The Effect of Spironolactone on Calcineurin Inhibitor Induced Nephrotoxicity—The Spiren Trial

Abstract BACKGROUND AND AIMS Improving long-term allograft survival has been a challenge for nephrologists for decades. A common feature in late allograft failure is progressive interstitial fibrosis and tubular atrophy.[1] Increasing evidence points towards the mineralocorticoid hormone aldosterone to contribute to renal fibrosis.[2] The SPIREN trial was designed to test the hypothesis that the mineralocorticoid receptor antagonist spironolactone attenuates renal injury in kidney transplant patients treated with calcineurin inhibitors evaluated as measured glomerular filtration rate, proteinuria and renal fibrosis.[3] METHOD The SPIREN trial was a randomized, placebo-controlled, double-blind clinical trial including 188 prevalent renal transplant patients from four Danish sites. Patients were randomized 1:1 to spironolactone 25–50 mg daily or placebo for 3 years. At baseline and yearly hereafter, we performed chrome-EDTA clearance, 24-h urine samples, ambulatory blood pressure measurements, and blood and urine samples. In a subgroup, an allograft biopsy was made at baseline and after 2 years (n = 48). Numeric data were analysed using mixed-effects linear regressions. Biopsies were scored according to the Banff classification and the extent of fibrosis was additionally evaluated using point counting. All analyses were performed as intention to treat. RESULTS In total, 180 patients were randomized to spironolactone (n = 90) or placebo (n = 90). The groups were comparable at baseline (Table 1) except a difference in the age of the allograft [median 4.4 (IQR 1.1–10.0) versus 2.0 (0.7–6.6) years]. There was a significant reduction in chrome-EDTA clearance in the spironolactone group after 1 year independently of time since transplantation and blood pressure. This persisted throughout the trial. This reduction corresponded to a reduction of eGFR after 1 week of treatment as evaluated by the CKD-EPI formula. The renal function of the placebo group remained stable. Twenty-four-hour proteinuria was reduced significantly after 1 year in the spironolactone group, but this difference was not significant after 2 and 3 years. Ambulatory systolic blood pressure was reduced to 1–2 mmHg in the spironolactone group and increased to 1–4 mmHg in the placebo group (P