Congenital Anomalies of Kidney and Urinary Tract

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Summary

Congenital anomalies of the kidney and urinary tract anatomy (CAKUT) are common in children and represent approximately 30% of all prenatally diagnosed malformations. CAKUT is phenotypically variable and can affect the kidney(s) alone and/or the lower urinary tract. The spectrum includes more common anomalies such as vesicoureteral reflux and, rarely, more severe malformations such as bilateral renal agenesis. In young children, congenital anomalies are the leading cause of kidney failure and for kidney transplantation or dialysis. CAKUT can also lead to significant renal problems in adulthood and may present itself with hypertension and/or proteinuria. Congenital renal anomalies can be sporadic or familial, syndromic (also affecting nonrenal or non–urinary tract tissues), or nonsyndromic. Genetic causes have been identified for the syndromic forms and have shed some light into the molecular mechanisms of kidney development in human beings. The genetic causes for the more common nonsyndromic forms of CAKUT are unknown. The role of prenatal interventions and postnatal therapies as well as the benefits of screening affected individuals and their family members are not clear.

Section snippets

Normal Kidney Development

The development of the kidney is complex and proceeds through a series of successive phases, each marked by the development of a more advanced kidney. These phases include pronephros, mesonephros, and metanephros. During the pronephros phase, the kidney is in its most immature form and is considered nonfunctional in mammalians. The last phase, metanephros, arises at approximately day 35 of human gestation and persists as the definitive adult kidney.6

The pronephros appears in paired fashion

Anomalies of Kidney Development

According to the Genitourinary Database Molecular Anatomy Project,9 there may be several hundred genes involved in the process of kidney development and it would be too many to list and discuss in this review. Table 2 shows a list of genes involved in kidney and urinary tract development with known human syndromes featuring renal and urinary tract abnormalities. All gene loci and expression sites during development are listed based on the Genitourinary Database Molecular Anatomy Project9 and

Syndromic CAKUT

Genetic clues of how molecular mechanisms can lead to CAKUT come from studying multiorgan syndromes in which CAKUT is a component. This has led to the identification of several genes. Many of these human syndromes are listed in Table 2. Five of these genes (TCF2, PAX2, EYA1, SIX1, and SALL1) were tested in the Effect of Strict Blood Pressure Control and ACE Inhibition on CRF Progression in Pediatric Patients (ESCAPE) study in 99 unrelated patients of which approximately 25% had syndromic renal

Nonsyndromic CAKUT

Nonsyndromic CAKUT typically appears to occur sporadically, however, familial cases have been reported, which suggests a genetic predisposition. It is possible that familial cases are more common than we think and that the lack of reported cases is due to the inadequate work-up of family members. Mendelian inheritance has been reported and there is an increased recurrence risk among first-degree relatives.23 By using traditional family based linkage studies, only a few genetic loci have been

Diagnosis

Although anatomic and histologic evaluations are the gold standard for diagnosis of CAKUT, histology is often not available. Biopsies in fetuses are not feasible and are rarely performed in newborns and infants. Tissue samples are mainly obtained during surgery or in cases of fetal death. Therefore, CAKUT typically is diagnosed with imaging studies alone, which includes both fetal and postnatal radiology.

Ultrasonographic screening for fetal anomalies has become routine in the Western world and

Interventions, Therapies, and Outcomes

The most drastic intervention for CAKUT is the termination of a pregnancy, which is often undertaken in fetuses with bilateral renal agenesis. These fetuses are affected by pulmonary hypoplasia as a result of reduced amniotic fluid, referred to as Potter's syndrome.49 They frequently have malformations of other organ systems as well, including brain and heart. A common genetic etiology for these syndromes is chromosomal aberrations and trisomies. This also is reflected in patients with Down

Genetic Testing

The benefit of offering genetic testing to patients and their relatives is not clear because of a general concern about the appropriateness of genetic testing in CAKUT, a condition with several limitations in identifying a mutation and treatment of the underlying molecular etiology. A genetic basis in syndromic and nonsyndromic CAKUT clearly exists, as outlined earlier, and even in cases that appear to be isolated, a first-degree family member carries an up to 15-fold higher risk. According to

Conclusions

Renal tract malformations or CAKUT are a collection of different disease entities affecting the kidney, the urinary tract, or both. Despite significant variation in phenotype and clinical implications, CAKUT has a common genetic basis through various molecular mechanisms that share common pathways and affect kidney development. In human beings, the genotype-phenotype correlation is poorly understood. Our knowledge of the genetic basis is based mainly on syndromic cases of CAKUT and animal

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