Abstract: SA-PO638
Towards a Translatable Model for Studying Therapeutic Efficacy in Alport Syndrome
Session Information
- Genetic Kidney Diseases: Models, Mechanisms, and Therapies
October 26, 2024 | Location: Exhibit Hall, 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
- Zhang, Yanling, Unity Health Toronto, Toronto, Ontario, Canada
- Nghiem, Linda, Unity Health Toronto, Toronto, Ontario, Canada
- Wang, Hai, Unity Health Toronto, Toronto, Ontario, Canada
- Thai, Kerri, Unity Health Toronto, Toronto, Ontario, Canada
- Oliveira, Chiara, Unity Health Toronto, Toronto, Ontario, Canada
- Gilbert, Richard E., Unity Health Toronto, Toronto, Ontario, Canada
Background
Reducing GFR loss is the primary outcome for studying therapeutic effectiveness in Alport syndrome (AS). Unlike humans, standard dose ACE inhibition (ramipril 10 mg/kg) almost completely normalizes the kidney in the Col4a3 KO (AS) mouse. We sought to establish a model with more similarity to its human counterpart by (1) comparing the reliability of GFR methods, and (2) using GFR as the primary outcome to establish a model for testing agents on top of ACE inhibition.
Methods
Study 1 GFR was measured (mGFR) in wild type and Col4a3 KO mice comparing the gold standard of fluorescein-labeled sinistrin (inulin analogue) with plasma creatinine, BUN and cystatin C.
In Study 2, having established cystatin C as a preferred method, we assessed the ACE inhibitor dose-response relationship, aiming for an approximate 50% improvement in GFR, akin to human disease. Urinary ACR, glomerulosclerosis and interstitial fibrosis were also assessed.
Results
Study 1. At 8 weeks of age, the between group difference between WT and Col4a3 KO was 11-fold for sinistrin-GFR, 4.9 fold for plasma creatinine, 2.6 fold for BUN and 6.9 fold for cystatin C. All comparisons p <0.001.
Study 2 (Table 1). In comparison with untreated Col4a3 KO mice, ramipril induced dose-dependent reductions in cystatin C. ACR, glomerulosclerosis and interstitial fibrosis while near-normalized by ramipril 10 mg/kg were unaffected by lower doses.
Conclusion
Changes in cystatin C most closely resemble sinistrin-based mGFR. ACE inhibition with ramipril provided dose-dependent improvements in cystatin C with an approximate 50% reduction at 1 mg/kg, akin to findings of standard of care in humans. Accordingly, 1 mg/kg may be an appropriate dose to use in studies testing the efficacy of new additive agents. The dynamic range for UACR, GSI and IF may be too narrow to allow for such testing.
Renal function parametres and histologic analysis
| WT | RO water | ramipril 0.1 | ramipril 1 | ramipril 10 | |
| cystatin C mmol/l | 306 ± 21 | 2360 ± 158 | 1450 ± 168† | 1129 ± 191†‡ | 502 ± 52†‡§ |
| UACR (mg/mmol) | 3.1 (2.9 – 7.9) | 423 (292 – 635 | 484 (325 – 807) | 303 (187 – 474) | 15 (7 – 126)† |
| GSI | 0.2 (0.2 – 0.7) | 3.8 (3.3 – 3.9) | 3.7 (2.4 – 3.9) | 3.7 (2.9 – 3.9) | 0.5 (0.4 – 1.0)† |
| IF (%) | 1.2 ± 0.3 | 11 ± 2.5 | 10 ± 4.6 | 6.9 ± 2.6 | 2.2 ± 1.0* |
* p<0.05 versus RO water ; † p≤0.001 versus RO water; ‡ p<0.01 versus 0.1 ramipril; § p<0.01 versus 1 ramipril WT, wild type; RO, reverse osmosis water. RO water and ramipril-treated mice were all studied in Col4a3 KO mice.
Funding
- Government Support – Non-U.S.