www.jasn.org
underway (Study of Diabetic Nephropathy with Atrasentan [SONAR]). However, for ET blockers to realize their potential, further information must be obtained regarding the basic mechanisms of how and when they work. An incremental advance is the study by Lenoir et al., which demonstrates that the ETB receptor may need to be targeted as well to maximize renal protection in diabetic nephropathy. However, because of the adverse effect profile related to ETB blockade (particularly the sodium retention), basic research elucidating the mechanisms involved in ET–blockade-induced adverse effects is needed so that better strategies can be devised to correct or override them, and as a result provide a more favorable risk/benefit profile. In summary, there is a critical need to develop additional therapies to improve the treatment of diabetic nephropathy; ET antagonists hold considerable promise. However, for this promise to be fulfilled, researchers must continue to identify the basic mechanisms by which ET-1 contributes to diabetic nephropathy, as well as the mechanisms of adverse effects induced by ET antagonists. Despite the vast volume of basic research on the ET system, the clinical trials have just emphasized the need to return to the bench to further our understanding of its fundamental mechanisms. This is important for the development of maximally effective therapeutic strategies with minimal adverse effects. ACKNOWLEDGMENTS L.A.J. is supported in part by the National Institute of General Medical Sciences of the National Institutes of Health under award number P20-GM104357 and by the John D. Bower Foundation.
DISCLOSURESS L.A.J. is a regional investigator in the SONAR study, which evaluates the effect of atrasentan (a selective ETA receptor blocker on the progression of diabetic nephropathy).
REFERENCES 1. Yanagisawa M, Kurihara H, Kimura S, Tomobe Y, Kobayashi M, Mitsui Y, Yazaki Y, Goto K, Masaki T: A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature 332: 411–415, 1988 2. Barton M, Yanagisawa M: Endothelin: 20 years from discovery to therapy. Can J Physiol Pharmacol 86: 485–498, 2008 3. Lüscher TF, Barton M: Endothelins and endothelin receptor antagonists: Therapeutic considerations for a novel class of cardiovascular drugs. Circulation 102: 2434–2440, 2000 4. Speed JS, Pollock DM: Endothelin, kidney disease, and hypertension. Hypertension 61: 1142–1145, 2013 5. Kitamura K, Tanaka T, Kato J, Eto T, Tanaka K: Regional distribution of immunoreactive endothelin in porcine tissue: Abundance in inner medulla of kidney. Biochem Biophys Res Commun 161: 348–352, 1989 6. Kohan DE: The renal medullary endothelin system in control of sodium and water excretion and systemic blood pressure. Curr Opin Nephrol Hypertens 15: 34–40, 2006 7. Kohan DE, Pollock DM: Endothelin antagonists for diabetic and nondiabetic chronic kidney disease. Br J Clin Pharmacol 76: 573–579, 2013
J Am Soc Nephrol 25: 865–874, 2014
EDITORIALS
8. Hocher B, Schwarz A, Reinbacher D, Jacobi J, Lun A, Priem F, Bauer C, Neumayer HH, Raschack M: Effects of endothelin receptor antagonists on the progression of diabetic nephropathy. Nephron 87: 161–169, 2001 9. Benz K, Amann K: Endothelin in diabetic renal disease. Contrib Nephrol 172: 139–148, 2011 10. Takahashi K, Ghatei MA, Lam HC, O’Halloran DJ, Bloom SR: Elevated plasma endothelin in patients with diabetes mellitus. Diabetologia 33: 306–310, 1990 11. Barton M: Therapeutic potential of endothelin receptor antagonists for chronic proteinuric renal disease in humans. Biochim Biophys Acta 1802: 1203–1213, 2010 12. Saleh MA, Pollock JS, Pollock DM: Distinct actions of endothelin A-selective versus combined endothelin A/B receptor antagonists in early diabetic kidney disease. J Pharmacol Exp Ther 338: 263–270, 2011 13. Kohan DE, Pritchett Y, Molitch M, Wen S, Garimella T, Audhya P, Andress DL: Addition of atrasentan to renin-angiotensin system blockade reduces albuminuria in diabetic nephropathy. J Am Soc Nephrol 22: 763–772, 2011 14. Lenoir O, Milon M, Virsolvy A, Hénique C, Schmitt A, Massé JM, Kotelevtsev Y, Yanagisawa M, Webb DJ, Richard S, Tharaux PL: Direct action of endothelin-1 on podocytes promotes diabetic glomerulosclerosis. J Am Soc Nephrol 25: 1050–1062, 2014 15. Mann JF, Green D, Jamerson K, Ruilope LM, Kuranoff SJ, Littke T, Viberti G, Group AS; ASCEND Study Group: Avosentan for overt diabetic nephropathy. J Am Soc Nephrol 21: 527–535, 2010 16. Kohan DE, Cleland JG, Rubin LJ, Theodorescu D, Barton M: Clinical trials with endothelin receptor antagonists: What went wrong and where can we improve? Life Sci 91: 528–539, 2012 17. de Zeeuw D, Coll B, Andress D, Brennan JJ, Tang H, Houser M, CorreaRotter R, Kohan D, Lambers, Heerspink HJ, Makino H, Perkovic V, Pritchett Y, Remuzzi G, Tobe SW, Toto R, Viberti G, Parving HH: The endothelin antagonist atrasentan lowers residual albuminuria in patients with type 2 diabetic nephropathy. J Am Soc Nephrol 25: 1083–1093, 2014 18. Rubio DM, Schoenbaum EE, Lee LS, Schteingart DE, Marantz PR, Anderson KE, Platt LD, Baez A, Esposito K: Defining translational research: Implications for training. Acad Med 85: 470–475, 2010
See related articles, “Direct Action of Endothelin-1 on Podocytes Promotes Diabetic Glomerulosclerosis,” and “The Endothelin Antagonist Atrasentan Lowers Residual Albuminuria in Patients with Type 2 Diabetic Nephropathy,” on pages 1050–1062 and 1073–1083, respectively.
