Hippokratia 2012, 16, 4: 294-302
Eleftheriadis T1, Leivaditis K2, Antoniadi G1, Liakopoulos V2
1 Department of Nephrology, Medical School, University of Thessaly, Larissa, 2 Department of Nephrology, Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece
Hyperkalemia is a relative common and sometimes life threatening electorlyte disorder. Although its symptomatic treatment is relatively easy, since precise therapeutic algorithms are available, its differential diagnosis is more complicated. The present review aims to unfold the differential diagnosis of hypekalemia using a pathophysiological, albeit clinically useful, approach. The basic elements of potassium homeostasis are provided, the causes of hyperkalemia are categorized and analysed and finally the required for the diferrential diagnosis laboratory tests are mentioned.
Keywords: hyperkalemia, potassium homeostasis, potassium intake, pottasium shift, potassium excresion
Hyperkalemia is a relative common and sometimes life threatening electorlyte disorder1,2. Although its symptomatic treatment is relatively easy, since precise therapeutic algorithms are available3, its differential diagnosis is more complicated. The present review aims to unfold the differential diagnosis of hypekalemia using a pathophysiological, albeit clinically useful, approach.
Diagnosis of hyperkalemia requires plasma potassium (K+) concentration more than 5mEq /L or serum K+ concentration greater than 5.5mEq /L.
However, in rare cases, serum or plasma potassium elevation is factitious due to cell release within the sample tube. Causes of pseudohyperkalemia include errors during venipuncture that lead to hemolysis including sustained tourniquet application, use of thin needles, bad sample handling or systems of pneumatic tube transport4. Besides hemolysis, pseudohyperkalemia can be seen in polycytaemia as well as with WBC>100000/mm3 or platelet count >1000000/mm3, although there is a discrepancy concerning the role of white blood cell count5,6. Furthermore, familial pseudohyperkalemia is a rare disease in which potassium is released by red blood cells in the test tube because of a disorder in the permeability of the erythrocyte membrane7.
2. Potassium homeostasis
Potassium is the major intracellular cation with concentrations reaching 120-150 mEq/L. On the contrary, the extracellular fluid potassium concentration is much lower and kept within very narrow levels between 3.5-5.0 mEq/L. The above difference is attributed to Na+-K+-ATPase, a pump which is located in almost all cells and moves 3 sodium ions out of the cell and 2 potassium ions inside the cell. This K+ concentration gradient across the membrane is mainly responsible for the resting potential of the cellular plasma membrane. Maintaining this potential is of cardinal importance for the function of muscular and neuronal tissue 8-10 (Figure 1).
Figure 1: Potassium, through its role in resting and action membrane potential, is of cardinal importance for the function of excitable tissues.
Prevention of fatal hyperkalemia after a rich meal is attributed to postprandial secretion of insulin which moves K+ inside the cell. Insulin is secreted as a response to postprandial elevation of blood glucose (and blood K+) and increases Na+-K+- ATPase activity8,11. Urine K+ excretion is also increased postprandially as discussed later. During physical exercise, catecholamines act in the same way in order to regulate K+ homeostasis8,12,13.
Typical Western diet provides 50-100mEq of K+ per day. 90% is secreted in the urine, 5-10% is excreted by the gut and 1-10% through the skin. Potassium absorption by the small intestine is not subjected to any regulation. Although potassium secretion by colonic epithelial cells is greatly increased in cases of hyperkalemia, up to three times in patients with end stage renal disease, this effect has a minor impact in K+ balance. Given the fact that aldosterone promotes intestinal K+ excretion, a study in dialysis patients was designed. 0.1 mg of fludrocortisone was daily administered for three months in these patients but no alterations in serum K+ concentrations were observed14. Currently, big K+ channels, also called maxi K+ channels, in the colonic crypts are considered to be involved in intestinal K+ excretion. These channels are upregulated in chronic hyperkalemia15.
Distal nephron is mainly involved in the regulation of K+ homeostasis. K+ is freely filtered in the glomerulus and is mainly reabsorbed in the proximal tubule and the thick ascending limb of Henle’s loop. Proximal reabsorption is passive, while in Henle’s loop, the Na+-K+-2Cl- cotransporter (NKCC2) is required. Approximately 10% of the filtered load reaches the distal nephron. K+ excretion which takes place in the early distal nephron and the cortical collecting duct (CCD) is subject to strict regulation. The principal cells which are responsible for this process, mediate K+ excretion via Na+-K+- ATPase in their basal membrane. This pump creates a concentration gradient which promotes both K+ secretion from the principal cell to the tubule and Na+ reabsorption via certain channels (Figure 2). K+ concentration gradient between the principal cell and the tubular lumen, electric potential gradient between cell and lumen and luminal membrane permeability to potassium are the major forces regulating K+ excretion by the principal cells. These forces are mostly affected by Mineralocorticoids and distal sodium and water delivery16-19.
Figure 2: The principal cells and the potassium excretion in the cortical collecting duct.
Aldosterone is secreted by the zona glomerulosa of the adrenal glands, is bound to its intracellular receptor in the principal cells and increases K+ excretion by 3 ways: 1. it increases the likelihood of epithelial sodium channels (ENaC) to be open to the luminal side while it inhibits their degradation by proteasomes. In this way, sodium reabsorption is increased, luminal electronegativity is increased and therefore, potassium secretion is enhanced, 2. it promotes Na+-K+-ATPase activity in the basal side and therefore increases intracellular potassium concentration and enhances K+ secretion to the lumen, and 3. it increases luminal membrane permeability to K+ 16-19.
Sodium and water supply to the distal nephron plays an important role in K+ excretion. Increased distal Na and water delivery enhances K+ excretion by creating a favorable electric potential and concentration gradient respectively.
Two types of channels for K+ excretion have been identified in the principal cells. Renal Outer Medullary Potassium channels (ROMK) and the big K+ channels, also called maxi K+ channels. The former are activated under typical physiological conditions while the latter in cases of increased sodium and water delivery which via mechanical pressure results in elevation of intracellular calcium in the principal cells16-19. Mechanical pressure mediated by increased sodium and water delivery also results in increased ENaC action and Na+ reabsorption20.
It has been demonstrated that a diet rich in K+ promotes kaliuresis and this effect is independent of Mineralocorticoids action. In this case, increased kaliuresis is attributed to movement of ROMK and maxi K+ channels to the luminal side of the principal cells’ membrane. These changes are associated with the action of WNK (with-no-lysine kinases) kinases family. WNK1 kinase is expressed in many tissues but a smaller fraction is solely expressed in the kidney [kidney specific (KS)-WNK1]. Under normal circumstances, 85% of this kinase is found as KS-WNK121. K+ rich diets increase the KS-WNK1 to WNK1 ratio,and KS-WNK1, by counteracting WNK1 actions, inhibits ROMK endocytosis resulting in increased K+ excretion. Furthermore, KS-WNK1 promotes ENaC activity and sodium reabsorption thus creating an electrochemical gradient which favors K+ excretion22-24.
