Lipid abnormalities in renal disease.

Kidney international, Vol. 39 (1991), pp. 169—183

NEPHROLOGY FORUM

Lipid abnormalities in renal disease Principal discussant: GERALD APPEL Columbia-Presbyterian Medical Center, New York, New York

ued taking the resin binder, and the total cholesterol increased to 422

mg/dl (LDL, 301 mg/dl; VLDL, 101 mg/dl; HDL, 23 mgIdl; total

Editors JORDAN J. COHEN JOHN T. HARRINGTON JEROME P. KASSIRER

NIcot.Aos E. MADIAS

Managing Editor CHERYL J. ZUSMAN

triglyceride, 574 mg/dl). Nicotinic acid, in a dose of 1500 to 2500 mg daily, was prescribed, but the patient could not continue taking this drug because of flushing and gastrointestinal complaints. The plasma lipid level did not fall significantly with nicotinic acid, and treatment

with the resin binder was resumed. The patient discontinued this medication and was followed only sporadically between 5 and 7 years ago. During that time, nephrotic syndrome and hyperlipidemia persisted. Hypertension was controlled by propranolol and hydralazine, and he was told to eat a low-sodium, low-cholesterol, low-protein diet. His renal function progressively deteriorated, and another renal biopsy showed marked progression of the focal sclerosing glomerulonephritis.

Four years ago, the serum creatinine was 9 mg/dl and creatinine

State University of New York at Stony Brook and Tufts University School of Medicine

clearance was less than 10 cc/mm; an arteriovenous fistula was created in preparation for dialysis. Despile continued proteinuria of 5 to 7 g daily, the total plasma protein had increased to 5.6 g/dl and the albumin to 3.3 g/dl; the plasma cholesterol had decreased to 264 mg/dl. Four

years after initial presentation, at the age of 36 years, the patient

Case presentation A 32-year-old white man developed swelling of his feet and ankles

developed episodic, exertional, "burning" left chest pain, which was associated with electrocardiographic changes suggestive of ischemia. Cardiac catheterization revealed significant stenotic lesions of the left anterior descending (LAD) coronary artery and of several diagonal vessels. The major LAD lesion was successfully dilated by balloon angioplasty; angina disappeared and a followup stress test was nega-

and facial swelling in the mornings. Physical examination revealed tive. blood pressures ranging between 130—140/95—100 mm Hg and peripheral

edema. Laboratory evaluation showed: BUN, 9 mg/dl; plasma creatinine, 0.9 mg/dl; plasma total protein, 3.5 g/dl; plasma albumin, 1.7 g/dl; and plasma cholesterol, 448 mg/dl. Urinalysis disclosed 4+ protein and microhematuria. A 24-hour urine collection contained 17 g of protein; creatinine clearance was 112 mllmin. Appropriate serologic tests were negative, and a diagnosis of idiopathic nephrotic syndrome was made. A renal biopsy yielded 14 glomeruli; one was globally sclerotic and 3 others had lesions of segmental sclerosis. Immunofluorescence and electron microscopy established the diagnosis of focal segmental gbmerulosclerosis. The patient was treated with sodium restriction and diuretics for his

edema, and prednisone, 120 mg every other day, for longer than 3 months; the proteinuria did not abate. Proteinuria ranged from 11.7 to 15.8 g daily, plasma albumin from 1.9 to 1.5 g/dl, total protein from 3.6 to 4.5 g/dl, and total cholesterol from 575 to 700 mg/dl (Chem 20 panel

He started dialysis one month after the angioplasty and did well. Two months after beginning dialysis, his fasting total triglyceride level was 281 mg/dl and total plasma cholesterol was 198 mgldl. After one year of

dialysis, he underwent a successful cadaveric renal transplant. At discharge, plasma creatinine was 2.0 mg/dl and total cholesterol was 171 mg/dl; his immunosuppressive regimen consisted of prednisone, cycbos-

porine, and azathioprine. He had mild to moderate hypertension controlled by hydralazine, atenolol, and verapamil; only mild proteinuria was present. Two months after receiving the allograft, his total cholesterol was 232 mgldl; 3 months later, while taking a maintenance dose of 10 mg prednisone daily, his total cholesterol ranged from 267 to

280 mg/dl. (The LDL was 145 mgldl; HDL, 58 mgldl; and total triglyceride, 250 mg/dl.) He was reinstructed in a low-cholesterol, low-saturated-fat diet, and recently resin binders were restarted.

results). After the corticosteroids were tapered, the patient was in-

Discussion

structed in a 300 mg cholesterol, low-saturated-fat diet. After 2 months of this diet, his plasma lipids were accurately measured by ultracentrifugation: cholesterol, 399 mgldl; LDL cholesterol, 329 mg/dl; VLDL cholesterol, 33 mgldl; HDL cholesterol, 37 mg/dl; and total triglyceride,

Presbyterian Hospital, and Professor of Clinical Medicine,

378 mg/dl. The cholesterol-binding resin colestipol hydrochloride (Colestid) was prescribed for 3 months; total cholesterol decreased to 341 mgldl (LDL cholesterol, 276 rng/dl; VLDL cholesterol, 32 mgldl; HDL cholesterol, 33 mg/dl; triglyceride, 405 mg/dl). He then discontin-

Presentation of the Forum is made possible by grants from Pfizer, Incorporated; Merck Sharp & Dohme International; Sandoz; Incorporated; and Marion Laboratories, Inc.

© 1991 by the International Society of Nephrology

DR. GERALD APPEL (Director, Clinical Nephrology, The Columbia-Presbyterian Medical Center, New York, New York):

This patient's history illustrates many of the interactions between lipid metabolism and renal disease. Lipid analysis performed at the onset of his nephrotic syndrome revealed marked elevations of both total and low-density lipoprotein (LDL) cholesterol but not of high-density lipoprotein (HDL) cholesterol. This pattern of lipid abnormality, commonly observed in nephrotic patients, probably placed him in a group that is at significant risk for atherosclerotic complications. Dietary management was initiated, and lipid-lowering medications were

Nephrology Forum: Lipids in renal disease

170

Table 1. Cornmon lipid abnormalities in renal disease Cholesterol

Total LDL VLDL HDL ja I N-I N Nephrotic syndrome

Nascent

Triglycerides

HOL

Renal abnormality

N-I

Uremia N-D N-D N-D N-D I N-D N-D N-D N-D I Hemodialysis I I I N I Peritoneal dialysis 1b jb 1b N-I-D" 1' Transplantation a N = normal, I = increased, D = decreased, b Variable percent increased; varies with time after transplantation.

-l

(APOC)

LCAT

0

subsequently administered. Despite responding to this treatment, he did not continue the drug regimen, and hyperlipidemia

returned. As his renal function declined, so did his serum cholesterol. Whether hyperlipidemia contributes to a decline in renal function is unknown, but some evidence supports such a hypothesis. By the time he was on dialysis, the patient's total

Fig. 1. Simplfied view of lipoprotein metabolism.

