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Saudi Journal of Kidney Diseases and Transplantation
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EDITORIAL Table of Contents   
Year : 2001  |  Volume : 12  |  Issue : 1  |  Page : 3-8
Lipid Lowering in End-Stage Renal Disease


Department of Medicine, Division of Nephrology, University of Würzburg, Würzburg, Germany

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How to cite this article:
Wanner C, Metzger T, Krane V. Lipid Lowering in End-Stage Renal Disease. Saudi J Kidney Dis Transpl 2001;12:3-8

How to cite this URL:
Wanner C, Metzger T, Krane V. Lipid Lowering in End-Stage Renal Disease. Saudi J Kidney Dis Transpl [serial online] 2001 [cited 2019 Nov 13];12:3-8. Available from: http://www.sjkdt.org/text.asp?2001/12/1/3/33878
Chronic renal failure patients suffer from a secondary form of complex dyslipidemia. This complex form is similar to the so called atherogenic dyslipidemia in insulin­resistent patients or to diabetic dyslipi­demia. The most important abnormalities are increased serum levels of triglyceride, very low-density lipoproteins (VLDL), remnants/intermediate-density lipoproteins (IDL) and low-density lipoprotein (LDL) particles and decreased serum levels of high-density lipoprotein (HDL) cholesterol. The highly atherogenic subclass of LDL, namely LDL-6 or small-dense LDL, accumulates in hyper-triglyceridemic diabetic hemodialysis patients.

All these lipoprotein particles contain apoB; thus, the complex disorder can more precisely be summarized as an elevation of triglyceride-rich apoB containing complex lipoprotein particles (LP-Bc). Growing evidence suggests that all of the compo­nents of this type of dyslipidemia are independently atherogenic. There are further profound disturbances of the dynamics of cholesterol transport between the various lipoprotein particles and from cells to catabolic sites. The European Joint Task Force and the National Cholesterol Education Program expert panels have issued guidelines for the general population to lower the cardiovascular risk in hyper­and dyslipidemias. There is preliminary consensus that these guidelines should, in general, also be applied to dialysis patients although the genesis of atherosclerosis in the dialysis population is probably different and an actual benefit from lipid-lowering has not yet been demonstrated in this population.


   The significance of triglyceride rich lipo­proteins (VLDL-remnants/IDL) Top


In the MARS and CLAS studies, a number of correlations were found between the annualized rate of change in the distal common carotid artery far wall intima­media thickness (IMT) and on-trial risk factors. [1] Several of these risk factors, such as apoB, apoC-III, and apoE, which are components of triglyceride-rich lipoproteins, are common in renal patients and are correlated to coronary artery progression. The strongest risk factor found in relation to progression of carotid IMT (high-resolution B-mode ultrasonographic) was the total IDL mass. [2] Progression of common carotid artery IMT is significantly correlated with the progression of coronary artery disease (CAD) as measured by quantitative coronary angiography. The progression of the distal common carotid artery far wall IMT over a 2-year period is also significantly predictive of clinical coronary events in the sub­sequent 12 years. [3] Thus, it is tempting to speculate that IDL particles, which accumulate during impairment of renal function in the course of progressive renal disease and in dialysis patients, may considerably contribute to the progression of atheromatous disease in the renal patients. Indeed Shoji et al [4] found that IDL were independent risk factors for aortic atherosclerosis in 280 hemodialysis patients as determined by pulse wave doppler sonography.


   Association between particle sub-classes and atherosclerosis Top


Individuals with elevated triglycerides are observed to have high-risk lipoprotein sub­class profiles. The triglyceride-rich lipo­proteins drive the metabolic reactions that produce LDL particles with abnormal composition. The best known example is small dense LDL, which confers at least a 3-fold higher risk compared with large LDL. [5] Dialysis patients, especially hyper­triglyceridemic diabetics on hemodialysis, accumulate large amounts of small-dense LDL which may confer a potential risk to these patients. [6],[7] Elevated IDL, which is included as part of the LDL fraction as measured by standard methods, is also associated with increased risk. [8] Thus, persons or patients with the same LDL cholesterol levels have very different amounts of small LDL and IDL. It is not surprising that they may differ markedly in their susceptibility to developing CAD. In the triglyceride-rich VLDL category, a recent study showed that levels of the largest particles (chylomicron remnants) have a strong positive relationship with an arteriographic end-point, independent of total plasma triglycerides and other lipid risk factors. [9]

