TREATMENT OF LIPID ABNORMALITIES

Claude Jacobs Service de N6phroiogie, Hdpital de La Pitl6, Paris, France

17

The rationale for advocating an active therapeutic intervention aimed at correcting the plasma lipid abnormalities which are frequently present in pa- tients treated by maintenance dialysis methods rests upon a certainty and two hitherto unproven assumptions.

The certainty stems from the results of numerous surveys carried out over the past 20 years, which show that cardiovascular complications, mainly of atherosclerotic nature, are the leading cause of mor- bidity and mortality among the dialysis population (I).

The first of the two as yet unproven assumptions is that plasma lipid abnormalities are an unequivo- cally documented independent risk factor for the development of cardiovascular complications in di- alysis patients (2), and the second is that there is a truly beneficial preventive effect of normalizing these metabolic disturbances, in particular by long- term prescription of lipid-lowering drugs (LLD). At the present time a sharp contrast exists between the increasingly deeper descriptive and pathophysio- logical knowledge concerning the lipid abnormali- ties documented in uremic patients and the scarcity of well-conducted long-term clinical studies whose results would be sufficiently convincing for delin- eating therapeutic options that could generate a consensus among the physicians involved in the care of dialysis patients.

The excess mortality from cardiovascular disease (CVD) in patients with chronic renal failure (CRF) has been extensively documented, mainly on the basis of data collected through regional, national, or international registries (1). This excess cardiovas- cular mortality ranges from 3 to 25 times that re- corded in the general population, but differs widely among various geographical areas. In a recently published paper, Brown et al. reported that the mortality of CVD in patients on renal replacement therapy (RRT) was 10.1 times that of the corre- sponding population of the northwest region of En- gland and was increased 44 times in diabetic pa- tients (3).

Lipids abnormalities are considered one among several risk factors for atherosclerosis-related car- diovascular complications in uremic (and non- uremic) patients, including hypertension, left ven- tricular hypertrophy, glucose intolerance, smoking, and obesity, to which have to be added the effects of the patient's advance in age and/or other specific disturbances of the metabolic environment (2). The nature of the lipid and lipoprotein abnormalities en- countered in dialysis patients has been extensively described in the literature (4) and will not be de-

Address correspondence to: Prof. Claude Jacobs, Groupe Hos- pitaller Pltie-Solpetriere, Service de N6phrologie. 83, Bouievard de L'Hopital, 75651 Paris Cedex 13, France. Seminars in DidysikVoI 8, No 1 (Jan-Feb) 1995 pp 17-19

tailed again here. A regular in-depth investigation of plasma lipids and lipoproteins is probably not war- ranted for the routine follow-up of most dialysis pa- tients but remains mandatory for conducting any prospective therapeutic protocol. In the clinical set- ting, an at least quarterly determination of plasma triglycerides, total and high-density lipoprotein (HDL) cholesterol (-C) should be done. Lipopro- tein(a) (Lp[a]) has been recently identified as a pos- sible key factor in the high cardiovascular mortality of uremic patients. Its plasma concentration is markedly elevated in many dialysis patients, re- gardless of the dialysis technique employed. Whether to measure plasma Lp(a) concentration routinely remains debated, however, and such mea- surement may be limited to patients with other well- documented atherogenic risk factors, such as ele- vated LDL-C levels. Further supporting this ap- proach are the observations that Lp(a) levels are mainly genetically determined and not significantly influenced by currently available LLD.

Altogether, the lipid abnormalities routinely found in dialysis patients are quantitatively rela- tively mild (3, 4) and remain stable over time (5 ) . For example, in the 46 patients who were treated by continuous ambulatory peritoneal dialysis (CAPD) in our unit during the past three months, the mean plasma total cholesterol (average of three consecu- tive monthly determinations) was 6.15 +1 1.60 mmol/L (upper limit of normal range: 6.50 mmoYL). In contrast, the mean triglyceride level was mark- edly elevated: 2.49 -+ 1.27 mmoYL (upper limit of normal range: 1.65 mmol/L). No statistical differ- ence was found for cholesterol and triglyceride lev- els between the 8 diabetic and the 38 nondiabetic patients who composed the group. Only three pa- tients (6.5%) were on LLD (fenofibrate: 2; simva- statin: 1).

