Renal Grand Rounds - A Chilling Case of Hyperkalemia

A 62 year old man with ischemic cardiomyopathy (EF 35%) and CKD (baseline Cr ~3 mg/dl) had a witnessed out-of-hospital cardiac arrest.  EMS arrived within 3 minutes.  He received CPR and was shocked out of ventricular fibrillation (VF).  He was intubated and therapeutic hypothermia was initiated in the field. He was admitted to the CCU, where therapeutic hypothermia was continued for 24 hours.  He received aggressive KCl repletion for hypokalemia (see graph below) and supraventricular arrhythmias.  On the second hospital day the patient was rewarmed, developed severe DIC (INR 10), worsening shock requiring 3 pressors, and renal was consulted for hyperkalemia and oliguric AKI on CKD.

Clinical pearls: Hypokalemia is a frequent complication of hypothermia for two major reasons: 

1) cold diuresis, which is believed to result from peripheral vasoconstriction, increased venous return, and increased ANP; 

2) catecholamine-induced shift of KCl into cells.  

Interestingly, the latter seems to depend on the type of protocol used to induce hypothermia.  Core cooling increases norephinephrine but not epinephrine, and therefore does not cause a shift of K into cells.  In contrast, external cooling (which was used in this case, with the application of cooling pads) increases epinephrine disproportionately to norepinephrine.  The B₂ agonist actions of epinephrine cause a shift of K into cells.  It is therefore critically important to avoid KCl repletion during rewarming due to the risk of rebound hyperkalemia, particularly in oliguric patients such as this one who are unable to deal with the excess potassium load once it moves back out of the cells during rewarming.

Posted by David Leaf

Electrolyte Disorders involving Tubular Channels

Though adult nephrologists infrequently encounter these disorders in clinic, the Board Exam loves them. Below a short table describing some of these gain- and loss-of-function channel disorders that are worth remembering. The diuretic-targeted channels are shown under parenthesis as a reference.

Mg & K

It is well known that hypokalemia does not correct easily if it is accompanied by hypomagnesemia. A medical student I met looked into this topic and found a “Science in Renal Medicine” article. According to this article, one of the mechanisms through which hypokalemia occurs in a hypomagnesemic state is through renal potassium wasting. Several observations have shown that magnesium infusion decreases renal K secretion in the distal nephron.

A study from Nature found that ROMK (aka Kir), one of two potassium channels in the distal nephron, is responsible for the distal renal K wasting in hypomagnesemia. The mechanism is that the intra-cellular free Mg blocks the pore of the ROMK channel and limits potassium secretion in a concentration-dependent manner; therefore low intracellular Mg level increases potassium secretion.

Some renal Mg wasting disorders (e.g. Mg channel TRPM6 mutation) do not always present with hypokalemia. Why is that? The reason is that you need 2 components for potassium excretion. One is increased K permeability of the ROMK, and the other is a driving force to secrete K like increased distal Na delivery or an elevated aldosterone level (via enhanced Na reabsorption in the distal nephron). It seems in these disorders you don’t have the second determinant for K secretion.

Another fascinating renal physiology article! Now we are still confused but have a better understanding of hypomagnesemia in a case of hypokalemia. 

Posted by Tomoki Tsukahara

Hold the potassium

It was not an unusual event during my clinical fellowship to get a call from the cardiac team asking for dialysis in a patient with hyperkalemia and acute renal failure. On a few occasions the hyperkalemia seemed disproportionate to the level of renal function and on further investigation, this was found to the as a result of the zealous correction of the potassium level to >4 mEq/L in patients in the cardiac unit. I have often wondered about this practice and whether or not there was firm evidence for keeping the potassium in the 4-5 mEq/L range (or even 4.5-5.5 as suggested by some authors) and so it was with interest that I read this paper that just appeared in JAMA.

As mentioned in the paper, the data suggesting that low potassium levels are associated with increased mortality are relatively old and date from an era when ventricular arrhythmias were more common following an MI. They were also generally relatively small studies. The authors of this study used a database of patients presenting to 67 US hospitals with an ICD9 code for MI and increased cardiac biomarkers. In total >39,000 patients were included.

They were looking primarily at post-admission potassium levels and their relationship with in-hospital mortality and the occurrence of arrhythmias. AS one would expect, there was a U-shaped curve for the relationship between in-hospital mortality and the potassium level. What was unexpected, however, was that the lowest mortality was seen in patients with a potassium between 3.5 and 4.5 mEq/L and that the mortality doubled in patients with a potassium between 4.5 and 5 mEq/L.

