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Therapeutic Apheresis and Dialysis 2014; ••(••):••–•• doi: 10.1111/1744-9987.12219 © 2014 The Authors Therapeutic Apheresis and Dialysis © 2014 International Society for Apheresis
Randomized, Double-Blind, Placebo-Controlled Trial of Spironolactone for Hypokalemia in Continuous Ambulatory Peritoneal Dialysis Patients Somchai Yongsiri,1 Jiranuch Thammakumpee,2 Suriya Prongnamchai,1 Pechngam Tengpraettanakorn,1 Rachaneeporn Chueansuwan,1 Siriporn Tangjaturonrasme,1 and Pakaphan Dinchuthai1 1
Facutly of Medicine, Burapha University, and 2Internal Medicine Department, Chonburi Hospital, Mueng Chonburi, Thailand
Abstract: The incidence of hypokalemia in continuous ambulatory peritoneal dialysis (CAPD) patients is about 15–60%, leading to significant complications. There is no standard treatment other than potassium supplement in this setting. The aim of this study was to evaluate effect of spironolactone 25 mg/day in CAPD patients who have a history of hypokalemia. This is a randomized, double-blind, placebo-controlled, cross-over study in CAPD patients who had a history of hypokalemia. Study intervention is 4 weeks of oral spironolactone 25 mg/day or placebo, crossover after a 2-week wash-out period. The primary outcome was the difference of serum potassium before and after 4 weeks of spironolactone treatment. Serum potassium was measured every 2 weeks, serum magnesium, urine and peritoneal fluid potassium measured before and after each treatment period. We enrolled 24 patients, and 20 com-
pleted the cross-over study. Ten patients were anuric. The total doses of potassium supplement were the same during the study period. Serum potassium levels before and after study intervention were not significantly different in both groups (4.23 ± 0.64 vs. 3.90 ± 0.59 mEq/L for spironolactone P = 0.077 and 3.84 ± 0.62 vs. 3.91 ± 0.52 for placebo P = 0.551). Total 24-h potassium, magnesium, sodium excretion, urine volume and ultrafiltration volume were not affected by spironolactone or placebo. There was one episode of hyperkalemia (5.6 mEq/L) during the spironolactone treatment period. Spironolactone 25 mg/ day does not have a significant effect on serum potassium or urine and peritoneal excretion rate in CAPD patients who have a history of hypokalemia. Key Words: End stage renal disease, Hypokalemia, Peritoneal dialysis, Spironolactone.
Approximately 11% of end stage renal disease (ESRD) patients worldwide are being treated with peritoneal dialysis (PD) (1). The incidence of hypokalemia in PD patients, defined by a serum K+ of less than 3.5 mEq/L or required potassium supplements to maintain a normal serum K+, is about 15–58% (2). It can be associated with weakness (3), malnutrition (4), peritonitis (5) and increased risk of death (4). There has been no standard treatment in this setting except for the treatment of malnourishment if it exists. Spironolactone, a
potassium sparing diuretic, may be used safely in hemodialysis (HD) (6) and PD patients with close monitoring of serum potassium (7). The use of low dose spironolactone in HD patients increases serum potassium with low incidence of severe hyperkalemia (8). There were limited data on serum potassium in spironolactone-treated PD patients.A study by Taheri et al. demonstrated that spironolactone at a dose of 25 mg every other day in normokalemic PD patients with congestive heart failure increased serum potassium from 4.6 to 5.0 mEq/L over 6 months (7). The safety of spironolactone in continuous ambulatory peritoneal dialysis (CAPD) patients has also been demonstrated in a long-term study by the Nagoya Spiro Study Group (9). Spironolactone has a high bioavailability of about 90%. After ingestion, it is
Received October 2013; revised March 2014. Address correspondence and reprint requests to Dr Somchai Yongsiri, Nephrologist, Faculty of Medicine, Burapha University, Chonburi 20131, Thailand. Email: [email protected]
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S Yongsiri et al.
