Introduction

Scope of the problem

In patients with chronic kidney disease (CKD), loss of nephron mass is normally counterbalanced by an adaptive increase in the secretory rate of K+ in remaining nephrons, such that K+ homeostasis is generally well maintained until the glomerular filtration rate (GFR) falls below 15–20 mL/min.1 More severe renal dysfunction invariably leads to K+ retention and hyperkalemia unless the rate of dietary intake is reduced. In a random sample of 300 CKD patients (serum creatinine concentration ranging from 1.5 to 6.0 mg/dL), excluding patients with diabetes and those taking drugs that interfere in angiotensin-II synthesis or effect, the incidence of hyperkalemia was measured to be 55% (K+ ≥ 5.5 mEq/L).2

Causes of hyperkalemia

While loss of kidney function is the single most important cause of hyperkalemia, in clinical practice this electrolyte disorder is usually the result of a combination of factors limiting renal K+ excretion superimposed on renal dysfunction (see Table 1).3 Such is the case in patients with diabetes where decreased mineralocorticoid activity is often an early manifestation of hyporeninemic hypoaldosteronism, or in advanced stages of heart failure with accompanying reductions in distal delivery of Na+ combined with concurrent use of drugs which interfere with the renin-angiotensin-aldosterone system. In these settings, hyperkalemia is common and can develop with only mild or moderate reductions in the GFR.


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The frequency of hyperkalemia in the CKD patient makes a strong argument for early referral and management of these patients in a clinic environment that is focused on the management of this common electrolyte disorder.4 As such, one study attempted to identify all of the factors known to interfere in K+ homeostasis that are simultaneously present during a single clinic visit in a population of CKD patients.5 These patients were receiving regular follow-up in a clinic designed and structured to optimize the care of patients with advanced CKD.

Despite the hyperkalemia focus, the mean serum K+ concentration was increased to 5.1 mEq/L in 54.2% of patients. While the average estimated GFR (eGFR) of this study population was 14.4 mL/min/1.73m2, patients with hyperkalemia had a significantly lower eGFR compared to those without (14.8 vs 13.5 mL/min/1.73m2). In addition to having worse renal function, hyperkalemic subjects had significantly lower serum bicarbonate concentrations (22.5 vs 24.1 mEq/L).

Causes of hyperkalemia

Even though there are adaptive mechanisms in the patient with CKD that are designed to attenuate cardiac toxicity from increased serum K+, hyperkalemic events still account for an increased risk of death in this population.6 The electrocardiogram in a hyperkalemic subject can progress from normal to ventricular tachycardia and asystole in a precipitous manner, which emphasizes the need for careful monitoring.7 (For more information about this, see also the article by Epstein and Ketteler in this supplement.) 8

Normal renal potassium handling

Potassium is freely filtered by the glomerulus. The bulk of filtered K+ is reabsorbed in the proximal tubule and loop of Henle so that only 10% of the filtered load reaches the distal nephron. In the proximal tubule, K+ absorption is passive and is approximately proportional to Na+ and water absorption. In the thick ascending limb of Henle, K+ reabsorption occurs via transport on the apical membrane Na+-K+-2Cl co-transporter. Secretion of K+ occurs in the distal nephron, primarily in the initial collecting duct and the cortical collecting duct. Under most conditions, K+ delivery to the distal nephron remains small and is fairly constant. As recently reviewed, the rate of K+ secretion by the distal nephron varies significantly and is highly regulated according to physiologic needs.9

The specialized cell which is responsible for K+ secretion in the initial collecting duct and the cortical collecting duct is the principal cell. Mineralocorticoid activity and distal delivery of Na+ and water are important factors regulating K+ secretion in this segment. Aldosterone increases the rate of K+ secretion by increasing cell K+ concentration, increasing luminal membrane K+ permeability, and making the luminal potential more negative by stimulating Na+ reabsorption across the luminal membrane through the epithelial sodium channel (ENaC).

Read also: Clinical and electrophysiological consequences of hyperkalemia 

When K+ is secreted in the collecting duct the luminal K+ concentration increases, which decreases the diffusion gradient and slows further K+ secretion. At high luminal flow rates the same amount of K+ secretion will be diluted by the larger volume; such that the increase in luminal K+ concentration will be less, thus facilitating ongoing K+ secretion. An increase in the distal delivery of Na+ stimulates K+ secretion by causing the luminal potential to become more negative.