This was borne out in the fully adjusted model. The OR for in-hospital mortality was 1.96 (CI 1.64-2.34) for patients with a potassium between 4.5 and 5 mEq/L. Interestingly, the risk of a ventricular arrhythmia was the same in patients in the midrange of potassium values and only increased in patients with a potassium of below 3 or above 5 mEq/L. This contrasted with the mortality data and the authors suggested that this might be in part a result of incorrect coding of ventricular arrhythmias and is a potential limitation of the study. Also, this study certainly does not prove that replacing potassium to a level above 4.5 mEq/L is dangerous. This could only be answered by a randomized trial. There may be some residual confounders that have not been accounted for in the model. Still, as the authors point out, this study challenges current guidelines and suggest that a better target for potassium in patients following an acute MI would be 3.5-4.5 mEq/L. Perhaps we might see less of this particular consult in the future?

Linked: Sodium and Potassium

Emily mentioned in her recent post on the Rule of 6s that potassium administration needs to be taken into account when correcting the plasma sodium in cases of hyponatremia.



Why is this the case?



When potassium is given most of it will move into to cells (remember that 98% of total body potassium resides here.) As this occurs, electroneutrality is maintained in three ways, all of which act to raise the plasma sodium concentration.


1. Intracellular sodium exits cells directly increasing the plasma sodium concentration.

2. Extracellular Cl will enter cells along with potassium. The addition of intracellular KCl raises intracellular osmolality causing water to move into cells. The loss of extracellular water causes the plasma sodium concentration to rise.

3. Intracellular protons exit cells as potassium enters. Proton movement is osmotically neutral as they combine both intra and extracellularly with buffers. This is in contrast to potassium, which raises intracellular osmolality and causes water to move into cells. This loss of extracellular water again causes the plasma sodium concentration to rise.

The Practical Point: If solute is part of your hyponatremia treatment plan and you need to additionally replete potassium remember that each mEq of potassium given will act on the plasma sodium like a mEq of sodium.

Cool New Cell Paper Demonstrates Molecular Basis for Thyroxic Hypokalemic Periodic Paralysis

The periodic paralysis syndromes are characterized by episodic attacks of acute muscle weakness, typically due to rapid fluxes in the serum potassium concentration, based on an abnormality in intracellular potassium shift. While there have been several instances of inherited mutations that cause periodic paralysis, there is also a subset of individuals who have thyrotoxic periodic paralysis (TPP), in which the presence of hyperthyroidism predisposes to attacks of transient paralysis. An article in this month's Cell by Ryan et al helps determine the molecular basis of TPP in many (but not all) cases, and characterizes this disorder as yet another example of a channelopathy: a disorder of ion channels.

Although thyrotoxicosis is a predisposing factor to this disease, there was also a clue that genetics was involved: Latin American and Asian populations appeared especially susceptible to TPP. The investigators identified a novel inward-rectifying potassium channel, Kir2.6 (interestingly, a gene which had escaped detection in all versions of the human genome thus far!), and sequenced this gene in affected individuals. In 33% of the unrelated patients in their sample, they identified mutations in Kir2.6 which appear to alter the function of this potassium channel and lead to an altered skeletal muscle excitability. Interestingly, the transcription of Kir2.6 was found to be altered by thyroid hormone, providing an explanation as to why the disease manifests itself most commonly during episodes of thyrotoxicosis.

Gordon Syndrome

File "Gordon Syndrome" under "interesting causes of hyperkalemia and metabolic acidosis you may never see."

Also called pseudohypoaldosteronism type II, Gordon Syndrome is relevant less so for the number of patients afflicted but more due to the interesting insights into normal acid-base and electrolyte physiology.

Briefly, patients with Gordon Syndrome, a genetically-inherited condition, exhibit salt-sensitive hypertension, hyperkalemia, and a non-anion gap metabolic acidosis in association with a normal GFR. These metabolic derangements tend to be highly responsive to thiazide diuretics, correctly implying the disease is due to a constitutive activation of thiazide-sensitive Na channels in the distal convoluted tubule. In fact, Gordon Syndrome can be thought of as a mirror image of Gitelman's Syndrome, in which there is inactivation of the thiazide-sensitive Na channels causing the exact opposite metabolic abnormalities (hypokalemia and metabolic alkalosis).

