Potassium homeostasis in chronic kidney disease – NephrologyNews.com

Introduction

Scope of the problem

In patients along 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 A lot 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.five to 6.0 mg/dL), excluding patients along 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.five mEq/L).²

Causes of hyperkalemia

While loss of kidney function is the single essential cause of hyperkalemia, in clinical method 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 along with diabetes where decreased mineralocorticoid activity is regularly an early manifestation of hyporeninemic hypoaldosteronism, or in advanced stages of heart failure along with accompanying reductions in distal delivery of Na⁺ combined along with concurrent use of drugs which interfere along with the renin-angiotensin-aldosterone system. In these settings, hyperkalemia is common and can easily create along with only mild or moderate reductions in the GFR. The frequency of hyperkalemia in the CKD patient makes a durable 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 throughout 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 along 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 standard estimated GFR (eGFR) of this study population was 14.4 mL/min/1.73m², patients along with hyperkalemia had a significantly lower eGFR compared to those devoid of (14.8 vs 13.five mL/min/1.73m²). In addition to having worse renal function, hyperkalemic subjects had significantly lower serum bicarbonate concentrations (22.five vs 24.1 mEq/L).

Even though there are adaptive mechanisms in the patient along 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 easily progress from normal to ventricular tachycardia and asystole in a precipitous manner, which emphasizes the reason for careful monitoring.⁷ (For A lot more short article regarding this, see additionally the information 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 first gathering duct and the cortical gathering 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 first gathering duct and the cortical gathering duct is the principal cell. Mineralocorticoid activity and distal delivery of Na⁺ and water are vital factors regulating K⁺ secretion in this segment. Aldosterone improves the rate of K⁺ secretion by increasing cell K⁺ concentration, increasing luminal membrane K⁺ permeability, and making the luminal potential A lot more negative by stimulating Na⁺ reabsorption across the luminal membrane through the epithelial sodium channel (ENaC).

When K⁺ is secreted in the gathering duct the luminal K⁺ concentration increases, which decreases the diffusion gradient and slows further K⁺ secretion. At higher luminal flow rates the same quantity of K⁺ secretion will certainly be diluted by the larger volume; such that the increase in luminal K⁺ concentration will certainly 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 A lot more negative.

Two populations of K⁺ channels have actually been identified in the cells of the cortical gathering duct. The ROMK (renal outer medullary K⁺) channel is considered to be the major K⁺-secretory pathway. This channel is characterized by having reasonable conductance and a higher 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 vital role in mediating flow-dependent increased K⁺ secretion.

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. As soon as the cause is acute tubular necrosis or tubulointerstitial renal disease, there is regularly widespread injury to the late distal tubule and gathering duct, leading to direct injury of cells responsible for K⁺ secretion. Acute kidney injury is regularly associated along 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 create adequately. In patients along with A lot 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 much less common since distal delivery of salt and water is plentiful. Patients along with acute kidney injury are A lot more most likely to have actually severe acidosis, increased catabolism, and tissue breakdown, all leading to the release of intracellular K⁺ in to the extracellular compartment. This release of K⁺ in the setting of impaired renal K⁺ secretion makes life-threatening hyperkalemia a common occurrence in patients along with acute kidney injury.

Renal potassium handling in CKD

CKD is A lot more complicated compared to acute kidney injury. In addition to the decreased GFR and secondary decrease in distal delivery of K⁺, there is nephron dropout and a smaller sized number of gathering ducts to secrete K⁺. However, this is counterbalanced by an adaptive process in which the remaining nephrons create an increased ability to excrete K⁺. As a result, hyperkalemia (K⁺ > 5.five mEq/L) is uncommon in patients along with CKD until the GFR falls below 15–20 mL/min.

Studies both in experimental pets and in humans have actually given suggestions in to the nature and localization of the adaptive increase in renal K⁺ secretion. In conscious dogs along with a unilateral remnant kidney, K⁺ secretion per nephron improves 4-fold by 18 hours and approaches 85% of the manage pets 7 days after removal of the contralateral intact kidney.¹ The ability to keep urinary K⁺ secretion in the face of a marked reduction in functioning nephron mass calls for the quantity of K⁺ excreted per unit of GFR (fractional excretion of K⁺) to markedly increase.

In a study of normokalemic patients along with stage 4 CKD, the fractional excretion of K⁺ was 126% compared along with 26% in normal manage 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 along with CKD compared along with 19.5% in manage patients. These findings support the suggestion that patients along with CKD are able to keep normal serum K⁺ concentrations through an adaptive increase in renal K⁺ secretion that is largely amiloride-sensitive.

Despite this adaptation, the ability to further augment K⁺ secretion in response to an exogenous load is very limited, such that hyperkalemia can easily result from even modest improves in K⁺ intake. As soon as dogs along with remnant kidneys were challenged along with an acute intravenous infusion of K⁺ the increment in renal K⁺ secretion was approximately 50% much less compared to in manage animals, resulting in marked hyperkalemia.¹¹ In both remnant and manage groups, renal K⁺ excretion was directly related to the serum K⁺ concentration; however, the partnership was markedly attenuated in the remnant group. In the initial five hours following the K⁺ infusion, manage pets excreted 65% of the K⁺ load as compared to only 35% in the remnant group. A period of nearly 24 hours was called for to re-establish K⁺ balance in the dogs along with low renal mass. throughout this time, plasma K⁺ and aldosterone levels were significantly better compared to in manage animals. Studies in patients along with CKD additionally prove to a similar impairment in the ability to acutely excrete a K⁺ load, and these patients create A lot more severe and prolonged hyperkalemia following a K⁺ challenge.¹²

