To the Editor:
Alport syndrome (AS) is the most common inherited glomerular disease. The condition always progresses to end-stage kidney disease between adolescence and age 40.1 According to its current management guideline,2 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 in addition to RASi in diabetes.3 A preclinical trial in mice with AS suggested that triple RAS/SGLT2/mineralocorticoid receptor blockade could improve renal outcome.4 We thus aim to analyze the effect of mineralocorticoid receptor antagonists in patients with AS 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 (Supplementary Table S1). After adding SGLT2i for 3 months, the urinary protein had decreased slightly to 3.32 g/d, which was a mean ratio reduction (±SE) of about 9.65 ± 6.24%. Thus, an add-on finerenone 10 mg/d was adopted on top of RASi and SGLT2i combination. A significant reduction in the urinary protein at the first 2 to 3 months was observed. The mean proteinuria decreased to 2.19 g/d and mean ratio reduction (±SE) in the 24-hour urinary protein was 33.19 ± 6.53%. However, a small reversible early decrease in estimated glomerular filtration rate was also noted (12.02%; 95% confidence interval: 4.67%–19.36%). The antiproteinuric effect was stable during the next 3 to 4 months follow-up (Figure 1 and Supplementary Table S2). No adverse reaction such as hypotension or hyperkalemia was observed during the 6 months follow-up after the triple therapy.
Figure 1.
Changes in UTP, eGFR, Scr, Alb, and serum potassium during treatment. The figure shows the trends during treatment in UTP (a), eGFR (c), Scr (d), Alb (e) and serum potassium (f). The results are displayed using line charts. The red line represents the therapeutic effect trend when using RASi alone. The green line represents the trend when adding SGLT2i on the basis of RASi. The yellow line represents the trend when adding MRA on top of RASi and SGLT2i combination. The figure (b) shows a comparison of the mean urinary proteins between treatments of RASi, RASi+SGLT2i, and RASi+SGLT2i+MRA. The height of the bar indicates the mean urinary protein, and the error bar indicates the standard deviation. Dots represent data from one follow-up visit. Alb, serum albumin; CKD-EPI, Chronic Kidney Disease Epidemiology Collaboration; eGFR, estimated glomerular filtration rate (calculated using the CKD-EPI equation); m, month; MRA, mineralocorticoid receptor antagonists; RASi, renin-angiotensin-system inhibitors; Scr, serum creatinine; SGLT2i, sodium-glucose transporter 2 inhibitors; UTP, 24h urine protein.
This pilot study suggests that mineralocorticoid receptor antagonists therapy induces an appreciable reduction in proteinuria on top of RASi and SGLT2i combination. The reduction ratio in proteinuria seems to be comparable to what was observed in the preclinical trial in mice with AS and our previous case reports.4,5 Anyhow, prospective large scale randomized studies are needed to demonstrate that a nonsteroidal mineralocorticoid receptor antagonists can be added to a RASi and an SGLT2i for treatment of AS or other proteinuric kidney diseases.
Disclosure
All the authors declared no competing interests.
Acknowledgments
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).
Ethical Statement
The patients have given consent for their clinical information to be published in the journal.
Data Availability Statement
The data will be available on request.
Footnotes
Supplementary Methods.
Table S1. Basic information about four patients with Alport syndrome.
Table S2. Changes during follow-up in four patients with Alport syndrome.
Supplementary Material
Supplementary Methods.
Table S1. Basic information about four patients with Alport syndrome.
Table S2. Changes during follow-up in four patients with Alport syndrome.
References
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Supplementary Materials
Data Availability Statement
The data will be available on request.