Postprandial lipoprotein metabolism is disturbed in dialysis patients, thus leading to accumulation of chylomicron remnants in plasma. [10]


   High-density lipoproteins in chronic renal failure Top


Uremia can be considered to be a state of activated acute phase response. In the micro-inflammatory milieu, a number of atherogenic proteins [fibrinogen, lipo­protein(a) (Lp(a))] are elevated in serum and, a number of anti-atherogenic factors are diminished. Among the latter, low levels of HDL-cholesterol and apolipo­protein A-I are the most prominent. Van Lenten et al [11] recently described that during an acute phase response, alterations in HDL occur changing it from an anti-oxidant to a pro-oxidant lipoprotein. Among the reported alterations were an increase in apolipo­protein J and serum amyloid A and a decrease in paraoxonase activity in both HDL and in plasma. Recent findings of Morena et al demonstrated in hemodialysis patients, a reduced capacity of HDL to protect LDL from oxidation. [12]


   Lipoprotein(a) Top


Lp(a) was found to be consistently elevated in a considerable proportion of patients with end-stage renal failure and has been shown to have the characteristics of an acute phase reactant. [13],[14] Kronenberg et al [15] demonstrated that hemodialysis patients with low-molecular-weight phenotypes of apo(a) had significantly more carotid arterial sites affected by atherosclerotic plaques than those with high-molecular­weight phenotypes. The low molecular weight apo(a) phenotype also predicted independently CAD in a cohort of 440 unselected hemodialysis patients in a prospective study over 5-years. [16] It has been suggested that the apo(a) size and the Lp(a) plasma concentration play a synergistic role in advanced atherosclerosis. [17]


   Modifications of apoB containing lipo­protein particles Top


In addition to quantitative changes of lipoprotein particles, several compositional qualitative lipoprotein changes have been demonstrated to occur including modifi­cation of the apolipoprotein B moiety such as oxidation, carbamylation and glycation or transformation by advanced glycation end-products (AGEs). Modified lipoproteins are not readily recognized by the LDL receptor. [18] They may remain in the circulation for prolonged periods of time until they are taken up by non-saturable scavenger receptor pathways. [19] Glycated lipoproteins are highly susceptible to oxidation, [20] ultimately leading to formation of foam cells and progressive athero­sclerosis.


   The concept of high-risk versus high­cholesterol Top


The quantities of abnormal lipoprotein particles in uremia and their associated CAD risk are underestimated by the conventional cholesterol measurement. How should we understand currently available lipid values in the daily clinical practice? Should we treat a potential atherogenic condition in order to approach target LDL cholesterol levels? A possible answer is coming from growing consensus that most patients on hemodialysis and especially those with type-2 diabetes, belong to a category of patients with high short-term risk. Therefore, the hemodialysis patients constitute a special case in risk assessment, and hemodialysis and diabetes enhance the absolute risk by far. When the risk factors (traditional and non-traditional) of these patients are summed, their risk already approaches that of patients with established CAD. [21] The absolute risk of patients on dialysis and with type-2 diabetes usually exceeds all known risk scores including the Framingham score for hyperglycemia because multiple risk factors almost always coexist. Another reason to elevate the end-stage renal failure patient to the highest ever established risk category (suggested by Consensus Conference and Task Force guideline scoring) is the poor prognosis of these patients once they develop CAD.[22] However, it is important to determine whether the risk is originating from dyslipidemia alone, at least in part, or from the sum of many traditional and non­traditional cardiovascular risk factors. Data indicate that the genesis of atherosclerosis in the dialysis population is different from that in the general population. [23] It may also be justified to await the results from ongoing clinical trials (4D-study, UK­HARP trial and CHORUS study) before pharmacological lipid lowering is advised in HD patients. However, there is always a case for treatment in individual borderline patients.


