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Alteration of HDL Protein Composition with Hemodialysis Initiation

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Alteration of HDL Protein Composition with Hemodialysis Initiation Article Alteration of HDL Protein Composition with Hemodialysis Initiation Ke Wang,1,2 Leila R. Zelnick ,1,2 Andrew N. Hoofnagle,1,2,3 Tomas Vaisar,1 Clark M. Henderson,3 Peter B. Imrey ,4,5 Cassianne Robinson-Cohen ,6 IanH.deBoer,1,2 Yan-Ting Shiu,7 Jonathan Himmelfarb,1,2 Gerald J. Beck,4,5 and Bryan Kestenbaum,1,2 on behalf of the HFM Study Abstract Departments of Background and objectives HDL particles obtained from patients on chronic hemodialysis exhibit lower 1 fl fl Medicine and cholesterol ef ux capacity and are enriched in in ammatory proteins compared with those in healthy individuals. 3Laboratory Medicine Observed alterations in HDL proteins could be due to effects of CKD, but also may be influenced by the and 2Kidney Research hemodialysis procedure, which stimulates proinflammatory and prothrombotic pathways. Institute, University of Washington, Seattle, Washington; Design, setting, participants, & measurements We compared HDL-associated proteins in 143 participants who 4Department of initiated hemodialysis within the previous year with those of 110 participants with advanced CKD from the Quantitative Health Hemodialysis Fistula Maturation Study. We quantified concentrations of 38 HDL-associated proteins relative to Sciences, Lerner total HDL protein using targeted mass spectrometry assays that included a stable isotope–labeled internal Research Institute, standard. We used linear regression to compare the relative abundances of HDL-associated proteins after Cleveland Clinic, # Cleveland, Ohio; adjustment and required a false discovery rate q value 10% to control for multiple testing. We further assessed 5Department of the association between hemodialysis initiation and cholesterol efflux capacity in a subset of 80 participants. Medicine, Cleveland Clinic Lerner College ResultsAfter adjustment for demographics,comorbidities, and other clinical characteristics, eight HDL-associated of Medicine of Case fi Western Reserve proteins met the prespeci ed false discovery threshold for association. Recent hemodialysis initiation was University, Cleveland, associated with higher HDL-associated concentrations of serum amyloid A1, A2, and A4; hemoglobin-b; Ohio; 6Department of haptoglobin-related protein; cholesterylester transfer protein; phospholipid transfer protein; and apo E. The trend Medicine, Vanderbilt for participants recently initiating hemodialysis for lower cholesterol efflux capacity compared with individuals University, Nashville, Tennessee; and with advanced CKD did not reach statistical significance. 7 Division of Nephrology and Conclusions Compared with advanced CKD, hemodialysis initiation within the previous year is associated with Hypertension, higher concentrations of eight HDL proteins related to inflammation and lipid metabolism. Identified associations University of Utah differ from those recently observed for nondialysis-requiring CKD. Hemodialysis initiation may further School of Medicine, Salt Lake City, Utah impair cholesterol efflux capacity. Further work is needed to clarify the clinical significance of the identified proteins with respect to cardiovascular risk. Correspondence: Clin J Am Soc Nephrol 13: 1225–1233, 2018. doi: https://doi.org/10.2215/CJN.11321017 Dr. Ke Wang, Kidney Research Institute, Harborview Medical Center, 325 9th Introduction proatherosclerotic processes, such as LDL oxidation, Avenue, Box 359606, Cardiovascular disease is the leading cause of death and macrophage activation, and platelet adhesion (2,6). Seattle, WA 98104. disability among patients on chronic dialysis, account- Among patients on chronic dialysis, absolute HDL Email: kewang@ uw.edu ing for approximately one half of all deaths (1). CKD is cholesterol concentrations are inconsistently associ- associated with a unique pattern of dyslipidemia that may ated with cardiovascular risk, suggesting that func- contribute to cardiovascular risk. Specific lipid abnormal- tional alterations of HDL particles may be clinically ities observed in patients with CKD include an increase in important (7). In this regard, several studies have circulating triglycerides, a reduction in total HDL choles- shown lower cholesterol efflux capacity and a greater terol, and a disposition towards dense atherogenic LDL abundance of inflammatory proteins in HDL particles particles (2,3). Hepatic hydroxymethyl glutaryl–CoA re- obtained from patients on chronic hemodialysis com- ductase inhibitors, which specifically target LDL choles- pared with healthy individuals (8–12). However, these terol, do not reduce cardiovascular outcomes in clinical findings do not distinguish the potential effects of trials of patients on chronic dialysis (4,5). longstanding