3. Differential diagnosis
A carefully obtained, detailed history is mandatory for the differential diagnosis of hyperkalemia. Diagnostic thought should be guided towards the three main causes of hyperkalemia: increased K+ intake, K+ release from cells and impaired renal K+ excretion.
3.1 Excessive potassium intake
Under circumstances of intact kidney function, renal K+ excretion is normal. Thus increased K+ uptake does not cause significant problems. Otherwise, when kidney function is impaired, consumption of foods rich in K+ can lead to life threatening hyperkalemia. This cause accounts for most cases of hyperkalemia in patients with end stage renal disease. Additional dietary sources of K+ include commercially available salt substitutes and K+ enriched foods which are reported to have a beneficial effect on blood pressure control and cardiovascular morbidity25-27.
Individuals with normal K+ excretion require an extremely high amount (>160mEq) of orally administered potassium in order to develop dangerous hyperkalemia28. Besides common sources of K+, coconut juice and noni contain high amounts of K+29,30. Certain types of pica disorders like geophagia31 or cautopyreiophagia32 can also lead to increased K+ intake. In case of neonates, serious hyperkalemia can be induced accidentally due to salt substitute ingestion33 or iatrogenically by intravenous administration of penicillin or blood transfusions34. In stored blood, K+ is gradually released by the red blood cells and after 3 weeks, its concentration can reach 30mEq/L in total blood or 90mEq/L in packed RBCs. It is therefore preferable to use fresh or almost fresh blood (<5 days) whenever massive transfusions are required35, 36.
3.2 Potassium release from cells
3.2.1 Potassium release due to cells lysis
K+ shift from intracellular to extracellular space is a common cause of acute hyperkalemia. It can be secondary to tissue damage as in tumor lysis syndrome (associated or not with chemotherapy), acute intravascular hemolysis due to infection, transfusion reactions, severe hemolytic anemia, hemolysis within large hematomas, extended burns, rhabdomyolysis, ischemic colonic necrosis or hypothermia37-41. In these cases, serum biochemistry can be helpful in identifying the cause e.g. elevated serum urate and phosphate in tumor lysis syndrome, increased serum creatine phosphokinase (CPK) in rhabdomyolysis or high levels of serum lactate dehydrogenase (LDH) in cases of hemolysis.
3.2.2. Potassium release with intact cell plasma membrane
However, increased K+ shift out of cells can be promoted even if the cell membrane is intact. Use of drugs that inhibit Na+-K+-ATPase is an example. Beta adrenergic receptor blockers promote K+ shift out of cells which is usually less than 0.5mEq/L. If K+ balance is disrupted, severe hyperkalemia may occur. In these cases, selective β1 adrenergic receptor blockers like atenolol should be preferred42-45. Usual dose of digitalis also results in Na+-K+-ATPase inhibition in a dose dependent way but severe hyperkalemia is developed, in cases of digitalis toxicity46,47. Succinylcholine, a paralytic drug, acts as a depolarizing agent. Cell membrane depolarization makes the inner cell less electronegative, a fact that enhances K+ shift out of the cell. In healthy individuals, K+ rise is less than 0.5mEq/L but it is much higher in patients with kidney failure, neuromuscular disease, extended burns or tetanus48, 49.
Physical exercise may also cause K+ shift possibly due to a delay between rapid K+ shift out of muscle cells (during repolarization) and K+ reuptake by Na+-K+-ATPase (Figure 1). In rigorous exercise, ATP consumption enhances the opening of extra ATP dependent K+ channels and therefore promotes additional K+ shift out of cells12,13. Local tissue K+ induces a desirable vasodilatation but K+ concentration is also increased in systemic circulation up to 2 mEq/L and returns to normal levels after a few minutes50. Although intense exercise induced hyperkalemia is well tolerated, concomitant underlying conditions which affect K+ homeostasis like exhausting exercise induced rhabdomyolysis or use of beta blockers can contribute to the development of life threatening hyperkalemia51-53.
Metabolic acidosis can move K+ to the extracellular space so that cell membrane electric voltage is maintained after H+ cations enter the cell. For this to occur, acid load should be derived from a non organic acid. Experimentally, intravenous HCl administration results in a rise in serum K+ but this is not the case when lactic acid is administered. This is because chloride (Cl-), the main extracellular anion, enters cells in a limited degree, a fact that results in less electronegativity in the internal of the cells due to H+ entry and therefore promotes K+ shift out of cells. K+ concentration rises by 0.2 to 1.7 mEq/L for every 0.1 fall in arterial pH. On the contrary, intrinsic monocarboxylic organic acids like lactic acid or β-hydroxy-butyrate follow H+ entry into cells thanks to the presence of the monocarboxylic acid transporter in the cell membrane. Stimulation of insulin production by monocarboxylic acids which is accompanied by Na+-K+-ATPase activation and K+ entry into cells could be another potential explanation. As exogenous non monocarboxylic acids like citric acid are unable to enter cells and reduce plasma bicarbonates, they cause acidosis. This leads to bicarbonate shift out of cells in exchange with Cl- via the appropriate cotransporter. However, Cl- moves out from cells via Cl- channels, so cells become less electronegative and K+ excretion is enhanced54-57. Hyperkalemia observed in cases of acidosis by endogenous organic acids seems to develop from other causes. For example, hyperkalemia in lactic acidosis seems to be secondary to ischemic tissue necrosis and compromised kidney function. In diabetic ketoacidosis, insulin deficiency, hyperglycemia and decreased renal perfusion seem to be involved in the pathogenesis of hyperkalemia. Non organic acid induced hyperkalemia is caused in cases of administration of HCl precursor substances like arginine chloride salts used in the treatment of metabolic alkalosis58. In hemodialysis patients, administration of sevelamer hydrochloride for the management of hyperphosphatemia leads to mild acidosis by non-organic acid since for every bound molecule of phosphate, one molecule of HCl is released. This last case can be easily managed by raising dialysate bicarbonate concentration to 40 mEq/L59.
Hyperkalemia due to K+ shift from cells is encountered in patients with diabetic ketoacidosis or severe hyperglycemia without ketoacidosis. Despite the fact that, in these patients, total body K+ is reduced, insulin deficiency is the cause of hyperkalemia11,60,61. Additionally, hyperglycemia induced hyperosmolality promotes K+ shift out of cells. This is mostly because water movement out of cells causes a rise in intracellular K+ concentration which promotes K+ movement to the extracellular space via K+ channels. In addition, water shift via water channels also drifts K+ out of the cells. In general, for every 10 mosm/kg rise in plasma osmolality, K+ concentration increases by 0.3-0.8 mEq/L62. This is the reason why mannitol administration or other hypertonic solutions can cause hyperkalemia63. Life threatening hyperkalemia can also be documented in diabetic hemodialysis patients with poor blood glucose control64.
