodium. The thirst mechanism is the ultimate defense for the prevention of hypernatremia, which usually develops through insensible loss of water. When dietary salt intake increases, urinary sodium excretion increases, but it does not match intake immediately and thus generates a positive Na+ balance until excretion again equals intake /44/.

The effect on the thirst mechanism is diminished in persons with hypodipsia, in spite of the stimuli provoked by hyper osmolality and decreased arterial blood pressure. If the free water deficiency is mild and AVP secretion remains unchanged, renal regulation can compensate for the insufficient water intake and hypernatremia does not occur /11/. Diseases and conditions with hypernatremia

The water deficiency can be due to (Fig. 8.2-3 – Differential diagnosis of hypernatremia):

  • Loss of free water. This is the case in renal concentrating disorders caused by diuretics, osmotic diuresis or renal water loss due to decreased AVP secretion /20/.
  • Loss of hypotonic fluid. Although insensible water loss in critically ill patients is immediately compensated for by the breathing of humidified air, the following possibilities for the loss of hypotonic body fluids are present: nasogastric aspiration, glucosuria, loop diuretics, high urea excretion during catabolism, parenteral nutrition, corticosteroid therapy. In spite of the free water deficiency the patients can, due to an increase in isotonic fluid, become volume overloaded /21/.
  • Accidental intake of Na+. Thus, patients in intensive care or during operations often receive large quantities of hypertonic salt solutions for the maintenance of an adequate circulatory system function. Hypertonic NaCl or NaHCO3 solutions are also administered within the framework of reanimation, or to compensate for metabolic acidosis. Furthermore, Na+-rich penicillin solutions can be responsible /10/. Volume overload and edema do not rule out the loss of free water /24/.

The incidence of hypernatremia is 0.3–1% in in-patients. While 20–40% already manifest this at admission, most acquire the hypernatremia during their in-patient stay. The typical patient admitted with hypernatremia is old, often arrives from an old age home and has an infectious disease. Alternatively small children, who as yet do not have access to water, are involved /15/.

In patients who acquire hypernatremia in the hospital, this is due primarily to iatrogenic causes related to insufficient water intake, for (e.g., in intubated patients, cases with reduced mental status, inadequate infusion of free water).

Clinically relevant are serum Na+ levels above 150 mmol/L. Due to ECF hyper osmolality, these lead to cellular dehydration and shrinkage with neurological symptoms like restlessness, excitability, muscle tremor, hyperreflexia; the late symptoms are cramps and coma. This is particularly the case in patients with Na+ concentrations greater than 160 mmol/L. Mortality due to hypernatremia is 40–55%. However, not the hypernatremia per se but rather the underlying disease is often the reason for the high mortality rate /15/. Diagnostic examinations in hypernatremia

Additionally, the following examinations are required for the clarification of hypernatremia (Fig. 8.2-3 – Differential diagnosis of hypernatremia/10/:

  • Urine volume; criteria for differentiation are volume below 1,000 mL/24 h and above 2,500 mL/24 h
  • Serum osmolality; decision criterion is the upper reference range value
  • Urine osmolality; decision criterion is the value of 700 mmol/kg.

Severe hypernatremia with a level of greater than 155 mmol/L are mainly due to extrarenal fluid loss. Na+ excretions in the urine are below 20 mmol/L in these cases and urine osmolality is above 700 mmol/kg.

The constellation of findings occurring in hypernatremia are listed in Fig. 8.2-3, and the diseases and causes that go hand in hand with hypernatremia are shown in Tab. 8.2-3 – Diseases and causes that can lead to hypernatremia. Therapy of hypernatremia

A 5% isotonic dextrose solution in distilled water is infused. In a person weighing 60 kg, some 200 mL of free water (0.7% of 30 liters) have to be infused for a Na+ increase of 1 mmol/L (0.7%), in order to compensate for the hypernatremia /21/.

8.2.6 Comments and problems

Pre-analytical effects /2/

The NCCLS recommends the following pre-analytical conditions for the determination of Na+ and K+:

  • The tourniquet should not stop blood flow in the veins for more than a minute before the blood is drawn
  • The blood should be drawn using a lithium heparin containing tube
  • The samples should be stored at room temperature (20–25 °C) until the measurements are performed
  • The separation of plasma and blood cells should be carried out within 60 minutes of sampling.

Serum, plasma, whole blood /2/

For the Na+ determination, no significant differences between the three specimens are seen if the determination is performed via direct ISE measurement using the same analysis system. If differences are seen they are attributed primarily to changes in the liquid-junction potential due to erythrocytes and can be minimized with the use of properly designed systems and electrolyte solutions.

Method of determination /2/

Basic methodologies in the measurement of Na+ are:

  • Flame photometry (FP); measures the concentration of Na+. FP is the reference method according to a recommendation of the International Federation of Clinical Chemistry.
  • Potentiometric determination with ISE. The activity of the respective electrolyte ion relative to the pure solvent (e.g., plasma water) is measured. In order to avoid confusion for the clinician, the ion activity is converted in terms of substance concentration (i.e., mmol/L). For this purpose, the manufacturers use either calibrators that are adapted to flame photometric values (supplementary assigned values) or the analyzers perform a conversion using algorithms. The determination using ISE is performed either on the undiluted sample (direct ISE) or on a previously diluted sample (indirect ISE). With indirect ISE the sample is diluted in the analysis system such that the activity of the ion to be measured corresponds very closely to that of the calibrator. Under these conditions the measured ion activity of the electrolyte is proportional to its concentration.

Differences in the measured values between direct ISE, indirect ISE and flame photometry are based upon the volume displacement effect and the binding of the electrolytes to organic and inorganic ligands.

Solvent displacement effect /2/

The difference in the Na+, K+ and Clresults between the direct and indirect methods is mainly due to the electrolyte exclusion effect. This effect is caused by the solvent displacement effect of lipids and proteins in the plasma. The electrolytes Na+, K+ and Cl are exclusively in the water phase of plasma. Because the volume fraction of plasma water is 93% indirect ISE and the flame photometer produce results that are 7% lower than the direct ISE method. In one study /22/, 16% more samples with protein concentrations of over 80 g/L indicated pseudo hyponatremia with indirect ISE measurements, if direct ISE was taken as the reference. The difference in the Na+ level between direct and indirect ISE measurements in hyperproteinemia is believed to be calculable according to the following equations /23/:

Difference (mmol/L) = 0.0196 × total protein (g/L) – 5.9528
Difference (%) = [0.0849 total protein (g/L) – 4.1199] × 100

Ligand binding

The concentration of Na+ in undiluted samples is calculated from the potential of its relative molal activity. The molal activity derived concentration of Na+ is, however, higher by 1.5% in comparison with free Na+ since Na+ is also bound to ligands (bicarbonate and proteins).

Comparison of direct and indirect methods

Direct and indirect ISE measurements, and flame photometry, are compared with one another using correction factors.

In accordance with the NCCLS /2/ this takes place using normal plasma specimens. These specimens are defined as having mass concentration of plasma water 0.93 ± 0.01 kg/L, total CO2 24 ± 2 mmol/L, total protein 63–79 g/L, albumin 35–50 g/L, cholesterol 150–250 mg/dL (3.9–6.5 mmol/L), triglycerides 50–150 mg/dL (0.57–1.71 mmol/L), pH 7.35–7.45.

Interference factors /2/

Changes in the concentrations of analytes beyond the reference interval lead to a difference in the direct ISE and indirect ISE measured values. Only direct ISE, that is to say, measurement on undiluted samples, reflects the pathophysiological status of Na+ in the plasma water.

The comparison of capillary and venous blood via direct ISE measurement shows a good correlation but, nonetheless, with a value for capillary blood that is, on average, 1.7 mmol/L lower.

There may be a poor correlation between capillary blood, estimated with a direct ISE measurement using a point-of-care testing (POCT) analyzer, and venous plasma, determined in a central laboratory using indirect ISE. Thus, the mean difference was only 0.6 mmol/L, but the variation in the 2.5th and 97.5th interval of all values was, nonetheless, 10.6 mmol/L /24/.

Hyperlipidemia, hyperproteinemia: with flame photometry and indirect ISE, too low Na+ values are obtained.

Hemolysis /2/: the Na+ concentration in erythrocytes is one-tenth that of plasma. For example, hemolysis resulting in plasma hemoglobin of 500 mg/dL would decrease a 140-mmol/L plasma Na+ concentration by only 0.4%. Na+ concentrations are markedly effected only by severe hemolysis (> 1 g Hb /dL).


1. Hermann R, Onkelinx C. Quantities and units in clinical chemistry: nebulizer and flame properties in flame emission and absorption spectrometry. J Clin Chem Clin Biochem 1985; 23: 365–71.

2. NCCLS. Standardization of sodium and potassium ion selective electrode systems to the flame photometric reference method; approved standard. NCCLS Document C29-A, Vol 15 No 1. Villanova: NCCLS, 1995.

3. Burnett RW, Covington AK, Fogh-Andersen N, Külp­mann WR, Lewenstam A, Maas AHJ, et al. Use of ion selective electrodes for blood-electrolyte analysis. Recommendations for nomenclature, definitions and conventions. JIFCC 1997; 9: 16–22.

4. Lewenstam A. Design and pitfalls of ion selective electrodes. Scand J Clin Lab Invest 1994; 54, Suppl 217: 11–19.

5. Berry MN, Mazzachi RD, Peake MJ. Enzymatic determination of sodium in serum. Clin Chem 1988; 34: 2295–8.

6. Payne RB, Levell MJ. Redefinition of the normal range for sodium. Clin Chem 1968; 14: 172–8.

7. Soldin SJ, Brugnara C, Wong EC. Pediatric reference ranges. Washington: AACC Press, 2003: 170.

8. Lin M, Liu DJ, Lim IT. Disorders of water imbalance. Emerg Med Clin N Am 2005; 23: 749–70.

9. Kapsner CO, Tzamaloukas AH. Unterstanding serum electrolytes. Postgrad Med 1991; 90: 151–61.

10. Sterns RH. Disorders of plasma sodium – causes, consequences, and correction. N Engl J Med 2015; 55–65.

11. DeLuca L, Klein L, Udelson JE, Orlandi C, Sardella G, Fedele F, et al. Hyponatremia in patients with heart failure. Am J Cardiol 2005; 96, suppl: 19L–23L.

12. Clayton JA, Le Jeune IR, Hall IP. Severe hyponatriaemia in medical patients: aetiology, assessment and outcome. QJM 2006; 99: 505–11.

13. Anderson RJ, Chung HM, Kluge R, et al. Hyponatremia: A prospective analysis of its epidemiology and the pathogenetic role of vasopressin. Ann Intern Med 1985; 102: 164–8.

14. Ellison DH, Felker GM. Diuretic treatment in heart failure. N Engl J Med 201/; 377: 1964–75.

15. Fried LF, Palevsky PM. Hyponatriemia and hypernatriemia. Med Clin North Am 1997; 81: 585–609.

16. Decaux G, Musch W, Soupart A. Hyponatriemia in the intensive care: From diagnosis to treatment. Acta Clinica Belgica 2000; 55: 68–78.

17. Sterns RH, Ocdol H, Schrier RW, Narins RG. Hypo­Natremia: Pathophysiology, diagnosis, and therapy. In: Narins RG (ed). Clinical disorders of fluid and electrolyte metabolism. New York; McGraw Hill 1995: 615–883.

18. Passare G, Viitanen M, Törring O, Winblad B, Fastbom J. Sodium and potassium disturbances in the elderly. Clin Drug Invest 2004; 24: 535–44.

19. Long CA, Marin P, Bayer AJ, Shetty HGM, Pathy MJS. Hypernatremia in an adult in-patient population. Postgrad Med J 1991; 67: 643–5.

20. Androgue H, Madias NE. Hypernatremia. NEJM 2000; 342: 1493–8.

21. Anonymous. Hypernatremia in the intensive care unit: Instant quality – just give water. Crit Care Med 1999; 27: 1041–2.

22. Lang T, Prinsloo P, Broughton AF, Lawson N, Marenah CB. Effect of low protein concentration on serum sodium measurement: pseudohypernatraemia and pseudonormonatraemia. Ann Clin Biochem 2002; 39: 66–7.

23. Jones BJ, Twomey PJ. Relationship of the absolute difference between direct and indirect ion selective electrode measurement of serum sodium and total protein concentration. J Clin Pathol 2008; 61: 645–7.

24. Loughrey CM, Hanna EV, McDonnell M, Archbold GP. Sodium measurement: effects of differing sampling and analytical methods. Ann Clin Biochem 2006; 43: 488–93.

25. Schrier RW, Bertl T. Disorders of water metabolism. In: Schrier RW (ed). Renal and electrolyte disorders, 2nd ed. Boston: Little, Brown, 1980: 1–64.

26. Hsu JL, Chiu JS, Lu KC, Chau T, Lin SH. Biochemical and etiological characteristics of acute hyponatremia in the emergency department. J Emergency Med 2005; 29: 369–74.

27. Klein L, O’Connor CM, Leimberger JD, Gattis-Stough W, Pina IL, Felker M, et al. Lower serum sodium is associated with increased short-term mortality in hospitalized patients with worsening heart failure. Circulation 2005; 111: 2454–60.

28. Lee WH, Packer M. Prognostic importance of serum sodium concentration and its modification by converting enzyme inhibition in patients with severe chronic heart failure. Circulation 1986; 73: 257–67.

29. Rich MW, Beckham V, Wittenberg C, Leven CL, Freedland KE, Caney RM. A multidisciplinary intervention to prevent the readmission of elderly patients with congestive heart failure. N Engl J Med 1995; 333: 1190–5.

30. Gheorgiade M, Adams KF, O’Connor CM. Improvement of hponatremia during hospitalization for worsenening of heart failure is associated with improved outcomes: Insights from the Acute and Therapeutic Impact of Vasopressin Antagonist in Chronic Heart Failure (ACTIV in CHF). J AM Coll Cardiol 2005; 45: suppl 145A.

31. Clayton JA, Rodgers S, Blakely J, Avery A, Hall IP. Thiazide diuretic prescription and electrolyte abnormalities in primary care. Br J Clin Phamacol 2006; 61: 87–95.

32. Ring T, Frische S, Nielsen S. Clinical review: renal tubular acidosis – a physicochemical approach. Crit Care 2005; 9: 573–80.

33. Oliver JA, Verna EC. Afferent mechanisms of sodium retention in cirrhosis and hepatorenal syndrome. Kidney Int 2010; 77: 669–80.

34. Biccins SW, Rodriguez HJ, Bacchetti P, Bass NM, Roberts JP, Terrault NA. Serum sodium predicts mortality in patients listed for liver transplantation. Hepatology 2005; 41: 32–9.

35. Machek P, Jirka T, Moissl U, Chamney P, Wabel P. Guided optimization of fluid status in haemodialysis patients. Nephrol Dial Transplant 2010; 25: 538–44.

36. Wizemann V, Rode C, Chamney PW, et al. Fluid overload and malnutrition assessed with bioimpedance spectroscopy are strong predictors of mortality in hemodialysis patients. Nephrol Dial Transplant Plus 2008; 1, suppl 2: ii16–ii17.

37. Howard RL, Bichet DG, Schrier RW. Pathogenesis of hypernatremic and polyuric states. In: Seldin DW, Giebisch G (eds). Clinical disturbances of water metabolism. New York: Raven, 1993: 189–209.

38. Siegel AJ, d’Hemecourt P, Adner MM, Shirey T, Brown JL, Lewandrowski KB. Exertional dysnatremia in collapsed marathon runners. Am J Clin Pathol 2009; 132: 336–40.

39. Darmon M, Timsit JF, Francais A, Nguile-Makao M, Adrie C, Cohen Y, et al. Association between hypernatraemia acquired in the ICU and mortality: a cohort study. Nephrol Dial Transpl 2010; 25: 2510–5.

40. Konetzny G, Bucher HU, Arlettaz R. Prevention of hypernatraemic dehydration in breastfed newborn infants by daily weighing. Eur J Pediatrics 2008; 10.1007/s00431-008-0841-8.

41. Palmer BF,Clegg DJ. Electrolyte disturbances in patients with chronic alcohol-use disorder. N Engl J Med 2017; 377: 1368–77.

42. Berl T. Impact of solute intake on urine flow and water excretion. J Am Soc Nephrol 2008; 19: 1076–8.

43. Karin A, Brinc D, Leung F, Jung BP. Inaccuracy of sodium measurement in patients with severe hypernatremia. JALM 2021; 6 (2): 463–7.

44. Ellison DH, Welling P. Insights into salt handling and blood pressure. N Engl J Med 2021; 385: 1981–93.

45. Lefevre CR, Gilbert C, Maucorps L, Vase J, Michel M, Chupin M, et al. Pseudohyponatremia: interference of hyperglycemia on indirect potentiometry. doi: 10.1515/cclm-2022-0766.

8.3 Chloride

Lothar Thomas

Chloride is the essential anion (Cl) in the extracellular fluid compartment (ECF); it makes up 2/3 of all of the ECF anions, the concentration of which is 154 mmol/L. Chloride, as the counter ion to Na+ plays an essential role in the maintenance of the distribution of water between the ECF and the intracellular fluid compartment (ICF). See Section 8.1.5 – Volume homeostasis.

8.3.1 Indication

  • Disturbances of acid-base balance
  • Disturbances of Na+ and water balance
  • Acute situations in intensive internal, surgical and pediatric medicine
  • Calculation of the anion gap
  • Determination of the strong ion difference.

8.3.2 Method of determination

Ion-selective electrode

Principle: the ion-selective electrode contains a silver chloride crystal which is separated from the specimen by a membrane. The Cl in the specimen shifts across the membrane and become embedded in the crystal grid structure. During this process, a potential is created, which is measured against the constant voltage of a reference electrode. The difference of the potential is proportional to the Cl concentration in the specimen.

Coulometric titration at the chloride meter

Principle: silver ions are released from metallic silver in an acid buffer by means of electrolysis. Together with the Cl in the specimen, these silver ions form a silver chloride precipitate. The turnover is quantitatively determined by using the measurement set-up described here in detail. The set-up consists of two generator silver electrodes and two measuring electrodes. All four electrodes are submerged in an acid buffer. In order to measure the Clconcentration a defined sample volume is added to the buffer, a stabilized voltage is attached to the silver electrodes, and a chronometer is started. A constant amount of silver anions is released per unit of time, leading to the precipitation of Cl in the form of silver chloride. In order to detect the titration endpoint, the conductivity of the buffer is continuously monitored by means of two measuring electrodes. The titration endpoint is reached when free silver ions occur. The required time period is proportional to the Cl concentration in the specimen. In modern instruments, the impulse rate of the time counter has been adjusted so that the results are shown in mmol/L.

Mercurimetric titration

Principle: the Cl concentration of the specimen is titrated in an acidic solution with mercury (II) nitrate in the presence of the indicator diphenylcarbazone. Excessive mercury and the indicator react to yield a purple color, thus indicating the endpoint titration.

Spectrophotometric determination

Reaction with mercury chloranilate

Principle: Cl of the sample release equivalent amounts of the purple-colored chloranilinic acid from mercury chloranilate. The color intensity is proportional to the Cl concentration in the specimen and is measured spectrophotometrically at 500 nm.

Reaction with mercury thiocyanate

Principle: Cl of the sample release equivalent amounts of thiocyanate from mercury thiocyanate. Together with iron ions, thyocyanate forms a red-colored complex. The color intensity of the complex is proportional to the Cl concentration in the specimen and is measured spectrophotometrically at 480 nm.

Reference method

Inductively coupled plasma-isotope dilution mass spectrometry (ICP-IDMS).

8.3.3 Specimen

Serum, heparin anticoagulated blood: 1 mL

8.3.4 Reference range

Refer to references /12/ and Tab. 8.3-1 – Reference intervals for chloride.

8.3.5 Clinical significance

Chloride (Cl) is the most important anion from Na+ and is co-responsible for the extracellular fluid volume (ECFV) and the osmolality of the plasma /3/. The Cl follow the Na+ passively whenever the Na+ concentration changes in the body compartments. Cl is thereby also subject to the influence through mechanisms that are responsible for volume homeostasis. The Cl concentration in serum often behaves in a manner parallel to that of Na+. Refer to Tab. 8.1-1 – Neurohormonal mechanisms with regulatory effects on volume homeostasis.

Cl and HCO3 in plasma often have a reciprocal relationship. This holds true for both acidosis and alkalosis, and has led to the terms hyperchloremic acidosis and hypochloremic alkalosis. Plasma HCO3 concentrations are regulated by the strong ion difference, where Cl and lactate are the strong ions. Strong ion difference (SID)

Cl belongs, with Na+, K+, Ca2+ and Mg2+ to the group of strong ions, in contrast to albumin, phosphate and HCO3, which are weak ions /4/. Some authors count, apart from Cl, lactate as well among the strong anions. Strong ions, but not weak ions, are completely dissociated in plasma. In plasma, the strong cations outnumber the strong anions. The difference between strong cations (mainly Na+) and strong anions (predominantly Cl) is 40–42 mmol/L. For the maintenance of the principle of electroneutrality, the remaining negative charges come from CO2 and from weak acids.

Calculation of the SID without lactate:

SID (mmol/L) = Na+ (mmol/L) + K+ (mmol/L) + Ca++ (mmol/L) + Mg++ (mmol/L) – Cl (mmol/L)

The SID has a strong electrochemical effect on water dissociation and thereby on the plasma H+concentration:

  • With an increase in SID the concentration of H+ decreases, the HCO3 in the plasma and the pH increase
  • When the SID declines, acidosis increases and HCO3 in the plasma decreases.

Strong anions and cations are ingested with the diet in similar quantities. The regulation of their concentrations in the body, their excretion, and thereby the SID value is determined by the kidneys. The kidneys regulate the accumulation of acids via the excretion of Cl. In order that Na+ and K+ are spared, renal ammonia formation is utilized and Cl in the form of NH4Cl is excreted.

In vomiting, the loss of Cl and not the loss of H+ is the determining factor with regard to plasma pH. If Cl, as a strong anion, is lost without the simultaneous loss of a strong cation, the SID is raised, the H+ concentration in the plasma is reduced, and the pH is increased. If H+ is lost as water, and not as HCl, neither the SID nor the pH change. Chloride level in metabolic acidosis

Metabolic acidosis is the consequence of a reduction of the SID due to the increase in Cl (Cl loss is less marked than Na+ loss). Due to electrochemical forces, increased H+ is released from water and its concentration is raised; the pH decreases. A situation such as this occurs in:

  • Conditions which are associated with the formation of free anions (ketone bodies, lactate)
  • Cation loss (diarrhea)
  • Renal-tubular disorders (renal-tubular acidosis)
  • Iatrogenic acidosis (intake of acids and poisons).

The differentiation of renal and non-renal causes of metabolic acidosis are listed in Tab. 8.3-2 – Differential diagnosis of the metabolic acidosis by determining the SID in the urine. The differentiation of diseases and disorders that go hand in hand with elevated serum Cl and a decrease in the SID is provided in Tab. 8.3-3 – Diseases and disorders associated with an increase in serum chloride. Chloride level in metabolic alkalosis

Metabolic alkalosis results from inappropriately high SID and is based upon a marked loss of Cl relative to Na+. Causes are:

  • Vomiting, diuretics
  • High exogenous intake of strong cations relative to strong anions (large volumes of banked blood).

Refer to Tab. 8.3-4 – Diseases associated with a decrease in serum chloride.

In all forms of metabolic alkalosis with an increase in HCO3 a corresponding decrease of other anions occurs, particularly of Cl.

Two forms of hypochloremic metabolic alkalosis are distinguished from one another:

  • Cl-sensitive form, which can be corrected with salt intake and which occurs in vomiting or medication with diuretics, due to the loss of H+ and Cl and also due to the loss of Cl in the stools because of villous adenoma or congenital factors. Significant characteristics are a decrease of the ECFV and urine Cl concentrations greater than 20 mmol/L.
  • Cl-resistant form, which cannot be corrected with salt administration and is observed in hyperaldosteronism and in the Bartter syndrome. The Cl excretion in the urine corresponds to its intake.

8.3.6 Comments and problems

Possibilities for methodological errors

Bromide and iodide interfere with the Cl determination. Results with chloride meter determinations are elevated simply by the extent of the halogen concentration (additive effect). Major errors occur with measurements using ion selective electrodes and the photometric method (multiplicative effect) /5/.

ISE measurements /12/

Measurement of Cl by direct and indirect methods lacks harmonization and exceeds the desirable bias based on biological variation. Accuracy of indirect Cl electrodes of ISE platforms show a HCO3 concentration-dependent systemic bias compared to the ICP-IDMS method. All BGA analyzers show a HCO3 dependent bias for Cl from the reference method ranging from –3.8% for the low HCO3 concentrations to +4.85 for samples with high HCO3 concentrations.

BGA (blood gas analysis) overestimates Cl compared to the reference method in high HCO3 concentration samples. The Cl in BGA shows variation in bias between different platforms.


In serum up to 1 week in a closed tube; prompt separation of the serum (plasma) following blood sample collection is necessary, otherwise erroneously low Cl concentration is determined.


1. Beeler MF. SI-units and the AJCP. AJCP 1987; 87: 140–51.

2. Soldin SJ, Brugnara C, Wong EC. Pediatric reference ranges. Washington; AACC Press, 2003: 51.

3. Weinstein AM. Sodium and chloride transport. In: Seldin DW, Giebisch G (eds). The kidney: physiology and pathophysiology, 2nd ed. New York; Raven 1992: 1925–2039.

4. Kellum JA. Determinants of plasma acid-base balance. Crit Care Clin 2005; 21: 329–46.

5. Story DA, Morimatsu H, Bellomo R. Hyperchloremic acidosis in the critically ill III: one of the strong acidoses? Anesth Analg 2006; 103: 144–8.

6. Ring T, Frische S, Nielsen S. Clinical review: renal tubular acidosis – a physiochemical approach. Crit Care 2005; 9: 573–80.

7. Stokes JB. Potassium intoxication: pathogenesis and treatment. In: Seldin DW, Giebisch G (eds). The regulation of potassium balance. New York: Raven, 1989: 269–301.

8. Emancipator K, Kroll MH. Bromide interferences: is less really better? Clin Chem 1990; 36: 1470–3.

9. Bhandari S, Turney JH. The molecular basis of hypothalaemic alkalosis: Bartter’s and Gitelman’s syndromes. Nephron 1998; 80: 373–9.

10. Clive DM. Bartter’s syndrome: the unresolved puzzle. Am J Kidney Dis 1995; 6: 813–23.

11. Zimmermann J, Reincke M, Schramm L, Harlos J, Allolio B. Das Gitelman-Syndrom – eine Differentialdiagnose zum Bartter-Syndrom. Med Klin 1994; 89: 40–4.

12. Kootstra-Ros JE, van der Hagen EAE, van Schrojenstein Lantman M, Thelen M, van Berkel M. (In)direct chloride ISE measurements, room for improvement. Clin Chem Lab Med 2022; 60 (7): e168–e171.

8.4 Anion gap

Lothar Thomas

The anion gap in plasma or serum equals the difference between the serum concentrations of the major cation (Na+) and the major measured anions (Cl and HCO3). The anion gap is a useful tool for identifying the cause of a metabolic acidosis and is of value when evaluating a variety of unmeasured anions in conditions such as monoclonal gammopathy or bromism. The normal anion gap results from anions such as phosphate, sulphate, organic acids and anionic proteins, of which albumin is the most important.

8.4.1 Indication

Diagnostic workup of patients with metabolic acidosis e.g.,

  • Inborne errors of metabolism
  • Lactic acidosis
  • Uremia
  • Toxicity from methanol, ethylene glycol, isopropanol, diethylene glycol, paraldehyde, salicylates
  • Dysproteinemias such as hypoalbuminemia, multiple myeloma, polyclonal hypergammaglobulinemia.
  • Bromism.

8.4.2 Method of determination

The anion gap is mostly calculated by subtracting the concentrations of anions Cl and bicarbonate HCO3 from the concentration of the cation sodium Na+.

Anion gap (mmol/L) = Na+ (mmol/L) – Cl (mmol/L) – HCO3 (mmol/L)

8.4.3 Specimen

Serum: 1 mL

8.4.4 Reference interval

Anion gap: 3–11 mmol/L /1/

Clinical laboratorians need to establish (or at least verify) the anion gap reference interval for the instrumentation used in their laboratory /2/.

8.4.5 Clinical significance Metabolic acidosis

When organic acids enter the extracellular fluid, the dissociated H+ reacts with HCO3- to generate CO2 and water. As a consequence , the HCO3- concentration decreases and the salt level of the organic acid concentration increases; this accounts for the increase in the anion gap. The excretion of the organic acid salt into the urine with sodium or potassium (rather than hydrogen and ammonium) produces contraction of the extracellular fluid volume and stimulates renal retention of dietary sodium chloride /3/.

Acidemia should not be confused with acidosis. Acidemia refers to a blood pH less than 7.40 /4/.

If the baseline anion gap is low, it might not rise above the upper reference limit despite considerable accumulation of organic acid anions. Also, the anion gap rises as metabolism progresses.

The anion gap differentiates two types of metabolic acidosis:

  • normal anion gap acidosis; decreased HCO3 concentration is compensated by increased Cl concentration
  • elevated anion gap acidosis; the concentration of other anions than Cl or HCO3 is increased. Normal anion gap metabolic acidosis

The metabolic acidosis results from:

  • An increase of both Cl and H+
  • A decrease of HCO3 with the retention of Cl.

In both cases electroneutrality is preserved.

Patients with normal anion gap metabolic acidosis may have /5/:

  • Primary respiratory alkalosis (with secondary metabolic acidosis)
  • Primary metabolic acidosis with the etiologies described in Tab. 8.4-1 – Normal anion gap metabolic acidosis.
  • Other causes with a reduction in HCO3. Diarrhea is the prototype of this group. Due to intestinal loss of HCO3 increased tubular reabsorption of Cl occurs, with resulting hyperchloremia, thus the HCO3 loss is compensated for. The anion gap remains normal.

A normal anion gap acidosis may occur with several toxins that produce an anion gap; therefore, a normal anion gap should not be used to exclude a possible cause of metabolic acidosis /4/. Elevated anion gap metabolic acidosis

This acidosis occurs when an organic acid is associated with an unmeasured anion (e.g. lactate, toxic alcohol) /4/. An increased anion gap occurs only if electrically neutral substances e.g., salts of organic acids, are formed. Increased anion gaps are associated with renal failure, ketoacidosis, lactic acidosis and with poisoning. Conditions of metabolic acidosis with increased anion gap are described in Tab. 8.4-2 – Metabolic acidosis with increased anion gap.

The metabolic pathways of toxic alcohols are described in Tab. 8.4-3 – Metabolic pathways of toxic alcohols.


1. Winter SD, Pearson JR, Gabow PA, et al. The fall of the serum anion gap. Arch Intern Med 1990; 150: 311–3.

2. Roberts WL, Johnson RD. The serum anion gap. Has the reference interval really fallen? Arch Pathol Lab Med 1997; 121: 568–72.

3. Palmer BF,Clegg DJ. Electrolyte disturbances in patients with chronic alcohol-use disorder. N Engl J Med 2017; 377: 1368–77.

4. Hoshitsuki K, Molinelli A, Inaba H, Rubnitz J, Barker PJ. Metabolic acidosis in a peditric patient with leukemia and fungal infection. Clin Chem 2020; 66, 4: 518–24.

5. Walmsley RN, White HG. Normal anion gap (hyperchloremic) acidosis. Clin Chem 1985; 31: 309–13.

6. Hoshitsuki K, Molinelli AR, Inaba H, Rubnitz JE, Barker P. Metabolic acidosis in a pediatric patient with leukemia and fungal infection. Clin Chem 2020; 66 (4): 518–24.

7. Felton D, Ganetsky M, Berg AH. Osmolal gap without anion gap in a 43-year-old man. Clin Chem 2014; 60: 446–50.

8. Adams BD, Bonzani TA, Hunter CJ. The anion gap does not accurately screen for lactic acidosis in emergency department patients. Emerg Med J 2006; 23: 179–82.

9. Kraut JA, Mullins ME. Toxic alcohols. N Engl J Med 2018; 378: 270–80.

8.5 Osmolality in serum and urine

Lothar Thomas

If two aqueous solutions with different concentrations of solutes are separated by a semi-permeable membrane, water will flow across the membrane from the compartment with the low solute concentration into that with the higher concentration. This shift of water is called osmosis and the pressure that is required to stop the flow of water is called osmotic pressure. Osmotic pressure is determined by the number of particles and is independent of their molecular structure /1/. The number of particles depends upon their dissociation in water. A NaCl solution exerts an osmotic pressure that is double that of a glucose solution of the same molarity. The unit of osmolality is the osmol and, in accordance with the SI system, is expressed as mmol/kg. The measurements are made predominantly in serum, plasma and urine.