The nature of the adaptive process which facilitates K⁺ excretion in patients along with CKD is believed to be similar to the adaptive process which occurs in response to higher dietary K⁺ intake in normal subjects.¹³ Chronic K⁺ loading in pets augments the secretory capacity of the distal nephron so that renal K⁺ excretion is significantly increased for any offered plasma K⁺ level. Increased K⁺ secretion under these conditions occurs in association along 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 gathering 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 prove to that the cortical gathering duct is an vital site of K⁺ adaptation in the surviving nephrons of pets along with low renal mass. K⁺ secretion is increased in perfused cortical gathering tubules taken from remnant kidneys of uremic rabbits fed a normal diet.¹⁴ However, if dietary K⁺ intake is low in proportion to the reduction in renal mass, this adaptation is prevented and K⁺ secretory rates continue to be 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 As soon as dietary K⁺ intake is increased in pets along with intact kidneys.¹⁵ Loss of renal mass additionally 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 vital 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 gathering duct in remnant kidneys are similar to just what is seen in experimental models of chronic mineralocorticoid administration.¹⁷ There is a wide variability in aldosterone levels in patients along with CKD, along with studies showing either increased, normal, or decreased values. section of this variability is because of the failure to think about the prevailing plasma K⁺ concentration and variations in Na⁺ intake. In addition, several patients along with CKD have actually reasonable plasma renin activity. In this setting, impaired aldosterone secretion and hypoaldosteronism are the result of reasonable circulating renin levels. As soon as normalized for the plasma renin activity, levels of aldosterone are usually in the normal range As soon as the GFR is
> 50–60 mL/min.¹⁸ However, along with A lot more severe reductions in renal function there is a progressive increase in plasma aldosterone levels.

Extrarenal K⁺ homeostasis in CKD

Under normal circumstances, improves in plasma K⁺ concentration following K⁺ ingestion are lowered by physiologic mechanisms which shift K⁺ in to 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 additionally influence K⁺ distribution within the body.

As renal function declines, the cellular uptake of K⁺ becomes an vital defense versus the development of hyperkalemia. Studies in humans and experimental models of low renal mass have actually made 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-physique K⁺ content since these are either normal or, often, reduced.^20,21 Decreased intracellular K⁺ content has actually 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 prove to diminished activity of the pump which can easily be reversed As soon as cells are incubated in normal plasma. Pump activity has actually additionally been shown to improve following dialysis.²² On the others hand, red blood cells taken from normal people and incubated in uremic plasma acquire the defect.

Studies in skeletal muscle from uremic patients prove to decreased K⁺ concentration, increased Na⁺ concentration, and decreased resting membrane potential. After 7 weeks of hemodialysis these physiologic parameters can easily be restored to normal, suggesting the presence of a circulating inhibitor of the Na⁺-K⁺-ATPase in some uremic patients.²³ In others patients, there might be reductions in the number of pump sites quite compared to decreased activity. Therefore, decrements either in pump activity or in number of sites might 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 along with advanced CKD As soon as compared to normal manage patients.²⁴ Additionally, the metabolic clearance rate of insulin falls along with loss of renal function. The increase in circulating insulin and catecholamine levels might 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 A lot more overtly impaired. Fernandez and colleagues compared the disposition of an oral K⁺ load (0.2five mEq/kg/physique weight) in a group of dialysis patients to that in normal manage patients.²⁵ The normal manage 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 manage group. The impairment in K⁺ disposal persisted even As soon as the K⁺ load was accompanied by oral glucose, even though glucose-induced stimulation of insulin attenuated the maximal rise in K⁺ levels.

Gastrointestinal excretion of K⁺ in CKD

In patients along with renal failure, a considerable proportion of everyday K⁺ excretion occurs via the gastrointestinal tract. Gastrointestinal losses are vital 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 everyday K⁺ intake was lost in the feces.²⁶ The quantity of K⁺ excreted in the stools correlates directly along with the wet stool weight. Therefore, constipation need to be avoided because it will certainly decrease the gastrointestinal elimination of K⁺ and increase the tendency toward hyperkalemia.

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

Elevated levels of plasma aldosterone might play a role in stimulating the gastrointestinal excretion and cellular uptake of potassium in patients along with ESRD. Exogenous administration of mineralocorticoids has actually 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 along 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 along with pretreatment values in patients that received the drug.

A recent study examined the effects of glycyrrhetinic acid meals 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 gathering duct however additionally in epithelial cells in the colon. This enzyme converts cortisol to cortisone; thereby ensuring that the mineralocorticoid receptor remains free to interact only along with aldosterone, since cortisone has actually no affinity for the receptor. In 9 of 10 patients offered the supplement there was a persistent decrease in measured predialysis serum K⁺ concentration. In addition, treatment along with the supplement significantly decreased the frequency of severe hyperkalemia. These practical effects occurred devoid of weight gain or improves in systemic blood pressure, suggesting that glycyrrhetinic acid supplementation might be of benefit in improving colonic K⁺ secretion and minimizing the risk of hyperkalemia in dialysis patients.

Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers have actually both been reported to cause hyperkalemia in patients treated along with hemodialysis and peritoneal dialysis.^32,33 The development of hyperkalemia along with these drugs might be because of 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 actually been attributed to up-regulation of angiotensin-II receptors in the colon, suggesting that angiotensin II has actually a direct effect in stimulating colonic K⁺ excretion.³⁴ Blocking the mineralocorticoid receptor along with spironolactone offered at a dose of 2five mg/day does not raise the serum K⁺ concentration in hemodialysis patients.³⁵

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

Summary

Adaptive improves in renal and gastrointestinal excretion of K⁺ guidance to stay away from hyperkalemia in patients along 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 easily 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 actually participated in an advisory board for Relypsa, Inc.

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