cholesterol had returned to normal, but he had developed known as apoproteins (Apo) or apolipoproteins, are important hypertriglyceridemia, common in dialysis patients. Coronary angiography demonstrated severe atherosclerotic disease, despite his being only 36 years old. Risk factors for accelerated atherosclerosis in this patient included hypertension in addition to the hyperlipidemia. Ultimately the patient underwent successful renal transplantation and developed a characteristic rise in serum cholesterol; this occurrence again posed dilemmas as to the optimal form and goal of therapy. The association between renal disease and hyperlipidemia has been known for more than 100 years [1]. Only recently, however, have we defined the patterns seen in the various

for activation of enzymes and for recognition of lipoproteins by

receptors. The various particles carrying cholesterol and triglycerides are classified according to density, electrophoretic mobility, and composition; these particles include: chylomicrons, very-low-density lipoproteins (VLDL), LDL, and HDL. Chylomicrons, the largest and least dense particles, are formed in the intestinal mucosa; they transport exogenous diet-derived lipids into the lymphatics and blood and have a large content of triglyceride. The next largest particles, the VLDL, carry most of the circulating triglyceride in the fasting state. Low-density

lipoproteins transport most of the cholesterol in the plasma. The densest and smallest particles, HDL, have the greatest of the lipid abnormalities and how to treat such abnormalities protein-to-lipid ratio and serve as scavengers of tissue choles[2—51. The association between hyperlipidemia and accelerated terol. cardiovascular disease is now well accepted, and many recent Lipid transport occurs by two pathways, (1) an exogenous studies have focused on the nature and significance of lipid pathway concerned with the absorption of dietary fat, its abnormalities in patients with renal disease [1—5] (Table 1). transport by chylomicrons, and the eventual breakdown of the Hypercholesterolemia and lipid abnormalities are, of course, an derived triglyceride into glycerol and fatty acids, and (2) an integral part of the nephrotic syndrome. Although hypertriglyc- endogenous pathway. In the endogenous pathway (Fig. 1), the eridemia is common in patients with renal failure and in those liver secretes triglyceride-rich VLDL particles, the triglycerundergoing hemodialysis or peritoneal dialysis, the pattern of ides of which are cleaved into glycerol and fatty acids by the lipid abnormalities, and the pathogenesis, in fact, differ in these enzyme lipoprotein lipase (LPL) located in the endothelium of patients. I'll return to this later. Likewise, some renal transplant adipose and other tissues. This enzyme requires Apo CII as an patients, whether treated with azathioprine or cyclosporine, ex- activator. The VLDL particles are reduced in size and become hibit abnormal lipid profiles. Recent studies have reported the remnants or intermediate-density lipoproteins (IDL). The IDL results of dietary therapy or lipid-lowering medications in these (that is, the VLDL remnants) normally are present only tranvarious subsets of patients. In addition, a burgeoning literature siently in the plasma, and can either be taken up by the liver (via suggests that lipid alterations might influence the progression of the same receptors as LDL) or lose ApoE and be converted to renal disease. I will review much of this literature in a few LDL particles. The LDL particles contain Apo Bl00 (which minutes, when we look at questions that arise in hyperlipidemic binds to the LDL receptor) as well as a considerable amount of patients with renal disease. These queries include: (1) What is cholesterol, but very little triglyceride. The LDL particles the lipid abnormality, and what are the mechanisms causing it? transport cholesterol to hepatocytes and peripheral tissues and forms of renal disease, and begun to understand the significance

(2) What are the atherogenic or other risks posed by the specific lipid abnormality? (3) How can the hyperlipidemia be treated, and do the benefits of therapy outweigh the risks of treatment? Physiology

are removed from the circulation both by the receptor-mediated

action of hepatocytes and other cholesterol-requiring tissues and by nonspecific binding to hepatocytes and peripheral tissue. The HDL particles, secreted by the liver and other tissues, are transformed in the circulation from HDL3 to HDL2 particles by

The common plasma lipids are highly hydrophobic and the acquisition of additional protein moieties. The HDL particles readily take up free cholesterol and transport it between

insoluble in aqueous solutions [2—6]. Carried in the plasma in globular particulate form, they have a polar hydrophilic outer surface composed in part of protein moieties. These proteins,

cells in the body; these particles are important in the removal of cholesterol from certain tissues. The major apoprotein associ-


ated with HDL, Apo Al is an activator of the enzyme lecithin cholesterol acyltransferase (LCAT). This enzyme esterifies free cholesterol in HDL, allowing HDL to transfer the cholesterol

esters to other lipoprotein particles (VLDL and LDL) for transport to the liver and subsequent removal. Risk of atherosclerosis Numerous studies have confirmed the association between elevated plasma lipids, in particular hypercholesterolemia, and an increased risk of atherosclerotic cardiovascular complica-

tions [71. A specific fraction of the cholesterol, the HDL component, is protective against atherosclerotic disease, whereas other fractions (especially the LDL) are associated

171

Table 2. Clinical studies on cardiovascular disease in nephrotic patients Inclusion of Incidence of Duration of Number nephrotic syndrome with minimalof coronary nephrotic artery disease change pattern patients syndrome — 33% > 1 year 15 [26} — > 1 year 30% 10 [25] ? 0 l8[24] >lyear + 0 Weeks to years 31 [28] + ? 0 49[27] + Not increased 159 [221 1/3 N.S. at 4 years + ? Increased 157 [23] a Number in brackets refers to reference.

with accelerated atherosclerosis [8—10]. The Framingham study found high levels of HDL cholesterol to be strongly associated with a low risk of atherosclerotic heart disease [11]. this study, however, many patients had minimal-change disThe relationship between hypertriglyceridemia and athero- ease, and only one-third were nephrotic at 4 years. Moreover, sclerotic heart disease is far less clear; some studies have found the major cause of mortality was "renal failure" (defined as a it to be a risk factor in cardiovascular disease, but others have plasma creatinine greater than 11 mgldl) or the need for dialysis not [12—14]. High plasma triglyceride levels might promote or transplantation. Given the high incidence of cardiovascular atherogenesis by elevating levels of other atherogenic lipopro- disease in the population with end-stage renal disease, some of

teins and by lowering levels of protective lipoproteins (HDL) [15]. Recent studies using dietary intervention and lipid-lowering agents have shown that the incidence of adverse cardiovascular events can be reduced by lowering the plasma cholesterol [16—18]. Moreover, small changes in the plasma cholesterol appear to translate into major decreases in adverse atherosclerotic complications. The Lipid Research Clinics Trial found that lowering plasma cholesterol 1% with cholestyramine led to a 1.5% to 2.0% decrease in cardiac ischemic events [16]. Likewise, studies have shown that raising the HDL cholesterol has similiar beneficial effects [17, 18]. Both the American Heart Association and the National Heart, Lung, and Blood Institute recommend decreasing plasma cholesterol to 200 mgldl if it contains large amounts of LDL, and if additional risk factors for atherosclerosis are present.

these patients listed as "renal failure" deaths probably died from ischemic coronary events. It is difficult in retrospective studies to sort out the risk of atherosclerosis due to hyperlipidemia from that due to hypertension, steroid therapy, and renal failure per se. Moreover, the slow rate at which atherosclerosis

and its complications develop makes it unlikely that true prospective studies will be (lone. However, a recent study compared 157 non-diabetic nephrotic patients with a matched control group and found, over a 5.6 year followup, a relative risk of coronary artery disease death of 5.5; risk of myocardial infarction, 5.3; and of all coronary artery disease, 2.5 versus the controls [23].

Few data are available on the pathology of the coronary arteries in nephrotic patients. In an autopsy study reviewing the coronary arteries of 20 such patients, significantly more athero-

sclerotic plaque and coronary luminal narrowing were found than were encountered in non-nephrotic patients [29]. However, 17 of the 20 nephrotic patients had underlying diseases typically associated with vascular complications; 4 had diabetes mellitus and 13 systemic lupus erythematosus. Moreover, the study was not controlled for steroid use, hypertension, or the presence of renal failure. One cannot conclude from this study nephrotic syndrome. As recently as 1981, workers reached that nephrotic patients without other major risk factors for diametrically opposite conclusions regarding the risk of athero- ischemic heart disease have accelerated atherosclerosis. Recently attention has focused on the pattern of lipoprotein sclerotic complications in hyperlipidemic nephrotics and their need for therapy [20, 21]. Unfortunately the data on which these abnormalities found in the nephrotic syndrome. The majority of conclusions were based were limited and remain so. Few studies have found that total cholesterol and LDL cholesterol clinical studies have assessed the incidence of coronary artery (and often VLDL cholesterol) are increased in most nephrotic disease in the nephrotic syndrome (Table 2) [22—28]. Most of patients [26-37]. As patients develop greater degrees of proteinthese studies are retrospective and flawed by small numbers, uria and more profound hypoalbuminemia, these lipid moieties selection bias, and lack of control for other atherosclerotic risk rise to even higher levels [30, 31]. Baxter et al also found greatly factors (such as smoking, hypertension, and steroid therapy). increased levels of VLDL cholesterol with a smaller rise in the Some studies included patients with minimal-change disease LDL cholesterol in the most hypoalbuminemic nephrotics [31]. who would most likely not remain nephrotic and hence not The data on HDL cholesterol have been less consistent, with remain at risk for the long-term complications of hyperlipid- values ranging from high to low [1, 19, 26—38]. Again, many emia. One large study involving a control group concluded that studies are flawed by the inclusion of patients with diabetes, there was no increased risk of ischemic heart disease, angina, or renal insufficiency, and steroid use, and by a lack of appropriate Nephrotic syndrome Hyperlipidemia often has been considered an integral part of the nephrotic syndrome [1, 19]. Only recently, however, have the lipoprotein patterns been well defined and the significance of the hyperlipidemia clarified. Moreover, there have been few studies of the effect of treatment of the hyperlipidemia of the

