Poor exercise capacity and elevated N-terminal prohormone of brain natriuretic peptide in the prediction of long-term cardiovascular events and mortality in advanced chronic kidney disease - The CADKID study.

Introduction Chronic kidney disease (CKD) is an important risk factor for cardiovascular disease and mortality. However, data on the prediction of long-term adverse outcomes in advanced predialysis CKD patients is lacking. Methods We studied the factors associated with mortality and major adverse cardiovascular and cerebrovascular events (MACCE, including cardiovascular death, myocardial infarction, stroke and coronary revascularization) in a cohort of 210 patients with non-dialysis CKD stage 4-5 during a five-year follow-up. The participants underwent stress ergometry testing to study maximal exercise capacity (Wmax%), a plain lateral abdominal radiograph to study abdominal aortic calcification score (AAC) and laboratory tests including cardiac troponin T (TnT) and N-terminal pro-B-type natriuretic peptide (ProBNP). Furthermore, a dichotomous composite covariate was created and explored by combining ProBNP and Wmax% using the cut-offs determined with the Youden index. The associations between covariates of interest and study outcomes were explored using multivariable Cox proportional hazards models adjusted with age, sex, coronary artery disease (CAD) and incident kidney transplantation (KTx). Results Median age at baseline was 65 (52-73) years and eGFR 12 (10-15) ml/min/1.73 m2, 34.8 % were female and 44.8 % had diabetes. Altogether 67 (31.9 %) patients died during follow-up and 65 (31.0%) were observed with a MACCE. In separate multivariable Cox proportional hazards models adjusted for age, gender, CAD and KTx, Wmax% (HR 0.983 [95 % CI: 0.968-0.999], p=0.019), TnT (HR 1.004 [95 % CI: 1.002-1.005], p<0.001 and) and ProBNP (HR 1.036 per 1000 ng/l [95 % CI: 1.014-1.059], p=0.002 were independently associated with mortality. In similarly adjusted multivariable Cox models Wmax% (HR 0.977 [95 % CI: 0.962-0.992], p=0.003), TnT (HR 1.004 [95 % CI: 1.002-1.005], p<0.001) and ProBNP (HR 1.034 per 1000 ng/l [95 % CI: 1.010-1.058], p=0.006) were independently associated with the occurrence of MACCE during follow-up. AAC was associated with the risk of an incident MACCE (HR 1.080 [95% CI 1.028-1.135], p=0.002) but, surprisingly, not with mortality (HR 1.046 [95% CI 0.994-1.101], p=0.083). Finally, in participants with Wmax ≤50 % and ProBNP ≥1270 ng/l the risk of mortality (HR 8.760 [95 % CI: 4.730-16.222], p<0.001) and MACCE (HR 3.293 [95 % CI: 1.850-5.862], p<0.001) was significantly greater than those with Wmax>50% and/or ProBNP <1270 ng/L. Conclusion Wmax% and ProBNP separately and together as a composite risk factor may serve as important predictors of long-term all-cause mortality and MACCE in patients with CKD stage 4-5 not undergoing dialysis at baseline.