Read also: Patterns, causes, and effects of hyperkalemia

Two populations of K+ channels have been identified in the cells of the cortical collecting duct. The ROMK (renal outer medullary K+) channel is considered to be the major K+-secretory pathway. This channel is characterized by having low conductance and a high probability of being open under physiologic conditions. The maxi-K+ channel, or BK channel, is characterized by a large single-channel conductance and is relatively quiescent in the basal state. This channel becomes activated under conditions of increased flow. In addition to increased delivery of Na+ and dilution of luminal K+ concentration, recruitment of maxi-K+ channels plays an important role in mediating flow-dependent increased K+ secretion.

Read also: Heart failure with reduced ejection fraction 

Potassium homeostasis in acute kidney injury

There are a number of features characteristic of acute kidney injury that make hyperkalemia particularly common in these patients. When the cause is acute tubular necrosis or tubulointerstitial renal disease, there is often widespread injury to the late distal tubule and collecting duct, leading to direct injury of cells responsible for K+ secretion. Acute kidney injury is often associated with severe reductions in the GFR (< 10 mL/min) which, in and of itself, becomes rate-limiting for K+ secretion. The rapidity of renal function loss precludes adequate time for normal renal and extrarenal adaptive mechanisms to develop adequately. In patients with more severe injury manifested clinically by oligo-anuria, there is a marked reduction in distal delivery of salt and water which contributes to decreased distal K+ secretion. In non-oliguric acute kidney injury, hyperkalemia tends to be less common since distal delivery of salt and water is plentiful. Patients with acute kidney injury are more likely to have severe acidosis, increased catabolism, and tissue breakdown, all leading to the release of intracellular K+ into the extracellular compartment. This release of K+ in the setting of impaired renal K+ secretion makes life-threatening hyperkalemia a common occurrence in patients with acute kidney injury.

Renal potassium handling in CKD

CKD is more complicated than acute kidney injury. In addition to the decreased GFR and secondary decrease in distal delivery of K+, there is nephron dropout and a smaller number of collecting ducts to secrete K+. However, this is counterbalanced by an adaptive process in which the remaining nephrons develop an increased ability to excrete K+. As a result, hyperkalemia (K+ > 5.5 mEq/L) is uncommon in patients with CKD until the GFR falls below 15–20 mL/min.

Studies both in experimental animals and in humans have provided insight into the nature and localization of the adaptive increase in renal K+ secretion. In conscious dogs with a unilateral remnant kidney, K+ secretion per nephron increases 4-fold by 18 hours and approaches 85% of the control animals 7 days after removal of the contralateral intact kidney.1 The ability to maintain urinary K+ secretion in the face of a marked reduction in functioning nephron mass requires the amount of K+ excreted per unit of GFR (fractional excretion of K+) to markedly increase.

In a study of normokalemic patients with stage 4 CKD, the fractional excretion of K+ was 126% compared with 26% in normal control patients.10 The fractional excretion of Na+ in the two groups was 2.3% and 15%, respectively. Following intravenous administration of amiloride, the fractional excretion of K+ decreased by 87% in the patients with CKD compared with 19.5% in control patients. These findings support the idea that patients with CKD are able to maintain normal serum K+ concentrations through an adaptive increase in renal K+ secretion that is largely amiloride-sensitive.

Read also: Clinical and electrophysiological consequences of hyperkalemia

Despite this adaptation, the ability to further augment K+ secretion in response to an exogenous load is extremely limited, such that hyperkalemia can result from even modest increases in K+ intake. When dogs with remnant kidneys were challenged with an acute intravenous infusion of K+ the increment in renal K+ secretion was approximately 50% less than in control animals, resulting in marked hyperkalemia.11 In both remnant and control groups, renal K+ excretion was directly related to the serum K+ concentration; however, the relationship was markedly attenuated in the remnant group. In the first 5 hours following the K+ infusion, control animals excreted 65% of the K+ load as compared to only 35% in the remnant group. A period of nearly 24 hours was required to re-establish K+ balance in the dogs with reduced renal mass. During this time, plasma K+ and aldosterone levels were significantly greater than in control animals. Studies in patients with CKD also show a similar impairment in the ability to acutely excrete a K+ load, and these patients develop more severe and prolonged hyperkalemia following a K+ challenge.12

The nature of the adaptive process which facilitates K+ excretion in patients with CKD is thought to be similar to the adaptive process which occurs in response to high dietary K+ intake in normal subjects.13 Chronic K+ loading in animals augments the secretory capacity of the distal nephron so that renal K+ excretion is significantly increased for any given plasma K+ level. Increased K+ secretion under these conditions occurs in association with structural changes characterized by cellular hypertrophy, increased mitochondrial density, and proliferation of the basolateral membrane in cells in the distal nephron and principal cells of the collecting duct. Increased serum K+ and mineralocorticoids independently initiate amplification of this process, which is accompanied by an increase in Na+-K+-ATPase activity.

