Protective Effects of Selective Mineralocorticoid Receptor Antagonist in Alport Syndrome on Top of Renin-Angiotensin-System/ Sodium-Glucose Transporter 2 Blockade

Alport syndrome (AS) is the most common inherited glomerular disease. The condition always progresses to end-stage kidney disease between adolescence and age 401. According to its current management guideline2Savige J. Lipska-Zietkiewicz B.S. Watson E. et al.Guidelines for Genetic Testing and Management of Alport Syndrome.Clin J Am Soc Nephrol. 2022; 17: 143-154Crossref PubMed Scopus (38) Google Scholar, renin-angiotensin-system inhibition (RASi) is the only standard treatment to retard progression. Human landmark clinical studies unequivocally demonstrated the renoprotective effect of sodium-glucose transporter 2 inhibitors (SGLT2i) and mineralocorticoid receptor antagonists (MRA) in addition to RASi in diabetes3Bakris G.L. Agarwal R. Anker S.D. et al.Effect of Finerenone on Chronic Kidney Disease Outcomes in Type 2 Diabetes.N Engl J Med. 2020; 383: 2219-2229Crossref PubMed Scopus (947) Google Scholar. A preclinical trial in mice with AS suggested that triple RAS/SGLT2/MR blockade could improve renal outcome4Zhu Z. Rosenkranz K.A.T. Kusunoki Y. et al.Finerenone Added to RAS/SGLT2 Blockade for CKD in Alport Syndrome. Results of a Randomized Controlled Trial with Col4a3-/- Mice.J Am Soc Nephrol. 2023; 34: 1513-1520Crossref Scopus (1) Google Scholar. We thus aim to analyze the effect of MRA in AS patients with stable RASi and SGLT2i but residual proteinuria. Four patients with AS who had been treated with a stable dose of RASi for at least 3 months but still had mean proteinuria of 3.61 g/day received SGLT2i therapy (Table S1). After adding SGLT2i for 3 months, the urinary protein had decreased slightly to 3.32 g/day, which was about 9.65±6.24% in the mean ratio reduction (±SE). Thus, an add-on finerenone 10 mg/day was adopted on top of RASi and SGLT2i combination. It was observed a significant reduction in the urinary protein at the first 2-3 months. The mean proteinuria decreased to 2.19 g/day and mean ratio reduction (±SE) in the 24-hour urinary protein was 33.19±6.53%. However, a small reversible early dip in eGFR was also noted (12.02%, 95% CI, 4.67% to 19.36%). The antiproteinuric effect was stable during the next 3-4 months follow-up (Figure 1 and Table S2). No adverse reaction like hypotension or hyperkalemia was observed during the 6 months follow-up after triple therapy. This pilot study suggests that MRA therapy induces an appreciable reduction in proteinuria on top of RASi and SGLT2i combination. The reduction ratio in proteinuria seemed to be comparable to that was observed in the preclinical trial in mice with AS and our previous case reports4Zhu Z. Rosenkranz K.A.T. Kusunoki Y. et al.Finerenone Added to RAS/SGLT2 Blockade for CKD in Alport Syndrome. Results of a Randomized Controlled Trial with Col4a3-/- Mice.J Am Soc Nephrol. 2023; 34: 1513-1520Crossref Scopus (1) Google Scholar,5Song Z.-R. Li Y. Zhou X.-J. et al.Efficacy of Dapagliflozin in Adult Autosomal Recessive Alport Syndrome.Kidney Int Rep. 2022; 7: 2116-2117Abstract Full Text Full Text PDF Google Scholar. Anyhow, prospective large scale randomized studies are needed to demonstrate a nonsteroidal MRA can be added to a RASi and an SGLT2i for treatment of AS or other proteinuric kidney diseases. All authors declared no conflict of interest. 1Groopman E.E. Marasa M. Cameron-Christie S. et al.Diagnostic Utility of Exome Sequencing for Kidney Disease.N Engl J Med. 2019; 380: 142-151Crossref PubMed Scopus (363) Google Scholar, 1.. Support was provided by National High Level Hospital Clinical Research Funding (Interdisciplinary Clinical Research Project of Peking University First Hospital, 2022CR41); China International Medical Foundation (Z-2017-26-2202-2). Data Statement The data will be available on request. Ethical Statement The patients have given consent of their clinical information to be published in the journal. Download .pdf (.17 MB) Help with pdf files