Calculation of osmolality

The formula that is acceptable for clinical purposes is as follows /2/:

mmol/kg = 2 × Na+ (mmol/L) + urea-N (mg/dL) + glucose (mg/dL)/18


mmol/kg = 2 × Na+ (mmol/L) + urea-N (mg/dL) + glucose (mmol/L)


In clinical usage the expressions osmolality and tonicity are often considered to be synonyms. Attention should be paid to the fact that osmolality is a physical property, relating to all of the particles in a solution, while tonicity is determined by the selectivity of the biological membrane. In this regard urea, alcohol and acetone permeate freely across the cell membrane, they therefore have no effect on tonicity, but they do increase osmolality. Tonicity describes the distribution of water between two compartments.

Colloid osmotic pressure

The term colloid is used to describe particles in solution of molecular weight greater than 30 kDa. Colloid osmotic pressure, also known as oncotic pressure, describes the pressure required to maintain two solutions which are separated by a semi-permeable membrane, and one of which is a colloid, in equilibrium. The measurement of colloid osmotic pressure in pulmonary edema fluid is of prognostic value in critically ill patients /3/.

8.5.1 Indication


  • Assessment of the distribution of water between the intra- and extracellular fluid compartments (tonicity) with serum Na+ concentrations outside the reference interval
  • Disturbances of water metabolism (e.g., in suspected diabetes insipidus, primary polydipsia, water intoxication or hypodipsia)
  • Suspicion of non-ionic low molecular weight substances in the blood, particularly in suspected intoxications e.g., toxic alcohols
  • Recognition of pseudo-hyponatremia
  • Investigation of the osmotic gap and of free water clearance.


  • Evaluation of poly uric states
  • Assessment of renal concentrating capacity
  • As part of a water loading test or a standard fluid deprivation test
  • Investigation of free water clearance.

8.5.2 Method of determination

Freezing point osmometer, vapor pressure osmometer, and colloid osmotic pressure osmometer are employed /4/. Most frequently used is the freezing point osmometer.

Freezing point osmometer

Principle: the osmometer consists of a cooling element and an electric thermometer whose resistance is proportional to the temperature. Initially the specimen is cooled. Then, using a vibrator, the process of crystallization is initiated. During this process, warmth is generated, the temperature rises and reaches a plateau below the freezing point which is compared to the plateau of known standard solutions. Finally, the measuring scale of the instrument directly displays osmolality.

8.5.3 Specimen

Serum, heparin anticoagulated blood, urine: 1 mL

8.5.4 Reference interval

Refer to references /56/ and Tab. 8.5-1 – Reference intervals for osmolality.

8.5.5 Clinical significance

Poisonings by toxic alcohols (methanol, ethylene glycol, isopropanol, diethylene glycol, and propylene glycol refer to Ref. /15/ and Tab. 8.4-2 – Metabolic acidosis with increased anion gap. Osmolality in serum and plasma

The osmolality of the plasma and its essential determinant, the Na+ concentration, are kept constant within a narrow range. In spite of greatly varying intake of water and salt, as well as of other solutes, only changes of ± 2% from the mean plasma osmolality of 287 mmol/kg occur physiologically. This constancy is ensured through the concerted action of two feedback systems which regulate total body water and thereby counteract a change in the concentration of Na+, its anions and the osmolality /678/.

The objective is the maintenance of normal water distribution between the intracellular fluid compartment (ICF) and the extracellular fluid compartment (ECF).

The two feedback systems that regulate water balance are:

  • The secretion of arginine vasopressin (AVP). At a plasma osmolality of below 280 mmol/kg, AVP is not secreted. The result is water diuresis, in consequence plasma osmolality rises, accompanied by a linear increase in plasma AVP level, thus renal water excretion is restrained. Volume status is less relevant with regard to AVP secretion. The most important role of AVP secretion is to protect the organism from water intoxication.
  • The thirst mechanism. An increase in plasma osmolality to above 290 mmol/kg activates the thirst mechanism. Under such conditions, the ingestion of water results in the normalization of plasma osmolality, a complete inhibition of thirst, and a reduction in AVP secretion. The most important function of the thirst mechanism is the prevention of dehydration. The thirst mechanism by itself is capable of maintaining the plasma osmolality, if adequate quantities of water are available for oral intake.

Changes in plasma osmolality due to water loss or water intake result in a readjustment of the water distribution between the ECF and the ICF. This implies that either cellular edema or cellular dehydration occurs. Volume changes affecting nerve cells result in fatal neuropsychiatric symptoms.

The clinical symptoms accompanying abnormal plasma osmolality depend upon the etiology, the abruptness of the change and the nature of the solute /9/. Thus, as an example, slow decreases in plasma osmolality of 60–80 mmol/kg can occur without fatal consequences.

Plasma osmolality increases due to water loss, or increases if solutes are infused that do not permeate the cell membrane, such as Na+ and glucose. Hyper osmolality can lead to coma and subsequent death if the plasma osmolality is elevated by 40–60 mmol/kg. Freely diffusible substances like urea, acetone and ethanol, on the other hand, are harmless since they do not create large osmolality gradients between ECF and ICF.

In summary, the following remains to be noted:

  • The plasma osmolality is the most important measured variable for the assessment of internal water balance (between ICF and ECF), while the monitoring of body weight is the most useful parameter for the evaluation of external fluid balance (intake and excretion)
  • In euglycemic patients and with normal renal function, changes in plasma osmolality usually follow any changes in Na+ concentration in a parallel fashion
  • Knowledge of the simultaneously determined Na+­ value is therefore an important differential diagnostic criterion for the clinical assessment of the measured osmolality. Urea and glucose are clinically relevant only if present at abnormally high concentrations. Serum/plasma osmolal gap

Plasma osmolality is determined by the physiological solutes Na+, Cl, HCO3, glucose and urea. Since every Na+­ is accompanied by an anion, only Na+­, urea and glucose have to be measured for the calculation of osmolality /78/.

An osmolal gap between measured and calculated osmolality is encountered, if a hyper osmolar state occurs in the presence of other solutes, in addition to Na+, Cl, HCO3, glucose and urea.

The osmolal gap is the difference between the serum osmolarity measured by the freezing-point depression and the serum osmolarity estimated from the equation given in the section "calculation of osmolality".

Osmolal gap (mmol/kg) = Measured osmolality – calculated osmolality

An osmolal gap is present in conditions where the measured osmolality exceeds the calculated one by > 10 mmol/kg (sensitivity 100%, specificity 86%)

Tab. 8.5-2 – Plasma osmolality and osmotic gap for diseases and conditions with hypo- and hypernatremia reviews diseases and clinical settings which are associated with changes in plasma osmolality and a normal or increased osmolal gap.

The calculation of the osmolal gap is important (see also Section 8.4 – Anion gap):

  • In intoxications for the recognition and monitoring of exogenous low molecular weight substances which lead to a rise in plasma osmolality such as ethanol, methanol, ethylene glycol, isopropanol, dichloromethane
  • In metabolic diseases as an indication of enhanced formation of endogenous substances like ketone bodies and organic acids. Osmolality in the urine

The measurement of urine osmolality is an important investigation for the assessment of free water formation by the kidney and is indicated for the evaluation of increased urine volume /712/. See Section 8.1.6 – Renal regulation of water and sodium excretion). It is necessary to differentiate between renal concentrating defects with, generally, a urine volume of less than 2 liters/24 h, and polyuria due to osmotic diuresis or water diuresis with a urine volume of ≥ 2.5–3 liters/24 h. Urine osmolality in healthy persons

Renal concentrating capacity

Healthy individuals excrete 450–600 mmol of solutes in 24 hours (e.g., 150 mmol of Na+, 75 mmol of K+, 400 mmol of urea and 50 mmol of other non-electrolytes). The 24-hour urine volume is 1–1.5 L. Since, the urine osmolality, in complete fluid deprivation, rises to 1,000–1,200 mmol/kg within 8–18 hours, a urine volume of about 500 mL/24 hours is required for the excretion of solutes. Oliguria is present if, with maximally concentrated urine, such a volume is not reached.

Renal excretion of free water

In order to prevent hyponatremia the kidneys are capable of excreting large quantities of water (up to 0.1 liters/minute). The excretion begins 30 minutes following the excess water intake. The urine osmolality can fall to below 50 mmol/kg. In the presence of euvolemia (normal total body sodium), urine osmolality of below 180 mmol/kg confirms the excess of free water due to exogenous intake. The Na+ concentration in the urine is below 20 mmol/L.

The amount of actual excess of free water (i.e. water free from solutes) can be calculated according to the following equation by means of free water clearance:

C H2O = V × Na (U) + K (U) Na (P) + K (P)

K, K+ (mmol/L); Na, Na+ (mmol/L); V, urine volume (mL); U, urine; P, plasma

Free water clearance describes the difference, in mL, between the actual urine volume per unit time and the volume that is required in order to excrete isotonic (to plasma) urine. It is positive in cardiac insufficiency and negative in the presence of the SIADH. Urine osmolality in renal disease

A prerequisite for the preservation of the concentrating capacity of the kidneys is the maintenance of hypertonicity in the medullary interstitium so that concentration of the urine can take place in the loop of Henle. Prerequisites for this are /13/:

  • A sufficient number of nephrones, in order to maintain a sufficient GFR. If this is not the case, the urine cannot be concentrated and its osmolality will be equal to that of plasma (isosthenuria). Due to a lower GFR, the maximal concentrating capacity is reduced in the elderly in comparison to young adults.
  • Adequate release and efficacy of arginine vasopressin. The efficacy can be disturbed in tubulointerstitial nephropathy, hypokalemia, hypercalcemia, or is drug-induced (e.g., due to lithium).

In the presence of renal concentrating defects, urine osmolality generally does not rise to more than 400–500 mmol/kg. Urine osmolality in poly uric states

In adults, polyuria is associated with a urine volume of above 2.5–3.0 L/24 h, or a excretion rate of greater than 2 mL/min., and is due to osmotic or water diuresis. In the differentiation of the causes of the diuresis, appropriate and inappropriate forms are differentiated /13/.

Osmotic diuresis

Osmotic diuresis is based upon an accumulation of solutes such as glucose, mannitol, salt, and urea in the ECF. It results in a rise in serum osmolality, osmotic diuresis, in the loss of Na+ and water, an ECF decline, and a shrinking of the cells. Loop diuretics like furosemide inhibit the Na+ reabsorption in the loop of Henle, thus leading to osmotic diuresis via impaired urine concentrating capacity.

Water diuresis

Increased excretion of free water is present. The water diuresis may be:

  • The normal response to an excess of water
  • The result of primary polydipsia
  • or it may be due to diabetes insipidus.

Appropriate and inappropriate diuresis

Appropriate diuresis is the result of water overload, while inappropriate diuresis is caused by diabetes insipidus. Appropriate diuresis is due to, for example, the accumulation of glucose and urea or administration of mannitol, while inappropriate diuresis is the result of volume expansion. The concentration of Na+ in urine is 50–80 mmol/L in inappropriate diuresis. The diagnosis can be made based on /13/:

  • Glucosuria, where excretion is usually greater than 45 mg/dL and the urine osmolality is above 250 mmol/kg.
  • Urea nitrogen excretion above 0.7 g/dL (117 mmol/L) due to, for example, high protein intake or hyper-alimentation. Urine osmolality is 700–900 mmol/kg. A decrease of the ECFV can develop due to hypernatremia.

Differentiation between water diuresis and osmotic diuresis

Osmolality of over 400 mmol/kg in a random urine sample is an indication of osmotic diuresis. A value of around 300 mmol/kg also speaks for the likelihood of osmotic diuresis, but in this case further clarification is necessary /13/.

Osmolality of less than 150 mmol/kg is indicative of water diuresis. For the etiological clarification and for the differentiation of water diuresis from mixed water-electrolyte diuresis with an osmolality of 150–300 mmol/kg, the fluid deprivation test is performed (Tab. 8.5-3 – Investigation of water diuresis by the fluid deprivation test and evaluation of DDAVP sensitivity).

Further findings that permit a differentiation are:

  • An abrupt onset of the diuresis, suggesting central diabetes insipidus (DI) since nephrogenic DI develops slowly
  • Mild polyuria of 4–5 L/24 h; this is indicative of acquired DI
  • The desire for ice water suggests the presence central DI.

Typical changes in Na+, osmolality, and effective osmolality in serum in various clinical conditions are shown in Tab. 8.5-4 – Sodium, osmolality and tonicity in serum for various conditions with hyponatremia or hypernatremia.

8.5.6 Comments and problems


The osmolalities in serum and plasma are almost identical, since fibrinogen which precipitates during the clotting process is not osmotically active. Plasma and urine protein content has only a minor effect on osmolality. Heparin that is present in heparinized plasma does not lead to a relevant change in osmolality.

Dilution of the sample

The relationship between osmolality and concentration is linear only in solutions of monovalent ions such as Na+, Cl, and specifically up to 1–2 mmol/kg. In serum and urine as in solutions containing calcium chloride, sucrose, dextrose, mannitol, or sorbitol, the osmolality is higher than predicted if the sample is diluted. Therefore, if an adequate amount of sample is available for the measurement, it must not be diluted /4/.


Serum and urine can be stored for several days at 4 °C in a tightly sealed container. The sample should be brought to room temperature prior to the measurement in order to reverse any sedimentation.

Calculation of osmolality

Serum osmolality (mmol/L): Serum Na+ × 2 (Blood glucose/18) + (Blood urea nitrogen/2.8)

Urine osmolality (mmol/L): Urine K+ × 2 (Blood glucose/18) + (Blood urea nitrogen/2.8)

Blood glucose and blood urea nitrogen are expressed in mg/dL


1. Gennari FE. Serum osmolality: uses and limitations. N Engl J Med 1984; 310: 102–5.

2. Krahn J, Khajuria A. Osmolality gaps: diagnostic accuracy and long-term variability. Clin Chem 2006; 52: 737–9.

3. Sprung CL, Isikoff SK, Hauser M, Eisler BR. Comparison of measured and calculated colloid osmotic pressure of serum and pulmonary edema fluid in patients with pulmonary edema. Crit Care Med 1980; 8: 613–5.

4. Sweeney TE, Beuchat CA. Limitations of methods of osmometry: measuring the osmolality of biological fluids. Am J Physiol 1993; 33: R 469–80.

5. Davies DP. Plasma osmolality and protein intake in preterm infants. Arch Dis Child 1973; 48: 575–9.

6. Robertson GL. Regulation of vasopressin secretion. In: Seldin DW, Giebisch G (eds). Clinical disturbances of water metabolism. New York: Raven, 1993: 99–118.

7. Star RA. Pathogenesis of diabetes insipidus and other polyuric states. In: Seldin DW, Giebisch, G (eds). Clinical disturbances of water metabolism. New York: Raven, 1993: 211–24.

8. Knepper MA, Kwon TH, Nielsen S. Molecular physiology of water balance. N Engl J Med 2015; 372: 1349–58.

9. Macknight ADC, Grantham J, Leaf A. Physiologic responses to changes in extracellular osmolality. In: Seldin DW, Giebisch G (eds). Clinical disturbances of water metabolism. New York: Raven, 1993: 31–49.

10. Davidson DF. Excess osmolal gap in diabetic acidosis explained. Clin Chem 1992; 38: 755–7.

11. Demedts P, Theunis L, Wauters A, Franck F, Daelemans R, Neels H. Excess serum osmolality gap after ingestion of methanol: a methodology-associated phenomon? Clin Chem 1994; 40: 1587–90.

12. Howard RL, Bichet DG, Schrier RW. Pathogenesis of hypernatremic and polyuric states. In: Seldin DW, Giebisch G (eds). Clinical disturbances of water metabolism. New York: Raven, 1993: 189–209.

13. Oster JR, Singer I, Thatte L, Grant-Taylor I, Diego JM. The polyuria of solute diuresis. Arch Intern Med 1997; 157: 721–9.

14. Oster JR, Singer I. Hyponatremia, hypoosmolality, and hypotonicity. Arch Intern Med 1999; 159: 333–6.

15. Kraut JA, Mullins ME. Toxic alcohols. N Engl J Med 2018; 378: 270–80.

8.6 Arginine vasopressin (AVP), copeptin (CT-proAVP)

Lothar Thomas

In spite of marked differences in water intake, plasma osmolality is kept within narrow limits (280–295 mmol/kg). The concerted action of the thirst mechanism, renal water management and neurohypophyseal antidiuretic hormone is responsible for the organism’s water balance /1/. The antidiuretic hormone arginine vasopressin (AVP) is formed from pre pro vasopressin, a molecule of 164 amino acids (AA). AAs 1–19 are the signal peptide, AAs 20–28 are the AVP, AAs 32–124 are the neurophysin, and AAs 126–164 are the copeptin, also known as CT-proAVP. Following proteolytic cleavage, the peptides are stored in neurosecretory vesicles. The function of CT-proAVP is unknown but it’s secretion is equimolar to that of AVP /2/.

8.6.1 Indication

Differentiation of the polyuric-polydipsia syndrome:

  • Nephrogenic diabetes insipidus
  • Central diabetes insipidus
  • Primary polydipsia
  • Unclear hyponatremia
  • The SIADH from the cerebral salt wasting syndrome.

8.6.2 Method of determination

Arginine vasopressin

Radioimmunoassay following extraction of the sample (e.g., with column chromatography). The assays employ antibodies directed against AVP which is bound to a protein such as thyroglobulin /3/. Commercial kits are usually calibrated against the 1st International Standard for arginine vasopressin 77/501.

cT-proAVP (copeptin)

Commercial immunoluminometric sandwich assay /4/.

8.6.3 Specimen

AVP: EDTA plasma 1 mL; blood collection with chilled tubes, centrifugation within 30 min. at 4 °C, plasma removed and deep frozen at –20 °C.

cT-proAVP: serum, plasma (EDTA, heparin)

8.6.4 Reference interval


8.6.5 Clinical significance

The concentration of AVP is regulated primarily via osmotic stimuli. Increases in osmolality lead to enhanced AVP secretion. Secondary non-osmotic stimuli are low blood pressure, reduced blood volume, stress, nausea, vomiting, pain, hypoxia, hypoglycemia, fever and medicines.

Nonetheless, there exists inter individual variability in osmolality thresholds for the release of AVP. This is likely due to different osmoreceptor sensitivity. Below the threshold (280–284 mmol/kg) AVP is not released, while above the threshold a steep increase in AVP secretion occurs. Plasma hypo-osmolality is associated with AVP values below the limit of detection, and with maximally diluted urine /5/.

The measurement of AVP or CT-proAVP is not recommended in suspected AVP deficiency with urine osmolality of > 100 mmol/kg, because as of this value AVP and CT-proAVP are always detectable /6/.

Physiological AVP release occurs in the plasma osmolality range of 280–295 mmol/kg; there is a linear relationship between plasma osmolality and AVP concentration (Fig. 8.6-1 – Relationship between osmolality and AVP in plasma (top) and AVP in plasma and osmolality in urine). Thus, a 1% change in plasma osmolality leads to an increase or decrease in AVP levels of 1 ng/L (0.93 pmol/L). With plasma osmolality of less than 280–284 mmol/kg, AVP is undetectable. With > 295 mmol/kg the AVP level is greater than 3–4 ng/L (2.8–3.7 pmol/L). Maximal urine anti diuresis is reached at around 5 ng/L (4.7 pmol/L) (Fig. 8.6-1/7/.

The osmotic regulation of plasma osmolality is genetically determined and varies in an inter individual manner. Sensitive persons manifest a change in AVP concentrations with osmolality fluctuations of around 0.5 mmol/kg, others only at of 5 mmol/kg /8/.

The relationship between plasma osmolality and AVP concentration, illustrated in Fig. 8.6-1, is only valid if hypovolemia, hypoglycemia, hyperglycemia, hypercalcemia, urea elevation, treatment with lithium and angiotensin-dependent vasoconstriction have been ruled out. If this is not the case, the slope of the curve is steeper.

If an increase in urea or glucose is present, the AVP concentration can be converted to a corrected plasma osmolality (cPos) according to the following equation:

cPos = mPos - (U + G – 7.5)

cPos, corrected plasma osmolality; mPos, measured plasma osmolality; U, urea (mmol/L); G, glucose (mmol/L) Elevation of the effective arterial blood volume

The effective arterial volume is registered by the low pressure baroreceptor in the right atrium of the heart and in the lungs, and by the high pressure baroreceptor in the aortic arch. The release of AVP occurs, however, only if the effective arterial volume decreases by approximately 10%. A volume reduction of over 10% leads to a marked increase in AVP and in CT-proAVP in the plasma. Thus, decreases in the effective arterial volume of 20–30% cause a 20 to 30-fold elevation of the AVP level /8/. The relationship of blood volume, osmolality and AVP concentrations is shown in Fig. 8.6-2 – Relation of blood volume, osmolality and AVP concentration. Assessment of plasma AVP concentration

AVP and CT-proAVP must be assessed relative to plasma osmolality. Within the range of 280–295 mmol/kg there exists a linear relationship between osmolality and AVP or CT-proAVP. Deviations from this relationship have been found in systemic disorders (Fig. 8.6-3 – Diseases and syndromes with disturbed relationship between plasma osmolality and AVP secretion):

  • With excess AVP secretion, also named SIADH
  • With insufficient AVP secretion, also called diabetes insipidus (DI). Central DI is differentiated from renal DI.
  • With the cerebral salt wasting syndrome. Syndrome of inappropriate antidiuretic hormone (ADH) secretion (SIADH)

The SIADH is based on elevated AVP secretion. The result is decreased excretion of free water and hyponatremia, which is secondary in nature and due to the increase in total body water. SIADH patients release AVP in spite of the fact that their serum osmolality lies below the threshold for the stimulation of AVP secretion.

SIADH is a diagnosis of exclusion /1/; the patients must fulfill the criteria provided in Tab. 8.6-2 – Laboratory results in SIADH .

The SIADH is manifested clinically by neuropsychiatric symptoms, since hyponatremia and water intoxication lead to cerebral edema and metabolic encephalopathy. The symptoms are weakness, apathy, headache, nausea, seizures and disturbances of concentration ability. Disturbances of consciousness and coma only occur with Na+ values below 125 mmol/L. Focal neurological disturbances may also be consequences of an SIADH.

The causes of SIADH are listed in Tab. 8.6-3 – Diseases and conditions associated with SIADH.

The concentration of AVP in relation to the plasma osmolality is shown in Fig. 8.6-3 – Diseases and syndromes with disturbed relationship between plasma osmolality and AVP secretion.

The determination of AVP is hardly helpful in SIADH, because hyponatremia is usually associated with elevated AVP or CT-proAVP. Elevated AVP is, in fact, a symptom of SIADH but it is not the diagnostic criterion. Approximately 10–20% of the patients manifest all the criteria of an SIADH, but do not have measurably elevated AVP or CT-proAVP /6/.

More than 50% of SIADH cases are associated with a malignant tumor. In the majority of the cases small cell lung cancer, with the formation of ectopic AVP, is present. The prevalence of clinically manifest SIADH with neuropsychiatric symptoms is 1.3–9.5% in small cell lung cancer, while that of SIADH identified through laboratory investigations is 5–40% /1/.

Exclusion of volume depletion in suspected SIADH

It is important to exclude volume depletion before making a diagnosis of SIADH, because this is associated with increased AVP secretion /6/. If there is uncertainty, volume depletion can be excluded by the infusion of sodium chloride. The normalization of the hyponatremia following sodium chloride infusion indicates volume depletion. Two liters of physiological NaCl are infused over a period of 24–48 hours.

Differentiation of the SIADH from the cerebral salt wasting syndrome (CSWS)

It can be difficult to separate the SIADH from the CSWS (Tab. 8.6-4 – Differentiation of CSWS from SIADH). In subarachnoid bleeding, the hyponatremia is based upon SIADH in 71% of the cases /12/. Diabetes insipidus (DI)

DI is characterized by elevated excretion of diluted urine. Excretion is > 40 mL/kg body weight in adults, and > 100 mL/kg body weight in children, over 24 hours. Excretion in adults is > 3 liters in 24 hours /7/. The organism is incapable of conserving free water. Independent of an organism’s water balance, a large volume of water passes through the kidneys, and this leads to a marked sensation of thirst, exaggerated water intake, exsiccosis and constipation. DI is characterized by the excretion of a large volume of urine and polydipsia. One of the following mechanisms is responsible:

  • The partial or absolute reduction in osmotically regulated AVP secretion (central, hypothalamic DI)
  • The partial or total resistance of the kidneys to respond antidiuretically to AVP (nephrogenic DI)
  • Primary excessive drinking of water in the presence of normal AVP secretion and action.

The relationship between osmolality and AVP in DI is shown in Fig. 8.6-4 – Relationship between osmolality and AVP in cases of diabetes insipidus (DI).

DI must be differentiated from osmotic diuresis in poorly controlled diabetes mellitus and from renal insufficiency. In both cases, plasma and urine osmolality are high (see also Section 8.5 – Osmolality). Laboratory diagnostics

Important laboratory diagnostic criteria of DI are:

  • Polyuria (> 2.5 to 3 liters/24 h)
  • Urine osmolality. A value below 200 mmol/kg is indicative, an osmolality higher than 300 mmol/kg and a high glucose concentration of higher than 1 g/L indicate diabetes mellitus, while elevated serum creatinine points to renal disease.
  • The determination of CT-proAVP. In nephrogenic DI, the serum concentration is > 20 pmol/L, while in complete central DI it is < 2.6 pmol/L /13/
  • Functional tests, or the CT-proAVP increase in relation to serum Na+ level in the standard fluid deprivation test. The test enables the differentiation between partial central DI and primary polydipsia.

The copeptin, also known as CT-proAVP, correlates strongly over a wide range of osmolalities in healthy individuals. Therefore, the measurement of copeptin is an alternative to vasopressin measurements /14/.

Functional tests

The following functional tests are employed for the diagnosis of DI:

The clinical and laboratory findings in diseases with a disturbance of water balance and altered AVP and CT-proAVP are described in Tab. 8.6-8 – Disorders of the water balance with increase of AVP and CT-proAVP and Tab. 8.6-9 – Disorders of water balance with reduced or normal AVP and CT-proAVP.

8.6.6 Comments and problems

Reference range

AVP shows a circadian rhythm with high values during the night and lower values during the daytime.


AVP is hydrolyzed by peptidases and it is therefore necessary, following blood sampling, to perform the additional pre-analytical steps at 4 °C. CT-proAVP is stable for 3 days at room temperature.

For the determination of AVP in pregnant women, a peptidase inhibitor should be present in the blood collection tubes; this is because lysine amino peptidase, which hydrolyse AVP, is sometimes found in the plasma of pregnant women.

8.6.7 Pathophysiology

AVP is synthesized as a pre pro hormone (Fig. 8.6-5 – Primary structure of vasopressin andits analogues). The pre pro hormone is packaged in secretory vesicles and is converted into the final secretory form when the vesicles, located in magno cellular neurons, migrate to the nerve endings in the arteries of the adenohypophysis. There, AVP is stored along with neurophysin II, and is secreted in response to increased firing of the vasopressinergic neurons. The primary stimulus is the rise in plasma osmolality, while secondary stimuli are a decline in blood pressure and volume depletion. The circulating half-life time of AVP is 10–20 minutes. Effects of AVP

The effect of AVP is mediated via the three receptors V1–V3, which are located in the plasma membrane. These receptors belong to the family of G-protein-coupled receptors, which form the intracellular messenger cyclic AMP via adenylate cyclase. See Fig. 6.2-4 – Gs-protein-mediated signal transmission).

The distribution of the receptors is as follows:

  • V1 on smooth muscle cells of the blood vessels, in the liver, in thrombocytes, and in the central nervous system
  • V2 on the basolateral membrane of the tubular cells of the distal nephron
  • V3 in the corticotrophe part of the adenohypophysis. Renal water management

Renal management of water is regulated osmotically and is under the direct control of AVP. A rise in osmolality of 1–2% causes the release of AVP, which binds to the V2 receptors in the basolateral membrane of the distal nephron. The result is the secretion of proteins for the formation of aquaporin water channels (AQP) from intracellular vesicles of the apical membrane of the collecting duct cells (Fig. 8.6-6 – Effect of AVP for increasing the water permeability in the renal collecting duct cells). These are integrated into the cell membrane and lead to water reabsorption along an osmotic gradient. Of the 11 known AQPs of the organism, 7 are found in the kidney. AQP1 is localized in the apical and basolateral membrane of the proximal tubular cell. AQP2 is found in the collecting ducts, where it is responsible for AVP-dependent water transport. Activation of the V2 receptor leads to the expression of the genes coding the AQP2 water channels. AQP2 proteins are synthesized, and these are then arranged to form water channels. In consequence, increased quantities of water are transported from the collecting ducts into the interstitium.


1. Wong LL, Verbalis JG. Systemic diseases associated with disorders of water hemostasis. Endocrinol Metab Clin N Am 2002; 31: 121–40.

2. Fenske W, Quinkler M, Lorenz D, Zopf K, Haagen U, Papassotiriou J, et al. Copeptin in the differential diagnosis of the polydipsia-polyuria syndrome – revisiting the direct and indirect water deprivation tests. J Clin Endocrin Metab 2011; 96: 1506–15.

3. Robertson GL, Mahr EA, Athar S, et al. The development of clinical application of a new method for the radioimmunoassay of arginine vasopressin in human plasma. J Clin Invest 1973; 52: 2340–52.

4. Morgenthaler NG, Struck J, Alonso C, Bergmann A. Assay for the measurement of copeptin, a stable peptide derived from the precursor of vasopressin. Clin Chem 2006; 52. 112–9.

5. Robertson GL. The use of vasopressin assays in physiology and pathophysiology. Sem Nephrol 1994; 4: 368–83.

6. Ellison DH, Berl T. The syndrome of inappropriate antidiuresis. N Engl J Med 2007; 356: 2064–72.

7. Ball SG. Vasopressin and disorders of water balance: the physiology and pathophysiology of vasopressin. Ann Clin Biochem 2007; 44: 417–31.

8. Robertson GL. Regulation of vasopressin secretion. In: Seldin DE, Giebisch G (eds). Clinical disturbances of water metabolism. New York: Raven, 1993: 99–118.

9. Robertson GL, Shelton RL, Athar S. The osmoregulation of vasopressin. Kidney Int 1976; 10: 25–37.

10. Howard RL, Bichet DG, Schrier RW. Pathogenesis of hypernatremic and polyuric states. In: Seldin DW, Giebisch G, eds. Clinical disturbances of water metabolism. New York: Raven, 1993: 189–209.

11. Beyersdorf S, Albrecht C, Wallaschofski H. Differentialdiagnostik des Syndrom der inadäquaten ADH-Sekretion gegenüber dem zerebralen Salzverlust-Syndrom. J Lab Med 2008; 32: 19–25.

12. Hannon MJ, Behan LA, O’Brien MM, Tormey W, Ball SG, Javadpur M, et al. Hyponatremia following mild/moderate subarachnoid hemorrhage is due to SIAD and glucocorticoid deficiency and not cerebral salt wasting. J Clin Endocrinol Metab 2014; 99: 291–8.

13. Fenske W, Christ-Crain M. Stellenwert von CT-proAVP (Copeptin) in der Abklärung des Polyurie-Polydipsie Syndroms. Med Welt 2011; 62: 39–44.

14. Balanescu S, Kopp P, Gaskill MB, Morgenthaler NG, Schindler C, Rutishauser J. Correlation of plasma copeptin and vasopressin concentrations in hypo-, iso-, and hyperosmolar states. J Clin Endocrinol Metab 2011; 96: 1046–52.

15. Bichet DG. Nephrogenic diabetes insipidus. Adv Chron Kidney Dis 2006; 13: 96–104.

16. Sorensen JB, Andersen MK, Hansen HH. Syndrome of inappropriate secretion of antidiuretic hormone (SIADH) in malignant disease. J Intern Med 1995; 238: 97–110.

17. Jochberger S, Mayr VD, Luckner G, Wenzel V, Ulmer H, Schmid S, et al. Serum Vasopressin concentrations in critically ill patients. Crit Care Med 2006; 34: 293–9.

18. Vincent JL. Vasopressin in hypotensive and shock states. Crit Care Clin 2006; 22: 187–97.

19. Landry DW, Levin Hr, Gallant EM, et al. Vasopressin deficiency contributes to the vasodilation in septic shock. Circulation 1997; 95: 122–5.

20. Liu BA, Mittmann N, Knowles SR, Shear NH. Hyponatremia and the syndrome of inappropriate secretion of antidiuretic hormone associated with the use of selective serotonin reuptake inhibitors: a review of spontaneous reports. Can Med Ass 1996; 155: 519–27.

21. Buonocore CM, Robinson AG. The diagnosis and management of diabetes insipidus during medical emergencies. Endocrinol Metab Clin N A 1993; 22: 411–23.

