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Potassium Metabolism in Chronic Kidney Disease
C H A P T E R
32 Potassium Metabolism in Chronic Kidney Disease Biff F. Palmer Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA
INTRODUCTION This chapter deals with potassium (K+) metabolism in patients with CKD. The scope of the problem, normal renal K+ homeostasis, and adaptations in renal K+ handling which characterize CKD are considered. The approach to and treatment of K+ disorders in patients with CKD up to the point at which RRT is required are unique.
SCOPE OF THE PROBLEM In patients with CKD loss of nephron mass is counterbalanced by an adaptive increase in the secretory rate of K+ in remaining nephrons, such that K+ homeostasis is generally well maintained until the GFR falls below 15 to 20 mL/min.1 More severe renal dysfunction invariably leads to K+ retention and hyperkalemia unless the rate of dietary potassium intake is reduced. In a random sample of 300 CKD patients (S[Cr] ranging from 1.5 to 6.0 mg/dL) excluding diabetics and those taking drugs that interfere in angiotensin II synthesis or effect, the incidence of hyperkalemia was 55% (K+ ≥5.5 mEq/L).2 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 (Table 32.1). Such is the case in diabetics where decreased mineralocorticoid activity is often an early finding due to hyporeninemic
P. Kimmel & M. Rosenberg (Eds): Chronic Renal Disease. DOI: http://dx.doi.org/10.1016/B978-0-12-411602-3.00032-9
hypoaldosteronism, or in patients with advanced stages of heart failure with accompanying reductions in distal delivery of Na+ combined with concurrent use of drugs which interfere with the RAAS. In these settings hyperkalemia is common and can develop with only mild or moderate reductions in GFR. One study attempted to identify all of the factors known to interfere in K+ homeostasis simultaneously present during a single clinic visit in a population of CKD patients.3 These patients were receiving regular follow-up in a clinic specifically designed and structured to optimize the care of advanced CKD. Despite the focus of the clinic the mean S[K+] was increased at 5.1 mEq/L in 54.2% of patients. While the average eGFR of the entire study population was 14.4 mL/ min/1.73 m2 those with hyperkalemia had a significantly lower eGFR compared to those without (14.8 vs. 13.5 mL/min/1.73 m2). In addition to worse renal function, hyperkalemic subjects had significantly lower serum bicarbonate concentrations (22.5 vs. 24.1 mEq/L). While adaptive mechanisms in the CKD patient may attenuate cardiac toxicity from increased K+, hyperkalemic events are still associated with an increased risk of death in this population.4 The electrocardiogram in a hyperkalemic subject can progress from normal to ventricular tachycardia and asystole in a precipitous manner.5 The frequency of hyperkalemia in the CKD patient makes a strong argument for early referral and management of these patients in a clinic environment focused on the management of this common electrolyte disorder.6
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TABLE 32.1 Causes of Hyperkalemia Pseudohyperkalemia Cellular redistribution Mineral acidosis Cell shrinkage (hypertonicity) Deficiency of insulin β-Blockers Hyperkalemic periodic paralysis Cell injury Excess intake (very rare) Decreased renal excretion Decreased distal delivery of Na+ (oliguric renal failure) Mineralocorticoid deficiency Defect of cortical collecting tubule
Principal cell Lumen
Interstitium Mineralocorticoids
Distal delivery of Na+
3Na+ Na+
Na+
2K+
3Na+ 2K+
(–) K+
K+
FIGURE 32.1 Cell model for renal regulation of K+ secretion by the principal cell in the collecting tubule.
NORMAL POTASSIUM HOMEOSTASIS Potassium plays a key role in maintaining cell function. All cells possess a Na+-K+-ATPase which pumps Na+ out of the cell and K+ into the cell. This leads to a K+ gradient across the cell membrane (K+in > K+out) which is partially responsible for maintaining the potential difference across the membrane. This potential difference is important to the function of all cells, but is especially important in excitable tissues such as nerve and muscle. For these reasons, there are numerous mechanisms for defense of S[K+]. Total body K+ is approximately 50 mEq/kg, which in a 70 kg person would be 3500 mEq. The vast majority, approximately 98%, of this K+ is within cells, with only about 2% in the extracellular fluid. The normal concentration of K+ in the extracellular fluid is 3.5 to 5.3 mEq/L. Large deviations from these values are not compatible with life. The typical American diet includes 50 to 100 mEq/day of K+. Approximately 90% of the daily K+ intake is excreted in the urine, while 10% is excreted by the GI tract. The kidney and gastrointestinal tract respond directionally when K+ intake increases or decreases.
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 such that only 10% of the filtered load reaches the distal nephron. In the proximal tubule K+ absorption is passive and is in rough proportion 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 physiologic and pathologic conditions,
K+ delivery to the distal nephron remains small and is fairly constant. By contrast, the rate of K+ secretion by the distal nephron varies significantly and is highly regulated according to physiologic needs. K+ secretion in the distal nephron is generally responsible for most of the urinary K+ excretion. The specialized cell which is responsible for K+ secretion in the initial collecting duct and the cortical collecting duct is the principal cell (Figure 32.1). The cellular determinants of K+ secretion include the cell K+ concentration, luminal K+ concentration, the transepithelial potential difference (voltage) across the luminal membrane, and the permeability of the luminal membrane for K+. Two of the most important factors which influence these determinants are mineralocorticoid activity and the distal delivery of Na+ and water. Aldosterone interacts with the intracellular mineralocorticoid receptor in the principal cell to stimulate K+ secretion by affecting several of the cellular determinants discussed above. First, aldosterone stimulates Na+ reabsorption across the luminal membrane by increasing the open probability of the epithelial sodium channel on the apical membrane (ENaC), which increases the electronegativity of the lumen, thereby increasing the electrical gradient favoring K+ secretion. Second, aldosterone increases the intracellular K+ concentration by stimulating the activity of the Na+-K+-ATPase in the basolateral membrane. Third, aldosterone directly increases the permeability of the luminal membrane to K+. Thus, aldosterone increases the rate of K+ secretion by increasing cell K+ concentration, increasing luminal membrane K+ permeability, and making the luminal potential more negative. An increase in the distal delivery of Na+ stimulates + K secretion by causing the luminal potential to become more negative. 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 of
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Potassium Homeostasis in CKD
tubular fluid such that the increase in luminal K+ concentration will be less, thus facilitating ongoing K+ secretion. Two populations of K+ channels have been identified in the cells of the cortical collecting duct.1 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.2
POTASSIUM HOMEOSTASIS IN ACUTE KIDNEY INJURY There are a number of features characteristic of acute kidney injury (AKI) which makes 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. AKI is often associated with severe reductions in the GFR (<10 mL/min) which 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 adequately develop. 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 AKI, hyperkalemia tends to be less common since distal delivery of salt and water is plentiful. Patients with AKI are more likely to have severe acidosis, increased catabolism, and tissue breakdown all leading to 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 AKI.
