Hyperkalaemia: again

Peter Gross and Frank Pistrosch

Nephrology, Department of Medicine, University Medical Center C. G. Carus, Dresden, Germany

Correspondence and offprint requests to: Peter Gross, MD, Nephrologie, Medizinische Klinik III, Universitätsklinikum C. G. Carus, Fetscherstrasse 74, D-01307 Dresden, Germany. Email: peter.gross{at}mailbox.tu-dresden.de

Keywords: aldosterone antagonists; hyperkalaemia; hyporeninaemic hypoaldosteronism



   Introduction
 Top
 Introduction
 Hyperkalaemia has changed with...
 Hyperkalaemia is now common...
 What went wrong after...
 What are the risk...
 Future perspectives
 Anything else new in...
 Hyporeninaemic hypoaldosteronism...
 The treatment of hyperkalaemia
 Conclusion
 References
 
Before 1999—and if one was a nephrologist— it was rare to be called to consult on a case of hyperkalaemia. No doubt cases of hyperkalaemia occurred at that time, too—for instance in patients in the moderate to advanced stages of renal failure—but physicians apparently had sufficient understanding of kidney function to call for dialysis treatment or similar alternative measures where appropriate and take care of severe hyperkalaemia. This has changed recently. Now, it is almost routine to be called by the Emergency Room because of ‘another severe’ hyperkalaemia—and one that is not related to uraemia. Why?



   Hyperkalaemia has changed with the advent of the RALES study
 Top
 Introduction
 Hyperkalaemia has changed with...
 Hyperkalaemia is now common...
 What went wrong after...
 What are the risk...
 Future perspectives
 Anything else new in...
 Hyporeninaemic hypoaldosteronism...
 The treatment of hyperkalaemia
 Conclusion
 References
 
In 1999 the ‘randomized aldactone evaluation study investigators’ (RALES [6]) reported the results of a 24 month observation in 1663 patients with advanced congestive heart failure (CHF). In that landmark trial which had been conducted in a prospective controlled fashion, the addition of spironolactone to the patients’ treatment improved morbidity and mortality from CHF significantly [1]. This important result meant that plenty of CHF patients who were already receiving treatments with angiotensin-converting enzyme (ACE) inhibitors and possibly AT-1 receptor antagonists as well would now be scheduled to receive a mineralocorticoid antagonist on top of their previous treatment. When one adds to this equation that most CHF patients will be elderly, having some degree of renal insufficiency ‘constitutively’, it is fair to say that the signs (of hyperkalaemia) were clearly on the wall. Of note, in 2003, another landmark study using eplerenone [2], a novel selective mineralocorticoid antagonist, confirmed the previous results of the RALES study [6]. Eplerenone was again associated with a rate of serious hyperkalaemia of 5.5% vs 3.9% in the placebo group [1]. So, did the predictions come true?



   Hyperkalaemia is now common and it may be fatal
 Top
 Introduction
 Hyperkalaemia has changed with...
 Hyperkalaemia is now common...
 What went wrong after...
 What are the risk...
 Future perspectives
 Anything else new in...
 Hyporeninaemic hypoaldosteronism...
 The treatment of hyperkalaemia
 Conclusion
 References
 
Almost immediately following the publication of the RALES study [6], reports of instances of pernicious hyperkalaemia popped up [3–5]. In one such report, no less than 25 patient episodes that had to be treated in the Emergency Room were described [4]. Four of the 25 required cardiovascular resuscitation measures and two out of the 25 died (Figure 1). Several authors estimated an incidence of clinically significant hyperkalaemia of ~10% in patients receiving the ‘RALES treatment’ or a similar regimen.



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Fig. 1. ECG tracing in a patient taken when the serum potassium concentration was 4.8 mmol/l (left) and at 9.5 mmol/l (right). The right panel shows broadening of the QRF complex and tenting of the T-wave. Both tracings were taken in lead V-2 (the P-wave was indistinct to begin with and may have disappeared altogether).

