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The genetics and pathogenesis of CAKUT

Nature Reviews Nephrology volume 19, pages 709–720 (2023)Cite this article

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Abstract

Congenital anomalies of the kidney and urinary tract (CAKUT) comprise a large variety of malformations that arise from defective kidney or urinary tract development and frequently lead to kidney failure. The clinical spectrum ranges from severe malformations, such as renal agenesis, to potentially milder manifestations, such as vesicoureteral reflux. Almost 50% of cases of chronic kidney disease that manifest within the first three decades of life are caused by CAKUT. Evidence suggests that a large number of CAKUT are genetic in origin. To date, mutations in ~54 genes have been identified as monogenic causes of CAKUT, contributing to 12–20% of the aetiology of the disease. Pathogenic copy number variants have also been shown to cause CAKUT and can be detected in 4–11% of patients. Furthermore, environmental and epigenetic factors can increase the risk of CAKUT. The discovery of novel CAKUT-causing genes is challenging owing to variable expressivity, incomplete penetrance and variable genotype–phenotype correlation. However, such a discovery could ultimately lead to improvements in the accurate molecular genetic diagnosis, assessment of prognosis and multidisciplinary clinical management of patients with CAKUT, potentially including personalized therapeutic approaches.

Key points

  • Congenital anomalies of the kidney and urinary tract (CAKUT) cause almost 50% of cases of chronic kidney disease in patients aged ≤30 years.

  • Mutations in ~54 genes have been shown to cause human CAKUT, contributing to 12–20% of the aetiology of the disease.

  • Other genetic causes of CAKUT include pathogenic copy number variants, which have been detected in 4–11% of patients; gene–environment interactions and epigenetic factors also contribute to the pathogenesis of the disease.

  • The discovery of monogenic human CAKUT genes has led to the understanding that defects in nephrogenesis arise from dysregulated signalling and that disruption of genes that regulate bladder innervation leads to bladder dysfunction and subsequent upper urinary tract anomalies.

  • Next-generation sequencing technologies and artificial intelligence approaches can facilitate the discovery of potential novel CAKUT-causing genes.

  • Knowledge of the genetic cause of CAKUT in individual patients can help to guide their clinical management and enables exploration of potential novel therapeutic approaches.

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Fig. 1: Mammalian nephrogenesis.
Fig. 2: Signalling molecules and pathways in nephrogenesis that have been implicated in the pathogenesis of CAKUT.
Fig. 3: Monogenic causes of bladder dysfunction.
Fig. 4: Decision-making for calling a variant identified from exome sequencing as likely to cause disease.

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Acknowledgements

C.M.K.’s work is supported by a grant from the German Research Foundation (DFG, KO 6579/2-1 (708037 - 809683); 499462148). F.H. is the William E. Harmon Professor of Paediatrics. His work is also supported by the Begg Family Foundation. The authors’ work was additionally supported by grants from the National Institutes of Health to F.H. (DK076683, DK088767 and DK068306).

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  1. Department of Medicine, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, USA

    Caroline M. Kolvenbach, Shirlee Shril & Friedhelm Hildebrandt

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All authors researched data for the article, contributed substantially to discussion of the content, wrote the article and reviewed and/or edited the manuscript before submission.

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Glossary

Crispants

A F0 mutant generated using the CRISPR/Cas9 genome editing approach.

Epigenetic modulators

Factors that modify chromatin accessibility without introducing changes in DNA sequence.

Machine learning

An artificial intelligence approach in which computers are trained to learn and analyse based on data already available.

Phenotypic expansion

The occurrence of additional phenotypes that had not previously been described in a defined syndrome.

Recurrent CNVs

CNVs that occur in the same genomic locations.

Variant calling

Identification of DNA changes in sequencing data.

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Kolvenbach, C.M., Shril, S. & Hildebrandt, F. The genetics and pathogenesis of CAKUT. Nat Rev Nephrol 19, 709–720 (2023). https://doi.org/10.1038/s41581-023-00742-9

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