22. Baylis PH, Phillips EMG. The endocrine investigation of disorders of sodium and water homeostasis. JIFCC 1994; 6: 158–63.

23. Star RA. Pathogenesis of diabetes insipidus and other polyuric states. In: Seldin DW, Giebisch G (eds). Clinical disturbances of water metabolism. New York: Raven, 1993: 211–24.

8.7 Potassium

Lothar Thomas

Quantitatively, potassium is the most important intracellular cation (K+). It plays an important role in the control of cellular volume, in the maintenance of the electrochemical potential across the cell membrane of excitable (nerve, muscle) and non-excitable tissues, and in acid-base balance. Potassium also plays a meaningful role in numerous cell functions such as growth, DNA and protein synthesis, and the activity of various enzymes /1/.

The regulation of K+ homeostasis between the intracellular fluid compartment (ICF) and the extracellular fluid compartment (ECF) occurs rapidly through the Na+-K+ pumps of the cell membrane, and time-delayed by gastrointestinal K+ uptake and renal K+ excretion. The plasma K+ is only a moderate indicator of total body potassium, but it is physiologically important for the assessment of the transmembrane electrochemical gradient. See also Section 8.1 – Water balance and fluid compartments).

8.7.1 Indication

  • Hypertension
  • Cardiac arrhythmias
  • Chronic ingestion of potassium depleting medications (diuretics, laxatives)
  • Long-term therapy with corticosteroids
  • Acute and chronic renal insufficiency
  • Diarrhea, vomiting
  • Disorders of water and electrolyte balance
  • Disorders of acid-base balance
  • Monitoring of intensive care patients
  • Hypomagnesemia
  • Suspicion of renal tubular acidosis
  • Decrease in renal function.

8.7.2 Method of determination

Flame photometry

Principle: see Section 8.2.2 – Method of determination. Flame photometry, although used only to a minor extent in routine diagnostics for the determination of electrolytes, is the reference method according to the recommendation of the National Committee for Clinical Laboratory Standards (NCCLS) /2/.

Potentiometer with ion selective electrode (ISE)

Principle: see Section 8.2.2 – Method of determination. The determination using ISE is performed in routine diagnostics on both undiluted and diluted samples. The ion-selective membrane of the measurement electrode contains valinomycin as the ionophore. It has high selectivity for K+ (e.g., K+ relative to Na+ 5,000 : 1).

Enzymatic spectrometric determination

Principle: in the presence of K+ the enzyme pyruvate kinase (EC is activated. The concentration of K+ is the rate-limiting step for the enzymatically catalyzed conversion of phosphoenolpyruvate into pyruvate. Pyruvate is then reduced to lactate. During this latter process NADH2 is consumed, and its decline is measured kinetically at 340 nm. In order to obtain a good measurement signal within the clinically relevant range, a cryptand is added to the reaction mixture prior to the start of the enzymatic reaction. This cryptand captures a constant proportion of K+ /3/.

8.7.3 Specimen

Serum, plasma (lithium, ammonium heparinate): 1 mL

8.7.4 Reference range

Refer to Ref. /456/ and Tab. 8.7-1 – Reference intervals for potassium.

8.7.5 Clinical significance

Regulation of body K+ balance requires that the kidney excrete most of the K+ gained each day from diet. Filtered K+ is largely reabsorbed by proximal nephron segments, and that excreted K+ is secreted by distal segments. High K+ intake not only lowers blood pressure but also reduces salt sensitivity. Basic principles for assessing the plasma potassium concentration

The total-body potassium content is 50–55 mmol/kg body weight. The plasma K+ concentration is /7/:

  • On the one hand, regulated by total body K+ and reflects this. It must be noted, however, that with normal plasma serum K+ level and total body potassium of 3,500 mmol, of which 10% is extracellular, the acute loss of 1% of total body K+ (35 mmol) leads to a significant disturbance of the K+ balance between the intracellular fluid (ICF) and the extracellular fluid (ECF) and to a decrease in serum K+ concentration. Thus, reduced serum levels are not automatically the indicator of a marked reduction in total body K+.
  • On the other hand, changes in circulating K+ are controlled by mechanisms like the renin-angiotensin-aldosterone system, which attempts to maintain total body K+ constant by altered renal K+ excretion.

Increases or decreases in serum K+ levels are always the result of a disturbance in K+ distribution between the ICF and the ECF. Disorders of the external potassium balance

The external K+ balance is regulated by K+ secretion of the kidneys. In high potassium intake serum K+ level rises within 2 hours after the meal and returns to the reference interval before the next meal. Dietary intake of 400 mmol/day causes progressively increased renal excretion so that the external balance is restored within 3 days. Modulators of renal K+ excretion and, accordingly, of the external K+ balance, are /8/:

  • The amount of K+ that is provided with food
  • Sodium content and flow rate in the distal tubule
  • The current acid-base status
  • The activity of mineralocorticoids and mineralocorticoid-like substances
  • The responsiveness of the distal tubule to mineralocorticoids
  • The type and availability of anions.

Amount of K+ ingested

Maintenance of a healthy steady state requires a continuing balance between intake and excretion of K+. The rates are 50–100 mmol/day (e.g., around 1 mmol/kg body weight in 24 hours).

Sodium content and flow rate in the distal tubule

A rise in the ECF volume leads, via an increase in the glomerular filtration rate (GFR), to the delivery of greater quantities of water and Na+ to the distal tubule; the consequence is increased K+ excretion. A reduction of the ECF has the opposite effect, via the same mechanisms. Acid-base status

Acid-base derangements affect the excretion of K+. Extracellular acidosis leads to hyperkalemia through the loss of K+ from the intracellular to the extracellular fluid compartment, while alkalosis causes hypokalemia via the displacement of K+ from the extracellular to the intracellular fluid compartment. In metabolic acidosis, K+ exits from the cells in exchange for H+.

Acute metabolic acidosis

Gavage of NH4Cl or HCl cause acute hyperkalemia and renal secretion of K+ due to the direct efflux of K+ from the cell. Acidosis caused by the accumulation of organic acids like lactate or ketone bodies does not directly lead to hyperkalemia. Instead, hyperkalemia only develops secondarily due to volume depletion and decreased urinary flow rate which is present under such circumstances. In addition the renin-angiotensin aldosterone system is activated.

Acute and chronic respiratory alkalosis

Both of these disturbances have a minimal effect on K+ balance and manifest a mild tendency toward hypokalemia.

Chronic metabolic acidosis

With high PCO2 and increased renal HCO3 reabsorption, a high K+ excretion with hypokalemia develops. Mineralocorticoids and glucocorticoids

Mineralocorticoids and glucocorticoids stimulate tubular K+ excretion. Mineralocorticoids have a direct stimulatory effect on K+ secretion at the distal tubule. The K+ secretion is dependent upon the delivery of Na+­ to the distal tubule. If this is low, hypokalemia does not develop. Glucocorticoids act indirectly. They elevate the GFR and hence the urinary flow and, via increased Na+ delivery to the distal tubule, lead to increased K+ excretion.

Responsiveness of the distal tubules to mineralocorticoids

Diseases such as interstitial nephritis can lead to damage to the distal tubules and the collecting ducts and, in consequence, to decreased responsiveness to aldosterone. A K+ excretion disorder is the result, with the development of hyperkalemia and severe acidosis. Derangements of K+ excretion are also described in obstructive nephropathy, systemic lupus erythematosus and sickle cell anemia, and following kidney transplantation.

Potassium-sparing diuretics such as triamterene and amiloride suppress renal K+ secretion by blocking the Na+ channels of the luminal cell membrane. Spironolactone blocks the aldosterone receptor and thereby inhibits renal K+ secretion. Type and availability of anions

Normally, Na+ is reabsorbed in the distal tubule together with an anion such as Cl in order to preserve electroneutrality.

If, in metabolic acidosis, the fraction of poorly permeable anions like HCO3 in the distal tubule is increased, more K+ is secreted, and hypokalemia results.

In secondary hyperaldosteronism the reabsorption of Na+ as well as the secretion of K+ and H+ is increased in the distal tubules; hypokalemia develops. If the availability of exchangeable Na+ is low due to strict limitation of salt intake, no Na+-K+ exchange occurs and hypokalemia does not develop. Disorders in internal potassium balance

Internal balance disorders alter the serum level of K+, but not total body K+.


The effect of catecholamines on internal K+ distribution is mediated by β2-receptors. The stimulation of the receptors leads to a decline in K+ concentrations in the ECF due to a shift of K+ to the intracellular fluid compartment. Medication with β2-blockers elevates serum K+. The α-adrenergic system has the opposite effect. Post-operatively, the administration of catecholamines protects against the development of potential hyperkalemia /7/.


Insulin increases the K+ uptake by non-renal tissues and can rapidly lower the serum K+ level. This is the case in non-diabetic individuals following a meal rich in carbohydrates.

In diabetics, the deficiency of insulin reduces the cellular uptake of K+. In consequence, hyperkalemia should, theoretically, develop. However, due to the existing osmotic diuresis and the associated hyperkaluria, this does not occur. If, however, the diabetic patient has renal insufficiency or hyporeninemic hypoaldosteronism, hyperkalemia develops /7/. Important differential diagnostic examinations

For the assessment of a pathological plasma K+ level, blood and urine evaluations can provide, in addition to anamnestic and clinical data, important differential diagnostic information.


  • Sodium, chloride, creatinine
  • Magnesium, calcium, phosphate
  • Acid-base status
  • Cortisol, (ACTH)
  • Renin, aldosterone
  • Digoxin, digitoxin


  • Excretion of potassium, chloride, sodium
  • Diuretics. Hypokalemia

More than 20% of hospitalized patients have hypokalemia with a lower reference value of 3.6 mmol /79/. The prevalence of hypokalemia in patients taking diuretics is as high as 50%. The most frequent hypokalemias are:

  • gastrointestinal losses
  • hypomagnesemia
  • alcohol excess
  • diuretic use.

Hypokalemia causes concentration-dependent muscular symptoms and paralysis /10/:

  • Levels of 3.0–3.5 mmol/L may be associated with mild muscular weakness, myalgia and easy fatigability. In persons with normal heart function, hypokalemia of 3.0–3.5 mmol/L generally does not lead to cardiac problems; in individual cases, however, ventricular arrhythmia may occur.
  • Concentrations < 3.0 mmol/L are considered to be severe hypokalemia, since at these levels the risk of cardiac arrhythmia is elevated. Therefore, potassium substitution should immediately be provided. In the range of 2.5–3.0 mmol/L, muscular weakness (particularly of the proximal limbs and the head musculature) occurs. In one study /11/ 2.6% of the 37,458 hospital admissions had severe hypokalemia. Of these, 0.7% had a level below 2.0 mmol/L, 8.5% a value of 2.0–2.4 mmol/L, and 91% a value of 2.5–2.9 mmol/L. The hypokalemia was associated with the ingestion of a medication in 75% of the cases, primarily with furosemide, with other diuretics, and with corticosteroids and amphotericin B.
  • Concentrations below 2.5 mmol/L can lead to rhabdomyolysis with segmental muscle necrosis, vacuolar degeneration of the muscle fibers and myoglobinuria. Tetany occurs in association with alkalosis. Cerebral symptoms are rare.

Usually, clinical symptoms only accompany rapid, and not slow, decreases in K+ levels. The redistribution of K+ from the ECF to the ICF has only minimal effects on symptoms as seen:

  • After strenuous physical activity.
  • During infusion of glucose and/or insulin.

The causes of hypokalemia are classified as follows:

  • Renal loss
  • Extrarenal loss
  • Shift from the extracellular to the intracellular fluid compartment.

Diseases and conditions of hypokalemia are listed in Tab. 8.7-2 – Diseases and conditions associated with hypokalemia. Hypokalemia and urinary potassium excretion

If hypokalemia is present, the determination of urinary K+ excretion is the most important test for establishing the etiology /711/. The findings of a random sample can only be assessed if, anamnestically, it can be assumed that the urine volume is normal (1–1.5 L). Otherwise the determination must be performed using a timed urine collection. This is particularly important in patients with hypokalemia, since reduced total body K+ is associated with polydipsia and a renal concentrating defect.

Based upon urinary K+ excretion, hypokalemia is differentiated etiologically into:

  • Internal balance disorders. In these cases an increase in catecholamines or in insulin causes a trans cellular shift in K+ from the extracellular to the intracellular fluid compartment. The result is hypokalemia, but no change in renal K+ excretion.
  • External balance disorders with reduced total body K+. The cause can be reduced nutritional intake of K+, or renal or extrarenal loss of K+.

Based on the premise that in hypokalemia compensatory renal K+ excretion is limited, the urine findings can be interpreted as follows:

  • The combination of hypokalemia and low K+ excretion (below 10 mmol/L) suggests non-renal K+ loss
  • The combination of hypokalemia and K+ excretion of greater than 10 mmol/L indicates renal loss
  • A dissociation between serum K+ level and urinary K+ excretion suggests stress-related hypokalemia caused by catecholamines or diuretic-induced hypokalemia.

Apart from the urinary K+ excretion, the blood pH and Cl excretion in the urine provide further important differential diagnostic information for hypokalemia (see Section 8.8 – Renal electrolyte excretion).

Hypokalemia in association with reduced renal potassium excretion

With additional blood pH information, the following types of hypokalemia can be differentiated:

  • With metabolic acidosis (Cl in the serum elevated) in diarrhea, with villous adenomas of the intestine and in laxative abuse
  • With metabolic alkalosis (Cl reduced in the serum) with Cl losing diarrhea
  • With normal pH (Cl in the serum is normal) with decreased K+ intake or K+ loss through the skin and the gastrointestinal tract.

Hypokalemia in association with increased renal potassium excretion

Based upon blood pH, the following types of hypokalemia can be differentiated:

  • With metabolic hyperchloremic acidosis (like renal tubular acidosis) or acidosis with increased anion gap (as in diabetic or alcoholic ketoacidosis)
  • With normal blood pH due to trans cellular K+ displacement due to catecholamine increases (e.g., as seen in stressful situations and in the alcohol withdrawal syndrome)
  • With metabolic alkalosis. In these cases the Cl excretion allows further differentiation.

Hypokalemia in association with increased renal chloride excretion

Cl excretion of over 20 mmol/L and metabolic alkalosis are found in:

  • The Bartter syndrome, as well as in patients who take non-potassium-sparing diuretics such as furosemide, bumetanide and thiazides. If these diuretics are discontinued shortly before the visit to the doctor, however, Cl excretion is below 10 mmol/L.
  • Hypertensive patients with hyperaldosteronism or hypercortisolism. Hyperaldosteronism can be primary or secondary in nature; it is differentiated by the determination of plasma renin. Hypercortisolism can be medication-dependent or endogenous (e.g., hypophyseal adenoma with increased ACTH secretion, para neoplastic ectopic ACTH synthesis or adrenocortical adenoma). In hyperaldosteronism or hypercortisolism, renal excretion of both K+ and Cl is higher than 20 mmol/L.
  • Hypertensive patients with low aldosterone (e.g. in adrenal hyperplasia with 11β-hydroxylase deficiency, 17α-hydroxylase deficiency, or in the Liddle syndrome). In the Liddle syndrome, plasma cortisol values are normal, while in adrenal hyperplasia they are elevated.

Hypokalemia in association with reduced renal chloride excretion

Cl excretion of below 10 mmol/L in hypokalemia occurs with vomiting, after the discontinuation of non-potassium-sparing diuretics, and in chronic hypercapnia due to respiratory insufficiency of a wide variety of etiologies. Hyperkalemia

Hyperkalemia is a potentially life-threatening disease. In the United Kingdom by the Royal College of Pathologists’ Critical Communication Document, which requires that all K+ results ≥ 6.5 mmol/L be communicated within 2 h. Clinically relevant are serum K+ concentrations of ≥ 5.5 mmol/L. Hyperkalemia of 5.6–6.0 mmol/L is considered to be mild, levels of 6.1–6.9 moderate to severe, and values ≥ 7.0 mmol/L as very severe  /9/.

Hyperkalemia is most commonly caused in renal disease due to a decline of glomerular filtration rate (GFR). As approximately 98% of the body’s K+ is in the intracellular space any shift of K+ from the intracellular to extracellular space will lead to hyperkalemia. Such hyperkalemias are true hyperkalemias as the K+ concentration in serum reflects the in-vitro picture /44/.

Refer to Tab. 8.7-3 – Diseases and conditions associated with hyperkalemia.

Recently publicated data /44/ showed that more than half of serum K+ results of ≥ 6.0 mmol/L in specimen from primary care were due to pseudohyperkalemia. An estimated GFR (eGFR) of ≥ 90 [mL × min–1 × (1.73 m2)–1] gave a negative predictive value (NPV) of 100%, that is, true hyperkalemia was not associated with normal renal function. A second study /45/ found that for initial K+ results of ≥ 6.0 mmol/L, eGFR of ≥ 90 [mL × min–1 × (1.73 m2)–1] had an NPV of 72%; this increased to 83% when only initial K+ results of ≥ 6.5 mmol/L were included and to 100% when only those samples with initial K+ results of ≥ 6.5 mmol/L and concomitant normal blood count were included. The authors of both publications suggest that there is no need to telephone K+ results ≥ 6.5 mmol/L to out-of hours primary care providers if GFR is ≥ 90 [mL × min–1 × (1.73 m2)–1].

Hyperkalemia in association with reduced renal potassium excretion

Causes of decreased K+ excretions are:

  • A marked reduction of the GFR in acute or chronic renal insufficiency. The kidneys are the key organ with regard to K+ excretion; 90% of the K+ that is ingested with food is eliminated by the renal route and 10% by the gastrointestinal route. Nonetheless, the capability of excreting K+ is maintained for long periods of time in spite of severe renal insufficiency. Therefore, hyperkalemia is manifested only in acute renal failure or in stages IV and V of chronic renal insufficiency.
  • Selective hypo aldosteronism, which can be idiopathic in nature or occurs in a secondary manner in diabetics with chronic tubular interstitial nephritis. In some patients cardiac arrhythmias are a consequence of the hyperkalemia.
  • Adrenocortical insufficiency. Due to the deficiency in mineralocorticoids the patients manifest, apart from hyperkalemia, hyponatremia, hypovolemia, and a marked decline in blood pressure when moving from supine to upright position.
  • ACE inhibitors and angiotensin receptor blockers are used in hypertensive patients, in order to reduce cardiovascular risks. Hyperkalemia can develop as a side effect. This is particularly the case in patients who likely have an existing deficiency in K+ excretion, like those with chronic renal insufficiency and with diabetes mellitus. If, additionally, a K+ sparing diuretic is administered, as in patients with congestive heart failure, hyperkalemia is even more likely to occur and strict serum K+ monitoring is necessary /19/.

Hyperkalemia in association with increased renal potassium load

The kidneys are normally capable of eliminating all of the excess ingested K+. This is, however, not the case in patients:

  • With chronic renal insufficiency or in dialysis patients who do not observe their dietary instructions
  • With the tumor lysis syndrome, rhabdomyolysis, intravascular hemolysis, catabolic state because of high fever with K+ efflux from the intracellular fluid. Marked hyperkalemia does not, however, develop until renal function becomes limited.

Redistribution of potassium

For the assessment of K+ redistribution from the intracellular fluid (ICF) to the extracellular fluid (ECF) following is to be noted:

  • The K+ release from the ICF into the ECF takes place in the following situations: in metabolic acidosis, renal insufficiency, ketoacidosis, lactic acidosis, heparin therapy, digitalis overdose, infusion of hypertonic solutions such as 50% dextrose or mannitol, infusion of arginine chloride or lysine chloride for the treatment of metabolic alkalosis, and under therapy with β-receptor blockers
  • In metabolic acidosis, a decrease in pH of 0.1 leads to an increase in serum K+ of 0.5–1.2 mmol/L, in respiratory acidosis of 0.1–0.9 mmol/L
  • The extent to which serum K+ is influenced is dependent upon the duration of the acidosis, the acid equivalents, and the HCO3 concentrations. Thus, inorganic acids (HCl and NH4Cl) are more efficacious than organic acids (lactate, ketoacids).

Deficient tubular response to aldosterone

Deficient tubular secretion of K+ occurs due to possibly faulty binding of aldosterone to its receptors in the distal tubule. This can be the case in systemic lupus erythematosus, sickle cell anemia, amyloidosis, and following kidney transplantation. Clinical symptoms in hyperkalemia

Clinical manifestations of hyperkalemia include muscle weakness or paralysis, cardiac arrhythmias and death.

Clinical symptoms occur less frequently in hyperkalemia than in hypokalemia. The consequences of hyperkalemia are, however, more severe, since a reduced ratio of intracellular to extracellular K+ causes depolarization of the cell membrane with a decrease of the resting membrane potential. On electrically excitable cells, this leads to a delay in the rate of rise of the action potential and to a delay in the spread of the excitation. This has consequences, in particular, with regard to cardiac and skeletal muscle cells. At admission, many of the patients with hyperkalemia have, anamnestically, chronic kidney disease, diabetes mellitus, or high blood pressure.

Cardiac disorders /13/

At serum K+ levels of 6.0 mmol/L some 30% of patients have hyperkalemia-dependent electrocardiogram (ECG) changes; with values over 7.5 mmol/L almost all patients. With the increase in the K+ concentration the following ECG changes are caused chronologically: elevation of the T-wave amplitude, prolongation of the PQ interval, broadening of the QRS complex. The cardiac events are amplified by simultaneous hypocalcemia, hyponatremia and acidosis.

Skeletal muscles /13/

General muscle weakness, especially of the lower limbs. Paresthesia that begins distally, weakened tendon reflexes, and a feeling of heaviness in the limbs occur at serum K+ levels of ≥ 8 mmol/L. Pseudo­hyper­kalemia

Pseudohyperkalemia is an in vitro increase in serum K+ and does not reflect pathological in vivo changes. To distinguish between true hyperkalemia and pseudohyperkalemia renal function (eGFR) should be assessed. It is rare to develop true and severe hyperkalemia in the absence of decreased renal function. Normal ECG finding is a hint for pseudohyperkalemia.

There are multiple causes of pseudo­hyper­kalemia /44/:

  • erythrocytosis, thrombocytosis, leukocytosis; cheque plausibility of blood count
  • medications (K+ sparing diuretics)
  • excessive intake or infusion of K+ containing salts
  • repeated first clenching during phlebotomy
  • sample hemolysis
  • potassium-EDTA or potassium-oxalate in sample collection tube
  • prolonged tourniquet application
  • vigorous tube inversions
  • pneumatic tube transport
  • delay in sample centrifugation
  • seasonal cold temperatures
  • salt substitutes such as KCl or NH4Cl and the ingestion of K+ sparing diuretics, beta blockers, ACE inhibitors, and prostaglandin synthetase inhibitors should be inquired anamnestically. Hyperkalemia and urinary potassium excretion

If hyperkalemia is present, urinary K+ excretion is the additional test for the differentiation of renal and extrarenal hyperkalemia. K+ excretion of:

  • Greater than 40 mmol/L (i.e., normal K+ excretion, indicates extrarenal hyperkalemia)
  • Below 40 mmol/L indicates renal hyperkalemia.

Hyperkalemia in association with normal renal potassium excretion

Different forms are distinguished based on the underlying cause (i.e., due to):

  • Reduced trans cellular K+ shift from the extracellular fluid compartment (ECF) to the intracellular fluid compartment (ICF). The shift is regulated by the catecholamines, acting via the β2-receptors, as well as insulin. An inadequate shift in K+ into the ICF occurs with the blockade of β2-receptors by β-blockers, or strenuous physical activity, or in the case of insulin deficiency and digitalis intoxication.
  • Increased exogenous K+ intake. This may occur with the ingestion with food, salt intake, or for therapeutic reasons (e.g., KCl infusion or the administration of potassium gluconate, potassium phosphate or potassium citrate).
  • Increased K+ release from the ICF due to cellular damage (intravasal hemolysis, tumor cell lysis), muscle relaxants, hypertonic solutions or metabolic acidosis.

Hyperkalemia in association with reduced renal potassium excretion

From the clinical perspective, this hyperkalemia is differentiated into:

  • Conditions with hypo aldosteronism and low renin (similar to acute and chronic renal failure), and those with normal or elevated renin activity (Addison’s disease) or isolated aldosterone deficiency
  • Conditions with normal aldosterone in which, however, end organ resistance (lack of responsiveness of the kidneys to aldosterone) is present.

8.7.6 Comments and problems

Blood sampling

K+ values in serum are dependent upon the environmental temperature at the time of blood sampling. During the winter time the veins are less well filled than in summer and therefore, in winter, patients are more frequently requested to open and close their hand. This activity leads to the release of K+ from blood cells so that the frequency of hyperkalemia above 5.2 mmol/L increases from 0.6% in summer to 0.9% in winter /31/.


In vitro sample contamination with potassium EDTA is common and is caused by /32/:

  • Decanting of blood from potassium EDTA containing tubes to other tubes
  • Direct transfer of blood from potassium EDTA containing tubes to other tubes by back flow. Back flow is the regurgitation of blood from the evacuated blood collection tube back into the needle or vein. If blood is first collected from EDTA containing tubes, the regurgitated blood may be contaminated with EDTA which is then transferred to the following sample tubes.
  • If blood is collected with a syringe and distributed into tubes, and in the process the approach cone of the syringe is contaminated with potassium EDTA.


K+ concentrations in erythrocytes are around 25 times higher than in plasma. The blood must be collected without causing hemolysis and the erythrocytes have to be separated within 1 hour in order to prevent hyperkalemia.

Unduly delayed centrifugation of the blood sample is at 12.5% the most frequent cause of spurious hyperkalemia /33/.

Re centrifugation of the sample after 4 hours or more is, likewise, a frequent cause of spurious hyperkalemia. In Japan, for example, samples are re centrifuged in 70% of the laboratories /34/.

Difference between serum and plasma

K+ levels in serum are, on the average, higher by 0.3 mmol/L than in heparin plasma. In the presence of hypokalemia, the mean difference is greater than 0.5 mmol/L /4/.


In vitro hemolysis is defined as the release of intracellular constituents to the extracellular fluid compartment. Hemolysis is visible to the naked eye as a reddish-brown discoloration, if the free hemoglobin (Hb) concentration is ≥ 0.3 g/L. The mean elevations of K+ are, respectively, 0.28, 0.70 and 1.4 mmol/L, with mild (1 g Hb/L), moderate (2.5 g Hb/L) and severe (5 g Hb/L) hemolysis /35/.


In chronic lymphatic leukemia the cells manifest increased fragility. Low mechanical stress (compression of the upper arm during blood sampling or blood sampling with Vacutainer or serum separator tubes) leads to pseudo hyperkalemia. This is also the case if the transport for the sample tubes is carried out with pneumatic post /36/.

In myeloid leukemia with an elevated cell count pseudo hypokalemia may occur in vitro. The cause is believed to be increased Na+ permeability with activation of the Na+-K+-ATPase, leading to increased K+ uptake in the cells /37/.


Thrombocytoses > 500 × 109/L is associated with a serum to plasma K+ difference of > 0.5 mmol/L /38/.

Method of determination

Lipemic samples and samples with total protein of greater than 80 g/L cause spurious hypokalemia if assessed with flame photometry and indirect potentiometry.

Ammonium-containing (e.g., ammonium heparinate) anticoagulants and ammonium values of 20 mmol/L in samples lead to a rise in K+ levels of 0.3 mmol/L, if K+ is determined by ion-selective electrodes /39/. Disturbances due to ammonium are observed in quality control sera which include ammonium carbonate-containing dilution media, or have these or similar substances in the matrix. ­Ion-selectively measured K+ is also increased by ethylene glycol, which is used to stabilize quality control sera, as well as procainamide, employed in cardiac arrhythmias, at concentrations of 8 mg/L.

Storage of samples

The concentration of K+ in serum/plasma prior to centrifugation is a function of storage conditions e.g., time and temperature. In a study /42/ a decrease then an increase in K+ level was observed at 20–25 °C. A decrease then an increase at 4 °C from –1% to 9.6% between 2 and 24 h was measured due to leakage from cells. In summary K+ did not remain stable beyond 4 h after sampling.

Stability in plasma and serum

At least 1 week in closed tubes at room temperature or 4 °C. For direct ISE measurements only fresh serum or plasma are to be used, as an increase in HCO3 in stored samples leads to an increase in pH and a decline in measurable ion activity /40/.


1. Wright FS, Giebisch G. Regulation of potassium excretion. In: Seldin DW, Giebisch G (eds). The kidney, physiology and pathophysiology. New York; Raven, 1992: 2209–47.

2. NCCLS. Standardization of sodium and potassium ion selective electrode systems to the flame photometric reference method; approved standard. NCCLS Document C29-A, Vol 15 No 1. Villanova: NCCLS, 1995.

3. Berry MN, Mazzachi RD, Pejakovic M, Peake MJ. Enzymatic determination of potassium in serum. Clin Chem 1989; 34: 2295–8.

4. Drogies T, Ittermann T, Lüdemann J, Klinke D, Kohlmann T, Lubenow K, et al. Potassium – reference intervals for lithium-heparin plasma and serum from population-based cohort. J Lab Med 2010; 34: 39–44.

5. Rodriguez-Soriano J. Potassium homeostasis and its disturbances in children. Pediatr Nephrol 1995; 9: 364–74.

6. Soldin SJ, Brugnara C, Wong EC. Pediatric reference ranges. Washington: AACC-Press, 2003: 152.

7. Gumz ML, Rabinowitz L, Wingo CS. An integrated view of potassium homeostasis. N Engl J Med 2015; 373: 60–72.

8. Berns JS, Hayslett JP. Renal and extrarenal excretion of potassium. In Seldin DW, Giebisch G (eds). The regulation of potassium balance. New York: Raven, 1989: 157–74.

9. Mandal AK. Hypokalemia and hyperkalemia. Med Clin North Am 1997; 81: 611–39.

10. Riggs JE. Neurologic manifestations of electrolyte disturbances. Neurologic Clinics 2002; 20: 227–39.

11. Paltiel O, Salakhov E, Ronen I, Berg D, Israeli A. Man-agement of severe hypokalemia in hospitalized patients. Arch Intern Med 2001; 161: 1089–95.

12. Palmer BF. Managing hyperkalemia caused by inhibitors of renin-angiotensin-aldosteron system. N Engl J Med 2004; 351: 585–92.

13. Stein G, Ritz E. Klinik und Diagnostik der Hyperkali­ämie. Dtsch Med Wschr 1990; 115: 899–902.

14. Gennari FJ. Hypokalemia. N Engl J Med 1998; 339: 451–8.

15. Reincke M, Seiler L, Rump LC. Normokaliämischer primärer Hyperaldosteronismus. Dt Ärztebl 2003; 100: B169–74.

16. Beal AL, Scheltema KE, Beilman GJ, Deuser WE. Hypokalemia following trauma. Shock 2002; 18: 107–10.

17. Penney MD, Oleesky DA. Renal tubular acidosis. Ann Clin Biochem 1999; 36: 408–22.

18. Amirlak I, Dawson KP. Bartter syndrome: an overview. Q J Med 2000; 93: 207–15.

19. Barakat AJ, Rennert OM. Gitelman’s syndrome (famial hypokalemia-hypomagnesemia). J Nephrol 2001; 14: 43–7.

20. Jones BJ, Twomey PJ. Comparison of reflective and reflex testing for hypomagnesaemia in severe hypokalemia. J Clin Pathol 2009; 62: 816–9.

21. Lapie P, Lory P, Fontaine B. Hypokalemic periodic paralysis: an autosomal dominant muscle disorder caused by mutations in a voltage-gated calcium channel. Neuromuscular Disorders 1997; 7: 234–40.

22. Duke M. Thiazide-induced hypokalemia: association with acute myocardial infarction and ventricular fibrillation. JAMA 1978; 239: 43–5.

23. Burl RD, Sebastian A, Cheitlin MW, Christiansen M, Schambelan M. Pseudohyperkalemia caused by first clenching during phlebotomy. N Engl J Med 1990; 322: 1290–2.

24. Colussi G, Cipriani D. Pseudohyperkalemia in extreme leukocytosis. Am J Nephrol 1995; 15: 450–2.

25. Wulkan RW, Michiels JJ. Pseudohyperkalemia in thrombocythemia. J Clin Chem Clin Biochem 1990; 28: 489–91.

26. Alani FSS, Dyer T, Hindle E, Newsome DA, Ormerod LP, Mahoney MP. Pseudohyperkalemia associated with hereditary spherocytosis in four members of a family. Postgrad Med J 1994; 70: 749–51.

27. Hawkins RC. Serum potassium in renal impairment: At what concentration of estimated GFR does it rise? Clin Chim Acta 2009; 408: 135–6.