It turns out that Gordon Syndrome is caused by mutations in two different, related genes which encode for a type of kinase: either gain-of-function mutations in WNK1, or loss-of-function mutations in WNK4 ("WNK kinase" stands for "with no lysine kinase"). WNK4 is responsible for tonic inhibition of the thiazide-sensitive Na; its loss-of-function therefore results in unregulated Na reabsorption in the distal tubule. This leads to decreased Na delivery to the collecting duct, resulting in reduced tubular lumen electronegativity, the driving force for aldosterone-mediated potassium and H+ secretion. WNK1 is a negative regulator of WNK4 and this explains why gain-of-function in WNK1 can cause the same phenotype as loss-of-function in WNK4. Part of the clinical phenotype seen in these patients may also have to do with WNK effects on the potassium channel ROMK, illustrating the complex molecular biology of this pathway.

Drugs Associated with Hyperkalemia

There are a variety of drugs which can result in hyperkalemia, via a variety of mechanisms. Here are a list of some of the common offenders, categorized loosely based on mechanism, though admittedly there is some overlap between categories:

1. Drugs which cause translocation of K from the intracellular to the extracellular fluid: these include succinylcholine, isoflurane, minoxidil, and beta-blockers.

2. Potassium-Sparing Diuretics: drugs such as spironolactone (mineralocorticoid receptor antagonists) and amiloridine/triamterene (blockers of the ENaC) are common causers of hyperkalemia.

3. Inhibitors of renin-angiotensin-aldosterone axis: ACE-inhibitors, angiotensin receptor blockers.

4. Hyperosmolarity: hyperosmolarity induces water efflux out of cells, and by solvent drag increases intravascular potassium concentrations. Drugs such as mannitol can therefore cause translocational hyperkalemia.

5. NSAIDs: NSAIDs can lower renin secretion, which is normally mediated in part by locally-produced prostaglandins.

6. Bactrim: the hyperkalemia induced by Bactrim is via an ENaC inhibitory effect exerted by the trimethoprim moiety. Pentamidine induced hyperkalemia via a similar mechanism.

7. calcineurin inhibitors (e.g., cyclosporine, tacrolimus): it is postulated that these medications inhibit renal tubular responsiveness to aldosterone.

8. heparin & ketoconazole: these drugs may be associated by hyperkalemia by inhibiting aldosterone synthesis.

9. digitalis: digitalis inhibits the Na-K ATPase (which pumps 3 Na out of the cell and 2 K in); as such, it can result in hyperkalemia and a variety of cardiac arrhythmias.

A Wide Range of Potassium Behaviors

Very interesting results of the RFN Poll of the Week regarding different opinions regarding managing the potassium bath in a patient with hyperkalemia!

Of the options give, there was a near three-way split between the first three answers (giving a 1K bath, giving a 2K bath, or a giving a 1K bath and then changing to a 2K bath after one hour).  In my opinion, this speaks to the overall lack of data describing what one should do in managing hyperkalemia during dialysis!  I would also imagine that an individual's choice would be highly influenced as to where they trained or what the practice patterns are at their individual hospitals.  

Personally, I was taught the "rule of 7's"--the patient's serum K plus their dialysate bath K should equal approximately 7.  Unfortunately this tends to break down at higher potassium levels.  

Check out the latest Thursday Poll of the Week question on the right!

A sweet alternative to kayexelate?

Trust the Swiss to approach a problem from a confectioners viewpoint. The options for managing hyperkalemia in dialysis patients have always been limited and unpalatable, but this preliminary clinical study from Berne provides some hope. It suggests that giving glycyrrhetinic acid may be effective. This compound, commonly found in liquorice, usually just makes up the numbers somewhere near the bottom of lists of causes of secondary hyperaldsteronism. It works by inhibiting the enzyme 11b-hydroxy-steroid dehydrogenase II, increasing cortisol availability at the mineralocorticoid receptor. It appears that there is significant expression of this receptor in the colon, potentially explaining the potassium-lowering effect in ESRD.

Over 6 months of follow-up, the frequency of severe hyperkalemia significantly decreased from 9% to 0.6% in the treatment arm of this small, prospective RCT. Mean pre- and post dialysis systolic/diastolic blood pressure values were comparable on GA and placebo. However, before you start reaching for the Allsorts, be aware that this was a tiny study (10 patients) and needs a longer term study of toxicity before widespread use can be proposed.

