**6.1 Surgical models**

#### **6.1.1 Ureteral ligation/Unilateral ureteral obstruction**

The vast majority of data on the progression of renal injury following urinary tract obstruction has come from experiments involving surgical ligation of a ureter, a technique known as unilateral ureteral obstruction (UUO) (Bing et al., 2003; de Souza et al., 2004; Eroglu et al., 2004; Flynn et al., 2002; Hanai et al., 2002; Klahr & Morrissey, 2002; Stanton et al., 2003; Thiruchelvam et al., 2003). Several studies have examined partial or complete ureteral ligations in embryonic rabbits, opossums, and sheep (Becker & Baum, 2006; Kitajima et al., 2010; Steinhardt et al., 1994). In these models, animals develop hydroureteronephrosis *in utero* with variable degrees of renal dysplasia depending on the timing and severity of obstruction.

managed, along with any complications of CKD such as hypertension, proteinuria, electrolyte abnormalities, metabolic acidosis, anemia, dyslipidemia, or renal bone disease. In young adult patients with congenital obstructive nephropathy and CKD, there is a strong correlation between proteinuria and rate of decline in renal function. The ItalKid Project found no benefit from angiotensin converting enzyme inhibitors (ACEi) in a population of patients with renal hypodysplasia, many of whom also had congenital obstructive nephropathy (Ardissino, 2007). However, a later study in young adults with congenital obstructive nephropathy or primary VUR with hypodysplasia indicated that ACEi can slow this decline in renal function, but impact renal outcome only when the estimated glomerular filtration rate is greater than 35 ml/min (Neild, 2009b). In patients with post-obstructive bladder dysfunction, an individualized voiding regimen designed to maintain bladder volume below a critical

filling volume can stabilize deteriorating renal function (Hale et al., 2009).

obstructive nephropathy (Morita et al., 2009).

Dr. Mendelsohn's excellent review (Mendelsohn, 2009).

**6.1.1 Ureteral ligation/Unilateral ureteral obstruction** 

**6.1 Surgical models** 

timing and severity of obstruction.

**5.6 End-stage kidney disease due to congenital obstructive nephropathy** 

**6. Experimental models of congenital obstructive nephropathy** 

For patients with congenital obstructive nephropathy who progress to ESRD, renal transplantation is generally a safe and effective therapy, with 5 year graft survival rates approximately 85% for living donor transplants and 72% for deceased donor grafts in patients with a primary diagnosis of obstructive nephropathy (NAPRTCS, 2009). Appropriate and effective management of any residual urinary tract dysfunction is critical to long-term outcomes following renal transplantation in patients with congenital

The experimental analysis of urological obstructions dates back to antiquity. The physician Galen of Pergamon described ligature of both the ureter and the urethra in animals in the 2nd century A.D. (Galen, 1914). In the 21st century, surgical introduction of a urologic obstruction is still an important research tool. Other animal models of congenital obstructive nephropathy have been created by non-surgical approaches, including genetic manipulation and chemical induction. This review focuses on animal models for investigating the consequences of obstruction on the subsequent maturation and function of the kidneys and urinary tract. For an analysis of how mouse models have contributed to understanding ureter and bladder organogenesis from the earliest stages of development, we recommend

The vast majority of data on the progression of renal injury following urinary tract obstruction has come from experiments involving surgical ligation of a ureter, a technique known as unilateral ureteral obstruction (UUO) (Bing et al., 2003; de Souza et al., 2004; Eroglu et al., 2004; Flynn et al., 2002; Hanai et al., 2002; Klahr & Morrissey, 2002; Stanton et al., 2003; Thiruchelvam et al., 2003). Several studies have examined partial or complete ureteral ligations in embryonic rabbits, opossums, and sheep (Becker & Baum, 2006; Kitajima et al., 2010; Steinhardt et al., 1994). In these models, animals develop hydroureteronephrosis *in utero* with variable degrees of renal dysplasia depending on the The majority of investigations using UUO have employed postnatal and adult rats, mice and pigs. In these species, nephrogenesis continues for a limited period after birth (Moritz & Wintour, 1999), so postnatal ligation in these animals may have some relevance to congenital ureteral obstructions. Even though postnatal models do not reproduce the fetal environment, the delay in renal maturation in rodents versus humans permits relative comparisons of the effects of obstruction on kidney development to be made. In addition, postnatal surgical models can isolate the effects of mechanical obstruction on the developing urinary tract from parallel renal maldevelopment, a concern that often confounds analysis of genetic models of congenital obstructive nephropathy. However, many obstructive lesions that lead to congenital obstructive nephropathy in humans arise earlier in the course of renal development, or exert their effects on the kidney more gradually, than the circumstances modeled by UUO. Therefore, the precise pathophysiological applicability of this model to congenital obstructive nephropathy remains to be determined.

UUO in rodents has been shown to have profound and often irreversible effects on renal growth, maturation, and function in neonatal and adult animals. The progressive renal injury associated with UUO has been characterized as four overlapping stages: 1) interstitial inflammation, 2) tubular and myofibroblast proliferation, 3) tubular apoptosis, and 4) interstitial fibrosis (Bascands & Schanstra, 2005; Chevalier, 2006; Klahr & Morrissey, 2002). The renin-angiotensin and transforming growth factor (TGF-) pathways appear to play critical roles in these changes (Bascands & Schanstra, 2005; Chevalier, 2006; Esteban et al., 2004; Inazaki et al., 2004).