POTASSIUM HOMEOSTASIS IN CKD CKD is more complicated than AKI, when potassium handling is considered. In addition to the decreased GFR and secondary decrease in distal delivery, there is nephron dropout and a smaller number of collecting ducts to secrete K+ in CKD. However, this is counterbalanced by an adaptive process in which the remaining
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nephrons develop an increased ability to excrete K+. As a result hyperkalemia (S[K+] greater than 5.5 mEq/L) is uncommon in patients with CKD until the GFR falls below 15 to 20 mL/min. Studies both in experimental animals and 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 four-fold by 18 hours and approaches 85% of the control animals 7 days after removal of the contralateral intact kidney.7 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 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 controls.8 The fractional excretion of Na+ in the two groups was 2.3% and 15%, respectively. Following the intravenous administration of amiloride, the fractional excretion of K+ decreased by 87% in the CKD patients compared with 19.5% in control patients. These findings support the idea that patients with CKD are able to maintain a normal serum K+ concentration through an adaptive increase in renal K+ secretion that is largely amiloride sensitive. Despite this adaptation in CKD 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 are challenged with an acute intravenous infusion of K+ the increment in renal K+ secretion is approximately 50% less than in controls and marked hyperkalemia develops.9 In both the remnant and control groups renal K+ excretion is directly related to the S[K+] but the relationship is markedly attenuated in the remnant group. In the first 5 hours following the K+ infusion, control animals excreted 65% of the K+ load, compared to only 35% in the remnant group. Nearly 24 hours is required to re-establish K+ balance in the dogs with reduced renal mass. During this time, plasma K+ and aldosterone levels are significantly greater than in controls. Studies in patients with CKD also show a similar impairment in the ability to acutely excrete a K+ load. CKD patients develop more severe and prolonged hyperkalemia following a K+ challenge.10,11 The nature of the adaptive process which facilitates K+ excretion in CKD patients is thought to be similar to the adaptive process which occurs in response to high dietary K+ intake in normal subjects.12 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
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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 S[K+] and mineralocorticoids independently initiate the amplification process which is accompanied by an increase in Na+-K+-ATPase activity. Studies in animal models show the cortical collecting duct is an important site of K+ adaptation in 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.13 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.14–16 Loss of renal mass also leads to an increase in Na+ delivery and apical Na+ transport in this segment.17 Increased apical Na+ entry provides a further stimulatory effect on Na+-K+-ATPase activity. Changes in S[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 that seen in experimental models of chronic mineralocorticoid administration.18 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 greater than 50 to 60 mL/min.19 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 regarding whether disturbances in extrarenal K+ disposal are a characteristic feature in CKD.20 To the extent 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.21,22 Decreased intracellular K+ content has been attributed to decreased activity of the Na+-K+ATPase, which is a characteristic finding in uremia.23,24 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.23,25–27 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.28 After 7 weeks of HD, these physiologic parameters can be restored to normal, suggesting the presence of a circulating inhibitor of the Na+-K+-ATPase in some uremic patients.29 In other patients, there may be a decrease in the number of pump sites rather than decreased activity. Decreased pump activity or decreased number of pumps may account for the impaired extrarenal K+ disposal reported in some uremic patients. Plasma norepinephrine (noradrenaline) and epinephrine (adrenaline) concentrations as well as sympathetic nerve activity (at least to the leg muscles) are increased in patients with advanced stage CKD compared to normal controls.30,31 In addition the metabolic clearance rate of insulin falls with loss of renal function.32 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.33 By the time patients reach ESRD extrarenal K+ homeostasis becomes more overtly impaired.34 Fernandez et al. compared the disposition of an oral K+ load (0.25 mEq/ kg/body weight) in a group of dialysis patients and in normal controls.35 The normal controls 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 increment in plasma K+ was significantly different between the two groups. The plasma K+ concentration increased by 1.06 mEq/L in the dialysis patients. Only a 0.39 mEq/L increase was noted in the control group.
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Approach to the Hyperkalemic Patient with CKD
The impairment in K+ disposal persists even when the K+ load is accompanied by oral glucose, although glucose-induced stimulation of insulin attenuates the maximal rise in K+ levels.3
GASTROINTESTINAL EXCRETION OF K+ IN CKD In patients with CKD, 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 HD 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 PD, 25% of the daily K+ intake was lost in the feces.36,37 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 to develop hyperkalemia. The mechanism of increased gastrointestinal K+ loss is not known. The process appears to be due to active secretion, as it is unrelated to plasma K+ or total body K+.38,39 HD patients continue to have enhanced rectal K+ secretion even after dialysis. Their plasma K+ is less than that of controls. Potassium transport in the large intestine was recently studied in patients with ESRD using a rectal dialysis technique.40 Rectal K+ secretion was found to be three-fold greater in ESRD patients 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 while 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 a low level of expression was 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 ESRD patients. Exogenous administration of mineralocorticoids decreases S[K+] in anuric dialysis patients, presumably by increasing colonic potassium excretion.41 In a prospective study, fludrocortisone administered at 0.1 mg/d was compared with no treatment in 21 hyperkalemic HD patients.42 At the end of 10 months, the S[K+] in the two groups was not statistically different. However, there was a decrease in S[K+] compared with pretreatment values in patients who received the drug.
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A recent study examined the effects of glycyrrhetinic acid food supplementation on the S[K+] in a group of maintenance HD patients.43 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 the mineralocorticoid receptor remains free to only interact 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 S[K+]. 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 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 (ACEis) and angiotensin receptor blockers (ARBs) have both been reported to cause hyperkalemia in patients treated with HD and PD.44,45 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. Enhanced colonic K+ excretion in renal failure has been attributed to upregulation of angiotensin II receptors in the colon, suggesting that angiotensin II has a direct effect in stimulating colonic K+ excretion.46 Blocking the mineralocorticoid receptor with spironolactone given at a dose of 25 mg/day does not raise the serum K+ concentration in HD patients.47
APPROACH TO THE HYPERKALEMIC PATIENT WITH CKD Pseudohyperkalemia is an in vitro phenomenon due to the mechanical release of K+ from cells during the phlebotomy procedure or specimen processing. This diagnosis is made when the S[K+] exceeds the plasma K+ concentration by greater than 0.5 mmol/L. Common causes of pseudohyperkalemia include fist clenching during the phlebotomy procedure, application of tourniquets and the use of small-bore needles. Pathologic causes of pseudohyperkalemia are mostly seen in the setting of hematologic disorders such as thrombocytosis and pronounced leukocytosis. The incidence of pseudohyperkalemia increases during the winter when samples are likely to be exposed to lower ambient temperatures during transport. Higher ambient temperatures decrease the frequency of this complication. A spurious increase in plasma K+ concentration should be considered when accompanied by a very low plasma Ca++ concentration. In vitro contamination with potassium ethylenediaminetetraacetic acid (K-EDTA), a
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liquid used as an anticoagulant in certain sampling tubes, can cause this problem through Ca++ chelation and simultaneous release of K+. After excluding pseudohyperkalemia, one has to consider increased dietary intake of K+ as the underlying cause of hyperkalemia. Dietary sources particularly enriched with K+ include melons, citrus juices and salt substitutes. Other hidden sources of K+ reported to cause life-threatening hyperkalemia include raw coconut juice (K+ concentration of 44.3 mmol/L) and Noni juice (56 mEq/L). While clay ingestion can cause hypokalemia due to binding in the gastrointestinal tract, river bed clay is K+ enriched (100 mEq K+ in 100 g clay) and can cause life-threatening hyperkalemia in CKD patients. Ingestion of burnt match heads (cautopyreiophagia) can also be a hidden source of K+. This activity was found to add an additional 80 mmol of K+ to one dialysis patient’s daily intake and produced a plasma K+ concentration of 8 mmol/L.