Finally, the syndrome of hyperkalemic periodic paralysis is an autosomal dominant disorder and is caused by a mutation in the gene encoding a specific alpha-subunit of a special population of sodium channels found in skeletal muscles. Under normal circumstances, during muscle contraction, sodium channels are closed when action potential reaches 50mV (Figure 1). In patients with hyperkalemic periodic paralysis these channels do not close adequately and create a less electronegative internal cell environment which promotes K+ exit from cells. A history of episodes of muscle weakness or paralysis with increased K+ concentration that last for 1-2 hours raise suspicion of this syndrome. The diagnosis is set by reproducing muscle weakness and hyperkalemia after a meal containing 0.5-1 mEq/kg of K+. Symptoms can also be exacerbated in response to a cold stimulus or exercise. Beta adrenergic agonists, like albuterol can be used in the management of acute episodes. Several measures are recommended for the prevention of acute episodes including refrain from physical exercise, meals rich in carbohydrates and poor in K+, thiazide diuretics and alatocorticoid administration (which cause mild potassium deficiency). Acetazolamide can be also helpful possibly by increasing renal K+ excretion65-68.
4. Impaired renal potassium excretion
Patient’s history helps to diagnose decreased K+ excretion but sometimes additional evaluation is required. The transtubular potassium gradient (TTKG) which is estimated by the formula TTKG = [Ku :(Uosm / Sosm)]:Ks expresses the magnitude of K+ concentration in the excreted urine (higher) compared with the concentration in the early CCD (lower) due to K+ excretion. To eliminate the effect of water reabsorption across the collecting duct, urine K+ (Ku) is divided by the urine to serum osmolality ratio (Uosm/Sosm). This approach is based on the assumption that besides water, no significant electrolyte or urea transport takes place in the medullary collecting duct. Furthermore, urine osmolality should be equal or higher than serum and urine Na+ should be more than 25mEq/L so that adequate sodium is delivered to the CCD. Normal TTKG values are 8-9 but it can be over 11 in cases of increased K+ intake. In patients with chronic hyperkalemia, TTKG values less than 5 are indicative of impaired renal K+ excretion69,70. Alternatively, it has been proposed that in an urine spot from a hyperkalemic patient a ratio of urine K+ to urine creatinine less than 200mEq K+/gr creatinine indicates a renal defect in K+ excretion71.
Potassium excretion by the kidneys is disturbed in three cases. Renal failure, effective plasma volume reduction and impaired aldosterone action. The latter can be either due to decreased production or CCD resistance to its action.
4.1 Hyperkalemia due to renal failure
Differential diagnosis of hyperkalemia requires serum creatinine and glomerular filtration rate (GFR) evaluation. In acute kidney injury, rapid decline of GFR leads to decreased Na+ and water delivery to the CCD and therefore reduced K+ excretion. This can explain the observation that hyperkalemia is associated with oligoanuric forms of acute kidney injury rather than non oliguric. In chronic kidney disease (CKD), the ability of each nephron to excrete K+ is increased under the influence of aldosterone and upregulated Na+-K+-ATPase activity72-75. As kidney function worsens and urine output is reduced, decreased Na+ and water is delivered to the CCD and hyperkalemia ensues76. If, after the administration of a K+ load, the renal K+ excretion (urine [K+] x urine volume) is divided by the GFR, the result will be the same in the absence or presence of CKD, a fact that implies that K+ retention is due to nephron loss and not to the impaired excretory ability of the residual nephrons73. For this to occur, GFR must fall below 20ml/min. In cases of hyperkalemia in patients with mild or moderate kidney disease, other additional causes should be sought. Additionally, in patients with CKD, K+ entry into cells is reduced since intracellular K+ concentration is lower (in the presence of normokalemia or hyperkalemia) and also, cellular K+ uptake is decreased after K+ administration77,78. Several mechanisms have been proposed to explain the latter observation, including reduced Na+-K+-ATPase activity in skeletal muscles, insulin resistance and metabolic acidosis79-81.
4.2 Hyperkalemia due to reduced effective plasma volume
As discussed earlier, renal K+ excretion depends on Na+ and water delivery to the CCD. If it is decreased, K+ excretion is impaired even in the presence of normal or high aldosterone levels as observed in cases of reduced effective plasma volume. Measurement of aldosterone levels can be helpful in difficult diagnostic cases of hyperkalemia. Reduction in effective plasma volume can occur in hypovolemia but also in hypervolemia, for a variety of reasons including liver or heart failure, third space plasma losses, renal, skin or gastrointestinal fluid losses. Usually, the lost fluids are rich in K+ but the decreased plasma volume impairs renal K+ excretion. Additional factors are required for hyperkalemia to develop in such cases including frequent hypotension per se and subsequent sympathetic activation which-via afferent vasoconstriction-reduce GFR, as well as renin-angiotensin-aldosterone system activation which results in angiotensin II induced proximal Na+ reabsorption82-85.
4.3 Hyperkalemia due to decreased aldosterone action
Another cause of hyperkalemia due to defective K+ excretion is impaired aldosterone action which can be either due to decreased synthesis or due to resistance to aldosterone action secondary to CCD dysfunction. Evaluation of plasma renin and aldosterone levels is required for a correct diagnosis. Renin levels are measured by two methods. If plasma renin activity is estimated, plasma is incubated at 370C so that plasma angiotensinogen is converted by renin to angiotensin I. The latter is measured by radioimmunoassay (RIA) and plasma renin activity is equivalent to the amount of angiotensin I produced after 90 minutes of incubation. Normal values are 1-4 ng/ml/h86-88. Plasma active renin can also be measured and normal values are between 8 and 35mU/L. However, it should not be preferred to plasma renin activity because plasma active renin levels change inversely to the concentration of the substrate. Estrogens for example, decrease plasma active renin since they increase angiotensinogen89. Renin levels are increased during sodium restriction and reduced in salt consumption. It is higher in the morning, increases during pregnancy and the luteinizing phase of the menstruation circle, in CKD and in postural position. Diuretics, angiotensin II type I receptor blockers and dihydropyridine calcium channel blockers increase renin levels. Non steroid anti inflammatory drugs (NSAIDs) via prostaglandin inhibition, beta adrenergic activity inhibitors including beta blockers, clonidine and methyldopa suppress renin levels90-92. Normal plasma aldosterone levels in the morning are 5-30mg/dl93. Aldosterone levels are elevated in the morning, during pregnancy (up to 10 times higher in the third trimester), in salt restriction and postural position92,94,95.
Besides hyperkalemia, various degree of Na+ loss and metabolic acidosis (type IV renal tubular acidosis) are seen in hypoaldosteronism, since aldosterone promotes salt and water retention and H+ secretion, both indirectly via Na+ reabsorption induced reduction of the lumen electronegativity and directly by H+-ATPase stimulation96, 97. Acidosis is partly secondary to hyperkalemia per se, given that correction of hyperkalemia also corrects metabolic acidosis98. It is possible that high tubular K+ concentration inhibits ammonium connection to the K+ segment of the Na-K-2Cl cotransporter in the thick ascending limb of Henle’s loop and therefore disturbs ammonium recycling and accumulation in the renal medullary interstitium and secretion in the medullary collecting duct99.