other atherosclerotic complications in a group of 159 adults with the nephrotic syndrome followed for a mean of 5 years [22]. In

controls. Recent, well-controlled studies of consecutive patients with uncomplicated nephrotic syndrome have found

172


Table 3. Percentage of 100 consecutive nephrotic patients with lipoprotein abnormalities

N Tot. Chol

200 mg/dl 240 mg/dI

> 9Oth%"

LDL Chol > 130 mgldl > 160 mg/dl > 9Oth%

MC FSGS Memba DM Othera Total 12

18

24

20

26

100

92 92 92

86 71

81 71

83

63

65 40 30

69 54 42

77 63 58

83 75 67

81

71

76 72

67 50

60 40 25

65 50 46

71 60 50

8

11

8

5

Il

9

HDL Chol

>90%

a MC = Minimal-change disease; FSGS = focal sclerosis; Memb = membranous nephropathy; DM = diabetes; Other proliferative GN,

heroin nephropathy, transplant nephropathy, amyloid. b Over 90th percentile for age and sex by Lipid Research Clinics.

increased levels of total, LDL, and VLDL cholesterol but normal levels of HDL cholesterol in the majority of subjects [30, 381. For example, we reported 5 years ago that 14 of 20 patients each had a total plasma cholesterol greater than the

with labeled glycerol and mevalonate have shown increased synthesis of triglyceride and cholesterol [49]. Thus, increased hepatic synthesis of both the lipid and protein moieties of the lipoproteins is established. In the nephrotic syndrome, clearance of circulating lipoproteins from plasma is impaired, and removal of labeled lipoproteins and clearance of labeled triglyceride are decreased [48, 49]. Activity of certain liporegulatory enzymes is altered, and LPL activity is decreased 30% to 60% [41]. Likewise, LCAT is

lost in the urine of nephrotic rats [46], and plasma LCAT activity is decreased in nephrotic humans [50]. Urinary loss of HDL, which is only a slightly larger substance than albumin, and of Apo Al (the major Apo in HDL) have been documented both in nephrotic rats and humans [38, 46, 50—52]. Thus, the abnormalities in plasma lipoproteins in the nephrotic patient reflect the dynamic interaction of increased hepatic synthesis, altered and diminished catabolism, and abnormal urinary losses [1, 19, 41, 53]. Workers have attempted to identify the signal to the liver that increases lipoprotein synthesis in the nephrotic syndrome. In 1960, Baxter and coworkers noted a close inverse relationship between lipid levels and the plasma albumin concentration [31].

They hypothesized that the liver responds to a decrease in 95th percentile for age and sex, and 11 of 20 had an LDL serum albumin or oncotic pressure by a generalized increase in cholesterol over the 95th percentile, but only one had an HDL the synthesis and secretion of plasma proteins, including the cholesterol level greater than the 95th percentile [30]. Moreover, 6 of the 20 patients had HDL cholesterol values less than the 10th percentile when compared with age- and sex-matched controls. The ratio of HDL cholesterol/total cholesterol was low in 85% of patients.

lipoproteins [31]. Infusion of albumin or oncotic substances into

Some studies have reported that patients with minimal-

triglyceride by cultured rat hepatocytes was inhibited by increasing the viscosity of the bathing media, but not the mass

change nephrotic syndrome have higher levels of HDL cholesterol than do other nephrotic patients [39, 401. In a recent study of 100 consecutive adult nephrotics, however, HDL levels in patients with minimal-change disease did not differ from those in nephrotics with other histopathologic findings [411 (Table 3). If the risk of atherosclerosis is increased to the same extent in

hyperlipidemic nephrotics as it is in other populations with similar degrees and patterns of hyperlipidemia, nephrotic patients also should have an increased risk of atherosclerotic coronary vascular disease. The risk to the individual patient, however, will depend on multiple other factors, including genetic predisposition, the pattern and level of the elevated lipids, the duration of unremitting nephrotic syndrome and hyperlipidemia, concurrent hypertension, renal insufficiency, and the use of lipid-altering medications, such as corticosteroids [41].

Mechanisms. The mechanisms responsible for the altered lipoprotein metabolism in the nephrotic syndrome remain unclear. Many studies support a major role for increased hepatic synthesis and secretion of lipoproteins [41]. Studies in isolated perfused livers and in slices and homogenates of livers from nephrotic rats show increased secretion of all lipoproteins and also increased incorporation of amino acids and of lipid precur-

sors into lipoproteins [42—45]. Some studies also show increased total hepatic cholesterol mass as well as increased hydroxy-methylglutaryl CoA reductase activity [45, 46]. Kinetic studies in nephrotic humans showing an increased absolute catabolic rate of LDL imply that increased synthesis accounts for elevated serum levels [47, 48]. Turnover studies

nephrotic rats and humans promptly reduced the level of plasma lipids [54, 551. However, Yedgar et al proposed that the liver might respond not to alterations in oncotic pressure but to changes in plasma viscosity [56, 57]. The secretion of VLDL concentration or osmolality of the media [56]. In nephrotic rats,

increasing plasma viscosity delayed or reduced the level of hyperlipidemia [57]. In humans with the nephrotic syndrome, however, the plasma viscosity usually is normal or elevated; thus, decreased plasma viscosity does not appear to be the stimulus for increased hepatic lipogenesis [30]. Moreover, an inverse relationship does not exist between plasma viscosity and cholesterol, as it does between the cholesterol and both the

plasma albumin concentration and plasma oncotic pressure [30]. It is still possible, however, that individual hepatocytes sense a reduced "effective viscosity," because circulating macromolecules such as lipoproteins contribute to the measured plasma viscosity in the nephrotic syndrome but are unable to pass into the hepatic sinusoids. Kaysen and colleagues measured the rate of albumin synthesis, urinary albumin loss, and lipids in 13 nephrotic patients in whom albumin synthesis and urinary protein excretion were altered by changes in dietary protein content [58]. Despite an elevated level of cholesterol and triglyceride, the rate of albumin synthesis in the nephrotics on a low-protein diet was similar

to control rates. Increasing the rate of albumin synthesis by increasing the dietary protein did not change the plasma lipid levels significantly. Thus, the serum cholesterol concentration was completely independent of the rate of albumin synthesis and only dependent on the rate of clearance of albumin [58]. The authors speculated that urinary loss of albumin or another liporegulatory substance, rather than hypoalbuminemia or low plasma oncotic pressure, stimulates hepatic lipogenesis. Yet

Nephrology Forum: Lipids in renal disease Urinary Loss of AIb or reg. substance

Altered Viscosity

Low PaIb-Ponc

0

LIPOPROTEIN ABNORMALITIES IN THE NEPHROTIC SYN.