A. Impaired Renal Excretion In the absence of pseudohyperkalemia or increased dietary K+ intake, development of hyperkalemia in a previously stable CKD patient can be traced to one or more of three abnormalities: a primary decrease in distal delivery of salt and water, a primary decrease in mineralocorticoid levels, or an abnormal cortical collecting duct.48
B. Decreased Distal Delivery of Sodium Mild to moderate reductions in renal perfusion do not typically cause distal delivery of Na+ to fall to a level that impairs K+ secretion sufficiently to result in clinically significant hyperkalemia. In untreated congestive heart failure S[K+] is typically normal or high normal despite the reduction in distal Na+ delivery as long as the impairment in cardiac function and renal perfusion is not severe. When such patients are treated with ACEIs or ARBs the fall in circulating aldosterone concentration is typically counterbalanced by increased distal Na+ delivery so that the S[K+] remains stable. The increase in distal Na+ is due to the afterload-reducing effects of these drugs, causing an improvement in cardiac output and renal perfusion. When renal perfusion becomes more severely reduced, as in patients with intractable congestive heart failure, proximal reabsorption can become so intense that very little Na+ escapes into the distal nephron. A lack of Na+ availability can begin to impair renal K+ secretion, particularly in the setting of CKD, where baseline aldosterone levels are often reduced and the capacity for increased production is limited.
Elderly subjects are prone to intravascular volume depletion due to poor intake and impaired renal Na+ conservation. The resultant decrease in distal Na+ delivery puts these patients at risk for hyperkalemia, since age is also associated with impaired release of renin and aldosterone in response to volume depletion.49 This risk increases further with concurrent use of RAAS blockers.
C. Primary Decrease in Mineralocorticoid Activity Decreased mineralocorticoid activity can result from disturbances that originate at any point along the reninangiotensin-aldosterone system (RAAS). Such disturbances can be the result of a disease state or be due to effects of various drugs (Figure 32.2). Hyporeninemic hypoaldosteronism is a common feature in CKD patients with a GFR of 20 to 60 mL/min, particularly in the setting of diabetes mellitus or interstitial renal disease. The hypoaldosteronism is primarily the result of reduced plasma renin and angiotensin II activity. In some patients plasma renin activity is normal but the secretory response of aldosterone is blunted in response to angiotensin II infusion, suggesting an intra-adrenal defect.50 In diabetic animals the impaired response of the zona glomerulosa cells to angiotensin II is caused by a post-receptor defect and is specific to angiotensin II since the aldosterone secretory response to ACTH is not diminished.51 In patients with normal renal function hypoaldosteronism alone may not be sufficient to cause marked hyperkalemia, since any rise in S[K+] will have a direct effect to enhance distal tubular K+ secretion. This direct effect is diminished in the setting of CKD, suggesting hypoaldosteronism and decreased renal function have synergistic effects in impairing renal tubular K+ secretion. Several factors have been proposed to cause both the renal and adrenal functional changes. These include a defect in prostaglandin production and/or presence of volume expansion. Prostaglandins normally stimulate renin secretion by the juxtaglomerular cells in the kidney and facilitate the stimulatory effect of angiotensin II on aldosterone release in the adrenal gland.52 Volume expansion promotes the release of atrial natriuretic peptide which in turn suppresses both renin secretion and aldosterone release.53 ACEIs and ARBs impair urinary potassium excretion by interfering in the stimulatory effect of angiotensin II on aldosterone secretion in the adrenal gland. The development of hyperkalemia is usually seen when mineralocorticoid levels are already decreased prior to the administration of the drugs either as a result of a disease state or the effects of other drugs (Table 32.2).
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Distal Tubular Defects
Angiotensin II
Angiotensin I
Angiotensin receptor blockers
Angiotensinconverting enzyme inhibitors Directrenin inhibitor Afferent arteriole Renin Juxtaglomerular cells
Impaired release of renin
NSAIDs Beta blockers Cyclosporine, tacrolimus diabetes elderly
Aldosterone
Impaired aldosterone metabolism
Adrenal gland
Sodium channel blockers Amiloride triamterene trimethoprim pentamidine
Adrenal disease heparin ketoconazole Collecting duct (principal cell)
Na+ Na+ Lumen (–)
K+ K+ Aldosterone receptor blockers Spironolactone eplerenone drospirenone
FIGURE 32.2 The RAAS and regulation of renal K+ excretion. Aldosterone binds to a cytosolic receptor in the principal cell and stimulates
Na+ reabsorption across the luminal membrane through a well-defined Na+ channel. As Na+ is reabsorbed, the electronegativity of the lumen increases, thereby providing a more favorable driving force for K+ secretion through an apically located K+ channel. The permeability of the anion that accompanies Na+ also influences K+ secretion. Less permeable anions have a greater stimulatory effect on K+ secretion. Disease states or drugs that interfere at any point along this system can impair renal K+ secretion and increase the risk of hyperkalemia. In many patients this risk is magnified due to disturbances at multiple sites along this system. NSAIDs: non-steroidal anti-inflammatory drugs.
TABLE 32.2 Risk Factors for Hyperkalemia When Using Drugs that Interfere with the RAAS CKD: risk is inversely related to GFR and increases substantially below 30 mL/min Diabetes mellitus Decompensated congestive heart failure Volume depletion Elderly patients Concomitant use of drugs that interfere with renal potassium excretion Non-steroidal anti-inflammatory drugs β-Blockers Calcineurin inhibitors: Cyclosporin, Tacrolimus Heparin Ketoconazole Potassium sparing diuretics: spironolactone, eplerenone, amiloride, triamterene Trimethoprim Pentamidine Potassium supplements including salt substitutes and certain herbs
Hyperkalemia has been reported to develop in 44 to 73% of kidney transplant patients treated with the immunosuppressive drugs cyclosporine or tacrolimus.54 These drugs suppress renin release and directly
interfere with renal K+ secretion in the collecting duct.55 Beta adrenergic blockade can predispose to the development of hyperkalemia through two potential mechanisms.56 These drugs block the stimulatory effect of the sympathetic nervous system on renin release. In addition, these drugs can interfere in the cellular uptake of K+ through decreased activity of the Na+-K+-ATPase.57
DISTAL TUBULAR DEFECTS Certain interstitial renal diseases can affect the distal nephron specifically, and lead to the development of hyperkalemia in the presence of only mild decreases in GFR and normal aldosterone levels. Amiloride and triamterene inhibit Na+ transport, which makes the luminal potential more positive and secondarily inhibits K+ secretion. A similar effect occurs with trimethoprim and accounts for the development of hyperkalemia following the administration of the antibiotic trimethoprimsulfamethoxazole.58 Spironolactone and eplerenone compete with aldosterone and thus block the mineralocorticoid effect.
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TREATMENT OF HYPERKALEMIA IN THE CKD PATIENT The initial approach is to review the patient’s medication profile and whenever possible discontinue drugs that can impair renal K+ excretion. Patients should be specifically questioned regarding the use of over-thecounter non-steroidal anti-inflammatory drugs as well as herbal remedies, since herbs may be a hidden source of dietary potassium. Patients should be placed on a low K+ diet with specific counseling against the use of K+ containing salt substitutes. Diuretics are particularly effective in minimizing hyperkalemia. Diuretics enhance renal K+ excretion by increasing the delivery of Na+ to the collecting duct. In patients with an eGFR greater than 30 mL/min/1.73 m2, thiazide diuretics can be used, but in those with more severe decrements in renal function, loop diuretics are required. In patients with CKD and metabolic acidosis administration of sodium bicarbonate is an effective strategy to minimize increases in S[K+]. This drug increases renal K+ excretion as a result of increased distal Na+ delivery and shifts K+ into cells as the acidosis is corrected. Ensuring that the patient is first on effective diuretic therapy will lessen the likelihood of developing volume overload as a complication of sodium bicarbonate administration. The development of hyperkalemia after the administration of RAAS blockers is of particular concern, because patients at highest risk for this complication are often the same ones who derive the greatest cardiovascular benefit (Table 32.3). In addition to the steps mentioned previously, the risk of hyperkalemia with these
drugs can be minimized by initiating therapy at low doses. The S[K+] should be checked within 1 week of starting the drug. If the S[K+] is normal then the dose of the drug can be titrated upwards. With each increase in dose the S[K+] should be remeasured 1 week later. For increases in the S[K+] up to 5.5 mEq/L, one can try lowering the dose. In some cases the S[K+] will improve, allowing the patient to remain on the RAAS blocker, albeit at a lower dose. In patients at risk for hyperkalemia, ARBs and direct renin inhibitors should be used with the same caution as ACEIs. Sodium polystyrene sulfonate is commonly used to treat hyperkalemia in the acute setting. However, chronic use is poorly tolerated because the resin is usually given in a suspension with hypertonic sorbitol to promote an osmotic diarrhea. In addition, chronic use had been associated with mucosal injury in the lower and upper gastrointestinal tract.