28. Perazella MA. Drug-induced hyperkalemia: old culprits and new offenders. Am J Med 2000; 109: 307–14.

29. Cairo MS, Bishop M. Tumour lysis syndrome: new therapeutic strategies and classification. Br J Haematol 2004; 127: 3–11.

30. Oster JR, Singer I, Fishman LM. Heparin-induced aldosterone suppression and hyperkalemia. Am J Med 1995; 98: 575–86.

31. Bailey IR, Thurlow VR. Is suboptimal phlebotomy technique impacting on potassium results for primary care? Ann Clin Biochem 2008; 45: 266–9.

32. Cornes MP, Ford C, Gama R. Spurious hyperkalaemia due to EDTA contamination: common and not always easy to identify. Ann Clin Biochem 2008; 45: 601–3.

33. Kapoor AK, Ravi A, Twomey PJ. Investigation of outpatients referred to a chemical pathologist with potential pseudohyperkalaemia. J Clin Pathol 2009; 62: 920–3.

34. Hira K, Aoki N, Fukui T. Pseudohyperkalaemia at commercial laboratories in Japan: a questionnaire survey. Ann Clin Biochem 2004; 41: 155–6.

35. Hawkins RC. Poor knowledge and faulty thinking regarding hemolysis and potassium elevation. Clin Chem Lab Med 2005; 43: 216–20.

36. Dsatych M, Cermakova Z. Pseudohyperkalaemia in leukaemic patients: the effect of test tube type and form of transport to the laboratory. Ann Clin Biochem 2014; 51: 110–3.

37. Polak R, Huisman R, Sikma MA, Kersting S. Spurious hypokalaemia and hypophosphaemia due to extreme hyperleukocytosis in a patient with haematological malignancy. Ann Clin Biochem 2010; 47: 179–81.

38. Thurlow V, Ozevlat H, Jones SA, Bailey IR. Establishing a practical blood platelet threshold to avoid reporting spurious potassium results due to thrombocytosis. Ann Clin Biochem 2005; 42: 196–9.

39. Marsoner HJ, Harnoncourt K. Potentiometrische Bestimmung der Kaliumkonzentration im Plasma. Ärztl Lab 1977; 23: 327–9.

40. Boink FBT, Bijster B, Vink KL, Maas AH. Direct potentiometric determination of sodium in blood. III. Influence of bicarbonate. Clin Chem 1985; 31: 523–6.

41. Palmer BF, Clegg DJ. Electrolyte disturbances in patients with chronic alcohol-use disorder. N Engl J Med 2017; 377: 1368–77.

42. Dupuy AM, Cristol JP, Vincent B, Bargnoux AN, Mendes M, Philibert P, Kloche K, Badiou S. Stability of routine biochemical analytes in whole blood and plasma/serum: focus on potassium stability from lithium heparin. Clin Chem Lab Med 2018, 56: 413–21.

43. Ellison DH, Welling P. Insights into salt handling and blood pressure. N Engl J Med 2021; 385: 1981–93.

44. Morris TG, Lambda S, Fitzgerald T, Roulston G, Johnstone H, Mirzazadeh M. The potential role of the GFR in differentiating between true and pseudohyperkalaemia. Ann Clin Biochem 2020; 57(6): 444–55.

45. Bealing E, Lundquist D, Stock S. The use of estimated glomerular filtration rate (GFR) in identifying pseudohyperkalemia in primary care. Ann Clin Biochem 2022; 0 (0): 1–2.

46. Vokoun CW, Murphy MC, Reynolds KL, Haines MS. Case1-2023: a 49-year-old man with hypokalemia and paranoia. N Engl J Med 2023; 388 (2): 165–175.

8.8 Renal electrolyte excretion

Lothar Thomas

The kidneys are responsible for electrolyte and water homeostasis, and they carry out this function through glomerular filtration, re uptake and secretion of water and solutes. This is performed by special nephron transporters, cotransporters and ion channels, which have a specific tubular localization. For urine formation, a daily volume of 160 liters of glomerular filtrate is produced, 99% of which is reabsorbed in the tubules, along with most of the solutes. The excretion of the solutes is determined ultimately by the relationship between the amount of solutes filtered and the quantity reabsorbed into the peritubular capillaries, which is thereby returned to the systemic circulation /1/.

In the proximal tubule specific channels and a Na+-K+-ATPase dependent transport system permit the movement of selected ions, for glucose, phosphate and amino acids through cellular tubular membranes and the re-uptake from the tubulus lumen into the cell. Cotransporters, responsible for the reabsorption of organic solutes (glucose and amino acids) and inorganic substances (Cl and phosphate), are also localized in the tubular cells. The concentrating functions of the filtrate are localized in the distal tubules, while the final composition of the urine occurs in the collecting ducts.

Congenital and acquired disorders of channel proteins, termed channelopathies, have critical roles enabling Na+ and K+ re uptake or excretion along the nephron, in Mg2+ homeostasis, in the control of water reabsorption in the collecting duct, and in determining glomerular permeability /2/. Evaluations of electrolyte excretion are helpful in order to localize disorders of electrolyte and water balance and to quantify their scope.

In a study follow-up  /18/ of 8.8 years participants of mean age 51 and median 24-hour Na+ excretion of 3270 mg, higher Na+ excretion, lower K+ excretion and a higher Na+/K+ ratio were associated with a higher cardiovascular risk. Each daily increment of 1,000 mg in Na+ excretion was associated with an 18% increase in cardiovascular risk (hazard ratio 1.18) and each daily increment of 1,000 mg in K+ excretion was associated with an 18% decrease in risk (hazard ratio 0.82).

8.8.1 Urinary electrolyte determination

The investigation of urinary electrolyte excretion includes, depending upon the clinical issue, the determination of Na+, K+, H+ (pH), ammonium ions (NH4+), Cl and HCO3. For purposes of differentiation of the disorders, the urinary anion gap, osmotic gap and fractional excretion (FE) of Na+ (FENa) are calculated. Indication


  • Etiological evaluation of states associated with hypernatremia or hyponatremia
  • Suspection of disturbances of water balance.


  • Differentiation of renal and extrarenal causes in states associated with hyperkalemia or hypokalemia
  • Suspected intake of non-potassium-sparing diuretics.

Chloride, pH, bicarbonate

  • Diagnosis of metabolic acidosis. Method of determination


Na+-selective electrode (ISE), flame photometry; for principle see Section 8.2.2 – Method of determination


K+-selective ISE, flame photometry; for principle see Section 8.2.2 – Method of determination and Section 8.6.2 – Method of determination


Cl-selective ISE, coulometric titration (chloride meter), mercurimetric titration; for principle see Section 8.3 – Chloride


Spectrophotometric determination using glutamate dehydrogenase (EC and electrochemical determination with potentiometry or conductimetry

H ions

Determination by means of pH meter

Bicarbonate (HCO3)

Spectrophotometric determination using the enzymes phosphoenolpyruvate carboxylase and malate dehydrogenase. Determination of urinary PCO2 and pH and calculation of HCO3 according to the following equation:

HCO3 (mmol/L) = 10(pH pK) × 0.03 × PCO2

pK = 6.1 Specimen

Na+, K+, Cl

For determination of the concentration: fresh spot urine sample. Send the full urine volume to the laboratory or, after having measured the volume, at least 10 mL.

For determination of the excretion: send 24-hour urine sample without supplement to the laboratory.


In the morning fresh random urine is voided into a vessel containing mineral oil; this covers the fluid surface, thus preventing the loss of CO2.


Fresh early morning voided urine sample, see Na+, K+, Cl.


Fresh early morning voided random urine sample, see Na, K, Cl. Reference interval

Refer to references /345/ and Tab. 8.8-1 – Urinary electrolyte reference intervals.

8.8.2 Disturbances of sodium excretion

Excessive salt consumption is a risk factor for the development of hypertension and cardiovascular disease. Na+ excretion in 24-hour urine is an indicator of the amount of salt that is ingested with food. The intake of 0.6 g of salt represents 10 mmol of excreted Na+. In the industrialized nations of the Western world, salt intake is 10–15 g (160–250 mmol of Na+) per day, instead of the adequate amount of 3 g of NaCl (50 mmol Na+). Na+ excretion in 24-hour urine is a good marker for the assessment of daily salt intake. With Na+ intake of 250 mmol/day, 252 ± 65 mmol/24 h are excreted, while with an intake of 50 mmol/day, 46 ± 27 mmol/24 h are excreted /6/.

Some 30% of the Na+ is reabsorbed in the distal tubules and the collecting ducts. In the distal tubules this is accomplished in accordance with the principle shown in Fig. 8.8-1 – Pathways of Na+, K+, Mg++ and Ca++ reabsorption in the thick ascending limb of the loop of Henle.

The composition of the Na+ and K+ concentrations of the final urine takes place in the collecting ducts (Fig. 8.8-2 – Reabsorption of solutes in the collecting duct). Na+ is reabsorption takes place in exchange for K+ via respective special channels.

The lining of the luminal membrane of the collecting duct cells with ion channels is regulated by aldosterone, which acts via the mineralocorticoid receptors. A deficiency of aldosterone, or resistance of the receptors to aldosterone, reduces the synthesis of ion channels /2/.

Renal salt and water excretion adjusts to the daily dietary intake, so that a dynamic equilibrium between intake and excretion is created and, as a result, the Na+ concentration in the extracellular fluid (ECF) is held constant. Small changes in renal reabsorption of Na+ and water can lead to considerable alterations in the volume of the ECF. Thus, with a sodium-free diet, Na+ excretion in healthy individuals declines to below 3 mmol/24 h after 3–5 days.

Since Cl is the principal anion of Na+, renal excretion of Na+ and Cl is, in many ways, identical. The determination of renal Na+ excretion is diagnostically important for the differentiation of hyponatremia and hypernatremia. See Section 8.2 – Sodium. Sodium excretion in hyponatremia

Renally induced Na+ losses are associated with the excretion of more than 20 mmol/L in the random urine sample /78/.

Conditions with reduced extracellular fluid volume decline (ECFV) due to extra-renal fluid losses (except for vomiting) and Na+ losses in the third space (edema) are associated with Na+ excretion of less than 20 mmol/L.

In conditions with hyponatremia, renal Na+ excretion is an indicator of the volume status of the ECFV. Accordingly, in patients with hypo osmolar hyponatremia, renal Na+ excretion is:

  • In euvolemia above 20 mmol/L
  • In hypovolemia (volume depletion) below 20 mmol/L
  • In hypervolemia below 20 mmol/L.

The differential diagnostic significance of Na+ excretion in hyponatremia is shown in Tab. 8.8-2 – Differential diagnostic significance of urinary Na+ excretion in hyponatremia. Sodium excretion in hypernatremia

The major cause of hypernatremia is the more marked loss of water in comparison with that of Na+. For this reason, the serum is hyper osmolar /9/.

In conditions with hypernatremia, renal Na+ excretion is an indicator of the volume status of the ECFV. Thus, in patients with hyper osmolar hypernatremia, renal Na+ excretion is:

  • In volume depletion below 20 mmol/L.
  • In hypervolemia above 20 mmol/L.
  • In states with loss of free water (renal or hypothalamic) variable. See Section 8.5 – Osmolality).

The differential diagnostic significance of Na+ excretion in hypernatremia is shown in Tab. 8.8-3 – Differential diagnostic significance of urinary Na+ excretion in hypernatremia.

8.8.3 Fractional sodium excretion (FENa)

The FENa test determines the excreted fraction of glomerular filtered Na+ and is a measure of tubular Na+ reabsorption /10/. It serves to differentiate between pre renal azotemia and tubular necrosis in patients with acute renal failure in the oliguric phase. Patients with pre renal failure have a FeNa less than 1%, patients with acute tubular necrosis have a FeNa of more than 2%.

FE NA (%) = Na (U) × creatinine (S) × 100 Na (S) × creatinine (U)

U, urine; S, serum; Na in mmol/L, creatinine in μmol/L or mg/dL

Interpretation of the FENa test

The FENa provides better information concerning volume status than does urinary Na+ concentration. Healthy individuals with a glomerular filtration rate (GFR) of 120 [mL × min–1 × (1.73 m2)–1] and a normal Na+ excretion of 120 mmol/L have an FeNa of 0.19–0.78%.

In pre renal failure, the nephron attempts to conserve Na+. The Na+ excretion in a random urine sample is below 20 mmol/L, urine osmolality is above 500 mmol/kg and the FeNa is less than 1%. This is the case, for example, in patients with severe heart failure in NYHA stages III and IV with an ejection fraction below 35%.

In renal failure the reabsorption of Na+ is diminished, Na+ excretion is above 20 mmol/L, urine osmolality is below 300 mmol/kg, and the FeNa is greater than 2%.

It must be noted that the FENa provides no information in patients treated with diuretics. In these patients it is false high with values of up to 20%.

8.8.4 Disturbances of chloride excretion

Cl is the most important counter ion to Na+ and is reabsorbed electroneutrally with Na+ in the renal tubules. In many pathological conditions the excretion of Na+ and Cl behave similarly. A dissociation of renal Na+ and Cl excretion occurs in vomiting.


In sustained vomiting the excretion of Cl in the random urine sample is below 20 mmol/L in the presence of elevated Na+ and K+ excretion. The cause of this is that during continuous vomiting NaCl, HCl and KCl are lost via the gastric juices. Due to the loss of H+ the concentration of HCO3 is elevated and metabolic alkalosis develops. The increased delivery of HCO3 to the distal tubules leads to enhanced excretion of Na+ and K+. The patient’s volume status in chronic vomiting is more accurately provided by the excretion of Cl than by that of Na+.

Metabolic alkalosis /9/

In the therapy of metabolic alkalosis Cl excretion below 10 mmol/L provides an indication of improvement of the disorder through salt intake. In Cl-resistant alkalosis excretion is measured as a function of salt intake. See also metabolic alkalosis in Section – Chloride level in metabolic alkalosis.

8.8.5 Fractional chloride excretion (FECl)

The FECl test determines the fraction of Cl filtered by the glomeruli that is excreted in the urine; it is a measure of tubular Cl reabsorption. The normal FECl value is 1–3%. In alkalosis and extrarenal Cl loss (vomiting, congenital chloridorrhea), the FECl is below 1% and in metabolic acidosis above 3%.

FE Cl (%) = Cl (U) × creatinine (S) × 100 Cl (S) × creatinine (U)

U, urine; S, serum; Cl in mmol/L, creatinine in μmol/L or mg/dL

8.8.6 Urinary anion gap (UAG)

Polyuria, caused by electrolyte diuresis, usually results from increased NaCl excretion and are the consequence of intravenous administration of NaCl, excessive oral salt intake, renal loss of salt, or the medication of loop diuretics /12/.

For the evaluation of whether an anion other than Cl is present in meaningful concentrations as a counter ion to Na+ or whether cations other than Na+ and K+, especially NH4+, are excreted, the urinary anion gap (UAG) is determined (Tab. 8.8-4 – Interpretation of the urinary anion gap).

The calculation of the UAG is performed in a pH-dependent manner according to the following equations:

1. Urine pH below 6.5:

UAG = Na+ (mmol/L) + K+ (mmol/L) – Cl (mmol/L)

2. Urine pH above 6,5:

UAG = Na+ (mmol/L) + K+ (mmol/L) – Cl (mmol/L) – HCO3 (mmol/L)

8.8.7 Disorders of H ions, ammonium and bicarbonate excretion

The kidneys are the principal organ in the regulation of the systemic pH value. Alterations in acid-base status result in corresponding changes in H+ secretion, HCO3 reabsorption and NH4+ formation. These regulatory changes take place preferentially in the proximal tubule and the collecting duct. Their effectiveness is based upon a rapid change in the net trans epithelial flux of H+ and HCO3. Approximately 80–90% of the reabsorption of filtered HCO3 occurs in the proximal tubules. Basic mechanisms in the proximal tubules are the allosteric pH controlled Na+–H+ exchange of the luminal membranes (Fig. 8.8-3 – Acid-base homeostasis in the proximal convoluted tubulus) and an electrogenic Na+ and 3 HCO3 cotransport system in the basolateral cell membrane /13/.

Proximal tubule mechanisms

Fundamental mechanisms in the proximal tubule are allosteric pH-controlled Na+-H+ exchange at the luminal cell membrane via the Na+-H+ exchanger (NHE-3) and the HCO3 transport at the basolateral membrane mediated by the 1 Na+–3 HCO3 cotransporter (NBC-1) (Fig. 8.8-3).The high trans cellular HCO3 transport rates occur at a rather constant cytosolic pH. K+ channel regulation by cytosolic pH adjusts HCO3 export to import..If luminal H+ secretion exceeds basolateral HCO3 transport cytosolic pH alkalinizes. This leads to the activation of K+ channels which hyperpolarize the membrane potential, giving an enhanced driving force for electrogenic HCO3 export /1314/.

Collecting duct mechanisms

In the collecting duct α-type intercalated cells secrete H+ via a vacuolar type H+-ATPase and a H+–K+ -ATPase. HCO3 is exchanged with Cl to the blood site /1314/. β-type intercalated cells exchange Cl and HCO3 at the luminal site. H+ leave the cell via basolateral Na+–H+ exchange (not shown in Fig. 8.8-4 – H+ Secretion into the cortical collecting tubule.

Systemic acid disorders

In this condition, the luminal secretion of H+ by the nephron exceeds the basolateral (blood side) HCO3 export, and the cytosolic pH becomes alkaline. This activates the K+ channels, whereby the cell membrane is hyperpolarized and enhanced electrogenic exit of HCO3 from the cells into the tubular lumen occurs. In addition, renal glutaminase is induced and hepatic glutamine synthetase is activated. In this way, renal glutamine metabolism is able to form large quantities of NH4+. Contingent upon its charge and the alkaline pK value, NH4+ remains in the tubular lumen /1314/.

Systemic alkalosis

In this condition, luminal secretion of H+ by the nephron is reduced relative to basolateral (blood side) HCO3 secretion, and the cytosolic pH is acidic. In order to maintain intracellular homeostasis, trans cellular transport of HCO3 from the tubular lumen into the blood is decreased /14/. Renal-tubular acidoses (RTA)

The term RTA comprises a group of transport defects in the reabsorption of HCO3, the excretion of H+ or both. In RTA, the glomerular filtration rate (GFR) is usually normal and metabolic acidosis, hyperchloremia and a normal anion gap in the plasma are present. In contrast, in uremic acidosis a low GFR is found and the metabolic acidosis is associated with an increased anion gap and a normochloremia or hyperchloremia.

RTA is differentiated into three types /15/:

  • Distal RTA, type 1. This type is the most common form of RTA and it is subdivided into a classical, complete form and an incomplete form. The complete type is caused by a defect in the vacuolic H+-ATPase (Fig. 8.8-4 – H+ secretion into the cortical collecting tubule). The result is impaired distal acidification and inability to lower urine pH maximally (< 5.5).
  • Proximal RTA, type 2. This type is characterized by a decreased renal HCO3 threshold in the proximal tubule (Fig. 8.8-3 – Maintaining the acid-base homeostasis in the proximal tubulus). Distal acidification mechanisms are intact.
  • Hyperkalemic RTA, type 4. This type of RTA is mainly caused by impaired ammoniogenesis. Type 4 is most frequently observed in states of hypo- or pseudo hypo aldosteronism. Laboratory diagnosis of RTA

In general RTA should be suspected (Tab. 8.8-5 – Renal-tubular acidoses (RTAs)):

  • In cases where metabolic acidosis is accompanied by hyperchloremia and normal anion gap in plasma [Na+ – Cl + HCO3] = 8 – 16 mmol/L, in a patient without evidence of gastrointestinal HCO3 losses and who is not taking acetazolamide or ingesting exogenous acid /13/.
  • If hypokalemia is present, and diuretics are not being taken.

A series of functional tests are available for the typing of RTA. Of these, the HCO3 loading test and the ammonium chloride loading test are employed most frequently. Tests for the functional evaluation of proximal HCO3 reabsorption (diagnosis of proximal RTA) and distal acidification of the urine (diagnosis of distal RTA) are listed in Tab. 8.8-6 – Laboratory diagnostics of renal-tubular acidoses (RTAs).

Diagnostic work-up

In suspected RTA, one should proceed as follows /13/:

  • Determination of the anion gap and the osmotic gap in a random voided morning urine sample. If the patient has hyperchloremic metabolic acidosis, a negative anion gap or an osmotic gap exceeding 100 mmol/L, proximal RTA is likely. Gastrointestinal loss of HCO3 and the intake of acidifying salts must be ruled out (Fig. 8.8-5 – Diagnostic work-up for patients with hyperchloremic metabolic acidosis and negative urinary anion gap). Furthermore, repeated use of laxatives which, in low Na+ excretion must be taken into consideration, should be asked about in adults. The definitive diagnosis of proximal RTA (RTA type 2) is established if the fractional HCO3 and the urine-plasma PCO2 difference (U-B PCO2) is likewise elevated and the anion gap is negative (Tab. 8.8-7 – Differentiation of the renal-tubular acidoses (RTA) by biochemical tests).
  • When a random voided morning urine sample from a patient with hyperchloremic metabolic acidosis has a positive anion gap or an osmotic gap below 100 mmol/L, a defect in the distal urinary acidification should be suspected. The next step is the determination of K+ in the plasma. If the value is normal or decreased, the inability of the kidneys to lower urine pH below 5.5 after ammonium chloride loading establish the diagnosis of distal RTA (RTA type 1) (Fig. 8.8-6 – Diagnostic work-up for patients with hyperchloremic metabolic acidosis and positive urinary anion gap).
  • When in hyperchloremic metabolic acidosis, the random voided morning urine sample anion gap is positive and the osmotic gap is below 100 mmol/L, a defect in the distal urinary acidification should be suspected. The next step is the determination of K+ in serum. When the K+ level is increased, even modestly, attention should be paid to the value of the urine pH. The finding of pH higher than 5.5 after ammonium chloride loading will permit the identification of patients with hyperkalemic distal RTA (RTA type 4) caused by a voltage dependent defect (Fig. 8.8-6).

8.8.8 Disturbances of potassium excretion

Although trans cellular shifting of K+ is a rapid, efficient mechanism to reduce serum K+ must be excreted by the kidney to maintain external K+ balance. Distal nephron K+ delivery is approximately 10% of filtered K+ regardless of the glomerular filtration rate. However in addition to ingested potassium additional K+ excretion is possible. This situation is impossible with regard to sodium balance.

The most important factors influencing K+ secretion by the by the distal nephron are prior to potassium exposure /16/:

  • Mineralocorticoids such as aldosterone
  • Extracellular fluid volume which inhibits the effect of aldosterone but by raising the flow rate increases the availability of Na+ in the distal tubules and thus, leading to an increased excretion of K+
  • Systemic alkalosis, which enhances K+ excretion
  • The intake of diuretics such as thiazides, furosemide and bumetanide, which cause an increase in K+ excretion by raising the flow rate in the first third of the collecting ducts.

Normal K+ excretion is greater than 40 mmol/L. With normal K+ intake the kidneys are capable to maintain K+ excretion with a decrease of GFR to approximately 10 [mL × min–1 × (1.73 m2)–1].

The determination of renal K+ excretion is an important step toward differentiation of the various forms of hypokalemia and hyperkalemia. Potassium excretion in hypokalemia

For the K+ stores of the organism (e.g.,most is in muscle 3000–5000 mmol), serum K+ levels are useful only to a limited degree. In K+ deficiency, the K+ determination in the random urine sample aids in the localization of the losses.

A value below 10 mmol/L in the presence of hypokalemia is indicative of extrarenal loss, while a value greater than 10 mmol/L suggests renal loss (Tab. 8.8-8 – Renal potassium excretion in hypokalemia).

The diseases associated with hyperkaliuric hypokalemia are listed in Tab. 8.8-9 – Hyperkaliuric hypokalemia. Elevated excretion is also measured in:

  • Metabolic acidosis as an effect of distribution disorders of K+ (efflux of K+ from the intracellular fluid).
  • Metabolic alkalosis, as replacement cation for Na+, K+ along with H+ and NH4+ are excreted. Potassium excretion in hyperkalemia

In hyperkalemia, K+ excretion below 40 mmol/L indicates renal etiology, while a value of ≥ 40 mmol/L is suggestive of extrarenal causes (Tab. 8.8-10 – Renal potassium excretion in hyperkalemia).

The causes of hypocaliuric hyperkalemia are shown in Tab. 8.8-11 – Hypocaliuric hyperkalemia.

8.8.9 Fractional excretion of urinary electrolytes

Reference intervals

FENa 0.19–0.78%; FEK 4.9–10.3%; FECl 0.35–1.07%; FECa 0.6–1.0%; FEMg 1.4–1.8% /17/.


1. Sayer JA, Pearce SHS. Diagnosis and clinical biochemistry of inherited tubulopathies. Ann Clin Biochem 2001; 38: 459–70.

2. Loudon KW, Fry AC. The renal chanelopathies. Ann Clin Biochem 2014; 51: 441–58.

3. Krieg M, Gunßer KJ. Vergleichende quantitative ANalytik klinisch-chemischer Kenngrößen im 24-Stunden-Urin und Morgenurin. J Clin Chem Clin Biochem 1986; 24: 863–9.

4. Bingham S, Williams R, Cole TJ, Price C, Cummings JH. Reference values for analytes of 24-h urine collections known to be complete. Ann Clin Biochem 1988; 25: 610–9.

5. Illich JZ, Blanusa M, Orlic ZC, Orct T, Kostial K. Comparison of calcium, magnesium sodium, potassium, zinc, and creatinine concentration in 24-h and spot urine samples in women. Clin Chem Lab Med 2009; 4: 216–22.

6. Pimeta E, Gaddam K, Oparil S, Aban I, Husain S, Dell’Ìtalia LJ, et al. Effects of dietary sodium reduction on bood pressure in subjects with resistant hypertension: results from a randomized trial. Hypertension 2009; 54: 475–81.

7. Bichet DG, Kluge R, Howard RL, Schrier RW. Pathogenesis of hypoNatremic states. In: Seldin DW, Giebisch G (eds). Clinical disturbances of water metabolism. New York: Raven, 1993: 169–88.

8. Bichet DG, Kluge R, Howard RL, Schrier RW. Pathogenesis of hyponatremic states. In: Seldin DW, Giebisch G (eds). Clinical disturbances of water metabolism. New York: Raven, 1993: 169–88.

9. Howard RL, Bichet DG, Schrier RW. Pathogenesis of hyperNatremic and polyuric states. In: Seldin DW, Giebisch G (eds). Clinical disturbances of water metabolism. New York: Raven, 1993: 189–209.

10. Espinel CH. The FeNa test. Use in the differential diagnosis of acute reNal failure. JAMA 1976; 236: 579–81.

11. Schmidt LH, Wessing H, Ehrhardt W. Electrolytes in urine: possibilities and limits of interpretation. Klin Lab 1992; 38: 616–8.

12. Oster JR, Singer I, Thatte L, Grant-Taylor I, Diego JM. The polyuria of solute diuresis. Arch Intern Med 1997; 157: 721–9.

13. Bleich M. Tubular function and acid – base disturbances. Nephrol Dial Transplant 1995; 10: 1540–1.

14. Soriano JR. Renal tubular acidosis: the clinical entity. J Am Soc Nephrol 2002; 13: 2160–70.

15. Ring T, Frische S, Nielsen S. Clinical review: renal tubular acidosis – a physicochemical approach. Crit Care 2005; 9: 573–80.

16. Linas SL, Berl T. Clinical diagnosis of abnormal potassium balance. In: Seldin DW, Giebisch G (eds). The regulation of potassium balance. New York: Raven 1989: 177–205.

17. Gross P, Reimann D. Das Gitelman-Syndrom. Nephro-News 2002; 3: 1–5.

18. Ma Y, He FJ, Sun Qui, Changzheng Y, Kieneker LM, Curhan GC, et al. 24-hour urinary sodium and potassium excretion and cardiovascular risk. N Engl J Med 2021. doi: 10.1056/NEJMoa2109794.

19. Davison AS, Devlin L, Panicker JJ. Severe Hypokalemia associated with paralysis after a large carbohydrate intake following exercise. Clin Chem 2024; 70 (4): 584–8.

8.9 Cystic fibrosis

Lothar Thomas

Cystic fibrosis is an autosomal recessive disease caused by mutations in the gene CFTR. The cFTR protein is involved in the regulation of transepithelial ion and water transport. The CFTR gene encodes for the ion channel protein cFTR that is evolved in the regulation of water- and electrolyte balance on the surface of many organs. Deletion of three base pairs in the CFTR gene lead to the loss of the amino acid phenylalanine at position 508 in the cFTR protein. The number of CFTR gene variants is more than 2000 and about 700 disease-causing mutations are registered by the Cystic fibrosis Foundation /1/. Cystic fibrosis variants have different implications with respect to cFTR production. The absence or dysfunction of cFTR protein leads to decreased Cl and HCO3 secretion at the apical membrane of the secretory cell.

8.9.1 Indication

Newborn screening

8.9.2 Method of determination

The diagnosis of cystic fibrosis is based on:

  • a positive sweat chloride test
  • genetic testing for common CFTR variants: in the case of three disease-causing CFTR variants cystic fibrosis is proven
  • most screening programs use blood trypsinogen concentrations, which are increased in infants with cystic fibrosis.

8.9.3 Specimen

  • Sweat 0.01 mL; sweat chloride test
  • Blood 0.5 mL for testing of immunoreactive trypsinogen determination in the first 24 to 72 hours of life: above the 99. percentile
  • Blood 0.5 mL for discovery of the CF gene.

8.9.4 Reference ranges

  • Sweat chloride test: Cl concentration < 60 mmol/L
  • Blood: immunoreactive trypsinogen determination in the first 24 to 72 hours of life: above the 99. percentile
  • Genetic testing: no gene variant.

8.9.5 Clinical significance

The diagnosis of cystic fibrosis is based on many organ manifestations that is consistent with /2/:

  • a positive sweat test (refer to section 47.10 – Sweat), or
  • genetic testing (three base base pairs in the CFTR leading to the loss of the amino acid phenylalanin at position 508).

About 85% of the cystic fibrosis variants in patients in the United States of America are F508del and results in defective protein folding /1/.

Cystic fibrosis causing variants have different implications in the production of cFTR protein expression, processing, and function. The implications can result in /2/:

  • premature termination codons with reduced/absent cFTR formation (class I variant)
  • premature degradation due to protein misfolding (class II variant)
  • abnormalities of channel gating (class III variant)
  • conductance deficiency (class IV variant)
  • splicing abnormalities (class V variant)
  • increased cell-surface turnover (class VI variant).

A given variant can cause more than one molecular defect.

Cystic fibrosis is based on one or more organ manifestations.

Clinically important are /2/:

  • lung infection with acute pulmonary exacerbations /3/ (S. aureus, Pseudomonas aeruginosa, Burkholderia complex, Stenotrophomonas maltophilia, Burkholderia species)
  • pancreatic insufficiency
  • effects on nutrition; a positive relationship between body mass index and survival is documented
  • effects on the liver (cystic fibrosis related liver disease can cause isolated, often transient increase of bilirubin, ALT, and AST)
  • fertility: in females thickened secretions in the fallopian tubes and the cervix and in males thickened secretion of the vas deferens can impede pregnancy.

8.9.6 Pathophysiology

On the surface of many organ systems the protein cFTR is involved in the regulation of transepithelial ion transport. Normal CFTR gene function in the sweat gland results in the absorption of Cl from isotonic sweat fluid.

In individuals with cystic fibrosis and CFTR dysfunction that causes decreased absorption of Cl in the ducts of the sweat glands and elevated concentrations of Cl are measured in the sweat test.

In the airway epithelium dysfunction of CFTR leads to decreased Cl and HCO3 secretion at the apical cell membrane. The persistent Na+ absorption through loss of CFTR-mediated inhibition of the epithelial Na+ channel, which causes absorption of airway surface fluid, has consequences in fluid balance. The fluid imbalance causes thickened secretions and reduced mucocillary transport, resulting in mucus retention and plugging of airways. This pathophysiology stimulates an inflammatory response in the airways /4/. Retention of mucus favors bacterial infections and consecutively increased inflammation.


1. Cystic fibrosis Foundation patient registry 2021 annual data report. Bethesda, MD: Cystic Fibrosis Foundation 2022. www.cff.org/media/26771/download.

2. Grasemann H, Ratjen F. Cystic fibrosis. N Engl J Med 2023; 389: 1693–1707.

3. Stoltz DA, Meyerholz DK, Welsh MJ. Origins of cystic fibrosis lung disease. N Engl J Med 2015; 35–62.

4. Despotes KA, Donaldson SH. Current state of CFTR modulators for treatment of cystic fibrosis. Curr Opin Pharmacol 2022; 65: 102239. doi: 10.1016/j.coph.2022.102239.

