CLINICAL RESEARCH www.jasn.org HDL Cholesterol, Apolipoproteins, and Cardiovascular Risk in Hemodialysis Patients †‡ | Günther Silbernagel,* Bernd Genser, § Christiane Drechsler,§ Hubert Scharnagl,¶ † | | Tanja B. Grammer, Tatjana Stojakovic,¶ Vera Krane,§ Eberhard Ritz,** Christoph Wanner,§ ††‡‡ and Winfried März¶ *Department of Angiology, Swiss Cardiovascular Center, Inselspital, University of Bern, Bern, Switzerland; †Mannheim Institute of Public Health, Social and Preventive Medicine, and ††Medical Clinic V (Nephrology, Hypertensiology, Endocrinology, Diabetology, Rheumatology), Department of Internal Medicine, Mannheim Medical Faculty, University of Heidelberg, Mannheim, Germany; ‡Institute of Public Health, Federal University of Bahia, Salvador, Brazil; §Division of Nephrology, Department of Medicine I, and |Comprehensive Heart Failure Centre, University of Würzburg, Würzburg, Germany; ¶Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria; **Division of Nephrology, Department of Internal Medicine, University of Heidelberg, Heidelberg, Germany; and ‡‡Synlab Academy, Synlab Services LLC, Mannheim, Germany ABSTRACT High concentrations of HDL cholesterol are considered to indicate efficient reverse cholesterol transport and to protect from atherosclerosis. However, HDL has been suggested to be dysfunctional in ESRD. Hence, our main objective was to investigate the effect of HDL cholesterol on outcomes in maintenance hemodialysis patients with diabetes. Moreover, we investigated the associations between the major protein components of HDL (apoA1, apoA2, and apoC3) and end points. We performed an exploratory, post hoc analysis with 1255 participants (677 men and 578 women) of the German Diabetes Dialysis study. The mean age was 66.3 years and the mean body mass index was 28.0 kg/m2.Theprimary end point was a composite of cardiac death, myocardial infarction, and stroke. The secondary end point included all-cause mortality. The mean duration of follow-up was 3.9 years. A total of 31.3% of the study participants reached the primary end point and 49.1% died from any cause. HDL cholesterol and apoA1 and apoC3 quartiles were not related to end points. However, there was a trend toward an inverse association between apoA2 and all-cause mortality. The hazard ratio for death from any cause in the fourth quartile compared with the first quartile of apoA2 was 0.63 (95% confidence interval, 0.40 to 0.89). The lack of an association between HDL cholesterol and cardiovascular risk may support the concept of dysfunctional HDL in hemodialysis. The possible beneficial effect of apoA2 on survival requires confir- mation in future studies. J Am Soc Nephrol 26: 484–492, 2015. doi: 10.1681/ASN.2013080816 Reverse cholesterol transport is considered to pro- Received August 1, 2013. Accepted June 1, 2014. 1,2 tect from atherosclerosis. HDLs represent the G.S. and B.G. contributed equally to this work. major vehicle of reverse cholesterol transport.1,2 They primarily consist of phospholipids, choles- Published online ahead of print. Publication date available at www.jasn.org. terol, and proteins.1,2 The two major protein con- stituents of HDL are apoA1 and apoA2.1,2 ApoC3 Correspondence: Dr. Günther Silbernagel, Department of Angiology, Swiss Cardiovascular Center, Inselspital, University 3,4 forms another component of HDL. Whereas of Bern, 3010 Bern, Switzerland. Email: guenther.silbernagel@ apoA1 is regarded as beneficial to cardiovascular insel.ch health, apoC3 is rather regarded as proathero- – genic.3 6 The role of apoA2 has not been sufficiently Copyright © 2015 by the American Society of Nephrology 484 ISSN : 1046-6673/2602-484 J Am Soc Nephrol 26: 484–492, 2015 www.jasn.org CLINICAL RESEARCH examined.7,8 Nevertheless, recent data tend to support anti- RESULTS atherogenic effects.7–9 High concentrations of HDL cholesterol are generally Patient Characteristics at Baseline thought to reflect efficient reverse cholesterol transport.2,5 The 1255 (677 men and 578 women) participants of the 4D However, HDL composition and function are impaired in study had a mean age of 66.3 years and a mean body mass index CKD.10,11 In addition, dysfunctional HDL has been observed of 28.0 kg/m2. in patients on hemodialysis.12 Hence, high HDL cholesterol Tables 1–4 show the baseline characteristics of the study does not necessarily indicate efficient reverse cholesterol participants according to the quartiles of HDL cholesterol and transport in renal disease. apoA1, apoA2, and apoC3. Supplemental Table 1 shows the We conducted an exploratory, post hoc analysis of the baseline characteristics of the subgroups with HDL cholesterol German Diabetes Dialysis (4D) study to investigate whether levels #50 mg/dl and .50 mg/dl within the fourth quartile of HDL cholesterol predicts mortality and cardiovascular risk in HDL cholesterol. Supplemental Table 2 shows the baseline patients on maintenance hemodialysis treatment.13,14 More- characteristics of the propensity score–matched cohort. over, we sought to analyze the relationships of the major pro- In the entire cohort, the HDL cholesterol quartiles were tein components of HDL, namely apoA1, apoA2, and apoC3, inversely related to the proportion of men, to body mass index, with outcomes. triglycerides, apoC3, and C-reactive protein and they were Table 1. Baseline patient characteristics according to quartiles of HDL cholesterol Quartile of HDL Cholesterol Characteristic P Value Q1 Q2 Q3 Q4 Participants (n) 312 308 317 318 Range (mg/dl) 17.3–33.4 33.5–39.3 39.4–46.9 47.0–115.5 Age (yr) 65.3 (8.3) 66.0 (8.6) 67.2 (8.1) 66.7 (8.0) 0.03 Men (%) 205 (66) 185 (60) 156 (49) 131 (41) ,0.001 Ever smoking, n (%) 146 (47) 123 (40) 120 (38) 118 (37) 0.06 Body mass index (kg/m2) 30.0 (4.7) 28.2 (5.0) 27.7 (5.0) 26.2 (4.3) ,0.001 BP (mmHg) Systolic 145 (22) 147 (22) 144 (21) 147 (22) 0.19 Diastolic 75 (11) 76 (12) 76 (11) 77 (11) 0.13 Time receiving dialysis (mo) 8.9 (6.7) 8.3 (7.2) 8.1 (7.0) 7.8 (6.6) 0.24 History of disease, n (%)a Arrhythmia 76 (24) 52 (17) 49 (15) 59 (19) 0.03 MI, CABG, PCI, or CHD 103 (33) 94 (31) 79 (25) 93 (29) 0.16 Congestive heart failureb 132 (42) 107 (35) 102 (32) 103 (32) 0.03 Stroke or TIA 57 (18) 63 (20) 55 (17) 49 (15) 0.42 Peripheral vascular disease 148 (47) 147 (48) 125 (39) 140 (44) 0.13 Hemoglobin (g/dl) 10.8 (1.4) 11.0 (1.3) 10.8 (1.3) 11.0 (1.4) 0.08 Glycated hemoglobin (%) 6.84 (1.31) 6.72 (1.24) 6.61 (1.27) 6.72 (1.21) 0.15 Phosphate (mg/dl) 5.98 (1.72) 6.07 (1.56) 5.97 (1.51) 6.09 (1.63) 0.71 Albumin (g/dl) 3.83 (0.3) 3.81 (0.26) 3.80 (0.32) 3.81 (0.31) 0.47 Cholesterol (mg/dl) LDL 119.4 (26.9) 125.0 (30.2) 128.3 (30.4) 129.5 (40.0) ,0.001 HDL 29.6 (3.0) 36.1 (1.7) 43.0 (2.2) 56.9 (9.6) ,0.001 Apolipoprotein (mg/dl) A1 107.9 (14.4) 118.5 (16.8) 129.0 (16.1) 149.5 (23.2) ,0.001 A2 24.5 (4.4) 27.1 (4.5) 29.1 (4.9) 32.2 (6.1) ,0.001 C3 22.3 (10.6) 20.8 (10.0) 19.5 (8.8) 19.1 (8.1) ,0.001 Triglycerides (mg/dl) 349.0 (200.7) 291.6 (170.1) 236.2 (134.1) 181.4 (95.6) ,0.001 C-reactive protein (mg/L) 11.0 (4.3–13.6) 6.6 (2.8–12.0) 5.7 (2.5–11.7) 4.5 (1.9–11.1) ,0.001 NT-pro-BNP (ng/L) 3585 (1492–9949) 3117 (1416–6842) 2698 (1246–8375) 3953 (1686–11,115) 0.03 Data are presented as the mean (SD) or median (25th percentile to 75th percentile), unless otherwise specified. P values for comparison of groups were derived from an analysis of covariance model (for continuous variables) or logistic regression model (for categorical variables), both adjusted for age and sex. Q, quartile; MI, myocardial infarction; CABG, coronary artery bypass grafting surgery; PCI, percutaneous coronary intervention; CHD, coronary heart disease, documented by coronary angiography; TIA, transitory ischemic attack; NT-pro-BNP, N-terminal pro-brain natriuretic peptide. aTypes of disease and intervention are not mutually exclusive. bPredominantly New York Heart Association II. J Am Soc Nephrol 26: 484–492, 2015 HDL Cholesterol and Outcomes in 4D 485 CLINICAL RESEARCH www.jasn.org positively related to LDL cholesterol and apoA1 and apoA2 different end points according to HDL cholesterol and apolipo- (Table 1). The apoA1 quartiles were inversely related to the protein quartiles are shown in Supplemental Tables 3–6. The proportion of men, triglycerides, and C-reactive protein and interaction terms between components of HDL and randomi- they were positively associated with albumin, LDL cholesterol, zation group were not significant for any end point in pooled and apopliproteins (Table 2). The apoA2 quartiles were inversely analyses. These findings were corroborated by analyses stratified related to C-reactive protein, N-terminal pro-brain natriuretic by randomization group (data not shown). peptide, congestive heart failure, and arrhythmia and they were Table 5 shows a summary of the pooled time-to-event anal- positively associated with hemoglobin, albumin, and LDL cho- yses. The quartiles of HDL cholesterol were not associated lesterol (Table 3). The apoC3 quartiles were inversely related to with any end point (Table 5). Further stratification of the age and N-terminal pro-brain natriuretic peptide and they were fourth quartile in patients with HDL cholesterol #50 mg/dl positively associated with body mass index, glycated hemoglo- and in those with HDL cholesterol .50 mg/dl did not reveal bin, LDL cholesterol, and triglycerides (Table 4).