kidney failure from those of the hemo- HDL particles are circulating noncovalently bound dialysis procedure itself, which stimulates proinflam- assemblies of lipids and proteins that mediate reverse matory and prothrombotic pathways. A recent study of cholesterol transport by retrieving excess cholesterol HDL composition among patients not on dialysis from peripheral tissues. HDL particles exhibit anti- across a wide range of kidney function showed asso- oxidative and anti-inflammatory functions and inhibit ciations of lower eGFR with higher HDL-associated www.cjasn.org Vol 13 August, 2018 Copyright © 2018 by the American Society of Nephrology 1225 1226 Clinical Journal of the American Society of Nephrology concentrations of retinol binding protein 4 (RBP4) and APOC3 chromatography-tandem mass spectrometry on a Q-Exactive and lower HDL-associated concentrations of APOL1 and mass spectrometer (Thermo). The same amount of HDL vitronectin (13). protein (10 mg) was analyzed for each sample. We sought to estimate the effect of the hemodialysis procedure on the HDL proteome. To accomplish this goal, Data Reduction we measured 38 HDL-associated proteins in 143 patients The peak area for each endogenous peptide was nor- who recently initiated hemodialysis and 110 patients who malized to the peak area of an internal standard peptide had advanced CKD and were awaiting dialysis initiation in from the stable isotope–labeled internal standard protein to the Hemodialysis Fistula Maturation (HFM) Study. We generate a peak area ratio for each peptide in each sample. hypothesized that dialysis initiation would be associated Peak area ratios for each protein were averaged, and protein with structural transformation of the HDL proteome to a peak area ratios were normalized to protein peak area ratios fl more in ammatory phenotype, which in turn, would lead for calibrator samples included in each digestion batch. to impaired HDL function. Because the same amount of HDL protein was used for each sample, changes in relative protein concentrations represent changes in the amount of protein per 10 mgtotalHDL Materials and Methods protein. We quantified 38 proteins that are abundant in the Study Population HDL proteome and have been previously assayed using the We analyzed plasma samples collected from the HFM same protocol (13,15–17). Study, a prospective cohort study of arteriovenous fistula (AVF) maturation that enrolled 602 participants undergoing planned creation of an upper extremity AVF at seven study Cholesterol Efflux Capacity fl sites across the United States (14). The institutional review Serum HDL cholesterol ef ux capacity was assessed in 3 boards of each of these institutions and the Data Coordinat- J774 macrophages labeled with H-cholesterol and stimulated fl ing Center approved the study. Each participant provided with a cAMP analog (18). Ef ux by the ATP binding cas- informed consent before study enrollment. The HFM Study sette transporter A1 (ABCA1) pathway was measured with participants were either receiving maintenance dialysis or BHK cells expressing mifepristone-inducible human ABCA1 3 fl expected to start dialysis within 3 months of planned AVF that were radiolabeled with H-cholesterol (19). Ef ux of 3 surgery. Exclusion criteria were age ,18 years old, age $80 H-cholesterol was measured after 4 hours of incubation in years old if not receiving maintenance dialysis, or a life medium with or without serum depleted of apoB (2.8% vol/ fl expectancy of ,9 months. For purposes of this ancillary study, vol). The serum HDL cholesterol ef ux capacity is calculated 3 we excluded 349 participants from our analysis (288 without as the amount of H-cholesterol in the media normalized to 3 adequate plasma sample for HDL proteome assays, 59 HFM the total amount of H-cholesterol in the media and the cells. Study participants who had received maintenance dialysis for .1 year, and two participants who were receiving peritoneal Ascertainment of Other Study Data dialysis), leaving a final analytic sample of 253 participants. At the baseline study visit, the HFM Study personnel used We assessed cholesterol efflux capacity in a subset of 80 study patient interviews and medical records to obtain patient de- participants; we matched 40 participants who initiated he- mographics; medical histories; ESRD history, including modal- modialysis to 40 participants with advanced CKD according ity and number of years undergoing dialysis; social habits; and to age within one year, race, and sex. home medication use. Demographics included age, sex, self- reported race and ethnicity, and smoking status. Comorbid HDL Isolation and Quantification of HDL-Associated conditions included a prevalent history of cardiovascular Proteins disease (angina, myocardial infarction, coronary artery bypass, Blood samples were collected at a baseline preoperative or percutaneous
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