Whereas a high total cholesterol level is consid- ered a potent predictor of cardiac death, particu- larly in uremic patients with diabetes mellitus, the vascular risk linked to hypertriglyceridemia is far less substantiated. Indeed, recent epidemiological studies conducted among the general population of several countries have shown that the relation of triglyceride levels to coronary heart disease (CHD) is observed only in persons with a ratio of LDW HDL-C greater than 5 and in those with high tri- glyceride and low HDL2-C concentrations along with an increase of apolipoprotein B (a profile very frequently evidenced in dialysis patients); LDL-C is considered the really important atherogenic li- poprotein and the principal target of therapeutic in- tervention (6).

A wide panel of therapeutic interventions aimed at correcting the IipidAipoprotein abnormalities that may develop in uremic patients is currently avail- able. Although some novel pharmaceutical agents

18 Jacobs

are remarkably effective in for returning the lipid parameters to normal, there is still no convincing evidence based on long-term prospective, well- conducted studies which clearly demonstrate a sig- nificant reduction of cardiovascular morbidity/ mortality of dialysis patients that can be specifically attributed to the normalization of their lipid disor- ders.

The therapeutic approaches which may be con- sidered include mainly (i) dietary and life-style mod- ifications, (ii) selective use of some technical com- ponents of dialysis systems, and, of course, (iii) the judicious prescriptions of LLD.

Dietary prescriptions are easy to recommend, but not very well accepted by the patients in the long run. Recommendations include weight reduction in obese patients and reduced intake of carbohydrate as well as fat (the latter should not account for more than 30% of the total daily caloric intake). These dietary restrictions have to be carefully evaluated in order to avoid the development of malnutrition by caloric deficiency, which is very common in pa- tients who may also have, for various reasons, a negative nitrogen (protein) balance. While these di- etary modifications may minimize the production of very low-density lipoprotein (VLDL) triglycerides by the liver, they have no effect on the enzymatic deficiencies related to the uremic state and thus have no effect on the impaired elimination of these triglycerides.

Several manipulations of dialysis techniques, such as substituting bicarbonate for acetate or rais- ing or decreasing the glucose concentration in the dialysis fluid, have been tried out with inconclusive results. Recent studies have shown a decrease of triglyceride levels and increased HDL2-C in pa- tients undergoing high-flux hemodialysis (HD) with a highly permeable membrane compared with levels in patients treated on conventional cellulose acetate dialyzers. This result is attributed to an enhanced elimination by the highly permeable membrane of a lipoprotein-lipase inhibitor possibly present in the uremic plasma (7). Replacement of conventional heparin by low-molecular weight heparin during the dialysis sessions has yielded controversial results. For example, in a 12-month study the use of Frag- min@ was associated with a significant decrease of total and low-density lipoprotein (LDL), but also HDL-C plasma concentrations, a decrease of apo- lipoprotein B, with no decrease in triglycerides (8); other authors reported more encouraging results with an increase of HDL-C and decline of triglyc- eride concentrations.

In patients on CAPD, both the transperitoneal loss of proteins (which may lead to a situation quite similar to the nephrotic syndrome with marked to- tal-C elevation and hypoalbuminemia) along with the daily absorption of large amounts of glucose via the dialysis fluid may exacerbate the lipid disorders with, in particular, much higher plasma triglyceride levels than in HD patients. It is thus necessary to reduce to a minimum the use of high-glucose con-

centration dialysis fluid and whenever possible re- place part of the daily conventional dialysate vol- ume by a solution containing a nonglucose osmotic agent. Interestingly, it has been recently shown in a prospective study conducted in HD and CAPD pa- tients that erythropoietin administration, in addition to correcting the patients’ anemia, was also associ- ated with a significant reduction of plasma total-C, triglycerides and apoprotein B 100. These favorable effects are however challenged by results of other studies.

