Research Awards Recipients

Lay Abstract

Background: Chronic renal disease greatly affects general population health and puts an enormous strain on the public health care system. Congenital anomalies of the kidney and urinary tract (CAKUT) are the most common cause of chronic renal disease before 30 years of age. CAKUT are physical abnormalities that present from birth and can involve the kidney, the ureter (the duct connecting the kidney to the bladder), the bladder, and the urethra (the duct by which the urine is conveyed out of the body from the bladder). CAKUT can be caused by environmental, sporadic, or genetic causes. The genetic information is stored on DNA, which is short for deoxyribonucleotide acid. DNA is found in every cell of the human body. The information is stored in different sections of the DNA. These sections are called genes. Genes are the blueprints for the building blocks (i.e., proteins) that make up all structures of our body. Changes of the information contained in a gene can change the function of the corresponding protein, which can cause a genetic disease. The changes in the genes are called 'mutations' and they are like a spelling mistake in a book chapter. While some cases of CAKUT occur sporadically (i.e., isolated) and can be due to environmental causes, it is estimated that at least 50% of CAKUT cases are genetic. However, in many cases the gene that is responsible for CAKUT cannot be identified. Importantly, there is evidence to suggest that children with CAKUT due to a gene are more likely to develop renal disease and are at higher risk of loss of kidney function. Once renal function is lost, patients either require regular treatment with hemodialysis (which is a procedure that filters toxins out of the blood), or renal transplantation. While patients with a kidney transplant typically have a better survival compared to dialysis, there are not enough donor kidneys available. In 2017, more than 200 patients died while awaiting an organ transplant. This highlights the urgent need to early identify patients at risk of chronic renal disease and to develop new treatment strategies to prevent progression to complete renal failure. Purpose: The goal of the here proposed study is to better understand which genes can possibly cause CAKUT and renal disease in children. Methods: We will first use whole-exome sequencing to identify possible genetic causes in a cohort of more than 250 patients with CAKUT. Whole-exome sequencing is a technology that allows us to analyze all genes that are stored on the DNA at once. This will enable us to identify novel genes that were previously not known to cause CAKUT. To confirm that these genes and their mutations are important for kidney development, we will use zebrafish. Zebrafish are used to study many developmental diseases, since they share many of their structures with humans. By injecting zebrafish embryos with a technology that allows to make specific genes non-functional, we will identify those that are associated with abnormal kidney development. Anticipated outcomes: We aim to identify novel genes that can cause CAKUT in children. This work is important since genetic causes of CAKUT are likely associated with an increased risk for renal failure. Identification of children at increased risk is paramount for early surveillance and the development of personalized treatment strategies. Relevance to Patients/Community: It is important for patients, family members, and clinicians to know if a patient has a genetic cause of CAKUT, because: 1) children with confirmed genetic CAKUT appear at higher risk to develop progressive kidney disease and may have other associated health issues, 2) if a genetic cause is confirmed, we can identify other family members at risk and inform parents on the risk for future pregnancies, and 3) knowing the exact underlying cause will hopefully enable the treatment of novel personalized therapies. Conclusion: We aim to better understand the underlying mechanisms involved in CAKUT, which is important for the development of personalized treatment strategies in the future.