Key Points Spironolactone is safe for kidney transplant patients.Spironolactone reduces kidney function by an acute effect, whereafter it remains stable.Spironolactone does not affect the progression of interstitial fibrosis in protocol biopsies. Background Long-term kidney allograft survival is hampered by progressive interstitial fibrosis and tubular atrophy. The SPIREN trial tested the hypothesis that the mineralocorticoid receptor antagonist spironolactone stabilizes kidney function and attenuates glomerular barrier injury in kidney transplant patients treated with calcineurin inhibitors. Methods We conducted a randomized, placebo-controlled, double-blind clinical trial including 188 prevalent kidney transplant patients. Patients were randomized to spironolactone or placebo for 3 years. GFR was measured along with proteinuria and kidney fibrosis. The primary end point was change in measured GFR. Secondary outcomes were 24-hour proteinuria, kidney allograft fibrosis, and cardiovascular events. Measured GFRs, 24-hour proteinuria, and BP were determined yearly. Kidney biopsies were collected at baseline and after 2 years (n=48). Fibrosis was evaluated by quantitative stereology and classified according to Banff. Results The groups were comparable at baseline except for slightly older allografts in the spironolactone group. Spironolactone reduced measured GFRs (up to –7.6 [95% confidence interval, −10.9 to −4.3] ml/min compared with placebo) independently of time since transplantation and BP with no effect on the kidney function curve over time and reduced 24-hour proteinuria after 1 year. There was no significant effect of spironolactone on the development of interstitial fibrosis. Conclusions Spironolactone added to standard therapy for 3 years in kidney transplant patients did not improve kidney function, long-term proteinuria, or interstitial fibrosis. Clinical Trial registration number NCT01602861.