An unusual case of hyperkalemia and renal failure: matchsticks

Okay, you're probably not going to see this in your lifetime, but imagine how cool you'll seem when you whip out "matchstick ingestion" as part of the differential diagnosis for hyperkalemia and AKI.

Matchstick heads are comprised of over 50% potassium chlorate (KClO3); it is an oxidizing agent which makes matches flammable and can also be found in many explosives and fireworks. Unfortunately, it also happens to be nephrotoxic. In this interesting case report by Mutlu et al, the authors describe a 21-year-old man who attempted to commit suicide by ingesting 120 matchsticks. When he first presented to the ED, he had a serum potassium of 7.4 with peaked T-waves. The potassium chlorate results in a rapid oxidative destruction of RBCs while also causing methemoglobinemia, and acute renal failure is common. A toxic dose is listed as being 5 grams; the patient in this case report only ingested 2 grams was fortunately treated successfully using acute potassium-lowering therapy and hyperbaric oxygen therapy (for the methemoglobinemia).

EAST Syndrome

A relatively recent study by Bockenhauer et al in NEJM reports the identification of a new disease gene in a rare tubulopathy syndrome that sheds light on the physiologic mechanisms of salt transport in the kidney.

The article describes children with an autosomal recessive inherited condition termed "EAST Syndrome", which stands for epilepsy, ataxia, sensorineural deafness, and tubulopathy. Specifically, patients had evidence of renal salt wasting with low-normal blood pressure, resulting in activation of the renin-angiotensin system and a resultant hypokalemic metabolic alkalosis. Individuals also demonstrated significant hypomagnesemia and hypocalciuria. Genetic studies identified the cause of EAST Syndrome: mutations in the gene KCNJ10, a potassium channel which is expressed in all of the affected tissues (brain, inner ear, and kidney) in this disorder. They go on to demonstrate that mice made deficient for KCNJ10 show a similar salt wasting phenotype as in affected humans.

What does KCNJ10 do? The authors propose that this potassium channel sits at the basolateral membrane of tubular epithelial cells where it recycles potassium, which is necessary for maintaining the activity of the Na/K-ATPase. Although rare, EAST Syndrome helps provide greater molecular detail of how the kidney absorbs salt, and suggests that researchers look for polymorphisms in this gene which may explain some of the genetic predisposition towards hypertension and salt handling by the kidney.

Potassium-Sparing Diuretics

The potassium-sparing diuretics consist of the following 4 medications--only some of which (spironolactone & eplerenone in the list below) are structurally similar.  

Spironolactone is an antagonist of the aldosterone receptor, which like other steroid receptors is an intracellular receptor.  The binding of spironolactone to the aldosterone receptor within collecting duct cells decreases the activity of apical ENac, thereby preventing Na reabsorption and K excretion.  Although spironolactone on its own has a weak diuretic effect, when used in combination with other diuretics may be clinically useful in reducing edema.  It also has well-documented beneficial effects in patients with congestive heart failure (see the 1999 RALES trial for details).  Aside from having the obvious side effect of hyperkalemia, spironolactone also has anti-androgen activity based on its interaction with the androgen receptor, which prevents binding of dihydrotestosterone.  Thus spironolactone is associated with the often unpleasant side effects of gynecomastia, decreased libido, testicular atrophy, and menstrual irregularities.

The drug eplerenone is structurally related to spironolactone, but has greater specificity for the aldosterone receptor (as opposed to the androgen receptor), thus allowing for its use as an effective K-sparing diuretic without the sex hormone side effects. 

Both amiloride and triamterine work by direct inhibition of ENac.   

Pendred Syndrome

Pendred Syndrome is an autosomal recessive disorder caused by mutations in the solute carrier family 26 member 4 gene (SLC26A4) which has some relevance to nephrology and acid-base metabolism. Its main phenotypic manifestations are thyroid goiter and sensorineural deafness. Where does the nephrology come in? It does not appear that these individuals have acid-base problems at baseline, but there are reports of their developing a severe hypokalemic metabolic alkalosis when treated with thiazide diuretics. I'll explain.