   Management of lipid disorders Top


The US "Adult Treatment Panel II" of the National Cholesterol Education Program [24] recommended that the goal of therapy is to achieve a reduction of LDL cholesterol to less than 2.6 mmol/l (100 mg/dl) in high­risk patients or, patients being treated for secondary prevention. Lipid-lowering drug therapy should be initiated if the LDL cholesterol concentration is greater than 3.4 mmol/l (135 mg/dl). In a recent consensus conference, the American Diabetes Asso­ciation recommended an identical threshold for drug therapy. With regard to the potential benefits of lowering serum triglycerides in diabetic patients, much less information is available from clinical trials. Nevertheless, the American Diabetes Association recom­mended drug therapy for triglyceride levels greater than 4.5 mmol/l (400 mg/dl). In presence of a further CAD risk factor, pharmacological therapy should be considered if the triglyceride concentration exceeds 2.3 mmol/l (200 mg/dl) and in diabetic patients with clinical vascular disease, if the triglyceride concentration exceeds 1.7 mmol/l (150 mg/dl). Regarding the concentration of HDL cholesterol and triglycerides, no definitive target levels are given. However, an unfavorable condition is present when HDL cholesterol is lower than 40 mg/dl or the serum triglyceride is > 180 mg/dl. The results of the Veterans Affairs High-density Lipoprotein Cholesterol Intervention Trial (VA-HIT) encourage the use of gemfibrozil in those with hyper­triglyceridemia and low HDL cholesterol. The data show that a decrease of serum triglyceride by 31% and a rise of HDL cholesterol by 6% in the presence of unchanged value of LDL cholesterol resulted in a reduction of myocardial events (non-fatal mycocardial infarction or coronary death) by 22%. [25]


   Non-pharmacological lipid lowering Top


Generally, in patients with any form of dyslipidemia, a dietary approach is recommended. However, in end-stage renal failure patients treated by dialysis, a specific diet protocol for lipid lowering should be avoided. Physical activity is strongly encouraged.


   Lipid-lowering drugs Top


The most useful classes of hypolipidemic drugs for use in both the diabetic and non­diabetic population on dialysis are gemfib­rozil and HMG-CoA reductase inhibitors (statins). Since nicotinic acid aggravates insulin resistance and bears specific side effects similar to uremia-associated symptoms, this drug is not recommended. However, acipimox may overcome these effects being useful in combination therapy with fish-oil in patients with excessive hyper-triglyceridemia.

Statins

These drugs were shown to be highly effective in reducing LDL cholesterol concentrations in both diabetic and non­diabetic patients with chronic renal failure.

Statins also lower the levels of atherogenic IDL. [26] In severe renal insufficiency, therapy with statins appears to be safe, but experience is limited and maximal doses should be used with caution. The most important, but rare, side-effect is rhabdo­myolysis with muscle pain and an increase in creatine kinase. The risk for developing rhabdomyolysis is usually low, but is high in those receiving additional drug therapy, particularly cyclosporin and gemfibrozil. Therefore, patients should be advised to present when myositis develops, and statins should be withdrawn when creatine kinase levels reach 10 times the normal value or when clinical symptoms occur.

Fibric acid derivatives

Fibric acid derivatives have been shown to improve lipoprotein lipase activity and inhibit hepatic synthesis of VLDL choles­terol [27],[28] resulting in a reduction of trigly­cerides and an increase in HDL cholesterol. Fibrate drugs do not adversely affect glycemic control and some also reduce plasma fibrinogen levels. In principle, they appear to be suitable lipid-lowering agents in patients with diabetic nephropathy. However, fibrates are primarily excreted by the kidney and accumulate in advanced renal insufficiency. The risk of side-effects, mainly rhabdomyolysis, is increased. Therefore, in severe renal failure clofibrate and fenofibrate should not be used. The dose of bezafibrate has to be reduced to 200-400 mg/week. Among the second generation of fibric acid analogues, gemfibrozil has been found to be the drug of choice in patients with renal insuf­ficiency. Low to moderate dosages of gemfibrozil (900 mg/day) are well tolerated in these patients. [29],[30],[31]