URINARY LOSS OF HDL

DECREASED PLASMA REMOVAL

Decreased LPL

11 adult nephrotic patients in a 6-week trial; the drug lowered total cholesterol 15%, LDL cholesterol 13%, triglyceride 51%, and increased HDL cholesterol 18% [71]. In recent short-term

studies, the hydroxy-methylglutaryl CoA reductase inhibitor lovastatin (or a similar agent, simvastatin) has been used to treat the hyperlipidemia of the nephrotic syndrome and has produced a decrease in total cholesterol of 18% to 36% and a

INCREASED 1-IEPATIC SYNTHESIS

Altered lipoprotein remodeling (low LCAT)

173

0

Urinary Loss of reg. substance(s)

Fig. 2. Proposed factors that alter plasma lipoproteins in the nephrotic

syndrome. (From Ref. 41.)

decrease in LDL cholesterol of 18% to 47% [41, 48, 67—69]. The

HDL cholesterol was increased or unchanged in these studies [48, 67, 68]. The decrease in the total and LDL cholesterol clearly is directly related to the dose of lovastatin [67]. Longer followup in small numbers of nephrotic patients has disclosed similar results without major adverse effects [41]. In accord with our current understanding of the risk-benefit

ratio for therapy of nephrotic hyperlipidemia, I favor the following individualized approach to treatment [41]. All nephrotic patients should be instructed in a low-saturated-fat, low-cholesterol (less than 300 mg/day) diet. This approach might not only have beneficial effects on atherogenesis, but also

another study proposed that the lipid abnormalities in the could prevent lipid-induced glomerular damage. I'll return to nephrotic syndrome are the result not of hypoalbuminemia but this point later. Other atherosclerotic risk factors such as smoking, hypertension, and medications that elevate plasma substrate available to the liver for lipogenesis [59]. Figure 2 lipids should be eliminated. Patients with unremitting nephrotic of decreased renal mevalonate metabolism, which increases the

depicts many of the factors affecting lipid levels in the nephrotic syndrome [41]. Therapy. Several published trials have studied the treatment of the hyperlipidemia of the nephrotic syndrome [60—70]. Early studies with cholestyramine, nicotinic acid, and tryptophan led

syndrome and with significantly elevated levels of lipoproteins and unfavorable lipoprotein patterns, as well as hypercholes-

terolemic patients with preexisting vascular disease or other risk factors for atherosclerotic disease (hypertension, male gender, smoking, etc.), are most likely to benefit from drug to lowered levels of plasma lipids, but trials with clofibrate treatment. Although the antihyperlipidemic agent of choice is produced unacceptable muscle toxicity [70]. Given the uncer- not yet known, the lipoprotein pattern of the patient during tain risks of atherosclerosis and the limited evidence on efficacy therapy should be monitored to ensure lowering of total choand safety of drug therapy, many nephrologists chose not to lesterol and LDL cholesterol without lowering HDL cholesterol treat hyperlipidemic nephrotic patients. At present, good evi- levels. dence indicates that specific lipoproteins raise or lower the risk Uremic and dialyzed patients of coronary artery disease [8—11], and that lowering plasma Considerable evidence indicates that patients undergoing lipids by diet and medication in hyperlipidemic populations without renal disease reduces the risk of adverse coronary chronic dialysis have a high incidence of coronary artery events. Moreover, more effective and safer new medications disease and accelerated atherosclerosis [72—75]. Lindner and colleagues observed a 56% mortality rate at the end of 13 years are now available. Although dietary therapy alone is often recommended as the of followup of long-term hemodialysis patients; more than initial therapeutic intervention, it rarely lowers the extremely one-half of the deaths were attributed to arteriosclerotic comelevated plasma lipid levels of severely nephrotic patients. A plications [72]. Ritz et al noted the relative risk of fatal controlled trial combining a low-cholesterol (300 mg/day) and myocardial infarction to be 9- to 170-fold greater in dialyzed low-saturated-fat diet with the bile-acid-binding resin colestipol patients than in the general population [76]. Samples from the resulted in a 20% lowering of total cholesterol and a 31% renal and internal iliac arteries of uremic patients also have decrease in LDL cholesterol, without producing any significant shown accelerated atherosclerotic and vascular aging changes change in the HDL cholesterol level [63]. The drug was well as compared with vessels from control populations [77, 78]. tolerated, and few patients complained of gastrointestinal side Cardiovascular deaths remain a leading cause of mortality in effects or unpalatable taste. A trial with the bile-acid-binding dialysis patients [79]. Considerable debate remains as to resin cholestyramine yielded an 8% decrease in total cholesterol whether the high risk of cardiovascular morbidity is related to and a 19% decrease in LDL cholesterol [68]. Two trials with the dialytic process, but researchers agree that many patients probucol lowered mean total cholesterol and LDL cholesterol enter dialysis with accelerated atherosclerosis, which can lead by almost 25% but decreased HDL cholesterol 12% to 24% [63, to a high risk of early mortality during the first years of dialysis 66]. Probucol was generally well tolerated. This drug might [73, 76]. Although many factors undoubtedly contribute to the accelhave an added beneficial effect on atherogenesis by inhibiting oxidation of LDL, thus preventing LDL uptake by macro- erated atherosclerosis, lipid abnormalities have been suggested phages in the vascular wall [65]. In small numbers of patients, as a major cause, and hyperlipidemia has correlated with

short-term use of nicotinic acid produced good results in increased cardiovascular mortality in some studies [76, 79—81]. lowering total and LDL cholesterol [63]. Gemfibrozil, a fibric A number of recent reviews have focused on the subject of acid derivative, has been used successfully and safely to treat

renal failure, dialysis, and lipid abnormalities [2—5, 82].

174


Lipid patterns. Aside from patients with an associated state producing lipid abnormalities (such as the nephrotic syndrome), the cause of the renal failure does not seem to influence the pattern of lipid abnormality. Hypertriglyceridemia is the most common abnormality in patients with renal failure. Most large studies have found elevated triglyceride in 50% to 75% of all dialyzed patients [3, 74, 75, 81, 83—90]. In one study, the hypertriglyceridemia initially appeared in some patients when the glomerular filtration rate was as high as 50 mI/mm, and the prevalence of hypertriglyceridemia increased as the GFR of the studied population declined [89]. Hypertriglyceridemia occurs in undialyzed patients with renal failure, those on hemodialysis, and those on peritoneal dialysis; typically it is associated with increased levels of VLDL and the type-IV Fredrickson pattern of hyperlipidemia. Norbeck and coworkers reported an altered composition of the various lipoprotein fractions, with increased triglyceride in VLDL and IDL, and decreased cholesterol in HDL [91]. Abnormal accumulation of remnants of triglyceriderich lipoproteins, probably IDL, in dialysis patients has been proposed as an explanation for the presence of certain apoproteins not usually found in the serum [86, 90]. Hypercholesterolemia rarely occurs in uremic and dialyzed patients, and a number of studies have found low total choles-

CAPD showed no increase in HDL cholesterol over time on CAPD [98]. Two studies were able to correlate the hyperlipidemia with the amount of glucose absorption from the peritoneum during CAPD (100—200 g/24 hours) [95, 96].

Dialysate drained from CAPD patients contains both lowand high-density lipoproteins. Although Al, All, CII, CIII, and B all have been detected in the dialysate, Breckinridge et al

believe that removing these lipoproteins from the dialysate produces only a small change in plasma lipoprotein levels [98].

Other researchers have found greater loss of the Apo Al and All (associated with HDL) than of Apo B (associated with LDL) and concluded that these losses might be significantly large to influence serum levels and alter the atherogenic risk profile of CAPD patients [82, 97]. Mechanisms of hyperlipidemia. Most evidence supports de-

creased triglyceride and VLDL removal as the cause of the hypertriglyceridemia found in patients with renal failure. Thus, studies found impaired clearance of exogenously administered

chylomicrons and delayed disappearance of radiolabeled triglyceride in experimental animals, as well as delayed triglycer-

ide turnover in patients with renal failure both before and during treatment with either hemo- or peritoneal dialysis [83, 99]. The impairment in peripheral catabolism of VLDL and removal of terol levels in this population [74, 82, 90, 92]. The HDL triglyceride is secondary to impaired hepatic triglyceride lipase cholesterol values have been reported to be low in 50% to 75% activity and lipoprotein lipase activity [3, 86, 99]. Triglyceride of undialyzed uremic and hemodialyzed patients [81, 82, 90, in VLDL and chylomicrons are normally hydrolyzed by LPL.

