The relationship between reduced renal function and cardiovascular disease

Abstract: This thesis examines the relationship between measures of renal function and cardiovascular disease (CVD) in patients with hypertension (the NORDIL study) and in the healthy population (Malmö Diet and Cancer Study, MDC) and whether antihypertensive treatment response and the risk of CVD is affected by genetic variation of a regulator of the renal amiloroide sensitive sodium channel (NORDIL). In study 1 we tested creatinine, estimated glomerular filtration rate (eGFR) with Cockroft-Gault (CG) and the MDRD equations and also microalbuminuria (MA) as predictors of CVD, stroke and CVD death. In Study 2 we tested cystatin C and compared it to eGFR estimated with the MDRD, CKD-EPI 2009 and the CKD-EPI-comb (combining creatinine and cystatin C) formulas as predictors of CVD, CVD mortality and all-cause mortality. In study 3 we investigated whether or not there is a causal relationship between cystatin C and the risk of coronary artery disease (CAD) using a Mendelian Randomization approach. In study 4 we related common genetic variance of a renal sodium channel (ENaC) remover/regulator (NEDD4L) to the 6-month blood pressure lowering effect and risk of CVD in patients treated with ?-blockers and/or thiazide diuretics and in patients treated with the Ca+-channel blocker diltiazem. In patients with hypertension, creatinine and CG predicted CVD endpoints in a linear fashion, whereas the risk associated with MDRD increased steeply at a GFR < 40 ml/min/1.73m2. Presence of MA increased the risk with 30% but there was also a significant interaction between MA and reduced eGFR. In the healthy population, plasma cystatin C was a stronger predictor of all endpoints than creatinine based eGFR. CKD-EPI-comb was better than purely creatinine based eGFR but not as good as cystatin C. We observed no increase in risk of CAD in subjects with genetically elevated cystatin C suggesting that cystatin C not is causally related to CAD development but rather reflects other CAD risk factors such as impaired renal function. Hypertensive patients who carry the G-allele (GG and GA) of the NEDD4L rs4149601 variant and were treated with ?-blockers or diuretics had greater reduction in BP and better protection against CVD compared AA allele carriers. In contrast, there was no difference in treatment response or CVD risk in G allele carriers compared to AA allele carriers in hypertensive patients treated with Diltiazem. In conclusion, the relationship between creatinine based eGFR and CVD is dependent on presence of MA. Cystatin C is a better predictor of CVD than creatinine-based measures of eGFR but does not seem to be causally related to CVD. Genetic variation of NEDD4L may identify responders to antihypertensive therapy with ?-blockers or diuretics.