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Volume: 12 Issue: 4 August 2014

FULL TEXT

ARTICLE
Acidosis and Hyperkalemia Caused By Losartan and Enalapril in Pediatric Kidney Transplant Recipients

Objectives: To evaluate the efficacy and safety of losartan and enalapril in pediatric kidney transplant recipients.

Materials and Methods: A retrospective review was performed in 31 pediatric kidney transplant recipients who were treated with losartan (50 mg/d, oral) for 1 to 6 months because of mild hypertension and persistent proteinuria. All patients were treated concurrently with enalapril (5 or 10 mg daily, oral), and 12 patients (39%) also were treated with amlodipine (5 or 10 mg daily, oral). Demographic and clinical characteristics of the patients were reviewed.

Results: Losartan use was associated with a significant decrease in mean systolic (before losartan was started, 123 ± 14 mm Hg; before losartan was stopped, 111 ± 10 mm Hg; P ≤ .001) and diastolic blood pressure (before losartan was started, 78 ± 11 mm Hg; before losartan was stopped, 69 ± 10 mm Hg; P ≤ .001) and urinary protein excretion (before losartan was started, 51 ± 45 mg/m2/h; before losartan was stopped, 28 ± 34 mg/m2/h; P ≤ .001). However, losartan therapy was associated with a significant mean increase in serum potassium level (before losartan was started, 4.0 ± 0.4 mmol/L; before losartan was stopped, 5.7 ± 0.5 mmol/L; P ≤ .001) and decrease in pH (before losartan was started, 7.35 ± 0.0; before losartan was stopped, 7.23 ± 0.0; P ≤ .001). Losartan was stopped because of hyperkalemia and acidosis earlier in patients who were on tacrolimus than cyclosporine immunosuppression (tacrolimus, 3 ± 1 mo; cyclosporine, 4.7 ± 0.8 mo; P ≤ .001).

Conclusions: Losartan and enalapril may be beneficial in pediatric kidney transplant recipients by decreasing blood pressure and proteinuria, with maintenance of stable graft function, but may be associated with serious adverse events including hyperkalemia and life-threatening acidosis.


Key words : Acidosis, Adverse events, Angiotensin receptor blocker, End-stage renal disease, Hyperkalemia

Introduction

Kidney transplant is the most effective treatment for end-stage renal disease, but chronic complications can threaten long-term graft survival.1 Chronic kidney transplant failure is a major cause of terminal renal insufficiency, and allograft failure accounts for 20% patients who begin maintenance dialysis.2-4 In these patients, the cause of renal insufficiency is multifactorial and may include immunologic factors such as chronic rejection and nonimmunologic factors such as hypertension, hyperuricemia, and hyperlipidemia.3,5-8 Hypertension, hyperuricemia, posttransplant erythrocytosis, and proteinuria are prevalent after kidney transplant and have been associated with lower graft survival.1,4 Toxicity of immunosuppressive therapy and recurrent and de novo kidney disease also contribute to chronic renal insufficiency.5,9,10

Various strategies may delay impairment of renal function in kidney transplant recipients, including adjustment of immunosuppressive therapy; treatment of hypertension with angiotensin-converting enzyme inhibitor drugs, angiotensin II type 1 receptor blocker drugs, or calcium channel blocker drugs; and lipid control.3,4,10 The angiotensin-converting enzyme inhibitor and angiotensin II type 1 receptor blocker drugs may delay the progression of kidney disease and have antiproteinuric effects. These drugs are used commonly in adults, but there are concerns about the efficacy and safety of these drugs in children, in whom the causes of chronic kidney disease may be different than adults.11,12

Losartan is a potent, orally active, and selective nonpeptide blocker of the angiotensin II type 1 receptor. Losartan reduces blood pressure, proteinuria, serum uric acid level, and hemoglobin level and may have positive effects on renal excretory function and posttransplant erythrocytosis in adult patients who have chronic kidney disease and who are kidney transplant recipients.1,3,4,8,11-14 However, there is no previous study about the efficacy and tolerability of losartan or losartan and enalapril in pediatric kidney transplant recipients.