Table 8.1-1 Neurohormonal mechanisms with regulatory effects on volume homeostasis /1/

Vasoconstrictory effect and retention of Na+ and water (antidiuretic)

  • Sympathetic nervous system
  • Renin-angiotensin-aldosterone system
  • Non osmotic release of the antidiuretic hormone arginine vasopressin (AVP)
  • Endothelin, thromboxane A2, neuropeptide Y

Vasodilatory effect and excretion of Na+ and water (diuretic)

  • Natriuretic peptides
  • NO, prostaglandins, kallikrein-kinin system, calcitonin gene-related peptide, substance P, β-endorphin, vasoactive intestinal peptide, adrenomodulin

Table 8.1-2 Examination for the diagnosis of disorders of the electrolyte and water balance



Sodium (serum)

Disorder of the fluid and electrolyte balance

Sodium excretion (urine)

Hyponatremia: differentiation of renal from non renal Na+ losses

Fractional Na excretion (FeNa)

Distinguishing the prerenal failure from renal failure

Osmolality (serum)

Assessing the internal water balance

Osmolality (urine)

Assessment of the renal formation of free water in cases of polyuria

Osmotic gap (serum)

Suspicion of intoxication with ethanol, methanol and ethylene glycol

Body weight

Assessment of external water balance

Free water clearance (urine)

Assessment of the quantity of the current excess water (i.e., water free from osmotically active substances)

Potassium (serum)

Rough estimate of the K+ content of the body

Potassium (urine)

Localization of the losses of K+ in cases of hypokalemia

Chloride (serum)

Diagnosis of metabolic acidosis

Chloride (urine)

Assessment of metabolic alkalosis

Anion gap (serum)

Differentiation of metabolic acidoses

Anion gap (urine)

Indirect measurement of the renal ammonium excretion. Decreased excretion is an indicator of renal tubular acidosis type 1.

Ammonium (urine)

Assessment of renal capacity to excrete H+.

Table 8.1-3 Cases of disorders in electrolyte and water balance. Courtesy of Lit. /16/

Clinical and laboratory findings

Polyuria and hypernatremia

Case 1: Diabetes insipidus centralis following surgery for a craniopharyngioma.

Laboratory findings: serum Na+ 155 mmol/L, urine osmolality 120 mmol/kg.

Comment: osmolality ≤ 300 mmol/L is indicative of water diuresis, while values > 300 mmol/L suggest osmotic diuresis.

What was responsible for this polyuria? Because of the findings the basis for the polyuria was a water diuresis. What was the cause of the water diuresis?

Comment: the urine osmolality was 120 mmol/kg despite the presence of a stimulus for the release of vasopressin. The measured urine flow rate was 6 mL/min. The normal the urinary flow rate/min. is approximately 1 mL/min. and the normal excreted osmoles are 0.5–0.6 mmol/min., corresponding to 800 mmol/24 h with normal nutritional intake. Electrolytes make up half of the osmoles, and urea the other half. The likely diagnosis was central diabetes insipidus.

Administration of vasopressin: to confirm that the diabetes insipidus was central rather than nephrogenic in origin, vasopressin was administered. Measurement of the decline of the urinary flow rate and the increase in urine osmolality. The urine flow rate decreased to below 1 mL/min. and electrolytes excreted at a concentration of 600 mmoles/L.

What was the basis of the hypernatremia?

Comment: the cause is either the increased sodium supply or a water deficit. The increase in serum Na+ from 140 mmol/L to 155 mmol/L requires a positive balance of 450 mmol of Na+ (some 30 liter of extracellular water × 15 mmol/L) or a loss of extracellular water of 10%, corresponding to 3 liter (10% × 30 liter), in order for serum Na+ to increase by 10%. For the purpose of differentiation, it is calculated whether or not increased excretion of free water is the cause of the hypernatremia. The urine volume was 4 liters and its Na+ and K+ concentration was 50 mmol/L. This solution can be divided into two imaginary components, 1.3 liter of isotonic saline solution (15 mmol Na+ + K+/liter) and 2.7 liters of electrolyte-free water (Fig. 8.8-3 – Maintaining the acid-base homeostasis in the proximal tubulus). The excretion of this quantity of free water is believed to be the cause of the 15 mmol/L Na+ elevation, since 15 mmol/L corresponds to 140 mmol/L × 30/27.3. For treatment 2.7 liter of free water, in the form of isotonic dextrose solution (50 g of glucose/L), must be administered.

Case 2: Diabetes insipidus renalis. Patient after post-bone marrow transplantation, gentamicin therapy, hypotension and therefore saline infusion, incipient renal insufficiency.

What is the basis of the polyuria?

Findings: excretion of 6 liter of urine with an osmolality of 524 mmol/kg, corresponding to 3144 mmol/24 h, concentration of Na+ and K+ in the urine 42 mmol/L.

Comment: osmotic diuresis is present. The diuresis is based upon the catabolism of muscle protein. Per kg of muscle, 180 g of protein are lost and per 100 g of metabolized protein 16 g of urea-N, which is converted to 96 g (572 mmol) of urea, are formed. The etiology of the high osmolality is the excretion of urea. The cause of the low urinary Na+ and K+ concentration is the treatment of the patient with gentamicin. Cationic substances such as gentamicin bind to calcium receptors in the ascending limb of the loop of Henle and they induce an intracellular signaling cascade in a similar manner to loop diuretics with the inhibition of K+ loss in the tubular lumen. The overall result is a defect in the renal concentrating mechanism, with elevated excretion of Na+. The relatively low urinary Na+ concentration results from the urea-induced osmotic diuresis.

What is the basis of the hypernatremia?

Comment: a tonicity balance calculation revealed that the basis for the hypernatremia was the positive balance of 1378 mmol of Na+ and K+ because there was a positive balance of 1 liter of water(7 liter of a hypotonic salt solution of 90 mmol/L were infused and 6 liter of urine were excreted). Thus the extracellular volume was expanded (Na+ gain) rather than being contracted (a deficit of water will cause hypernatremia with a contracted extracellular fluid volume).

Hyponatremia – Generalized

It is important to evaluate whether hyponatremia is an acute condition (course is less then 48 hours), or if it is chronic. Acute hyponatremia must be treated promptly, in order to prevent brain cell swelling. The main danger in chronic hyponatremia is osmotic demyelation syndrome that occurs secondary to its treatment.

– Acute hyponatremia

If even mild symptoms begin in a patient with acute hyponatremia, a dramatic situation can develop within hours. To develop hyponatremia there must be both increased supply of free water and a means to decrease its rate of excretion.

Case 1: 17-month-old child, body weight 10 kg with gastroenteritis.

Laboratory findings: serum Na+ 134 mmol/L, urine osmolality 320 mmol/kg.

Comment: in spite of the only slightly decreased serum Na+, an infusion of hypotonic saline of 750 mL, with a total of 37.5 mmol of Na+, was administered. Ingestion of 200 mL of water. The clinical condition improved rapidly, but serum Na+ levels following 20 hours were 121 mmol/L. Possible causes of the hyponatremia include: increased release of ADH due to non-osmotic stimuli related to the gastroenteritis, the administration of free water, or the formation of free water by the kidneys. The latter possibility is through a process of desalination of the infused sodium chloride solution (Fig. 8.1-3 – Formation of electrolyte-free water by the kidneys). Through the administration of 7 mmol/L of Na+, the extracellular fluid compartment of the child was increased by 20%, and this represents a stimulus to Na+ excretion.

– Chronic hyponatremia

Patient: 68 years of age, lethargic, long term ingestion of thiazide diuretics due to hypertension.

Serum: Na+ 107 mmol/L, K+ 2.2 mmol/L, Cl 67 mmol/L, glucose 90 mg/dL (5 mmol/L), urea 11 mg/dL (4 mmol/L), osmolality 220 mmol/kg.

Urine: Na+ 10 mmol/L, K+ 25 mmol/L, Cl 10 mmol/L, urea 320 mg/dL, osmolality 402 mmol/kg.

Table 8.1-4 Examinations for differentiating prerenal from renal acute renal failure /8/




Na+ in the urine (mmol/L)

< 20

> 40

Urine osmolality (mmol/kg)

> 500

< 400

Urea/creatinine (mg/dL) (serum)

> 40

< 20

Creatinine (urine/serum ratio)

> 0,1

< 0,05

Osmolality (urine/serum ratio)

> 1,5

> 1,0

FENa (%)

< 1

> 2

FE Urea (%)

< 25

> 25

FE, fractional excretion

Table 8.2-1 Reference intervals for serum/plasma sodium

Adults /6/


Children /7/

0–7 days


7–31 days


1–6 months


6 months – 1 year


> 1 year


Expressed in mmol/L

Table 8.2-2 Diseases and causes that can lead to hyponatremia /10, 25/

Clinical and laboratory findings

Patients from the general patient population /12/

Patients from the general patient population with Na+ value ≤ 125 mmol/L at admission or during their in-patient stay have a 3-fold higher mortality during the following 2 years than patients with higher values. It concerns principally an older population with multiple comorbidities, and in the majority of the patients the etiology of the hyponatremia is multifactorial. Frequent etiologies were thiazide diuretics, congestive heart failure, and liver diseases. In spite of the fact that in many patients the criteria of SIADH were fulfilled, this diagnosis was not made by the referring physician because, among other reasons, a considerable portion of the patients was on diuretic therapy.

Acute hyponatremia in the emergency ward

Acute hyponatremia develops within 48 hours and is associated with neurological manifestations. Following an examination /26/ the incidence is 0.8% and the mean Na+ concentration is 115 ± 4 mmol/L. Additional laboratory findings were hypouricemia and reduced urea concentrations. Water intake was 2.5–10 liters prior to the day of presentation at the emergency ward. The major etiologies were: diuretic therapy in hypertensive patients, colonoscopy pretreatment with polyethylene glycol, tea for weight reduction, oxytocin-induced abortion, primary polydipsia during the ingestion of neuroleptics, ecstasy abuse.

Heart failure /14/

Approximately 5% of patients with chronic heart failure have hyponatremia. It develops in advanced heart failure as a compensatory response to reduced cardiac output and reduced effective circulating blood volume. The latter is signaled by the baroreceptors and the renin-angiotensin-aldosterone system, the sympathetic nervous system and the secretion of arginine vasopressin (AVP) are activated. As a result water and Na+ are retained in spite of increased total body water. Hyper- volemic hypernatremia develops. These patients have elevated AVP concentrations which do not decrease even with acute water loading.

The prognosis in heart failure patients who are admitted to the hospital due to progressive decline in systolic function is dependent upon the Na+ concentration at admission. Thus, patients with levels of 134 (132–135) mmol/L had, in comparison with those with 142 (141–144) mmol/L, a hospital mortality of 5.9% versus 1% and a 60-day mortality of 15.9% versus 6.4% /27/. In another study /28/ median survival time with Na+ values of ≤ 130 mmol/L was only 99 days, compared with 337 days with values above that level. Another evaluation /29/ has shown that repeated admissions within 90 days are 20% higher if the Na+ value at the first admission was 3 mmol/L below the lower reference interval value.

In the ACTIV-CHF study, an increase of the Na+ concentration of 2 mmol/L in heart failure in-patients reduced the 60-day mortality to 16%; in comparison, mortality was 30% in the patients who did not manifest a Na+ increase /30/.

Biochemistry and physiology /18/: following a water loading of 20 mL/kg body weight, healthy individuals excrete more than 80% of this volume within 5 hours. The normalization of water balance is based upon a reduction in AVP secretion as of Na+ concentrations in the plasma below 135 mmol/L and a decrease in urine osmolality to less than 100 mmol/kg. Patients with severe heart failure (New York Heart Association, Class III and IV) are not capable of achieving this. They have, in comparison with healthy individuals, mild hyponatremia with an average urine osmolality of 273 mmol/kg and the urine Na+ concentration is below 20 mmol/L.

Diuretics /14/

In patients from the general population with a unique etiology, the intake of loop diuretics (furosemide, bumetanide, torsemide) is the most frequent cause of hyponatremia. Loop diuretics are organic anions that circulate bound to proteins (> 90%), limiting their volumes of distribution. Loop diuretics activate the renin-angiotensin-aldosterone system and dilate blood vessels directly, but they also increase the level vasodilatory prostaglandins and the pressure within the proximal tubule. A dose of loop diuretic increases urinary excretion of NaCl for several hours, but this is then followed by a period of very low sodium excretion, often termed post-diuretic sodium retention.

Up to one third of the patients who have hyponatremia on admission as in-patients take thiazides, and 14% of those who are prescribed thiazides as out-patients have hyponatremia /31/. Diuretic-induced Na+ depletion can lead to a non osmotic stimulation of AVP, which results in water retention. However, in patients with chronic heart failure who are taking loop diuretics the outcome is, rather, volume depletion with a consequent reduction in glomerular filtration rate and increased sodium reabsorption in the proximal tubule. In this way the delivery of primary urine to the diluting segments (loop of Henle, distal convoluted tubule) is decreased and less free water is excreted. Loop diuretic induced hyponatremia generally sets in 2 weeks following the start of therapy.

Loop diuretics such as furosemide can also cause hyponatremia, which, however, is manifested only after a long interval. These diuretics activate the renin-angiotensin-aldosterone system and elevate angiotensin-II concentrations, which causes the non-osmotic stimulation of AVP. Since diuretics increase the concentration of sodium chloride and water, thirst is a side effect which also contributes to the hyponatremia.


A hyponatremia of less than 125 mmol/L is commonly associated with the syndrome of inappropriate antidiuretic hormone secretion (SIADH). The SIADH is the consequence of the increase in total body water. Generally edema is then not present. If total body Na+ increases as well, edema is manifested. As a rule hyponatremia occurs along with hypo osmolality. The SIADH occurs in three groups of diseases: malignant tumors, pulmonary disturbances, and disorders of the central nervous system. Na+ concentration in the urine is above 20 mmol/L but can, nonetheless, fall to below 10 mmol/L in cases of Na+ restriction or reduced ECFV. Urine osmolality is higher than serum osmolality. See also Section 8.6 – Arginine vasopressin (AVP), copeptin (CT-proAVP).

Renal insufficiency

In advanced renal insufficiency, in both chronic and acute renal failure, hyponatremia may occur along with the formation of edema. Causes of edema and hyponatremia are:

  • Na+ retention because, due to the reduced GFR, only an insufficient amount of Na+ can be excreted. Thus, with a GFR reduced to 5 mL/min. and serum Na+ level of 140 mmol/L, instead of 20,000 mmol Na+ only 1000 mmol are excreted daily.
  • Decreased renal water excretion. Here, with a GFR of 5 mL/min. only approximately 2 L of free water can be generated by the kidneys. If the daily water intake is greater than this quantity, a positive water balance and hyponatremia ensue. The capability of these patients of diluting their urine is, nonetheless, not nearly so markedly as limited as is their ability to concentrate it. Na+ concentrations in the urine are above 20 mmol/L.

The majority of patients with renal insufficiency and a glomerular filtration rate of less than 15 [mL × min–1 × (1.73 m2)–1] can, with low dietary salt intake, only limit renal Na+ excretion in an inadequate manner. Normal individuals reduce the renal excretion to 1–3 mmol/L 1–3 days following the restriction. In advanced renal insufficiency, 1–3 weeks are required; the Na+ concentration in the urine does not fall below 20 mmol/L. With normal dietary intake of sodium chloride, this group of patients can manage their water balance so that hyponatremia does not occur. There is, however, also a group of patients with severe salt loss, and they require the administration of sodium chloride in order to avoid volume reduction and hyponatremia.

Mineralocorticoid deficiency

Mineralocorticoid deficiency causes hyponatremia and a reduction in ECFV. It is believed that the reduction in ECFV activates the secretion of AVP via non-osmoreceptor-mediated pathways. Hyperkalemia is present, the Na+ concentration in the urine cannot be kept below 20 mmol/L.

Glucocorticoid deficiency

In spite of hypo osmolality, the secretion of AVP is inadequately suppressed. Renin concentrations are low-normal. It is believed that normal cortisol concentrations are required for the inhibition of AVP secretion /10/. Na+ concentration in the urine is above 20 mmol/L.

Osmotic diuresis

Osmotic diuresis can lead to the loss of sodium chloride and water with hyponatremia and a reduction in ECFV. This concerns, for example, diabetics with glucosuria and patients with urea diuresis following the removal of a urinary tract obstruction. Na+ concentration in random sample is above 20 mmol/L.

Renal-tubular acidosis (RTA), metabolic alkalosis /32/

In patients with proximal RTA (RTA Type II) and in conditions of metabolic alkalosis, (e.g., due to severe vomiting) the excretion of bicarbonate is elevated. Because bicarbonate is a relatively impermeable anion it causes, in order to ensure electroneutrality, the excretion of cations such as Na+, K+ and Ca++. Bicarbonaturia is present, the Na+ concentration in the urine is above 20 mmol/L. RTA type II is caused by defective bicarbonate reabsorption in the proximal tubule and, accordingly, reduced H+ secretion.

Pancreatitis, peritonitis, ileus, burns

Extrarenal loss of water and Na+ leads to a decrease in ECFV. This is the case in fluid loss in the third space (e.g., the abdominal cavity in peritonitis, the intestinal lumen in ileus or pancreatitis, severe muscle trauma or burns). In such cases the urine is concentrated and the Na+ concentration is below 20 mmol/L.

Vomiting, diarrhea

With gastrointestinal fluid loss following vomiting and diarrhea, K+, bicarbonate and H+ are also lost. Metabolic alkalosis occurs in severe vomiting, while metabolic acidosis is seen as a result of diarrhea. In severe vomiting the bicarbonaturia leads to Na+ concentration in the urine of greater than 20 mmol/L and Cl concentrations of below 10 mmol/L. In cases of extrarenal fluid loss, urine osmolality is above 800 mmol/kg.


In poorly controlled diabetics, due to the excretion of negatively charged ketone bodies to maintain electroneutrality, Na+, K+ and NH4+ are excreted. This results in hyponatremia with a reduction in ECFV. Na+ concentration in random samples is above 20 mmol/L. This concerns patients with hyponatremia who manifest no signs of hypovolemia or edema. The disturbance is based upon the retention of osmotically active substances and free water.


Severe hypothyroidism goes hand in hand with non osmotic release of AVP. Due to the low cardiac output, too few osmotically active substances arrive at the diluting segments, and this leads to the stimulation of AVP release /15/.

Psychotic patients

Some 10% of chronic psychiatric patients drink large quantities of water, and approximately 5% have water intoxication. Functional changes in the osmoreceptors, an inappropriate response to the thirst mechanism, renal hypersensitivity to AVP, and an AVP-independent disorder of urine dilution are all to be taken into consideration as causes.

Postoperative conditions

Some 5% of postoperative patients have hyponatremia. The cause is believed to be increased AVP secretion, stimulated via the baroreceptors.

Medications – Generalized

Pharmaceutical agents can inhibit renal water excretion and lead to hyponatremia.

– Nicotine

Nicotine reduces renal water excretion through the stimulation of AVP secretion.

– Isoproterenol

Isoproterenol is believed to increase AVP secretion via the stimulation of baroreceptors.

– Morphine

Morphine causes increased AVP secretion via specific receptors.

– Clofibrate

Clofibrate acts through the release of AVP from the neurohypophysis.

– Carbamazepine

Carbamazepine is believed to reduce renal water excretion via a direct effect on the renal distal tubular cells or via an increase in the sensitivity of the tubular cell to AVP.

– Chlorpropamide

Chlorpropamide and high doses of tolbutamide cause hyponatremia in 4% of diabetics. The mechanisms is believed to be based upon elevated AVP release, stimulation of the synthesis of adenyl cyclase, or the inhibition of cyclic AMP phosphodiesterase.

– Anti-depressives

Hyponatremia in connection with the ingestion of tricyclic anti-depressives and monoamine oxidase inhibitors has been described.

– Indomethacin

Indomethacin stimulates the secretion of AVP by inhibiting prostaglandins. These apparently influence the effect of AVP via a reduction of the AVP stimulating effect on cyclic AMP.

– Trimethoprim/sulfamethoxazole (Tmp-Smx)

In patients with Pneumocystis carinii infections who are treated with Tmp-Smx in large doses (12 g/d), severe hyponatremia of 109 mmol/L and hyperkalemia of 6.6 mmol/L on the third or the fourth day of therapy are described. The disturbance is assumed to be based upon a direct effect of Tmp-Smx on the tubular cells /13/.


Total body Na+ and water are increased in diseases that are associated with edema, such as congestive heart failure, cirrhosis of the liver, renal failure, and the nephrotic syndrome. The cause of the edema is a reduction in the effective arterial blood volume, due to reduced renal water excretion caused by:

  • An increase in fluid and water resaborption in the proximal tubules. In this manner, the delivery of water to the diluting segments of the distal convoluted tubules is reduced.
  • Activation of arterial baroreceptors. These stimulate the three vasoconstrictor systems such as the renin-angiotensin-aldosterone system (RAA system), the sympathetic nervous system, and AVP secretion. The activation of the RAA system results in secondary hyperaldosteronism, which leads to augmented reabsorption of Na+ at the distal tubule. The Na+-retaining effect occurs along with increased K+ excretion.

Since diuretics are often prescribed in patients with edema, it is normally not possible to ascertain whether the reduced water excretion and the hyponatremia are due to the primary disease or the ingestion of diuretics.

Liver cirrhosis

Patients with liver cirrhosis in the absence of edema or ascites manifest normal water excretion. In advanced cirrhosis of the liver, fluid retention, accompanied by edema and ascites, occurs; in late stages of the disease, severe Na+ retention develops, a condition which, in an extreme situation, is termed the hepatorenal syndrome. Na+ concentration in the urine is below 20 mmol/L. The causes of the ECFV increase and hyponatremia are the reduced delivery of water in the diluting distal convoluted tubules and the increased AVP secretion.

It is believed that the hepatic blood circulation has afferent sensors available, which regulate the efferent blood flow. The restriction of the hepatic venous flow due to the cirrhosis increases the intrahepatic resistance, raises the sinusoidal pressure, reduces the blood flow in the portal vein, and augments the hepatic arterial flow. Either because of increased intrahepatic forces or due to a change in the hepatic blood mix, the activation of an elevated renal Na+ retention may be expected to occur /33/. The placing of a portocaval shunt corrects the renal Na+ retention.

Liver transplantation /34/

In the USA, patients who are under consideration for a liver transplantation are selected according to the Model of Endstage Liver Disease (MELD) score. This takes bilirubin and creatinine in the serum and the International Normalized Ratio (INR) into consideration. A further predictive parameter is the Na+ concentration in the serum. In patients with cirrhosis of the liver, concentrations below 126 mmol/L during the listing or prior to the transplantation are associated with significantly elevated mortality 3–6 months after transplantation.

Nephrotic syndrome

Na+ concentrations are usually reduced in patients with the nephrotic syndrome only following acute water loading or with diuretic therapy. Pseudohyponatremia due to hyperlipidemia may be present if the Na+ determination is not made via a direct ISE measurement. Na+ concentration in the urine is below 20 mmol/L.

The reduced water excretion is due to intrarenal factors such as decreased GFR, leading to reduced fluid delivery to the distal tubules, and extrarenal factors such as increased release of AVP.

Hemodialysis /35/

Normohydration and normal Na+ level in the serum are an important therapeutic goal. Fluid overload leads to left ventricular hypertrophy, while fluid deficiency results in other complications. Patients with an ECFV overload of greater than 15% have increased mortality. Some 25% of patients regularly receiving dialysis have a volume overload of more than 2.5 L (greater than 15%) prior to the start of dialysis, resulting in a 2-fold increase in mortality /36/.

Chronic alcohol-use disorder /41/

Metabolic acidosis and hyponatremia are often present on admission in patients with alcohol-use disorder. Other serum concentrations of constiuents may be normal. After initiation of therapy designed to treat acidosis and restore extracellular fluid volume signs of chronic alcohol ingestion are decreases in plasma concentration of K+, Ca2+ , Mg2+ and phosphate 24 to 36 hours after admission.

Acute ingestion of alcohol

Acute ingestion of alcohol induces water diuresis, owing to suppression of vasopressin, predisposing patients to dehydration and hypernatremia.

Chronic alcohol abuse

In prolonged or continuous exposure of alcohol the suppressive effect of vasopressin is absent. In these patients vasopressin concentrations increase, resulting in elevated urine osmolality and decreased clearence of free water. As a result, hyponatremia is a common disorder that occurs in as many as 17% of patients with chronic alcohol-use disorder.

Beer potomania

Beer potomania refers to a vasopressin-independent mechanism of hyponatremia in persons who drink large volumes of beer without adequate food intake. Low excretion of soluble substances (solutes) in urine limits excretion of renal water, since solute excretion determines the upper limits for the volume of renal water excretion /42/. Beer has low Na+ and protein content, and unless it is ingested with food, it provides little solute for excretion in the urine.

Table 8.2-3 Diseases and causes that can cause hypernatremia /1537/

Clinical and laboratory findings

Sweating, insensible water loss

Massive water loss without adequate Na+ loss causes a reduction of the ECFV and hypernatremia. Often, extrarenal (insensible) water loss is the cause of hypernatremia (e.g., sweating, loss of hypotonic fluid via the intestines or the skin). In addition, reduced water intake, particularly in geriatric or hospitalized patients with altered sensorium or sedation by medication, leads to hypernatremia, although the osmotic regulation of the body’s water is still in order. There is a reduced sense of thirst, however. Clinically speaking there is resultant exsiccosis. This is defined as dehydration with a loss of more than 3% of the body weight, a serum Na+ ≥ 148 mmol/L and a urea-creatinine ratio (mg/dL/mg/dL) of more than 25.

Laboratory findings: urine volume below 1,000 mL/24 h, urine osmolality above 700 mmol/kg.

Osmotic diuresis e.g., hyperglycemia, profuse diarrhea

The loss of hypotonic fluid can occur:

  • Renally (e.g., based on osmotic diuresis through glucose, urine and mannitol)
  • Insensitively (i.e., extrarenally, due to diarrhea or massive sweating).

In children, laxatives containing sorbitol can lead to massive diarrhea with hypernatremia if more than 0.5 g of sorbitol/kg of body weight is ingested. In cases of diarrhea, a sufficient replacement of hypotonic fluids must be ensured so that the kidneys can maintain osmolar homeostasis. This is especially important for children with gastroenteritis. If they are given nourishment or replenishing fluids which contain a high proportion of osmotically active substances, rehydration is not possible and hypernatremic dehydration results. The WHO recommends oral rehydration with a fluid that contains 90 mmol/L sodium.

Laboratory findings: urine volumes below 1,000 ml/24 h, urine osmolality above 700 mmol/kg.

Diabetes insipidus (DI)

DI results from a reduced central AVP secretion (hypothalamically related) or an end organ resistance (renal tubular related). Severe DI is characterized by a strong polyuria and secondary polydipsia. More frequently, there are partial defects with moderate polyuria.

Central DI results from a necrosis of the AVP-secreting neurons, particularly via metastases of breast and lung cancer and granulomatous diseases with involvement of the brain.

Congenital renal DI is very rare. The acquired variety is often caused by medications, such as lithium, but also by chronic tubulointerstitial diseases, obstructive nephropathy, hypercalcemia, and severe calcium deficiency /15/.

Laboratory findings: in the case of partial central DI or acquired nephrogenic DI, the urine osmolality is below 700 mmol/kg, but higher than that of the serum.

Dysnatremia in marathon runners /38/

Dysnatremia was measured in 429 out of 1319 cooperating marathon runners (32.5%). Hypernatremia was found in 366 (27.7%) and hyponatremia in 63 (4.8%). In the hypernatremic runners, 314 had values of 146–150 mmol/L and 52 were above 150 mmol/L. Of the 63 runners with hyponatremia, 26 had a serum Na+ concentration of below 130 mmol/L.

Idiopathic hypernatremia syndrome

The idiopathic hypernatremia syndrome concerns patients who dilute or concentrate their urine, in comparison to normal individuals with higher plasma osmolality. Common to these patients is persistent hypernatremia that cannot be explained by loss of volume, a decrease or loss of thirst sensation, partial diabetes insipidus, and a normal response of the kidneys to AVP. Clinically speaking, many of these patients have hypothalamic lesions and can be noticeable due to adiposis, hypodypsia, episodic muscular weakness and reduction of psychomotor activity. Etiologically speaking, the following can be the underlying cause of the essential hypernatremia syndrome: metastases, pituitary adenoma, teratoma, dysgerminoma, craniopharyngioma, ectopic pinealoma, histiocytosis, sarcoidosis, skull trauma, meningioma.

Intensive care patients

Whereas hypernatremia has a prevalence of 1% in general medical and surgical cases, it is 10–26% for intensive care patients. Artificial respiration, sedation and coma are important risk factors. In one third of hypernatremic patients, hypernatremia already exists at the time they are placed in the ICU. In the remainder of patients, it only occurs there and is caused by renal water loss, incapability to communicate thirst, and inadequate regimen of fluids. In one study /39/ of 8441 ICU patients, 11% had mild hypernatremia (145–149 mmol/L) and 4.2% had moderate to severe hypernatremia (above 150 mmol/L). Whereas mortality was 15.2% for patients without hypernatremia, it was 29.5% for patients with mild hypernatremia and 46.2% for those with moderate to severe hypernatremia.

Ileus, pancreatitis, major intestinal obstruction

Conditions with loss of water and Na+, in which the water loss is greater than the loss of Na+, lead to hypernatremia with low total body sodium and volume depletion. Even if water is lost in the third space, in cases of insufficient water replenishment, the result can be hypernatremia.

Hypernatremia in the newborn periode

Newborn infants have a reduced renal concentration capability and greater insensible water loss compared to adults. If the fluid replenishment takes place solely via mother’s milk and this has a high Na+ concentration, hypernatremia can result. Another cause is hypertonic dehydration, which occurs in children who are exclusively fed mother’s milk during the first 3 to 4 days of life. One criterion of dehydration is weight loss on day 3–4 in comparison to the birth weight (≥ 2500 g) by more than 10%. In one study /40/ the incidence of moderate dehydration (Na+ 146–149 mmol/L) was 0.9%, in those with severe dehydration (Na+ ≥ 150 mmol/L) is was 0.6%.

Intake of concentrated sodium chloride

There is hypernatremia with high total body Na+. In addition to the intake of concentrated sodium chloride solution or of sodium bicarbonate, other causes are the drinking of sea water, excessive intake of table salt tablets in hot regions.

Laboratory findings: urine volume normal, urine osmolality above 700 mmol/kg.


Hypernatremia can occur if the dialysis is done to counter high concentration of salt in the dialysate. In cases of peritoneal dialysis, relatively more water than Na+ goes through the peritoneum. If the Na+ concentration in the dialysate is 132 mmol/L, for example, there is a relative rise of osmolality and of Na+ in the serum and a sense of thirst occurs. It is therefore recommended that the Na+ concentration in the dialysate be set lower.

Primary hyperaldosteronism

Primary hyperaldosteronism, due to its Na+-preserving effect, leads to an increase of the total body Na+ and to a slight volume expansion. Often, Na+ concentrations in the serum of 145–149 mmol/L are measured.

Table 8.3-1 Reference interval for chloride

Adults /1/


Children /2/

1–7 days


6 months – 1 year


7–30 days


> 1 year


1–6 months


Expressed in mmol/L

Table 8.3-2 Differential diagnosis of the metabolic acidosis by determining the strong ion difference (SID) in the urine /4/

Renal tubular acidosis

Urine SID: [Na+ ] + [K+ ] + [Ca2+ ] + [Mg2+ ] – [Cl– ] = > 0

  • Distal (type 1): urine pH > 5.5
  • Proximal (type 2): urine pH < 5.5 (low serum K+)
  • Aldosterone deficiency (type 4): urine pH < 5.5 (high serum K+)


Urine SID: [Na+ ] + [K+ ] + [Ca2+ ] + [Mg2+ ] – [Cl– ] = < 0

Gastrointestinal: diarrhea, small intestine or pancreas drainage

Iatrogenic: parenteral nourishment, increased salt intake

Table 8.3-3 Diseases and disorders associated with an increase in serum chloride

Clinical and laboratory findings

Critically ill patients with acute metabolic acidosis /5/

In critically ill patients metabolic acidosis is a far greater problem than metabolic alkalosis. It is due to an increase in chloride (Cl), lactate or other anions. Acute metabolic acidosis results from the increased formation of endogenous or from exogenous acid equivalents. The formation of endogenous acid equivalents is normally of the order of 80 mmol/24 h, and in acute lactate acidosis or ketoacidosis can be increased to up to 500 mmol/24 h. The differentiation of this condition is accomplished through the determination of SID in a random urine sample (Tab. 8.3-1 – Reference intervals for chloride). Acute metabolic acidosis is associated with an elevated anion gap.

The administration of a saline infusion leads to metabolic acidosis, not due to the dilution of HCO3, but rather, because of Cl. The administration of Cl decreases the SID and increases the dissociation of water, with a consequent rise in the H+ concentration.