metabolized by the liver and approximately 50% is excreted by the kidney (10). The aim of this randomized, double-blind, placebo-controlled crossover study is to evaluate the effects of spironolactone on serum potassium and potassium excretion rate in CAPD patients who have a history of hypokalemia. PATIENTS AND METHODS The study protocol was approved by the institutional review board of Burapha University and registered at http://www.clinicaltrials.in.th, identification number TCTR20130314001. The study was conducted in ESRD patients on CAPD after obtaining written informed consent. They were selected from screening through medical records of the CAPD clinic in Burapha University Hospital, Thailand. Block randomization was done by a computerized program. The inclusion criteria were ESRD patients aged > 20 years with at least 3 months of regular CAPD, had history of hypokalemia (serum K+ < 3.5 mEq/L) or required potassium supplements to maintain a normal serum K+ at any time in the past. The exclusion criteria were history of hyperkalemia (serum K+ > 5.5 mEq/L) at any time in the past and recent peritonitis within one month. Discontinuation criteria included unwillingness to continue study, intolerable side-effects, peritonitis and persistent elevation of serum potassium level >6 mEq/L after stopping oral potassium supplement. We used the Charlson comorbidity index to identify characteristics of our patients (11).
Study design This was a randomized, double-blind, placebocontrolled, cross-over study. The study was divided into two phases: the initial and the crossed phase. Each phase included a 2-week washout and a 4-week treatment period. After screening and the 2-week washout period, the patients were randomly assigned to spironolactone 25 mg daily or placebo for 4 weeks and then 2 weeks of washout and 4 weeks of crossover in a double-blind fashion, as illustrated in Figure 1. Blood samples were collected every 2 weeks and measured for BUN, creatinine and electrolytes. Serum calcium, phosphorus, albumin, magnesium, 24-h dialysate and urine samples were collected at baseline and after completion of each phase for measurement of dialysis adequacy, residual renal function, excretion of sodium, potassium and magnesium. Dialysis regimen was allowed to be adjusted according to the patients’ condition. Potassium supplement was continued and the dose was adjusted to maintain the patient’s serum potassium between 3.50–5.0 mEq/L. In the participants who were using angiotensin-converting enzyme inhibitors (ACE) inhibitors or angiotensin II receptor antagonists (ARBs), it was replaced by doxazosin to control blood pressure. Beta-blocking agents, loop diuretics, insulin and low-dose aspirin were allowed to continue. Medication count for spironolactone, placebo, potassium supplement and assessment of adverse drug reactions were done by a pharmacist. Dietary advice was provided to all patients and they were asked to maintain regular amounts of potassium in
FIG. 1. Study protocol. Note: four patients met discontinuation criteria during the first phase of study, one patient was unwilling to continue the study, and three patients had peritonitis.
Ther Apher Dial, Vol. ••, No. ••, 2014
© 2014 The Authors Therapeutic Apheresis and Dialysis © 2014 International Society for Apheresis
Spironolactone for Hypokalemic CAPD Patients their diet throughout the entire study. The daily dialysate glucose exposure was calculated by the sum of grams of glucose in each dialysis fluid bag. Statistical analysis On the assumption of equal numbers of patients in each study period, a sample size of 18 patients was required to achieve 80 percent power to detect a significant difference in serum potassium of 0.2 mEq/L with a variance of 0.5 and two-sided alpha error of 0.05. Continuous variables are presented as mean ± SD; categorical data are presented as percentages. Comparison used the paired t-test for continuous variables within the group and Student’s t-test for continuous variables between groups. Categorical variables were compared using χ2 test. All tests of statistical significance were two-tailed; there was a significant difference if the P-value was less than 0.05. Statistics were analyzed with program R version 3.01. Outcomes measurement The main outcome is the difference of serum potassium before and after 4 weeks of spironolactone treatment. We also measured the change of serum magnesium and total daily potassium, magnesium and sodium excretion. RESULTS Patient characteristics A total of 53 CAPD patients were screened, 26 patients met inclusion criteria and 24 patients were willing to participate. Of the 24 patients, 20 completed the cross-over study and were included in the final analysis. One was unwilling to continue the study after the first week and three had peritonitis during the first phase of this study, as outlined in Figure 1. Twelve patients were anuric. Eighteen patients were on oral potassium supplementation. Patient demographics were typical of the overall population of CAPD patients as shown in Table 1. Serum potassium, magnesium and daily excretion of potassium, magnesium, sodium Dwell volume and number of cycles per day in each patient were not changed during the study period. Total glucose exposures were not statistically different between the placebo and treatment period. The medication given in the studied patients that might have affected serum potassium such as beta blocking agents, loop diuretics, insulin and low dose aspirin were not changed during the study period. Mean insulin dose per day (62.4 ± 32.6 vs. 49.0 ± 34.50 © 2014 The Authors Therapeutic Apheresis and Dialysis © 2014 International Society for Apheresis
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TABLE 1. Patient demographics (N = 20) Values Age (years) Sex M : F Duration of dialysis (months) Body weight (kg) Body mass index (kg/m2) Mean systolic blood pressure (mm Hg) Mean diastolic blood pressure (mm Hg) Diabetes PET status Low Low average High average High Anuric Charlson comorbidity index Daily exchange volume (L/d) Daily urine volume (mL/d) Total Kt/V Renal Peritoneal Number of patients taking oral potassium supplement Mean dose of oral potassium supplement (mEq/day) Serum potassium (mEq/L) Serum magnesium (mEq/L)
52.42 ± 12.35 8:12 23.65 ± 10.96 65.79 ± 12.03 25.24 ± 4.23 124 ± 19 67 ± 7 13 3 7 9 1 10 7.48 ± 2.46 6.94 ± 3.18 895.00 ± 582.03 2.23 ± 0.83 0.74 ± 1.04 1.73 ± 0.38 18 13.52 ± 6.44 3.85 ± 0.44 2.02 ± 0.26
Values are given as number (%) or mean ± standard deviation (SD). DBP, diastolic blood pressure; PET, peritoneal equilibration test; SBP; systolic blood pressure.