4.3.1 Hyperkalemia due to decreased stimuli for aldosterone production
Impaired aldosterone synthesis can be secondary to an inadequate stimulus for its production from the adrenal glands. Hyporeninemic hypoaldosteronism is such an example, most commonly encountered in elderly diabetics (50%) with mild to moderate kidney disease. It accounts for the 50-75% of cases of hyperkalemia of initially unknown cause. This syndrome is characterized by low plasma renin (85%), a fact that explains low aldosterone levels. The pathogenesis of this condition remains unclear and besides inadequate renin production, impaired adrenal response seems to be present because 15% of patients have normal plasma renin levels and angiotensin II infusion in these patients does not always result in aldosterone release100. For renin underproduction, decreased prostaglandin synthesis101, hypervolemia and subsequent natriuretic peptide production which directly suppresses renin and aldosterone secretion102,103, and the incomplete conversion of prorenin to renin due to a defect in juxtaglomerular cells104,105 have been suggested as potential causes. In hyporeninemic hypoaldosteronism, hyperkalemia is usually mild, unless another cause of hyperkalemia, such as concomitant use of angiotensin converting enzyme inhibitors, is also present106. Hypoaldosteronism due to impaired adrenal stimulation can also be induced by drugs. Aliskiren, a renin activity inhibitor used as an anti-hypertensive drug, has been associated with hyperkalemia107, 108. Angiotensin converting enzyme inhibitors (ACEi) also suppress aldosterone production by blocking the conversion of angiotensin I to angiotensin II108, 109. Similarly but in a receptor level, angiotensin II type I receptor blockers (ARBs) can cause hyperkalemia108,110. These anti-hypertensive drugs are generally well tolerated; however, extra caution is required in case of CKD for the likelihood of development of severe hyperkalemia. NSAIDs inhibit the production of prostaglandins which are necessary for renin release. Therefore , these agents can cause hyperkalemia by inhibition of the renin-angiotensin-aldosterone axis111. Finally, cyclosporine can also cause a mild, in most cases, hyperkalemia by suppressing renin activity112.
4.3.2 Hyperkalemia due to primary defect in aldosterone production
Besides the cases of impaired adrenal stimulation, decreased aldosterone levels and hyperkalemia can also be observed in adrenal diseases. Primary adrenal insufficiency or Addison’s disease is secondary to adrenal destruction by infections (meningitidococcal septicemia, tuberculosis, HIV), autoimmune diseases or coagulation disorders with intraadrenal hemorrhage and is characterized by both cortisol and aldosterone deficiency. On the contrary, in secondary adrenal insufficiency cortisol production is mainly impaired due to decreased ACTH synthesis by the pituitary while aldosterone release, after the physiological stimuli that are hypovolemia, angiotensin II and hyperkalemia, remains intact113.
Furthermore, suppressed adrenal production of aldosterone can be secondary to inherited causes. Although hypokalemia is mostly seen in congenital adrenal hyperplasia, in congenital 21-hydroxylase deficiency, hyperkalemia is present. In general, congenital adrenal hyperplasia is characterized by cortisol deficiency which leads to elimination of the negative feedback of ACTH production. Overproduction of ACTH results in adrenal hyperplasia and increased metabolite production prior to enzyme deficiency. In 21-hydroxylase deficiency, these metabolites are converted to androgens. In one to two thirds of cases, hypoaldosteronism is also present. Therapeutic measures include cortisol substitution which decreases, via ACTH suppression, androgens and aldosterone overproduction. Another rare cause of hypoaldosteronism is isolated hypoaldosteronism which is an autosomal recessive disorder114, 115. Finally, heparin acts directly in the adrenal glands and suppresses aldosterone production but does not cause significant hyperkalemia if administered alone116.
4.3.3 Hyperkalemia due to resistance of distal nephron to aldosterone action
Drugs that counteract with aldosterone actions can cause hyperkalemia especially if CKD is also present but serum aldosterone levels are not suppressed. Potassium sparing diuretics spironolactone and eplerenone antagonize aldosterone to the level of its intracellular receptor. Occupation of aldosterone receptor by these agents results in insufficient K+ excretion via Na+-K+-ATPase, ENaC and ROMK inhibition in the principal cells. Potassium sparing diuretics amiloride and triamterene and the antibiotics trimethoprime and pentamidine have similar effects due to ENaC inhibition108,117-119. If sodium reabsorption is impaired in the principal cells, the relative electronegativity of the CCD lumen is reduced and K+ excretion is disrupted. Cyclosporine, besides reducing renin activity, also acts directly in the principal cells and decreases K+ excretion by Na+-K+-ATPase and possibly K+ channels inhibition120,121.
Pseudohypoaldosteronism is characterized by kidney resistance to aldosterone action which results in hypovolemia, Na+ loss, hyperkalemia and elevated renin and aldosterone levels122. Acquired pseudohypoaldosteronism results from a tubular defect secondary to obstructive nephropathy, chronic pyelonephritis, acute interstitial nephritis and amyloidosis123-125. There are two types (I and II) of inherited pseudohypoaldosteronism. In the autosomal recessive form of type I, all the target organs of aldosterone are involved and the defect is located in the ENaC channels in the principal cells. In type I autosomal dominant form, symptoms improve with age and the disorder is located in the mineralocorticoid receptor. Therapeutic management includes an initially sodium rich diet and, in refractory cases, high doses of fludrocortisone (1-2mg/d)126. Type II pseudohypoaldosteronism (also called Gordon’s syndrome) is characterized by hyperkalemia, metabolic acidosis, hypertension and low or normal plasma renin activity and aldosterone concentration. Salt (NaCl) consumption worsens symptoms; however, Na+ without Cl- administration is beneficial. Hypertension and hyperkalemia respond well to thiazide diuretics. Gordon’s syndrome is attributed to a defect in WNK1 and WNK4 kinases. Under normal circumstances, WNK4 reduces the expression of the thiazide sensitive Na/Cl cotransporter. It also enhances ROMK channels degradation in the principal cells. Mutated WNK4 loses the former ability of normal WNK4 but not the latter and the result is increased distal NaCl reabsorption and impaired K+ excretion in the CCD. Additionally, mutated WNK4 promotes paracellular Cl- absorption which results in decreased luminal electronegativity and disturbs K+ and H+ excretion127-130. Mutations that increase the activity of WNK1 kinase which normally inhibits WNK4, also lead to Gordon’s syndrome130, 131.
Finally, the hyperkalemic form of Type I renal tubular acidosis (hyperkalemic type I RTA) is a rare disorder characterized by a defect in H+ excretion which leads to metabolic acidosis and an inappropriately high urine pH more than 5.3. Hypokalemia is common in this disorder due to the fact that defective H+ excretion requires that Na+ reabsorption takes place in exchange with K+. However, hyperkalemia may occur in the setting of decreased distal Na+ reabsorption which reduces the electronegativity of the tubular lumen and impairs K+ and H+ excretion. This mostly happens in patients with obstructive nephropathy or sickle cell nephropathy, although these disorders can also be complicated by hyporeninemic hypoaldosteronism132-134. These two entities may both be present but they can be differentiated by measurement of serum aldosterone or urine pH. Management of hyperkalemic type I RTA includes diet poor in K+, alkali administration and, if necessary, a diuretic can be added to enhance Na+ and water delivery in the CCD.