Conditions with chronic metabolic acidosis

Insufficient renal excretion of acid equivalents, or a loss of HCO3 can be the cause; an equilibrium between the elimination and the formation of acid equivalents has, however, set in.

Laboratory findings: Cl is elevated, HCO3 and PCO2 are decreased. Clinical symptoms such as exhaustion and dyspnea on exertion appear when HCO3 is below 15 mmol/L and the arterial pH is less than 7.3. Severe clinical symptoms are the rule with HCO3of around 7 mmol/L and pH below 7.2.

Renal-tubular acidosis – RTA type I

Renal-tubular acidoses (RTA) /6/ cause hyperchloremic metabolic acidosis. Type-I RTA is the classic distal RTA. In spite of systemic acidosis, the kidneys are incapable of lowering the urinary pH below 5.5.

Clinical findings: osteomalacia, bone pain, myopathy, nephrocalcinosis, nephrolithiasis (especially phosphate stones). Family predispositions are common with RTA type I, and even incomplete variants without acidosis occur. The diagnosis can be confirmed by ammonium chloride loading (0.1 g/kg body weight). Urinary pH as well as HCO3 are measured hourly over an 8-hour period. RTA type I is likely if, with a reduction in HCO3 to below 20 mmol/L, the urinary pH does not decrease below 5.5.

Laboratory findings: hyperchloremia, acidosis with HCO3 below 20 mmol/L, hyperkalemia, increased renal excretion of Na+, K+, Ca2+, urinary pH is usually above 6, increase in serum ALP.

– RTA type II

RTA type II is proximal renal-tubular acidosis. It is caused by defective HCO3 reabsorption in the proximal tubule. An additional disorder, namely, of reabsorption of glucose, amino acids and phosphate, comprising the Fanconi syndrome, often occurs as well.

Clinical findings: RTA type II is diagnosed mainly at an early age. Under ammonium chloride load urinary pH falls below 5.5.

Laboratory findings: hyperchloremic acidosis, hypokalemia, urinary pH usually above 6.

– RTA type IV /7/

This form of RTA occurs most frequently. It is seen in progressive renal insufficiency and diabetes mellitus and is very likely to be present if both of these diseases exist concomitantly. Etiologically, the primary cause is a disturbance in renal K+ secretion, and the secondary cause is a dysfunction of H+ secretion. This is believed to be based upon defective tubular function, reduced aldosterone or renin secretion, or a combination of these three dysfunctions.

Laboratory findings: hyperchloremic acidosis, hyperkalemia, function for urine concentration is normal.

Chronic hyperventilation

Fever and central nervous systems disorders can lead to hyperventilation with the development of respiratory acidosis. A plasma electrolyte profile similar to that seen in RTA may occur.

Administration of chlorides

Exogenous hyperchloremic acidosis with a normal anion gap occurs with the administration of ammonium chloride, lysine chloride or arginine chloride.


If chloride-rich urine remains in the sigma for a long period of time, Cl will be exchanged for HCO3. The latter is lost in the feces. Normal anion gap in hyperchloremic acidosis.

Pseudohyperchloremia due to bromides /8/

Bromides lead to falsely elevated Cl values, since they are measured in the tests used in the Cl determination. If Cl is assayed using a chloride meter, the error is small, because with an increasing rise in bromide ions in the plasma the Cl concentration falls, so that the total plasma halogen concentration remains almost the same. The anion gap is normal, since the measured Cl value corresponds to the actual sum of Cl and bromide.

If the measurement is performed with a chloride selective electrode, or photometrically, bromides influence the result disproportionately in relation to their true concentrations. The anion gap is markedly reduced; it is often even negative. A negative anion gap is virtually pathognomonic for bromide.

Table 8.3-4 Diseases associated with a decrease in serum chloride /4/

Clinical and laboratory findings

Critically ill patients with acute metabolic alkalosis

Due to a rapid rise in HCO3 level, the renal HCO3 threshold is exceeded. The causes are vomiting, acute loss of acid equivalents, intake of HCO3 and the conversion of organic anions to HCO3 by citrate (e.g., poly transfusion of banked blood), or over-corrected lactic acidosis or ketoacidosis.

Laboratory findings: SID, urinary HCO3 concentration and pH are elevated.

Diseases with chronic metabolic alkalosis

The kidneys can normally excrete up to 500 mmol of HCO3 in 24 hours. In order that chronic metabolic alkalosis develop in patients with normal kidney function, conditions must be present which prevent the kidneys from excreting HCO3. Such condition are:

  • With decreased extracellular fluid volume (ECFV) and paradoxical acidic urine (Cl below 10 mmol/L) associated gastrointestinal disorders like chronic vomiting, stomach drainage, laxative abuse, congenital chloridorrhea, intake of diuretics (thiazides and furosemide), anorexia, posthypocapnic alkalosis. These conditions response to saline intake.
  • With elevated ECFV and with alkaline urine (Cl concentration above 20 mmol/L) associated disorders like primary and secondary hyperaldosteronism, primary hyperreninemia, Cushing’s syndrome, Liddle’s syndrome, intake of licorice and carbenoxolone (mineralocorticoid mimetic). The conditions are non responsive to saline intake.
  • With decreased or normal ECFV and with alkaline urine (Cl concentration greater than 20 mmol/L) associated disorders like Bartter syndrome, severe K+ depletion, tumor-induced hypercalcemia, renal excretion of non-absorbable anions such as penicillin or alkali intake with reduced kidney function. The conditions are non responsive to saline intake.

Laboratory findings: the urinary excretion of Cl serves to differentiate patients with volume depletion who respond to saline intake with correction of the alkalosis from those who do not respond. The former group has a urinary concentration of Clbelow 10 mmol/L, while for the latter group the corresponding value is over 20 mmol/L.

Intestinal HCl loss e.g.,vomiting, gastric juice drainage, congenital chloridorrhea

Na+ concentrations in the gastric juice are 120 mmol/L, while those of Cl are 200–300 mmol/L. When a marked loss of gastric juice occurs, hypochloremic, hypokalemic metabolic alkalosis follows; this can be corrected with the administration of NaCl.

Laboratory findings: hypokalemia, K+ concentration in the urine of greater than 40 mmol/L, urinary Cl concentration less than 10 mmol/L.

Congenital chloridorrhea is an inherited autosomal recessive disorder of the apical Cl/HCO3 transporter (solute carrier family 26, member 3 gene [SCA26A3] of the enterocyte) in the small and large intestine. The daily endogenous formation of Cl in the intestine is reabsorbed in the ileum and the colon. In congenital chloridorrhea this mechanism is interrupted and the elevated Cl concentration in the gut leads to the influx of water and Na+ in the intestinal lumen and the development of diarrhea and secondary hyperaldosteronism.

Laboratory findings: alkaline urine, Cl concentration in the feces of over 90 mmol/L, hypokalemia, fractional excretion of Cl in the urine (FECl) markedly decreased (normal 1–3%).

Loop diuretics e.g.,Furosemide, Bumetanide,Torsemide

Loop diuretics lead to hypochloremia via a decrease in tubular NaCl reabsorption. The Cl concentration in the urine is above 20 mmol/L. If the diuretics are discontinued shortly before the visit to the doctor, the Cl and Na+ concentrations in the urine are low. For further Information refer to Tab. 8.2-2 – Diuretics.

Hyperaldosteronism, Cushing’s syndrome, ACTH-producing tumors

Cl in the serum is low only if metabolic alkalosis is present. The alkalosis cannot be corrected with the administration of saline. In these diseases the alkalosis correlates mainly with the extent of the hypokalemia. The Cl concentrations in the urine are above 20 mmol/L.

Milk-alkali syndrome

With excessive alkali intake the hypochloremia correlates with the extent of the alkalosis. The Cl concentrations in the urine are above 20 mmol/L.

Chronic hypercapnia

In chronic hypercapnia due to respiratory insufficiency Cl and blood pH are decreased and PCO2 and of HCO3 are increased. Urinary Cl concentration is greater than 20 mmol/l.

Hypokalemic alkalosis

Congenital hypokalemic alkalosis is classified according to a number of metabolic abnormalities and is characterized by hypokalemia, metabolic alkalosis, hypomagnesemia, loss of Cl and hyper- or hypocalcemia. One group of autosomal recessive syndromes belonging to this family of diseases is genetically determined. The syndromes are based upon gene mutations which code ion transporters in the thick ascending loop of Henle or in the distal nephron. The Bartter, Gitelman and Liddle syndromes all belong to this group /9/. In the Bartter syndrome the defect is in the Henle’s loop, while in the Gitelman syndrome it is in the distal tubule (see Section 8.7 – Potassium).

Clinical findings: the patients are noticed at an early age due to muscle weakness and polyuria. They are normotensive in spite of the hyperaldosteronism /10/.

Laboratory findings: metabolic alkalosis, hyponatremia, hypochloremia, hypomagnesemia, hypokalemia, hyperreninemia, hyperaldosteronemia. Urine: Cl concentration over 20 mmol/L, Mg2+ over 5 mmol/L. In the Gitelman syndrome there is a tendency for hypocalciuria, in the Bartter syndrome a tendency for hypercalciuria /11/.

Table 8.4-1 Normal anion gap metabolic acidosis


  • Early uremic acidosis
  • Obstructive uropathy
  • RTA type IV
  • Ingestion or administration of NH4Cl, lysine Cl, arginine Cl, HCl, MgCl2


  • Diarrhea
  • RTA type I, II
  • Carboanhydrase inhibition (e.g., due to acetazolamide)
  • Ureterosigmoidostomy
  • Vesicocolic fistula
  • Post-hypocapnic acidosis


  • Topiramate, acetazolamide

Table 8.4-2 Metabolic acidosis with increased anion gap /467/

Clinical and laboratory findings

Diabetic ketoacidosis

Increase of the anion gap due to increased formation of the ketone acids acetoacetate and β-hydroxy butyrate. Acetone does not contribute to the anion gap. The size of the anion gap corresponds to the HCO3 deficit. This is only relevant, however, if the ketoacidosis has developed quickly or an excretion disorder exists for the keto anions. Over a protracted course or in the remission stage of the ketoacidosis, one generally only sees hyperchloremic acidosis (i.e., without an increased anion gap).

Lactate acidosis

Lactate acidosis is an important indicator for the prognosis of a patient with trauma, sepsis and various states of shock. Type A lactate acidosis develops acutely in cases of tissue hypoxia and continuous lactate determination is an important criterion for assessing the further course. See Section 5.6 – Lactate. The determination of the anion gap is not recommended for detecting lactate acidosis. An upper anion gap threshold value of 6 mmol/L is not specific enough and a threshold value of 12 mmol/L is too insensitive /8/.


In the final stage of renal insufficiency with restriction of the GFR to below 10 [mL × min–1 × (1.73 m2)–1], retention of organic acids from the metabolism occurs. With simultaneously reduced renal HCO3 formation, the HCO3 consumption exceeds the regeneration. Other anions such as phosphate and sulfate replace HCO3. An anion gap forms which usually does not exceed 20–25 mmol/L. Renal insufficiency with a GFR above 10 [mL × min–1 × (1.73 m2)–1] still does not cause an increased anion gap. There is a reduction of the renal tubular H+ secretion, which leads to a reduction of HCO3 , but no retention of organic acids takes place yet.


In alcoholics, the reduced intake of diet and the inhibition of gluconeogenesis due to alcohol leads to increased lipolysis. An increase of free fatty acids are generated, which are converted to ketone acids in the liver. Due to the simultaneous presence of ketone acids and alcohol, an increased anion gap and a sharply increased osmotic gap occur.

Intoxication with methanol, ethylene glycol, isopropanol, diethylene glycol /7/

Intoxitcation with toxic alcohols most commonly results from ingestion of /8/

  • Methanol contained in industrial products, windshield washer fluid and adulterated liquids. Clinical findings are depression of the sensorium and decreased vision.
  • Ethylene glycol contained in antifreeze and adulterated spirits. Clinical findings are organ dysfunction resulting from deposition of oxalate crystals in the lungs heart and kidney. Ethylene glycol poisoning leads to formation of oxalate crystals.
  • Isopropanol contained in various industrial products e.g., rubbing alcohol and hand sanitizer. Clinical findings are depression of the sensorium, respiratory dysfunction, cardiovascular problems, acute pancreatitis, hypotension, and lactic acidosis.
  • Diethylene glycol contained in various industrial products e.g., automotive brake fluids. Clinical findings are abdominal pain, nausea, vomiting, diarrhea, acute pancreatitis altered mental status, central and peripheral neuropathy.

For metabolic pathway of toxic alcohols see Tab. 8.4-3 – Metabolic pathways of toxic alcohols.

For adults, the minimum lethal dose of methanol is 100 mL, and the minimum lethal dose of ethylene glycol is 30 mL. After the intake of methanol or ethylene glycol, there is a latency period until the clinical picture develops. Shortly after drinking, ethylene glycol or methanol the osmolal gap is increased due to the accumulation of non ionized alcohols. As metabolism proceeds the osmolal gap decreases with the formation of ionized metabolites. Conversely, the serum anion gap is lowest before the alcohol is metabolized and increases with the formation of ionized metabolites. The time course of these changes typically evolves over several hours to over a day. The time course is shown in Ref. /8/.

The diagnostics of toxic alcohol ingestion can be difficult if the patient is admitted to the hospital very early or very late after being poisoned. Hemodialysis is used to eliminate ethylene glycol. It ends when the ethylene glycol concentration is < 20 mg/dL (3.2 mmol/L). Since ethylene glycol is difficult to determine, the surrogate marker is an osmolal gap of ≤ 10 mmol/kg. Such values can be misleading, because, in the early phase of poisoning, the osmolal gap can be slight for the ingested toxic ethylene glycol volume.

Salicylate intoxication /4/

The increase of the anion gap is related to the accumulation of salicylate anions and an increased formation of ionized metabolites. In adults, the combination of metabolic acidosis, an increase of the anion gap, and respiratory alkalosis are indicative of salicylate intoxication. In toxic concentrations, salicylate interferes with energy production by uncoupling oxidative phosphorylation and may produce renal insufficiency that causes accumulation of phosphoric and sulfuric acids. The metabolism of fatty acids is likewise increased, generating ketone body formation.

Acetaminophen /4/

This analgesic is commonly ingested or coingested during suicide attempt. A pH of less than 7.30 is used as one of the indicators for poor prognosis in acetaminophen-induced hepatotoxicity. Acetaminophen and its hepatotoxic metabolite N-acetyl-p-benzoquinone imine inhibit oxidative phosphorylation which subsequently leads to metabolic acidosis.

HIV therapy /4/

HIV positive patients taking antiretroviral therapy are at risk for lactic acidosis. Stavudine, zidovudine and other nucleoside analogue reverse transcriptase inhibitors impair oxidative phosphorylation by inhibiting mitochondrial DNA polymerase which may result in hepatic dysfunction and lactic acidosis.

Valproic acid therapy /4/

Metabolic acidosis is the consequence of valproic acid toxicity. Valproic acid is metabolized in the liver. The net effect of valproic acid metabolites is depletion of intra­mitochondrial coenzyme A and carnitine, which inhibits the β-oxidation of fatty acids, impairing ATP production. Carnitine supplementation may help to restore β-oxidation.

INH poisoning is characterized by refractory seizures, elevated anion gap metabolic acidosis, and coma. The mechanism underlying the development of metabolic acidosis include muscular activity from seizures, acidifying INH metabolites, and enhanced fatty acid metabolism that produces ketoacidosis.

Table 8.4-3 Metabolic pathway of toxic alcohols

Toxic alcohol



Methanol → ADH → Formaldehyde → ALDH Formic acid + H+

Ethylene glycol

Ethylene glycol → ADH → Glycoaldehyde → ALDHGlycolate + H+ Oxalate + H+

Diethylene glycol

Diethylene glycol → ADH → 2-Hydroxyethoxyacetaldehyde → ALDH2-Hydroxyethoxyacetate + H+ → Diglycolate + H+


Isopropanol → ADH → Acetone

ADH, alcohol dehydrogenase; ALDH, aldehyde dehydrogenase; the italics highlight the toxic metabolites

Table 8.5-1 Reference intervals for osmolality

Serum, plasma

  • Children /5/

1st day


7th day


28th day





Data expressed in mmol/kg

Table 8.5-2 Plasma osmolality and osmotic gap in diseases and different conditions /1011/

Clinical and laboratory findings

Osmolality and Na+ increased (calculated = measured osmolality): osmolar gap normal

Conditions associated with hypo- or euvolemia and hypernatremia such as: diarrhea and fever in children, osmotic diuresis in cases of hyperglycemia, hypothalamic disorders with hypodipsia, diabetes insipidus centralis or renalis, disorders of the osmotic center with reduced thirst and reduced arginine-vasopressin secretion.

Osmolality increased and Na+ decreased or normal (calculated = measured osmolality): osmolar gap normal

Larger quantities of osmotically active substances are accumulated in the plasma (e.g., in cases of renal failure with urea values around 140 mg/dL (49.9 mmol/L)). The osmolality is increased by around 50 mmol/kg. In cases of hyperglycemic coma with blood glucose levels around 600 mg/dL (33.3 mmol/L) there is an increase of the osmolality by approximately 35 mmol/kg.

Osmolality increased, Na+ decreased: osmolar gap increased

An osmolar gap exists due to the presence of osmotically active substances in the plasma (e.g., in cases of lactate acidosis, ketoacidosis, or renal acidosis). The osmolar gap is usually not increased greater than by factor of 2 and does not last long.

Ethanol and methanol poisonings and poisonings with other osmotically active substances cause a significantly increased osmolar gap of more than a factor of 2. The size of the osmolar gap often correlates to the severity of the poisoning. Thus, 1 per mill of ethanol in the plasma is equivalent to an increase of 22 mmol/kg. Patients with high alcohol levels also often have severe metabolic acidosis with an increased anion gap in addition to the osmolar gap.

In the hemorrhagic shock after severe traumas, sharply increased osmolar gaps can occur, without the solute being known.

This configuration can be found in pseudo-hyponatremia due to an increase of high-molecular mass substances, which make up part of the plasma volume, which is normally taken in by Na+ (e.g. in cases of hyperlipidemia and hyperproteinemia). Pseudo-hyponatremia only occurs if the Na+ determination is performed by means of other methods than direct ISE measurements. See also Section 8.1 – Water balance and fluid compartments.

Table 8.5-3 Investigation of water diuresis by the fluid deprivation test and evaluation of DDAVP sensitivity /7/


In a first stage, water deprivation is used to study the urine concentrating capacity through the assessment of the course of urinary osmolality. If no significant increase in urinary osmolality occurs, the kidneys are stimulated in a second step through the administration of arginine vasopressin (AVP) or deamino-8-D-arginine vasopressin (DDAVP) to form concentrated urine. In hypernatremic patients, only stage 1 is performed, since it is to be expected that in this group, elevated plasma AVP levels are already present.


Dehydration step: the test begins in the morning and initially body weight, serum Na+ and serum and urine osmolality are determined. Subsequently, while avoiding all fluid intake, urine volume, osmolality and body weight are recorded on an hourly basis.

The test is terminated when serum Na+ concentrations of 145–150 mmol/L are achieved, or if the urine osmolality reaches a plateau, or when an increase in urine osmolality of > 30 mmol/kg is not recorded in two consecutive hourly samples. No more than 4 hours later the patient is weighed and serum osmolality is again determined.

DDAVP step: following on step 1, 1 μg of AVP, intravenously, or 10 μg of DDAVP, as a nasal spray, is administered and the test is allowed to proceed for a further 3 hours.

In general it must be ensured that no marked loss of volume develops in the patient for e.g., if the urine excretion is greater than 700 mL per hour.


  • Healthy individuals manifest a maximal urine concentration to over 1000 mmol/kg; administration of AVP has no further effect.
  • Patients with complete central DI only respond during the DDAVP step, that is to say, following the administration of AVP, with a significant increase in urine osmolality of greater than 30 mmol/kg/h. At the end of the test an osmolality of approximately 600 mmol/kg is achieved.
  • In partial central DI a moderate increase in urine osmolality is recorded in step 1, followed by a further and more marked increase following AVP administration. The urine osmolality at completion of the test is about 800 mmol/kg.
  • In nephrogenic DI no increase in urine osmolality is seen, neither in step 1 nor in step 2 of the fluid deprivation test.
  • Patients with primary polydipsia manifest an increase in urine osmolality in step 1; no further increase occurs through AVP, however, since AVP secretion is already maximal. The osmolality upon completion of the test is 600–800 mmol/kg.

Table 8.5-4 Sodium, osmolality and effective osmolality (water distribution = tonicity) in serum for various clinical conditions with hyponatremia or hypernatremia /14/












5 (90)

5 (14)







Hyponatremia without additional osmolytes


5 (90)

5 (14)







Pseudo-hyponatremia *


5 (90)

5 (14)







Hyponatremia with hyperglycemia


75 (1350)

5 (14)








Hyponatremia (mannitol retention)


5 (90)

5 (14)







Hyponatremia (urea retention)


5 (90)

45 (126)








Hyponatremia (ethanol 40 mmol/L)


5 (90)

5 (14)










5 (90)

5 (14)







1) Expressed in mmol/L; 2) Expressed in mmol/L (mg/dL); 3) Expression in mmol/kg; Os-B, osmolality calculated; Os-G, osmolality measured; Os gap, measured minus calculated osmolality; tonicity = effective osmolality caused by sodium and glucose, but not by urea and ethanol. * Triglycerides sharply increased

Table 8.6-1 Reference intervals for AVP and CT-proAVP in the EDTA plasma depending on the serum osmolality /25/





< 1.5 (1.4)



< 2.5 (2.3)



1–5 (0.9–4.6)



2–7 (1.9–6.5)



4–12 (3.7–11.1)


1) Expressed in mmol/kg; 2) Expressed in ng/l (pmol/L); 3) Expressed in pmol/L

Conversion AVP: ng/L × 0.93 = pmol/L

Table 8.6-2 Laboratory findings in SIADH /6/

  • Hypoosmolality in the serum < 275 mmol/kg
  • Hyponatremia < 135 mmol/L
  • Na+ concentrations in the urine > 40 mmol/L if there is no sodium restriction or volume depletion
  • Urine osmolality > 100 mmol/kg (the maximum normal dilution capacity of the kidneys is < 50 mmol/kg)
  • Hypouricemia < 4 mg/dL (238 μmol/L)
  • Euvolemia
  • No hypothyreosis, no hypocortisolism, no renal failure, no administration of diuretics.

Table 8.6-3 Diseases and conditions associated with SIADH


  • Small-cell lung cancer
  • Duodenal carcinoma
  • Pancreatic cancer
  • Uterine cancer
  • Thymoma
  • Malignant lymphoma
  • Bladder carcinoma
  • Prostate carcinoma

Pulmonary diseases

  • Viral and bacterial pneumonia
  • Lung abscess
  • Tuberculosis
  • Aspergillosis
  • Asthma
  • Cystic fibrosis
  • Pneumothorax

Diseases of the central nervous system

  • Encephalitis
  • Meningitis
  • Brain abscess
  • Brain tumor
  • Skull trauma
  • Guillain-Barré syndrome
  • Acute intermittent porphyria
  • Subarachnoidal hemorrhage
  • Cavernous sinus thrombosis
  • Cerebral and cerebellar atrophy
  • Neonatal hypoxia
  • Multiple sclerosis


  • Inhibitors of serotonin uptake such as fluoxetine, fluvoxamine, paroxetine, sertraline

Table 8.6-4 Differentiation of cerebral salt wasting syndrome (CSWS) from SIADH /11/




Serum Na+

< 135

< 135

Urine Na+

> 40

> 40

Urine volume



Urine osmolality

< 100

> 100

Serum osmolality

< 290

< 275




Uric acid


< 4 mg/dL (238 μmol/L)


< 25

> 40





Elevated to normal

Significantly increased in 80% of the cases

Table 8.6-5 Interpretation of the standard fluid deprivation test in combination with the DDAVP sensitivity (Tab. 8.5-3) for the diagnosis of diabetes insipidus (DI) /7/

Hypothalamic (central) DI: in the standard fluid deprivation test, an increase in the serum osmolality to > 290 mmol/kg, but urine osmolality remains < 300 mmol/kg. After administration of DDVAP, an increase in the urine osmolality to > 750 mmol/kg.

Nephrogenic DI: in the standard fluid deprivation test, an increase in the serum osmolality to > 290 mmol/kg, but urine osmolality remains <  300 mmol/kg. After administration of DDVAP, no increase in the urine osmolality.

Dipsogenic DI: an increase in the urine osmolality in the standard fluid deprivation test without significant increase of plasma osmolality.

Table 8.6-6 Osmotic stimulation test /10/

Principle: by infusing hypertonic NaCl the capacity for the secretion of AVP is checked via the thirst mechanism.

Procedure: over 2 hours, 5% NaCl (850 mmol/L) is infused at a rate of 0.04 mL/kg body weight and minute.

Blood sampling for determining AVP: three times at 30-minute intervals after the start of the infusion; the plasma osmolality is also determined.

Assessment: the plasma AVP concentration during the osmotic test is interpreted in relation to the plasma osmolality (Fig. 8.6-4 – Relationship between osmolality and AVP in cases of diabetes insipidus).

Table 8.6-7 cT-proAVP in the standard fluid deprivation test /13/

Principle: the relative increase of CT-proAVP (pmol/L) in relation to Na+ (mmol/L) in serum is measured.

Procedure: thirsting from 8:00–16:00.

Blood samples: around 8:00 for determining CT-proAVP and around 16:00 for CT-proAVP and Na+.

Calculation: increase [pmol × L–1/mmol × L–1] = CT-proAVP (pmol/L) × 1000/Na+ (mmol/L)

Assessment: a value > 20 pmol × L–1/mmol × L–1 separates the primary polydipsia from the mild central diabetes insipidus with a diagnostic sensitivity of 87% and a specificity of 100%.

Table 8.6-8 Disorders of the water balance with increase of AVP and CT-proAVP /167/

Clinical and laboratory findings

Malignant tumor

Tumors are the most common cause of SIADH. In cases of small-cell lung cancer (SCLC), the prevalence is up to 15% /16/. The cause is the synthesis of the AVP or of the complete pro hormone by the tumor or its metastases. Any patient with unclarified polyuria should therefore be examined for SCLC. Also, 3% of the tumors of the head and neck area are associated with SIADH. In tumor patients with polyuria and no inadequate AVP secretion, an atrial natriuretic peptide (ANP) should be considered, because the production of mRNA for ANP has been evident for some tumors.

Reset osmostat

This is a variant of SIADH, in which the patients have a fully maintained capacity for concentrating and diluting urine, but regulate their osmolality from a lower threshold than normal. In comparison to normal individuals, too much AVP is secreted for the same plasma osmolality. The effect of this is increased renal water reabsorption. The patients satisfy all of the criteria of SIADH, but have a normal capacity for dilution. This means they excrete a standard water load up to 80% within 4 hours and have a urine osmolality of below 100 mmol/kg. The Na+ level in serum is slightly to moderately decreased. The reset osmostat is present in 15–20% of the SIADH cases and is found in association with tuberculosis, malnutrition, stomach cancer, pneumonia and encephalitis /1/.

CNS disease

Inflammatory diseases of the central nervous system (CNS) such as meningitis, systemic lupus erythematosus, encephalitis or Guillain-Barré syndrome can accompany SIADH. The cause is supposed to be disruptions of the signal transmission on the relatively long path from the osmoreceptors in the frontal hypothalamus to the AVP neurons.

Pulmonary disease

A variety of pulmonary diseases is associated with SIADH, especially those which cause hypoxia and hypercapnia. The patients have an increased AVP serum concentration. The inadequate AVP secretion exists particularly in the first days after being admitted in the clinic, if shortness of breath is severe and the patients are mechanically ventilated. There are also sporadic cases in patients with chronic obstructive pulmonary disease.


Patients with congestive heart failure and cirrhosis of the liver with ascites have a relatively increased intravascular volume and/or increased intravascular pressure. This results in retention of water due to a reduction of the glomerular filtrate and, secondarily, there is increased AVP secretion. Hypo osmolar hyponatremia develops. In cases of severe cardiac insufficiency, this all results from the organism’s attempt to compensate for the reduced filling of the vessels due to decreased cardiac output. The reduced vascular tone activates baroreceptors and thus the renin-angiotensin-aldosterone system and the adrenergic nervous system. Both systems also stimulate the AVP secretion and thus an attempt is made to increase the vascular resistance and to conserve water and Na+. For liver cirrhosis with ascites as well, water retention takes place via non-osmotic stimuli (see also Section 2.8 – B-type natriuretic peptide and Section 8.1.5– Volume homeostasis).

Critically ill patient

For various reasons, 24 hours after being admitted into the ICU, critically ill patients have significantly increased AVP levels /17/. The AVP values were 11.9 ± 20.6 ng/L in comparison to healthy individuals with values of 0.92 ± 0.38 ng/L. At 9.7 ± 19.5 ng/L, critically ill women have lower values than men (15.1 ± 20.6 ng/L). Patients with hemodynamic dysfunction have higher AVP concentrations (14.1 ± 27.1 ng/L) than those who do not (8.7 ± 10.8 ng/L).

In patients in septic shock and other forms of shock, the AVP concentration increases rapidly, but then declines unexpectedly and inexplicably sharp in relation to the decrease in blood pressure /18/. However, even the form of the shock is important for the AVP value. Thus, levels of 3.1 ± 0.4 ng/L were measured for septic shock, in comparison to cardiogenic shock with 22.7 ± 2.2 ng/L with a decreased blood pressure of the same duration /19/.

Langerhans cell histiocytosis

Tumors due to proliferation of monoclonal cells of the monocyte-macrophage line (Langerhans cells) in lungs, bones and hypothalamus can accompany a central DI in 5–50% of the cases.

Medications /20/

Older patients who take serotonin uptake inhibitors such as fluoxetine, fluvoxamine, paroxetine and sertarline have an increased risk of SIADH. It is known that these pharmaceuticals inhibit the cytochrome P450 isoenzymes. The hyponatremia develops relatively rapidly after the start of the therapy and can be reversed after therapy. Age appears to be a risk factor. Within the first 4 weeks after the start of therapy, the patients should be examined weekly for hyponatremia.

Cerebral salt waste (CSW) syndrome /21/

CSW, defined as the renal loss of Na+ within the scope of cerebral damage, accompanies hyponatremia and, secondarily, leads to a reduction of the extracellular fluid volume (ECFV). It develops within 10 days after neurosurgery, a stroke or in the case of brain tumors. A disrupted neuronal influence on the renal function leads to reduced reabsorption of Na+ and, secondarily, to a decrease in ECFV. The baroreceptors of the hypothalamus are thereby stimulated and the secretion of AVP is activated. The clinical symptoms are orthostatic dysregulation, tachycardia, nausea, vomiting and signs of exsiccosis, and the consequences of hyponatremia and hypovolemia.

Laboratory findings: the differences between CES and SIADH are shown in Tab. 8.6-4 – Differentiation of cerebral salt wasting syndrome from SIADH.

Table 8.6-9 Disorders of water balance with reduced or normal AVP and CT-proAVP /71122/

Clinical and laboratory findings

Hypothalamic (central) diabetes insipidus (HDI)

HDI results from factors which are related to the synthesis, the transport and the release of AVP. Plasma AVP levels are markedly reduced. Water balance is regulated by the perception of thirst and by adequate water intake. The most important clinical symptoms of central DI are polyuria and polydipsia. Any water deprivation, even for a short period, leads to dehydration with compulsive thirst and drinking, such that the patient awakes during the night. The complete form of HDI is rare; partial forms, with moderate diuresis, occur more frequently. The prevalence is 1 : 25,000. The causes of HDI are:

  • Malignancy-related systemic neuroendocrine diseases (craniopharyngioma, germinoma, lymphoma, meningioma), ischemic diseases such as Sheehan’s syndrome, meningeal infections and granulomatous diseases like neurosarcoidosis
  • Surgical procedures on the hypothalamus and the neurohypophysis as well as ischemia of these areas
  • Cranial radiation
  • Infections (meningitis, encephalitis) and autoimmune diseases
  • Intracranial edema or hemorrhage
  • Idiopathic etiology (a proportion of the cases are psychogenically conditioned)
  • Some medicines that lead to a transient decrease in AVP release are, for example, alcohol, vinblastine, dilantin, or clonidine.

In addition to the above mentioned etiologies there exists a hereditary form, which manifests clinically in adolescence. Hereditary DI makes up 1–2% of all DI cases. The following causes are known /12/:

  • A mutation in the neurophysin coding region of the AVP gene. Exons 1 and 3 are normal, but in nucleotide 1884 of exon 2 thymidine is replaced by guanine, resulting in an AVP molecule in which the amino acid glycine replaces valine. The mutation is heterozygous.
  • A mutation in the Pre pro vasopressin gene. In copeptin, valine is replaced with alanine.