 


   What went wrong after RALES?
 Top
 Introduction
 Hyperkalaemia has changed with...
 Hyperkalaemia is now common...
 What went wrong after...
 What are the risk...
 Future perspectives
 Anything else new in...
 Hyporeninaemic hypoaldosteronism...
 The treatment of hyperkalaemia
 Conclusion
 References
 
It is obvious that the RALES investigators were well aware of the potential risk of hyperkalaemia inherent in their study design. Thus, they first conducted a small-scale dose-finding study before actually proposing ‘RALES’ [6]. In this pilot study, they observed a dose-related risk of hyperkalaemia (>5.5 mmol/l) in response to the spironolactone (12.5 mg/day, risk 5%; 25 mg/day, 13%; 50 mg/day, 20%; 75 mg/day, 24%) [6]. They therefore proposed a daily dose of spironolactone not to exceed 25 mg as optimal. They also suggested that the serum potassium concentration ought to be measured sequentially during the first 2 months of treatment with spironolactone. Furthermore, the actual RALES study provided for criteria that listed a serum creatinine >230 µmol/l (~2.6 mg/dl) and a serum potassium concentration >5.0 mmol/l as causes for exclusion. Also of note, most of the original ‘RALES patients’ were receiving loop diuretics throughout the study. Even under these carefully crafted conditions, the RALES study [6] reported an incidence of ‘severe hyperkalaemia’ of 2%; the median serum potassium concentration increased by 0.3 mmol/l during the 24 months of study observation and the creatinine by 10 µmol/l, and all of these changes occurred in the spironolactone-receiving group only. As reported by the RALES investigators, the instances of severe hyperkalaemia were limited to patients receiving ≥50 mg/day of spironolactone (NB: the standard recommendation in the RALES study had been to prescribe 25 mg/day). Taken together, it is highly likely that the optimal conditions of observation and treatment with mineralocorticoid antagonist in a study setting such as that of Pitt et al. [1] or Hu et al. [5] are difficult to maintain in medical everyday life. This is currently the best explanation for the surge of serious hyperkalaemia in cardiac patients receiving mineralocorticoid antagonists for CHF.



   What are the risk factors for hyperkalaemia in the setting of ACE inhibitors plus mineralocorticoid antagonist?
 Top
 Introduction
 Hyperkalaemia has changed with...
 Hyperkalaemia is now common...
 What went wrong after...
 What are the risk...
 Future perspectives
 Anything else new in...
 Hyporeninaemic hypoaldosteronism...
 The treatment of hyperkalaemia
 Conclusion
 References
 
According to recently published literature, the following known risk factors must be considered in every single patient with CHF scheduled to receive a ‘RALES’-like treatment: (i) renal insufficiency and/or an increase of any such insufficiency in the most recent past [3]; (ii) a dose of spironolactone exceeding 25 mg/day [3]; (iii) simultaneous treatments by non-steroidal anti-inflammatory drugs (NSAIDs) or heparin [3]; (iv) the presence of diffuse arteriosclerosis [3]; and (v) diabetes mellitus, advanced age, dehydration and progressive worsening of an advanced stage of CHF [4]. In general, and in the presence of such risk factors in particular, it is strictly recommended to check for any possible side effects of the ‘RALES-like treatment’ repeatedly. This applies particularly to the first 3 months of such a treatment. It is recommended to obtain measurements of serum potassium, creatinine and urea repeatedly for these purposes.



   Future perspectives
 Top
 Introduction
 Hyperkalaemia has changed with...
 Hyperkalaemia is now common...
 What went wrong after...
 What are the risk...
 Future perspectives
 Anything else new in...
 Hyporeninaemic hypoaldosteronism...
 The treatment of hyperkalaemia
 Conclusion
 References
 
Whereas the ‘RALES treatment’ was originally devised for the therapy of CHF patients, it is now likely that the indications for mineralocorticoid antagonists as ‘tissue-protecting agents’ may be broadened further in the near future. Thus, mineralocorticoids are presently under active scrutiny as anti-progression agents in the setting of chronic kidney disease, including diabetic nephropathy [13]. Therefore, as regards the issues of hyperkalaemia: ‘stay tuned’, there may be more to come.