units/day P = 0.39) and fasting plasma glucose (159.12 + 67.52 vs. 153.21 + 58.39 mg/dL P = 0.77) were not different during the spironolactone and placebo period. Total dose of potassium supplement per day was not different throughout the study period (11.32 ± 7.29 vs. 11.16 ± 4.83 mEq/day during spironolactone and placebo period respectively, P = 0.64). Overall drug compliance as assessed by a pharmacist was > 95% in both phases. Serum potassium before and after the study intervention were not significantly different from each other (4.23 ± 0.64 vs. 3.90 ± 0.59 mEq/L for spironolactone P = 0.077 and 3.84 ± 0.62 vs. 3.91 ± 0.52 for placebo P = 0.551) as shown in Table 2. Blood pressure, total 24-h potassium, magnesium, sodium excretion, urine volume and ultrafiltration volume were not affected by spironolactone or placebo. There was one episode of hyperkalemia (5.6 mEq/L) during the spironolactone treatment period, but it resolved after stopping the oral potassium supplement. Subgroup analysis When classifying patients into subgroups by Kt/Vurea (≥1.7 or
Therapeutic Apheresis and Dialysis 2014; ••(••):••–•• doi: 10.1111/1744-9987.12219 © 2014 The Authors Therapeutic Apheresis and Dialysis © 2014 International Society for Apheresis
Randomized, Double-Blind, Placebo-Controlled Trial of Spironolactone for Hypokalemia in Continuous Ambulatory Peritoneal Dialysis Patients Somchai Yongsiri,1 Jiranuch Thammakumpee,2 Suriya Prongnamchai,1 Pechngam Tengpraettanakorn,1 Rachaneeporn Chueansuwan,1 Siriporn Tangjaturonrasme,1 and Pakaphan Dinchuthai1 1
Facutly of Medicine, Burapha University, and 2Internal Medicine Department, Chonburi Hospital, Mueng Chonburi, Thailand
Abstract: The incidence of hypokalemia in continuous ambulatory peritoneal dialysis (CAPD) patients is about 15–60%, leading to significant complications. There is no standard treatment other than potassium supplement in this setting. The aim of this study was to evaluate effect of spironolactone 25 mg/day in CAPD patients who have a history of hypokalemia. This is a randomized, double-blind, placebo-controlled, cross-over study in CAPD patients who had a history of hypokalemia. Study intervention is 4 weeks of oral spironolactone 25 mg/day or placebo, crossover after a 2-week wash-out period. The primary outcome was the difference of serum potassium before and after 4 weeks of spironolactone treatment. Serum potassium was measured every 2 weeks, serum magnesium, urine and peritoneal fluid potassium measured before and after each treatment period. We enrolled 24 patients, and 20 com-
pleted the cross-over study. Ten patients were anuric. The total doses of potassium supplement were the same during the study period. Serum potassium levels before and after study intervention were not significantly different in both groups (4.23 ± 0.64 vs. 3.90 ± 0.59 mEq/L for spironolactone P = 0.077 and 3.84 ± 0.62 vs. 3.91 ± 0.52 for placebo P = 0.551). Total 24-h potassium, magnesium, sodium excretion, urine volume and ultrafiltration volume were not affected by spironolactone or placebo. There was one episode of hyperkalemia (5.6 mEq/L) during the spironolactone treatment period. Spironolactone 25 mg/ day does not have a significant effect on serum potassium or urine and peritoneal excretion rate in CAPD patients who have a history of hypokalemia. Key Words: End stage renal disease, Hypokalemia, Peritoneal dialysis, Spironolactone.