A simplified, based on the etiology, the pathophysiology and the laboratory findings of hyperkalemia diagnostic approach is depicted in Figure 3. Certainly, albeit helpful, such algorithms cannot substitute a carefully obtained, detailed patient’s history since in real life hyperkalemia is usually multifactorial.
Figure 3: The differential diagnosis of hyperkalemia.
1. Gross P, Pistrosch F. Hyperkalaemia: again. Nephrol Dial Transplant. 2004; 19: 2163-2166.
2. Juurlink DN, Mamdani MM, Lee DS, Kopp A, Austin PC, Laupacis A, et al. Rates of hyperkalemia after publication of the Randomized Aldactone Evaluation Study. N Engl J Med. 2004; 351: 543-551.
3. Sood MM, Sood AR, Richardson R. Emergency management and commonly encountered outpatient scenarios in patients with hyperkalemia. Mayo Clin Proc. 2007; 82: 1553-1561.
4. Kellerman PS, Thornbery JM. Pseudohyperkalemia due to pneumatic tube transport in a leukemic patient. Am J Kidney Dis. 2005; 46: 746-748.
5. Sevastos N, Theodossiades G, Savvas SP, Tsilidis K, Efstathiou S, Archimandritis AJ. Pseudohyperkalemia in patients with increased cellular components of blood. Am J Med Sci. 2006; 331: 17-21.
6. Colussi G. Pseudohyperkalemia in leukemias. Am J Kidney Dis. 2006; 47: 373.
7. Stewart GW, Corrall RJ, Fyffe JA, Stockdill G, Strong JA. Familial pseudohyperkalaemia. A new syndrome. Lancet. 1979; 2: 175-177.
8. Gennari FJ. Disorders of potassium homeostasis. Hypokalemia and hyperkalemia. Crit Care Clin. 2002; 18: 273-288, vi.
9. Ganong W. Excitable Tissue: Nerve. In: Ganong W (ed.). Review of Medical Physiology. 17th edn. East Norwalk: Appleton & Lange. 1995; 43-55.
10. Ganong W. Excitable Tissue: Muscle. In: Ganong W (ed.). Review of Medical Physiology. 17th edn. East Norwalk: Appleton & Lange. 1995; 56-74.
11. DeFronzo RA, Sherwin RS, Dillingham M, Hendler R, Tamborlane WV, Felig P. Influence of basal insulin and glucagon secretion on potassium and sodium metabolism. Studies with somatostatin in normal dogs and in normal and diabetic human beings. J Clin Invest. 1978; 61: 472-479.
12. Sterns RH, Cox M, Feig PU, Singer I. Internal potassium balance and the control of the plasma potassium concentration. Medicine (Baltimore). 1981; 60: 339-354.
13. Daut J, Maier-Rudolph W, von Beckerath N, Mehrke G, Gunther K, Goedel-Meinen L. Hypoxic dilation of coronary arteries is mediated by ATP-sensitive potassium channels. Science. 1990; 247: 1341-1344.
14. Kaisar MO, Wiggins KJ, Sturtevant JM, Hawley CM, Campbell SB, Isbel NM, et al. A randomized controlled trial of fludrocortisone for the treatment of hyperkalemia in hemodialysis patients. Am J Kidney Dis. 2006; 47: 809-814.
15. Mathialahan T, Maclennan KA, Sandle LN, Verbeke C, Sandle GI. Enhanced large intestinal potassium permeability in end-stage renal disease. J Pathol. 2005; 206: 46-51.
16. Hebert SC, Desir G, Giebisch G, Wang W. Molecular diversity and regulation of renal potassium channels. Physiol Rev. 2005; 85: 319-371.
17. Wang WH. Regulation of ROMK (Kir1.1) channels: new mechanisms and aspects. Am J Physiol Renal Physiol. 2006; 290: F14-F19.
18. Satlin LM, Carattino MD, Liu W, Kleyman TR. Regulation of cation transport in the distal nephron by mechanical forces. Am J Physiol Renal Physiol. 2006; 291: F923-F931.
19. Nauli SM, Alenghat FJ, Luo Y, Williams E, Vassilev P, Li X, et al. Polycystins 1 and 2 mediate mechanosensation in the primary cilium of kidney cells. Nat Genet. 2003; 33: 129-137.
20. Morimoto T, Liu W, Woda C, Carattino MD, Wei Y, Hughey RP, et al. Mechanism underlying flow stimulation of sodium absorption in the mammalian collecting duct. Am J Physiol Renal Physiol. 2006; 291: F663-F669.
21. Subramanya AR, Yang CL, McCormick JA, Ellison DH. WNK kinases regulate sodium chloride and potassium transport by the aldosterone-sensitive distal nephron. Kidney Int. 2006; 70: 630-634.
22. O'Reilly M, Marshall E, Macgillivray T, Mittal M, Xue W, Kenyon CJ, et al. Dietary electrolyte-driven responses in the renal WNK kinase pathway in vivo. J Am Soc Nephrol. 2006; 17: 2402-2413.
23. Lazrak A, Liu Z, Huang CL. Antagonistic regulation of ROMK by long and kidney-specific WNK1 isoforms. Proc Natl Acad Sci U S A. 2006; 103: 1615-1620.
24. Cope G, Murthy M, Golbang AP, Hamad A, Liu CH, Cuthbert AW, et al. WNK1 affects surface expression of the ROMK potassium channel independent of WNK4. J Am Soc Nephrol. 2006; 17: 1867-1874.
25. Lawson DH. Adverse reactions to potassium chloride. Q J Med. 1974; 43: 433-440.
26. Wang Q, Domenighetti AA, Pedrazzini T, Burnier M. Potassium supplementation reduces cardiac and renal hypertrophy independent of blood pressure in DOCA/salt mice. Hypertension. 2005; 46: 547-554.
27. Chang HY, Hu YW, Yue CS, Wen YW, Yeh WT, Hsu LS, et al. Effect of potassium-enriched salt on cardiovascular mortality and medical expenses of elderly men. Am J Clin Nutr. 2006; 83: 1289-1296.
28. Illingworth RN, Proudfoot AT. Rapid poisoning with slow-release potassium. Br Med J. 1980; 281: 485-486.
29. Cheng CJ, Chiu JS, Huang WH, Lin SH. Acute hyperkalemic paralysis in a uremic patient. J Nephrol. 2005; 18: 630-633.
30. Burrowes JD, Van Houten G. Use of alternative medicine by patients with stage 5 chronic kidney disease. Adv Chronic Kidney Dis. 2005; 12: 312-325.
31. Gelfand MC, Zarate A, Knepshield JH. Geophagia. A cause of life-threatening hyperkalemia in patients with chronic renal failure. JAMA. 1975; 234: 738-740.
