Diabetic Nephropathy in Spontaneously Type 2 Diabetic Nonhuman Primates (Rhesus Monkeys Macaca mulatta): Comparator Validation of Angiotensin Receptor Blocker Valsartan
Authors: Hansen Barbara Caleen , Yang Zunyuan , Liang Yinan , Yao Zunwei , Zeng Licai , Wu Mingling , Yang Zhenyan , Gong Li , Sun Fengjiao , Newcomb Jennifer D. , Zeng Wen 
Published: April 2020

In patients, Type 2 Diabetes Mellitus (T2DM) and Diabetic Nephropathy (DN) have unknown initiation time points, likely well before their respective clinically‐defined features of elevated fasting glucose/HbA1c and reduced eGFR/microalbuminuria respectively, and have unknown preceding and/or causal mechanisms or events (genetic or otherwise). In part, this is due to animal models that do not fully reflect the human condition, do not show the same progressive processes preceding overt onset of clinically‐defined symptoms, and do not show similar associations of contributing factors including hypertension and cardiovascular disease (CVD)/metabolic syndrome (MetSyn). Nonhuman primates (NHPs, rhesus monkeys, Macaca mulatta) frequently, naturally and spontaneously develop obesity, MetSyn, T2DM and DN, with or without CVD, and in this study have been followed metabolically for diabetes‐related and cardiovascular disease features longitudinally from normal young adults to full expression of these diseases (colony N= 1198). We have identified the specific criteria for the identification of DN (eGFR CKD‐EPI 30–59 ml/min/1.73m2 or Iohexol clearance for direct GFR) and/or urine albumin/creatinine ratio (UACR ≥ 10 mg/g) and of CVD (cardiac function by ECHO HFpEF or HFrEF with LVEF <50%, e’<8 cm/s and E/e’ >10) in these animals and have examined these features in relation to the progression of DN and T2DM (using ADA DM diagnostic criteria as applied to patients). Of those with CKD (N=52), 58% also had CVD. In addition, we report here the responses of adult monkeys, selected for the presence of T2DM and diabetic nephropathy ((increased eGFR and decreased urine albumin/creatinine ratio (UACR)) to the validation drug, an angiotensin receptor blocker, Valsartan. Monkeys (N=8 with both CKD and CVD) were studied before and at 2‐week intervals during the 8 week treatment period for the effects on blood pressure, Creatinine, Cystatin C, BUN, and eGFR. Significant improvements compared to vehicle were observed in eGFR (‐increased 23%), UACR (decreased 76%) and SBP (decreased14%) (all p’s <0.05). There were no differences in cardiac ultrasound evaluations compared to vehicle. The similarities in all features and effects between the rhesus monkey and previous reports in humans in clinical settings are extraordinary. We have previously shown the histopathology of DN in monkeys to be “classical human glomerulopathy”, and show that these important similarities permit renal biopsies to be used at any desired intervals to follow changes in DN histopathology and molecular markers, and to evaluate their reversal or modification by therapeutic agents of direct relevance to human pathophysiology.

Support or Funding Information

NIH National Institute on Aging: HHSN263200800022C; SCPrimed Shines Biotech Co., Ltd, Chengdu, Sichuan, China