Background/Aims: Dyslipidemia and non-traditional cardiovascular (CV) risk factors, such as lipoprotein(a) (Lp(a)), homocysteine, oxidative stress and inflammation, are important determinants in the increased CV risk of hemodialysis (HD) patients. The aim of our study was to evaluate the effects of atorvastatin on these parameters in one of the groups with the highest CV risk: diabetic patients with end-stage renal disease under HD therapy. Methods: Twenty maintenance HD diabetic patients (mean age 64 ± 10 years, mean time on HD 25 ± 11 months) with low-density lipoprotein cholesterol (LDL-C) >2.59 mmol/l received atorvastatin (10 mg/day) for 4 months. Lipid profile, including total cholesterol (TC), LDL-C, high-density lipoprotein cholesterol (HDL-C), triglycerides (TG), apolipoproteins A1 and B (Apo-A and Apo-B), and the non-traditional risk factors Lp(a), homocysteine, autoantibodies against oxidized LDL-C (anti-LDLox), total antioxidant status (TAS), and high sensitive C-reactive protein (hs-CRP), were measured at baseline and at the end of the study. Safety was assessed by clinical and laboratory (liver and muscle enzymes) monitoring once a month. Results: Mean percent reductions for TC, LDL-C and TG were 18.5% (p < 0.001), 22% (p < 0.001) and 19% (p < 0.01), respectively. The ratios of TC/HDL-C and LDL-C/HDL-C decreased after treatment (p < 0.05), whereas the ratios of LDL-C/Apo-B (p < 0.01) and Apo-A/Apo-B (p < 0.001) increased. No significant changes were observed in HDL-C. Concerning the non-traditional risk factors, levels of homocysteine, Lp(a), anti-LDLox and TAS did not change significantly. However, hs-CRP decreased from 5.4 (range 0.9–67.8) to 2.3 mg/l (range 0.4–21) (p < 0.01), whereas a concomitant increase in serum albumin was observed (from 38 ± 2 to 40 ± 1.7 g/l, p < 0.01). At baseline, hs-CRP was inversely associated with HDL-C and Apo-A, and directly related to Lp(a). The change in hs-CRP was inversely associated with the change of HDL-C, whereas a direct correlation was found with the change of TG. Conclusions: Atorvastatin administration to diabetic patients on HD is associated with improvement of lipid profile and reduction of hs-CRP. These effects may be critical for the reduction of CV risk and mortality in HD population.

Keywords:
Albumin, Atorvastatin, Cardiovascular risk, Dyslipidemia, C-reactive protein, Hemodialysis
1.
Lindner A, Charra B, Sherrard DJ, Scribner BH: Accelerated atherosclerosis in prolonged maintenance hemodialysis. N Engl J Med 1974;290:697–701.
2.
Foley RN, Parfrey PS, Sarnak MJ: Clinical epidemiology of cardiovascular disease in chronic renal disease. Am J Kidney Dis 1998;32(suppl 3):112–119.
3.
Shoji T, Kawagishi T, Emoto M, et al: Additive impacts of diabetes and renal failure on carotid atherosclerosis. Atherosclerosis 2000;153:257–258.
4.
Kasiske BL: Hyperlipidemia in patients with chronic renal disease. Am J Kidney Dis 1998;32(suppl 3):142–156.
5.
Attman PO, Alaupovic P: Lipid abnormalities in chronic renal insufficiency. Kidney Int 1991;57:401–410.
6.
Attman PO, Knight-Gibson C, Tavella M, Samuelson O, Alaupovic P: The compositional abnormalities of lipoproteins in diabetic renal failure. Nephrol Dial Transplant 1998;13:2833–2841.
7.
Joki N, Hase H, Ishikawa H, et al: Coronary artery disease as a definitive risk factor of short-term outcome after starting hemodialysis in diabetic renal failure patients. Clin Nephrol 2001;55:109–114.
8.
Fellström BC, Holdaas H, Jardine AG: Why do we need a statin trial in hemodialysis patients? Kidney Int 2003;84(suppl 84):204–206.
9.
Quaschning T, Schömig M, Keller M, et al: Non-insulin-dependent diabetes mellitus and hypertriglyceridemia impair lipoprotein metabolism in chronic hemodialysis patients. J Am Soc Nephrol 1999;10:332–341.
10.