Studies in animal models show that the cortical collecting duct is an important site of K+ adaptation in the surviving nephrons of animals with reduced renal mass. K+ secretion is increased in perfused cortical collecting tubules taken from remnant kidneys of uremic rabbits fed a normal diet.14 However, if dietary K+ intake is reduced in proportion to the reduction in renal mass, this adaptation is prevented and K+ secretory rates remain within the normal range. Reduction in renal mass leads to amplification of the basolateral membrane area and an increase in Na+-K+-ATPase activity similar to that described when dietary K+ intake is increased in animals with intact kidneys.15 Loss of renal mass also leads to an increase in Na+ delivery and apical Na+ transport in this segment.16 Increased apical Na+ entry provides a further stimulatory effect on Na+-K+-ATPase activity. Changes in serum K+ concentration and mineralocorticoids independently mediate these adaptive structural and functional changes.

Aldosterone plays an important role in the ability to augment K+ secretion in the setting of CKD. The tubular hypertrophy, increased basolateral folding, and increase in Na+-K+-ATPase activity in the collecting duct in remnant kidneys are similar to what is seen in experimental models of chronic mineralocorticoid administration.17 There is a wide variability in aldosterone levels in patients with CKD, with studies showing either increased, normal, or decreased values. Part of this variability is due to the failure to consider the prevailing plasma K+ concentration and variations in Na+ intake. In addition, many patients with CKD have low plasma renin activity. In this setting, impaired aldosterone secretion and hypoaldosteronism are the result of low circulating renin levels. When normalized for the plasma renin activity, levels of aldosterone are typically in the normal range when the GFR is
> 50–60 mL/min.18 However, with more severe reductions in renal function there is a progressive increase in plasma aldosterone levels.

Extrarenal K+ homeostasis in CKD

Under normal circumstances, increases in plasma K+ concentration following K+ ingestion are minimized by physiologic mechanisms which shift K+ into cells pending its excretion by the kidney. This maintenance of internal K+ balance is primarily regulated by catecholamines, insulin, and—to a lesser extent—aldosterone. In pathologic states, changes in blood pH and plasma tonicity also influence K+ distribution within the body.

As renal function declines, the cellular uptake of K+ becomes an important defense against the development of hyperkalemia. Studies in humans and experimental models of reduced renal mass have produced conflicting results as to whether disturbances in extrarenal K+ disposal are a characteristic feature in CKD.19 To the extent that internal K+ homeostasis is impaired, the defect cannot be attributed to increased cellular or total-body K+ content since these are either normal or, often, reduced.20,21 Decreased intracellular K+ content has been attributed to decreased activity of the Na+-K+-ATPase, which is a characteristic finding in uremia. Studies in red blood cells taken from uremic patients show diminished activity of the pump which can be reversed when cells are incubated in normal plasma. Pump activity has also been shown to improve following dialysis.22 On the other hand, red blood cells taken from normal individuals and incubated in uremic plasma acquire the defect.

Studies in skeletal muscle from uremic patients show decreased K+ concentration, increased Na+ concentration, and decreased resting membrane potential. After 7 weeks of hemodialysis these physiologic parameters can be restored to normal, suggesting the presence of a circulating inhibitor of the Na+-K+-ATPase in some uremic patients.23 In other patients, there may be reductions in the number of pump sites rather than decreased activity. Therefore, decrements either in pump activity or in number of sites may account for the impaired extrarenal K+ disposal reported in some uremic patients.

Plasma norepinephrine and epinephrine concentrations as well as sympathetic nerve activity (at least to the leg muscles) are increased in patients with advanced CKD when compared to normal control patients.24 Additionally, the metabolic clearance rate of insulin falls with loss of renal function. The increase in circulating insulin and catecholamine levels may serve to attenuate uremic-induced alterations in cell function which normally are responsible for sequestering K+ in the intracellular compartment.