Approximately 11% of end stage renal disease (ESRD) patients worldwide are being treated with peritoneal dialysis (PD) (1). The incidence of hypokalemia in PD patients, defined by a serum K+ of less than 3.5 mEq/L or required potassium supplements to maintain a normal serum K+, is about 15–58% (2). It can be associated with weakness (3), malnutrition (4), peritonitis (5) and increased risk of death (4). There has been no standard treatment in this setting except for the treatment of malnourishment if it exists. Spironolactone, a
potassium sparing diuretic, may be used safely in hemodialysis (HD) (6) and PD patients with close monitoring of serum potassium (7). The use of low dose spironolactone in HD patients increases serum potassium with low incidence of severe hyperkalemia (8). There were limited data on serum potassium in spironolactone-treated PD patients.A study by Taheri et al. demonstrated that spironolactone at a dose of 25 mg every other day in normokalemic PD patients with congestive heart failure increased serum potassium from 4.6 to 5.0 mEq/L over 6 months (7). The safety of spironolactone in continuous ambulatory peritoneal dialysis (CAPD) patients has also been demonstrated in a long-term study by the Nagoya Spiro Study Group (9). Spironolactone has a high bioavailability of about 90%. After ingestion, it is
Received October 2013; revised March 2014. Address correspondence and reprint requests to Dr Somchai Yongsiri, Nephrologist, Faculty of Medicine, Burapha University, Chonburi 20131, Thailand. Email: [email protected]
1
2
S Yongsiri et al.
metabolized by the liver and approximately 50% is excreted by the kidney (10). The aim of this randomized, double-blind, placebo-controlled crossover study is to evaluate the effects of spironolactone on serum potassium and potassium excretion rate in CAPD patients who have a history of hypokalemia. PATIENTS AND METHODS The study protocol was approved by the institutional review board of Burapha University and registered at http://www.clinicaltrials.in.th, identification number TCTR20130314001. The study was conducted in ESRD patients on CAPD after obtaining written informed consent. They were selected from screening through medical records of the CAPD clinic in Burapha University Hospital, Thailand. Block randomization was done by a computerized program. The inclusion criteria were ESRD patients aged > 20 years with at least 3 months of regular CAPD, had history of hypokalemia (serum K+ < 3.5 mEq/L) or required potassium supplements to maintain a normal serum K+ at any time in the past. The exclusion criteria were history of hyperkalemia (serum K+ > 5.5 mEq/L) at any time in the past and recent peritonitis within one month. Discontinuation criteria included unwillingness to continue study, intolerable side-effects, peritonitis and persistent elevation of serum potassium level >6 mEq/L after stopping oral potassium supplement. We used the Charlson comorbidity index to identify characteristics of our patients (11).
Study design This was a randomized, double-blind, placebocontrolled, cross-over study. The study was divided into two phases: the initial and the crossed phase. Each phase included a 2-week washout and a 4-week treatment period. After screening and the 2-week washout period, the patients were randomly assigned to spironolactone 25 mg daily or placebo for 4 weeks and then 2 weeks of washout and 4 weeks of crossover in a double-blind fashion, as illustrated in Figure 1. Blood samples were collected every 2 weeks and measured for BUN, creatinine and electrolytes. Serum calcium, phosphorus, albumin, magnesium, 24-h dialysate and urine samples were collected at baseline and after completion of each phase for measurement of dialysis adequacy, residual renal function, excretion of sodium, potassium and magnesium. Dialysis regimen was allowed to be adjusted according to the patients’ condition. Potassium supplement was continued and the dose was adjusted to maintain the patient’s serum potassium between 3.50–5.0 mEq/L. In the participants who were using angiotensin-converting enzyme inhibitors (ACE) inhibitors or angiotensin II receptor antagonists (ARBs), it was replaced by doxazosin to control blood pressure. Beta-blocking agents, loop diuretics, insulin and low-dose aspirin were allowed to continue. Medication count for spironolactone, placebo, potassium supplement and assessment of adverse drug reactions were done by a pharmacist. Dietary advice was provided to all patients and they were asked to maintain regular amounts of potassium in
FIG. 1. Study protocol. Note: four patients met discontinuation criteria during the first phase of study, one patient was unwilling to continue the study, and three patients had peritonitis.