93]; these patients also have a low HDL cholesteroL/LDL Post-heparin lipolytic activity, an indirect measure of LPL, is decreased in uremic patients and in those on dialysis [85, 861. 86]. Ponticelli et al found no correlation in dialysis patients Such decreased post-heparin lipolytic activity in turn might be between plasma triglyceride levels and age, gender, dialysis due to low levels of Apo CII, a cofactor necessary for LPL duration, basal glucose level, or insulin response to intravenous activation. In one large study of lipid abnormalities in dialysis glucose [74]. One large study did identify major differences in patients, LPL activity correlated inversely with serum triglycthe lipoprotein patterns of dialyzed patients of different races eride levels and directly with HDL cholesterol levels [86]. In [94]. White males had higher levels of triglyceride, and lower hypertriglyceridemic patients on hemodialysis who were levels of HDL cholesterol, Apo A!, and Apo All than did black treated with the lipid-lowering drug clofibrate, plasma triglycmales. White males also had lower HDL2 levels than did black eride and VLDL triglyceride decreased, but HDL cholesterol males; the HDL2 levels correlated with a higher incidence of increased; these changes occurred in association with increases cholesterol or HDL cholesterol/total cholesterol ratio [3, 75, 85,

cardiovascular mortality in the white population. Another large in adipose tissue LPL and post-heparin LPL [100]. The absence study found that coronary heart disease was significantly more of a change in hepatic lipase activity suggested a major role for common in groups with high VLDL and low HDL cholesterol impaired LPL activity in the hypertriglyceridemia of renal

[81]. When followed sequentially over time, total and JIDL failure [100]. Drawing on experimental studies in dogs with chronic renal failure, Akmal et al recently have suggested that cholesterol levels both decline in hemodialysis patients [821. The lipoprotein abnormalities and the mechanism(s) causing excess parathyroid hormone decreases LPL activity and thus them appear to differ between CAPD and hemodialysis pa- causes impaired triglyceride removal from the circulation as tients. Most patients enter CAPD with lipoprotein abnormali- well as hyperlipidemia [101]. There is also evidence for under-

ties similar to those of the rest of the uremic population.

utilization of lipoproteins in a rat model of renal insufficiency; it

Hypertriglyceridemia, if not already present, develops in most such patients within 2 to 3 months after they begin CAPD [95, 96]. In addition, levels of VLDL, LDL, and total cholesterol as well as VLDL triglyceride all rise during the first months of CAPD [95, 961. One study that did not show a change in total cholesterol after 9 to 10 months of CAPD had baseline values that were higher when CAPD was begun [82]. The level of HDL cholesterol has varied among several studies, but it does not increase with time on CAPD [82, 95—97]. In one interesting study, Breckinridge and colleagues divided a group of CAPD patients into three subgroups. The normolipidemic, nondiabetic

is unclear whether this model is relevant, because uremic rats have significant elevations of all plasma lipids (cholesterol as well as triglyceride) [1021. Some evidence also suggests increased production of triglyc-

eride. Increased production could result from stimulation of hepatic VLDL synthesis by the provision, via the dialysate, of precursors of fatty acid synthesis (for example, acetate) or through impaired carbohydrate tolerance. An additional mechanism for abnormal lipid profiles in uremic individuals is lowered LCAT activity. Normally, increased levels of VLDL and triglyceride stimulate LCAT activity. But this does not appear

CAPD patients showed an increase in HDL cholesterol to to be the case in uremia; hence the VLDL might fail to promote normal values during 3 to 6 months of CAPD; the patients who its own clearance in uremia [92]. Dieplinger et al noted low were hypertriglyceridemic or who had diabetes at the onset of levels of both cholesterol esterification and cholesterol ester


175

transfer rates to VLDL and LDL in patients with end-stage best reserved for patients at highest risk for cardiovascular renal disease who are treated with hemodialysis, as compared complications. with controls [103]. The LDL triglyceride content was markedly increased, as contrasted with that of a CAPD group with Lipid abnormalities after renal transplantation normal values. Treatment. Studies have documented the efficacy of lowcholesterol, low-saturated-fat isocaloric diets in patients with renal failure, even in those treated with hemodialysis [104—1081.

Typically, levels of triglyceride, VLDL, and LDL cholesterol

Lipid patterns. Complications of accelerated atherosclerosis are a major cause of morbidity and mortality in renal transplant recipients [116—119], and the subset of hyperlipidemic patients seems to be at increased risk for these sequelae. Cardiovascular

decrease, and HDL and HDL cholesterolltotal cholesterol disease is responsible for approximately 40% of deaths after ratios increase. The cost of such diets, their acceptability, and transplantation [116]. Whereas hypertension and the presence of accelerated atherosclerosis consequent to the preceding their long-term benefits remain to be defined. Only limited studies are available on the effect of drug dialysis undoubtedly contribute to the development of cardiotherapy in controlling the hyperlipidemia of renal failure. Clofi- vascular disease, the lipid abnormalities specific to transplant

brate can cause myositis in patients with renal failure and should not be used in regular doses [1091. Several studies in a limited number of hemodialysis patients using low doses of clofibrate (1—2 glweek) have shown a significant decrease in plasma triglyceride and an increase in HDL cholesterol without evidence of significant muscle damage [100, 1101. Using a dietary supplement of fish oil capsules rich in eicosapentanoeic acid, Hamazaki et al achieved a significant decrease in plasma levels of triglyceride and total cholesterol in 12 hyperlipidemic dialysis patients [1111. However, in five-sixths nephrectomized rats fed fish oil instead of beef tallow, renal function declined faster and glomerulosclerosis progressed more rapidly [1121. Oral charcoal administered to 6 patients with renal insufficiency significantly reduced serum cholesterol and triglyceride in the three most hyperlipidemic patients [113]. Carnitine supplementation, postulated to stimulate long-chain fatty acid oxidation,

patients are thought by some to be a major factor in the morbidity of this group. In a study of more than 200 transplant

recipients, 7% had had a myocardial infarction [118]. The patients who had had infarcts also had significantly higher total cholesterol levels than did the rest of this transplant population [118]. In another, more recent study of more than 500 transplant

patients, cardiovascular and cerebrovascular occlusive episodes occurred in almost 10% [120]. Again, these events were significantly more common in the hyperlipidemic patients.

Unfortunately, early retrospective studies did not clearly define the nature of the lipid abnormalities, the associated factors, and the potential mechanisms of the hyperlipidemia. Such studies often focused on a limited cross-section of the transplant population, with patients receiving variable immunosuppressive regimens at variable time intervals following trans-

