Disease mechanisms of monogenic congenital anomalies of the kidney and urinary tract American Journal of Medical Genetics Part C

Abstract

Congenital Anomalies of the Kidney and Urinary Tract (CAKUT) is a developmental disorder of the kidney and/or genito-urinary tract that results in end stage kidney disease (ESKD) in up to 50% of children. Despite the congenital nature of the disease, CAKUT accounts for almost 10% of adult onset ESKD. Multiple lines of evidence suggest that CAKUT is a Mendelian disorder, including the observation of familial clustering of CAKUT. Pathogenesis in CAKUT is embryonic in origin, with disturbances of kidney and urinary tract development resulting in a heterogeneous range of disease phenotypes. Despite polygenic and environmental factors being implicated, a significant proportion of CAKUT is monogenic in origin, with studies demonstrating single gene defects in 10%-20% of patients with CAKUT. Here, we review monogenic disease causation with emphasis on the etiological role of gene developmental pathways in CAKUT.

Keywords: congenital anomalies of the kidney and urinary tract; monogenic disease causation; renal developmental gene.

Figure 1. Diagrammatic representation of embryonic development of the kidney

A. Nephric duct elongation and induction of the metanephric mesenchyme. The nephric ducts (ND) and the nephric cord (NC) arise from the intermediate mesoderm. The ND elongates caudally and fuses with the cloaca. The metanephric mesenchyme (MM) expresses GDNF which provides the signal to the ND to induce the ureteric bud (UB). B. Ureteric bud outgrowth/ Induction of cap mesenchyme. The UB is an outgrowth of the ND, that sprouts in the direction of the MM. The MM forms the cap mesenchyme (CM). C. Ureteric bud branching morphogenesis. Following induction from the UB, a portion of the CM then undergoes mesenchymal to epithelial transition (MET) progresses through various morphological stages including the comma-shaped body followed by the S-shaped body to form a nephron. The S-shaped body ultimately fuses with the collecting ducts. The UB tips continue to branch whilst the renal vesicle continues to mature into a nephron.