   Anything else new in ‘Hyperkalaemia-land’?
 Top
 Introduction
 Hyperkalaemia has changed with...
 Hyperkalaemia is now common...
 What went wrong after...
 What are the risk...
 Future perspectives
 Anything else new in...
 Hyporeninaemic hypoaldosteronism...
 The treatment of hyperkalaemia
 Conclusion
 References
 
It had been known before that indomethacin may precipitate severe hyperkalaemia [7]. In the same vein, there is now a report of an episode of life-threatening hyperkalaemia with tetraparesis attributed to a treatment with diclofenac [8]. There is also a case on record where hyperkalaemia led to the demise of a patient [9]. He had received a COX-2 inhibitor, an ACE inhibitor and a potassium-rich diet all together. It is held that such side effects may be attributable, at least in major part, to inhibition of the renin–angiotensin–aldosterone system and effects of NSAIDs on renal blood flow via their effects on inhibition of prostaglandin synthesis.

Trimethoprim-sulfamethoxazole (TMS) may precipitate hyperkalaemia. This applies primarily to situations where TMS is given in high dose, such as is now common in the treatment of pneumonia by Pneumocystis carinii [7,8]. It is known that TMS has direct actions on the distal nephron, and these actions resemble the effects of amiloride [9]—which could explain the hyperkalaemia.

Cyclosporin A and tacrolimus reportedly cause hyperkalaemia occasionally [10,11]. In their presence, the response of the distal nephron to mineralocorticoids is reduced [12]; it remains to be seen, however, whether a treatment using synthetic mineralocorticoid, fludrocortisone, is indeed going to ‘repair’ that hyperkalaemia.

Other new drugs with occasional hyperkalaemic side effects are the following: heparin and heparinoids; pentamidine; somatostatin and ß-blockers.



   Hyporeninaemic hypoaldosteronism (hypo-hypo): an old foe that doesn’t go away
 Top
 Introduction
 Hyperkalaemia has changed with...
 Hyperkalaemia is now common...
 What went wrong after...
 What are the risk...
 Future perspectives
 Anything else new in...
 Hyporeninaemic hypoaldosteronism...
 The treatment of hyperkalaemia
 Conclusion
 References
 
Although ‘hypo-hypo’ (Schambelan syndrome) has been known for >30 years and although it is by no means uncommon, it continues to be underdiagnosed and underappreciated by physicians. Perhaps internists in general are just not sufficiently familiar with it. The ‘usual sequence’ of events is like this: an elderly type II diabetic with arterial hypertension, overweight and mild renal insufficiency develops angina pectoris or low back pain. He is given aspirin, a ß-blocker, an ACE inhibitor or NSAID to remedy these ailments. About 2 weeks later, a routine blood sample unexpectedly shows a serum potassium between 6.0 and 7.0 mmol/l in an otherwise unremarkable patient. The internist refers the patient (hopefully) to the nephrologist with a note saying ‘New hyperkalaemia—why?’ The careful nephrologist will then find that the patient often will have had borderline hyperkalaemia to begin with, but that it worsened when the most recent drugs as mentioned above were added to his previous regimen. The present hyperkalaemia will turn out to be associated with a mild metabolic acidosis, a low aldosterone in plasma and 24 h urine (despite the fact that hyperkalaemia usually stimulates aldosterone) and a suppression of renin—even when it is measured under conditions of stimulation (furosemide; upright posture). The importance of Schambelan syndrome and its proper diagnosis relates to the significant risk for major hyperkalaemic complications under certain uncontrollable circumstances such as an inadvertent intake of a K+ load (fresh fruit in summertime; K+-containing salt substitutes in a hypertensive patient, etc.). (Incidentally, it may be true that a sizable segment of those CHF patients that did become hyperkalaemic under ‘RALES-like’ treatments may indeed have had subclinical ‘hypo-hypo’; but that was not looked into at the time.) Anyway, once it is diagnosed, ‘hypo-hypo’ is easy to treat. Most prefer furosemide over fludrocortisone (a synthetic mineralocorticoid), because of the arterial hypertension that is often worsened or even first observed after fludrocortisone has been started to correct hyperkalaemia.



   The treatment of hyperkalaemia
 Top
 Introduction
 Hyperkalaemia has changed with...
 Hyperkalaemia is now common...
 What went wrong after...
 What are the risk...
 Future perspectives
 Anything else new in...
 Hyporeninaemic hypoaldosteronism...
 The treatment of hyperkalaemia
 Conclusion
 References
 
The current mode of treatment of a clinically relevant hyperkalaemia (usually characterized by a serum potassium concentration >5.5 mmol/l) is listed in Table 1.