plantation, and with the variable presence of complicating and thereby decrease substrate availability for triglyceride features (for example, diabetes, heavy proteinuria, lipid-altersynthesis, has resulted in extremely variable responses of the ing antihypertensive therapy). Recent studies have overcome hyperlipidemia in dialysis patients [114]. A recent trial of the many of these problems by following large numbers of patients hydroxy-methylglutaryl-CoA reductase inhibitor lovastatin in sequentially [118, 120]. Nevertheless, there are few studies of 18 hyperlipidemic hemodialysis patients reduced mean total the effect of lipid-lowering therapy on the lipid abnormalities cholesterol from 280 to 213 mgldl and LDL cholesterol from 161 occurring after transplantation. Numerous studies have documented hyperlipidemia in some to 112 mgldl without altering HDL cholesterol levels [115]. renal transplant patients receiving azathioprine and prednisone Triglyceride values were only minimally changed in this study as their main immunosuppressive regimen. As early as 1973, [1151. Premature cardiovascular morbidity might relate to elevated Ghosh et al reported a significant elevation of both plasma VLDL levels, decreased HDL concentration, or abnormalities cholesterol and triglyceride in a group of 32 renal transplant of composition of the various lipoproteins in patients with renal recipients [121]. Subsequent studies have confirmed hyperlipfailure. In some studies, dialysis patients with cardiovascular idemia in a significant portion of the transplant population [74, disease have had a higher mean triglyceride level than did 75, 117, 118, 120—125]. The incidence of hypercholesterolemia patients without cardiovascular events. Other studies failed to ranges from 16% to 78%, and the incidence of hypertriglycerrelate cardiovascular events to hyperlipidemia, however [73, idemia from 9% to 66% in transplant recipients receiving 74]. It is unclear whether some studies had too short a followup prednisone and azathioprine [118, 119, 122—125]. The wide period to detect major cardiovascular events, or whether they variation in the incidence of lipid abnormalities largely reflects did not relate crucial lipid factors (such as HDL cholesterol) to the different populations. In patients followed sequentially, the the risk of arteriosclerotic complications. In one large study of onset of the hypercholesterolemia typically occurs within 3 almost 350 nondiabetic patients on chronic hemodialysis, white months after transplantation, and, by 6 months, 70% of patients males had the highest rate of cardiovascular mortality and who are going to manifest hypercholesterolemia have done so highest levels of plasma triglyceride, as well as the lowest levels [120, 121]. Plasma cholesterol levels peak at 4 to 10 months post of HDL cholesterol [94]. Therapy such as dietary restriction, transplant and tend to decline from 12 to 36 months afterward. exercise programs, avoidance of lipid-elevating medications, Plasma triglyceride values typically fall during the first month and correction of other risk factors for cardiovascular disease after transplantation, rise progressively (peaking at 4 to 12 (such as smoking) all seem logical. More drastic measures such months post transplantation), and then gradually decline [119— as the use of lipid-lowering drugs or changes in peritoneal 121, 123]. In one study of more than 200 transplant recipients dialysis regimens (such as avoiding high dextrose concentra- with well-functioning allografts, 27% of the patients were hytions or using osmotic agents other than glucose) are probably percholesterolemic at one year, and 23% were hypertriglycer-

176


idemic [1181. At last followup in that study (mean of 5 years), 30% were hypercholesterolemic and 29% hypertriglyceridemic.

Studies of the pattern of lipid abnormalities in transplant recipients have found elevated levels of total, LDL, and VLDL

cholesterol [85, 88, 121, 125]. Values for HDL cholesterol usually have been high or normal, with occasional reports of low values [85, 88, 119, 124]. In a study examining the subclasses of HDL in renal transplant recipients, total HDL and HDL2 were normal, and HDL3 was reduced, as in hemodialysis patients [126]. In one study of patients followed sequentially, HDL cholesterol was 52 mg!dl at one year post-transplant and increased to 64 mg/dl at last followup; the ratio of total! HDL cholesterol declined from 5.08 to 4.36 [1181. The LDL cholesterol did not change significantly during this period. The composition of lipoproteins also is abnormal in renal transplant recipients; HDL is enriched with triglyceride and Apo A [127,

emia, whereas others correlate with the level of only one lipid type in limited populations. Of all the relationships reported, the most compelling evidence is for a positive correlation between the daily or total cumulative dose of corticosteroids and hyperlipidemia. This correlation holds for both hypercholesterolemia and hypertriglyceridemia. In a few studies, the use of corticosteroids was believed to be the single most important factor in the pathogenesis of post-transplant hyperlipidemia [120, 126]. Abnormal lipid values decline with time after transplantation as the steroid dose is decreased [120]. In one study, hypercholesterolemia decreased in transplant patients after daily corticosteroid dos-

age was changed to an alternate-day regimen [133]. Other investigators have not found this to be true [123, 134]. Likewise, the withdrawal of corticosteroids from cyclosporine-

Recent investigations have examined the lipid patterns and abnormalities in patients treated with cyclosporine [120, 129]. In a short-term study of 43 patients, Markell et al showed an

prednisone treated patients has led to a dramatic and sustained decline in hypercholesterolemia; this finding correlates with animal data showing that corticosteroids can induce hypercholesterolemia, increase hepatic lipoprotein and triglyceride production, and impair triglyceride removal [119, 120]. In non-

increase in mean total serum cholesterol, to 253 mg!dl at 3

transplant populations receiving long-term corticosteroids,

months from a pretransplant level of 192 mgldl, and an increase in serum triglyceride, from a pretransplant level of 203 mg!dl to a 3-month value of 231 mgldl [129]. In a study of almost 500 transplant patients treated with cysclosporine and prednisone, 38% were severely hypercholesterolemic (total cholesterol > 300 mg/dl), and most patients developed the hypercholesterolemia within 6 months of transplantation [120]. Only 15% and 13% of patients remained hypercholesterolemic at 2 and 3 years post transplant respectively. Severe hypertriglyceridemia (triglyceride> 500 mg!dl) occurred in 15% of the patients, with the

hypercholesterolemia and hypertriglyceridemia also have been noted [122]. Ibels and colleagues documented impaired triglyceride clearance due to reduced post-heparin plasma lipolytic activity in patients with abnormal graft function [134]. Other workers,

peak incidence at 12 months post transplant. Only 7% of the patients remained hypertriglyceridemic at 2 and 3 years. There was no difference in the incidence and severity of hypercholesterolemia between patients treated with cyclosporine and prednisone and those treated with azathioprine and prednisone, but the azathioprine group did have more severe hypertriglyceridemia. These findings contrast with those of other studies that found a significant decrease in serum cholesterol and triglyceride after patients were converted from a regimen of cyclosporine-prednisone to one of azathioprine-prednisone [130]. Some studies also found a higher mean cholesterol value in patients treated with cyclosporine or with cyclosporine plus steroids in comparison with those treated with azathioprine plus steroids [129, 130, 131]. Lipoprotein analysis showed that LDL cholesterol values were significantly elevated, whereas HDL cholesterol values were normal or elevated [120, 130, 131]. In the few studies of patients treated with cyclosporine alone, the incidence of hypercholesterolemia has been reportedly lower than, or the same as, that in transplant patients treated with cyclosporine coupled with steroids [120, 131]. Mechanisms. The cause of the hyperlipidemia in renal transplant patients is multifactorial [132]. Factors reported to positively correlate with post-transplant hyperlipidemia include: (1) daily or total prednisone dose, (2) the use of cyclosporine, (3) relative body weight or obesity, (4) renal dysfunction, (5) blood

hypertriglyceridemia in 44% [124]. Turnover studies docu-

128].

although confirming impaired VLDL triglyceride removal, could not attribute this change to changes in post-heparin LPL activity [5, 99, 135]. Investigators have proposed increased hepatic triglyceride synthesis [5, 1241. Cattran et al studied 25 patients 18 to 36 months following transplantation and noted mented overproduction of triglyceride as the major hyperlipid-

emic effect [124]. This defect was partially ameliorated by changing patients to alternate-day steroid therapy. The correlation noted by this group and others between basal insulin levels and serum triglyceride concentrations suggested that glucocorticoid-stimulated hyperinsulinism might stimulate he-

patic triglyceride production. Although other studies have confirmed the relationship between increased triglyceride levels and prednisone dosage [118, 123, 125], not all researchers have found elevated basal insulin levels [75]. Moreover, some recent

studies have failed to document any positive independent relationship between steroid dosage and triglyceride levels, despite the positive correlation with cholesterol levels [118]. Finally, at least one large study confirmed a relationship between hypercholesterolemia and steroid dosage at only one year post transplant and not at long-term followup (mean of 5 years post transplant) [118]. This finding suggested to the authors that the major lipemic effect of corticosteroids occurs early in the posttransplant period. Several groups have documented a decrease in the levels of triglyceride and cholesterol following conversion from cyclosporine to azathioprine therapy; this decrease suggests that cyclosporine itself is a factor in the production of posttransplant hyperlipidemia [131, 132, 136]. Markell and Friedman noted a

glucose concentration, (6) proteinuria, (7) patient age and higher total cholesterol level in cyclosporine-prednisonegender, (8) the presence of diabetes, and (9) the use of certain treated cardiac transplant patients than in azathioprine-preddiuretics or beta-blocking drugs. Some of these factors strongly correlate with both hypercholesterolemia and hypertriglycerid-

nisone-treated patients [117]. Several other studies, however, have not been able to document a correlation between cyclo-

