| Abstract |
Studying rare diseases enables us to understand the underlying processes of common diseases, which tend to have many genetic and environmental factors driving disease development. In this project, studying the rare disease, Autosomal dominant tubulointerstitial kidney disease (ADTKD), will enhance understanding of the underlying processes of Chronic Kidney Disease (CKD) and kidney fibrosis (scarring), which affects 12% of the global population, in addition to finding specific treatments for families affected by ADTKD. Chronic kidney disease (CKD) is a common, silent and deadly disease for which there are very limited treatment options. ADTKD runs in families in a dominant fashion, where only one faulty copy of a gene is required to give half of your children the disease. ADTKD causes CKD, end stage kidney disease and early onset gout. ADTKD is among the top three causes of genetic CKD and is most often caused by faulty copies (mutations) in the UMOD gene. The UMOD gene makes the important protein 'Uromodulin', which is the most abundant protein in the urine of humans and it has many functions. In ADTKD, secondary to UMOD mutations, faulty (mutant) uromodulin accumulates in the cells of the kidney tubules (part of the kidney's filtering system) and triggers renal interstitial fibrosis (scarring of the kidney). Patients with ADTKD-UMOD present with a steady decline in renal function and invariably progress to end stage kidney disease requiring dialysis or kidney transplantation. There are currently no treatments. As ADTKD directly causes kidney scarring, it is an excellent model to study to help understand what causes kidney scarring and subsequent CKD in the general population and find treatments. Over 200 UK families with ADTKD have consented for their medical records, urine and blood samples to be used for research. Initial observations indicate large degrees of variability in disease progression in these families, that suggests modifier effects are at work (genes that are not directly linked to the genetic disease but influence the expression and severity of ADTKD). If these effects can be identified, it will enable identification of the cellular mechanisms that moderate the disease severity which could help target treatments for these patients. A number of population-based genetic studies have shown that faulty copies of the UMOD gene are strongly linked with markers of kidney function and risk of developing CKD and high blood pressure in the general population. Uromodulin has many functions; it protects against urinary tract infections, it prevents the formation of kidney stones, it reduces harm from acute kidney injury, regulates salt transport in the kidney and activates innate immunity. By studying ADTKD, a greater understanding of the factors that make Uromodulin become faulty will be achieved, that could help prevent and treat a variety of kidney problems related to UMOD or Uromodulin in the general population. In this project, the course of disease progression will be clearly and carefully defined in a group of over 200 patients with ADTKD. We will then examine in detail the genetic and other factors that lead to better and worse outcomes. We will then use kidney cells derived from patient urine samples to model the disease so we can better understand cellular mechanisms involved and to test treatments that may be used in the future to prevent the progression of CKD in this disease. This project will allow us to gain significant new knowledge regarding this genetic form of CKD and pave the way towards new therapies for patients with CKD caused by UMOD mutations and most other causes of CKD where kidney fibrosis (scarring) is the common endpoint. |