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Table 1. Therapy of hyperkalaemia

 


   Conclusion
 Top
 Introduction
 Hyperkalaemia has changed with...
 Hyperkalaemia is now common...
 What went wrong after...
 What are the risk...
 Future perspectives
 Anything else new in...
 Hyporeninaemic hypoaldosteronism...
 The treatment of hyperkalaemia
 Conclusion
 References
 
Hyperkalaemia has recently surged, presenting major management problems. This is primarily due to new recommendations on the treatment of CHF (RALES study [1]). Based on such studies, CHF patients are now prescribed spironolactone 25 mg q.d. in addition to their usual treatments (often including an ACE inhibitor). The risk of clinically significant hyperkalaemia under these treatments may be as high as 10%. Specific constellations of risk are: a dose of spironolactone >25 mg/day; simultaneous prescription of an NSAID or heparin; associated renal insufficiency; recent worsening of renal function or of the severity of CHF; old age, diabetes mellitus, generalized arteriosclerosis; and dehydration. In all of these situations, the initial response of the CHF patient to spironolactone over the first 2–3 months must be checked repeatedly. The syndrome of hyporeninaemic hypoaldosteronism (Schambelan syndrome) is another cause of hyperkalaemia to be remembered. It is too often overlooked or misdiagnosed by physicians.

Conflict of interest statement. None declared.



   References
 Top
 Introduction
 Hyperkalaemia has changed with...
 Hyperkalaemia is now common...
 What went wrong after...
 What are the risk...
 Future perspectives
 Anything else new in...
 Hyporeninaemic hypoaldosteronism...
 The treatment of hyperkalaemia
 Conclusion
 References
 

  1. Pitt B, Zannad F, Remme WJ et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. N Engl J Med 1999; 341: 709–717[Abstract/Free Full Text]
  2. Pitt B, Remme WJ, Zannad F et al. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med 2003; 348: 1309–1321[Abstract/Free Full Text]
  3. Fuster D, Frey FJ, Ferrari P. Bedrohliche Hyperkaliämie als Folge der neuen Behandlungsstrategien der Herzinsuffizienz. Praxis 2000; 89: 2073–2076[Medline]
  4. Schepkens H, Vanholder R, Billiouw JM, Lameire N. Life-threatening hyperkalemia during combined therapy with angiotensin-converting enzyme inhibitors and spironolactone. Am J Med 2001; 110: 438–441[CrossRef][ISI][Medline]
  5. Hu Y, Carpenter JP, Cheung AT. Life-threatening hyperkalemia: a complication of spironolactone for heart-failure in a patient with renal insufficiency. Anest Analg 2002; 95: 35–41
  6. The RALES investigators. Effectiveness of spironolactone added to an angiotensin-converting enzyme inhibitor and a loop diuretic for severe chronic congestive heart failure. Am J Cardiol 1996; 78: 902–907[CrossRef][ISI][Medline]
  7. Tan SY, Shapiro R, Franco R et al. Indomethacin-induced prostaglandin inhibition with hyperkalemia. Ann Intern Med 1979; 90: 783–785[ISI][Medline]
  8. Patel P, Mandal B. Hyperkalemic quadriparesis secondary to chronic diclofenac treatment. Postgrad Med J 2001; 77: 50–51[Abstract/Free Full Text]
  9. Hay E, Derazon H, Bukish N et al. Fatal hyperkalemia related to combined therapy with a COX-2 inhibitor, ACE-inhibitor and potassium rich diet. J Emerg Med 2002; 22: 348–352
  10. Caliskan Y, Kalayoglu-Besisik S, Sargin D et al. Cyclosporin-associated hyperkalemia: report of four allogeneic blood stem-cell transplant cases. Transplantation 2003; 75: 1069–1071[CrossRef][ISI][Medline]
  11. Oeshi M, Yagi T, Uroshihara N et al. A case of hyperkalemic distal renal tubular acidosis secondary to tacrolimus in living donor liver transplantation. Transplant Proc 2000; 32: 2225–2226[CrossRef][ISI][Medline]
  12. Kamel KS, Ethier JH, Quaggin S 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: 1279–1284[Abstract]
  13. Sato A, Hayashi K, Naruse M, Saruta T. Effectiveness of aldosterone blockade in patients with diabetic nephropathy. Hypertension 2003; 41: 64–68[Abstract/Free Full Text]
Received for publication: 16. 9.03
Accepted in revised form: 23. 3.04





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