177


sporine dose and concentrations and serum cholesterol or

Increased or abnormal lipoproteins

triglyceride levels [117, 125]. Moreover, a recent well-designed

study of more than 500 transplant patients documented a negative correlation between cyclosporine dose and both serum triglyceride and cholesterol levels [120]. The mean dosage of cyclosporine was lower in hyperlipidemic transplant patients

than in those without severe hyperlipidemia. Likewise, the

serum cholesterol level fell with corticosteroid withdrawal in a small group of patients maintained on cyclosporine immunosuppression alone. Several studies have documented a positive correlation between relative body weight or obesity and posttransplant hypertriglyceridemia and hypercholesterolemia [118—120, 1251.

Glomerular damage Altered hemodynamics; intraglomerular hypertension

Mesangial cell damage

Proliferation and cell death

0 Endothelial damage Altered function— platelets, macrophages, vasoactive and thrombogenic mediators

Glomeruloscierosis

Fig. 3. Potential mechanisms of lipid-induced renal damage.

Others have been unable to relate either diet or excessive cholesterol. In some models, glomerular enlargement, mesanweight gain to the hyperlipidemia [123, 124, 1291. Reduced renal

function correlates positively with hypertriglyceridemia and/or hypercholesterolemia in most studies [88, 118—120, 1251. It

remains unclear whether the effect actually is related to the effects of higher corticosteroid dosages or to the use of cyclosporine. Other factors associated with post-transplant hyperlipidemia

gial expansion, and hypercellularity precede focal glomerulosclerosis [144, 146, 147]. Endogenous hyperlipidemia in genetically obese Zucker rats also is associated with progressive glomerulosclerosis and alburninuria [148]. Progressive elevations of serum cholesterol levels in these animals correlate with the development of albuminuria and glomerular damage [147].

In obese Zucker rats, treatment with either lovastatin or

include increased age of the patient, female gender, and the clofibric acid (two unrelated lipid-lowering agents) decreased presence of diabetes mellitus [118, 120, 124, 125, 137]. Transplant patients with nephrotic-range proteinuria are often hyperlipidemic [118, 1201. As I noted earlier, some of the medications

used to treat fluid retention or hypertension—such as loop diuretics, thiazides, and beta blockers—have been associated with increased levels of triglyceride or cholesterol. Finally, elevated pre-transplant total, LDL, and VLDL cholesterol levels have been suggested in one study as the most important factor in predicting which patients will be hypercholesterolemic after transplantation [1181.

A number of studies have focused on treatment of post-

transplant hyperlipidemia. Dietary therapy has proven successful in some studies [122, 137, 1381. Some workers have found that changing to alternate-day steroid treatment is successful in

lowering lipid levels [121, 124, 133]; others have not had success with this maneuver [119, 122, 139]. Likewise, conversion from cyclosporine to azathioprine therapy has had mixed results [129, 136]. Therapy with lovastatin has lowered lipids successfully in azathioprine-treated transplant patients [129].

However, when this medication was used in cyclosporinetreated cardiac transplant recipients, it was associated with rhabdomyolysis and acute renal failure [140, 141]. Nevertheless, lovastatin appears to be efficacious and safe in cyclosporime-treated renal transplant recipients when used in low doses and monitored closely [142, 143].

Hyperlipidemia and the progression of renal disease Evidence indicates that lipids might play a causative role in progressive glomerular damage [144, 145]. Studies in animals fed lipogenic diets, in animal models of endogenous hyperlipidemia, and in hyperlipidemic animals treated with lipid-lowering drugs all support the adverse effect of hyperlipidemia on the progression of glomerulosclerosis [144, 146, 147]. Recent studies have suggested a number of possible mechanisms of this adverse effect. In several animal species, including the rat, guinea pig, and rabbit, lipogenic diets lead to focal glomerulosclerosis. The extent of glomerular injury often correlates with the serum

albuminuria and glomerulosclerosis [1481. Glomerular hemodynamics were no different than those in controls not treated with

the lipid-lowering drugs. In uninephrectomized animals with puromycin-aminonucleoside-induced nephrotic syndrome, reduction of secondary hypercholesterolemia by lovastatin reduces the extent of glomerular injury [149]. Similar favorable results have been obtained by lowering the lipid levels of rats with five-sixths nephrectomy. Animals treated with the lipidlowering medications lovastatin or clofibric acid had less albuminuria and less progressive glomerulosclerosis than did control animals [150]. No changes in systemic blood pressure or glomerular capillary pressure were noted. Protection from glomerular injury seemed to be more a function of lowering the serum cholesterol rather than of lowering the serum triglyceride, because clofibric acid, which affected only the cholesterol level, had a salutary effect equal to that of lovastatin, which lowered both the cholesterol and triglyceride levels. Likewise, in the Dahl salt-sensitive, hypertensive rat, lowering cholesterol with lovastatin reduced albuininuria and focal segmental gbmerulosclerosis [147]. Thus, in many forms of glomerular damage, lowering serum lipids and cholesterol is associated with a reduction of structural and functional renal damage. There has been much speculation about the mechanisms by which hyperlipidemia might accelerate glomerular damage (Fig. 3) [144—146]. Mesangial cells resemble modified smooth muscle

cells and can accumulate lipid material; they show specific binding and uptake of LDL [144, 146, 151] and proliferate in response to LDL. Most recently, mesangial cells have been shown to have receptors for oxidized LDL, and oxidized LDL uptake has been documented in vitro and in vivo by glomeruli.

This oxidized, more toxic form of LDL is thought to be involved in the production of atherosclerosis [152—154]. Intraglomerular lipid deposition also is seen in experimental focal glomerulosclerosis [155]. Recently, an increased content of cortical cholesteryl esters and abnormal phospholipid-fatty acid accumulation was closely linked to both glomerular and tubulointerstitial disease in an animal model of progressive renal damage [156, 157]. Moreover, cholesterol-fed animals also have

178


become hypercholesterolemic and develop glomeruloscierosis and tubulointerstitial disease in association with increased renal cortical cholesteryl ester accumulation [157, 158]. Micropuncture studies in this model demonstrate increased glomerular capillary pressure [157]. Infiltrating monocytes have been demonstrated in some of these models and might have a pathogenetic role in the production of glomerutosclerosis [157, 158]. Some investigators have proposed that it is the combination of hypercholesterolemia and intraglomerular hypertension that

with giving lovastatin to patients who are nephrotic, and what about patients who have borderline renal insufficiency? DR. APPEL: Certainly the albumin infusion data, which are old and harken back to Baxter and Goodman's work in the early l960s, are very persuasive. In terms of using lovastatin, it has

idemia causes or accelerates focal glomerulosclerosis in humans [144, 145, 157]. In a small number of morbidly obese nephrotic patients with focal glomerulosclerosis, dietary reduction leading to weight loss was associated with remission of the nephrotic syndrome and a dramatic reduction of proteinuria [160]. Although such results generally were associated with declines in the serum cholesterol level, the initial serum cho-

osclerosis, normal LDL cholesterol levels, hypertriglyceridemia, and low HDL cholesterol values. What do you do with those patients? I take it from your presentation that you would not recommend any form of medication. DR. APPEL: That's a good and difficult question. I recently

