**5.3 Antenatal intervention**

14 Novel Insights on Chronic Kidney Disease, Acute Kidney Injury and Polycystic Kidney Disease

Obstruction of the bladder outlet or urethra affects urologic and renal functions at all points proximal to the lesion. Extrarenal effects may also occur, primarily in the lungs due to associated oligohydramnios. The profound changes that can result are outlined in Figure 6.

Fig. 6. Cascade of physiological consequences associated with lower urinary tract obstruction.

As many as 70% of boys with PUV develop advanced chronic or end-stage kidney disease (CKD Stage 3-5; Parkhouse et al., 1988; Reinberg et al., 1992; Roth et al., 2001; Sanna-Cherchi, et al., 2009). Those with ultrasound findings at or before 24 weeks' gestation are significantly more likely to have a poor renal outcome than children with PUV detected later in pregnancy after a normal second trimester scan (Hutton, et al., 1994). Among patients with PUV who survive the perinatal period, bladder dysfunction and nadir serum creatinine greater than 1.0 mg/dl are independent risk factors for progression to end stage renal disease (Ansari, et al., 2010; DeFoor et al., 2008). Unilateral or bilateral VUR associated with

Long-term follow-up studies decades after treatment for PUV offer additional insight into the postnatal renal progression of this condition. Holmdahl and colleagues (2005) assessed Swedish men who were treated for PUV between 1956 and 1970. Over the 30 to 40 years between initial intervention and this follow-up assessment, the prevalence of ESRD in this population increased from 8% to 21%, and only 37% of the cohort had apparently normal renal function as adults (Holmdahl & Sillen, 2005). Kousidis et al. (2008) found that in a British cohort of patients diagnosed prenatally between 1984 and 1996, 28% died or

PUV may also have a significant impact on kidney function (Heikkila et al., 2009).

**5.2 Natural history of lower urinary tract obstruction** 

Antenatal intervention for suspected fetal obstructive nephropathy has been attempted by vesicoamniotic shunting, vesicocentesis, fetal cystoscopy, or open fetal bladder surgery. The results are variable and these methods remain controversial. A 2003 meta-analysis of the available data suggested improved perinatal survival following prenatal bladder drainage, particularly in cases with poor predicted prognoses (Clark et al., 2003). However, these procedures carry a high risk for complications including shunt malfunction or migration, urinary ascites, hemorrhage, chorioamnionitis, iatrogenic gastroschisis, premature labor, or miscarriage (Carr & Kim, 2010; Elder et al., 1987). The Percutaneous shunting in Low Urinary Tract Obstruction (PLUTO) study, a multicenter, prospective, randomized trial, was designed to systematically evaluate the prenatal and perinatal outcomes and risk/benefit ratio of *in utero* intervention for urological obstruction versus conservative management, and is currently in the data analysis phase (Kilby et al., 2007; Morris & Kilby, 2009; University of Birmingham, 2011).

## **5.4 Postnatal intervention**

In cases where renal function is affected or threatened, surgical relief of the obstruction or diversion of the urine path is necessary. Stents, catheters, or percutaneous drains may be useful to provide temporary drainage, but long-term management requires surgery. Discussion of the variety of surgical techniques and approaches that may be implemented in the management of congenital urinary obstructions is beyond the scope of this review.

Although such surgical interventions can relieve some of the effects of congenital impairment of urine flow, many developmental and pathologic changes associated with this condition appear irreversible. Many patients with congenital obstructive nephropathy, including the majority of patients with PUV, do not have complete recovery of kidney function following postnatal intervention (Parkhouse, et al., 1988; Reinberg, et al., 1992; Roth, et al., 2001; Sanna-Cherchi, et al., 2009).

### **5.5 Progressive chronic kidney disease in congenital obstructive nephropathy**

Given the frequency of chronic and progressive renal impairment, the importance of longterm monitoring of all patients with congenital obstructive nephropathy cannot be overemphasized. Serial measurements of renal function, periodic urinalysis, blood pressure checks, and monitoring of growth should be performed for all patients with a history of congenital urinary obstruction. Renal impairment, if detected, should be fully evaluated and

Congenital Obstructive Nephropathy: Clinical Perspectives and Animal Models 17

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

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.,

Surgical introduction of a bladder outlet obstruction has been investigated in fetal sheep, immature guinea pigs, and young rats (Cendron et al., 1994; Kitagawa et al., 2001; Kitagawa et al., 2004; Mostwin et al., 1991; O'Connor et al., 1997). As in ureteral obstruction models, the effects of these urethral manipulations are also highly dependent on the timing and severity of the obstruction. Experimental urethral ligation resulted in a spectrum of findings ranging from minimal renal pathology to hydronephrosis, renal dysplasia, pulmonary hypoplasia and/or Potter's sequence. Unfortunately, the data on surgical models of *in utero* bladder outlet obstruction are limited by small numbers of animals, and by the lack of complementary genetic studies since many of the large animal models are not easily

The antineoplastic anthracycline antibiotic Adriamycin has well-known teratogenic effects, and has been used in pregnant rats to generate an animal model of congenital obstructive nephropathy (Kajbafzadeh et al., 2011; Thompson et al., 1978). At Adriamycin dosages above 1.5mg/kg/d, bladder hypoplasia or agenesis occurs in all offspring, but fetal viability is low. At decreased doses, Kajbafzadeh et al. (2011) observed a high frequency of hydronephrosis with coexisting bladder anomalies and minimal fetal lethality. The kidneys of these animals demonstrated cortical thinning and cystic dilatation of collecting ducts. However, Adriamycin-treated rats display multiple extrarenal anomalies consistent with the VATER/VACTERL association, including vertebral defects, anal atresia, tracheoesophageal

congenital obstructive nephropathy remains to be determined.

2004; Inazaki et al., 2004).

**6.1.2 Bladder outlet obstruction models** 

amenable to genetic manipulation.

**6.2 Chemically-induced models** 

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).
