Abstract: TH-PO469
Efficacy and Mechanism of Dapagliflozin in Alport Syndrome
Session Information
- Genetic Diseases: Glomerulopathies - I
November 02, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Genetic Diseases of the Kidneys
- 1202 Genetic Diseases of the Kidneys: Non-Cystic
Authors
- Zheng, Qimin, Shanghai Jiao Tong University Medical School Affiliated Ruijin Hospital, Shanghai, China
- Yu, Shuwen, Shanghai Jiao Tong University Medical School Affiliated Ruijin Hospital, Shanghai, China
- Jun, Tong, Shanghai Jiao Tong University Medical School Affiliated Ruijin Hospital, Shanghai, China
- Jin, Yuanmeng, Shanghai Jiao Tong University Medical School Affiliated Ruijin Hospital, Shanghai, China
- Fang, Zhengying, Shanghai Jiao Tong University Medical School Affiliated Ruijin Hospital, Shanghai, China
- Weng, Qinjie, Shanghai Jiao Tong University Medical School Affiliated Ruijin Hospital, Shanghai, China
- Du, Wen, Shanghai Jiao Tong University Medical School Affiliated Ruijin Hospital, Shanghai, China
- Li, Junru, Shanghai Jiao Tong University Medical School Affiliated Ruijin Hospital, Shanghai, China
- Xiaoxia, Pan, Shanghai Jiao Tong University Medical School Affiliated Ruijin Hospital, Shanghai, China
- Gu, Xiangchen, Shanghai Jiao Tong University Medical School Affiliated Ruijin Hospital, Shanghai, China
- Xie, Jingyuan, Shanghai Jiao Tong University Medical School Affiliated Ruijin Hospital, Shanghai, China
Background
Alport syndrome(AS) is a hereditary kidney disease caused by COL4A3/4/5 mutation. Currently, the standard therapy is merely RAASi, thus new treatment for AS is urgently needed. SGLT2 inhibitor has been approved for the treatment of diabetic nephropathy and chronic kidney disease, while its therapeutic effect on AS is unknown.
Methods
We conducted an observational, single-arm, prospective study based on AS patients with heterozygous mutations of COL4A3/A4/A5 from May 1, 2021, to August 1, 2022, in Shanghai Ruijin Hospital. Participants were treated with dapagliflozin 10mg per day. Proteinuria and serum creatinine were assessed every 3 to 6 months. We also investigated the effect of dapagliflozin on AS mice. Col4a3 p.C1615Y homozygous mutant mice were used as an AS model. Mutant and wild-type mice（16-17-week -old) were administered with dapagliflozin (10mg/kg), or vehicle in drinking water, and the blood, urine, and kidney samples were collected after 28 days of treatment.
Results
Nine AS patients with heterozygous mutations of COL4A3/A4/A5 were included in this study. There are five males and four females, the average age was 40 years, and all patients were followed up 12 (11.5-17.0) months. The urine protein was 1.66 (1.06-1.90) g at baseline and 0.70 (0.50-2.21) g at the last follow-up time, with a 58% decrease from baseline . The eGFR at last time was 72.5 (61.7-80.1) ml/min/1.73m2, no statistical significance was shown compared with the baseline 66.3 (55.7-101.5) ml/min/1.73m2. No adverse events were observed in these patients.
Consistent with the observational study, the animal study also showed that Dapagliflozin significantly alleviated proteinuria (urinary albumin creatinine ratio) . We also observed that mutant mice treated with dapagliflozin exhibited significantly reduced transcript levels of renal proinflammatory cytokines and fibrotic markers, including Ccl2, Ccl5, Cxcl10, Vimentin, and Col1a1 as compared to vehicle-treated mutant mice. These data were also supported by H&E and F4/80 IHC staining showing decreased immune cell infiltration in kidney tissues of dapagliflozin-treated mutant mice.
Conclusion
Altogether, these results suggest that dapagliflozin is a promising treatment for AS patients, and further studies are required to elucidate the precise mechanism of SGLT2 inhibitors on retarding AS progression.
Funding
- NIDDK Support