A translational approach to the genetics of renal disease

PhD ceremony: Ms. C.R.C. Doorenbos, 16.15 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: A translational approach to the genetics of renal disease

Promotor(s): prof. G.J. Navis

Faculty: Medical Sciences

The influence of genetics on nephrology research has increased in the past decades. Still, the genetic base of progressive renal function loss is largely unknown. Such research requires a translational approach. Both exploratory and focused genetic studies aim to find associations between a characteristic of renal disease and genetic variation. A precise definition of characteristics of renal disease is therefore essential. Large-scale clinical trials often rely on estimated renal function. In renal transplant recipients this measure lacks precision. Sources of bias are age, gender, BMI and true renal function. Vitamin D binding protein is a promising novel marker for fibrosis of the space between tubular cells, a final common pathway for many renal diseases. Normally this protein, bound to vitamin D, is reabsorbed from the glomerular filtrate into tubular cells, where vitamin D is activated. Fibrosis causes tubular dysfunction and inhibits reabsorption of vitamin D binding protein. This mechanism however, did not explain lower vitamin D levels often seen in renal patients, that are associated with worse prognosis. An exploratory study of urinary albumin loss identified three areas in mouse DNA. The causal genes are still unknown. A focused study identified seven genetic variations in vitamin D metabolism genes that are more prevalent in renal transplant recipients than in kidney donors. Although much research is required before such genetic discoveries prove clinical relevance, our results provide a strategy for improved integration of genetics and nephrology.