The most debated issue is the value of adminis- tration of LLD, taking into account (i) their efficacy for correcting the lipid abnormalities considered po- tentially harmful in uremic patients (ii), the fre- quency and gravity of their side/adverse effects, and (iii) their cost.

Administration of fish-oil rich in omega-3 polyun- saturated fatty acids has yielded favorable results with a significant decrease of total-C and triglycer- ides, increase of HDL-C, along with a marked de- crease in blood pressure. The trials have, however, been conducted for short periods (up to 28 weeks) and this LLD has not yet gained wide acceptance.

Based on the fact that plasma and tissue concen- trations of carnitine are reduced in dialysis patients, it has been hypothesized that carnitine deficiency may play a role in the occurrence of lipid disorders. Several authors have thus administrated high doses of L-carnitine, either orally, intravenously, or via the dialysis fluid. Although carnitine supplementa- tion increased plasma levels and tissue carnitine pools, the effects on lipid abnormalities have been rather disappointing.

The two most widely used LLD are currently the fibric acids (clofibrate, fenofibrate, gemfibrozil, etc.) and, more recently, the HMG-CoA reductase inhibitors (statins). Fibrates are theoretically partic- ularly well suited for correcting the dyslipidemias of dialysis patients since they reduce the hepatic syn- thesis of c. and triglycerides and enhance the ac- tivity of lipoprotein lipase. The dosage of fibrates has to be carefully adjusted in uremic patients in order to avoid myopathic complications caused by accumulation of these compounds normally ex- creted by the kidney. Several recent studies have reported favorable results on all the lipid disorders usually documented in HD as well as in CAPD pa- tients. In particular, bezofibrate has been found ef- ficacious and devoid of side effects at doses ranging from 400 to 600 mg per week (9). The major recent therapeutic advance in this area has been the (pro- lific) development of HMG-CoA reductase inhibi- tors. These have proved very effective for correct- ing various dyslipidemic profiles and are generally well tolerated by uremic patients. Numerous stud- ies have been published over the past four years reporting the results obtained in HD and CAPD pa- tients, mainly with lovastatin or simvastatin. Al- though not unanimously, most trials report a bene- ficial effect of statin administration in dialysis pa- tients, with a reduction of serum concentrations of

TREATMENT OF LIPID ABNORMALITIES 19

total-C, LDL-C, triglycerides, and AP,-B, a (fre- quently modest) rise of HDL-C and no effect on Lp(a), with simvastatin being found by some au- thors more effective than lovastatin for achieving these results (10). No notable side effects have been reported with the use of statins in dialysis patients; however, a slowly progressive increase in drug dose and regular follow-up of liver and muscle enzymes remain indicated (10).

Based on the above, the following guidelines for treating the lipid disorders of dialysis patients can be set forward: 1.

2.

3.

4.

For patients with no identified cardiovascular risk factors and mild to moderate elevation of serum triglyceride concentration as the sole ab- normality of their lipid profile: dietary recom- mendations, cessation of smoking, exercise and no use of LLD. For hypertriglyceridemic patients with clearly identified risk factors, diabetics, or patients with previous manifestations of CHD, interventions aiming at normalizing lipid disorders are war- ranted: carefully monitored administration of fi- brates or omega-3 fatty acids may be the medi- cations of first choice. For all patients who, in addition to an elevated plasma triglyceride concentration, also have a marked increase in total-C and LDL-C, and a decrease in HDL-C, an in-depth investigation of all lipidflipoprotein parameters (including Lp[a]) may be indicated. This should be done prior to selecting either fibrates or statins, both utilized at progressively higher doses and according to the individual patient’s clinical tolerance or oc- currence of side effects. A less conservative, more “aggressive” ap-

proach for treating lipid abnormalities of dialysis patients remains to be substantiated by the still lacking demonstration of an unequivocally ben- eficial effect on cardiovascular morbidity] mortality attributable to the normalization of the serum lipid/lipoprotein disorders commonly doc- umented in uremic patients.