32. Abu-Hamdan DK, Sondheimer JH, Mahajan SK. Cautopyreiophagia. Cause of life-threatening hyperkalemia in a patient undergoing hemodialysis. Am J Med. 1985; 79: 517-519.
33. Kallen RJ, Rieger CH, Cohen HS, Sutter MA, Ong RT. Near-fatal hyperkalemia due to ingestion of salt substitute by an infant. JAMA. 1976; 235: 2125-2126.
34. Scanlon JW, Krakaur R. Hyperkalemia following exchange transfusion. J Pediatr. 1980; 96: 108-110.
35. Simon GE, Bove JR. The potassium load from blood transfusion. Postgrad Med. 1971; 49: 61-64.
36. Leveen HH, Pasternack HS, Lustrin I, Shapiro RB, Becker E, Helft AE. Hemorrhage and transfusion as the major cause of cardiac arrest. J Am Med Assoc. 1960; 173: 770-777.
37. Lordon RE, Burton JR. Post-traumatic renal failure in military personnel in Southeast Asia. Experience at Clark USAF hospital, Republic of the Philippines. Am J Med. 1972; 53: 137-147.
38. Arseneau JC, Bagley CM, Anderson T, Canellos GP. Hyperkalaemia, a sequel to chemotherapy of Burkitt's lymphoma. Lancet. 1973; 1: 10-14.
39. Kalemkerian GP, Darwish B, Varterasian ML. Tumor lysis syndrome in small cell carcinoma and other solid tumors. Am J Med. 1997; 103: 363-367.
40. Fortner RW, Nowakowski A, Carter CB, King LH Jr, Knepshield JH. Death due to overheated dialysate during dialysis. Ann Intern Med. 1970; 73: 443-444.
41. Rampello E, Fricia T, Malaguarnera M. The management of tumor lysis syndrome. Nat Clin Pract Oncol. 2006; 3: 438-447.
42. Brown MJ, Brown DC, Murphy MB. Hypokalemia from beta2-receptor stimulation by circulating epinephrine. N Engl J Med. 1983; 309: 1414-1419.
43. Carlsson E, Fellenius E, Lundborg P, Svensson L. beta-Adrenoceptor blockers, plasma-potassium, and exercise. Lancet. 1978; 2: 424-425.
44. Arthur S, Greenberg A. Hyperkalemia associated with intravenous labetalol therapy for acute hypertension in renal transplant recipients. Clin Nephrol. 1990; 33: 269-271.
45. Castellino P, Bia MJ, DeFronzo RA. Adrenergic modulation of potassium metabolism in uremia. Kidney Int. 1990; 37: 793-798.
46. Asplund J, Edhag O, Mogensen L, Nyquist O, Orinius E, Sjogren A. Four cases of massive digitalis poisoning. Acta Med Scand. 1971; 189: 293-297.
47. Reza MJ, Kovick RB, Shine KI, Pearce ML. Massive intravenous digoxin overdosage. N Engl J Med. 1974; 291: 777-778.
48. Birch AA, Jr., Mitchell GD, Playford GA, Lang CA. Changes in serum potassium response to succinylcholine following trauma. JAMA. 1969; 210: 490-493.
49. Cooperman LH. Succinylcholine-induced hyperkalemia in neuromuscular disease. JAMA. 1970; 213: 1867-1871.
50. Lindinger MI, Heigenhauser GJ, McKelvie RS, Jones NL. Blood ion regulation during repeated maximal exercise and recovery in humans. Am J Physiol. 1992; 262: R126-136.
51. Ledingham IM, MacVicar S, Watt I, Weston GA. Early resuscitation after marathon collapse. Lancet. 1982; 2: 1096-1097.
52. McKechnie JK, Leary WP, Joubert SM. Some electrocardiographic and biochemical changes recorded in marathon runners. S Afr Med J. 1967; 41: 722-725.
53. Lim M, Linton RA, Wolff CB, Band DM. Propranolol, exercise, and arterial plasma potassium. Lancet. 1981; 2: 591.
54. Perez GO, Oster JR, Vaamonde CA. Serum potassium concentration in acidemic states. Nephron. 1981; 27: 233-243.
55. Adrogue HJ, Chap Z, Ishida T, Field JB. Role of the endocrine pancreas in the kalemic response to acute metabolic acidosis in conscious dogs. J Clin Invest. 1985; 75: 798-808.
56. Graber M. A model of the hyperkalemia produced by metabolic acidosis. Am J Kidney Dis. 1993; 22: 436-444.
57. Adrogue HJ, Madias NE. Changes in plasma potassium concentration during acute acid-base disturbances. Am J Med. 1981; 71: 456-467.
58. Bushinsky DA, Gennari FJ. Life-threatening hyperkalemia induced by arginine. Ann Intern Med. 1978; 89: 632-634.
59. Sonikian M, Metaxaki P, Iliopoulos A, Marioli S, Vlassopoulos D. Long-term management of sevelamer hydrochloride-induced metabolic acidosis aggravation and hyperkalemia in hemodialysis patients. Ren Fail. 2006; 28: 411-418.
60. Adrogue HJ, Lederer ED, Suki WN, Eknoyan G. Determinants of plasma potassium levels in diabetic ketoacidosis. Medicine (Baltimore). 1986; 65: 163-172.
61. Arieff AI, Carroll HJ. Nonketotic hyperosmolar coma with hyperglycemia: clinical features, pathophysiology, renal function, acid-base balance, plasma-cerebrospinal fluid equilibria and the effects of therapy in 37 cases. Medicine (Baltimore). 1972; 51: 73-94.
62. Nicolis GL, Kahn T, Sanchez A, Gabrilove JL. Glucose-induced hyperkalemia in diabetic subjects. Arch Intern Med. 1981; 141: 49-53.
63. Moreno M, Murphy C, Goldsmith C. Increase in serum potassium resulting from the administration of hypertonic mannitol and other solutions. J Lab Clin Med. 1969; 73: 291-298.
64. Montoliu J, Revert L. Lethal hyperkalemia associated with severe hyperglycemia in diabetic patients with renal failure. Am J Kidney Dis. 1985; 5: 47-48.
65. Griggs RC, Ptacek LJ. Mutations of sodium channels in periodic paralysis: can they explain the disease and predict treatment? Neurology. 1999; 52: 1309-1310.
66. Fontaine B, Lapie P, Plassart E, Tabti N, Nicole S, Reboul J, et al. Periodic paralysis and voltage-gated ion channels. Kidney Int. 1996; 49: 9-18.
67. Clausen T, Wang P, Orskov H, Kristensen O. Hyperkalemic periodic paralysis. Relationships between changes in plasma water, electrolytes, insulin and catecholamines during attacks. Scand J Clin Lab Invest. 1980; 40: 211-220.
68. Wang P, Clausen T. Treatment of attacks in hyperkalaemic familial periodic paralysis by inhalation of salbutamol. Lancet. 1976; 1: 221-223.
