"Congenital anomalies of the urinary tract (CAKUT) as multifactorial diseases: genetic, environmental and epigenetic factors"

Abstract

Congenital anomalies of the kidney and urinary tract cover a wide range of structural malformations which are present in 3 to 7 out of 1.000 births, accounting for 23% of birth defects. CAKUT represent the cause of 40-50% of pediatric and 7% of adult end-stage renal disease worldwide. This heterogeneous group of anomalies includes many different forms of defects that range from renal dysplasia and renal agenesis to various malformations and obstructions of the ureters. Thanks to long-term and comprehensive research, is confirmed that CAKUT are the result of many factors, some of which many times do not have anything in common; abnormalities in these cases can cause those defects. These factors can be conventional genetic factors, which are mainly genes and their mutations, as well as various environmental and epigenetic causes. The latter of them involve changes that affect gene activity and expression without alterations in the DNA sequence.

The goal of this post-graduate study is the presentation and analysis of all established or candidate causes that lead or might lead to CAKUT: the way that they affect the manifestation of those defects, their importance in conjunction with the direction and perspective of future research. This study is based on recent references and material in order to describe the current state of play.

The first chapter of the study consists of a short introduction in the developmental process of the kidney and urinary tract, including a special analysis of the signaling pathways that are activated during the various phases of this developmental process. The CAKUT-causing factors determine the development of the kidney and urinary tract (as well as of other systems), either by affecting one or more parameters that take part in the signaling pathways, or by being part of these pathways themselves. As a result, the understanding of the connection that exists between those factors and the signaling pathways requires the presentation and analysis of nephrogenesis prior to the one of the CAKUT-causing factors.

The second chapter of the study includes the presentation of various forms of CAKUT. For each individual CAKUT, there is a description of the phenotype, the frequency of its occurrence and the methods of identifying and possibly rectifying the disease. In the next chapter, it will be described the connection between each of these anomalies with one or more possible causes.

The third and final chapter of the study focuses on the presentation and analysis of the various CAKUT causes, often by specific reference to each individual factor that might be a candidate for the occurrence of these anomalies. It is a fact that despite all the previous studies that have been conducted in that field, the international scientific community does not share a common opinion about neither the impact, nor the frequency of most of these factors in relevance to CAKUT occurrence. Furthermore, only a small percentage of the recorded CAKUT cases have been attributed to specific causes and confirmed beyond any doubt, whereas the causes of the majority of them have yet to be identified. In a nutshell, it seems that the road to identifying, understanding and connecting each candidate factor of causing a CAKUT with one or more of these anomalies, is still a long one.

More research is required to clarify most of the aforementioned cases. However, achieving this goal will lead to a better understanding of the signaling pathways that regulate the development of the kidney and urinary tract and the way that the latter is affected by the defects of the former. This understanding will ultimately lead to innovative methods of prenatal prognosis and targeted therapeutic approaches.

PATSIAS Christodoulos