Nephrology Dialysis Transplantation 2004 19(9):2163-2166; doi:10.1093/ndt/gfh284
Nephrol Dial Transplant Vol. 19 No. 9 © ERA-EDTA 2004; all rights reserved
Editorial Comment
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
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Introduction
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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?
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Hyperkalaemia has changed with the advent of the RALES study
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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?
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Hyperkalaemia is now common and it may be fatal
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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).
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What went wrong after RALES?
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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.
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What are the risk factors for hyperkalaemia in the setting of ACE inhibitors plus mineralocorticoid antagonist?
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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.
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Future perspectives
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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.
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Anything else new in ‘Hyperkalaemia-land’?
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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.
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Hyporeninaemic hypoaldosteronism (hypo-hypo): an old foe that doesn’t go away
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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.
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The treatment of hyperkalaemia
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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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Conclusion
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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.
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References
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- 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]
- 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]
- Fuster D, Frey FJ, Ferrari P. Bedrohliche Hyperkaliämie als Folge der neuen Behandlungsstrategien der Herzinsuffizienz. Praxis 2000; 89: 2073–2076[Medline]
- 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]
- 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
- 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]
- Tan SY, Shapiro R, Franco R et al. Indomethacin-induced prostaglandin inhibition with hyperkalemia. Ann Intern Med 1979; 90: 783–785[ISI][Medline]
- Patel P, Mandal B. Hyperkalemic quadriparesis secondary to chronic diclofenac treatment. Postgrad Med J 2001; 77: 50–51[Abstract/Free Full Text]
- 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
- 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[Medline]
- 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[Medline]
- 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]
- 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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Introduction
Hyperkalaemia has changed with...