FC 118: The Effect of Spironolactone on Calcineurin Inhibitor Induced Nephrotoxicity—The Spiren Trial
Authors: Aas Mortensen Line , Jespersen Bente , Sophie Lind Helligsø Anne , Cibulskyte-Ninkovic Donata , Godskesen Tougaard Birgitte , Egfjord Martin , Boesby Lene , Marcussen Niels , Madsen Kirsten , Jensen Boye L , Petersen Inge , Bistrup Claus , Charlotte Thiesson Helle 
Published: May 2022

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 &lt; 0.05). Data regarding urine albumin/creatinine ratio and quantitative biopsy data are pending.

CONCLUSION
Spironolactone added to standard therapy for three years in renal transplant patients did not improve renal function or long-term proteinuria. The reduction of chrome-EDTA clearance in the spironolactone group occurred within the first year of treatment and was most likely due to the well-known, reversible and presumed hemodynamic adverse effect of spironolactone on renal function. Whether spironolactone reduced progression of interstitial fibrosis remains to be analysed.