Levey AS, Beto JA, Coronado BE, et al: Controlling the epidemic of cardiovascular disease in chronic renal disease: What do we know? What do we need to learn? Where do we go? Am J Kidney Dis 1998;32:853–906.
11.
Kronenber F, Utermann G, Dieplinger H: Lipoprotein(a) in renal disease. Am J Kidney Dis 1996;27:1–25.
12.
Moustapha A, Naso A, Nahlawi M, et al: Prospective study of hyperhomocysteinemia as an adverse cardiovascular risk factor in end-stage renal disease. Circulation 1998;97:138–141.
13.
Loughrey CM, Young IS, Lightbody JH, et al: Oxidative stress in haemodialysis. Q J Med 1994;87:679–683.
14.
Zimmermann J, Herrlinger S, Pruy A, Metzger T, Wanner C: Inflammation enhances cardiovascular risk and mortality in hemodialysis patients. Kidney Int 1999;55:648–658.
15.
LaRosa JC, He J, Vupputuri S: Effect of statins on risk of coronary disease: A meta-analysis of randomized controlled trials. JAMA 1999;282:2340–2346.
16.
Nishizawa Y, Shoji T, Emoto M, et al: Reduction of intermediate density lipoprotein by pravastatin in hemo- and peritoneal dialysis patients. Clin Nephrol 1995;43:268–277.
17.
Saltissi D, Morgan C, Rigby R, Westhuyzen J: Safety and efficacy of simvastatin in hypercholesterolemic patients undergoing chronic renal dialysis. Am J Kidney Dis 2002;39:283–290.
18.
Chang JW, Yang WS, Min WK, Lee SK, Park JS, Kim SB: Effects of simvastatin on high-sensitivity C-reactive protein and serum albumin in hemodialysis patients. Am J Kidney Dis 2002;39:1213–1217.
19.
Jones P, Kadonek S, Laurora I, Hunninghake D: Comparative dose efficacy study of atorvastatin versus simvastatin, pravastatin, lovastatin, and fluvastatin in patients with hypercholesterolemia (the CURVES study). Am J Cardiol 1998;81:582–587. Erratum in Am J Cardiol 1998;82:128.
20.
Hufnagel G, Michel C, Vrtovsnik F, Queffeulou G, Kossari N, Mignon F: Effects of atorvastatin on dyslipidaemia in uraemic patients on peritoneal dialysis. Nephrol Dial Transplant 2000;15:684–688.
21.
Harris KP, Wheeler DC, Chong CC, for the Atorvastatin in CAPD Study Investigators: A placebo-controlled trial examining atorvastatin in dyslipidemic patients undergoing CAPD. Kidney Int 2002;61:1469–1474.
22.
National Cholesterol Education Program Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults. Executive summary of the third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults (ATP III). JAMA 2001;285:2486–2497.
23.
Wood D, Durington P, McInnes G, et al: Joint British recommendations on prevention of coronary heart disease in clinical practice. Heart 1998;80(suppl):1–29.
24.
Manninen V, Tenkanen L, Koshinen P, et al: Joint effects of serum triglyceride and LDL cholesterol and HDL cholesterol concentrations on coronary heart disease risk in the Helsinki Heart Study: Implications for treatment. Circulation 1992;85:37–45.
25.
Lemieux I, Lamarche B, Couillard C, et al: Total cholesterol/HDL cholesterol ratio vs. LDL cholesterol/HDL cholesterol ratio as indices of ischemic heart disease risk in men. Arch Intern Med 2001;161:2685–2692.
26.
Elisaf M, Bairaktari H, Tziallas C, Germanos N, Siamopoulos K: Atherogenic lipid and lipoprotein parameters in hemodialysis patients. Dial Transplant 1995;24:642.
27.
Austin MA, Breslow JL, Hennekens CH, Buring JE, Willet WC, Krauss RM: Low-density lipoprotein subclass patterns and risk of myocardial infarction. JAMA 1988;260:1917–1921.
28.
Grundy SM: Small LDL, atherogenic dyslipidemia, and the metabolic syndrome. Circulation 1997;95:1–4.
29.
Ishigami M, Yamshita S, Sakai N, et al: Atorvastatin markedly improves type III hyperlipoproteinemia in association with reduction of both exogenous and endogenous apolipoprotein B-containing lipoproteins. Atherosclerosis 2003;168:359–366.
