Chronic Kidney Disease (CKD) has emerged as a global public health challenge, characterized by chronic, progressive decline in renal function. Renal fibrosis, particularly tubulointerstitial fibrosis, represents the final common pathway leading to end-stage renal disease in nearly all progressive CKD cases. The pathogenesis is complex, involving chronic inflammation, TGF-β signaling, oxidative stress, metabolic disturbances, and genetic susceptibility.
To advance the understanding of CKD pathogenesis and develop new therapeutic strategies, effective disease models are crucial. Among these, the Unilateral Ureteral Obstruction (UUO) model stands out for its ability to better replicate the pathological processes of obstructive nephropathy in humans.
Advantages of Non-Human Primate (NHP) CKD Models
Non-human primate (NHP) models of chronic kidney disease offer several key advantages in simulating human CKD and its progression to fibrosis:
- Progressive Renal Fibrosis: NHP models exhibit gradual development of interstitial fibrosis, characterized by excessive deposition of extracellular matrix (ECM) proteins such as collagen, mirroring the fibrotic process seen in human CKD.
- Inflammatory Response: Similar to human CKD, NHP models show sustained inflammatory responses within the kidney, including inflammatory cell infiltration and the release of pro-fibrotic cytokines.
- Decline in Renal Function: NHP models demonstrate a progressive decline in renal function, as measured by glomerular filtration rate (GFR) and other indicators, reflecting the functional deterioration observed in human CKD.
- Comparable Histopathological Features: NHP models display histopathological features closely resembling human renal fibrosis, including tubular atrophy, interstitial inflammation, and glomerulosclerosis.
Compared to rodent models, NHP CKD models offer unique advantages:
- Closer Human Disease Mimicry: The kidney and immune system of NHPs are more analogous to humans, allowing for a more accurate representation of disease progression and therapeutic response.
- Larger Kidney Size: The larger size of NHP kidneys permits more detailed imaging studies and comprehensive analysis of renal structure and function, offering deeper insights into disease mechanisms.
- Similar Drug Metabolism: NHPs share more similar drug metabolism pathways with humans compared to rodents, providing more reliable predictions of drug efficacy and safety in clinical trials.
Prisys Biotech's Renal Fibrosis Model
Prisys Biotech has established a well-characterized chronic kidney disease model in cynomolgus monkeys, utilizing this model to successfully support the preclinical efficacy evaluation of multiple novel therapeutics.
Model Construction:
Prisys Biotech's cynomolgus monkey CKD model replicates the pathological features of CKD through a precisely performed unilateral ureteral obstruction (UUO) surgery. The disease progression and pathological changes in this model closely mirror those seen in humans.
Clinical Endpoints:
- Renal fibrosis histopathology
- Hydroxyproline levels
- Renal function metrics
- Inflammatory response markers
- Kidney size
Model Advantages:
Prisys Biotech's cynomolgus monkey CKD-UUO model exhibits a slower fibrosis progression, accurately simulating the pathological characteristics of human tubulointerstitial fibrosis, including significant tubular basement membrane expansion and interstitial cell infiltration. This model is highly suitable for evaluating the efficacy, target engagement, and pharmacokinetics of anti-fibrotic drugs.
Prisys Biotech's nephrology platform expands on the achievements of their cynomolgus monkey CKD-UUO model by developing additional models, including Acute Kidney Injury (AKI) , Focal Segmental Glomerulosclerosis (FSGS), and IgA Nephropathy (IgAN). These models provide powerful tools for studying the mechanisms, pathology, and therapeutic approaches for various kidney diseases, driving progress in nephrology research and drug development.
Huang, Linghong, et al. "The effect of TG2-inhibitory monoclonal antibody zampilimab on tissue fibrosis in human in vitro and primate in vivo models of chronic kidney disease." Plos one 19.5 (2024): e0298864.
Huang, Linghong, et al. "Development of a unilateral ureteral obstruction model in cynomolgus monkeys." Animal Models and Experimental Medicine 4.4 (2021): 359-368.
