SP748TREATMENT WITH SPIRONOLACTONE FOR 1 YEAR DOES NOT IMPROVE NITRIC OXIDE METABOLISM IN RENAL TRANSPLANT PATIENTS

Abstract

INTRODUCTION AND AIMS: End stage renal disease is associated with high risk of adverse cardiovascular outcome. Kidney transplantation improves cardiovascular outcomes but cardiovascular risk in renal transplant patients remains significantly elevated. Endothelial dysfunction is recognized as an important predictor of cardiovascular disease in renal transplant patients. The mineralocorticoid hormone aldosterone induces endothelial dysfunction through decreased production of the potent vasodilator nitric oxide. The present substudy was designed to test the hypothesis that the mineralocorticoid receptor antagonist spironolactone for one year would improve nitric oxide bioavailability in renal transplant patients compared to placebo. METHODS: The present investigation was an exploratory substudy from an ongoing, double‐blinded randomized clinical intervention trial in renal transplant patients testing the effect of treatment with spironolactone (25‐50 mg/day) or placebo on preservation of renal function (ClinicalTrials.gov: NCT01602861). Ambulatory blood pressure was measured at baseline and follow‐up. Plasma samples at baseline and after one year were evaluated by ELISA and HPLC for aldosterone and the following components of nitric oxide metabolism: nitrite, nitrate, cyclic GMP, the amino acids arginine, citrulline, ornithine and the endogenous nitric oxide synthase (NOS) inhibitors: asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA) and NG‐monomethyl‐L‐arginine (MMA). RESULTS: Plasma samples from the first 80 patients to complete one year of treatment were analyzed blinded to the allocation (n=39 in spironolactone group, n=41 in placebo group). Baseline data including dialysis vintage, comorbidity, plasma potassium and plasma aldosterone were similar for the two groups. Median age at baseline was 56 (23‐74) years and mean blood pressure 136614/8267 mmHg with no differences between groups. After one year of spironolactone there was a significant increase in plasma aldosterone compared to the placebo group (to 109635 vs. 65617pg/mL, p<0.001), which was paralleled by an increase in plasma potassium (to 4.6±0.5 vs. 4.360.5 mmol/L, p<0.001). Blood pressure was not significantly changed between the groups. No changes were detected in plasma concentrations of nitrite, nitrate, cGMP, citrulline, arginine, ornithine or ADMA, SDMA andMMAin the spironolactone group compared to placebo. CONCLUSIONS: Mineralocorticoid blockade at blood pressure‐neutral level did not improve substrates for NOS or plasma markers for endothelial function while plasma potassium was slightly increased. Thus no major beneficial effect of aldosterone antagonism on nitric oxide metabolism was detected at systemic level in renal transplant patients. Aldosterone may have adverse cardiovascular effects by blood pressure or pathways not related to nitric oxide.