Alteration of HDL Protein Composition with Hemodialysis Initiation
Abstract
Background and objectives
HDL particles obtained from patients on chronic hemodialysis exhibit lower cholesterol efflux capacity and are enriched in inflammatory proteins compared with those in healthy individuals. Observed alterations in HDL proteins could be due to effects of CKD, but also may be influenced by the hemodialysis procedure, which stimulates proinflammatory and prothrombotic pathways.
Design, setting, participants, & measurements
We compared HDL-associated proteins in 143 participants who initiated hemodialysis within the previous year with those of 110 participants with advanced CKD from the Hemodialysis Fistula Maturation Study. We quantified concentrations of 38 HDL-associated proteins relative to total HDL protein using targeted mass spectrometry assays that included a stable isotope–labeled internal standard. We used linear regression to compare the relative abundances of HDL-associated proteins after adjustment and required a false discovery rate q value ≤10% to control for multiple testing. We further assessed the association between hemodialysis initiation and cholesterol efflux capacity in a subset of 80 participants.
Results
After adjustment for demographics, comorbidities, and other clinical characteristics, eight HDL-associated proteins met the prespecified false discovery threshold for association. Recent hemodialysis initiation was associated with higher HDL-associated concentrations of serum amyloid A1, A2, and A4; hemoglobin-β; haptoglobin-related protein; cholesterylester transfer protein; phospholipid transfer protein; and apo E. The trend for participants recently initiating hemodialysis for lower cholesterol efflux capacity compared with individuals with advanced CKD did not reach statistical significance.
Conclusions
Compared with advanced CKD, hemodialysis initiation within the previous year is associated with higher concentrations of eight HDL proteins related to inflammation and lipid metabolism. Identified associations differ from those recently observed for nondialysis-requiring CKD. Hemodialysis initiation may further impair cholesterol efflux capacity. Further work is needed to clarify the clinical significance of the identified proteins with respect to cardiovascular risk.
Podcast
This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2018_07_25_CJASNPodcast_18_8_W.mp3
Supplementary Material
Abstract
Background and objectives
HDL particles obtained from patients on chronic hemodialysis exhibit lower cholesterol efflux capacity and are enriched in inflammatory proteins compared with those in healthy individuals. Observed alterations in HDL proteins could be due to effects of CKD, but also may be influenced by the hemodialysis procedure, which stimulates proinflammatory and prothrombotic pathways.
Design, setting, participants, & measurements
We compared HDL-associated proteins in 143 participants who initiated hemodialysis within the previous year with those of 110 participants with advanced CKD from the Hemodialysis Fistula Maturation Study. We quantified concentrations of 38 HDL-associated proteins relative to total HDL protein using targeted mass spectrometry assays that included a stable isotope–labeled internal standard. We used linear regression to compare the relative abundances of HDL-associated proteins after adjustment and required a false discovery rate q value ≤10% to control for multiple testing. We further assessed the association between hemodialysis initiation and cholesterol efflux capacity in a subset of 80 participants.
Results
After adjustment for demographics, comorbidities, and other clinical characteristics, eight HDL-associated proteins met the prespecified false discovery threshold for association. Recent hemodialysis initiation was associated with higher HDL-associated concentrations of serum amyloid A1, A2, and A4; hemoglobin-β; haptoglobin-related protein; cholesterylester transfer protein; phospholipid transfer protein; and apo E. The trend for participants recently initiating hemodialysis for lower cholesterol efflux capacity compared with individuals with advanced CKD did not reach statistical significance.
Conclusions
Compared with advanced CKD, hemodialysis initiation within the previous year is associated with higher concentrations of eight HDL proteins related to inflammation and lipid metabolism. Identified associations differ from those recently observed for nondialysis-requiring CKD. Hemodialysis initiation may further impair cholesterol efflux capacity. Further work is needed to clarify the clinical significance of the identified proteins with respect to cardiovascular risk.
Podcast
This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2018_07_25_CJASNPodcast_18_8_W.mp3
Abstract
Values are expressed as mean (SD) or number (percentage). NA, not applicable; HDL-C, HDL cholesterol.
95% CI, 95% confidence interval; ABCA1, ATP binding cassette transporter A1.
