Renal Fibrosis: The Surgical Barrier in the UUO Model

Introduction: The "Gold Standard" of Renal Fibrosis Research

Renal fibrosis accompanying the progression of Chronic Kidney Disease (CKD) is a common pathway leading to end-stage renal failure, and overcoming it is the greatest challenge in the nephrology field. The Unilateral Ureteral Obstruction (UUO) model is the most widely used "gold standard" model for screening anti-fibrotic drugs because it can induce robust tubulointerstitial fibrosis in a short period (7-14 days) (Kidney Int. 2010).

However, because this model relies on surgical procedures, its data reproducibility and clinical relevance are often subjects of debate.

Challenges in Research: Variability in Technique and Limitations in Functional Assessment

1. Data "Noise" Caused by Surgical Technique

The severity of the UUO model is heavily influenced by the degree of ureteral ligation (complete obstruction or not) and physical damage to the kidney during surgery.

• Incomplete Ligation: Loose ligation delays the progression of hydronephrosis, resulting in mild fibrosis.
• Surgical Invasiveness: Accidental injury to the renal artery or nerves can cause excessive ischemia and inflammation, masking the effects of the drug. These factors cause large standard deviations (SD) within groups, especially in models created by inexperienced operators, leading to difficulties in achieving statistical significance.

2. The Dilemma of Impossible "Functional Assessment"

The biggest drawback of the UUO model is that the function (e.g., GFR) of the obstructed kidney cannot be measured. Because the contralateral healthy kidney compensates for function, serum creatinine and BUN levels do not rise. Therefore, researchers are forced to conclude that "fibrosis was histologically suppressed, but it is unclear whether renal function improved," which is sometimes pointed out as having low clinical predictability.

Solution: Microsurgical Excellence and Expansion to the IRI Model

1. "Microsurgical Excellence" by Skilled Technicians

At our partner CRO, skilled technicians specialized in microsurgery under a microscope perform the operations. By gently peeling and ligating only the ureter and minimizing invasion of surrounding tissues, we provide models with extremely low variability. In fact, in quantitative data of fibrosis markers (α-SMA, Collagen I), we achieve overwhelmingly tight SDs compared to competitors, enabling reliable drug efficacy evaluation even with a small number of animals (N).

2. Proposal of the "IRI Model" Enabling Functional Assessment

If "improvement of renal function" is the desired endpoint, we recommend the Ischemia-Reperfusion Injury (IRI) Model. The IRI model involves temporarily blocking the renal artery to cause ischemic Acute Kidney Injury (AKI), which then transitions to a chronic phase (AKI-to-CKD transition).

• Advantage: Functional efficacy evaluation is possible using increases in serum creatinine and BUN as indicators.
• Difficulty: It is a difficult model where slight deviations in ischemia time or body temperature management increase mortality, but our technicians enable stable pathology induction through strict protocol management.

Conclusion

"UUO data is unstable." "I want to evaluate function as well as tissue." These concerns in renal drug discovery research can be resolved by appropriate model selection and reliable techniques. Please consult us, as we have a rich lineup and track record of renal disease models.

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References

1. Chevalier RL, et al. Ureteral obstruction as a model of renal interstitial fibrosis and obstructive nephropathy. Kidney Int. 2009;75(11):1145-1152.
2. Basile DP, et al. Renal ischemia-reperfusion injury: a paradigm for acute kidney injury and renal fibrosis. Am J Physiol Renal Physiol. 2012;302(11):F1343-F1357.