HDL in CKD: How Good Is the “Good Cholesterol?” Ian H. de Boer*† and John D. Brunzell‡ Divisions of *Nephrology and ‡Metabolism, Endocrinology, and Nutrition, Department of Medicine, and †Kidney Research Institute, University of Washington, Seattle, Washington J Am Soc Nephrol 25: 871–874, 2014. doi: 10.1681/ASN.2014010062
Published online ahead of print. Publication date available at www.jasn.org. Correspondence: Dr. Ian de Boer, Division of Nephrology and Kidney Research Institute, Department of Medicine, University of Washington, Box 359606, 325 Ninth Avenue, Seattle, WA 98104. Email: [email protected] Copyright © 2014 by the American Society of Nephrology
Editorials
871
EDITORIALS
www.jasn.org
In this issue of JASN, Zewinger et al. report that associations of HDL cholesterol (HDL-C) with cardiovascular and all-cause mortality are modified by eGFR.1 The study was performed among 3316 participants in the Ludwigshafen Risk and Cardiovascular Health study, a cohort study of patients referred for coronary angiography in Germany. Among 1209 participants with an eGFR$90 ml/min per 1.73 m2 (calculated from serum creatinine and cystatin C), baseline HDL-C$50 mg/dl was associated with a 70% lower risk of cardiovascular mortality (adjusted hazard ratio, 0.30; 95% confidence interval, 0.13 to 0.73) compared with HDL-C#25 mg/dl. By contrast, among 456 participants with an eGFR,60, HDL-C was not associated with subsequent cardiovascular events (comparing HDL-C$50 mg/dl with HDL-C#25 mg/dl: adjusted hazard ratio, 0.82; 95% confidence interval, 0.40 to 1.69). The interaction of eGFR with HDL-C was statistically significant (P50.02). Zewinger et al. propose that HDL particles, which are generally thought to be atheroprotective, are rendered dysfunctional in CKD. This is an important and intriguing hypothesis that needs further experimentation. In the general population, higher plasma concentrations of HDL-C have long been known to be associated with a reduced risk of atherosclerotic cardiovascular diseases.2 This association may be causal in nature. HDL plays a key role in reverse cholesterol transport, in which cholesterol is removed from macrophages in the vascular wall to HDL particles via transporters such as ATP-binding cassette transporter A1. HDL may also have additional protective functions, including moderation of inflammation and oxidative stress in the vascular wall.3 However, recent studies have made it clear that raising the plasma HDL-C concentration does not necessarily reduce cardiovascular risk. For example, torcetrapib and niacin effectively raise HDL-C by reducing hepatic HDL catabolism, torcetrapib by inhibiting cholesteryl ester transfer protein (CETP), and niacin by inhibiting hepatic lipase.4 However, in phase 3 clinical trials, extended-release niacin did not reduce the rate of cardiovascular events when added to simvastatin and ezetimibe, and torcetrapib actually increased the risk of cardiovascular morbidity and mortality.5,6 In addition, genetic variants associated with a higher HDL-C concentration are not associated with a reduced risk of cardiovascular disease.7 With these studies, the field of HDL and cardiovascular disease has focused increasingly on HDL quality, as opposed to HDL quantity. HDL particles are complexes of lipid and protein that are formed and modified through complex interactions with the liver, vascular wall, and other lipoproteins, generally mediated by specific enzymes. The quality of these complex particles has been evaluated in three inter-related dimensions: size, composition, and function. Abundant evidence addressing these aspects of HDL quality suggests that not all “good cholesterol” is equally good. First, epidemiologic studies suggest that large, buoyant HDL particles, subclassified as HDL2, are most strongly associated with favorable cardiovascular outcomes.8 HDL2 particles are formed from smaller, denser HDL3 particles by the 872
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transfer of cholesterol and phospholipid from cells (by ATPbinding cassette transporter A1, such as during reverse cholesterol transport) and triglyceride-rich lipoproteins. Removal of cholesterol from HDL2 to the liver by CETP and hepatic lipase then recycles these particles to HDL3. By analogy, HDL is a “garbage truck” that picks up lipid debris and brings it to the liver for disposal. Under most circumstances, a high HDL2 concentration reflects a well maintained fleet of trucks actively engaged in clean-up. However, raising HDL2 by preventing it from dumping its greasy load (e.g., by pharmacologic inhibition of CETP or hepatic lipase) may not be beneficial and may even be harmful. Second, HDL particles vary in their protein and lipid composition. In addition to proteins necessary for HDL to interact with the vascular wall and other lipoproteins, HDL particles contain dozens of proteins related to complement regulation, proteolysis, and the acute-phase response.9 Various species of free cholesterol, cholesterol esters, phospholipids, and triglycerides are also present in variable proportions.10 To some extent, the “cargo load” of HDL proteins and lipids may reflect what it has picked up from the vascular wall. In addition, this cargo may alter the actions of HDL. Third, HDL particles vary in their functional capacity. Reduced HDL-mediated efflux of cholesterol from macrophages ex vivo has been