By the time patients reach end-stage renal disease (ESRD), extrarenal K+ homeostasis becomes more overtly impaired. Fernandez and colleagues compared the disposition of an oral K+ load (0.25 mEq/kg/body weight) in a group of dialysis patients to that in normal control patients.25 The normal control patients excreted 67% of the K+ load within 3 hours and translocated 51% of the retained K+ intracellularly. In contrast, the dialysis patients did not excrete any of the K+, and only 21% of the retained K+ was translocated intracellularly. The incremental increase in plasma K+ was significantly different between the two groups. The plasma K+ concentration increased by 1.06 mEq/L in the dialysis patients, whereas an increase of only
0.39 mEq/L was noted in the control group. The impairment in K+ disposal persisted even when the K+ load was accompanied by oral glucose, although glucose-induced stimulation of insulin attenuated the maximal rise in K+ levels.

Gastrointestinal excretion of K+ in CKD

In patients with renal failure, a significant proportion of daily K+ excretion occurs via the gastrointestinal tract. Gastrointestinal losses are important in maintaining K+ balance in chronic dialysis patients because hemodialysis removes approximately
80–100 mEq/treatment (300 mEq/week), yet dietary K+ intake is usually 400–500 mEq/week. In a balance study performed in patients on peritoneal dialysis, 25% of the daily K+ intake was lost in the feces.26 The amount of K+ excreted in the stools correlates directly with the wet stool weight. Therefore, constipation should be avoided because it will decrease the gastrointestinal elimination of K+ and increase the tendency toward hyperkalemia.

The mechanism of increased gastrointestinal K+ loss is not completely defined. The process appears to be due to active secretion, as it is unrelated to plasma K+ or total-body K+.27 In fact, hemodialysis patients continue to have enhanced rectal K+ secretion even after dialysis, their plasma K+ being less than that of control patients. Potassium transport in the large intestine was recently studied in patients with ESRD using a rectal dialysis technique.28 Rectal K+ secretion was found to be 3-fold greater in ESRD patients as compared to control patients with normal renal function. When barium (a K+ channel inhibitor) was placed in the lumen, colonic K+ secretion was reduced by 45% in the ESRD patients and no effect was seen in the control group. Immunostaining using an antibody directed to the α-subunit of the high-conductance K+ channel protein revealed greater expression of the channel in surface colonocytes and crypt cells in the ESRD patients, while only low levels of expression were observed in the control group. These data are consistent with increased expression of K+ channels as the mechanism for the adaptive increase in colonic K+ secretion in patients with ESRD.

Elevated levels of plasma aldosterone may play a role in stimulating the gastrointestinal excretion and cellular uptake of potassium in patients with ESRD. Exogenous administration of mineralocorticoids has been shown to decrease the serum potassium in anuric dialysis patients, presumably by increasing colonic potassium excretion.29 In a prospective study, fludrocortisone administered at 0.1 mg/day was compared with no treatment in 21 hyperkalemic hemodialysis patients.30 At the end of 10 months, the serum K+ concentration in the two groups was not statistically different; however, there was a decrease in serum K+ compared with pretreatment values in patients who received the drug.

A recent study examined the effects of glycyrrhetinic acid food supplementation on the serum K+ concentration in a group of maintenance hemodialysis patients.31 This substance inhibits the enzyme 11β-hydroxysteroid dehydrogenase II which is found not only in the principal cells of the renal collecting duct but also in epithelial cells in the colon. This enzyme converts cortisol to cortisone; thereby ensuring that the mineralocorticoid receptor remains free to interact only with aldosterone, since cortisone has no affinity for the receptor. In 9 of 10 patients given the supplement there was a persistent decrease in measured predialysis serum K+ concentration. In addition, treatment with the supplement significantly decreased the frequency of severe hyperkalemia. These beneficial effects occurred without weight gain or increases in systemic blood pressure, suggesting that glycyrrhetinic acid supplementation may be of benefit in enhancing colonic K+ secretion and minimizing the risk of hyperkalemia in dialysis patients.

Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers have both been reported to cause hyperkalemia in patients treated with hemodialysis and peritoneal dialysis.32,33 The development of hyperkalemia with these drugs may be due to decreased colonic K+ excretion resulting from lower circulating levels of aldosterone or decreased activity of angiotensin II. In this regard, enhanced colonic K+ excretion in renal failure has been attributed to up-regulation of angiotensin-II receptors in the colon, suggesting that angiotensin II has a direct effect in stimulating colonic K+ excretion.34 Blocking the mineralocorticoid receptor with spironolactone given at a dose of 25 mg/day does not raise the serum K+ concentration in hemodialysis patients.35

Risk factors for hyperkalemia

*A spectrum of abnormalities in the renin-angiotensin-aldosterone system have been described in patients with diabetes mellitus to include hyporeninemic hypoaldosteronism as well as normal renin release but a diminished capacity to release aldosterone.37 Hypoaldosteronism combined with dysfunction of collecting ducts due to diabetic nephropathy and treatment with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers make these patients at particularly high risk for hyperkalemia.38

Summary

Adaptive increases in renal and gastrointestinal excretion of K+ help to prevent hyperkalemia in patients with CKD as long as the GFR remains > 15–20 mL/min. Once the GFR falls below these values, the impact of factors known to adversely affect K+ homeostasis is significantly magnified. Impaired renal K+ excretion can be the result of conditions that severely limit distal Na+ delivery, decreased mineralocorticoid levels or activity, or a distal tubular defect (Table 2). In clinical practice, hyperkalemia is usually the result of a combination of factors superimposed on renal dysfunction.

Disclosure: Dr. Palmer has participated in an advisory board for Relypsa, Inc.