References 1. U.S. Renal Data System (USRDS): USRDS 1993 Annual Data Re-

port. Bethesda, MD; The National Institutes of Health, National In- stitute of Diabetes and Digestive and Kidney Diseases, 1993, pp. 49- 55

2. Ma KW, Greene EL, Raij L: Cardiovascular risk factors in chronic renal failure and hemodialysis populations. Am J Kidney Dis 19:505-

3.

4.

5 .

6.

7.

8.

9.

10.

513, 1992 Brown JH, Hunt LP, Vites NP, Short CD, Gokal R, Mallick NP: Comparative mortality from cardiovascular disease in patients with chronic renal failure. Nephrol Dial Transplant 9: 11361 142, 1994 Senti M, Romero R, Pedro-Botet J, Pelegri A. Nogues X, Rubies-hat J: Lipoprotein abnormalities in hyperlipidemic and nonnolipidemic men on hemodialysis with chronic renal failure. Kidney f n r 41:1394- 1399, 1992 Burrell D, Antignani A, Fein PA, Goldwasser PH, Mittman N, Avram MM: Longitudinal survey of apolipoproteins and atherogenic risk in hemodialysis and continuous ambulatory peritoneal dialysis patients. ASAIO Trans 36:M331-M335, 1990 Betteridge DJ: Hypertriglyceridaemia and vascular risk: Clinical im- plications. Lancer 342781-787, 1993 Josephson MA, Fellner SK, Das Gupta A: Improved lipid profiles in patients undergoing high-flux hemodialysis. Am J Kidney Dis 20:361- 366, 1992 Schmitt Y, Schneider H: Low molecular weight heparin (LWMH): Influence on blood lipids in patients on chronic hemodialysis. Nephrol Dial Transplant 8:43&142, 1993 Pelegri A, Romero R, Senti M, Nogues X, Pedro-Botet J, Rubies-Prat J: Effect of bezatibrate on lipoprotein (a) and triglyceride-rich, includ- ing intermediate density lipoproteins, in patients with chronic renal failure receiving hemodialysis. Nephrol Dial Transplant 7:623-626, 1992 Wanner C, Horl WH, Luley CH, Wieland H: Effects of HMG-CoA reductase inhibitors in hypercholesterolemic patients on hemodialy- sis. Kidney In1 39:754760, 1991

Mariana S. Markell Departments of Medicine and Surgery, Division of Nephrology, State University of New York Health Science Center, Brooklyn, New York

Although cardiovascular disease is the leading cause of death in dialyzed patients, the question posed by the title of this section might be better phrased, “Should the Lipid Abnormalities of Dial- ysis Patients be Treated?” There have been no large population studies of dialysis patients to sup- port the notion that lipid lowering will decrease the incidence of cardiovascular disease in this popula- tion, and most pharmacotherapy carries increased risk of side effects in the patient with poor renal function.

Address correspondence to: Marlana S. Markell, MD, Box 52, SUNY HSCB, 450 Clarkson Avenue, Brooklyn, NY 11203. Seminars in Uia/ysisVol 8, No 1 (Jan-Feb) 1995 pp 19-21

The primary lipid disturbance encountered in both hemodialysis and peritoneal dialysis (PD) pa- tients is hypertriglyceridemia (I) the treatment of which is controversial in the general population (2). Our approach is not to address the issue of hyper- triglyceridemia unless the problem is moderately severe (fasting triglycerides >400 mg/dL) or poten- tially life-threatening (triglycerides > 1,000 mg/dL, putting the patient at risk for pancreatitis and fatty liver). The approach is the same, regardless of the severity of the problem. The first step is dietary counseling for weight loss in obese patients and im- provement of blood glucose control in diabetics. Simple sugars and alcoholic beverages are to be avoided in all patients. Since heparin activates li-