associated with coronary artery disease in humans.11 Differences in other HDL functions, such as modulation of inflammation and oxidative stress, are less well developed. Patients with CKD tend to have alterations in both HDL quantity and HDL quality. Even a mildly impaired GFR is associated with low HDL-C concentrations, which become progressively worse through ESRD.12,13 Moreover, with CKD, HDL tends to be smaller and denser, due in part to decreased adipose tissue lipoprotein lipase activity.14 In addition, Holzer et al. found significant differences in both protein and lipid composition of HDL particles isolated from 27 hemodialysis patients compared with HDL isolated from 19 normal control participants.15 HDL from hemodialysis patients did not remove cholesterol from macrophages ex vivo as effectively as HDL from control participants. Serum amyloid A-1, albumin, and apolipoprotein C3 in the HDL of dialysis patients negatively correlated with cholesterol efflux, suggesting that HDL composition may affect HDL function. Speer et al. found that HDL isolated from 67 patients with CKD reduced nitric oxide production from human aortic endothelial cells ex vivo, in contrast with HDL from 25 normal controls that increased nitric oxide.16 HDL from patients with CKD contained high levels of symmetric dimethylarginine, and the addition of symmetric dimethylarginine to HDL induced endothelial dysfunction. The studies by Holzer et al. and Speer et al. are limited by small samples of patients from single sites, comparisons with control participants who differ in terms of age, comorbidity, or medication use, and the absence of clinical outcomes. Nonetheless, these studies identified HDL abnormalities that may be of great importance. In this context, the article by Zewinger et al. serves as a motivating study to further investigate lipoprotein J Am Soc Nephrol 25: 865–874, 2014
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metabolism and its clinical consequences in CKD. The null association of HDL-C with cardiovascular mortality among participants with an eGFR,60 ml/min per 1.73 m2 is consistent with the hypothesis that HDL particles are rendered dysfunctional in some manner in CKD. However, without data relating HDL composition or function to cardiovascular outcomes, this hypothesis remains untested. Other potential explanations for the interaction of HDL-C and eGFR include differences by eGFR in the range of HDL-C, the functional form of the association of HDL-C with mortality, confounders of the HDL-C–mortality association, the relationship of HDLC to other lipoproteins (e.g., atherogenic small, dense LDL particles17), or the nature of the observed cardiovascular events (e.g., a greater incidence of nonatherosclerotic cardiovascular deaths that are less strongly related to lipoproteins). Moreover, although the null association of HDL-C with mortality in the Ludwigshafen Risk and Cardiovascular Health study replicated in a smaller CKD cohort, apparently conflicting results have also been reported. In the Multi-Ethnic Study of Atherosclerosis, the association of lower HDL-C with carotid intima-media thickness strengthened with a lower eGFR (as did the association of small, dense LDL with intima-media thickness).18 Dissecting the complex interplay of HDL-C, HDL size, HDL composition, and HDL function with cardiovascular disease therefore needs further investigation. Moving research on HDL and cardiovascular disease in CKD forward will require studies that apply innovative assays of HDL quality using strong epidemiology designs. Such studies will require the following: large populations with external validation (as presented by Zewinger et al.); reliable measurements of HDL size, composition, and function; relevant measurements of vascular function in vivo or evaluation of clinical cardiovascular events; an ability to account for aspects of lipoprotein protein metabolism related to HDL (particularly differences in LDL size and density); and adequate consideration of the effects of common lipid-lowering medications, ideally further investigating the effects of these medications on HDL composition and function. Clinically, accumulating data, including those from Zewinger et al., suggest that HDL-C should not be used as a guide to therapy in patients with CKD. Indeed, recent Kidney Disease: Improving Global Outcomes (KDIGO) guidelines recommend that statins be prescribed with little regard to any circulating cholesterol concentrations, utilizing a “fire-andforget” strategy for patients with CKD not requiring dialysis in which neither LDL cholesterol nor HDL-C is used as a major therapeutic target.19 These findings follow the design and results of the Study of Heart and Renal Protection, in which a combination of simvastatin and ezetimibe reduced the risk of atherosclerotic cardiovascular events in CKD.20 KDIGO does not advocate any specific therapies based on HDL-C, a position congruent with that of the National Lipid Association.21 HDL may become a therapeutic target in CKD, but much additional work is needed to determine whether and how that should occur. J Am Soc Nephrol 25: 865–874, 2014
EDITORIALS
ACKNOWLEDGMENTS I.H.d.B. receives grant funding from the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases (R01-DK087726, R01-DK088762) and the National Heart, Lung, and Blood Institute (R01-HL096875).
DISCLOSURESS None.
