Associations between estimated glomerular filtration rate and cardiac biomarkers

Abstract Background Chronic kidney disease (CKD) is associated with an increased cardiovascular disease (CVD) mortality risk. Elevation of cardiac biomarkers in patients with renal dysfunction is ambiguous in the diagnosis of CVD. The purpose of this study was to investigate the associations between estimated glomerular filtration rate (eGFR) and cardiac biomarkers, and the influence of renal dysfunction on the cardiac biomarkers. Methods We examined the cross‐sectional associations of eGFR with cardiac troponin I (cTnI), creatine kinase (CK), CK‐MB, lactic dehydrogenase (LDH), hydroxybutyrate dehydrogenase (HBDH), and brain natriuretic peptide (BNP) in 812 adults and 215 child. Spearman correlation and logistic regression analysis were performed to evaluate the associations. Results For adults, lower eGFR CKD‐EPI had significantly higher cTnI, CK‐MB, LDH, HBDH, and BNP. There were negative correlations between eGFRCKD‐EPI and cTnI, CK‐MB, LDH, HBDH, and BNP. After adjustment for potential confounders, as compared with eGFRCKD‐EPI ≥ 90 mL/min/1.73 m2, eGFRCKD‐EPI < 60 mL/min/1.73 m2 remained associated with a 2.83 (1.08‐7.41) [ratio (95% CI)] times higher cTnI and a 6.50 (2.32‐18.22) [ratio (95% CI)] times higher HBDH. For child, lower eGFRSchwartz had significant higher CK and CK‐MB. There were negative correlations between eGFRSchwartz and CK, and eGFRSchwartz and CK‐MB. After adjustment for potential confounders, as compared with eGFRSchwartz ≥ 90 mL/min/1.73 m2, eGFRSchwartz < 90 mL/min/1.73 m2 revealed no significant higher CVD biomarkers. Conclusion Reduced eGFR is associated with elevated cTnI and HBDH among adults without clinically evident CVD, but not child.


| INTRODUC TI ON
For the patients with chronic kidney disease (CKD), which is defined as an estimated glomerular filtration rate (eGFR) < 60 mL/ min/1.73 m 2 for 3 months, the most frequently encountered cause of death is cardiovascular diseases (CVD), 1-3 such as myocardial infarction and heart failure. A large cohort study comprising >130 000 elderly participates showed that increased incidence of cardiovascular events was related to the renal insufficiency. 4 The diagnosis of CVD is usually based on clinical manifestation, electrocardiographic (ECG) changes, and positive cardiac biomarkers. Cardiac biomarkers, such as cardiac troponin I (cTnI), 5,6 creatine kinase (CK), 6 CK-MB, 7 lactic dehydrogenase (LDH), 8 hydroxybutyrate dehydrogenase (HBDH), 8 and brain natriuretic peptide (BNP), 9 play important roles in the diagnosis of CVD. Among them, cTnI is a sensitive and specific marker of myocardium damage and is a widely used predictor of cardiovascular events 10 and BNP has widespread utility as an adjunct to CVD diagnosis and management. 9 It is well known that cardiac biomarkers are often increased in patients with impaired renal function, which made the interpretation of cTnI, CK, CK-MB, LDH, HBDH, and BNP is ambiguous and the diagnosis of CVD is challenging in patients with impaired renal function. 11 Information on the association between cardiac biomarkers and eGFR is currently limited, and the elevation of the cardiac biomarkers at a given eGFR is not well clarified, especially in child. For example, Remy et al 12 found that eGFR 60 to <90 mL/min/1.73 m 2 was associated with a 1.19 (1.12-1.27) [ratio (95%CI)] times higher cTnI, but Tuncay et al 13 found that there was no significant relationship between eGFR and cTnI. Thus, the associations between eGFR and cardiac biomarkers need to be further evaluated.
In view of the above, we examined whether eGFR was associated with cTnI, CK, CK-MB, LDH, HBDH, and BNP in Chinese population, including both adults and child.

| Study population
In total, 1210 adults and 325 child who performed serum creati-

| Covariates
We LDL-C/HDL-C was calculated by dividing LDL-C by HDL-C.

| Characteristics of the study population
Altogether, 812 adults and 215 child were included in this study finally. For adults, the mean age of participants was 60.6 ± 16.5 years, and 58.3% were male. For child, the mean age of participants was 7.9 ± 5.0 years, and 52.1% were boys.
The clinical characteristics of the adults and child population stratified according to eGFR CKD-EPI and eGFR Schwartz categories were shown in Table 1 and   Figure S3).

| Association between eGFR and CVD biochemistry biomarkers
Participants with lower eGFR CKD-EPI had significantly higher cTnI, CK-MB, LDH, HBDH, and BNP (Table 1 and Figure 2). For child, lower eG-

| Additional analyses with eGFR MDRD
The median eGFR MDRD Table S4). When eGFR CKD-EPI was replaced by eGFR MDRD , the associations of eGFR with cardiac biomarkers became weaker.

| D ISCUSS I ON
In a cross-sectional study, we demonstrated that there were negative correlations between eGFR CKD-EPI and cTnI, CK-MB, LDH, HBDH,

TA B L E 4 Associations of eGFR CKE-EPI categories with biomarkers of cardiac injury
The population with reduced eGFR were at the highest risk for CVD. 2 There was a gradual and independent association between low eGFR and artery calcification, which is a well-known predictor of CVD. 22 The reduced eGFR may cause myocardial injury via chronic low-grade inflammation and endothelial dysfunction, 23 and may also reduce the renal elimination of cardiac biomarkers. 18, 24 We could not determine the relative contributions of lower renal elimination and myocardial injury to the associations of eGFR with the cardiac biomarkers in our study. The negative correlations were also observed after adjustment for ST-T wave abnormalities of ECG, which may indicate the lower renal elimination. However, the positive cardiac biomarkers may indicate minimal myocardial injury that is subclinical and not visible on an ECG.
More and more studies 12,23 hold the opinion that myocardial injury involved, not only lower renal elimination. Thus, the results of our study suggested that minimal myocardial injury may contribute to the CVD mortality in the lower eGFR.
In this study, both eGFR CKD-EPI and eGFR MDRD were associated with the cardiac biomarkers. Nevertheless, associations of eGFR This study has several limitations. On the one hand, owing to the cross-sectional design, it is difficult for us to make strong causal inferences. On the other hand, this study was intrinsically limited by its retrospective nature. So, the associations between eGFR and cardiac biomarkers need additional exploration in future studies.

CO N FLI C T O F I NTE R E S T S
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

E TH I C A L A PPROVA L
The research was in compliance with the Declaration of Helsinki and approved by the ethics committee of Peking University First Hospital (reference number: 1381).