Abstract: SA-PO102
Characterization and Establishment of Non-Human Primate Models of Diabetic CKD
Session Information
- Diabetic Kidney Disease: Basic - III
October 27, 2018 | Location: Exhibit Hall, San Diego Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Diabetic Kidney Disease
- 601 Diabetic Kidney Disease: Basic
Authors
- Perez, Rosario Manocom, Kunming Biomed International, Kunming City, China
- De Villa, Flordeliza Pontioso, Kunming Biomed International, Kunming City, China
- Wang, Dawei, Kunming Biomed International, Kunming City, China
- Gabriel, Joseph Arabejo, Kunming Biomed International, Kunming City, China
- Zhu, Luping, Kunming Biomed International, Kunming City, China
- Yang, Yong, Kunming Biomed International, Kunming City, China
- Yang, Lichuan, Kunming Biomed International, Kunming City, China
- Wang, Tony, Kunming Biomed International, Kunming City, China
- Ding, Zhiming, Kunming Biomed International, Kunming City, China
- Zhang, Bob, Kunming Biomed International, Kunming City, China
Background
The lack of translatable diabetic nephropathy animal models has greatly dampened the development of novel CKD therapies. This study aims to characterize a large cohort of high-fat diet (HFD)-induced type 2 diabetic nephropathy (T2DN) NHPs with substantial translational value to CKD drug development.
Methods
Animals with FBG >150 mg/dL and HbA1c >6% were screened from >1,500 male cynomolgus monkeys on HFD for >1.5 years. The following parameters were monitored: 24-h albumin-creatinine ratio (ACR); BP measurements; and, GFR by FITC-inulin. Animals were classified based on GFR severity grades and renal histology was scored based on the International Pathologic Classification of Glomerular Changes in Diabetic Kidney Disease.
Results
A 25% prevalence of T2DN-CKD was observed. Similar to human DN, albuminuria was confirmed as the earliest marker of glomerular disease. Serum creatinine was normal except in animals with kidney failure. DN-CKD monkeys had significantly elevated ACR levels compared to age-matched lean and obese monkeys, and to insulin-treated T2D monkeys. Systolic, diastolic and mean arterial pressure levels were significantly higher in DN-CKD. Over 75% had overt albuminuria with moderate to severe GFR reduction (GFR Stages 3-4) while 2% had kidney failure (GFR Stage 5). GFR reduction occurred even without substantive shifts from normo- or micro- to macroalbuminuria. No marked correlation between GFR and ACR was observed. These findings suggested that, as seen in human patients, macroalbuminuria did not represent an obligatory phase for renal function reduction in T2DN-CKD. Albuminuria with GFR Stages 3-4 were associated with mesangial expansion and thickening and/or fibrosis of the basement membranes (Class 1 to 2a/b). Kimmelstiel–Wilson lesions (Class 3) were seen with kidney failure.
Conclusion
A large cohort of DN-CKD monkeys was characterized using quantitative clinical laboratory and histopathologic indicators of DKD development and progression. The cynomolgus monkey CKD model resembles the disease characteristics in man and can be regarded as one of the most clinically relevant models for the efficacy evaluation of new therapeutic modalities for DN-CKD.