REFERENCES 1. Zewinger S, Speer T, Kleber ME, Scharnagl H, Woitas R, Lepper PM, Pfahler K, Seiler S, Heine GH, Marz W, Silbernagel G, Fliser D: HDLcholesterol is not associated with lower mortality. J Am Soc Nephrol 25: 1073–1082, 2014 2. Gordon T, Castelli WP, Hjortland MC, Kannel WB, Dawber TR: High density lipoprotein as a protective factor against coronary heart disease. The Framingham Study. Am J Med 62: 707–714, 1977 3. Rye KA, Barter PJ: Cardioprotective functions of HDL. J Lipid Res 55: 168–179, 2014 4. Brunzell JD, Zambon A, Deeb SS: The effect of hepatic lipase on coronary artery disease in humans is influenced by the underlying lipoprotein phenotype. Biochim Biophys Acta 1821: 365–372, 2012 5. Barter PJ, Caulfield M, Eriksson M, Grundy SM, Kastelein JJ, Komajda M, Lopez-Sendon J, Mosca L, Tardif JC, Waters DD, Shear CL, Revkin JH, Buhr KA, Fisher MR, Tall AR, Brewer B; ILLUMINATE Investigators: Effects of torcetrapib in patients at high risk for coronary events. N Engl J Med 357: 2109–2122, 2007 6. Boden WE, Probstfield JL, Anderson T, Chaitman BR, DesvignesNickens P, Koprowicz K, McBride R, Teo K, Weintraub W; AIM-HIGH Investigators: Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med 365: 2255–2267, 2011 7. Voight BF, Peloso GM, Orho-Melander M, Frikke-Schmidt R, Barbalic M, Jensen MK, Hindy G, Hólm H, Ding EL, Johnson T, Schunkert H, Samani NJ, Clarke R, Hopewell JC, Thompson JF, Li M, Thorleifsson G, Newton-Cheh C, Musunuru K, Pirruccello JP, Saleheen D, Chen L, Stewart A, Schillert A, Thorsteinsdottir U, Thorgeirsson G, Anand S, Engert JC, Morgan T, Spertus J, Stoll M, Berger K, Martinelli N, Girelli D, McKeown PP, Patterson CC, Epstein SE, Devaney J, Burnett MS, Mooser V, Ripatti S, Surakka I, Nieminen MS, Sinisalo J, Lokki ML, Perola M, Havulinna A, de Faire U, Gigante B, Ingelsson E, Zeller T, Wild P, de Bakker PI, Klungel OH, Maitland-van der Zee AH, Peters BJ, de Boer A, Grobbee DE, Kamphuisen PW, Deneer VH, Elbers CC, Onland-Moret NC, Hofker MH, Wijmenga C, Verschuren WM, Boer JM, van der Schouw YT, Rasheed A, Frossard P, Demissie S, Willer C, Do R, Ordovas JM, Abecasis GR, Boehnke M, Mohlke KL, Daly MJ, Guiducci C, Burtt NP, Surti A, Gonzalez E, Purcell S, Gabriel S, Marrugat J, Peden J, Erdmann J, Diemert P, Willenborg C, König IR, Fischer M, Hengstenberg C, Ziegler A, Buysschaert I, Lambrechts D, Van de Werf F, Fox KA, El Mokhtari NE, Rubin D, Schrezenmeir J, Schreiber S, Schäfer A, Danesh J, Blankenberg S, Roberts R, McPherson R, Watkins H, Hall AS, Overvad K, Rimm E, Boerwinkle E, Tybjaerg-Hansen A, Cupples LA, Reilly MP, Melander O, Mannucci PM, Ardissino D, Siscovick D, Elosua R, Stefansson K, O’Donnell CJ, Salomaa V, Rader DJ, Peltonen L, Schwartz SM, Altshuler D, Kathiresan S: Plasma HDL cholesterol and risk of myocardial infarction: A mendelian randomisation study. Lancet 380: 572–580, 2012 8. Lamarche B, Moorjani S, Cantin B, Dagenais GR, Lupien PJ, Després JP: Associations of HDL2 and HDL3 subfractions with ischemic heart disease in men. Prospective results from the Québec Cardiovascular Study. Arterioscler Thromb Vasc Biol 17: 1098–1105, 1997
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9. 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 Invest 117: 746–756, 2007 10. Yetukuri L, Söderlund S, Koivuniemi A, Seppänen-Laakso T, Niemelä PS, Hyvönen M, Taskinen MR, Vattulainen I, Jauhiainen M, Oresic M: Composition and lipid spatial distribution of HDL particles in subjects with low and high HDL-cholesterol. J Lipid Res 51: 2341–2351, 2010 11. 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 Med 364: 127–135, 2011 12. 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 Nephrol 3: 125–132, 2008 13. Attman PO, Samuelsson O, Alaupovic P: Lipoprotein metabolism and renal failure. Am J Kidney Dis 21: 573–592, 1993 14. Joven J, Vilella E, Ahmad S, Cheung MC, Brunzell JD: Lipoprotein heterogeneity in end-stage renal disease. Kidney Int 43: 410–418, 1993 15. 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 Nephrol 22: 1631–1641, 2011 16. Speer T, Rohrer L, Blyszczuk P, Shroff R, Kuschnerus K, Kränkel N, Kania G, Zewinger S, Akhmedov A, Shi Y, Martin T, Perisa D, Winnik S, Müller MF, Sester U, Wernicke G, Jung A, Gutteck U, Eriksson U, Geisel J, Deanfield J, von Eckardstein A, Lüscher TF, Fliser D, Bahlmann FH, Landmesser U: Abnormal high-density lipoprotein induces endothelial dysfunction via activation of Toll-like receptor-2. Immunity 38: 754– 768, 2013
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17. Lamarche B, Tchernof A, Moorjani S, Cantin B, Dagenais GR, Lupien PJ, Després JP: Small, dense low-density lipoprotein particles as a predictor of the risk of ischemic heart disease in men. Prospective results from the Québec Cardiovascular Study. Circulation 95: 69–75, 1997 18. Lamprea-Montealegre JA, Astor BC, McClelland RL, de Boer IH, Burke GL, Sibley CT, O’Leary D, Sharrett AR, Szklo M: CKD, plasma lipids, and common carotid intima-media thickness: Results from the Multi-Ethnic Study of Atherosclerosis. Clin J Am Soc Nephrol 7: 1777–1785, 2012 19. Kidney Disease Improving Global Outcomes (KDIGO): KDIGO clinical practice guideline for lipid management in chronic kidney disease. Kidney Int Suppl 3: 259–305, 2013 20. Baigent C, Landray MJ, Reith C, Emberson J, Wheeler DC, Tomson C, Wanner C, Krane V, Cass A, Craig J, Neal B, Jiang L, Hooi LS, Levin A, Agodoa L, Gaziano M, Kasiske B, Walker R, Massy ZA, Feldt-Rasmussen B, Krairittichai U, Ophascharoensuk V, Fellström B, Holdaas H, Tesar V, Wiecek A, Grobbee D, de Zeeuw D, Grönhagen-Riska C, Dasgupta T, Lewis D, Herrington W, Mafham M, Majoni W, Wallendszus K, Grimm R, Pedersen T, Tobert J, Armitage J, Baxter A, Bray C, Chen Y, Chen Z, Hill M, Knott C, Parish S, Simpson D, Sleight P, Young A, Collins R; SHARP Investigators: The effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (Study of Heart and Renal Protection): A randomised placebo-controlled trial. Lancet 377: 2181–2192, 2011 21. Toth PP, Barter PJ, Rosenson RS, Boden WE, Chapman MJ, Cuchel M, D’Agostino RB Sr, Davidson MH, Davidson WS, Heinecke JW, Karas RH, Kontush A, Krauss RM, Miller M, Rader DJ: High-density lipoproteins: A consensus statement from the National Lipid Association. J Clin Lipidol 7: 484–525, 2013