69. Choi MJ, Ziyadeh FN. The utility of the transtubular potassium gradient in the evaluation of hyperkalemia. J Am Soc Nephrol. 2008; 19: 424-426.
70. Musso C, Liakopoulos V, De Miguel R, Imperiali N, Algranati L. Transtubular potassium concentration gradient: comparison between healthy old people and chronic renal failure patients. Int Urol Nephrol. 2006; 38: 387-390.
71. Halperin M, Kamel KS, Goldstein MB. Hyperkalemia. In: Halperin M, Kamel KS, Goldstein MB (eds). Fluid, Electrolyte, and Acid-Base Physiology. 4th edn. Sounders, Philadelphia, 2010, 512-540.
72. Schultze RG, Taggart DD, Shapiro H, Pennell JP, Caglar S, Bricker NS. On the adaptation in potassium excretion associated with nephron reduction in the dog. J Clin Invest. 1971; 50: 1061-1068.
73. Bourgoignie JJ, Kaplan M, Pincus J, Gavellas G, Rabinovitch A. Renal handling of potassium in dogs with chronic renal insufficiency. Kidney Int. 1981; 20: 482-490.
74. Schrier RW, Regal EM. Influence of aldosterone on sodium, water and potassium metabolism in chronic renal disease. Kidney Int. 1972; 1: 156-168.
75. Schon DA, Silva P, Hayslett JP. Mechanism of potassium excretion in renal insufficiency. Am J Physiol. 1974; 227: 1323-1330.
76. Allon M. Hyperkalemia in end-stage renal disease: mechanisms and management. J Am Soc Nephrol. 1995; 6: 1134-1142.
77. Bilbrey GL, Carter NW, White MG, Schilling JF, Knochel JP. Potassium deficiency in chronic renal failure. Kidney Int. 1973; 4: 423-430.
78. Kahn T, Kaji DM, Nicolis G, Krakoff LR, Stein RM. Factors related to potassium transport in chronic stable renal disease in man. Clin Sci Mol Med. 1978; 54: 661-666.
79. Bonilla S, Goecke IA, Bozzo S, Alvo M, Michea L, Marusic ET. Effect of chronic renal failure on Na,K-ATPase alpha 1 and alpha 2 mRNA transcription in rat skeletal muscle. J Clin Invest. 1991; 88: 2137-2141.
80. Alvestrand A, Wahren J, Smith D, DeFronzo RA. Insulin-mediated potassium uptake is normal in uremic and healthy subjects. Am J Physiol. 1984; 246: E174-180.
81. Magner PO, Robinson L, Halperin RM, Zettle R, Halperin ML. The plasma potassium concentration in metabolic acidosis: a re-evaluation. Am J Kidney Dis. 1988; 11: 220-224.
82. Anderson HM, Laragh JH. Renal excretion of potassium in normal and sodium depleted dogs. J Clin Invest. 1958; 37: 323-331.
83. Popovtzer MM, Katz FH, Pinggera WF, Robinette J, Halgrimson CG, Butkus DE. Hyperkalemia in salt-wasting nephropathy. Study of the mechanism. Arch Intern Med. 1973; 132: 203-208.
84. Chakko SC, Frutchey J, Gheorghiade M. Life-threatening hyperkalemia in severe heart failure. Am Heart J. 1989; 117: 1083-1091.
85. Oster JR, Materson BJ. Renal and electrolyte complications of congestive heart failure and effects of therapy with angiotensin-converting enzyme inhibitors. Arch Intern Med. 1992; 152: 704-710.
86. Haber E, Koerner T, Page LB, Kliman B, Purnode A. Application of a radioimmunoassay for angiotensin I to the physiologic measurements of plasma renin activity in normal human subjects. J Clin Endocrinol Metab. 1969; 29: 1349-1355.
87. Workman RJ, Sussman CR, Burkitt DW, Liddle GW. Circulating levels of angiotensin I measured by radioimmunoassay in hypertensive subjects. J Lab Clin Med. 1979; 93: 847-856.
88. Sealey JE, Laragh JH. Radioimmunoassay of plasma renin activity. Semin Nucl Med. 1975; 5: 189-202.
89. Ferrari P, Shaw SG, Nicod J, Saner E, Nussberger J. Active renin versus plasma renin activity to define aldosterone-to-renin ratio for primary aldosteronism. J Hypertens. 2004; 22: 377-381.
90. Gordon RD, Wolfe LK, Island DP, Liddle GW. A diurnal rhythm in plasma renin activity in man. J Clin Invest. 1966; 45: 1587-1592.
91. Gordon RD. Primary aldosteronism. J Endocrinol Invest. 1995; 18: 495-511.
92. Weinberger MH, Kramer NJ, Grim CE, Petersen LP. The effect of posture and saline loading on plasma renin activity and aldosterone concentration in pregnant, non-pregnant and estrogen-treated women. J Clin Endocrinol Metab. 1977; 44: 69-77.
93. Al-Dujaili EA, Edwards CR. The development and application of a direct radioimmunoassay for plasma aldosterone using 125I-labeled ligand--comparison of three methods. J Clin Endocrinol Metab. 1978; 46: 105-113.
94. Katz FH, Romfh P, Smith JA. Diurnal variation of plasma aldosterone, cortisol and renin activity in supine man. J Clin Endocrinol Metab. 1975; 40: 125-134.
95. Tuck ML, Dluhy RG, Williams GH. Sequential responses of the renin-angiotensin-aldosterone axis to acute postural change: effect of dietary sodium. J Lab Clin Med. 1975; 86: 754-763.
96. Garg LC, Narang N. Effects of aldosterone on NEM-sensitive ATPase in rabbit nephron segments. Kidney Int. 1988; 34: 13-17.
97. Cohen EP, Bastani B, Cohen MR, Kolner S, Hemken P, Gluck SL. Absence of H(+)-ATPase in cortical collecting tubules of a patient with Sjogren's syndrome and distal renal tubular acidosis. J Am Soc Nephrol. 1992; 3: 264-271.
98. Szylman P, Better OS, Chaimowitz C, Rosler A. Role of hyperkalemia in the metabolic acidosis of isolated hypoaldosteronism. N Engl J Med. 1976; 294: 361-365.
99. DuBose TD, Jr., Good DW. Chronic hyperkalemia impairs ammonium transport and accumulation in the inner medulla of the rat. J Clin Invest. 1992; 90: 1443-1449.
100. Kigoshi T, Morimoto S, Uchida K, Hosojima H, Yamamoto I, Imaizumi N, et al. Unresponsiveness of plasma mineralocorticoids to angiotensin II in diabetic patients with asymptomatic normoreninemic hypoaldosteronism. J Lab Clin Med. 1985; 105: 195-200.
101. Campbell WB, Gomez-Sanchez CE, Adams BV, Schmitz JM, Itskovitz HD. Attenuation of angiotensin II- and III-induced aldosterone release by prostaglandin synthesis inhibitors. J Clin Invest. 1979; 64: 1552-1557.