 
   References Top

1.Hodis HN, Mack WJ, LaBree L, et al. Reduction in carotid arterial wall thickness using lovastatin and dietary therapy: A randomized controlled clinical trial. Ann Intern Med 1996;124:548-56.  Back to cited text no. 1  [PUBMED]  [FULLTEXT]
2.Hodis HN, Mack WJ, Dunn M, et al. Intermediate-density lipoproteins and prog-ression of carotid arterial wall intima-media thickness. Circulation 1997;95:2022-6.  Back to cited text no. 2  [PUBMED]  [FULLTEXT]
3.Hodis HN, Mack WJ, LaBree L, et al. The role of carotid arterial intima-media thickness in predicting clinical coronary events. Ann Intern Med 1998;126:262-9.  Back to cited text no. 3    
4.Shoji T, Nishizawa Y, Kawagishi T, et al. Intermediate density lipoproteins as an inde-pendent risk factor for aortic atherosclerosis in hemodialysis patients. J Am Soc Nephrol 1998;9:1277-84.  Back to cited text no. 4  [PUBMED]  
5.Austin MA, Breslow HL, Hennekens CH, Buring JE, Willet WC, Krauss RM. Low-density lipoprotein subclass patterns and risk of myocardial infarction. J Am Med Assoc 1988;260:1917-21.  Back to cited text no. 5    
6.Quaschning T, Schomig M, Keller M, et al. Non-insulin-dependent diabetes mellitus and hypertriglyceridemia impair lipoprotein meta-bolism in chronic hemodialysis patients. J Am Soc Nephrol 1999;10:332-41.  Back to cited text no. 6    
7.Deighan CJ, Caslake MJ, NcConnell M, Boulton-Jones JM, Packard CJ. Atherogenic lipoprotein phenotype in end-stage renal failure: origin and extent of small dense low-desity lipoprotein formation. Am J Kidney Dis 2000;35:852-62  Back to cited text no. 7    
8.Krauss RM. Relationship of intermediate and low-density lipoprotein subspecies to risk of coronary artery disease. Am Heart J 1987;113: 578-82.  Back to cited text no. 8  [PUBMED]  
9.Freedman DS, Otvos JD, Jeyarajah EJ, Barboriak JJ, Andersson AJ, Walker JA. Relation of lipoprotein subclasses as measured by proton nuclear magnetic resonance spectros-copy to coronary artery disease. Arterioscler Thromb Vasc Biol 1998;18:1046-53.  Back to cited text no. 9    
10.Weintraub M, Burstein A, Rassin T, et al. Severe defect in clearing postprandial chylo-micron remnants in dialysis patients. Kidney Int 1992;42:1247-52.  Back to cited text no. 10  [PUBMED]  
11.Van Lenten, Hama SY, de Beer FC, et al. Anti-inflammatory HDL becomes pro­inflammatory during the acute phase response. Loss of protective effect of HDL against LDL oxidation in aortic wall cell cocultures. J Clin Invest 1995;96:2758-67.  Back to cited text no. 11    
12.Morena M, Cristol J-P, Dantoine T, Carbonneau MA, Descomps B, Canaud B. Protective effects of high-density lipoprotein against oxidative stress are impaired in haemodialysis patients. Nephrol Dial Transplant 2000;15:389-95.  Back to cited text no. 12    
13.Maeda S, Abe A, Seishima M, Makino K, Noma A, Kawade M. Transient changes of serum lipoprotein(a) as an acute phase protein. Atherosclerosis 1989;78:145-50.  Back to cited text no. 13  [PUBMED]  
14.Zimmermann J, Herrlinger S, Pruy A, Metzger T, Wanner C. Inflammation enhances cardio-vascular risk and mortality in hemodialysis patients. Kidney Int 1999;55:648-58.  Back to cited text no. 14  [PUBMED]  [FULLTEXT]
15.Kronenberg F, Kathrein H, Konig P, et al. Apolipoprotein(a) phenotypes predict the risk for carotid atherosclerosis in patients with end-stage renal disease. Arterioscler Thromb 1994;14:1405-11.  Back to cited text no. 15    
16.Kronenberg F, Neyer U, Lhotta K, et al. The low molecular weight apo(a) phenotype is an independent predictor for coronary artery disease in hemodialysis patients: a prospective follow-up. J Am Soc Nephrol 1999;10:1027-36.  Back to cited text no. 16  [PUBMED]  [FULLTEXT]