CONCLUSION Adaptive increases in renal and gastrointestinal excretion of K+ help to prevent hyperkalemia in patients with CKD as long as the GFR remains greater than 15 to 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. In clinical practice hyperkalemia is usually the result of a combination of factors superimposed on renal dysfunction.
TABLE 32.3 Approach to Patients at Risk for Hyperkalemia When Using Drugs that Interfere with the RAAS
References
Accurately assess level of renal function to better define risk Discontinue drugs that interfere in renal potassium secretion, inquire about herbal preparations and discontinue non-steroidal antiinflammatory drugs, including the selective cyclo-oxygenase 2 inhibitors Low potassium diet, inquire about potassium containing salt substitutes Thiazide or loop diuretics (loop diuretics necessary when eGFR is less than 30 mL/min/1.73 m2) Sodium bicarbonate to correct metabolic acidosis in CKD patients Initiate therapy with low-dose ACEI or ARB Measure potassium 1 week after initiation of therapy or after increasing dose of drug For increases in S[K+] up to 5.5 mEq/L, decrease dose of drug, if taking some combination of ACEI, ARB, or aldosterone receptor blocker discontinue one and re-check S[K+] The dose of spironolactone should not exceed 25 mg daily when used with an ACEI or ARB. This combination of drugs should be avoided in CKD patients with GFR less than 30 mL/min For S[K+] ≥5.6 mEq/L despite above steps, discontinue drugs
1. van Ypersele, de Strihou C. Potassium homeostasis in renal failure. Kidney Int 1977;11:491–504. 2. Gennari FJ, Segal AS. An adaptive response in chronic renal insufficiency. Kidney Int 2002;62:1–9. 3. Sarafidis PA, Blacklock R, Wood E, Rumjon A, Simmonds S, Fletcher-Rogers J, et al. Prevalence and factors associated with hyperkalemia in predialysis patients followed in a low-clearance clinic. Clin J Am Soc Nephrol 2012;7:1234–41. 4. Einhorn LM, Zhan M, Hsu VD, Walker LD, Moen MF, Seliger SL, et al. The frequency of hyperkalemia and its significance in chronic kidney disease. Arch Intern Med 2009;169:1156–62. 5. Montague BT, Ouellette JR, Butler GK. Retrospective review of the frequency of ECG changes in hyperkalemia. Clin J Am Soc Nephrol 2008;3:324–30. 6. Palmer BF. Hyperkalemia in predialysis patients. Clin J Am Soc Nephrol 2012;7:1201–2. 7. 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;50:1061–8. 8. Levy YN, Fellet A, Arranz C, Balaszczuk AM, Adrogué HJ. Amiloride-sensitive and amiloride-insensitive kaliuresis in advanced chronic kidney disease. J Nephrol 2008;21:93–8.
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9. Bourgoignie JJ, Kaplan M, Pincus J, Gavellas G, Rabinovitch A. Renal handling of potassium in dogs with chronic renal insufficiency. Kidney Int 1981;20:482–90. 10. Gonick HC, Kleeman CR, Rubini ME, Maxwell MH. Functional impairment in chronic renal disease. 3. Studies of potassium excretion. Am J Med Sci 1971;261:281–90. 11. Perez GO, Pelleya R, Oster JR, Kem DC, Vaamonde CA. Blunted kaliuresis after an acute potassium load in patients with chronic renal failure. Kidney Int 1983;24:656–62. 12. Stanton BA. Renal potassium transport: morphological and functional adaptations. Am J Physiol 1989;257:R989–97. 13. Fine LG, Yanagawa N, Schultze RG, Tuck M, Trizna W. Functional profile of the isolated uremic nephron: potassium adaptation in the rabbit cortical collecting tubule. J Clin Invest 1979;64:1033–43. 14. Zalups RK, Stanton BA, Wade JB, Giebisch G. Structural adaptation in initial collecting tubule following reduction in renal mass. Kidney Int 1985;27:636–42. 15. Scherzer P, Wald H, Czaczkes JW. Na-K-ATPase in isolated rabbit tubules after unilateral nephrectomy and Na+ loading. Am J Physiol 1985;248:F565–73. 16. Mujais SK, Kurtzman NA. Regulation of renal Na-K-ATPase in the rat: effect of uninephrectomy. Am J Physiol 1986;251:F506–12. 17. Vehaskari VM, Hering-Smith KS, Klahr S, Hamm LL. Increased sodium transport by cortical collecting tubules from remnant kidneys. Kidney Int 1989;36:89–95. 18. Stanton B, Pan L, Deetjen H, Guckian V, Giebisch G. Independent effects of aldosterone and potassium on induction of potassium adaptation in rat kidney. J Clin Invest 1987;79:198–206. 19. Hené RJ, Boer P, Koomans HA, Mees EJ. Plasma aldosterone concentrations in chronic renal disease. Kidney Int 1982;21:98–101. 20. 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;18:421–40. 21. Montanari A, Graziani G, Borghi L, Cantaluppi A, Simoni I, Lorenzano E, et al. Skeletal muscle water and electrolytes in chronic renal failure: effects of long-term regular dialysis treatment. Nephron 1985;39:316–20. 22. Bergstrom J, Alvestrand A, Furst P, Hultman E, Widstam-Attorps U. Muscle intracellular electrolytes in patients with chronic uremia. Kidney Int 1983;24(Suppl. 16):S153–60. 23. Cheng J-T, Kahn T, Kaji DM. Mechanism of alteration of sodium potassium pump of erythrocytes from patients with chronic renal failure. J Clin Invest 1984;74:1811–20. 24. Zannad F, Royer RJ, Kessler M, et al. Cation transport in erythrocytes of patients with renal failure. Nephron 1982;32:347–50. 25. Quarello F, Boero R, Guarena C, Rosati C, Giraudo G, Giacchino F, et al. Acute effects of hemodialysis on erythrocyte sodium fluxes in uremic patients. Nephron 1985;41:22–5. 26. Kramer HJ, Gospodinov D, Kruck D. Functional and metabolic studies on red blood cell sodium transport in chronic uremia. Nephron 1976;16:344–58. 27. Izumo H, Izumo S, DeLuise M, Flier JS. Erythrocyte Na,K pump in uremia: acute correction of a transport defect by hemodialysis. J Clin Invest 1984;74:581–8. 28. Cotton JR, Woodard T, Carter NW, Knochel JP. Resting skeletal muscle membrane potential as an index of uremic toxicity. J Clin Invest 1979;63:501–6. 29. Kaji D, Kahn T. Na+-K+ pump in chronic renal failure. Am J Physiol 1987;252:F785–93. 30. Darwish R, Elias AN, Vaziri ND, Pahl M. Plasma and urinary catecholamines and their metabolites in chronic renal failure. Arch Intern Med 1984;144:69. 31. Converse Jr RL, Jacobsen TN, Toto RD, Jost CM, Cosentino F, Fouad-Tarazi F, et al. Sympathetic overactivity in patients with chronic renal failure. N Engl J Med 1992;327:1912.