Transient HDI develops frequently following neurosurgical procedures in the area of the pituitary gland. Permanent HDI develops only if the infundibulum is completely damaged. DI occurs in 2–35% of the latter cases. Thirst and polyuria are often the first symptoms of neurosarcoidosis. The onset of HDI is abrupt. In those cases where some AVP secretion persists, urine volume is 3–15 liters.

Laboratory findings: there is decreased AVP secretion, which is insufficient with regard to plasma osmolality. Approximately 90% of the AVP-secreting neurons have to be lost, before significant HDI develops. Urine osmolality is < 200 mmol/kg. The diagnosis of water diuresis is performed by the standard fluid deprivation test in combination with the DDAVP sensitivity test. For interpretation, see Tab. 8.6-5 – Interpretation of the standard fluid deprivation test and Fig. 8.6-4 – Relationship between osmolality and AVP in diabetes insipidus. In complete HDI the level of CT-proAVP is < 2.6 pmol/L /13/. For the diagnosis of mild HDI, see Tab. 8.6-8 – Disorders of the water balance with increase of AVP and CT-proAVP.

Nephrogenic DI (NDI)

In NDI there is resistance to the antidiuretic effect of AVP. The neurohypophysis is stimulated and plasma AVP concentrations are high or normal. Since the kidneys do not respond to AVP, they cannot form maximally concentrated urine.

Acquired NDI: the NDI begins incipiently, generally patients have a urine volume of 3–4 L/24 h. Causes are:

  • Medications: amphotericin B, colchicine, demeclocycline, gentamicin, lithium, loop diuretics, methoxyflurane, vinblastine, methicillin, cisplatin, isophosphamide
  • Kidney diseases: chronic renal failure, chronic interstitial kidney disease, pyelonephritis, obstructive uropathy, cystic kidney, post-renal transplantation
  • Electrolyte disorders: chronic hypo- and hyperkalemia
  • Diverse (pregnancy, multiple myeloma, sickle cell disease, protein deficiency).

Genetically determined: the following genetic disturbances are known:

  • V2 receptor gene mutations: some 90% of patients with V2 receptor gene mutations are male and have a X-linked recessive form of NDI which becomes clinically apparent during the first year of life. It is based upon missense mutations in the receptor gene and results in receptors that remain inside the cells; only a small number arrive at the surface of the tubular cells and/or they are incapable of binding AVP or of transmitting signals post-binding (Fig. 8.6-6 – Effect of AVP for increasing the water permeability in the renal collecting duct cells).
  • Aquaporin receptor gene mutations /15/: in some 10% of the cases of hereditary NDI, mutations in the Aquaporin-2 gene, which encodes the similarly named AVP-sensitive water pores of the renal cell membranes, are involved (Fig. 8.6-6). An autosomal recessive or autosomal dominant inheritance can be present. As with the V2 mutation, the disorder leads to defective signaling and expression of the pores. In families with NDI, early diagnosis has been made possible by perinatal testing and, in consequence, physical and mental disorders can be prevented.

In hereditary NDI either the tubules are resistant to AVP, or no hypertonic medullary interstitium corresponding to the requirements (e. g, absorption of water from the tubular lumen) can be achieved. The disorders become evident early. During the neonatal period, and during their early childhood the children suffer from episodes of dehydration, hypernatremia and fever, and develop mental retardation.

Laboratory findings: the urine volume ranges from 10–12 L/24 h, urine osmolality is < 50 mmol/kg. The concentration of CT-proAVP is > 20 pmol/L /13/. The diagnosis can also be performed in the fluid deprivation test in combination with DDAVP sensitivity (for interpretation, see Tab. 8.6-4 – Interpretation of the standard fluid deprivation test and Fig. 8.6-4 – Relationship between osmolality and AVP in cases of diabetes insipidus).

Primary polydipsia

Primary polydipsia is present if a patient, in spite of normal or elevated hydration, continues to drink water. It can be based upon direct stimulation by hypokalemia, hypercalcemia, inflammation, increased angiotensin-II synthesis or psychogenic factors.

The urine volume ranges from 5–15 L/24 h, the serum Na+ level and plasma osmolality are usually normal. One cause of primary polydipsia is a reduced individual osmolality threshold for the sensation of thirst, in comparison with normal individuals.

Laboratory findings: the diagnosis of water diuresis is performed by the standard fluid deprivation test in combination with the DDAVP sensitivity test. For interpretation, see Tab. 8.6-4 and Fig. 8.6-4.


Chronic hypercalcemia with a concentration > 11 mg/dL (2.75 mmol/L) leads to damage to the thick ascending limb of the loop of Henle, with reduced responsiveness to AVP. The process is reversible if serum calcium levels are reduced.


Persistent hypokalemia < 3.0 mmol/L decreases the renal concentrating capacity. The hypokalemia is believed to lead to reduced Na+ concentration and osmolality in the renal medulla, and this interferes with the development of a concentration gradient and results in resistance of the collecting duct cells to AVP.

Pregnancy /23/

A transitory thirst sensation, polyuria and polydipsia can occur in women during the last trimester of pregnancy and in the postpartum period. These symptoms are also observed with hydatid mole and in healthy individuals who have been administered hCG. It is hypothesized that, etiologically, hCG and a cysteine aminopeptidase are involved. The latter is synthesized from the placenta and hydrolyzes AVP.

Table 8.7-1 Reference intervals for potassium

Adults /4/





Children /6/

Premature babies /5/


Neonates /5/


1–7 days


8–31 days


1–6 months


6 months – 1 year


> 1 year


Data expressed in mmol/L.

* In patients with chronic heart failure the target value should be in the range of 4.0–4.8 mmol/L for serum and 3.8–4.6 mmol/L for plasma.

Table 8.7-2 Diseases and conditions associated with hypokalemia

Clinical and laboratory findings

Diuretics (Furosemide, Bumetanide, Thiazides)

Therapy with diuretics is the most frequent cause of hypokalemia. Non K+-sparing diuretics promote the excretion of Na+, Cl and K+. All diuretics, including thiazides, loop diuretics and carbonic anhydrase inhibitors, lead to varying degrees of kaliuresis and hypokalemia. In the presence of hypokalemia, urinary excretion of Na+ is greater than 50 mmol/L and of K+ and Cl it is over 20 mmol/L. If the patient discontinues taking his diuretic prior to seeing a doctor, the excretion values may be normal. In such cases the measurement of the diuretic in the urine can be helpful, even if its half life time has already been significantly exceeded. Hypokalemia begins only after the total exchangeable K+ of the intracellular fluid compartment has been depleted, and this can take up to several weeks. The development of hypokalemia shortly after the initiation of therapy is an indication that K+ depletion has already occurred, for example within the framework of secondary hyperaldosteronism, which can potentiate the hypokalemic effect of diuretics. Under therapy with the same diuretic dose, hypokalemia is more frequent in patients with cirrhosis of the liver, with congestive heart failure, and with the nephrotic syndrome than in hypertensive patients /9/.

Alcohol-use disorder

Hypokalemia occurs in about 50% of hospitalized patients with chronic alcohol disorder. As with magnesium and phosphorus, plasma K+ concentrations may be normal or only slightly reduced on admission, only to decrease over several days because of inward cellular shift that unmasks decreased total body stores. K+ deficiency results from inadequate intake and gastrointestinal losses due to diarrhea. Vomiting and ketoacidosis lead to increased loss of urinary K+ that is due to the coupling of increased aldosterone levels and increased delivery of Na+ to the distal nephron /41/.

Stress hypokalemia (e.g., myocardial infarction, bronchial asthma)

Through the stimulation of β-adrenergic receptors, the release of catecholamines leads to a trans cellular shift of K+ from the extracellular to the intracellular fluid compartment. Renal K+ secretion remains normal. The stimulation of the β2-adrenergic receptors by sympathomimetic drugs temporarily reduces serum K+ level. Thus, a standard dose of albuterol spray leads to a short-term reduction in serum K+ of 0.2–0.4 mmol/L. A second dose within 1 hour leads to a decrease of up to 1 mmol/L /14/.


Acute myeloid or myelomonocytic leukemia can cause mild to moderate hypokalemia. This is believed to be related to lysozymuria. It is assumed that high concentrations of lysozyme in the distal nephron, like penicillin or carbenicillin, lead to increased K+ secretion /9/.

Pyloric stenosis, gastrointestinal suction, drainage

These patients often lose K+, especially post-operatively via drainage. One cause is gastrointestinal K+ loss, and a further important reason is renal K+ loss, which results from volume depletion and activation of the renin-angiotensin system /9/.

Diarrhea, laxative abuse

Loss of water, electrolytes and HCO3 is proportional to the stool volume and therefore, in severe diarrhea, acidosis often occurs. Hypokalemia is particularly frequent in laxative abuse, and K+ values in serum are in such cases rather low (likewise for Na+ and Cl); often absence of or only mildly expressed alkalosis due to simultaneous HCO3 loss despite hyperaldosteronism.


This is a rare hereditary disorder with decreased total body K+ and metabolic alkalosis (see Section 8.3 – Chloride).

Villous adenomas

Rectal tumors form considerable K+-containing mucus. Metabolic acidosis usually develops due to the loss of potassium bicarbonate.


In patients with hypokalemia and hypertension who are not taking diuretics or laxatives, primary hyperaldosteronism should be suspected. If, in a hypertension cohort in a medical practice, one evaluates only hypokalemic hypertensives for Conn syndrome, the detection rate relative to all hypertensives will be below 1%; in specialized hypertensive out-patient clinics the rate is 1–4%. If, in contrast, all hypertensives, independent of their hypokalemia status, are evaluated according to the aldosterone-renin ratio, the detection rate will be 1–4% /15/.


Early hypokalemia, which develops within 1 hour and subsequently normalizes within 24 hours without K+ medication, is observed in up to 65% of trauma patients. There is no correlation with cardiovascular biomarkers, blood loss, blood pH, adrenalin or noradrenaline concentrations. Hyperkalemia occurs frequently in patients with head and spinal cord injuries. Traumatic hypokalemia occurs more frequently in children between the ages of 5 and 14 than in adults /16/.

Renal tubular acidosis (RTA)

Distal RTA (type I) and proximal RTA (type II) are associated with renal K+ loss and hypokalemia. In type II the kaliuresis results from increased HCO3 load in the distal tubule. In type I, H+ excretion is disturbed and K+ is secreted instead of H+ in order to ensure tubular Na+ reabsorption. In addition, the distal Na+ loss causes volume depletion with activation of the renin-angiotensin-aldosterone system /17/. A reduction of K+ in the plasma by 0.3 mmol/L corresponds to a loss of total body K+ of 100 mmol/L. Regarding RTA see also Section 8.8 – Renal electrolyte excretion.

Bartter syndrome

The Bartter syndrome is a congenital disease, characterized by hypokalemia and metabolic alkalosis. The syndrome is diagnosed mainly in children and young adults. Clinical symptoms are stunted growth, lethargy, muscular weakness, seizures, polyuria and normal blood pressure. Characteristic findings are, apart from hypokalemia and metabolic alkalosis, hyperreninemic hyperaldosteronism and elevated urinary excretion of Cl (above 100 mmol/L) and K+ /18/. Anatomically, these patients manifest hyperplasia of the juxtaglomerular apparatus of the renal nephrons.

Pseudo-Bartter syndrome

The laboratory diagnostic findings are similar to those of the Bartter syndrome. In contrast to the Bartter syndrome there are, however, no renal changes /18/.

Gitelman syndrome

Gitelman’s syndrome affect the thiazide sensitive NaCl cotransporter (NCC) expressed predominantly in the renal distal convoluted tubule. In Gitelman’s syndrome loss of function NCC mutations lead to salt wasting and hypotension despite an activating renin-angiotensin aldosterone system. Gitelman's is a rare chronic renal electrolyte disturbance with hypokalemia, hypomagnesemia, hypocalciuria, thiazide insensitivity of renal electrolyte excretion and high-normal or elevated excretion of Cl. Serum K+ levels are usually below 3.0 mmol/L with median values of 2.4 mmol/L, and median magnesium levels are 0.55 mmol/L. The Bartter and pseudo-Bartter syndromes, as well as diuretic abuse, should be distinguished, particularly if thiazides are being taken. If the urine is rich in Cl, it is important to differentiate the Gitelman syndrome from diuretic abuse by means of a diuretic determination /19/.

Liddle syndrome

Apart from the hypokalemia, this syndrome is characterized by a clinical picture which is opposite to that of the Bartter syndrome. Apart from hypokalemia, hyporeninemic normo- or hypoaldosteronism and elevated blood pressure are seen. The pathophysiology is unknown but hypersensitivity of the damaged tubular epithelium for mineralocorticoids, or a defect of the voltage-gated Na+ channels, are hypothesized /9/.

ACTH-producing tumor

Tumors, particularly small cell lung cancer, produce ACTH in a para neoplastic manner. The synthesis of cortisol and aldosterone is increased. A loss of renal K+ occurs. Patients with hypokalemia, metabolic alkalosis and hyper pigmentation are to be suspected in this regard /9/.

Cushing’s SynDrome

Cushing’s syndrome due to ectopic secretion of adrenocorticotropic hormone (ACTH) from small-cell lung cancer causes massive glucocorticoid production with hypokalemia and paranoia /46/.

Congenital adrenal hyperplasia

In 17α-hydroxylase deficiency, the reduced synthesis of cortisol leads to increased formation of corticosterone and deoxycorticosterone and elevated ACTH secretion. In 11β-hydroxylase deficiency, deoxycorticosterone and ACTH are increased. Hypokalemia occurs in only some of these cases.


For unknown reasons, hypomagnesemia leads to renal loss of K+. A magnesium deficiency should be suspected if, with normal blood pH, the hypokalemia cannot be normalized in spite of appropriate K+ intake. Hypomagnesemia occurs frequently with loop diuretic therapy, in alcoholics, and in patients with the malabsorption syndrome. In patients with K+ concentrations of less than 2.5 mmol/L, hypomagnesemia is also present in up to 70% of the cases /20/.

Licorice abuse

Licorice, used for chewing or as a laxative, contains glycyrrhizic acid. This substance inhibits the enzyme that catalyzes the conversion of cortisol to cortisone. In this way cortisol concentrations are raised, leading to kaliuresis accompanied by hypokalemia, hypervolemia and elevated blood pressure. As in the Liddle syndrome, hyporeninemic hypo aldosteronism is present /9/.

Hypokalemic periodic paralysis (HypoPP)

HypoPP is an autosomal dominant disorder which is accompanied by attacks of muscle weakness and hypokalemia. The cause is a mutation in the voltage-gated calcium channel, the dihydroxypyridine receptor (DHP receptor). Mutations of the S4 segment of domains II and IV lead to an exchange of arginine with histidine in position 528 or of histidine with glycine in position 1239 of the DHP receptor. The disorder occurs prior to the age of 16 in 60% of the afflicted individuals. All four limbs are affected by the attacks on the muscular tissue, and the frequency is variable, from once in a lifetime to a number of times per week. HypoPP is provoked by carbohydrate-rich food and by rest following effort. As a diagnostic test, glucose (2 g/kg body weight) and insulin (0.1 U/kg body weight) are infused. This leads to an influx of glucose into the muscle cells and to muscular paralysis with hypokalemia /21/.


Many antibiotics, but in particular penicillin, carbenicillin and gentamicin, lead to hypokalemia due to increased renal K+ excretion. Anionic penicillin and carbenicillin disrupt the electroneutrality of the tubules and thereby lead to kaliuresis. Gentamicin acts in this respect through lysozymuria /9/.

Mild to moderate hypokalemia increases the likelihood of cardiac arrhythmias in patients with cardiovascular disease, cardiac anomalies and ventricular hypertrophy. In patients with arrhythmias who are taking antiarrhythmic agents, hypokalemia can cancel out the effect of the antiarrhythmics. In all of these patients serum concentrations of K+ should be maintained, by means of appropriate potassium supplementation, at or above 4.0 mmol/L. In patients with acute myocardial infarction, the rate of ventricular fibrillation increases if K+ values fall below 3.9 mmol/L /22/.

Table 8.7-3 Diseases and conditions associated with hyperkalemia

Clinical and laboratory findings

Pseudo hyperkalemia

Sampling: application of the tourniquet for several minutes leads to an elevation of K+ concentration by 10–20%, particularly if, at the same time, the fist is opened and closed during the process. The cause is the development of acidosis, which leads to the exit of K+ from the cells /23/.

Hemolysis: the extravascular hemolysis of 0.5 g Hb/L increases a K+ concentration in the plasma of 5.0 mmol/L by 10% /2/.

Leukocytosis: with leukocyte counts above 50 × 109/L, K+ release occurs during the clotting process and when the blood is stored. In a female patient with a leukocyte count of 98 × 109/L, an increase in K+ from 3.5 to 4.4 mmol/L and to 5.2 mmol/L occurred when the blood was stored 2 hours and 4 hours, respectively. The shaking of the blood collection tube led to an almost 4-fold rise in K+ /24/.

Thrombocythemia: thrombocythemias of greater than 600 × 109/L cause hyperkalemia. Every increase of 100 × 109/L leads to a rise in K+ of 0.15 mmol/L. The release occurs during the degranulation phase of the coagulation process and not during the aggregation phase /25/. Some Kawasaki syndrome patients have elevated serum, but not plasma K+ concentrations. The elevation results from blood coagulation in the presence of a raised thrombocyte count.

Hereditary spherocytosis: the magnitude of the hyperkalemia is dependent upon the period of time between the sampling and the centrifugation of the samples. In whole blood, a rise in K+ concentration from 4.7 mmol/L to over 10 mmol/L occurs within 3 hours. If the whole blood is stored at 37 °C, the K+ level increases from 4.7 mmol/L to 5.5 mmol/L, while at 4 °C it increases to greater than 10 mmol/L /26/.

Renal insufficiency

Acute renal insufficiency /13/: in renal insufficiency, acute hyperkalemia or an acute increase in hyperkalemia are based upon a combination of balance and distribution disorders of K+. Acute oliguric renal failure always is associated with hyperkalemia; it’s extent, however, depends upon factors such as hyper catabolism (following surgery, steroid therapy, stress), tissue necrosis (burns, rhabdomyolysis, hemolysis), or the presence of metabolic acidosis. In acute and chronic renal failure the kidneys retain, over a long period of time, the capacity to excrete K+. This is particularly true in patients with a near normal urine volume. In non oliguric acute renal failure, the glomerular filtration rate (GFR) is normally below 10 [mL × min–1 × (1.73 m2)–1] before hyperkalemia occurs.

Chronic renal failure /9/: below a GFR of 60 [mL × min–1 × (1.73 m2)–1], plasma K+ levels begin to rise, but values greater than 5 mmol/L are achieved only in the final stages of chronic renal insufficiency with a GFR of below 10 [mL × min–1 × (1.73 m2)–1/27/. Concentrations of greater than 5 mmol/L are not a matter of course for chronic renal insufficiency. They occur frequently, however, due to loading with calcium-rich nutrition, trauma-induced exit of intracellular K+, infection, or medication-induced inhibition of tubular K+ secretion (e.g. during the treatment of a diabetic nephropathy patient with β-blockers). Hyperkalemia can also occur in chronic renal insufficiency with a GFR of greater than 10 [mL × min–1 × (1.73 m2)–1] if hyperchloremic metabolic acidosis is present in diabetic or interstitial nephropathy /13/. The cause for hyperkalemia in chronic renal failure is based on the reduced function of the Na+-K+ pump. Approximately 90% of hemodialysis patients do not develop K+ concentrations greater than 6 mmol/L during the period between two dialysis sessions, in spite of the lack of significant renal K+ excretion.

Chronic hyperkalemia

Chronic hyperkalemia is based upon hyporeninemic hypo aldosteronism. The cause is a K+ and acid transport disturbance in the cortical collecting duct (type IV renal-tubular acidosis). The disease pattern is quite common and occurs in diabetic or interstitial nephropathy.

Continuous transitions to reduced renal responsiveness to aldosterone are present, as seen in systemic lupus erythematosus, amyloidosis of the kidneys, cyclosporine therapy, and obstructive nephropathy. Critical elevations of K+ in the serum can occur in metabolic acidosis and under therapy with ACE inhibitors, beta blockers, and non-steroidal anti-inflammatory drugs /12/.

Increased external potassium intake

Hyperkalemia can develop with extremely reduced Na+ intake if the K+ intake is greater than 200 mmol/24 hours. This can be the case, for example, with therapeutic K+ substitution which should not exceed 20 mmol/h in patients with reduced Na+ intake.

Massive muscle trauma, rhabdomyolysis, tumor cell lysis

These events lead to moderate hyperkalemia with elevations in uric acid, creatinine and phosphate. It is important that the Na+ delivery in the distal tubules is increased by the administration of NaCl and of fluids so that K+ secretion can take place. The situation becomes critical if, due to myoglobinuria following muscle trauma or uric acid nephropathy in tumor cell lysis, renal insufficiency develops. In these cases the administration of sodium bicarbonate for the alkalinization of the urine is essential.

Addison’s disease

In adrenocortical insufficiency hypo aldosteronism and hypocortisolism are present. Hyperkalemia occurs in the setting of an Addisonian crises, but not in chronic insufficiency, if salt intake is adequate. In adrenocortical insufficiency renin levels are normal.

Premature infants

Non oliguric hyperkalemia is a frequent complication in extremely premature infants. The cause is a shift of K+ from the intracellular into the extracellular fluid compartment during the first days of life. Plasma K+ levels over 9 mmol/L occur. The risk of cardiac arrhytmias is high with values greater than 7 mmol/L /28/.

Hyperkalemic periodic paralysis

Hyperkalemic periodic paralysis is a rare autosomal dominant, inherited disorder. A shift of K+ from the intracellular to the extracellular fluid compartment occurs during physical effort, cold exposure, or at rest.

Tumor lysis syndrome

The tumor lysis syndrome is classified according to the following findings /29/:

  • Uric acid > 8 mg/dL (476 μmol/L) or an increase over 25% compared to the basal value
  • K+ > 6 mmol/L or an increase of over 25% compared to the basal value
  • Phosphate > 4.5 mg/dL (1.45 mmol/L) or an increase of over 25% compared to the basal value
  • Calcium ≤ 7.0 mg/dL (1.75 mmol/L) or a decrease of over 25% compared to the basal value.


Succinylcholine, a muscle relaxant, induces hyperkalemia in patients with exogenous K+ intake as well as in neuromuscular diseases. The cause is an intensified transmembrane shift of K+ from intracellular to the extracellular fluid compartment /28/.

Digitalis intoxication

Digitalis intoxication inhibits the effect of the renal tubular Na+-K+-ATPase so that less K+ is transported into the cells /28/.

ACE inhibitors

ACE inhibitors lead to hyperkalemia by the induction of a situation similar to that which occurs in hypo aldosteronism. They decrease K+ excretion through the reduction of the GFR in patients with volume depletion, renal arterial stenosis, and chronic renal insufficiency. Furthermore, post-glomerular arteriolar vasoconstriction is decreased. These effects lead to reduced delivery of Na+ and water to the distal tubules and, along with the hypo aldosteronism, result in diminished K+ excretion.

ACE inhibitors are responsible for 9–38% of the cases of hyperkalemia in hospitalized patients. Of these, 10% have K+ levels ≥ 6 mmol/L. The risk of ACE inhibitor induced hyperkalemia increases with the severity of the renal insufficiency. The high dose administration of captopril over 10 days induces elevated serum K+ levels, a positive K+ balance, and a reduction in aldosterone values with a creatinine clearance of 60 [mL × min–1 × (1.73 m2)–1]. The reduction of the ACE inhibitor dose and a slightly limited K + intake attenuate the hyperkalemia /28/.

Beta blockers

Non-selective beta blockers can cause hyperkalemia which is, nonetheless, only rarely severe. Two mechanisms are responsible for this effect: firstly, beta blockers suppress catecholamine-induced renin release and thereby reduce the synthesis of aldosterone. Secondly, cellular uptake of K+ is blocked. Non-selective beta blockers are responsible for 4–17% of the hyperkalemia cases in clinic patients /28/.

Trimethoprim/sulfamethoxazole, pentamidine

Trimethoprim/sulfamethoxazole and pentamidine, which are structurally similar to amiloride, competitively inhibit the Na+ transport channels of the luminal cell membrane in the distal tubules. In this way, K+ secretion is indirectly inhibited, since the negative luminal charge, generated by the Na+ shift, is reduced. Urinary pH of less than 6 increases the protonated form of trimethoprim, the avidity of which for the Na+ channel is thereby elevated and, as a result, the trimethoprim also inhibits K+ secretion.

Half of the HIV patients treated with trimethoprim for Pneumocystis carinii infection develop K+ levels over 5.0 mmol/L. With pentamidine therapy for longer than 6 days, 24% of HIV patients have K+ levels ≥ 5.2 mmol/L /28/.

Nonsteroidal anti-inflammatory drugs (NSAID)

As prostaglandin synthetase inhibitors, NSAID cause hyporeninemic hypo aldosteronism. Prostaglandins, as vasodilators, induce the renal synthesis of renin and, thereby, of aldosterone as well. With NSAID therapy up to 46% of clinical patients develop an increase in K+ levels, or hyperkalemia /28/. In addition, the new selective cyclooxygenase-2 inhibitors can, apparently, promote the development of hyperkalemia.

Potassium-sparing diuretics

K+-sparing diuretics such as spironolactone, amiloride and triamterene are a frequent cause of hyperkalemia.

Spironolactone is an aldosterone antagonist that inhibits the binding of aldosterone to its cytoplasmic receptors and, in consequence, its cellular uptake. The secretion of K+ is thereby suppressed. Spironolactone is recommended for the treatment of NYHA stages III and IV congestive heart failure. Therapy is initiated with a dose of 12.5–25 mg per day which is increased to 50 mg if hyperkalemia does not occur.

Amiloride and triamterene suppress K+ secretion through the inhibition of renal tubular Na+ reabsorption. The secretion of K+ is blocked due to a reduction of the electrical gradient across the cell membrane. Moderate to severe hyperkalemia occurs in 4–19% of the patients. Hyperkalemia develops more frequently in diabetics and in patients with chronic renal insufficiency /28/.

Angiotensin II receptor antagonists

Angiotensin II receptor antagonists are used in the treatment of hypertension. Like ACE inhibitors, these drugs can lead to hyperkalemia via a decrease in the synthesis of aldosterone. There are no differences between angiotensin II receptor antagonists and ACE inhibitors in the frequency of development of hyperkalemia. The frequency is 1.3% and the relative rise can, in older patients, be greater than 0.5 mmol/L. The presence of diabetic nephropathy and of serum creatinine levels over 1.3 mg/dL (115 μmol/L) are predictive factors for a significant K+ increase /28/.

Cyclosporin, tacrolimus

The immunosuppressive agents cyclosporin and tacrolimus lead to a rise in serum K+ levels in 44–74% of transplanted patients. In allogenic bone marrow transplantation, hyperkalemia of greater than 5.5 mmol/L is frequently linked to reduced kidney function.

Cyclosporin leads to hyperkalemia through the induction of hypo aldosteronism, and both cyclosporin and tacrolimus also inhibit the Na+-K+-ATPase of the basolateral membrane of renal tubular cells /28/.


Fractionated and unfractionated heparin induces aldosterone suppression. This is based, on the one hand, on the reduction of the angiotensin II receptors in the zona glomerulosa of the adrenal cortex and, on the other hand, on the direct inhibition of C18 hydroxylation of aldosterone. Heparin therapy of longer than 3 days with more than 5000 IU serum K+ increases of 0.2–1.7 mmol/L can occur /30/.

Table 8.8-1 Urinary electrolyte reference intervals

24 h urine collection

Volume (mL)

1349 ± 412 /3/

660–3620 /4/

Na+ (mmol)

158 ± 64 /3/

67–268 /4/

K+ (mmol)

67 ± 23 /3/

34–126 /4/

Cl (mmol)

166 ± 71 /3/


6.2 ± 0.5 /3/

5.2–7.4 /4/

Ammonium (mmol)

8 ± 3

4–17 /4/

HCO3 (mmol)

< 50

Creatinine (mmol)

14.6 ± 4.2 /3/

8.3–22.8 /4/

Values expressed as x ± s in Ref. /3/ and values are the 2.5th and 97.5th percentiles in Ref. /4/

Morning urine specimen after 8 hours of bed rest /3/

Volume (mL)

298 ± 166

Na+ (mmol/L)

118 ± 54

K+ (mmol/L)

44 ± 27

Cl (mmol/L)

106 ± 52

Creatinine (mmol/L)

16 ± 4.8 (1.81 ± 0.55 g/L)

Values expressed as x ± s. In a study /5/ the mean ratios for 24-hour urine and spot urine expressed as mg/mg or mmol/mol of creatinine were in women 2.0 for Na+ and 1.0 for K+.

Table 8.8-2 Differential diagnostic significance of urinary Na+ excretion in hyponatremia /7/



< 20 mmol/L

3–5 days after complete Na+ withdrawal.

In hypervolemia (increase of the ECFV):

  • Na+ losses in the third space due to cardiac failure, liver cirrhosis, nephrotic syndrome, in the form of edemas (ascites, ileus).

In hypovolemia (decrease of the ECFV):

  • Gastrointestinal losses such as vomiting, diarrhea, drainages (see Tab. 8.2-2).
  • Outside losses (sweating, burns, cystic fibrosis).

> 20 mmol/L

In hypovolemia (ECVF decline):

  • Acute tubulus necrosis in the oliguric and poly uric phase
  • Chronic renal failure; the Na+ excretion is 50–70 mmol/L. This declines to 10–15 mmol/L after 1–3 weeks if the Na+ intake is limited. Until then, there is a daily loss of 20–30 mmol/L of Na+.
  • Diuretics, osmotic diuresis due to hyperglycemia, mannitol, urea
  • Hypothyroidism.

In euvolemia (ECVF normal):

  • Mineralocorticoid and glucocorticoid deficiency

Table 8.8-3 Differential diagnostic significance of urinary Na+ excretion in hypernatremia /7/



< 20 mmol/L

In hypovolemia (ECFV decline):

  • Insensible losses due to excessive sweating
  • Gastrointestinal losses due to diarrhea, especially in children.

≥  20 mmol/L

In hypovolemia (ECFV decline):

  • Osmotic diuresis due to glucose, mannitol, urea

In hypervolemia (ECFV increase):

  • Primary hyperaldosteronism, Cushing’s syndrome
  • Intake of hypertonic saline solution
  • Intake of sodium carbonate


  • Diabetes insipidus (DI), hypodypsia in combination with partial DI
  • Insensible water losses via the mucocutaneous surfaces.

Table 8.8-4 Interpretation of the urinary anion gap /10/

Anion gap

Clinical and laboratory findings


Increased excretion of one or more anions other than Cl (e.g., HCO3). Indicates the presence of impaired urinary acidification in the distal tubules (e.g., distal renal-tubular acidosis; type 1). In this case, the anion gap is positive (32 mmol/L on average) and the renal NH4+ excretion is inadequately low in relation to the extent of the acidosis.


Increased excretion of a cation other than Na+ or K+ (e.g., NH4+):

  • Ammonium chloride poisoning. This substance is used to acidify the urine in patients with kidney stones containing phosphate. Patients with poor liver or kidney function tend to be poisoned with severe metabolic acidosis and coma.
  • Indication of increased gastrointestinal loss of HCO3 (e.g., in cases of diarrhea). In diarrhea patients and healthy individuals with NH4Cl-induced acidosis, the anion gap is –23 mmol/L on average and the NH4+ excretion is inadequately high in relation to the acidosis.
  • Proximal RTA (type 2). Due to inadequately high NH4Cl secretion, the anion gap is negative. See also Tab. 8.8-5 – Renal-tubular acidoses (RTAs).

Table 8.8-5 Renal-tubular acidoses (RTAs) /14/

Clinical and laboratory findings

Proximal RTA (Type 2)

Proximal RTA primarily occurs as an isolated entity or in combination with other tubular defects such as Fanconi syndrome (cystinosis, galactosemia, fructose intolerance, tyrosinemia, M. Wilson, Lowe syndrome, metachromatic leukodystrophy, multiple myeloma). The cause may be hereditary (mutations in the gene SLC4A4, which encodes the Na+ and HCO3 cotransporter NBC-1) or, secondarily, due to medications and toxins (e,g., acetazolamide, deteriorated tetracycline, aminoglycosides, valproic acid, 6 mercaptopurine, isophosphamide, lead, cadmium, mercury). Proximal RTA is also associated with other diseases such as vitamin D deficiency, hyperparathyroidism, Leigh syndrome, congenital cyanotic heart disease, Alport syndrome, amyloidosis , corticosteroid-resistant nephrotic syndrome, after a kidney transplantation.