The SLC26A4 gene product encodes an ion transporter which enables (1) iodine ion transport (hence the goiter) and (2) chloride-bicarbonate exchange. In the inner ear, impaired bicarbonate secretion leads to acidification of the endolymph and damage to the underlying hair cells, hence the deafness. In the kidney, the SLC26A4 gene product is expressed in beta-intercalated cells of the collecting duct. Recall that the collecting duct has two flavors of intercalated cells: the alpha-intercalated cells (which secrete protons) and the beta-intercalated cells (which secrete bicarbonate). A decreased ability to secrete bicarbonate, coupled with reduced NaCl reabsorption from thiazide diuretics, could therefore explain the metabolic alkalosis seen in Pendred Syndrome patients.

Have I ever seen a case? Not that I can think of, though I wouldn't necessarily know as I mentioned before that individuals don't typically get metabolic alkalosis unless treated with diuretic. It's uncommon but not that uncommon, as many sources cite Pendred Syndrome as accounting for up to 10% of heritable deafness.

Mineralocorticoid-Blocking Activity of Oral Contraceptives

I didn't learn this until recently, but some commonly used oral contraceptives--for example Yasmin-28 (the progestin-derivative drospirenone + ethinyl estradiol)--has some mineralocorticoid blocking effect, similar to that seen for spironolactone. It may therefore be associated with hyperkalemia, particularly in patients already on medications that predispose to higher serum K's. The package insert actually recommends monitoring K levels during the first month in patients receiving Yasmin who are also on ACE-I/ARBs, K-sparing diuretics, NSAIDs, or K-supplements, but this recommendation may be overlooked.

Acquired versus Hereditary Forms of Hypokalemic Periodic Paralysis

Hypokalemic periodic paralysis is a relatively rare disease in which individuals experience transient, severe episodes of hypokalemia as a result of rapid intracellular potassium shift into skeletal muscle. The attacks typically manifest as muscle cramps, muscle paralysis, or cardiac arrhythmias, and may are classically precipitated by rest following exercise, catecholamine excess, or carbohydrate-rich meals.

The acquired form in most instances is associated with thyrotoxicosis. Even though more women than men suffer from hyperthyroidism, there is a huge male predominance (up to a 70:1 M:F ratio) of hyperthyroid-induced hypokalemic periodic paralysis. The disorder seems to be especially common in Asian populations.

In contrast, the hereditary forms of hypokalemic periodic paralysis have a roughly equal M:F ratio, have a younger age of onset (<20 years of age), is most common in Caucasians, and the hypokalemic episodes tend to last longer. It is inherited in an autosomal dominant fashion and thus far mutations have been identified in the genes CACNA1S (a calcium channel subunit expressed in skeletal muscle), SCN4A (a skeletal muscle Na channel), and KCNE3 (a skeletal muscle K channel).

Page Kidney

In 1939, Irwin Page performed an experiment in a dog model in which one kidney was wrapped in cellophane. The resultant external compression on the kidney resulted in elevated renin-angiotensin-aldosterone levels and severe hypertension. Over time, a loss of renal function occurs due to some degree of renal ischemia and constrictive perinephritis. Because there are high levels of circulating aldosterone, renal K-wasting and hypokalemia can also be present.

Now, "Page Kidney" refers to any condition in which external compression of the kidney leads to activation of the renin-angiotensin-aldosterone system resulting in hypertension. The most common cause of a Page kidney is a subcapsular hematoma, which can result from blunt trauma or iatrogenesis, such as a renal biopsy or ESWL for kidney stones. Rarely, large cysts or tumors can also cause Page kidney.

Thiazide-Induced Hyperglycemia

In recent years, there has been the suggestion that thiazide diuretics--long considered a front-line therapy for hypertension based on the ALLHAT study and others--may increase the risk of diabetes. Subsequent retrospective analysis of other major historical cohorts by Eric Taylor and others--such as the Nurse's Health Study and Health Professionals Follow-Up Study--seem to indicate that the relative risk of being diagnosed with incident diabetes is somewhere between 1.2 to 1.46 in individuals taking thiazides compared to those not taking thiazides with similar baseline characteristics. What do we think about this data and should it change our clinical practice of prescribing thiazide monotherapy to an individual recently diagnosed with hypertension? Also, why should thiazides result in hyperglycemia?

Interestingly, there is data to suggest that the thiazide-induced hyperglycemia effect is a potassium effect: a 2006 review of >50 trials in which thiazides were compared to other blood pressure-lowering medications or placebo, it was found that for every 1 mEq/L decrease in K, there is a 10 mg/dL increase in glucose. Furthermore, normalization of serum potassium in patients on thiazides (with potassium supplements) will lower the serum glucose.

