1Division of Nephrology, 2Division of Cardiology, 3Quality of Care Unit, Division of Endocrinology and 4Laboratory of Clinical Chemistry, Department of Medicine, University Hospital, Geneva Medical School, Geneva, Switzerland
Correspondence and offprint requests to: Pierre-Yves Martin, MD, Associate Professor of Medicine, Division of Nephrology, Department of Medicine, University Hospital, Micheli-du-Crest 24, 1211 Geneva, Switzerland. Email: Pierre-Yves.Martin{at}hcuge.ch
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Abstract |
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Methods. The study design included a 2-week baseline period, followed by a 4-week treatment period in which doses of spironolactone were started at 12.5 mg three times/week for 2 weeks, then increased to 25 mg three times/week, and followed by a 2-week wash-out period. Fourteen patients receiving low-dose spironolactone after each dialysis were compared with 21 haemodialysis patients (control group).
Results. Low-dose spironolactone did not change mean serum potassium (4.9 ± 0.7 vs 4.9 ± 0.3 mmol/l: control). The mean plasma canrenone level induced by administration of spironolactone 25 mg three times/week in the 14 treated patients was 13 ± 5.3 ng/ml. Serum aldosterone was not significantly modified by the administration of spironolactone in these patients [before, median 0.35; interquartile range (IQR) 0.112.83 nmol/l vs after, median 0.22; IQR 0.120.60 nmol/l, NS]. Dietary potassium intake and the use of ion-exchange resin, angiotensin-converting enzyme inhibitors and ß-blockers were similar for the two groups throughout the study.
Conclusion. This non-randomized and non-blinded study shows that administration of 25 mg spironolactone thrice weekly is not associated with an increased frequency of hyperkalaemia in haemodialysis patients when they are carefully monitored. More studies are required, however, before concluding that spironolactone administration is safe in the chronic haemodialysis population.
Keywords: cardiovascular; haemodialysis; hyperkalaemia; spironolactone
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Introduction |
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Spironolactone has a bioavailability of 90% and is metabolized rapidly by the liver. Its active metabolites, canrenone and 7
methylspironolactone, have a long half-life (1520 h) and 95% plasma protein binding [12]. Both metabolites are partially eliminated by the kidney (
50%), and spironolactone dosage must be decreased in end-stage renal failure (ESRF). We hypothesized that 25 mg three times weekly in haemodialysis patients will be equivalent to the low-dose spironolactone regimen used (25 mg/day) in patients with normal or slightly impaired renal function [5] and may be administered without increased risk of severe hyperkalaemia.
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Subjects and methods |
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Design of the study
The study design included a 2-week baseline period, followed by a 4-week treatment period in which doses of spironolactone (Aldactone®, Pharmacia AG, Switzerland) were started at 12.5 mg three times/week taken just after the haemodialysis session for 2 weeks, then increased to 25 mg three times/week, and followed by a 2-week wash-out period. Throughout the study, measurements of serum potassium were performed before each dialysis session in both groups. All patients had a haemodialysis solution with 3 mmol/l of potassium, which is part of our routine procedure. Serum aldosterone levels of patients treated with spironolactone were determined after 2 weeks (run-in) and 6 weeks (spironolactone 25 mg three times/week). As spironolactone was administered three times a week and has a much shorter half-life than canrenone, its main metabolite, we measured the plasma level of canrenone after 6 weeks in the spironolactone-treated patients. This measurement was done before the dialysis session and the next administration of spironolactone. Prior to the observation period, dietary advice was provided to all haemodialysis patients, and a basic dietary survey was answered at each dialysis session throughout the study. Daily dietary potassium intake was then estimated by dietitians unaware of patient group attribution. Interdialytic dietary potassium intake was ranked from 5 to 1 (high, always >2700 mg/day; highmedium, not constantly >2700 mg/day; medium, always 20002700 mg/day, mediumlow, between 2700 and <2000mg/day; and low, always <2500 mg/day). ECGs were performed on a weekly basis in the spironolactone-treated group.
Serum aldosterone measurements
Blood was collected from supine patients and serum was frozen at 20°C. Before assay, samples were slowly thawed at room temperature and aldosterone was measured by direct solid-phase radioimmunoassay, using a commercially available kit (Diagnostic Products Corporation, Los Angeles, CA), according to the suppliers instructions. The intra-assay precision (CV) was between 2.7 and 8.3% and the interassay precision between 3.6 and 10.4%, with a limit of detection of 0.04 nmol/l. Cross-reactivity of the antibody with spironolactone was estimated to be 0.06%. Expected values for normal supine patients are 0.030.44 nmol/l [13].
Plasma canrenone measurements
Frozen plasma samples were analysed by reversed-phase high-performance liquid chromatography (HPLC) after solid phase extraction by a bioanalytical company (Biokinet GmbH, Vienna, Austria). HPLC was performed on a reverse phase C18 column with an eluent of methanol/acronitrile/water and UV detection at 280 nm [14].