There is reduced proximal-tubular HCO3 reabsorption, the threshold for young children is normally around 22 mmol/L and 26 mmol/L for older children and adults. If the HCO3 in the plasma decreases to low values, these can decrease the patients’ urine pH below 5.5 and secrete adequate quantities of NH4+ into the tubulus. If, however, the HCO3 in the plasma is brought to normal values by alkali loading (sodium bicarbonate loading test), then the distal nephron cannot handle these quantities and the fractional HCO3 excretion is over 10–15%. The diagnosis can often be made by determining the anion gap and osmotic gap if there is hyperchloremic metabolic acidosis. See Tab. 8.6-5 – Interpretation of the standard fluid deprivation test in combination with the DDAVP sensitivity for the diagnosis of diabetes insipidus (DI).

Distal RTA (Type 1)

Distal RTA is characterized by the inability to sufficiently acidify the urine (below pH 5.5. after acid loading in the ammonium chloride loading test). As with proximal RTA, the distal form’s loss of K+ is also an important characteristic. The reduced secretion of NH4+ is secondary to this defect. A distinction is made between the following forms:

  • Complete distal RTA, also called classical RTA. It has multiple etiologies and encompasses primary or idiopathic forms, genetic diseases, autoimmune diseases, hypercalcemia and hypocalcemia, dysproteinemia, and toxic geneses
  • Incomplete RTA, which involves a mild form of classical distal RTA. Under normal conditions, it is characterized by the absence of metabolic acidosis, but also with the inability to sufficiently acidify the urine (below pH 5.5, after acid loading in the ammonium chloride loading test). Increased excretion of NH4+ partially compensates for the reduced acid excretion.
  • In children, distal RTA is always related to a primary genesis. Some important clinical characteristics are reduced growth, loss of K+, polyuria, hypercalciuria, nephrocalcinosis, and nephrolithiasis. For some children, the autosomally dominant form is associated with mutations in the gene which encodes the Cl–HCO3 exchanger AE1 (Fig. 8.8-4 – H+ secretion into the cortical collecting tubule). In the autosomal recessive forms, which are seen in cases of mental deficiency, mutations were evident in the gene ATP6B1, which encodes the B1 subunit of the H+-ATPase.

Distal RTA develops when there is a true failure of the distal nephron to secrete H+ or when such capacity is intrinsically intact but secondarily impaired. The acquired forms are caused by monoclonal gammopathies, autoimmune diseases such as systemic lupus erythematosus, Sjögren syndrome (prevalence up to 40%), and chronic active hepatitis.

Hyperkalemic RTA (Type 4)

The inability to acidify the urine is caused by impaired ammoniogenesis. Type 4 is characterized by a normal ability to acidify the urine after an acid load (under pH 5.5 in the ammonium chloride loading test). The renal HCO3 reabsorption is reduced at normal plasma HCO3, but such reduction is not of sufficient magnitude to implicate an associated defect. Hyperkalemic RTA is often diagnosed within the scope of chronic kidney disease or in connection with hypo aldosteronism or pseudo hypo aldosteronism.

  • Hyperkalemic RTA and pseudo hypo aldosteronism type 1: this hereditary entity is characterized by salt-wasting, hyperkalemia, metabolic acidosis and increased concentrations of renin and aldosterone. In the autosomal dominant form, aldosterone resistance is limited to the kidney and is due to heterozygous mutations in the gene encoding the mineralocorticoid receptor.
  • Primary pseudo hypo aldosteronism type 2 (Gordon syndrome): there is increased reabsorption of NaCl in the thick ascending limb of Henle and early distal tubule, leading to reduced K+ and H+ secretion.

In adults, hyperkalemic RTA is an acquired disorder in the context of mineralocorticoid deficiency, either as a primary adrenal insufficiency or as secondary to hyporeninemia in patients with diabetic nephropathy, mild or moderate renal insufficiency from another cause, systemic lupus erythematosus, or AIDS nephropathy. Finally, other possibilities are medications and tubulo-interstitial diseases, which are associated with a reduced response to aldosterone and deficient K+ secretion.

RTA Type 3

This type appears to be a combination of proximal and distal RTA, but is no longer considered to exist.

Table 8.8-6 Laboratory diagnostics of renal-tubular acidoses (RTAs) /1314/

Clinical and laboratory findings

Suspected RTA

If hyperchloremic metabolic acidosis and a normal plasma anion gap exist (see also Section 8.5 – Osmolality), RTA is suspected if gastrointestinal losses of HCO3 and the ingestion of diuretics are excluded. Subsequently, urinary anion and osmotic gaps are also determined.

Urinary anion gap (UAG) and urinary osmotic gap

Na+, K+ and Cl and the UAG is calculated as follows:

UAG (mmol/L) = Na (mmol/L) + K (mmol/L) – Cl (mmol/L).

Na+, K+, urea and glucose are measured, and the osmolality is calculated as follows:

Osmolality (mmol/kg) = 1.86 (Na + K) + urea + 1.15 (glucose) + 14. All values in mmol/L.

Calculation of the osmotic gap (mmol/L): Measured osmolality – calculated osmolality.

Clinical significance: if hyperchloremic metabolic acidosis with a negative anion gap or an osmotic gap of greater than 100 mmol/L are documented, then RTA is present, as long as gastrointestinal losses of HCO3 can be ruled out.

Measurement of proximal HCO3 reabsorption

Proximal RTA (type 2) is characterized by decreased HCO3 reabsorption in the proximal tubule. Increased HCO3 is excreted in the urine. For the determination of tubular HCO3 reabsorption, a sodium bicarbonate loading test is performed and the rate of reabsorption is measured, based upon the excretion.

Sodium bicarbonate loading test

For the clarification of proximal RTA a normal plasma HCO3 concentration of approximately 22 mmol/L is achieved with the oral or systemic (by infusion) administration of sodium bicarbonate. Urine is collected over 8 hours and the excretion of HCO3 during this time period is determined. If the fractional excretion is above 10–15%, then proximal RTA is present.

Measurement of distal urinary acidification

Distal RTA is caused by impaired distal acidification of the urine and is characterized by the inability to lower urinary pH maximally (below pH 5.5) under the stimulus of systemic acidemia.

Urine pH

The determination is performed on a random voided morning urine sample. The activity of free H+, which is lower than 1% in the urine, is measured. However, a normal pH does not indicate that the distal acidification is normal, since the NH4+concentration may be low.

Urinary anion gap (UAG)

The UAG represents an indirect measure of urinary NH4+ excretion in patients with hyperchloremic metabolic acidosis. The UAG becomes progressively more negative as NH4+ increases. When urin pH exceeds 6.5 the accuracy of the UAG in assessing NH4+ excretion decreases as HCO3 becomes a significant anion contribution.

Urinary osmolal gap

High values of NH4+ increase the osmolal gap to over 100 mmol/L. Low NH4+ secretion, as in distal RTA, is associated with an osmolal gap of below 100 mmol/L.

Ammonium chloride loading test (acid loading)

This test is the most frequently test employed for the diagnosis of distal RTA. Implementation of the test:

  • Begin at 800 a.m. with the administration of 0.1 g NH4Cl per kg body weight, dissolved in 1 liter of distilled water, or given as gelatin capsules
  • Urine collection following 2, 4, 6 and 8 hours with pH determinations in each sample
  • If a pH of less than 5.5 is not achieved in any of the samples, on condition that the HCO3 plasma concentration falls below 20 mmol/L, then distal RTA is present.

Determination of PCO2 in the sodium bicarbonate loading test

In distal RTA the urine becomes markedly alkaline under alkali load (sodium bicarbonate loading test) and urinary PCO2 increases as a function of the distal H+ secretion. H+ reacts with luminal HCO3 to form H2CO3. Because the dehydration of H2CO3 occurs slowly, the determination of urinary PCO2 is a measure of H+ secretion. Provided that urinary pH and HCO3 concentration increase above 7.6 and 80 mmol/L, respectively, the urine-to-blood PCO2 gradient should be greater than 20 mm Hg in normal individuals.

Trans tubular K+ concentration gradient (TTKG)

The TTKG is determined for the diagnosis of RTA type 4. The action of aldosterone at the distal tubule is evaluated. The following is determined: K+ in the urine (KU) and in the plasma (KP), as well as urinary osmolality (OU) and plasma osmolality (OP). Calculation:

TTKG = K U × O P K P × O U

The TTKG is always above 4 in normal individuals. In hyperkalemic patients, a value of below 8 implies that the collecting duct is not responding appropriately to the prevailing hyperkalemia and that K+ secretion is impaired.

Table 8.8-7 Differentiation of renal-tubular acidoses (RTA) by biochemical tests /1314/


(type 2)

RTA type I

Distal RTA
with HCO3
(type 3)

Distal RTA

(type 4)

In situation of metabolic acidosis (spontaneously or after acid loading)

Serum K+




Anion gap in urine






Urine pH

< 5.5

> 5.5

> 5.5

> 5.5

< 5.5

NH4+ excretion


Fractional K+ excretion


Calcium excretion


Normal or

Citrate excretion



Acid loading

< 5.5

> 5.5

> 5.5

< 5.5

< 5.5

In situation of normal acid-base equilibrium (after alkali loading)

Fract. HCO3 excretion

> 10-15%

< 5%

> 5-15%

< 5%

> 5-15%

U-B PCO2 (mmHg)

> 20

< 20

< 20

> 20

> 20

Other tubular defects

Often present





Nephrocalcinosis/ lithiasis


Often present

Often present

Often present


Bone involvement

Often present

Rarely present

Rarely present

Rarely present


U-B PCO2, urine-blood PCO2-difference; decreased; increased; acid loading = ammonium chloride loading test

Table 8.8-8 Renal potassium excretion in hypokalemia



< 10 mmol/L

  • pH normal: reduced K+ intake or K+ losses through the skin, intestine, fistula, laxatives
  • Metabolic acidosis: diarrhea
  • Metabolic alkalosis: connatal chloridorrhea (Cl excretion below 10 mmol/L).

≥  10 mmol/L

  • pH normal: renal K+ losses (e.g., due to kidney disease or diuretics) K+ shift into the intracellular compartment (e.g., due to insulin and catecholamines)
  • Metabolic acidosis: hyper­chloremic renal-tubular acidosis type I and II, ureterosigmoidostomy, metabolic acidoses with increased plasma anion gap such as diabetic and alcoholic ketoacidosis
  • Metabolic alkalosis and Cl excretion below 10 mmol/L: diuretics (non-K+-sparing), intestinal HCI loss (e.g., due to frequent vomiting, gastric juice drainage)
  • Metabolic alkalosis and Cl excretion above 20 mmol/L: hyperaldosteronism, hypertonic patients with intake of diuretics.

Table 8.8-9 Hyperkaliuric hypokalemia /2/

Clinical and laboratory findings

Lowe syndrome*

Oculocerebral dystrophy; congenital cataract, mental retardation, progressive renal failure.

Laboratory findings: proteinuria, aminoaciduria, mild glucosuria, phosphaturia, renal-tubular acidosis.

Wilson disease*

Laboratory findings: aminoaciduria, hypercalciuria, hypophosphatemia, nephrocalcinosis and kidney stones.

Dent’s disease*

X-bound illness with rickets; disruption of renal chloride channel 5.

Laboratory findings: low molecular weight proteinuria, hypercalciuria, aminoaciduria, hypophosphatemia.

Bartter syndrome**

Incidence 1.2/1 million. The biochemical findings are identical to those of a long-term administration of diuretics. Mutations of the NKCC2, ROMK1 and CLC-Kb transporters are described (Fig. 8.8-1 – Pathways of Na+, K+, Mg++ and Ca++ reabsorption in the thick ascending limb of the loop of Henle). Most patients are already showing signs as newborn infants. See also Tab. 8.7-2 – Diseases and conditions associated with hypokalemia.

Laboratory findings: renal loss of salt and hypokalemic metabolic alkalosis with normocalciuria or hypercalciuria.

Gordon’s Syndrome (familial hyperkalemic hypertension)

Gordon’s syndrome and Gitelman’s syndrome affect the thiazide sensitive NaCl cotransporter (NCC) expressed predominantly in the renal distal convoluted tubule, but they do so in opposite directions. In Gordon’s syndrome, aberrant WNK (with no lysine; K) kinase signaling activates NCC, leading to excessive salt reabsorption and hypertension, despite normal aldosterone levels. Both hypertension and hyperkalemia are corrected with thiazides /18/.

Gitelman syndrome** /17/

Loss of function NCC mutations lead to salt wasting and hypotension, despite an activated renin-angiotensin-aldosterone system. This symptom is caused by the presence of mutants of the gene SLC12A3, which encodes the thiazide-sensitive distal Na+–Cl cotransporter (NCCT). Most patients are only diagnosed in adulthood, based on easy fatigability, exhaustion, low performance capability, dizziness, tingling in the fingers and muscle cramps. Due to the autosomally recessive inheritance, patients have a sister or a brother with the same syndrome (see also Tab. 8.7-2 – Diseases and conditions associated with hypokalemia).

Laboratory findings: K+ in the plasma around 2.4 mmol/L, Mg2+ around 0.55 mmol/L, Cl low-normal.

Liddle syndrome**

Autosomal dominant disease with hypertonia, hypokalemic metabolic alkalosis and hyporeninemic hypoaldosteronism. The activity of the Na+ transporters in the collecting ducts is increased due to gene mutations.

* Fanconi syndrome, the function of the proximal tubule is limited; ** Innate disorder of the loop of Henle and the distal tubule

Table 8.8-10 Renal potassium excretion in hyperkalemia


Clinical and laboratory findins

≥ 40 mmol/L

Normal K+ excretion in hyperkalemia is indicative of:

  • Increased K+ intake (e.g., with nourishment or salts such as potassium citrate, potassium gluconate, potassium phosphate and potassium penicillin)
  • Reduced shift of K+ in the intracellular compartment in insulin deficiency, beta adrenergic blockers, digitalis.
  • Increased shift of K+ in the extracellular fluid due to tissue destruction (e.g. hemolysis) but also due to metabolic acidosis or the infusion of hypertonic solutions.

< 40 mmol/L

The reduced K+ excretion in hyperkalemia suggests a renal cause (e.g., hypo- or pseudohypoaldosteronism.

Table 8.8-11 Hypokaliuric hyperkalemias /1112/

Clinical and laboratory findings

Pseudohypoaldosteronism type 1

Rare childhood disease with renal losses of salt, low blood pressure and increase of renin and aldosterone.

Type 1a: autosomal recessive form, which is caused by the inactivation of amiloride-sensitive Na+ channels (ENaC) of the distal tubules and of the collecting ducts (Fig. 8.8-2 – Reabsorption of solutes in the collecting duct).

Type 1b: autosomal dominant form, which is caused by the resistance of the renal mineralocorticoid receptor for its ligands (aldosterone) (Fig. 8.8-2). This form is clinically milder than type 1a.

Pseudohypoaldosteronism type 2

This disorder, also called Gordon syndrome, is an autosomal dominant disease and clinically evident in newborn infants or during adolescence. There is mild hyperkalemic metabolic acidosis and hypertonia. Pathogenetically due to an activated modification of the Na+and Cl cotransporter there is a distal tubular increase of Cl reabsorption (Fig. 8.8-3 – Maintaining the acid-base homeostasis in the proximal tubule).

hyperthyreotoxic periodic paralysis (HTPP)

The HTPP is one of the most common basic reasons of hypokalemia, and hypokalemic paralysis, especially when a large carbohydrate intake following exercise. HTTP is regarded as a rare channelopathy occurring in about 2% of patients with hyperthyroidism. HTTP is due to an imbalance of cellular K+ efflux and influx (i.e. Na+/K+-ATPase) with the imbalance favouring an increased influx via increased Na+/K+-ATPase activity /47/. The effect of insulin and TSH act synergistically in stimulating Na+/K+-ATPase.

Figure 8.1-1 Physiology of the water and volume homeostasis in cases of dehydration. Courtesy of Ref. /4/. Reduction of the body water leads to an increase of osmolality, which is registered by osmoreceptors of the hypothalamus. The sense of thirst and increased secretion of ADH are activated via neural stimuli. The effects are an increased fluid intake and a reduction of the renal water excretion (antidiuresis).

Dehydration Hyperosmolality Increased total body water Return of plasma osmolality to normal physiological range Activation of hypothalamic osmoreceptors Higher centres Supraoptic and para-ventricular nuclei Thirst Neurohypophyseal AVP secretion Fluid intake Antidiuresis

Figure 8.1-2 Renal-tubular handling of water and electrolytes. Courtesy of Ref. /5/. The bright arrows represent water and the dark ones represent electrolytes.

1) After filtration, water and electrolytes are isotonically reabsorbed in the proximal tubulus.

2) In the descending limb of the Henle’s loop, water is reabsorbed and an osmotic equilibrium with the interstitium is achieved. The osmolalities in the interstitium are expressed between ascending and descending Henle’s loop.

3a+b) In the diluting segments, electrolyte-free water is formed by selective absorption of electrolytes.

4a) In the absence of arginine-vasopressin, the collecting ducts remain relatively water-tight and diluted urine is excreted.

4b) If arginine-vasopressin is secreted, water is reabsorbed and concentrated urine is excreted.

300 600 9001200 2 1 3b 3a 4a 4b

Figure 8.1-3 Formation of electrolyte-free water by the kidney. If 2 liters of isotonic saline solution is infused, there is a reason to excrete 300 mmol Na+ in the urine. To accomplish this, the secretion of ADH is activated, 1 liter of free water is produced, and the 300 mmol/L Na+ are excreted with 1 liter of urine /7/.

2 litres 150 mmol/L Infused Urine Body 1 litres 300 mmol/L 1 litres 0 mmol/L ADH-stimulated reabsorption of water

Figure 8.1-4 Renal-tubular treatment of K+. Courtesy of Ref. /12/.

K + reabsorption 15–20% K + reabsorption 70–80% K + secretion K + secretion Proximaltubule Distaltubule Collecting tubule Urinary excretion90 mmol/24 h Filtered load600–700 mmol/24 h Early Middle Late

Figure 8.1-5 Mechanism of thiazide diuretics. Courtesy of Ref. /13/. Thiazides inhibit a cotransport protein of the Na+ transporter in the luminal cell membrane of the distal convoluted tubule.

Lumen Thiazide Cell Blood Na Cl Na K K ATP

Figure 8.1-6 The effect of medicines on the tubular cells of the distal nephron. Courtesy of Ref. /14/. Amiloride, triamterene, trimethoprim and pentamidine suppress the formation of Na+ channels of the luminal cell membrane. Digoxin, cyclosporin and tacrolimus reduce the activity of the Na+-K+-ATPase, while cyclosporin and non-steroidal anti-inflammatory drugs (NSAID) interfere with the functioning of the K+ channel of the luminal cell membrane.

Lumen Principal cell Blood ATPase 3 Na + 2 K + Na + K + (–)

Figure 8.1-7 Mechanism of the aldosterone-dependent K+ secretion and its suppression. Courtesy of Ref. /15/. Trans cellular Na+ transport from the lumen to the peri tubular space is stimulated by the insertion of Na+ channels into the luminal cell membrane and activation of Na+-K+-ATPase. A negative trans epithelial potential difference develops in the tubular lumen. In this way, the shift of K+ in the tubular lumen, in exchange for Na+, is encouraged. Heparin and spironolactone competitively inhibit the binding of aldosterone to its receptor. Non-steroidal anti-inflammatory drugs, angiotensin converting enzyme (ACE) inhibitors and angiotensin II receptor blockers reduce the synthesis of aldosterone, its stimulation of the Na+-K+-ATPase, and the Na+ channels.

Na+ Cell Aldosterone Renin Angiotensin I Beta blockers Heparin Converting enzyme inhibitors Angiotensin II Aldosterone 2 K + 3 Na + + K + ATP Angiotensin II-receptor antagonists Spironolactone Peritubular Lumen Nonsteroidal antiphlogistics Ciclosporin A

Figure 8.2-1 Ion-selective electrode unit for the determination of, for example, Na+. The electrochemical cell consists of the ion-selective electrode (inner electrode) and an outer reference electrode. Both electrodes are in contact with the test solution: the inner electrode via the inner electrolyte, the outer electrode via the bridge solution (concentrated KCl). The cell can be described as follows: Hg|HgCl2|KCl conc.||test solution|membrane|inner reference electrode solution|Ag|AgCl.

Liquidjunction Waste Sample Bridge solution KCI conc. Electrochemical cell Pump Inner electrolyte Membrane Innerreference electrode(Ag/AgCl) Outer reference electrode (Hg/HgCI 2 ) Pump

Figure 8.2-2 Differential diagnosis of hyponatremia, modified according to Ref. /19/. ECFV, extracellular fluid volume; TB, total body; RTA, renal-tubular acidosis; SIADH, syndrome of inappropriate antidiuretic hormone; U-sodium, sodium concentration in the random urine sample; , increased; , decreased

(Edema) Hyponatremia Greater ↓ in TB sodium than in TB water TB water ↑ Greater ↑ in TB waterthan TB sodium Renal lossDiuretic abuse,mineralocorticoid-deficiency, salt-losing-nephritis (RTA,metabolic alkalosis)osmotic diuresis Extrarenal lossVomiting diarrhea,burns, pancreatitis,acute severemuscle damage Glucocorticoid deficiencyhypothyroidism, pain,stress, emotion,drugs, SIADH Nephrotic syndrome,liver cirrhosis,cardiac failure Acute and chronicrenal failure Cause U-sodium > 20 mmol/L > 20 mmol/L > 20 mmol/L ECFV < 20 mmol/L < 20 mmol/L Moderate (no edema)

Figure 8.2-3 Differential diagnosis of hypernatremia, modified according to Ref. /19/. TB, total body; U-sodium, sodium concentration in the random urine sample; U-osmolality, osmolality in the random urine sample. Osmolality values in mmol/kg.

Hypernatremia Sodium intake C Renal lossOsmotic diuresis,mannitol, glucose,urea Extrarenal loss,Excessivesweating,diarrhea inchildren Renal loss,Diabetes insipidus(nephrogenic, central)hypodipsia, partialdiabetes insipidus Extrarenal loss,Respiratoryand dermalinsensiblelosses a Primary Hyperaldosteronism,Cushing’s syndrome, HypertonicDialysis, Hypertonic sodiumbicarbonate, sodium chloridetablets u s e U-osmolality Isotonic or Hypotonic Hypertonic Hypotonic, Isotonicor Hypertonic Hypertonic Isotonic or Hypertonic U-sodium > 20 mmol/L <10 mmol/L Variable Variable > 20 mmol/L TB-sodium Decreased Normal Increased Sodium +H 2 O losses H 2 O losses

Figure 8.6-1 Relationship between osmolality and arginine vasopressin (AVP) concentration in plasma (top) and AVP in plasma and osmolality in urine (bottom). Modified according to Ref. /5/.

1400 1200 1000 800 600 400 200 0 0 1 10 15 Urine osmolality (mosmol/kg H 2 O) Plasma AVP (ng/L) Plasma AVP (ng/L) 12 8 4 0 270 280 290 300 310 Plasma osmolality (mosmol/kg H 2 O) 2 3 4 5

Figure 8.6-2 Relation of blood volume, osmolality and AVP concentration. Courtesy of Ref. /9/. In cases of hypovolemia or hypotension, the arginine vasopressin (AVP) concentration increases. In cases of hypervolemia and hypertension, it decreases. The numbers in the circles express the percentage of increase or decrease of the plasma volume.

Hypovolemiaor hypertension 260 270 280 290 300 310 320 330 340 –20 –15 –10 +10 +15 +20 N Plasma osmolality (mmol/kg) Hypervolemiaor hypertension AVP in Plasma (ng/l) 1086420

Figure 8.6-3 Diseases and syndromes with disturbed relationship between plasma osmolality and AVP secretion. Modified according to Ref. /10/.

Arginine-Vasopressin (ng/L) Osmolality in plasma (mmol/kg) 50 Diabetes insipiduscentralis SIADH(Schwartz-Bartter- syndrome) 30 10 8 6 4 2 240 250 260 270 280 290 300 310 320 Normal range Diabetes insipidus renalis

Figure 8.6-4 Relationship between osmolality and AVP in cases of diabetes insipidus (DI).

Top: relationship of plasma osmolality and AVP concentration in the osmotic stimulation test (Tab. 8.6-6 – Osmotic stimulation test).

Bottom: relationship of AVP concentration in plasma and osmolality in urine during the standard fluid deprivation test (Tab. 8.6-5 – Interpretation of the standard fluid deprivation test in combination with the DDAVP sensitivity for the diagnosis of diabetes insipidus (DI)).

Description of symbols:  HDI, hypothalamic DI;  NDI, nephrogenic DI;  DDI, dipsogenic DI; LD, limit of detection. Courtesy of Ref. /10/.

AVP in plasma (pmol/l) Osmolality in plasma (mmol/kg) Osmolality in urine (mmol/kg) AVP in plasma (pmol/L) 20 15 10 5 0.3 (LD) HDI DDI NDI 280 300 320 s s s s s s s 1,200 800 400 0 0.3 (LD ) 2 4 6

Figure 8.6-5 Primary structure of vasopressin and its analogues /2/. Human vasopressin contains the amino acid arginine in position 8, hence the name Arginin-Vasopressin (AVP) for this antidiuretic hormone. DDAVP, desamino D-arginine-vasopressin. Asn, asparagine; Cy, cysteine; Glu, glutamine; Leu, leucine; Ile,isoleucine; Phe, phenylalanine; Pro, proline; Tyr, tyrosine; Val, valine. DDAVP = Desamino D-Arginine-Vasopressine.

NH 2 NH 2 Tyr Cy T yr 2 Cy 1 Tyr Cy Ile S Phe 3 S Phe S Gln S Gln 4 S Gln S Asn Cy Asn 5 Cy 6 Asn Cy Pro P ro 7 Pro Leu Arg 8 D-Arg Gly Gly 9 Gly NH 2 NH 2 NH 2 Oxytocin Vasopressin DDAVP

Figure 8.6-6 Effect of AVP for increasing the water permeability in the renal collecting duct cells. AVP is bound to the V2 receptor of the basolateral membrane. The adenylate cyclase is activated via various signaling steps (Gas), which increases the cyclic AMP (cAMP). The latter stimulates the pyruvate kinase A (PKA), which initiates the last step of the AVP effect, namely the exocytic incorporation of the specific water channels (AQP2) into the luminal cell membrane. The AQP2s are carried by cytoplasmic vesicles and microtubuli and actin filaments are required to guide the vesicles to the luminal cell membrane. The AQP2s are exclusively localized in the collecting duct cells of the inner medulla. AQP3 and AQP4 water canals transport water through the basolateral membrane into the interstitium of the kidneys. In cases of AVP deficiency, the AQP2s are recycled through endocytosis and the water reabsorption is maintained at a low level. Syntaxin 4 is a guanosine triphosphate-binding protein. Courtesy of Ref. /15/.

+ + Syntaxin 4 AQP2 H 2 O Actin-filament motor AQP2 Actin filament Microtubule Microtubulemotor GI PKA cAMP ATP G as G as VAMP2 Endocyticretrieval GI Recyclingvesicle AQP3 AVP V 2 receptor Adenylyl cyclase Luminal Basolateral AQP4 ExozyticInsertion +

Figure 8.8-1 Pathways of Na+, K+, Mg++ and Ca++ reabsorption in the thick ascending limb of the loop of Henle. Courtesy of Ref. /2/. Na+ and Cl are reabsorbed by the apical NKCC2 transporter. This electroneutral transport is driven by the low intracellular Na+ and Cl concentrations generated by the basolateral Na+-K+-ATPase and the basolateral Cl channel CLC-Kb. The availability of K+ is rate-limiting for NKCC2, so entering the cell K+ is recycled back to the lumen via the ROMK1 K+ channel. The K+ movement is electrogenic and drives para cellular resorption of Mg2+ and Ca2+ via paracellin-1. Mutations either in NKCC2, ROMK1 or CLC-Kb cause Bartter’s syndrome. Mutations in paracellin-1 lead to disruption of this paracellular pathway and the tubular disease known as hypomagnesemic hypercalcuric nephrolithiasis.

Tight junction K + Cl Basolateral Apical Cl Na + 2 Cl K + Mg 2+ Ca 2+ 2 K + 3 Na + NKCC2 ROMK1 Paracellin-1 ATP CLC-Kb

Figure 8.8-2 Reabsorption of solutes in the collecting duct. Courtesy of Ref. /2/. Na+ reabsorption occurs through the amiloride-sensitive epithelial Na+ channel (ENaC). This is influenced by the actions of aldosterone via the mineralocorticoid receptor (MR). In hyperaldosteronism ENaC is activated. Cortisol can also bind to the MR and transmit aldosterone-like effect, but the enzyme 11β-hydroxy steroid dehydrogenase (11β-HSD) transforms cortisol to cortisone which has no effect on the MR. The Na+ uptake drives the K+ secretion from principle cells and the H+ secretion from α-intercalated cells.

 The following disorders are known:

– Liddle syndrome; mutations cause increased activity of ENaC with increased Na+ reabsorption and loss of K+ and H+

– Pseudo hypo aldosteronism type Ia; loss of function mutations inactivate ENaC

– Pseudo hypo aldosteronism type Ib; MR abnormalities. Both types of pseudo hypo aldosteronism lead to reduced Na+ entry via ENAC, causing salt wasting and reduced secretion of K+ and H+.

– Licorice abuse inhibits the 11β-HSD, allowing cortisol to act as mineralocorticoid and causes high blood pressure and hypokalemic metabolic alkalosis.

Basolateral Apical Na + Na + 11β-HSD + MR 2 K + 3 Na + ENaC K + K + H + Principal cell Aldosterone Cortisol α-intercalated cell ATP ATP

Figure 8.8-3 Acid-base homeostasis in the proximal convoluted tubule and model of HCO3reabsorption. The processes occurring are H+ secretion at the luminal membrane via the specific Na+-H+ exchanger (NHE-3) and the HCO3 transport at the basolateral membrane via the 1Na–3HCO3 cotransporter (NBC-1). Cytoplasmic carbonic anhydrases (CA) II and membrane-bound carbonic anhydrase IV are necessary to reabsorb HCO3. The reabsorption of Cl- is mediated via the NBC-1. Modified according to Ref. /13/.

2 K + ATP K + 3 Na + 3 HCO 3 NBC-1 NHA-3 CA II Na H + HCO 3 H 2 CO 3 H 2 CO 3 CO 2 CO 2 H 2 O H 2 O Lumen Blood Na + Cl + H 2 O Na +

Figure 8.8-4 The secretion of H+ in cortical collecting tubule. The main pump for luminal H+ secretion in the α-type intercalated cell is a vacuolar H+-ATPase. A H+- K+-ATPase is also involved in H+ secretion. Intracellularly formed HCO3 leaves the cell via the Cl--HCO3 exchanger (AE1). Cytoplasmic carbonic anhydrase II (CAII) is required to secrete H+. Modified according to Ref. /13/.

CO 2 H 2 O 2 K + ATP K + 3 Na + AE1 H + -ATPase CA II HPO 4 2– NH 3 H 2 PO 4 1– Lumen + α-intercalated cell ATP ATP H + K + -ATPase Cl Cl H 2 CO 3 H + H + HCO 3 K + K + NH 4 + Blood

Figure 8.8-5 Diagnostic work-up for patients with hyperchloremic metabolic acidosis and negative urinary anion gap. Acid loading means ammonium chloride loading test. GI, gastrointestinal; UpH, urine pH; FEHCO3, fractional excretion of HCO3; U-B PCO2, difference of PCO2 urine to blood. Modified according to Ref. /13/.

Negative urine anion gap (Cl  > Na +  + K + ) GI HCO 3 loss (Anamnesis Urinary Na + ) Proximal RTA? Acid load U p H < 5.5 Sodium bicarbonate load FE HCO 3  > 10–15% U-B PCO 2  > 20 mmHg Proximal RTA Look for other tubular defects HCL intake(Anamnesis)

Figure 8.8-6 Diagnostic work-up for patients with hyperchloremic metabolic acidosis and positive urinary anion gap. Acid loading means ammonium chloride loading test. UpH, urine pH; FEHCO3, fractional excretion of bicarbonate; U-B PCO2, difference of PCO2 urine to blood. Modified according to Ref. /13/.

Positive urine anion gap (Cl  < Na +  + K + ) Distal renal defect Plasma K + Normal, Acid load Increased U-B PCO 2 < 20 mm Hg > 5.5 U p H > 5.5 < 5.5 Sodium bicarbonate load < 20 mm Hg ≥ 20 mm Hg Hyperkalemicdistal RTA Distal RTA Type 4-RTA Voltage-dependentdefect secretorydefect Look for sodiumtransport defect Look fornephrocalcinosis Look for aldosteronedeficiency and chronicrenal desease
Goto top <