Clinical and genetic risk factors in end-stage renal disease
(2011)
Files
Thèseversionfinale.pdf
Closed Access - Adobe PDF
- 5.08 MB
Details
- Authors
- Supervisors
- Abstract
- (en) Chronic kidney diseases (CKD) are an important public health problem which affects ~11% of European adults. In the advanced stage, CKD requires life-support treatment by dialysis or transplantation. Renal replacement therapy patients have a relatively poor prognosis, essentially due to the occurrence of cardiovascular disease (CVD). The general aim of this study is to get a better understanding of clinical and genetic determinants involved in CKD with the aim to improve the management of the complications linked to this disease. The first part of this work is devoted to the study of clinical and genetic factors involved in CVD in renal transplant recipients (RTR). To assess risk factors of vascular calcification, a surrogate calcification marker of CVD, we studied the influence of serum fetuin-A, a potent circulating inhibitor, as well as variants in the gene coding for this protein , on vascular calcification and cardiovascular events (CVE) in a cohort of RTR. We identified the determinants of fetuin-A level, which are plasma cholesterol, AHSG rs4918G allele and history of smoking. We also showed that a lower fetuin-A level was a determinant of aortic calcification and was independently associated with CVE and deaths. Moreover we showed that in the presence of inflammation, CVE-free survival was influenced by common variant in the AHSG gene. We also studied the vascular calcification progression (AoC and CAC) and demonstrated that the progression is substantial within 4 years in prevalent RTR and associated with traditional and non traditional risk factors. We studied another method of calcification detection, which is the pulse wave velocity (PWV), in RTR and showed that aortic stiffness is an independent predictor of outcome in this renal population. We also identified magnesium as an important predictor of PWV, especially in older patients and other known determinants but we could not show the influence of genetic variants on the PWV. The second part of this work is devoted to the study of the water channel AQP1, the molecular counterpart of the ultrasmall pore, which plays an essential role in the osmotic water flow across the peritoneal membrane (PM) during peritoneal dialysis (PD). We highlighted a common promoter variant in AQP1 gene influencing water transport across the PM and outcome of PD, in relation with a strong influence on the promoter activity and a decrease of AQP1 expression in the peritoneal capillaries. In the last part we showed the importance of genome-wide association studies (GWAS) to identify new variants involved in renal function and we presented a GWAS which allowed identifying common variants situated near NAT8 and SLC7A9 associated with serum creatinine, an important marker of renal function. This study also replicated the importance of SHROOM3 and UMOD variants in renal function. In conclusion, by identifying the importance of several genetic and clinical determinants involved in CKD and its complications, this work brought some highlights in the management of some complications in this population.
- Affiliations
Citations
Maréchal, C. (2011). Clinical and genetic risk factors in end-stage renal disease. https://hdl.handle.net/2078.5/155460