Spironolactone increases serum uric acid levels in patients with chronic kidney disease

Raised serum uric acid levels are associated with increased cardiovascular risk in many patient groups, including those with chronic kidney disease. Mineralocorticoid receptor antagonists are showing great promise as a means of lowering cardiovascular risk in patients with chronic kidney disease; yet their actions on serum uric acid are not known. The present study examined the actions of the mineralocorticoid receptor antagonist spironolactone on serum uric acid in patients with early chronic kidney disease. Several studies have demonstrated a relationship between raised serum uric acid levels and multiple cardiovascular (CV) conditions including hypertension and chronic kidney disease (CKD). Emerging data suggest that lowering serum uric acid levels might have both CV and renal benefits. The mineralocorticoid hormone aldosterone has also been implicated in the pathophysiology of both CV disease and CKD. However, studies of mineralocorticoid receptor antagonism have shown conflicting results on serum uric acid levels. In the CRIB-2 (Chronic Renal Impairment in Birmingham-2) study, the mineralocorticoid receptor antagonist spironolactone improved surrogate markers of CV disease including arterial stiffness and left ventricular mass in patients with CKD. The rationale and design of this study have been reported in detail elsewhere. In brief, 112 patients already treated with an angiotensin converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB) were randomised to receive either spironolactone 25 mg once daily or matching placebo for up to 40 weeks. None of the patients had any changes made to their medication during the study as per the protocol. Although serum uric acid levels were not measured as part of the protocol, some patients continued to attend regular clinic appointments. Serum uric acid is checked routinely at every clinic visit in our centre. We retrospectively examined these clinic records and found 30 patients (15 on placebo and 15 on spironolactone) who had attended these renal clinics and had had their serum uric acid measured at both the start (a maximum of 2 weeks before enrolment) and at the end of the study (between week 16 and week 28). There were no differences at baseline between groups in demographics, antihypertensive medication (including ACEi or ARB), diuretics, renal function, blood pressure or serum uric acid levels (placebo 376±125mmol l 1 (6.32±2.1 mg dl ): spironolactone 438±116 mmol l 1 (7.36±2.0 mg dl ); P1⁄4 0.99. One patient in each group had a history of gout treated with allopurinol. Although there were no changes in renal function or serum sodium concentrations, spironolactone increased serum uric acid levels by 7% to 472±110mmol l 1 (7.9±1.8 mg dl ), whereas there was a decrease by 4% to 361±124 mmol l 1 (6.0±2.0 mg dl ) in the placebo group, giving a statistically significant difference on repeated measures analysis of variance (P1⁄4 0.03; Figure 1). Serum uric acid increased in 10 of the patients on spironolactone and in 6 patients on placebo. There were no changes in serum creatinine or estimated glomerular filtration rate during this period (Figure 1). To the best of our knowledge, this is the first report that lowdose spironolactone increases serum uric acid levels in patients with CKD. The potential mechanism responsible for this increase is not clear. Some studies have suggested that mineralocorticoid receptor antagonism decreases renal excretion of uric acid. Correction of isolated adrenocorticotrophic hormone deficiency has been shown to decrease serum uric acid levels and increase renal uric acid excretion. This is mirrored in patients with primary aldosteronism who demonstrate an increase in serum uric acid levels and a decrease in urinary uric acid excretion after surgical removal of an adenoma. Both these studies suggest a direct role of aldosterone in the renal clearance of uric acid. The majority of filtered uric acid is reabsorbed by the proximal tubule. The renal urate-anion exchanger URAT-1 appears to be primarily responsible for this and its function is regulated by PDZK1, a regulatory protein with multiple PDZ domains. Aldosterone appears to modulate the interaction between URAT1 and PDZK1 by increasing intracellular calcium in the proximal tubule. There is no doubt that modulation of the renin–angiotensin– aldosterone system, mainly by using ACEi and ARB, has been a major advance in reducing CV risk and the progression of renal dysfunction in patients with CKD. A recent post hoc analysis of the RENAAL (Reduction of Endpoints in Non-insulin dependent diabetes mellitus with the Angiotensin II Antagonist Losartan)