Statistical analysis
We compared serum potassium in the spironolactone and control groups, adjusting for study period, and taking into account correlations among repeated observations in the same patient by means of generalized estimating equations. All tests of statistical significance for continuous (Students t-test) and categorical (2 test) were two-tailed. Non-parametric tests were used for non-normally distributed data. Calculations were performed using SPSS, version 10.0 (Chicago, IL) and STATA, version 7, Stata Corp (College Station, TX).
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Results |
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Discussion |
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This study does have some limitations, however. First, the dose used in this study is below the average dose used in the RALES study. Based on the metabolism of spironolactone, we have estimated that similar plasma drug levels in haemodialysis patients should be obtained with 25 mg given three times a week. However, the demonstration of a pharmacological effect using markers such as those used in the RALES dose-finding study (sodium retention test, N-terminal pro-ANF and PRA levels) was not possible in this study because of the renal failure. As no spironolactone or canrenone determination was performed in the RALES study, we do not know whether low-dose spironolactone three times/week in haemodialysis patients provides similar plasma levels as those reached after daily administration. Mean plasma canrenone level, determined at 48 h in our study group, was 50% lower than the mean plasma canrenone level obtained at 24 h in normal volunteers receiving a conventional dose of 50 mg spironolactone daily over 5 days [15]. Therefore, we estimate that 25 mg of spironolactone three times/week in haemodialysis patients is equivalent to the average dose used in the RALES study.
Another important limitation is the design of the study. This was a non-blinded, non-randomized study. To include only patients who accepted to receive spironolactone may have introduced some bias favouring a tighter potassium control. To examine this possibility, we enrolled all the patients who declined to receive spironolactone in the control group. The patients included in the study were closely monitored (serum potassium dosage at each dialysis), and most of them were compliant with the low potassium diet. Our dietary survey, however, did not detect major differences in dietary potassium intake between the two groups or in the use of exchange resins. It is unlikely that the participating subjects deliberately restricted their potassium intake. However, we cannot rule out the possibility that low-dose spironolactone would aggravate hyperkalaemia in the case of acutely increased dietary potassium intake, exertional hyperkalaemia, hyperglycaemia or digoxin toxicity. Similarly, more than half of our patients were also treated with ACEIs or angiotensin receptor blockers (ARBs). The low number of patients included in the study prevents us from asserting that low-dose spironolactone administration in haemodialysis patients treated concomitantly with ACEIs or ARBs is completely safe. In addition, most of the patients in the spironolactone-treated group had no residual renal function, and we cannot extrapolate our results to haemodialysis patients with residual diuresis, where renal potassium excretion, albeit reduced, is still present. Finally, due to its molecular weight and its high protein binding [12], plasma levels of spironolactone and its active metabolites should be unchanged by haemodialysis, but more data on the pharmacokinetics of these compounds during haemodialysis are necessary. Hyperkalaemia induces the activation of both renal and extrarenal homeostatic mechanisms to decrease serum potassium. Long-term extrarenal potassium homeostasis is regulated principally by gastrointestinal excretion in haemodialysis patients. However, low-dose spironolactone does not seem to interfere significantly with colonic adaptation to hyperkalaemia in haemodialysis patients. Our results are in agreement with a previous study investigating the action of aldosterone in anephric haemodialysis patients, where seven patients were challenged with 300 mg of oral spironolactone daily vs no medication during 3 days. Spironolactone was found to induce a small and transient rise in potassium levels after an acute potassium load. However, no persistent hyperkalaemia and no change in intestinal potassium excretion were demonstrated [11]. Recently, low-dose spironolactone (25 mg) administered every day for 10 months was not found to elevate serum potassium above 5.5 mmol/l in a patient treated by peritoneal dialysis and suffering from heart failure [16]. This treatment resulted in a significant improvement of his ejection fraction (from 32 to 46%).
Plasma aldosterone levels become elevated with advanced renal failure and participate in the adaptative mechanisms of chronic renal failure. Haemodialysis patients are characterized by high basal levels of plasma aldosterone [13] and, recently, plasma aldosterone concentrations were shown to be related to left ventricular hypertrophy in non-diabetic ESRF patients [15]. In our patients, mean basal serum aldosterone levels were not high, but a wide range of values was observed which might be due to concomitant reninangiotensin system blockade. Similarly, no significant change in serum aldosterone levels was demonstrated in the spironolactone-treated group, making it unlikely that low doses of spironolactone enhance aldosterone secretion.
We do not know whether 25 mg of spironolactone administered three times weekly would be effective in decreasing cardiovascular mortality in these patients, and it is unreasonable to expect cardiovascular data in a single centre short-term trial. Regarding the high cardiovascular mortality in these patients, the results of this study are encouraging because they open up the possibility of a treatment which has demonstrated its efficacity in patients with normal renal function. However, because of several limitations (non-randomized and non-blinded, administration of kayexelate, tight monitoring of serum potassium levels), this study has to be considered as a pilot study and we cannot conclude that spironolactone administration (25 mg three times/week) will be equally safe under other conditions. Indeed, more clinical trials to study thoroughly the pharmacokinetics of low-dose spironolactone during haemodialysis and to assess the safety of spironolactone in a larger haemodialysed population should be performed before drawning any conclusions regarding the safety of spironolactone in this population.
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Acknowledgments |
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Conflict of interest statement. None declared.
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References |
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