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32. Adrogué HJ. Glucose homeostasis and the kidney. Kidney Int 1992;42:1266. 33. Alvestrand A, Wahren J, Smith D, DeFronzo RA. Insulinmediated potassium uptake is normal in uremic and healthy subjects. Am J Physiol 1984;246:E174–80. 34. Alvo M, Krsulovic P, Fernandez V, Espinoza AM, Escobar M, Marusic ET, et al. Effect of a simultaneous potassium and carbohydrate load on extrarenal K homeostasis in end-stage renal failure. Nephron 1989;53:133–7. 35. 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;12:125–9. 36. Hayes Jr CP, Robinson RR. Fecal potassium excretion in patients on chronic intermittent hemodialysis. Trans Am Soc Artif Intern Organs 1965;11:242. 37. Hayes Jr CP, 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. 38. Sandle GI, Gaiger E, Tapster S, Goodship TH. Enhanced rectal potassium secretion in chronic renal insufficiency: evidence for large intestinal potassium adaptation in man. Clin Sci (Lond) 1986;71:393–401. 39. Martin RS, Panese S, Virginillo M, Gimenez M, Litardo M, Arrizurieta E, et al. Increased secretion of potassium in the rectum of humans with chronic renal failure. Am J Kidney Dis 1986;8:105–10. 40. 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. 41. Imbriano LJ, Durham JH, Maesaka JK. Treating interdialytic hyperkalemia with fludrocortisone. Semin Dial 2003;16:5–7. 42. Dong-Min K, Chung J, Yoon S, Kim H. Effect of fludrocortisones acetate on reducing serum potassium levels in patients with end-stage renal disease undergoing haemodialysis. Nephrol Dial Transplant 2007;22:3273–6. 43. Farese S, Kruse A, Pasch A, Dick B, Frey BM, Uehlinger DE, et al. Glycyrrhetinic acid food supplementation lowers serum potassium concentration in chronic hemodialysis patients. Kidney Int 2009;76:877–84. 44. Knoll GA, Sahgal A, Nair RC, Graham J, van Walraven C, Burns KD. Renin-angiotensin system blockade and the risk of hyperkalemia in chronic hemodialysis patients. Am J Med 2002;112:110–4. 45. Prakdeekitcharoen B, Leelasa-nguan P. Effects of an ACE inhibitor or angiotensin receptor blocker on potassium in CAPD patients. Am J Kidney Dis 2004;44:738–46. 46. Hatch M, Freel RW, Vaziri ND. Local up-regulation of colonic angiotensin II receptors enhances potassium excretion in chronic renal failure. Am J Physiol Renal Physiol 1998;274(43):F275–82. 47. Saudan P, Mach F, Perneger T, Schnetzler B, Stoermann C, Fumeaux Z, et al. Safety of low-dose spironolactone administration in chronic haemodialysis patients. Nephrol Dial Transplant 2003;18:2359–63. 48. Palmer BF. A physiologic based approach to the evaluation of a patient with hyperkalemia. Am J Kidney Ds 2010;56:387–93. 49. Weidmann P, De Myttenaere-Bursztein S, Maxwell M, de Lima J. Effect of aging on plasma renin and aldosterone in normal man. Kidney Intl 1975;8:325–33. 50. 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. 51. Azukizawa S, Kaneko M, Nakano S, Kigoshi T, Uchida K, Morimoto S. Angiotensin II receptor and postreceptor events in adrenal zona glomerulosa cells from streptozotocin-induced
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diabetic rats with hypoaldosteronism. Endocrinology 1991;129: 2729–33. 52. Nadler JL, Lee FO, Hsuch W, Horton R. Evidence of prostacyclin deficiency in the syndrome of hyporeninemic hypoaldosteronism. N Engl J Med 1986;314:1015–20. 53. Clark BA, Brown RS, Epstein F. Effect of atrial natriuretic peptide on potassium-stimulated aldosterone secretion: potential relevance to hypoaldosteronism in man. J Clin Endocrinol Metab 1992;75:399–403. 54. Kaplan B, Wang Z, Abecassis M, Fryer J, Stuart F, Kaufman D. Frequency of hyperkalemia of simultaneous pancreas and kidney transplants with bladder drainage. Transplantation 1996;62:1174–5.
55. Kamel K, Ethier J, Quaggin S, Levin A, Albert S, Carlisle EJ, et al. Studies to determine the basis for hyperkalemia in recipients of a renal transplant who are treated with cyclosporine. J Am Soc Nephrol 1992;2:1279–84. 56. McCauley J, Murray J, Jordan M, Scantlebury V, Vivas C, Shapiro R. Labetalol-induced hyperkalemia in renal transplant recipients. Am J Nephrol 2002;22:347–51. 57. Castellino P, Simonson D, DeFronzo R. Adrenergic modulation of potassium metabolism during exercise in normal and diabetic humans. Am J Physiol 1987;252:E68–76. 58. Perazella MA. Trimethoprim is a potassium-sparing diuretic like amiloride and causes hyperkalemia in high-risk patients. Am J Ther 1997;4:343–8.
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32 Potassium Metabolism in Chronic Kidney Disease Biff F. Palmer Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA
INTRODUCTION This chapter deals with potassium (K+) metabolism in patients with CKD. The scope of the problem, normal renal K+ homeostasis, and adaptations in renal K+ handling which characterize CKD are considered. The approach to and treatment of K+ disorders in patients with CKD up to the point at which RRT is required are unique.
SCOPE OF THE PROBLEM In patients with CKD loss of nephron mass is counterbalanced by an adaptive increase in the secretory rate of K+ in remaining nephrons, such that K+ homeostasis is generally well maintained until the GFR falls below 15 to 20 mL/min.1 More severe renal dysfunction invariably leads to K+ retention and hyperkalemia unless the rate of dietary potassium intake is reduced. In a random sample of 300 CKD patients (S[Cr] ranging from 1.5 to 6.0 mg/dL) excluding diabetics and those taking drugs that interfere in angiotensin II synthesis or effect, the incidence of hyperkalemia was 55% (K+ ≥5.5 mEq/L).2 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 (Table 32.1). Such is the case in diabetics where decreased mineralocorticoid activity is often an early finding due to hyporeninemic
P. Kimmel & M. Rosenberg (Eds): Chronic Renal Disease. DOI: http://dx.doi.org/10.1016/B978-0-12-411602-3.00032-9
hypoaldosteronism, or in patients with advanced stages of heart failure with accompanying reductions in distal delivery of Na+ combined with concurrent use of drugs which interfere with the RAAS. In these settings hyperkalemia is common and can develop with only mild or moderate reductions in GFR. One study attempted to identify all of the factors known to interfere in K+ homeostasis simultaneously present during a single clinic visit in a population of CKD patients.3 These patients were receiving regular follow-up in a clinic specifically designed and structured to optimize the care of advanced CKD. Despite the focus of the clinic the mean S[K+] was increased at 5.1 mEq/L in 54.2% of patients. While the average eGFR of the entire study population was 14.4 mL/ min/1.73 m2 those with hyperkalemia had a significantly lower eGFR compared to those without (14.8 vs. 13.5 mL/min/1.73 m2). In addition to worse renal function, hyperkalemic subjects had significantly lower serum bicarbonate concentrations (22.5 vs. 24.1 mEq/L). While adaptive mechanisms in the CKD patient may attenuate cardiac toxicity from increased K+, hyperkalemic events are still associated with an increased risk of death in this population.4 The electrocardiogram in a hyperkalemic subject can progress from normal to ventricular tachycardia and asystole in a precipitous manner.5 The frequency of hyperkalemia in the CKD patient makes a strong argument for early referral and management of these patients in a clinic environment focused on the management of this common electrolyte disorder.6
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TABLE 32.1 Causes of Hyperkalemia Pseudohyperkalemia Cellular redistribution Mineral acidosis Cell shrinkage (hypertonicity) Deficiency of insulin β-Blockers Hyperkalemic periodic paralysis Cell injury Excess intake (very rare) Decreased renal excretion Decreased distal delivery of Na+ (oliguric renal failure) Mineralocorticoid deficiency Defect of cortical collecting tubule
Principal cell Lumen
Interstitium Mineralocorticoids
Distal delivery of Na+
3Na+ Na+
Na+
2K+
3Na+ 2K+
(–) K+
K+
FIGURE 32.1 Cell model for renal regulation of K+ secretion by the principal cell in the collecting tubule.
