B-type natriuretic peptide and cardiac troponin I are associated with adverse outcomes in stable kidney transplant recipients

Authors: JAROLIM, PETR - Harvard University; CLAGGETT, BRIAN - Harvard University; CONRAD, MICHAEL - Harvard University; CARPENTER, MYRA - University Of North Carolina; INVANOVA, ANASTASIA - University Of North Carolina; BOSTOM, ANDREW - Rhode Island Hospital; KUSEK, JOHN - National Institute Of Diabetes And Digestive And Kidney Diseases; HUNSICKER, HUNSICKER - University Of Iowa; JACQUES, PAUL - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; GRAVENS-MUELLER, LISA - University Of North Carolina; FINN, PETER - Harvard University; SOLOMON, SCOTT - Harvard University; WEINER, DANIEL - Tufts University; LEVEY, ANDREW - Tufts University; PFEFFER, MARC - Harvard University

Submitted to: Transplantation
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 11/27/2015
Publication Date: 1/20/2016
Citation: Jarolim, P., Claggett, B., Conrad, M.J., Carpenter, M.A., Invanova, A., Bostom, A.G., Kusek, J.W., Hunsicker, H.G., Jacques, P.F., Gravens-Mueller, L., Finn, P., Solomon, S.D., Weiner, D.E., Levey, A.S., Pfeffer, M.A. 2016. B-type natriuretic peptide and cardiac troponin I are associated with adverse outcomes in stable kidney transplant recipients. Transplantation. doi: 10.1097/TP.0000000000001080.

Interpretive Summary: Approximately 17,000 kidney transplants are performed annually in the United States and about 70,000 are performed annually worldwide. Currently, there are approximately 200,000 living Kidney Transplant Recipients (KTR) in the US. Both cardiovascular disease (CVD) and kidney transplant failure are common and have a substantial impact on morbidity and mortality in this population. Biomarkers to identify KTR at increased risk for adverse outcomes may lead to improved management of these patients. Two biomarkers, the B-type natriuretic peptide (BNP) and cardiac troponin I (cTnI,) are elevated in chronic kidney disease (CKD) patients. However, whether these findings can be applied to KTR is not known. We conducted a case-cohort study of specimens collected from stable KTR during subjects' participation in a clinical trial of homocysteine lowering, the Folic Acid for Vascular Outcome Reduction In Transplantation (FAVORIT) trial, to assess whether plasma levels of BNP and cTnI are associated with adverse outcomes in stable kidney transplant recipients. Specimens from 510 stable kidney transplant participants were selected randomly. After enrichment for adverse outcomes, specimens from 1,131 participants were studied. BNP and high sensitivity cTnI (hs-cTnI) levels were divided into four groups with equal numbers of participants (quartile categories) and were included in this form in models that statistically adjusted for potential differences between participants in the categories of these biomarkers for baseline age, gender, race, treatment assignment, history of smoking, coronary heart disease, diabetes, urine albumin/creatinine ratio, estimated glomerular filtration rate, body mass index, blood pressure, lipid levels, graft vintage, and donor type. Combinations of normal and elevated hs-cTnI and BNP were also studied. Adverse outcomes among participants followed for a median of 3.9 years included all-cause death, dialysis-dependent kidney failure, and cardiovascular outcomes consisting of cardiovascular disease death, myocardial infarction, resuscitated sudden death, and stroke. Participants in the highest quartile category for BNP were more likely to experience all adverse outcomes considered than those in the lowest quartile category of BNP, and these associations were independent of hs-cTnI levels. The greatest elevation in risk was a 2.5-fold increased risk of dialysis dependent kidney failure. Risks of adverse events associated with hs-cTnI were generally weaker than those observed for BNP and no longer statistically significant after adjustment for BNP. Simultaneous elevations of BNP and hs-cTnI over clinical cutoffs were strongly associated with an 8.8-fold increased risk of dialysis dependent kidney failure and a 6.3-fold increased risk CVD outcomes relative to participants below the clinical cutoffs for these biomarkers. Use of these biomarkers to identify high risk subsets within the kidney transplant population may facilitate future research and targeted interventions to reduce adverse outcomes in these patients.

Technical Abstract: BACKGROUND: Approximately 200 000 kidney transplant recipients are living in the United States; they are at increased risk for cardiovascular and other adverse outcomes. Biomarkers predicting these outcomes are needed. Using specimens collected during the Folic Acid for Vascular Outcome Reduction in Transplantation trial, we determined whether plasma levels of B-type natriuretic peptide (BNP) and cardiac troponin I are associated with adverse outcomes in stable kidney transplant recipients. METHODS: Five hundred ten subjects were selected randomly from the 4110 Folic Acid for Vascular Outcome Reduction in Transplantation participants. This cohort was then enriched for all additional subjects with adverse outcomes (death, dialysis-dependent kidney failure (DDKF), and cardiovascular outcomes) for a total of 1131 participants studied. Quartiles of BNP and high-sensitivity cardiac troponin I (hs-cTnI) were included in adjusted models. Combinations of normal and elevated hs-cTnI (>26.2 ng/L) and BNP (>100 pg/mL) were also studied. RESULTS: Median concentrations (interquartile ranges) were 5.6 (3.3-10.5) ng/L for hs-cTnI and 39 (15, 94) pg/mL for BNP. Hazard ratios for each adverse outcome were higher with higher quartiles of BNP after adjustment and remained statistically significant after adding hs-cTnI to the model. The highest quartile hazard ratio for DDKF was 2.47 (95% confidence interval [95% CI], 1.21-5.05). Simultaneous elevations of BNP and hs-cTnI over clinical cutoffs were strongly associated with adverse outcomes with hazard ratios 8.8 (95% CI, 3.4-23.1) for DDKF and 6.3 (95% CI, 2.7-15.0) for cardiovascular outcomes. CONCLUSIONS: Higher BNP is associated with mortality and cardiovascular and kidney outcomes in stable kidney transplant recipients. Elevated BNP and hs-cTnI identify candidates for targeted risk reduction.