30.
Qureshi A, Giles W, Croft J, Guterman L, Hopkins N: Apolipoproteins A-1 and B and the likelihood of non-fatal stroke and myocardial infarction – Data from The Third National Health and Nutrition Examination Survey. Med Sci Monit 2002;8:CR311–CR316.
31.
Sasaki S, Kuwahara N, Kunitomo K, et al: Effects of atorvastatin on oxidized low-density lipoprotein, low-density lipoprotein subfraction distribution, and remnant lipoprotein in patients with mixed hyperlipoproteinemia. Am J Cardiol 2002;89:386–389.
32.
Smilde T, Wissen S, Wollersheim H, Trip M, Kastelein J, Stalenhoef A: Effect of aggressive versus conventional lipid lowering on atherosclerosis progression in familial hypercholesterolemia (ASAP): A prospective, randomized, double-blind trial. Lancet 2001;357:577–581.
33.
Ross R: Atherosclerosis – An inflammatory disease. N Engl J Med 1999;340:115–126.
34.
Panichi V, Migliori M, De Pietro S, et al: Plasma C-reactive protein in haemodialysis. Blood Purif 1999;17:142–148.
35.
Zimmermann J, Herrlinger S, Pruy A, et al: Inflammation enhances cardiovascular risk and mortality in hemodialysis patients. Kidney Int 1999;55:648–658.
36.
Yeun J, Levine R, Mantadilok V, Kaysen G: C-reactive protein predicts all-cause and cardiovascular mortality in hemodialysis patients. Am J Kidney Dis 2000;35:469–472.
37.
Jialal I, Stein D, Balis D, Grundy S, Adams-Huet B, Devaraj S: Effect of hydroxymethyl glutaryl coenzyme A reductase inhibitor therapy on high sensitive C-reactive protein levels. Circulation 2001;103:1933–1935.
38.
Kario K, Matsuo T, Kobayashi H, Matsuo M, Asada R, Koide M: High lipoprotein(a) levels in chronic hemodialysis patients are closely related to the acute phase reaction. Thromb Haemost 1995;74:1020–1024.
39.
Koda Y, Nishi S, Suzuki M, Hirasawa Y: Lipoprotein(a) is a predictor for cardiovascular mortality of hemodialysis patients. Kidney Int 1999;71(suppl):251–253.
40.
Koenig W, Sund M, Frölich M, et al: C-reactive protein, sensitive marker of inflammation, predicts future risk of coronary heart disease in initially healthy middle-aged men. Circulation 1999;99:237–242.
41.
Strandberg T, Vanhanen H, Tikkanen M: Associations between change in C-reactive protein and serum lipids during statin treatment. Ann Med 2000;32:579–583.
42.
Parjkrt D, Doran J, Koster F, et al: Anti-inflammatory effects of re-constituted high-density lipoprotein during human endotoxemia. J Exp Med 1996;184:1601–1608.
43.
Owen WF, Lew NL, Liu Y, Lowrie EG, Lazarus M: The urea reduction ratio and serum albumin concentrations as predictors of mortality in patients undergoing hemodialysis. N Engl J Med 1993;329:1001–1006.
44.
Lowrie EG, Lew NL: Death risk in hemodialysis patients: The predictive value of commonly measured variables and an evaluation of death rate differences between facilities. Am J Kidney Dis 1990;15:458–482.
45.
Kaysen GA: The microinflammatory state in uremia: Causes and potential consequences. J Am Soc Nephrol 2001;12:1459–1457.
46.
Kaysen GA, Rathore V, Shearer GC, Depner TA: Mechanisms of hypoalbuminemia in hemodialysis patients. Kidney Int 1995;48:510–516.
47.
Stenvinkel P, Heimbürger O, Paultre F, et al: Strong associations between malnutrition, inflammation and atherosclerosis in chronic renal failure. Kidney Int 1999:55:1899–1911.
48.
Qureshi AR, Alvestrand A, Danielsson A, et al: Factors influencing malnutrition in haemodialysis patients. A cross-sectional study. Kidney Int 1998;53:773–782.
49.
Kaysen GA, Stevenson FT, Depner TA: Determinants of albumin concentration in hemodialysis patients. Am J Kidney Dis 1997;29:658–668.
© 2003 S. Karger AG, Basel
2004
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.