References

  1. Schultze RG, Taggart DD, Shapiro H, et al. On the adaptation in potassium excretion associated with nephron reduction in the dog. J Clin Invest. 1971; 50: 1061–1068.
  2. Gennari FJ, Segal AS. Hyperkalemia: An adaptive response in chronic renal insufficiency. Kidney Int. 2002; 62: 1–9.
  3. Palmer BF. A physiologic based approach to the evaluation of a patient with hyperkalemia. Am J Kidney Dis. 2010; 56: 387–393.
  4. Palmer BF. Hyperkalemia in predialysis patients. Clin J Am Soc Nephrol. 2012; 7: 1201–1202.
  5. Sarafidis PA, Blacklock R, Wood E, et al. Prevalence and factors associated with hyperkalemia in predialysis patients followed in a low-clearance clinic. Clin J Am Soc Nephrol. 2012; 7: 1234–1241.
  6. Einhorn LM, Zhan M, Hsu VD, et al. The frequency of hyperkalemia and its significance in chronic kidney disease. Arch Intern Med. 2009; 169: 1156–1162.
  7. Montague BT, Ouellette JR, Buller GK. Retrospective review of the frequency of ECG changes in hyperkalemia. Clin J Am Soc Nephrol. 2008; 3: 324–330.
  8. Epstein M, Ketteler M. Clinical and electrophysiological consequences of hyperkalemia. In: Current concepts and emerging therapeutic options. supplement, Nephrol News Issues. 2016; 30: 14-19.
  9. Palmer BF. Regulation of potassium homeostasis. Clin J Am Soc Nephrol. 2015; 10: 1050–1060.
  10. Levy Yeyati N, Fellet A, Arranz C, et al. Amiloride-sensitive and amiloride-insensitive kaliuresis in advanced chronic kidney disease. J Nephrol. 2008; 21: 93–98.
  11. Bourgoignie JJ, Kaplan M, Pincus J, et al. Renal handling of potassium in dogs with chronic renal insufficiency. Kidney Int. 1981; 20: 482–490.
  12. Perez GO, Pelleya R, Oster JR, et al. Blunted kaliuresis after an acute potassium load in patients with chronic renal failure. Kidney Int. 1983; 24: 656–662.
  13. Stanton BA. Renal potassium transport: morphological and functional adaptations. Am J Physiol. 1989; 257: R989–997.
  14. Fine LG, Yanagawa N, Schultze RG, et al. Functional profile of the isolated uremic nephron: potassium adaptation in the rabbit cortical collecting tubule. J Clin Invest. 1979; 64: 1033–1043.
  15. Zalups RK, Stanton BA, Wade JB, et al. Structural adaptation in initial collecting tubule following reduction in renal mass. Kidney Int. 1985; 27: 636–642.
  16. Vehaskari VM, Hering-Smith KS, Klahr S, et al. Increased sodium transport by cortical collecting tubules from remnant kidneys. Kidney Int. 1989; 36: 89–95.
  17. Stanton B, Pan L, Deetjen H, et al. Independent effects of aldosterone and potassium on induction of potassium adaptation in rat kidney. J Clin Invest. 1987; 79: 198–206.
  18. Hené RJ, Boer P, Koomans HA, et al. Plasma aldosterone concentrations in chronic renal disease. Kidney Int. 1982; 21: 98–101.
  19. Salem MM, Rosa RM, Batlle DC. Extrarenal potassium tolerance in chronic renal failure: implications for the treatment of acute hyperkalemia. Am J Kidney Dis. 1991; 18: 421–440.
  20. Montanari A, Graziani G, Borghi L, et al. Skeletal muscle water and electrolytes in chronic renal failure. Effects of long-term regular dialysis treatment. Nephron. 1985; 39: 316–320.
  21. Bergström J, Alvestrand A, Furst P, et al. Muscle intracellular electrolytes in patients with chronic uremia. Kidney Int. 1983; 24(Suppl 16): S153–160.
  22. Cheng JT, Kahn T, Kaji DM. Mechanism of alteration of sodium potassium pump of erythrocytes from patients with chronic renal failure. J Clin Invest. 1984; 74: 1811–1820.
  23. Kaji D, Kahn T. Na+-K+ pump in chronic renal failure. Am J Physiol. 1987; 252: F785–793.
  24. Converse, RL Jr, Jacobsen, TN, Toto, RD, et al. Sympathetic overactivity in patients with chronic renal failure. N Engl J Med. 1992; 327: 1912–1918.
  25. Fernandez J, Oster JR, Perez GO. Impaired extrarenal disposal of an acute oral potassium load in patients with endstage renal disease on chronic hemodialysis. Miner Electrolyte Metab. 1986; 12: 125–129.
  26. Hayes CP Jr, McLeod ME, Robinson RR. An extrarenal mechanism for the maintenance of potassium balance in severe chronic renal failure. Trans Assoc Am Phys. 1967; 80: 207–216.
  27. Martin RS, Panese S, Virginillo M, et al. Increased secretion of potassium in the rectum of humans with chronic renal failure. Am J Kidney Dis. 1986; 8: 105–110.
  28. Mathialahan T, Maclennan KA, Sandle LN, et al. Enhanced large intestinal potassium permeability in end-stage renal disease. J Pathol. 2005; 206: 46–51.
  29. Imbriano LJ, Durham JH, Maesaka JK. Treating interdialytic hyperkalemia with fludrocortisone. Semin Dial. 2003; 16: 5–7.
  30. Kim DM, Chung JH, Yoon SH, et al. Effect of fludrocortisone acetate on reducing serum potassium levels in patients with end-stage renal disease undergoing haemodialysis. Nephrol Dial Transplant. 2007; 22: 3273–3276.
  31. Farese S, Kruse A, Pasch A, et al. Glycyrrhetinic acid food supplementation lowers serum potassium concentration in chronic hemodialysis patients. Kidney Int. 2009; 76: 877–884
  32. Knoll GA, Sahgal A, Nair RC, et al. Renin-angiotensin system blockade and the risk of hyperkalemia in chronic hemodialysis patients. Am J Med. 2002; 112: 110–114.
  33. Phakdeekitcharoen B, Leelasa-nguan P. Effects of an ACE inhibitor or angiotensin receptor blocker on potassium in CAPD patients. Am J Kidney Dis. 2004; 44: 738–746.
  34. Hatch M, Freel RW, Vaziri ND. Local up-regulation of colonic angiotensin II receptors enhances potassium excretion in chronic renal failure. Am J Physiol. 1998; 274: F275–282.
  35. Saudan P, Mach F, Perneger T, et al. Safety of low-dose spironolactone administration in chronic haemodialysis patients. Nephrol Dial Transplant. 2003; 18: 2359–2363
  36. Palmer BF, Clegg DJ. Hyperkalemia. JAMA. 2015; 314: 2405–2406.
  37. Palmer BF, Clegg DJ. Electrolyte and acid-base disturbances in patients with diabetes mellitus. N Engl J Med. 2015; 373: 548–559.
  38. Palmer BF. Managing hyperkalemia caused by inhibitors of the renin-angiotensin-aldosterone system.