Click here to view.Acknowledgments
The authors would like to acknowledge the technical assistance of Jennifer Wallace in the preparation of the HDL particles.
The Hemodialysis Fistula Maturation Study was funded by grants U01DK082218, U01DK082222, U01DK082232, U01DK082236, U01DK082240, U01DK082179, U01DK082189 from the National Institute of Diabetes and Digestive and Kidney Diseases. This study was funded by University of Washington Nutrition Obesity Research Center grants P30DK035816, T32DK00746733 (to K.W.), R01HL111375 (to A.N.H.), T32HL007028 (to C.M.H.), and R01DK094891 (to B.K.).
Because I.H.d.B. is a Deputy Editor of the Clinical Journal of the American Society of Nephrology, he was not involved in the peer review process for this manuscript. Another editor oversaw the peer review and decision-making process for this manuscript. Rajnish Mehrotra, the Editor-in-Chief, is at the same institution as some of the authors, including the Deputy Editor, and therefore, was also not involved in the peer review process for this manuscript.
Footnotes
Published online ahead of print. Publication date available at www.cjasn.org.
This article contains supplemental material online at http://cjasn.asnjournals.org/lookup/suppl/doi:10.2215/CJN.11321017/-/DCSupplemental.
References
- 1. Go AS, Chertow GM, Fan D, McCulloch CE, Hsu CY.: Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization.N Engl J Med351: 1296–1305, 2004 [[PubMed]
- 2. Vaziri ND: Dyslipidemia of chronic renal failure: The nature, mechanisms, and potential consequences.Am J Physiol Renal Physiol290: F262–F272, 2006 [[PubMed]
- 3. de Boer IH, Astor BC, Kramer H, Palmas W, Seliger SL, Shlipak MG, Siscovick DS, Tsai MY, Kestenbaum B.: Lipoprotein abnormalities associated with mild impairment of kidney function in the multi-ethnic study of atherosclerosis.Clin J Am Soc Nephrol3: 125–132, 2008
- 4. Wanner C, Krane V, März W, Olschewski M, Mann JF, Ruf G, Ritz E; German Diabetes and Dialysis Study Investigators .: Atorvastatin in patients with type 2 diabetes mellitus undergoing hemodialysis.N Engl J Med353: 238–248, 2005 [[PubMed]
- 5. Fellström BC, Jardine AG, Schmieder RE, Holdaas H, Bannister K, Beutler J, Chae DW, Chevaile A, Cobbe SM, Grönhagen-Riska C, De Lima JJ, Lins R, Mayer G, McMahon AW, Parving HH, Remuzzi G, Samuelsson O, Sonkodi S, Sci D, Süleymanlar G, Tsakiris D, Tesar V, Todorov V, Wiecek A, Wüthrich RP, Gottlow M, Johnsson E, Zannad F; AURORA Study Group .: Rosuvastatin and cardiovascular events in patients undergoing hemodialysis.N Engl J Med360: 1395–1407, 2009 [[PubMed]
- 6. Vaziri ND, Moradi H, Pahl MV, Fogelman AM, Navab M.: In vitro stimulation of HDL anti-inflammatory activity and inhibition of LDL pro-inflammatory activity in the plasma of patients with end-stage renal disease by an apoA-1 mimetic peptide.Kidney Int76: 437–444, 2009
- 7. Zewinger S, Speer T, Kleber ME, Scharnagl H, Woitas R, Lepper PM, Pfahler K, Seiler S, Heine GH, März W, Silbernagel G, Fliser D.: HDL cholesterol is not associated with lower mortality in patients with kidney dysfunction.J Am Soc Nephrol25: 1073–1082, 2014
- 8. Holzer M, Birner-Gruenberger R, Stojakovic T, El-Gamal D, Binder V, Wadsack C, Heinemann A, Marsche G.: Uremia alters HDL composition and function.J Am Soc Nephrol22: 1631–1641, 2011