NORMAL POTASSIUM HOMEOSTASIS Potassium plays a key role in maintaining cell function. All cells possess a Na+-K+-ATPase which pumps Na+ out of the cell and K+ into the cell. This leads to a K+ gradient across the cell membrane (K+in > K+out) which is partially responsible for maintaining the potential difference across the membrane. This potential difference is important to the function of all cells, but is especially important in excitable tissues such as nerve and muscle. For these reasons, there are numerous mechanisms for defense of S[K+]. Total body K+ is approximately 50 mEq/kg, which in a 70 kg person would be 3500 mEq. The vast majority, approximately 98%, of this K+ is within cells, with only about 2% in the extracellular fluid. The normal concentration of K+ in the extracellular fluid is 3.5 to 5.3 mEq/L. Large deviations from these values are not compatible with life. The typical American diet includes 50 to 100 mEq/day of K+. Approximately 90% of the daily K+ intake is excreted in the urine, while 10% is excreted by the GI tract. The kidney and gastrointestinal tract respond directionally when K+ intake increases or decreases.
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 such that only 10% of the filtered load reaches the distal nephron. In the proximal tubule K+ absorption is passive and is in rough proportion 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 physiologic and pathologic conditions,
K+ delivery to the distal nephron remains small and is fairly constant. By contrast, the rate of K+ secretion by the distal nephron varies significantly and is highly regulated according to physiologic needs. K+ secretion in the distal nephron is generally responsible for most of the urinary K+ excretion. The specialized cell which is responsible for K+ secretion in the initial collecting duct and the cortical collecting duct is the principal cell (Figure 32.1). The cellular determinants of K+ secretion include the cell K+ concentration, luminal K+ concentration, the transepithelial potential difference (voltage) across the luminal membrane, and the permeability of the luminal membrane for K+. Two of the most important factors which influence these determinants are mineralocorticoid activity and the distal delivery of Na+ and water. Aldosterone interacts with the intracellular mineralocorticoid receptor in the principal cell to stimulate K+ secretion by affecting several of the cellular determinants discussed above. First, aldosterone stimulates Na+ reabsorption across the luminal membrane by increasing the open probability of the epithelial sodium channel on the apical membrane (ENaC), which increases the electronegativity of the lumen, thereby increasing the electrical gradient favoring K+ secretion. Second, aldosterone increases the intracellular K+ concentration by stimulating the activity of the Na+-K+-ATPase in the basolateral membrane. Third, aldosterone directly increases the permeability of the luminal membrane to K+. Thus, aldosterone increases the rate of K+ secretion by increasing cell K+ concentration, increasing luminal membrane K+ permeability, and making the luminal potential more negative. An increase in the distal delivery of Na+ stimulates + K secretion by causing the luminal potential to become more negative. 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 of
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Potassium Homeostasis in CKD
tubular fluid such that the increase in luminal K+ concentration will be less, thus facilitating ongoing K+ secretion. Two populations of K+ channels have been identified in the cells of the cortical collecting duct.1 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.2
POTASSIUM HOMEOSTASIS IN ACUTE KIDNEY INJURY There are a number of features characteristic of acute kidney injury (AKI) which makes 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. AKI is often associated with severe reductions in the GFR (<10 mL/min) which 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 adequately develop. 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 AKI, hyperkalemia tends to be less common since distal delivery of salt and water is plentiful. Patients with AKI are more likely to have severe acidosis, increased catabolism, and tissue breakdown all leading to 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 AKI.
POTASSIUM HOMEOSTASIS IN CKD CKD is more complicated than AKI, when potassium handling is considered. In addition to the decreased GFR and secondary decrease in distal delivery, there is nephron dropout and a smaller number of collecting ducts to secrete K+ in CKD. However, this is counterbalanced by an adaptive process in which the remaining
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nephrons develop an increased ability to excrete K+. As a result hyperkalemia (S[K+] greater than 5.5 mEq/L) is uncommon in patients with CKD until the GFR falls below 15 to 20 mL/min. Studies both in experimental animals and 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 four-fold by 18 hours and approaches 85% of the control animals 7 days after removal of the contralateral intact kidney.7 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 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 controls.8 The fractional excretion of Na+ in the two groups was 2.3% and 15%, respectively. Following the intravenous administration of amiloride, the fractional excretion of K+ decreased by 87% in the CKD patients compared with 19.5% in control patients. These findings support the idea that patients with CKD are able to maintain a normal serum K+ concentration through an adaptive increase in renal K+ secretion that is largely amiloride sensitive. Despite this adaptation in CKD 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 are challenged with an acute intravenous infusion of K+ the increment in renal K+ secretion is approximately 50% less than in controls and marked hyperkalemia develops.9 In both the remnant and control groups renal K+ excretion is directly related to the S[K+] but the relationship is markedly attenuated in the remnant group. In the first 5 hours following the K+ infusion, control animals excreted 65% of the K+ load, compared to only 35% in the remnant group. Nearly 24 hours is required to re-establish K+ balance in the dogs with reduced renal mass. During this time, plasma K+ and aldosterone levels are significantly greater than in controls. Studies in patients with CKD also show a similar impairment in the ability to acutely excrete a K+ load. CKD patients develop more severe and prolonged hyperkalemia following a K+ challenge.10,11 The nature of the adaptive process which facilitates K+ excretion in CKD patients is thought to be similar to the adaptive process which occurs in response to high dietary K+ intake in normal subjects.12 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
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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 S[K+] and mineralocorticoids independently initiate the amplification process which is accompanied by an increase in Na+-K+-ATPase activity. Studies in animal models show the cortical collecting duct is an important site of K+ adaptation in 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.13 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.14–16 Loss of renal mass also leads to an increase in Na+ delivery and apical Na+ transport in this segment.17 Increased apical Na+ entry provides a further stimulatory effect on Na+-K+-ATPase activity. Changes in S[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 that seen in experimental models of chronic mineralocorticoid administration.18 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 greater than 50 to 60 mL/min.19 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 regarding whether disturbances in extrarenal K+ disposal are a characteristic feature in CKD.20 To the extent 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.21,22 Decreased intracellular K+ content has been attributed to decreased activity of the Na+-K+ATPase, which is a characteristic finding in uremia.23,24 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.23,25–27 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.28 After 7 weeks of HD, these physiologic parameters can be restored to normal, suggesting the presence of a circulating inhibitor of the Na+-K+-ATPase in some uremic patients.29 In other patients, there may be a decrease in the number of pump sites rather than decreased activity. Decreased pump activity or decreased number of pumps may account for the impaired extrarenal K+ disposal reported in some uremic patients. Plasma norepinephrine (noradrenaline) and epinephrine (adrenaline) concentrations as well as sympathetic nerve activity (at least to the leg muscles) are increased in patients with advanced stage CKD compared to normal controls.30,31 In addition the metabolic clearance rate of insulin falls with loss of renal function.32 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.33 By the time patients reach ESRD extrarenal K+ homeostasis becomes more overtly impaired.34 Fernandez et al. compared the disposition of an oral K+ load (0.25 mEq/ kg/body weight) in a group of dialysis patients and in normal controls.35 The normal controls 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 increment in plasma K+ was significantly different between the two groups. The plasma K+ concentration increased by 1.06 mEq/L in the dialysis patients. Only a 0.39 mEq/L increase was noted in the control group.
