The European Rare Kidney Disease Reference Network


Research Project

Project Title:

A novel approach to understand the molecular mechanisms causing structural kidney malformations in human

Project Type:

Translational research

Disease group(s):

Renal malformations

Project Summary:

Congenital anomalies of the kidney and urinary tract (CAKUT) comprise a spectrum of structural malformations that occur in 3-6 per 1000 live births. CAKUT is the major cause of end-stage renal disease in children, which requires kidney replacement therapy, i.e. dialysis and kidney transplantation. Despite the occurrence of human familial cases that clearly suggest a genetic background, the exact patterns and mechanisms of inheritance have not been conclusive. So far, CAKUT research has mainly focused on rare monogenic causes. However, only 10-20% of CAKUT cases seem to have a monogenic background. Thus, the underlying disease mechanisms are probably more complex in most cases. A novel approach that is aimed at the integration of -omics data is necessary to get more insight into this complex origin of CAKUT. The main objective of the study proposed here is to elucidate the molecular mechanisms that are disturbed in CAKUT patients. I hypothesize that an innovative systems biology approach will reveal the essential molecular pathways and variants causal for CAKUT. I will investigate whether CAKUT etiology can actually be explained by variants in a specific set of key genes and pathways. Here, I suggest a new strategy to investigate CAKUT etiology by integrating whole genome sequencing data with gene expression data and epigenetic data. The specific aims are as follows:
1. to identify genetic variation in severe CAKUT patients by whole genome sequencing
2. to annotate variants in non-coding regulatory DNA elements that are active during kidney development
3. to reveal and characterize key pathways involved in CAKUT etiology by using a systems biology approach

By using an innovative strategy, I expect to identify the essential molecular mechanisms involved in the etiology of multicystic dysplastic kidney and thereby push CAKUT research an important step forward. This step is essential for the improvement of diagnostics and will provide opportunities to improve genetic counseling and recurrence risk estimations for patients with CAKUT and their relatives.

Lead principal investigator(s):

Kirsten Renkema, Utrecht


Albertien vanEerde, Utrecht
Ernie Bongers, Utrecht
Ies Nijman, Utrecht
Rachel Giles, Utrecht
Michal Mokry, Utrecht
Edwin Cuppen, Utrecht
Lude Franke, Utrecht
Marc Lilien, Utrecht
Anukrati Nigam, Utrecht

Project Period:

01/2017   -   12/2021


National funding agency

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