- 9. Weichhart T, Kopecky C, Kubicek M, Haidinger M, Döller D, Katholnig K, Suarna C, Eller P, Tölle M, Gerner C, Zlabinger GJ, van der Giet M, Hörl WH, Stocker R, Säemann MD.: Serum amyloid A in uremic HDL promotes inflammation.J Am Soc Nephrol23: 934–947, 2012
- 10. Mangé A, Goux A, Badiou S, Patrier L, Canaud B, Maudelonde T, Cristol JP, Solassol J.: HDL proteome in hemodialysis patients: A quantitative nanoflow liquid chromatography-tandem mass spectrometry approach.PLoS One7: e34107, 2012
- 11. Holzer M, Schilcher G, Curcic S, Trieb M, Ljubojevic S, Stojakovic T, Scharnagl H, Kopecky CM, Rosenkranz AR, Heinemann A, Marsche G.: Dialysis modalities and HDL composition and function.J Am Soc Nephrol26: 2267–2276, 2015
- 12. Shao B, de Boer I, Tang C, Mayer PS, Zelnick L, Afkarian M, Heinecke JW, Himmelfarb J.: A cluster of proteins implicated in kidney disease is increased in high-density lipoprotein isolated from hemodialysis subjects.J Proteome Res14: 2792–2806, 2015
- 13. Rubinow KB, Henderson CM, Robinson-Cohen C, Himmelfarb J, de Boer IH, Vaisar T, Kestenbaum B, Hoofnagle AN.: Kidney function is associated with an altered protein composition of high-density lipoprotein.Kidney Int92: 1526–1535, 2017
- 14. Dember LM, Imrey PB, Beck GJ, Cheung AK, Himmelfarb J, Huber TS, Kusek JW, Roy-Chaudhury P, Vazquez MA, Alpers CE, Robbin ML, Vita JA, Greene T, Gassman JJ, Feldman HI; Hemodialysis Fistula Maturation Study Group .: Objectives and design of the hemodialysis fistula maturation study.Am J Kidney Dis63: 104–112, 2014
- 15. Henderson CM, Vaisar T, Hoofnagle AN.: Isolating and quantifying plasma HDL proteins by sequential density gradient ultracentrifugation and targeted proteomics.Methods Mol Biol1410: 105–120, 2016
- 16. Hoofnagle AN, Becker JO, Oda MN, Cavigiolio G, Mayer P, Vaisar T.: Multiple-reaction monitoring-mass spectrometric assays can accurately measure the relative protein abundance in complex mixtures.Clin Chem58: 777–781, 2012
- 17. Marsillach J, Becker JO, Vaisar T, Hahn BH, Brunzell JD, Furlong CE, de Boer IH, McMahon MA, Hoofnagle AN; DCCT/EDIC Research Group .: Paraoxonase-3 is depleted from the high-density lipoproteins of autoimmune disease patients with subclinical atherosclerosis.J Proteome Res14: 2046–2054, 2015
- 18. de la Llera-Moya M, Drazul-Schrader D, Asztalos BF, Cuchel M, Rader DJ, Rothblat GH.: The ability to promote efflux via ABCA1 determines the capacity of serum specimens with similar high-density lipoprotein cholesterol to remove cholesterol from macrophages.Arterioscler Thromb Vasc Biol30: 796–801, 2010
- 19. Vaughan AM, Oram JF.: ABCA1 and ABCG1 or ABCG4 act sequentially to remove cellular cholesterol and generate cholesterol-rich HDL.J Lipid Res47: 2433–2443, 2006 [[PubMed]
- 20. Benjamini Y, Hochberg Y.: Controlling the false discovery rate: A practical and power approach to multiple testing.J R Stat Soc Series B Stat Methodol57: 289–300, 1995 [PubMed]
- 21. Zhernakova A, Kurilshikov A, Bonder MJ, Tigchelaar EF, Schirmer M, Vatanen T, Mujagic Z, Vila AV, Falony G, Vieira-Silva S, Wang J, Imhann F, Brandsma E, Jankipersadsing SA, Joossens M, Cenit MC, Deelen P, Swertz MA, Weersma RK, Feskens EJ, Netea MG, Gevers D, Jonkers D, Franke L, Aulchenko YS, Huttenhower C, Raes J, Hofker MH, Xavier RJ, Wijmenga C, Fu J; LifeLines cohort study .: Population-based metagenomics analysis reveals markers for gut microbiome composition and diversity.Science352: 565–569, 2016
