Association of mineral and bone biomarkers with adverse cardiovascular outcomes and mortality in the German Chronic Kidney Disease (GCKD) cohort

Abstract

Mineral and bone disorder (MBD) in chronic kidney disease (CKD) is tightly linked to cardiovascular disease (CVD). In this study, we aimed to compare the prognostic value of nine MBD biomarkers to determine those associated best with adverse cardiovascular (CV) outcomes and mortality. In 5 217 participants of the German CKD (GCKD) study enrolled with an estimated glomerular filtration rate (eGFR) between 30-60 mL·min^-1 per 1.73 m² or overt proteinuria, serum osteoprotegerin (OPG), C-terminal fibroblast growth factor-23 (FGF23), intact parathyroid hormone (iPTH), bone alkaline phosphatase (BAP), cross-linked C-telopeptide of type 1 collagen (CTX1), procollagen 1 intact N-terminal propeptide (P1NP), phosphate, calcium, and 25-OH vitamin D were measured at baseline. Participants with missing values among these parameters (n = 971) were excluded, leaving a total of 4 246 participants for analysis. During a median follow-up of 6.5 years, 387 non-CV deaths, 173 CV deaths, 645 nonfatal major adverse CV events (MACEs) and 368 hospitalizations for congestive heart failure (CHF) were observed. OPG and FGF23 were associated with all outcomes, with the highest hazard ratios (HRs) for OPG. In the final Cox regression model, adjusted for CV risk factors, including kidney function and all other investigated biomarkers, each standard deviation increase in OPG was associated with non-CV death (HR 1.76, 95% CI: 1.35-2.30), CV death (HR 2.18, 95% CI: 1.50-3.16), MACE (HR 1.38, 95% CI: 1.12-1.71) and hospitalization for CHF (HR 2.05, 95% CI: 1.56-2.69). Out of the nine biomarkers examined, stratification based on serum OPG best identified the CKD patients who were at the highest risk for any adverse CV outcome and mortality.

Fig. 1

Cumulative incidence of (a) non-CV death, (b) CV death, (c) nonfatal MACE, and (d) hospitalization for congestive heart failure (CHF) according to OPG serum levels. Quintiles categorized as Q1, Q2, Q3, Q4, and Q5. Cumulative incidence derived from the unadjusted cause-specific hazard estimates (Model 1) by application of the Aalen-Johansen estimator. CV cardiovascular, OPG osteoprotegerin, MACE major adverse cardiovascular event

Fig. 2

Risk of outcomes for Q5 vs. Q1 biomarker levels in a cohort of n = 4 246 patients enrolled in the German Chronic Kidney Disease Study (GCKD) in Model 3. The evaluated biomarkers OPG, FGF23, iPTH, BAP, CTX1, phosphate, calcium, and 25-OH Vitamin D were statistically associated with selected outcomes, including (a) non-CV death, (b) CV death, (c) MACE, and (d) CHF. Data of Model 3, which adjusted for demographic characteristics of the study population and for biomarker levels other than the analyzed one. CV cardiovascular, HR hazard ratio, CI confidence interval, MACE major adverse cardiac event, CHF hospitalization due to congestive heart failure, OPG osteoprotegerin, FGF23 fibroblast growth factor-23, iPTH intact parathyroid hormone, BAP bone alkaline phosphatase, CTX1 cross-linked C-telopeptide of type I collagen, P1NP procollagen I intact N-terminal