From a molecular level, this is perhaps explained by the fact that the pancreatic b-cell secretion of insulin is regulated in large part by ATP-sensitive K channels in the beta-cell membrane. Alterations in the extracellular potassium concentration to which these cells are exposed could potentially lead to decreased insulin secretion.

If this mechanism is correct, it would imply that thiazide-induced hyperglycemia occurs by a different mechanism (decreased insulin secretion) than the standard type 2 diabetes (peripheral insulin resistance), and furthermore that thiazide-induced hyperglycemia is reversible with normalization of potassium levels. Thus, it is probably not necessary to remove thiazides from the list of useful first-line agents for treatment of hypertension. That being said, as a budding nephrologist I am always looking for a good reason to prescribe an ACE-inhibitor or ARB, and therefore I personally tend to add one of the RAAS blockers first given the population of clinic patients that I see.

Refeeding Syndrome

The clinical entity of refeeding syndrome was first described in U.S. POWs in Japan who had been starved for many months to years, then developed extreme electrolyte abnormalities upon the reintroduction of food.

The most common electrolyte abnormalities associated with refeeding syndrome are hypophosphatemia, hypomagnesemia, and hypokalemia. The mechanism is as follows: during starvation, the secretion of insulin is decreased in response to a reduced availability of carbohydrates, and in order to survive metabolism is shifted to using fat and protein stores. During this adaptation total-body phosphate, magnesium, and potassium stores are depleted, despite maintaining relatively normal serum concentrations of these electrolytes. When suddenly exposed to ample food (and in particular carbohydrates), there is a shift to a carbohydrate-based metabolism associated with a sudden surge in insulin secretion. As we all know, insulin stimulates a rapid intracellular shift of potassium and phosphate, which can lead to a profound decrease in this electrolytes. In particular hypophosphatemia can lead to catastrophic muscle dysfunction, including respiratory collapse, as phosphate is necessary to maintain ATP stores needed for muscle contraction. Hypokalemia is well-known to result in cardiac arrhyhthmias.

Patients with alcoholism, anorexia nervosa, prolonged hospitalizations, or cancer patients may also be subject to refeeding syndrome. It typically occurs within four days of refeeding. Either hyperglycemia or hypoglycemia may also be present. Careful monitoring of electrolytes in patients prone to refeeding syndrome, as well as searching for nutritional deficiencies which may go along with refeeding syndrome (e.g., thiamine deficiency) are the cornerstones of preventing this potentially dangerous complication.

Renal Adaptations to Hyperkalemia

Are ESRD patients "protected" from the arrhythmogenic effects of hyperkalemia if they are chronically exposed to elevated potassium levels? I'm not sure if there is a clear answer to this question, but it is certainly a relevant question. What do you do with the ESRD patient who comes into the Emergency Room at 7pm after skipping dialysis who has a K of 6.3? On the one hand, dialysis is a sure-fire way to rapidly lower the K and prevent any cardiac complication, which have the potential to be lethal. On the other hand, calling in the dialysis nurse and fellow uses valuable resources, and there is a belief by some that individuals who "live at a potassium in the 5's & 6's" are protected from the negative effects of hyperkalemia. What does the data show?

There certainly appears to be some degree of renal adaptation to hyperkalemia in chronic kidney disease. Early animal studies in which rats were exposed to varying degrees of infused potassium concentrations demonstrate that hyperkalemia dramatically regulates the degree of potassium secretion, primarily via aldosterone-mediated mechanism in the collecting duct. In addition, this 2002 Kidney International review argues that the hyperkalemia seen in CKD is an adaptive, physiologic response, reflecting a new steady state in which extracellular K rises to the level needed to stimulate K excretion so that it matches intake. There is less data as to what adaptive mechanisms are active in the complete absence of renal function, and furthermore, it's hard to know whether or not such adaptations to hyperkalemia would be operative in many ESRD patients where the K fluctuates dramatically with regards to pre- and post-K levels. One might expect different ion channels in the myocardium to be up/downregulated in order to guard against the cardiac effects of hyperkalemia, or perhaps key K transporters in skeletal muscle are upregulated to maintain the plasma K concentration within the appropriate range.

If anybody knows of other relevant studies looking at adaptations to hyperkalemia, let me know.