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Approach to the Hyperkalemic Patient with CKD
The impairment in K+ disposal persists even when the K+ load is accompanied by oral glucose, although glucose-induced stimulation of insulin attenuates the maximal rise in K+ levels.3
GASTROINTESTINAL EXCRETION OF K+ IN CKD In patients with CKD, 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 HD 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 PD, 25% of the daily K+ intake was lost in the feces.36,37 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 to develop hyperkalemia. The mechanism of increased gastrointestinal K+ loss is not known. The process appears to be due to active secretion, as it is unrelated to plasma K+ or total body K+.38,39 HD patients continue to have enhanced rectal K+ secretion even after dialysis. Their plasma K+ is less than that of controls. Potassium transport in the large intestine was recently studied in patients with ESRD using a rectal dialysis technique.40 Rectal K+ secretion was found to be three-fold greater in ESRD patients 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 while 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 a low level of expression was 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 ESRD patients. Exogenous administration of mineralocorticoids decreases S[K+] in anuric dialysis patients, presumably by increasing colonic potassium excretion.41 In a prospective study, fludrocortisone administered at 0.1 mg/d was compared with no treatment in 21 hyperkalemic HD patients.42 At the end of 10 months, the S[K+] in the two groups was not statistically different. However, there was a decrease in S[K+] compared with pretreatment values in patients who received the drug.
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A recent study examined the effects of glycyrrhetinic acid food supplementation on the S[K+] in a group of maintenance HD patients.43 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 the mineralocorticoid receptor remains free to only interact 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 S[K+]. 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 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 (ACEis) and angiotensin receptor blockers (ARBs) have both been reported to cause hyperkalemia in patients treated with HD and PD.44,45 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. Enhanced colonic K+ excretion in renal failure has been attributed to upregulation of angiotensin II receptors in the colon, suggesting that angiotensin II has a direct effect in stimulating colonic K+ excretion.46 Blocking the mineralocorticoid receptor with spironolactone given at a dose of 25 mg/day does not raise the serum K+ concentration in HD patients.47
APPROACH TO THE HYPERKALEMIC PATIENT WITH CKD Pseudohyperkalemia is an in vitro phenomenon due to the mechanical release of K+ from cells during the phlebotomy procedure or specimen processing. This diagnosis is made when the S[K+] exceeds the plasma K+ concentration by greater than 0.5 mmol/L. Common causes of pseudohyperkalemia include fist clenching during the phlebotomy procedure, application of tourniquets and the use of small-bore needles. Pathologic causes of pseudohyperkalemia are mostly seen in the setting of hematologic disorders such as thrombocytosis and pronounced leukocytosis. The incidence of pseudohyperkalemia increases during the winter when samples are likely to be exposed to lower ambient temperatures during transport. Higher ambient temperatures decrease the frequency of this complication. A spurious increase in plasma K+ concentration should be considered when accompanied by a very low plasma Ca++ concentration. In vitro contamination with potassium ethylenediaminetetraacetic acid (K-EDTA), a
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liquid used as an anticoagulant in certain sampling tubes, can cause this problem through Ca++ chelation and simultaneous release of K+. After excluding pseudohyperkalemia, one has to consider increased dietary intake of K+ as the underlying cause of hyperkalemia. Dietary sources particularly enriched with K+ include melons, citrus juices and salt substitutes. Other hidden sources of K+ reported to cause life-threatening hyperkalemia include raw coconut juice (K+ concentration of 44.3 mmol/L) and Noni juice (56 mEq/L). While clay ingestion can cause hypokalemia due to binding in the gastrointestinal tract, river bed clay is K+ enriched (100 mEq K+ in 100 g clay) and can cause life-threatening hyperkalemia in CKD patients. Ingestion of burnt match heads (cautopyreiophagia) can also be a hidden source of K+. This activity was found to add an additional 80 mmol of K+ to one dialysis patient’s daily intake and produced a plasma K+ concentration of 8 mmol/L.
A. Impaired Renal Excretion In the absence of pseudohyperkalemia or increased dietary K+ intake, development of hyperkalemia in a previously stable CKD patient can be traced to one or more of three abnormalities: a primary decrease in distal delivery of salt and water, a primary decrease in mineralocorticoid levels, or an abnormal cortical collecting duct.48
B. Decreased Distal Delivery of Sodium Mild to moderate reductions in renal perfusion do not typically cause distal delivery of Na+ to fall to a level that impairs K+ secretion sufficiently to result in clinically significant hyperkalemia. In untreated congestive heart failure S[K+] is typically normal or high normal despite the reduction in distal Na+ delivery as long as the impairment in cardiac function and renal perfusion is not severe. When such patients are treated with ACEIs or ARBs the fall in circulating aldosterone concentration is typically counterbalanced by increased distal Na+ delivery so that the S[K+] remains stable. The increase in distal Na+ is due to the afterload-reducing effects of these drugs, causing an improvement in cardiac output and renal perfusion. When renal perfusion becomes more severely reduced, as in patients with intractable congestive heart failure, proximal reabsorption can become so intense that very little Na+ escapes into the distal nephron. A lack of Na+ availability can begin to impair renal K+ secretion, particularly in the setting of CKD, where baseline aldosterone levels are often reduced and the capacity for increased production is limited.
Elderly subjects are prone to intravascular volume depletion due to poor intake and impaired renal Na+ conservation. The resultant decrease in distal Na+ delivery puts these patients at risk for hyperkalemia, since age is also associated with impaired release of renin and aldosterone in response to volume depletion.49 This risk increases further with concurrent use of RAAS blockers.
C. Primary Decrease in Mineralocorticoid Activity Decreased mineralocorticoid activity can result from disturbances that originate at any point along the reninangiotensin-aldosterone system (RAAS). Such disturbances can be the result of a disease state or be due to effects of various drugs (Figure 32.2). Hyporeninemic hypoaldosteronism is a common feature in CKD patients with a GFR of 20 to 60 mL/min, particularly in the setting of diabetes mellitus or interstitial renal disease. The hypoaldosteronism is primarily the result of reduced plasma renin and angiotensin II activity. In some patients plasma renin activity is normal but the secretory response of aldosterone is blunted in response to angiotensin II infusion, suggesting an intra-adrenal defect.50 In diabetic animals the impaired response of the zona glomerulosa cells to angiotensin II is caused by a post-receptor defect and is specific to angiotensin II since the aldosterone secretory response to ACTH is not diminished.51 In patients with normal renal function hypoaldosteronism alone may not be sufficient to cause marked hyperkalemia, since any rise in S[K+] will have a direct effect to enhance distal tubular K+ secretion. This direct effect is diminished in the setting of CKD, suggesting hypoaldosteronism and decreased renal function have synergistic effects in impairing renal tubular K+ secretion. Several factors have been proposed to cause both the renal and adrenal functional changes. These include a defect in prostaglandin production and/or presence of volume expansion. Prostaglandins normally stimulate renin secretion by the juxtaglomerular cells in the kidney and facilitate the stimulatory effect of angiotensin II on aldosterone release in the adrenal gland.52 Volume expansion promotes the release of atrial natriuretic peptide which in turn suppresses both renin secretion and aldosterone release.53 ACEIs and ARBs impair urinary potassium excretion by interfering in the stimulatory effect of angiotensin II on aldosterone secretion in the adrenal gland. The development of hyperkalemia is usually seen when mineralocorticoid levels are already decreased prior to the administration of the drugs either as a result of a disease state or the effects of other drugs (Table 32.2).