See related article, “HDL Cholesterol Is Not Associated with Lower Mortality in Patients with Kidney Dysfunction,” on pages 1073–1082.
J Am Soc Nephrol 25: 865–874, 2014
underway (Study of Diabetic Nephropathy with Atrasentan [SONAR]). However, for ET blockers to realize their potential, further information must be obtained regarding the basic mechanisms of how and when they work. An incremental advance is the study by Lenoir et al., which demonstrates that the ETB receptor may need to be targeted as well to maximize renal protection in diabetic nephropathy. However, because of the adverse effect profile related to ETB blockade (particularly the sodium retention), basic research elucidating the mechanisms involved in ET–blockade-induced adverse effects is needed so that better strategies can be devised to correct or override them, and as a result provide a more favorable risk/benefit profile. In summary, there is a critical need to develop additional therapies to improve the treatment of diabetic nephropathy; ET antagonists hold considerable promise. However, for this promise to be fulfilled, researchers must continue to identify the basic mechanisms by which ET-1 contributes to diabetic nephropathy, as well as the mechanisms of adverse effects induced by ET antagonists. Despite the vast volume of basic research on the ET system, the clinical trials have just emphasized the need to return to the bench to further our understanding of its fundamental mechanisms. This is important for the development of maximally effective therapeutic strategies with minimal adverse effects. ACKNOWLEDGMENTS L.A.J. is supported in part by the National Institute of General Medical Sciences of the National Institutes of Health under award number P20-GM104357 and by the John D. Bower Foundation.
DISCLOSURESS L.A.J. is a regional investigator in the SONAR study, which evaluates the effect of atrasentan (a selective ETA receptor blocker on the progression of diabetic nephropathy).
REFERENCES 1. Yanagisawa M, Kurihara H, Kimura S, Tomobe Y, Kobayashi M, Mitsui Y, Yazaki Y, Goto K, Masaki T: A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature 332: 411–415, 1988 2. Barton M, Yanagisawa M: Endothelin: 20 years from discovery to therapy. Can J Physiol Pharmacol 86: 485–498, 2008 3. Lüscher TF, Barton M: Endothelins and endothelin receptor antagonists: Therapeutic considerations for a novel class of cardiovascular drugs. Circulation 102: 2434–2440, 2000 4. Speed JS, Pollock DM: Endothelin, kidney disease, and hypertension. Hypertension 61: 1142–1145, 2013 5. Kitamura K, Tanaka T, Kato J, Eto T, Tanaka K: Regional distribution of immunoreactive endothelin in porcine tissue: Abundance in inner medulla of kidney. Biochem Biophys Res Commun 161: 348–352, 1989 6. Kohan DE: The renal medullary endothelin system in control of sodium and water excretion and systemic blood pressure. Curr Opin Nephrol Hypertens 15: 34–40, 2006 7. Kohan DE, Pollock DM: Endothelin antagonists for diabetic and nondiabetic chronic kidney disease. Br J Clin Pharmacol 76: 573–579, 2013
J Am Soc Nephrol 25: 865–874, 2014
EDITORIALS
8. Hocher B, Schwarz A, Reinbacher D, Jacobi J, Lun A, Priem F, Bauer C, Neumayer HH, Raschack M: Effects of endothelin receptor antagonists on the progression of diabetic nephropathy. Nephron 87: 161–169, 2001 9. Benz K, Amann K: Endothelin in diabetic renal disease. Contrib Nephrol 172: 139–148, 2011 10. Takahashi K, Ghatei MA, Lam HC, O’Halloran DJ, Bloom SR: Elevated plasma endothelin in patients with diabetes mellitus. Diabetologia 33: 306–310, 1990 11. Barton M: Therapeutic potential of endothelin receptor antagonists for chronic proteinuric renal disease in humans. Biochim Biophys Acta 1802: 1203–1213, 2010 12. Saleh MA, Pollock JS, Pollock DM: Distinct actions of endothelin A-selective versus combined endothelin A/B receptor antagonists in early diabetic kidney disease. J Pharmacol Exp Ther 338: 263–270, 2011 13. Kohan DE, Pritchett Y, Molitch M, Wen S, Garimella T, Audhya P, Andress DL: Addition of atrasentan to renin-angiotensin system blockade reduces albuminuria in diabetic nephropathy. J Am Soc Nephrol 22: 763–772, 2011 14. Lenoir O, Milon M, Virsolvy A, Hénique C, Schmitt A, Massé JM, Kotelevtsev Y, Yanagisawa M, Webb DJ, Richard S, Tharaux PL: Direct action of endothelin-1 on podocytes promotes diabetic glomerulosclerosis. J Am Soc Nephrol 25: 1050–1062, 2014 15. Mann JF, Green D, Jamerson K, Ruilope LM, Kuranoff SJ, Littke T, Viberti G, Group AS; ASCEND Study Group: Avosentan for overt diabetic nephropathy. J Am Soc Nephrol 21: 527–535, 2010 16. Kohan DE, Cleland JG, Rubin LJ, Theodorescu D, Barton M: Clinical trials with endothelin receptor antagonists: What went wrong and where can we improve? Life Sci 91: 528–539, 2012 17. de Zeeuw D, Coll B, Andress D, Brennan JJ, Tang H, Houser M, CorreaRotter R, Kohan D, Lambers, Heerspink HJ, Makino H, Perkovic V, Pritchett Y, Remuzzi G, Tobe SW, Toto R, Viberti G, Parving HH: The endothelin antagonist atrasentan lowers residual albuminuria in patients with type 2 diabetic nephropathy. J Am Soc Nephrol 25: 1083–1093, 2014 18. Rubio DM, Schoenbaum EE, Lee LS, Schteingart DE, Marantz PR, Anderson KE, Platt LD, Baez A, Esposito K: Defining translational research: Implications for training. Acad Med 85: 470–475, 2010