102. Clark BA, Brown RS, Epstein FH. Effect of atrial natriuretic peptide on potassium-stimulated aldosterone secretion: potential relevance to hypoaldosteronism in man. J Clin Endocrinol Metab. 1992; 75: 399-403.
103. Don BR, Schambelan M. Hyperkalemia in acute glomerulonephritis due to transient hyporeninemic hypoaldosteronism. Kidney Int. 1990; 38: 1159-1163.
104. Hsueh WA, Carlson EJ, Luetscher JA, Grislis G. Activation and characterization of inactive big renin in plasma of patients with diabetic nephropathy and unusual active renin. J Clin Endocrinol Metab. 1980; 51: 535-543.
105. Sowers JR, Beck FW, Waters BK, Barrett JD, Welch BG. Studies of renin activation and regulation of aldosterone and 18-hydroxycorticosterone biosynthesis in hyporeninemic hypoaldosteronism. J Clin Endocrinol Metab. 1985; 61: 60-67.
106. DeFronzo RA. Hyperkalemia and hyporeninemic hypoaldosteronism. Kidney Int. 1980; 17: 118-34.
107. Ali AK. Pharmacovigilance analysis of adverse event reports for aliskiren hemifumarate, a first-in-class direct renin inhibitor. Ther Clin Risk Manag. 2011; 7: 337-344.
108. Weir MR, Rolfe M. Potassium homeostasis and renin-angiotensin-aldosterone system inhibitors. Clin J Am Soc Nephrol. 2010; 5: 531-548.
109. Textor SC, Bravo EL, Fouad FM, Tarazi RC. Hyperkalemia in azotemic patients during angiotensin-converting enzyme inhibition and aldosterone reduction with captopril. Am J Med. 1982; 73: 719-725.
110. Maddirala S, Khan A, Vincent A, Lau K. Effect of angiotensin converting enzyme inhibitors and angiotensin receptor blockers on serum potassium levels and renal function in ambulatory outpatients: risk factors analysis. Am J Med Sci. 2008; 336: 330-335.
111. Ruilope LM, Garcia Robles R, Paya C, Alcazar JM, Miravalles E, Sancho-Rof J, et al. Effects of long-term treatment with indomethacin on renal function. Hypertension. 1986; 8: 677-684.
112. Bantle JP, Nath KA, Sutherland DE, Najarian JS, Ferris TF. Effects of cyclosporine on the renin-angiotensin-aldosterone system and potassium excretion in renal transplant recipients. Arch Intern Med. 1985; 145: 505-508.
113. Ten S, New M, Maclaren N. Clinical review 130: Addison's disease 2001. J Clin Endocrinol Metab. 2001; 86: 2909-2922.
114. White PC, New MI, Dupont B. Congenital adrenal hyperplasia. (1). N Engl J Med. 1987; 316: 1519-1524.
115. Ulick S, Wang JZ, Morton DH. The biochemical phenotypes of two inborn errors in the biosynthesis of aldosterone. J Clin Endocrinol Metab. 1992; 74: 1415-1420.
116. Oster JR, Singer I, Fishman LM. Heparin-induced aldosterone suppression and hyperkalemia. Am J Med. 1995; 98: 575-586.
117. Greenblatt DJ, Koch-Weser J. Adverse reactions to spironolactone. A report from the Boston Collaborative Drug Surveillance Program. JAMA. 1973; 225: 40-43.
118. Alappan R, Perazella MA, Buller GK. Hyperkalemia in hospitalized patients treated with trimethoprim-sulfamethoxazole. Ann Intern Med. 1996; 124: 316-320.
119. Kleyman TR, Roberts C, Ling BN. A mechanism for pentamidine-induced hyperkalemia: inhibition of distal nephron sodium transport. Ann Intern Med. 1995; 122: 103-106.
120. Tumlin JA, Sands JM. Nephron segment-specific inhibition of Na+/K(+)-ATPase activity by cyclosporin A. Kidney Int. 1993; 43: 246-251.
121. Ling BN, Eaton DC. Cyclosporin A inhibits apical secretory K+ channels in rabbit cortical collecting tubule principal cells. Kidney Int. 1993; 44: 974-984.
122. Kuhnle U, Nielsen MD, Tietze HU, Schroeter CH, Schlamp D, Bosson D, et al. Pseudohypoaldosteronism in eight families: different forms of inheritance are evidence for various genetic defects. J Clin Endocrinol Metab. 1990; 70: 638-641.
123. Luke RG, Allison ME, Davidson JF, Duguid WP. Hyperkalemia and renal tubular acidosis due to renal amyloidosis. Ann Intern Med. 1969; 70: 1211-1217.
124. Cogan MC, Arieff AI. Sodium wasting, acidosis and hyperkalemia induced by methicillin interstitial nephritis. Evidence for selective distal tubular dysfunction. Am J Med. 1978; 64: 500-507.
125. Rodriguez-Soriano J, Vallo A, Oliveros R, Castillo G. Transient pseudohypoaldosteronism secondary to obstructive uropathy in infancy. J Pediatr. 1983; 103: 375-380.
126. Furgeson SB, Linas S. Mechanisms of type I and type II pseudohypoaldosteronism. J Am Soc Nephrol. 2010; 21: 1842-1845.
127. Cai H, Cebotaru V, Wang YH, Zhang XM, Cebotaru L, Guggino SE, et al. WNK4 kinase regulates surface expression of the human sodium chloride cotransporter in mammalian cells. Kidney Int. 2006; 69: 2162-2170.
128. Lalioti MD, Zhang J, Volkman HM, Kahle KT, Hoffmann KE, Toka HR, et al. Wnk4 controls blood pressure and potassium homeostasis via regulation of mass and activity of the distal convoluted tubule. Nat Genet. 2006; 38: 1124-1132.
129. Golbang AP, Murthy M, Hamad A, Liu CH, Cope G, Van't Hoff W, et al. A new kindred with pseudohypoaldosteronism type II and a novel mutation (564D>H) in the acidic motif of the WNK4 gene. Hypertension. 2005; 46: 295-300.
130. Proctor G, Linas S. Type 2 pseudohypoaldosteronism: new insights into renal potassium, sodium, and chloride handling. Am J Kidney Dis. 2006; 48: 674-693.
131. Ohta A, Yang SS, Rai T, Chiga M, Sasaki S, Uchida S. Overexpression of human WNK1 increases paracellular chloride permeability and phosphorylation of claudin-4 in MDCKII cells. Biochem Biophys Res Commun. 2006; 349: 804-808.
132. Kimura H, Mujais SK. Cortical collecting duct Na-K pump in obstructive nephropathy. Am J Physiol. 1990; 258: F1320-1327.
133. Batlle DC. Segmental characterization of defects in collecting tubule acidification. Kidney Int. 1986; 30: 546-554.
134. Batlle D, Itsarayoungyuen K, Arruda JA, Kurtzman NA. Hy perkalemic hyperchloremic metabolic acidosis in sickle cell hemoglobinopathies. Am J Med. 1982; 72: 188-192.