17.Marcovina SM, Koschinsky ML. Lipo­protein(a) concentration and apolipoprotein(a) size: a synergistic role in advanced athero-sclerosis. Circulation 1999;100:1151-3.  Back to cited text no. 17  [PUBMED]  [FULLTEXT]
18.Gonen B, Baenziger J, Schonfeld G, Jacobson D, Farrar P. Nonenzymatic glycosylation of low-density lipoproteins in vitro. Effects on cell-interactive properties. Diabetes 1981;30:875-8.  Back to cited text no. 18    
19.Lyons TJ. Lipoprotein glycation and its metabolic consequences. Diabetes 1992;41 Suppl 2:67-73.  Back to cited text no. 19  [PUBMED]  
20.Berliner JA, Territo M, Navab M, et al. Minimally modified lipoproteins in diabetes. Diabetes 1992;41Suppl 2:74-6.  Back to cited text no. 20    
21.Haffner SM, Lehto S, Ronnemaa T, Pyorala K, Laakso M. Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med 1998; 339:229-34.  Back to cited text no. 21    
22.Herzog CA, Ma JZ, Collins AJ. Poor long-term survival after acute myocardial infarction among patients on long-term dialysis. N Engl J Med 1998;339:799­-805.  Back to cited text no. 22  [PUBMED]  [FULLTEXT]
23.Baigent C, Wheeler DC. Should we reduce blood cholesterol to prevent cardiovascular disease among patients with chronic renal failure? Nephrol Dial Transplant 2000;15: 1118-9.  Back to cited text no. 23  [PUBMED]  [FULLTEXT]
24.Summary of the Second Report of the National Cholesterol Education Program (NCEP) expert panel on detection, evaluation and treatment of high blood cholesterol in adults (Adult Treatment Panel II). J Am Med Assoc 1993;269:3015-23.  Back to cited text no. 24    
25.Rubins HB, Robins SJ, Collins D, et al. Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial Study Group. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high­density lipoprotein cholesterol. N Engl J Med 1999;341:410-8.  Back to cited text no. 25    
26.Nishizawa Y, Shoji T, Emoto M, et al. Reduction of intermediate-density lipoprotein by pravastatin in hemo- and peritoneal dialysis patients. Clin Nephrol 1995;43:268-77.  Back to cited text no. 26  [PUBMED]  
27.Tikkanen MJ. Fibric acid derivatives. Curr Opin Lipidol 1992;3:29-33.  Back to cited text no. 27    
28.Shepherd J. Mechanism of action of fibrates. Postgrad Med J 1993;69(Suppl 1):S34-41.  Back to cited text no. 28  [PUBMED]  
29.Pasternack A, Vanttinen T, Solakivi T, Kuusi T, Korte T. Normalization of lipoprotein lipase and hepatic lipase by gemfibrozil results in the correction of lipoprotein abnormalities in chronic renal failure. Clin Nephrol 1987; 27:163-8.  Back to cited text no. 29    
30.Chan MK. Gemfibrozil improves abnormalities of lipid metabolism in patients on continuous ambulatory peritoneal diaysis: The role of postheparin lipases in the metabolism of high-density lipoprotein subfractions. Metabolism 1989;38:939-45.  Back to cited text no. 30  [PUBMED]  
31.Samuelsson O, Attman PO, Knight­Gibson C, et al. Effect of gemfibrozil on lipoprotein abnormalities in chronic renal insufficiency: a controlled study in human chronic renal disease. Nephron 1997;75:286-94.  Back to cited text no. 31  [PUBMED]  

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Correspondence Address:
Christoph Wanner
Department of Medicine, Division of Nephrology, University Hospital, Josef-Schneider-Str.2, D-97080 Würzburg
Germany
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PMID: 18209353

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    The significance...
    Association betw...
    High-density lip...
    Lipoprotein(a)
    Modifications of...
    The concept of h...
    Management of li...
    Non-pharmacologi...
    Lipid-lowering drugs
    References
 

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