Safety and Efficacy of Maximally Tolerated RAS Therapy Alone or in Combination With Spironolactone in Diabetic Kidney Disease: Effect on Proteinuria and eGFR in the MRA-ACE Trial

Background: DKD is generally characterized by proteinuria and progressive of CKD. Although RAS inhibitors reduce proteinuria and slow the progression there is a high residual risk for ESRD at 8-10 years. Despite these benefits, few studies have examined the combination of mineralocorticoid receptor antagonists (MRA) with maximally tolerated RAS therapy (maxRAS). Herein we present the results of the MRA-ACE trial; a prospective, randomized, open labeled study investigating the safety/efficacy of spironolactone in combination with (maxRAS) therapy on proteinuria, delta eGFR and hyperkalemia (HK). Methods: Thirty-two pts with T2D and DKD were randomized to (maxRAS) alone or in combination with spironolactone 25 mg/day (Spiro). Pts developing HK (K+ > 5.5 mmol/L) during therapy received patiromer 8.4 gm Q MWF and titrated as needed. Twenty-seven (85%) of the 32 pts had biopsies confirming DKD. At entry all patients were 1) receiving insulin or oral agents, 2) BP <140/90 mm/Hg on max tolerated ACE or ARB, 3) two consecutive, pre-study UP/Cr >500 mg/gm, 4) CKD-Epi eGFR >20 ml/min/1.73M2. The primary endpoint was reduction in proteinuria at 24 months. A complete response was as defined UP/Cr <500 mg/gm, while a partial response was >50% reduction from baseline. Mean follow-up was 29 months. Results: Results appear in Table-1. Addition of Spiro to RAS reduced UP/Cr at 24 months (p<0.028). The rate of complete/partial response was significantly higher with Spiro (76.6%) vs. maxRAS (38.8%) (P<0.025). HK occurred in 22.2% maxRAS and 57.1% Spiro pts (p<0.027). There were no withdrawals due to HK. ESRD developed in 8 pts; maxRAS-(6) and Spiro-(2). There was 3 deaths; 2-controls and 1-Spriro group; none due to HK. All HK patients were successfully controlled with Patiromer.Table-1Conclusions: Combination therapy with Spironolactone and max-RAS was more effective than max RAS alone in reducing nephrotic range proteinuria and slowing eGFR decline DKD, with a trend to fewer cases of ESRD. Patiromer was effective in management of HK in both groups, and enabled continuous therapy. Funding: Commercial Support - Vifor Pharmaceuticals, Private Foundation Support, Clinical Revenue Support