- 22. Fu W, Browning SR, Browning BL, Akey JM.: Robust inference of identity by descent from exome-sequencing data.Am J Hum Genet99: 1106–1116, 2016
- 23. Storey JD, Tibshirani R.: Statistical significance for genomewide studies.Proc Natl Acad Sci U S A100: 9440–9445, 2003
- 24. Aulchenko YS, Ripke S, Isaacs A, van Duijn CM.: GenABEL: An R library for genome-wide association analysis.Bioinformatics23: 1294–1296, 2007 [[PubMed]
- 25. Pamir N, Hutchins P, Ronsein G, Vaisar T, Reardon CA, Getz GS, Lusis AJ, Heinecke JW.: Proteomic analysis of HDL from inbred mouse strains implicates APOE associated with HDL in reduced cholesterol efflux capacity via the ABCA1 pathway.J Lipid Res57: 246–257, 2016
- 26. Shah AS, Tan L, Long JL, Davidson WS.: Proteomic diversity of high density lipoproteins: Our emerging understanding of its importance in lipid transport and beyond.J Lipid Res54: 2575–2585, 2013
- 27. Khera AV, Cuchel M, de la Llera-Moya M, Rodrigues A, Burke MF, Jafri K, French BC, Phillips JA, Mucksavage ML, Wilensky RL, Mohler ER, Rothblat GH, Rader DJ.: Cholesterol efflux capacity, high-density lipoprotein function, and atherosclerosis.N Engl J Med364: 127–135, 2011
- 28. Baldán A, Pei L, Lee R, Tarr P, Tangirala RK, Weinstein MM, Frank J, Li AC, Tontonoz P, Edwards PA.: Impaired development of atherosclerosis in hyperlipidemic Ldlr-/- and ApoE-/- mice transplanted with Abcg1-/- bone marrow.Arterioscler Thromb Vasc Biol26: 2301–2307, 2006 [[PubMed]
- 29. Rohatgi A, de Lemos JA, Shaul PW.: HDL cholesterol efflux capacity and cardiovascular events.N Engl J Med372: 1871–1872, 2015 [[PubMed]
- 30. Yamamoto S, Yancey PG, Ikizler TA, Jerome WG, Kaseda R, Cox B, Bian A, Shintani A, Fogo AB, Linton MF, Fazio S, Kon V.: Dysfunctional high-density lipoprotein in patients on chronic hemodialysis.J Am Coll Cardiol60: 2372–2379, 2012 [[PubMed]
- 31. Kaseda R, Tsuchida Y, Yang HC, Yancey PG, Zhong J, Tao H, Bian A, Fogo AB, Linton MRF, Fazio S, Ikizler TA, Kon V.: Chronic kidney disease alters lipid trafficking and inflammatory responses in macrophages: Effects of liver X receptor agonism.BMC Nephrol19: 17, 2018
- 32. Memoli B, Libetta C, Rampino T, Dal Canton A, Conte G, Scala G, Ruocco MR, Andreucci VE.: Hemodialysis related induction of interleukin-6 production by peripheral blood mononuclear cells.Kidney Int42: 320–326, 1992 [[PubMed]
- 33. Pupim LB, Himmelfarb J, McMonagle E, Shyr Y, Ikizler TA.: Influence of initiation of maintenance hemodialysis on biomarkers of inflammation and oxidative stress.Kidney Int65: 2371–2379, 2004 [[PubMed]
- 34. Chenoweth DE, Cheung AK, Henderson LW.: Anaphylatoxin formation during hemodialysis: Effects of different dialyzer membranes.Kidney Int24: 764–769, 1983 [[PubMed]
- 35. Hakim RM, Fearon DT, Lazarus JM.: Biocompatibility of dialysis membranes: Effects of chronic complement activation.Kidney Int26: 194–200, 1984 [[PubMed]
- 36. He R, Sang H, Ye RD.: Serum amyloid A induces IL-8 secretion through a G protein-coupled receptor, FPRL1/LXA4R.Blood101: 1572–1581, 2003 [[PubMed]