See related articles, “Direct Action of Endothelin-1 on Podocytes Promotes Diabetic Glomerulosclerosis,” and “The Endothelin Antagonist Atrasentan Lowers Residual Albuminuria in Patients with Type 2 Diabetic Nephropathy,” on pages 1050–1062 and 1073–1083, respectively.
HDL in CKD: How Good Is the “Good Cholesterol?” Ian H. de Boer*† and John D. Brunzell‡ Divisions of *Nephrology and ‡Metabolism, Endocrinology, and Nutrition, Department of Medicine, and †Kidney Research Institute, University of Washington, Seattle, Washington J Am Soc Nephrol 25: 871–874, 2014. doi: 10.1681/ASN.2014010062
Published online ahead of print. Publication date available at www.jasn.org. Correspondence: Dr. Ian de Boer, Division of Nephrology and Kidney Research Institute, Department of Medicine, University of Washington, Box 359606, 325 Ninth Avenue, Seattle, WA 98104. Email: [email protected] Copyright © 2014 by the American Society of Nephrology
Editorials
871
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In this issue of JASN, Zewinger et al. report that associations of HDL cholesterol (HDL-C) with cardiovascular and all-cause mortality are modified by eGFR.1 The study was performed among 3316 participants in the Ludwigshafen Risk and Cardiovascular Health study, a cohort study of patients referred for coronary angiography in Germany. Among 1209 participants with an eGFR$90 ml/min per 1.73 m2 (calculated from serum creatinine and cystatin C), baseline HDL-C$50 mg/dl was associated with a 70% lower risk of cardiovascular mortality (adjusted hazard ratio, 0.30; 95% confidence interval, 0.13 to 0.73) compared with HDL-C#25 mg/dl. By contrast, among 456 participants with an eGFR,60, HDL-C was not associated with subsequent cardiovascular events (comparing HDL-C$50 mg/dl with HDL-C#25 mg/dl: adjusted hazard ratio, 0.82; 95% confidence interval, 0.40 to 1.69). The interaction of eGFR with HDL-C was statistically significant (P50.02). Zewinger et al. propose that HDL particles, which are generally thought to be atheroprotective, are rendered dysfunctional in CKD. This is an important and intriguing hypothesis that needs further experimentation. In the general population, higher plasma concentrations of HDL-C have long been known to be associated with a reduced risk of atherosclerotic cardiovascular diseases.2 This association may be causal in nature. HDL plays a key role in reverse cholesterol transport, in which cholesterol is removed from macrophages in the vascular wall to HDL particles via transporters such as ATP-binding cassette transporter A1. HDL may also have additional protective functions, including moderation of inflammation and oxidative stress in the vascular wall.3 However, recent studies have made it clear that raising the plasma HDL-C concentration does not necessarily reduce cardiovascular risk. For example, torcetrapib and niacin effectively raise HDL-C by reducing hepatic HDL catabolism, torcetrapib by inhibiting cholesteryl ester transfer protein (CETP), and niacin by inhibiting hepatic lipase.4 However, in phase 3 clinical trials, extended-release niacin did not reduce the rate of cardiovascular events when added to simvastatin and ezetimibe, and torcetrapib actually increased the risk of cardiovascular morbidity and mortality.5,6 In addition, genetic variants associated with a higher HDL-C concentration are not associated with a reduced risk of cardiovascular disease.7 With these studies, the field of HDL and cardiovascular disease has focused increasingly on HDL quality, as opposed to HDL quantity. HDL particles are complexes of lipid and protein that are formed and modified through complex interactions with the liver, vascular wall, and other lipoproteins, generally mediated by specific enzymes. The quality of these complex particles has been evaluated in three inter-related dimensions: size, composition, and function. Abundant evidence addressing these aspects of HDL quality suggests that not all “good cholesterol” is equally good. First, epidemiologic studies suggest that large, buoyant HDL particles, subclassified as HDL2, are most strongly associated with favorable cardiovascular outcomes.8 HDL2 particles are formed from smaller, denser HDL3 particles by the 872
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transfer of cholesterol and phospholipid from cells (by ATPbinding cassette transporter A1, such as during reverse cholesterol transport) and triglyceride-rich lipoproteins. Removal of cholesterol from HDL2 to the liver by CETP and hepatic lipase then recycles these particles to HDL3. By analogy, HDL is a “garbage truck” that picks up lipid debris and brings it to the liver for disposal. Under most circumstances, a high HDL2 concentration reflects a well maintained fleet of trucks actively engaged in clean-up. However, raising HDL2 by preventing it from dumping its greasy load (e.g., by pharmacologic inhibition of CETP or hepatic lipase) may not be beneficial and may even be harmful. Second, HDL particles vary in their protein and lipid composition. In addition to proteins necessary for HDL to interact with the vascular wall and other lipoproteins, HDL particles contain dozens of proteins related to complement regulation, proteolysis, and the acute-phase response.9 Various species of free cholesterol, cholesterol esters, phospholipids, and triglycerides are also present in variable proportions.10 To some extent, the “cargo load” of HDL proteins