Congenital anomalies of the kidneys and urinary tracts (CAKUT) are disorders caused by defects in the development of the kidneys and their outflow tracts. The formation of the kidneys begins at week 3 and nephrogenesis continues until week 36, therefore, the kidneys and outflow tracts are susceptible to environmental risk factors that perturb development throughout gestation. Many genes have been implicated in kidney and outflow tract development, and mutations have been identified in patients with CAKUT. In severe cases of CAKUT, when the kidneys do not form, the fetus will not survive. However, in less severe cases, the baby can survive with combined kidney and outflow tract defects or they may only be identified in adulthood. In this review, we will cover the clinical presentation of CAKUT, its epidemiology, and its long-term outcomes. We will then discuss risk factors for CAKUT, including genetic and environmental contributions. Although severe CAKUT is rare, low nephron number is a much more common disorder with its effect on kidney function increasingly apparent as a person ages. Low nephron number appears to arise by the same mechanisms as CAKUT, but it differs in terms of the magnitude of the insult and the timing of when it occurs during gestation. By understanding the causes of CAKUT and low nephron number, we can begin to identify preventive treatments and establish clinical guidelines for how these patients should be followed.

Background: Congenital nephrotic syndrome arises from a defect in the glomerular filtration barrier that permits the unrestricted passage of protein across the barrier, resulting in proteinuria, hypoalbuminaemia, and severe oedema. While most cases are due to mutations in one of five genes, in up to 15% of cases, a genetic cause is not identified. We investigated two sisters with a presumed recessive form of congenital nephrotic syndrome. Methods and results: Whole exome sequencing identified five genes with diallelic mutations that were shared by the sisters, and Sanger sequencing revealed that ARHGDIA that encodes Rho GDP (guanosine diphosphate) dissociation inhibitor α (RhoGDIα, OMIM 601925) was the most likely candidate. Mice with targeted inactivation of ARHGDIA are known to develop severe proteinuria and nephrotic syndrome, therefore this gene was pursued in functional studies. The sisters harbour a homozygous in-frame deletion that is predicted to remove a highly conserved aspartic acid residue within the interface where the protein, RhoGDIα, interacts with the Rho family of small GTPases (c.553_555del(p.Asp185del)). Rho-GTPases are critical regulators of the actin cytoskeleton and when bound to RhoGDIα, they are sequestered in an inactive, cytosolic pool. In the mouse kidney, RhoGDIα was highly expressed in podocytes, a critical cell within the glomerular filtration barrier. When transfected in HEK293T cells, the mutant RhoGDIα was unable to bind to the Rho-GTPases, RhoA, Rac1, and Cdc42, unlike the wild-type construct. When RhoGDIα was knocked down in podocytes, RhoA, Rac1, and Cdc42 were hyperactivated and podocyte motility was impaired. The proband's fibroblasts demonstrated mislocalisation of RhoGDIα to the nucleus, hyperactivation of the three Rho-GTPases, and impaired cell motility, suggesting that the in-frame deletion leads to a loss of function. Conclusions: Mutations in ARHGDIA need to be considered in the aetiology of heritable forms of nephrotic syndrome.

While some reports in humans have shown that nephron number is positively correlated with height, body weight or kidney weight, other studies have not reproduced these findings. To understand the i...

RET, a tyrosine kinase receptor essential for kidney development, has recently been shown to be important for the formation of the urinary tract. When RET is overexpressed in the HoxB7/Ret transgenic mouse, kidneys are small and cystic, and in some of the mice, the ureters are grossly dilated. Here, we report that the observed ureteral dilatation is associated with the urinary tract abnormality vesicoureteric reflux (VUR), in which urine flows retrogradely from the bladder to the ureter. Reflux was determined in vitro by injecting methylene blue into the bladders of HoxB7/Ret and wild-type mice. At postnatal day 1, 30% of HoxB7/Ret mice had VUR compared with 4% of wild-type mice ( P < 0.05). The length of the intravesical ureteral tunnel was shorter in HoxB7/Ret mice compared with wild-type mice, on both the right and the left sides ( P < 0.05), suggesting a basis for the higher incidence of VUR in these mutants. At embryonic day 11, the ureteric bud was found to exit more caudally from the mesonephric duct in HoxB7/Ret mice, and this may predispose them to VUR ( P < 0.05). Wild-type and HoxB7/Ret mice were tested for reflux at embryonic day 17, and both showed a high frequency of VUR (59 and 75%, respectively). These results suggest that VUR may occur transiently during normal urinary tract development before the ureter has completed its insertion into the bladder. In the HoxB7/Ret mouse, overexpression of RET appears to delay the maturation of the distal ureter, resulting in postnatal VUR. The HoxB7/Ret mouse is thus an important model in which to examine how vesicoureteric reflux arises during urinary tract development.