This study sought to evaluate the efficacy and safety of losartan in pediatric kidney transplant recipients who were treated concurrently with enalapril, and to determine whether losartan might reduce blood pressure, proteinuria, serum uric acid, and hemoglobin levels in pediatric kidney transplant recipients as effectively as in adult kidney transplant recipients.

Materials and Methods

Subjects
From January 2012 to January 2013, there were 31 pediatric kidney transplant recipients who were treated in our pediatric nephrology clinic with losartan (50 mg/d, oral) for 1 to 6 months because of mild hypertension and persistent proteinuria (> 3 mo). These patients all were included in the present study (Table 1). All patients were treated concurrently with enalapril (5 or 10 mg daily, oral), and 12 patients (39%) also were treated with amlodipine (5 or 10 mg daily, oral). Kidney transplant had been performed ≥ 1 year earlier, and all patients had stable allograft function for ≥ 6 months. Patients received immunosuppressive therapy with either tacrolimus or cyclosporine with mycophenolate mofetil and prednisolone (Table 1). All protocols were approved by the ethics committee of the institution before the study began, and the protocols conformed with the ethical guidelines of the 1975 Helsinki Declaration. Written, informed consent was obtained from all patients.

Evaluation
The medical records were reviewed retrospectively for demographic and clinical characteristics including age, sex, weight, primary kidney disease, antihypertensive and immunosuppressive drugs, duration of losartan treatment, systolic and diastolic blood pressure, and laboratory parameters including hemoglobin, serum creatinine, uric acid, potassium, albumin, and bicarbonate levels, pH, glomerular filtration rate, and urinary protein excretion. Clinical data were recorded before losartan was started and before losartan was discontinued.

Blood pressure was measured by sphygmomano-meters available in the clinic. Hypertension was diagnosed when the patient had 2 consecutive values of both systolic and diastolic blood pressure ≥ 95th percentile for age. Renal artery stenosis (both native and transplanted kidneys) was excluded in all patients with color Doppler ultrasonography. Proteinuria was defined by urinary protein level > 4 mg/m2/h in a 24-hour urine sample. The biochemical and hematologic parameters were measured by typical laboratory techniques available at the hospital. Urinary protein levels were measured with an autoanalyzer (Abbott Architect C8000 autoanalyzer, Abbott Diagnostics, Santa Clara, CA).

Statistical analyses
Data analyses were performed with statistical software (SPSS, version 9.0, IBM Corporation, Armonk, NY). Comparisons were evaluated with Kolmogorov-Smirnov test, t test for normal continuous variables, and Mann-Whitney U test for continuous variables that were not normally distributed. Categorical variables were compared with the chi-square test. Continuous variables were reported as mean ± standard deviation (SD). Statistical significance is defined by P ≤ .05.

Results

The primary kidney disease most commonly was glomerulonephritis or urologic problems (Table 1). Mean duration of losartan treatment was 4 ± 1 months (Table 1). Few patients had glomerular filtration rate < 60 mL/min/1.73 m2 before losartan was started (Table 2). Losartan use was associated with a significant decrease in mean systolic and diastolic blood pressure and urinary protein excretion; increase in mean serum potassium and albumin level; and decrease in mean blood pH and bicarbonate and uric acid level (Table 2). Losartan was discontinued in all patients because of life-threatening acidosis (Table 2). There was no change in mean hemoglobin or creatinine level or glomerular filtration rate with losartan treatment, and no patients had hypotension while taking losartan (Table 2).

Patients who received an immunosuppressive regimen based on tacrolimus were younger and had shorter mean duration of losartan therapy than patients who received cyclosporine-based immuno-suppression (Table 3). The effects of losartan on blood pressure and laboratory parameters were similar in both immunosuppression groups (data not shown).