and lipids may reflect what it has picked up from the vascular wall. In addition, this cargo may alter the actions of HDL. Third, HDL particles vary in their functional capacity. Reduced HDL-mediated efflux of cholesterol from macrophages ex vivo has been associated with coronary artery disease in humans.11 Differences in other HDL functions, such as modulation of inflammation and oxidative stress, are less well developed. Patients with CKD tend to have alterations in both HDL quantity and HDL quality. Even a mildly impaired GFR is associated with low HDL-C concentrations, which become progressively worse through ESRD.12,13 Moreover, with CKD, HDL tends to be smaller and denser, due in part to decreased adipose tissue lipoprotein lipase activity.14 In addition, Holzer et al. found significant differences in both protein and lipid composition of HDL particles isolated from 27 hemodialysis patients compared with HDL isolated from 19 normal control participants.15 HDL from hemodialysis patients did not remove cholesterol from macrophages ex vivo as effectively as HDL from control participants. Serum amyloid A-1, albumin, and apolipoprotein C3 in the HDL of dialysis patients negatively correlated with cholesterol efflux, suggesting that HDL composition may affect HDL function. Speer et al. found that HDL isolated from 67 patients with CKD reduced nitric oxide production from human aortic endothelial cells ex vivo, in contrast with HDL from 25 normal controls that increased nitric oxide.16 HDL from patients with CKD contained high levels of symmetric dimethylarginine, and the addition of symmetric dimethylarginine to HDL induced endothelial dysfunction. The studies by Holzer et al. and Speer et al. are limited by small samples of patients from single sites, comparisons with control participants who differ in terms of age, comorbidity, or medication use, and the absence of clinical outcomes. Nonetheless, these studies identified HDL abnormalities that may be of great importance. In this context, the article by Zewinger et al. serves as a motivating study to further investigate lipoprotein J Am Soc Nephrol 25: 865–874, 2014
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metabolism and its clinical consequences in CKD. The null association of HDL-C with cardiovascular mortality among participants with an eGFR,60 ml/min per 1.73 m2 is consistent with the hypothesis that HDL particles are rendered dysfunctional in some manner in CKD. However, without data relating HDL composition or function to cardiovascular outcomes, this hypothesis remains untested. Other potential explanations for the interaction of HDL-C and eGFR include differences by eGFR in the range of HDL-C, the functional form of the association of HDL-C with mortality, confounders of the HDL-C–mortality association, the relationship of HDLC to other lipoproteins (e.g., atherogenic small, dense LDL particles17), or the nature of the observed cardiovascular events (e.g., a greater incidence of nonatherosclerotic cardiovascular deaths that are less strongly related to lipoproteins). Moreover, although the null association of HDL-C with mortality in the Ludwigshafen Risk and Cardiovascular Health study replicated in a smaller CKD cohort, apparently conflicting results have also been reported. In the Multi-Ethnic Study of Atherosclerosis, the association of lower HDL-C with carotid intima-media thickness strengthened with a lower eGFR (as did the association of small, dense LDL with intima-media thickness).18 Dissecting the complex interplay of HDL-C, HDL size, HDL composition, and HDL function with cardiovascular disease therefore needs further investigation. Moving research on HDL and cardiovascular disease in CKD forward will require studies that apply innovative assays of HDL quality using strong epidemiology designs. Such studies will require the following: large populations with external validation (as presented by Zewinger et al.); reliable measurements of HDL size, composition, and function; relevant measurements of vascular function in vivo or evaluation of clinical cardiovascular events; an ability to account for aspects of lipoprotein protein metabolism related to HDL (particularly differences in LDL size and density); and adequate consideration of the effects of common lipid-lowering medications, ideally further investigating the effects of these medications on HDL composition and function. Clinically, accumulating data, including those from Zewinger et al., suggest that HDL-C should not be used as a guide to therapy in patients with CKD. Indeed, recent Kidney Disease: Improving Global Outcomes (KDIGO) guidelines recommend that statins be prescribed with little regard to any circulating cholesterol concentrations, utilizing a “fire-andforget” strategy for patients with CKD not requiring dialysis in which neither LDL cholesterol nor HDL-C is used as a major therapeutic target.19 These findings follow the design and results of the Study of Heart and Renal Protection, in which a combination of simvastatin and ezetimibe reduced the risk of atherosclerotic cardiovascular events in CKD.20 KDIGO does not advocate any specific therapies based on HDL-C, a position congruent with that of the National Lipid Association.21 HDL may become a therapeutic target in CKD, but much additional work is needed to determine whether and how that should occur. J Am Soc Nephrol 25: 865–874, 2014
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ACKNOWLEDGMENTS I.H.d.B. receives grant funding from the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases (R01-DK087726, R01-DK088762) and the National Heart, Lung, and Blood Institute (R01-HL096875).