- 37. Lee HY, Kim MK, Park KS, Shin EH, Jo SH, Kim SD, Jo EJ, Lee YN, Lee C, Baek SH, Bae YS.: Serum amyloid A induces contrary immune responses via formyl peptide receptor-like 1 in human monocytes.Mol Pharmacol70: 241–248, 2006 [[PubMed]
- 38. Kopecky C, Genser B, Drechsler C, Krane V, Kaltenecker CC, Hengstschläger M, März W, Wanner C, Säemann MD, Weichhart T.: Quantification of HDL proteins, cardiac events, and mortality in patients with type 2 diabetes on hemodialysis.Clin J Am Soc Nephrol10: 224–231, 2015
- 39. Kuivenhoven JA, Jukema JW, Zwinderman AH, de Knijff P, McPherson R, Bruschke AV, Lie KI, Kastelein JJ; The Regression Growth Evaluation Statin Study Group .: The role of a common variant of the cholesteryl ester transfer protein gene in the progression of coronary atherosclerosis.N Engl J Med338: 86–93, 1998 [[PubMed]
- 40. Kimura H, Gejyo F, Yamaguchi T, Suzuki S, Imura T, Miyazaki R, Arakawa M.: A cholesteryl ester transfer protein gene mutation and vascular disease in dialysis patients.J Am Soc Nephrol10: 294–299, 1999 [[PubMed]
- 41. Kimura H, Miyazaki R, Suzuki S, Gejyo F, Yoshida H.: Cholesteryl ester transfer protein as a protective factor against vascular disease in hemodialysis patients.Am J Kidney Dis38: 70–76, 2001 [[PubMed]
- 42. Lie J, de Crom R, van Gent T, van Haperen R, Scheek L, Sadeghi-Niaraki F, van Tol A.: Elevation of plasma phospholipid transfer protein increases the risk of atherosclerosis despite lower apolipoprotein B-containing lipoproteins.J Lipid Res45: 805–811, 2004 [[PubMed]
- 43. Robins SJ, Lyass A, Brocia RW, Massaro JM, Vasan RS.: Plasma lipid transfer proteins and cardiovascular disease. The Framingham Heart Study.Atherosclerosis228: 230–236, 2013
- 44. Vaziri ND: HDL abnormalities in nephrotic syndrome and chronic kidney disease.Nat Rev Nephrol12: 37–47, 2016 [[PubMed]
- 45. Kwan BC, Kronenberg F, Beddhu S, Cheung AK.: Lipoprotein metabolism and lipid management in chronic kidney disease.J Am Soc Nephrol18: 1246–1261, 2007 [[PubMed]
- 46. Vaisar T, Pennathur S, Green PS, Gharib SA, Hoofnagle AN, Cheung MC, Byun J, Vuletic S, Kassim S, Singh P, Chea H, Knopp RH, Brunzell J, Geary R, Chait A, Zhao XQ, Elkon K, Marcovina S, Ridker P, Oram JF, Heinecke JW.: Shotgun proteomics implicates protease inhibition and complement activation in the antiinflammatory properties of HDL.J Clin Invest117: 746–756, 2007
- 47. Mooijaart SP, Berbée JF, van Heemst D, Havekes LM, de Craen AJ, Slagboom PE, Rensen PC, Westendorp RG.: ApoE plasma levels and risk of cardiovascular mortality in old age.PLoS Med3: e176, 2006
- 48. Watanabe J, Chou KJ, Liao JC, Miao Y, Meng HH, Ge H, Grijalva V, Hama S, Kozak K, Buga G, Whitelegge JP, Lee TD, Farias-Eisner R, Navab M, Fogelman AM, Reddy ST.: Differential association of hemoglobin with proinflammatory high density lipoproteins in atherogenic/hyperlipidemic mice. A novel biomarker of atherosclerosis.J Biol Chem282: 23698–23707, 2007 [[PubMed]
- 49. Watanabe J, Grijalva V, Hama S, Barbour K, Berger FG, Navab M, Fogelman AM, Reddy ST.: Hemoglobin and its scavenger protein haptoglobin associate with apoA-1-containing particles and influence the inflammatory properties and function of high density lipoprotein.J Biol Chem284: 18292–18301, 2009