Discussion

The present study shows that all pediatric kidney transplant recipients who were treated with losartan developed life-threatening acidosis and hyperkalemia that necessitated withdrawal of losartan. Rapid resolution of the acidosis and hyperkalemia was observed in all patients after discontinuation of losartan (data not shown). Previous studies have shown that losartan can cause life-threatening acidosis in patients who have severe kidney dysfunction. In the present study, only 5 patients had glomerular filtration rate < 60 mL/min/1.73 m2 before losartan was given. The addition or administration of an angiotensin II type 1 receptor blocker drug may increase the incidence of hyperkalemia, independent of kidney function in patients who have diabetes mellitus.15 In addition, there is no difference in the effect of losartan on kidney function, serum potassium level, or systemic blood pressure between patients who have serum creatinine level > or ≤ 265.2 μmol/L.16 The risk of hyperkalemia may be increased in patients who have predisposing disorders such as diabetes mellitus and renal insufficiency or who receive combined renin-angiotensin-aldosterone system inhibitors.17 Therefore, hyperkalemia and life-threatening acidosis observed in all patients in the present study may have been caused by losartan directly or by an adjuvant effect of losartan on enalapril, independent of kidney function. Losartan was discontinued because of hyperkalemia and life-threatening acidosis earlier in patients treated with tacrolimus than cyclosporine (Table 3), possibly because of a diabetogenic effect of tacrolimus.

This study shows that losartan was highly effective in controlling blood pressure in pediatric kidney transplant recipients. The antiproteinuric effect of losartan also was evident, with a significant decrease in proteinuria observed (Table 2). These results are consistent with previous studies that showed decreased proteinuria after adding losartan to drug regimens that include angiotensin-converting enzyme inhibitor drugs.18,19 Kidney function was preserved, and serum creatinine and glomerular filtration rate remained unchanged during treatment in the present patients (Table 2).

The use of angiotensin II type 1 receptor blocker drugs after kidney transplant may decrease hemoglobin concentration, and losartan may be effective in treating hyperuricemia and posttransplant erythrocytosis.1,3,8,14,20,21 In contrast with previous studies, hemoglobin levels remained unchanged throughout the treatment in all patients, and posttransplant erythrocytosis was not observed (Table 2). A small but significant reduction was observed in serum uric acid levels in the present patients (Table 2), consistent with previous studies. The only difference observed between patients treated with tacrolimus or cyclosporine was the duration of losartan therapy (Table 3).

Limitations of the present study include the retrospective design and small number of patients. Previous studies have included prospective, double-blind, randomized controlled trials that compared the use of losartan with enalapril and/or amlodipine in patients with chronic kidney disease or kidney transplant.1,4,11,12,22-24 However, randomized controlled trials may not be feasible in children for some conditions. In the present study, losartan was added during follow-up in patients who had hypertension and proteinuria that could not be controlled with enalapril alone or in combination with amlodipine.

In summary, the present study showed that losartan and enalapril may be beneficial in pediatric kidney transplant recipients by decreasing blood pressure and proteinuria, with maintenance of stable graft function, but may be associated with serious adverse events including hyperkalemia and life-threatening acidosis (Table 2). Use of losartan and enalapril in these patients may be feasible only for a short course of treatment, and prudent practice may include monitoring potassium levels and pH.


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Volume : 12
Issue : 4
Pages : 310 - 313
DOI : 10.6002/ect.2013.0172


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From the Division of 1Pediatric Nephrology and 2General Surgery, Baskent University Faculty of Medicine, Ankara, Turkey
Acknowledgements: The authors have no conflicts of interest to declare, and there was no funding for the study.
Corresponding author: Hale Sakallı, MD, Department of Pediatric Nephrology, Baskent University Faculty of Medicine Hoca Cihan Saray Mah. Saray Cad. No:1 Selçuklu, Konya, Turkey
Phone: +90 332 2570606 (3516)
Fax: +90 332 2570637
E-mail: hales1972@yahoo.com