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Distal Tubular Defects
Angiotensin II
Angiotensin I
Angiotensin receptor blockers
Angiotensinconverting enzyme inhibitors Directrenin inhibitor Afferent arteriole Renin Juxtaglomerular cells
Impaired release of renin
NSAIDs Beta blockers Cyclosporine, tacrolimus diabetes elderly
Aldosterone
Impaired aldosterone metabolism
Adrenal gland
Sodium channel blockers Amiloride triamterene trimethoprim pentamidine
Adrenal disease heparin ketoconazole Collecting duct (principal cell)
Na+ Na+ Lumen (–)
K+ K+ Aldosterone receptor blockers Spironolactone eplerenone drospirenone
FIGURE 32.2 The RAAS and regulation of renal K+ excretion. Aldosterone binds to a cytosolic receptor in the principal cell and stimulates
Na+ reabsorption across the luminal membrane through a well-defined Na+ channel. As Na+ is reabsorbed, the electronegativity of the lumen increases, thereby providing a more favorable driving force for K+ secretion through an apically located K+ channel. The permeability of the anion that accompanies Na+ also influences K+ secretion. Less permeable anions have a greater stimulatory effect on K+ secretion. Disease states or drugs that interfere at any point along this system can impair renal K+ secretion and increase the risk of hyperkalemia. In many patients this risk is magnified due to disturbances at multiple sites along this system. NSAIDs: non-steroidal anti-inflammatory drugs.
TABLE 32.2 Risk Factors for Hyperkalemia When Using Drugs that Interfere with the RAAS CKD: risk is inversely related to GFR and increases substantially below 30 mL/min Diabetes mellitus Decompensated congestive heart failure Volume depletion Elderly patients Concomitant use of drugs that interfere with renal potassium excretion Non-steroidal anti-inflammatory drugs β-Blockers Calcineurin inhibitors: Cyclosporin, Tacrolimus Heparin Ketoconazole Potassium sparing diuretics: spironolactone, eplerenone, amiloride, triamterene Trimethoprim Pentamidine Potassium supplements including salt substitutes and certain herbs
Hyperkalemia has been reported to develop in 44 to 73% of kidney transplant patients treated with the immunosuppressive drugs cyclosporine or tacrolimus.54 These drugs suppress renin release and directly
interfere with renal K+ secretion in the collecting duct.55 Beta adrenergic blockade can predispose to the development of hyperkalemia through two potential mechanisms.56 These drugs block the stimulatory effect of the sympathetic nervous system on renin release. In addition, these drugs can interfere in the cellular uptake of K+ through decreased activity of the Na+-K+-ATPase.57
DISTAL TUBULAR DEFECTS Certain interstitial renal diseases can affect the distal nephron specifically, and lead to the development of hyperkalemia in the presence of only mild decreases in GFR and normal aldosterone levels. Amiloride and triamterene inhibit Na+ transport, which makes the luminal potential more positive and secondarily inhibits K+ secretion. A similar effect occurs with trimethoprim and accounts for the development of hyperkalemia following the administration of the antibiotic trimethoprimsulfamethoxazole.58 Spironolactone and eplerenone compete with aldosterone and thus block the mineralocorticoid effect.
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TREATMENT OF HYPERKALEMIA IN THE CKD PATIENT The initial approach is to review the patient’s medication profile and whenever possible discontinue drugs that can impair renal K+ excretion. Patients should be specifically questioned regarding the use of over-thecounter non-steroidal anti-inflammatory drugs as well as herbal remedies, since herbs may be a hidden source of dietary potassium. Patients should be placed on a low K+ diet with specific counseling against the use of K+ containing salt substitutes. Diuretics are particularly effective in minimizing hyperkalemia. Diuretics enhance renal K+ excretion by increasing the delivery of Na+ to the collecting duct. In patients with an eGFR greater than 30 mL/min/1.73 m2, thiazide diuretics can be used, but in those with more severe decrements in renal function, loop diuretics are required. In patients with CKD and metabolic acidosis administration of sodium bicarbonate is an effective strategy to minimize increases in S[K+]. This drug increases renal K+ excretion as a result of increased distal Na+ delivery and shifts K+ into cells as the acidosis is corrected. Ensuring that the patient is first on effective diuretic therapy will lessen the likelihood of developing volume overload as a complication of sodium bicarbonate administration. The development of hyperkalemia after the administration of RAAS blockers is of particular concern, because patients at highest risk for this complication are often the same ones who derive the greatest cardiovascular benefit (Table 32.3). In addition to the steps mentioned previously, the risk of hyperkalemia with these
drugs can be minimized by initiating therapy at low doses. The S[K+] should be checked within 1 week of starting the drug. If the S[K+] is normal then the dose of the drug can be titrated upwards. With each increase in dose the S[K+] should be remeasured 1 week later. For increases in the S[K+] up to 5.5 mEq/L, one can try lowering the dose. In some cases the S[K+] will improve, allowing the patient to remain on the RAAS blocker, albeit at a lower dose. In patients at risk for hyperkalemia, ARBs and direct renin inhibitors should be used with the same caution as ACEIs. Sodium polystyrene sulfonate is commonly used to treat hyperkalemia in the acute setting. However, chronic use is poorly tolerated because the resin is usually given in a suspension with hypertonic sorbitol to promote an osmotic diarrhea. In addition, chronic use had been associated with mucosal injury in the lower and upper gastrointestinal tract.
CONCLUSION Adaptive increases in renal and gastrointestinal excretion of K+ help to prevent hyperkalemia in patients with CKD as long as the GFR remains greater than 15 to 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. In clinical practice hyperkalemia is usually the result of a combination of factors superimposed on renal dysfunction.
TABLE 32.3 Approach to Patients at Risk for Hyperkalemia When Using Drugs that Interfere with the RAAS
References
Accurately assess level of renal function to better define risk Discontinue drugs that interfere in renal potassium secretion, inquire about herbal preparations and discontinue non-steroidal antiinflammatory drugs, including the selective cyclo-oxygenase 2 inhibitors Low potassium diet, inquire about potassium containing salt substitutes Thiazide or loop diuretics (loop diuretics necessary when eGFR is less than 30 mL/min/1.73 m2) Sodium bicarbonate to correct metabolic acidosis in CKD patients Initiate therapy with low-dose ACEI or ARB Measure potassium 1 week after initiation of therapy or after increasing dose of drug For increases in S[K+] up to 5.5 mEq/L, decrease dose of drug, if taking some combination of ACEI, ARB, or aldosterone receptor blocker discontinue one and re-check S[K+] The dose of spironolactone should not exceed 25 mg daily when used with an ACEI or ARB. This combination of drugs should be avoided in CKD patients with GFR less than 30 mL/min For S[K+] ≥5.6 mEq/L despite above steps, discontinue drugs
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