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Updated: Oct 8, 2025
An Immature Murine Model of Reversible Unilateral Ureteral Obstruction
Published on: April 4, 2025
Development of a unilateral ureteral obstruction model in cynomolgus monkeys
Linghong Huang1, Jia Ni2,3, Tanika Duncan1
1Immunology Therapeutic Area UCB Pharma Slough UK.
Background:
Chronic kidney disease (CKD) has a high global prevalence and large unmet need. Central to developing new CKD therapies are in vivo models in CKD. However, next-generation antibody, protein, and gene therapies are highly specific, meaning some do not cross-react with rodent targets. This complicates preclinical development, as established in vivo rodent models cannot be utilized unless tool therapeutics are also developed. Tool compounds can be difficult to develop and, if available, typically have different epitopes, sequences, and/or altered affinity, making it unclear how efficacious the lead therapeutic may be, or what dosing regimen to investigate. To address this, we aimed to develop a nonhuman primate model of CKD.
Methods:
In vivo rodent unilateral ureteral obstruction (UUO) models kidney fibrosis and is commonly used due to its rapidity, consistency, and ease. We describe translation of this model to the cynomolgus monkey, specifically optimizing the model duration to allow adequate time for assessment of novel therapeutics prior to the fibrotic plateau.
Results:
We demonstrated that disease developed more slowly in cynomolgus monkeys than in rodents post-UUO, with advanced fibrosis developing by 6 weeks. The tubulointerstitial fibrosis in cynomolgus monkeys was more consistent with human obstructive disease than in rodents, having a more aggressive tubular basement expansion and a higher fibroblast infiltration. The fibrosis was also associated with increased transglutaminase activity, consistent with that seen in patients with CKD.
Conclusion:
This cynomolgus monkey UUO model can be used to test potential human-specific therapeutics in kidney fibrosis.
Insights
A new cynomolgus monkey model of chronic kidney disease (CKD) using unilateral ureteral obstruction (UUO) allows testing of human-specific therapeutics. This nonhuman primate model better mimics human kidney fibrosis than rodent models.
Area of Science:
- Nephrology
- Translational Medicine
- Preclinical Models
Background:
- Chronic kidney disease (CKD) affects millions globally, with significant unmet needs for effective therapies.
- Current in vivo rodent models are inadequate for testing highly specific, human-targeted antibody, protein, and gene therapies due to cross-reactivity issues.
- Developing specific tool compounds for rodent models is challenging and may not accurately predict therapeutic efficacy.
Purpose of the Study:
- To develop a nonhuman primate model of CKD that accurately reflects human disease.
- To translate the established rodent unilateral ureteral obstruction (UUO) model to cynomolgus monkeys.
- To optimize the UUO model duration in nonhuman primates for preclinical therapeutic assessment.
Main Methods:
- Adapted the unilateral ureteral obstruction (UUO) surgical procedure in cynomolgus monkeys.
- Monitored disease progression and characterized kidney fibrosis development over time.
- Assessed key pathological features and molecular markers relevant to human kidney disease.
Main Results:
- Advanced kidney fibrosis in cynomolgus monkeys was observed by 6 weeks post-UUO, developing slower than in rodents.
- The observed tubulointerstitial fibrosis in monkeys showed greater consistency with human obstructive disease, including tubular basement expansion and fibroblast infiltration.
- Increased transglutaminase activity was noted, aligning with findings in human CKD patients.
Conclusions:
- The cynomolgus monkey UUO model provides a valuable preclinical platform for evaluating novel, human-specific therapeutics for kidney fibrosis.
- This model addresses limitations of rodent models in assessing targeted therapies for chronic kidney disease.
- The enhanced fidelity to human disease pathology makes this a robust model for advancing CKD drug development.
