Objective: The role of biochemical and functional markers of microvascular dysfunction to predict cardiovascular outcomes in nondialyzed chronic kidney disease (CKD) remains unclear. In this prospective cohort study, we assessed whether biochemical [serum level of angiopoietin-2 (Ang-2), asymmetric and symmetric dimethylarginin] and functional (laser Doppler flowmetry) measures of microvascular function predicted cardiovascular events, cardiovascular and all-cause mortality in CKD patients.
Methods: Postocclusive reactive hyperemia area (PORHHA), acetylcholine and sodium nitroprusside-mediated flow changes were estimated by laser Doppler flowmetry, and Ang-2, asymmetric and symmetric dimethylarginin were assessed in 105 CKD patients at baseline. Multiple failure time Cox-regression analyses with backward elimination were performed to determine the predictors of the combined endpoint of cardiovascular mortality and cardiovascular events or all-cause mortality and cardiovascular events during a median of 66.6 (interquartile range 39.8–80.4) months of follow-up.
Results: In univariate models lnAng-2 and lnPORHHA both predicted the cardiovascular outcome besides age, diabetes, baseline cardiovascular disease, brachial pulse pressure and log C-reactive protein. In multivariate analysis lnPORHHA [hazard ratio: 0.66 (95% confidence interval: 0.49–0.89) per ln(mU s)], age [1.03 (1.01–1.06) per year], log C-reactive protein [1.31 (1.06–1.64) per ln(mg/l)] and diabetes [3.33 (1.70–6.53)] remained significant predictors of the cardiovascular outcome, whereas lnAng-2 did not enter the model. Neither of the microvascular variables were an independent predictor of all-cause mortality and cardiovascular events.
Conclusion: Among the functional and biochemical microvascular parameters PORHHA seems to improve cardiovascular risk assessment in CKD. Nevertheless the robustness of traditional risk factors seems to outweigh the role of microvascular biomarkers on all-cause mortality and cardiovascular events at this time.
aDepartment of Family Medicine, Semmelweis University
bHealth Service of Zugló (ZESZ)
cDepartment of Transplantation and Surgery, Semmelweis University, Budapest, Hungary
dDepartment of Internal Medicine II, University Hospital Regensburg, Regensburg
eDivision of Nephrology and Hypertension, Department of Medicine, Hannover Medical School, Hannover
fDivision of General Internal Medicine, Nephrology, and Rheumatology, Department of Medicine D, University Hospital Münster, Münster, Germany
g1st Department of Medicine, Semmelweis University
hNephrology Division, Uzsoki Teaching Hospital
iDepartment of Cardiology, St. Imre Teaching Hospital
jDivision of Angiology, Department of Medicine, St. Imre Teaching Hospital
kB Braun Avitum Nephrological Network
lDivision of Nephrology, Department of Medicine, St. Imre Teaching Hospital, Budapest, Hungary
Correspondence to János Nemcsik, MD, PhD, Department of Family Medicine, Semmelweis University, 4. Kútvölgyi Street, 1125 Budapest, Hungary. Tel: +36 209827367; fax: +36 13558530; e-mail: firstname.lastname@example.org
Abbreviations: ACh, the magnitude of the change in skin perfusion after the second administered dose of acetylcholine as the ratio between peak and baseline perfusion, expressed as percent of baseline; ACR, urinary albumin-to-creatinine ratio; ADMA, asymmetric dimethylarginin; Ang-2, angiopoietin-2; CKD, nondialyzed chronic kidney disease; eGFR, estimated glomerular filtration ratio calculated using the four-variable Chronic Kidney Disease Epidemiology Collaboration equation; LDF, laser Doppler flowmetry; NRI, net reclassification improvement; PORHHA, postocclusive reactive hyperemia area; PP, pulse pressure; PU, perfusion unit; RAAS, renin–angiotensin–aldosterone system; SDMA, symmetric dimethylarginin; SNP, the magnitude of the change in skin perfusion after the second administered dose of sodium nitroprusside as the ratio between peak and baseline perfusion, expressed as percent of baseline
Received 22 June, 2016
Revised 6 December, 2016
Accepted 15 December, 2016