DISCLOSURESS None.
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9. 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 Invest 117: 746–756, 2007 10. Yetukuri L, Söderlund S, Koivuniemi A, Seppänen-Laakso T, Niemelä PS, Hyvönen M, Taskinen MR, Vattulainen I, Jauhiainen M, Oresic M: Composition and lipid spatial distribution of HDL particles in subjects with low and high HDL-cholesterol. J Lipid Res 51: 2341–2351, 2010 11. 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 Med 364: 127–135, 2011 12. 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 Nephrol 3: 125–132, 2008 13. Attman PO, Samuelsson O, Alaupovic P: Lipoprotein metabolism and renal failure. Am J Kidney Dis 21: 573–592, 1993 14. Joven J, Vilella E, Ahmad S, Cheung MC, Brunzell JD: Lipoprotein heterogeneity in end-stage renal disease. Kidney Int 43: 410–418, 1993 15. 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 Nephrol 22: 1631–1641, 2011 16. Speer T, Rohrer L, Blyszczuk P, Shroff R, Kuschnerus K, Kränkel N, Kania G, Zewinger S, Akhmedov A, Shi Y, Martin T, Perisa D, Winnik S, Müller MF, Sester U, Wernicke G, Jung A, Gutteck U, Eriksson U, Geisel J, Deanfield J, von Eckardstein A, Lüscher TF, Fliser D, Bahlmann FH, Landmesser U: Abnormal high-density lipoprotein induces endothelial dysfunction via activation of Toll-like receptor-2. Immunity 38: 754– 768, 2013
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17. Lamarche B, Tchernof A, Moorjani S, Cantin B, Dagenais GR, Lupien PJ, Després JP: Small, dense low-density lipoprotein particles as a predictor of the risk of ischemic heart disease in men. Prospective results from the Québec Cardiovascular Study. Circulation 95: 69–75, 1997 18. Lamprea-Montealegre JA, Astor BC, McClelland RL, de Boer IH, Burke GL, Sibley CT, O’Leary D, Sharrett AR, Szklo M: CKD, plasma lipids, and common carotid intima-media thickness: Results from the Multi-Ethnic Study of Atherosclerosis. Clin J Am Soc Nephrol 7: 1777–1785, 2012 19. Kidney Disease Improving Global Outcomes (KDIGO): KDIGO clinical practice guideline for lipid management in chronic kidney disease. Kidney Int Suppl 3: 259–305, 2013 20. Baigent C, Landray MJ, Reith C, Emberson J, Wheeler DC, Tomson C, Wanner C, Krane V, Cass A, Craig J, Neal B, Jiang L, Hooi LS, Levin A, Agodoa L, Gaziano M, Kasiske B, Walker R, Massy ZA, Feldt-Rasmussen B, Krairittichai U, Ophascharoensuk V, Fellström B, Holdaas H, Tesar V, Wiecek A, Grobbee D, de Zeeuw D, Grönhagen-Riska C, Dasgupta T, Lewis D, Herrington W, Mafham M, Majoni W, Wallendszus K, Grimm R, Pedersen T, Tobert J, Armitage J, Baxter A, Bray C, Chen Y, Chen Z, Hill M, Knott C, Parish S, Simpson D, Sleight P, Young A, Collins R; SHARP Investigators: The effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (Study of Heart and Renal Protection): A randomised placebo-controlled trial. Lancet 377: 2181–2192, 2011 21. Toth PP, Barter PJ, Rosenson RS, Boden WE, Chapman MJ, Cuchel M, D’Agostino RB Sr, Davidson MH, Davidson WS, Heinecke JW, Karas RH, Kontush A, Krauss RM, Miller M, Rader DJ: High-density lipoproteins: A consensus statement from the National Lipid Association. J Clin Lipidol 7: 484–525, 2013
See related article, “HDL Cholesterol Is Not Associated with Lower Mortality in Patients with Kidney Dysfunction,” on pages 1073–1082.
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