Longitudinal and cross-sectional associations of myocardial stress markers with kidney function and chronic kidney disease in the BiomarCaRE project

Abstract

Given the complex relationship between cardiovascular disease (CVD) and chronic kidney disease (CKD), CVD-related markers may serve as CKD biomarkers. We examined associations of three major CVD-markers [mid-regional pro-adrenomedullin (MR-proADM), MR-pro-atrial natriuretic peptide (MR-proANP), and N-terminal pro-B-type natriuretic peptide (NT-proBNP)] with CKD. Cross-sectional analyses included up to 61,830 participants, and longitudinal analyses (NT-proBNP only) 4205 individuals. Kidney function was assessed by estimated glomerular filtration rate (eGFR) using creatinine, cystatin C, or both (eGFRcr-cys). Markers were categorized into four groups. Cross-sectional analyses found that higher levels of all three markers were consistently associated with lower eGFR and higher CKD prevalence. For example, per 1 standard deviation (SD) increase in log-transformed NT-proBNP, corresponding to a 2.71-fold increase in the original concentration, was associated with -2.35 (-2.49, -2.21) ml/min/1.73m² lower eGFRcr-cys, and the highest NT-proBNP group had a 5.72-fold higher odds of CKDcr-cys (eGFRcr-cys < 60 ml/min/1.73m²) compared with the lowest. Associations with eGFR were stronger among participants with CVD and diabetes. In longitudinal analyses, participants with higher baseline NT-proBNP had faster declines in eGFR, with a 10-year decline of -1.37 (-1.77, -0.98) ml/min/1.73m² eGFRcr-cys per 1 SD increase, and higher CKD incidence. These findings suggest MR-proADM, MR-proANP, and NT-proBNP as CKD biomarkers.

Keywords: Chronic kidney disease; Kidney function; MR-proADM; MR-proANP; NT-p; roBNP.

Fig. 1

Cross-sectional associations of 3 myocardial stress markers with kidney function and CKD. (A). Linear regression was used to estimate beta coefficients and 95% CI of eGFR per 1 SD increase in log-transformed markers. (B). Logistic regression was used to estimate odds ratios of CKD. Detailed information on adjusted models is described in Table 2 & 3. Data from 61,830 participants for NT-proBNP, 9499 for MR-proANP, and 9327 for MR-proADM were included in these analyses. CI, confidence interval; CKD, chronic kidney disease; cr, creatinine-based; cys, cystatin C-based; cr-cys, combined creatinine and cystatin C-based; eGFR, estimated glomerular filtration rate; MR-proADM, mid-regional pro-adrenomedullin; MR-proANP, mid-regional pro-atrial natriuretic peptide; NT-proBNP, N-terminal pro-B-type natriuretic peptide; SD, standard deviation; ^* p < 0.05, ^** p < 0.01, ^*** p < 0.001.

Fig. 2

Longitudinal associations of NT-proBNP with 10-year change in kidney function. Linear mixed-effects model was used to estimate beta coefficients and 95% CI of the change in eGFR for G2-4 compared with G1 of NT-proBNP, as well as for per 1 SD increase in log-transformed NT-proBNP. The follow-up duration was used as a timescale and divided by 10 to give a 10-year change. Detailed information on adjusted models is described in Table 4. A maximum of 4205 participants with 10,208 observations were included in these analyses. Categories of NT-proBNP: G1: < 48; G2: 48–125; G3: 125–300; G4: ≥ 300 pg/ml. CI, confidence interval; G, group; eGFR, estimated glomerular filtration rate; eGFRcr, creatinine-based eGFR; eGFRcys, cystatin C-based eGFR; eGFRcr-cys, creatinine and cystatin C-based eGFR; NT-proBNP, N-terminal pro-B-type natriuretic peptide; SD, standard deviation; ^* p < 0.05, ^** p < 0.01, ^*** p < 0.001.

Fig. 3

Longitudinal associations of NT-proBNP with incident CKD. Interval-censored Cox regression was used to estimate HR and 95% CI (1000 bootstrap samples for 95% CI estimation) of incident CKD for G2-4 compared with G1 of NT-proBNP, as well as for per 1 SD increase in log-transformed NT-proBNP. A total of 4167 participants free of CKDcr, 2557 free of CKDcys, and 2621 free of CKDcr-cys at baseline were included in these analyses. Detailed results are presented in Table S9. Categories of NT-proBNP: G1: < 48; G2: 48–125; G3: 125–300; G4: ≥ 300 pg/ml. CI, confidence interval; CKD, chronic kidney disease; CKDcr, creatinine-based CKD; CKDcys, cystatin C-based CKD; CKDcr-cys, creatinine and cystatin C-based CKD; G, group; HR, hazard ratio; NT-proBNP, N-terminal pro-B-type natriuretic peptide; SD, standard deviation; ^* p < 0.05, ^** p < 0.01, ^*** p < 0.001.

Fig. 4

Cross-sectional associations of 3 myocardial stress markers with kidney function stratified by CVD and diabetes. Interaction terms of standardized log-transformed markers with CVD or diabetes were included in linear regression, applying model 2 described in Table 2, to test the significance of interaction. Data from 61,830 participants for NT-proBNP, 9499 for MR-proANP, and 9327 for MR-proADM were included in these analyses. Please refer to Table S10-12 for detailed results. CVD, cardiovascular disease; eGFR, estimated glomerular filtration rate; eGFRcr, creatinine-based eGFR; eGFRcys, cystatin C-based eGFR; eGFRcr-cys, creatinine and cystatin C-based eGFR; MR-proADM, mid-regional pro-adrenomedullin; MR-proANP, mid-regional pro-atrial natriuretic peptide; NT-proBNP, N-terminal pro-B-type natriuretic peptide; SD, standard deviation; ^* p < 0.05, ^** p < 0.01, ^*** p < 0.001.