Ther Apher Dial, Vol. ••, No. ••, 2014
© 2014 The Authors Therapeutic Apheresis and Dialysis © 2014 International Society for Apheresis
Spironolactone for Hypokalemic CAPD Patients their diet throughout the entire study. The daily dialysate glucose exposure was calculated by the sum of grams of glucose in each dialysis fluid bag. Statistical analysis On the assumption of equal numbers of patients in each study period, a sample size of 18 patients was required to achieve 80 percent power to detect a significant difference in serum potassium of 0.2 mEq/L with a variance of 0.5 and two-sided alpha error of 0.05. Continuous variables are presented as mean ± SD; categorical data are presented as percentages. Comparison used the paired t-test for continuous variables within the group and Student’s t-test for continuous variables between groups. Categorical variables were compared using χ2 test. All tests of statistical significance were two-tailed; there was a significant difference if the P-value was less than 0.05. Statistics were analyzed with program R version 3.01. Outcomes measurement The main outcome is the difference of serum potassium before and after 4 weeks of spironolactone treatment. We also measured the change of serum magnesium and total daily potassium, magnesium and sodium excretion. RESULTS Patient characteristics A total of 53 CAPD patients were screened, 26 patients met inclusion criteria and 24 patients were willing to participate. Of the 24 patients, 20 completed the cross-over study and were included in the final analysis. One was unwilling to continue the study after the first week and three had peritonitis during the first phase of this study, as outlined in Figure 1. Twelve patients were anuric. Eighteen patients were on oral potassium supplementation. Patient demographics were typical of the overall population of CAPD patients as shown in Table 1. Serum potassium, magnesium and daily excretion of potassium, magnesium, sodium Dwell volume and number of cycles per day in each patient were not changed during the study period. Total glucose exposures were not statistically different between the placebo and treatment period. The medication given in the studied patients that might have affected serum potassium such as beta blocking agents, loop diuretics, insulin and low dose aspirin were not changed during the study period. Mean insulin dose per day (62.4 ± 32.6 vs. 49.0 ± 34.50 © 2014 The Authors Therapeutic Apheresis and Dialysis © 2014 International Society for Apheresis
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TABLE 1. Patient demographics (N = 20) Values Age (years) Sex M : F Duration of dialysis (months) Body weight (kg) Body mass index (kg/m2) Mean systolic blood pressure (mm Hg) Mean diastolic blood pressure (mm Hg) Diabetes PET status Low Low average High average High Anuric Charlson comorbidity index Daily exchange volume (L/d) Daily urine volume (mL/d) Total Kt/V Renal Peritoneal Number of patients taking oral potassium supplement Mean dose of oral potassium supplement (mEq/day) Serum potassium (mEq/L) Serum magnesium (mEq/L)
52.42 ± 12.35 8:12 23.65 ± 10.96 65.79 ± 12.03 25.24 ± 4.23 124 ± 19 67 ± 7 13 3 7 9 1 10 7.48 ± 2.46 6.94 ± 3.18 895.00 ± 582.03 2.23 ± 0.83 0.74 ± 1.04 1.73 ± 0.38 18 13.52 ± 6.44 3.85 ± 0.44 2.02 ± 0.26
Values are given as number (%) or mean ± standard deviation (SD). DBP, diastolic blood pressure; PET, peritoneal equilibration test; SBP; systolic blood pressure.
units/day P = 0.39) and fasting plasma glucose (159.12 + 67.52 vs. 153.21 + 58.39 mg/dL P = 0.77) were not different during the spironolactone and placebo period. Total dose of potassium supplement per day was not different throughout the study period (11.32 ± 7.29 vs. 11.16 ± 4.83 mEq/day during spironolactone and placebo period respectively, P = 0.64). Overall drug compliance as assessed by a pharmacist was > 95% in both phases. Serum potassium before and after the study intervention were not significantly different from each other (4.23 ± 0.64 vs. 3.90 ± 0.59 mEq/L for spironolactone P = 0.077 and 3.84 ± 0.62 vs. 3.91 ± 0.52 for placebo P = 0.551) as shown in Table 2. Blood pressure, total 24-h potassium, magnesium, sodium excretion, urine volume and ultrafiltration volume were not affected by spironolactone or placebo. There was one episode of hyperkalemia (5.6 mEq/L) during the spironolactone treatment period, but it resolved after stopping the oral potassium supplement. Subgroup analysis When classifying patients into subgroups by Kt/Vurea (≥1.7 or