now been used in many nephrotic patients, and it has been

extremely well tolerated. Our own patients have had no trouble with liver abnormalities, gastrointestinal side effects, or rhabdomyolysis. DR. SCHAEFER: Have those nephrotic patients had mildly leads to progressive glomerular damage [159]. Also, LDL cholesterol can cause monocyte adherence to vascular endo- elevated creatinine levels? thelial cells, and this adherence can occur in the glomerulus. DR. APPEL: Some of them have a serum creatinine in the 2-4 Foam cells found in the glomeruli in certain diseases can result mg/dl range, but we have not treated nephrotic patients who from the uptake of modified LDL by monocytes/macrophages have more severe renal insufficiency. I do not know whether or mesangial cells. Elevated levels of LDL cholesterol also can lovastatin is safe and effective for patients whose serum creatmine is greater than 4 mg/dl. cause vascular endothelial damage. DR. SCHAEFER: My last question relates to hemodialysis Although in-vitro evidence suggests many of these potential mechanisms, no conclusive evidence has verified that hyperlip- patients with chronic renal failure who have established ather-

was at a symposium attended by many lipid experts and nephrologists with considerable expertise in dialysis [164]. No

lesterol value was not elevated in one such patient, and it consensus emerged as to how to treat this population. It was remained elevated in another despite major reductions in pro- clear that the majority of nephrologists and lipid experts were teinuria. A small number of other patients with genetic defects offering no treatment other than dietary therapy. I'd even be of lipid metabolism [161, 162] or various other glomerular reluctant to use dietary therapy in some dialysis patients who

diseases [163] have been shown to have evidence of large are less than optimally nourished. In general, yes, I think amounts of glomerular lipid deposition. Thus, despite great everybody should be on a low-saturated-fat diet and eat less interest and considerable research, the role of lipids in produc- than 300 mg of cholesterol. But when you impose more rigid ing progressive glomerular damage in humans remains to be diets, with only 150 mg of cholsterol daily and less than 20% fat clarified. of the total in a population in which you're already restricting In summary, lipoprotein abnormalities are common in many other things as well, I think that's difficult for the patient. DR. NICOLAOS E. MADIAS (Chief, Division of Nephrology, forms of renal disease. The exact role of hyperlipidemia in the cardiovascular morbidity and mortality in patients with these New England Medical Center, Boston): In terms of the mech-

renal diseases or in the progression of glomerular damage anism of the altered lipoprotein pattern in the nephrotic synremains to be defined. Nevertheless, a better understanding of drome, are other hypoalbuminemic states associated with simthe patterns of hyperlipidemia, the mechanisms leading to ilar lipid abnormalities? them, and the potential risks of these lipid abnormalities has DR. APPEL: It's very difficult to find other hypoalbuminemic evolved in recent years. In the individual patient, the potential states that correlate well with this. Analbuminemic people have benefits of treatment with dietary intervention or drug therapy been studied, but they have other plasma proteins and usually still must be weighed against the potential drawbacks of ther- aren't protein depleted. Further, peritoneal dialysis patients can lose large amounts of albumin in the dialysate but, as I've apy. discussed, their situation is complicated. Many other hypoalbuminemic states such as starvation are associated with low Questions and answers plasma lipid levels. DR. MICHAEL P. MADAIO (Division of Nephrology, New DR. ERNST SCHAEFER (Director, Lipid Clinic, New England England Medical Center): Could you be more specific about the Medical Center; and Chief, Lipid Metabolism Laboratory, USDA Human Nutrition Research Center on Aging at Tufts approach to therapy of hyperlipidemia in patients with kidney University, Boston, Massachusetts): I'd like to congratulate transplants? More specifically, when do you initiate therapy? you on an excellent overview. I have one comment and two Are there absolute or relative contraindications to any therapy? questions. In patients with nephrotic syndrome, albumin infu- What are your end points? DR. APPEL: First, in terms of initiating therapy, it appears sion can transiently correct hypercholesterolemia [54]. This finding is consistent with your concept about oncotic pressure that the percentage of patients who are hypercholesterolemic and albumin, and would undermine the concept that urinary decreases with time alter transplantation. It seems prudent to loss of a regulatory substance causes hyperlipidemia. A high- delay therapy other than dietary intervention in transplant molecular-weight species (3 x 106 million), LDL contributes to patients during the early posttransplant period, when they are the oncotic pressure of plasma. Have you run into any problems receiving higher doses of corticosteroids and are likely to be


treated for rejection episodes. Thus, approximately 6 months after transplantation is when we should direct vigorous therapy towards control of hyperlipidemia. Patients who are hypercholesterolemic and who have a high LDL cholesterol will probably benefit most from antihyperlipidemic drug therapy. We

have used the HMG CoA reductase inhibitor lovastatin in patients who are receiving azathioprine and corticosteroids for immunosuppression. We have not used this drug in the group treated with cyclosporine and prednisone maintenance basically because we fear the occurrence of rhabdomyolysis, which has been seen in the cardiac transplant population. However, at least three centers have reported that low-dose lovastatin (20

mg/day) is well tolerated in the cyclosporine-treated renal transplant population. So perhaps this is the way to the future. We've had some vigorous debates about whether to treat our patients on cyclosporine therapy who are still hyperlipidemic after dietary therapy with lovastatin or other lipid-lowering agents. Lovastatin is certainly more effective than any of the other lipid-lowering agents in terms of reducing LDL and total cholesterol. DR. JOHN T. HARRINGTON (Chief of Medicine, NewtonWellesley Hospital, Newton, Massachusetts): At the British

Renal Association meeting in Glasgow in 1989, the higher annual death rate in U.S. dialysis patients than in European dialysis patients, approximately 23% versus 10% to 12% per year, was discussed. Could you speculate on how much of this difference might be related to differences in hypercholesterolemia and cardiovascular disease? DR. APPEL: Those are interesting figures. I do not know how

significant is the role of hyperlipidemia in such mortality

179

cardiovascular events account for a large proportion of terminal

events during the first year. Whether a large controlled trial

would be useful is unclear. Good evidence indicates that hypertriglyceridemia itself does not correlate well as an independent risk factor for atherosclerotic disease. On the other hand, high triglyceride levels often are associated with low HDL levels and abnormal HDL composition. These are the abnormalities you would be trying to treat. DR. MADIAS: Are the lipoprotein patterns you described representative of children with renal disease, or do they apply only to adults? DR. APPEL: I know that for some populations like the transplant population, the data seem pretty much the same. Several studies have suggested that children with minimalchange nephrotic syndrome might have a more favorable pattern of hypercholesterolemia with a higher HDL than do adults.

That is, they would not be at risk for ischemic heart disease later. On the other hand, one could argue that children with minimal-change nephrotic syndrome are most likely to go into long-term remission and therefore they are not at risk for the chronic atherosclerotic complications of hyperlipidemia in any case.

DR. HARRINGTON: One of your criteria for treating the hypercholesterolemia of the nephrotic syndrome is that it be sustained. How long is it safe to not treat a nephrotic patient whose cholesterol is 350 mgldl or higher? DR. APPEL: That's a very important question. Stewart Cameron has suggested that patients should be nephrotic for 2 years before you consider them to be at high risk [1]. I disagree. By "sustained" I mean a pattern of nephrotic syndrome that is not

statistics. It would be interesting to look at whether the dietary differences correlate from country to country with mortality. DR. ANDREW S. LEVEY (Division of Nephrology, New England Medical Center): I want to follow up on Dr. Schaefer and Dr. Harrington's point that the prevalence of coronary artery

likely to go into remission either spontaneously or with therapy. In a patient with minimal-change nephrotic syndrome, I would not treat the hyperlipidemia, because one way or another we're going to get the patient into remission. On the other hand, many

mality related to atherosclerosis in this population? Also, would

patient will remain nephrotic for several months, I would begin

patients with membranous nephropathy, focal sclerosis, and disease and other clinical expressions of atherosclerosis in amyloidosis are more likely to remain nephrotic over the long patients on hemodialysis is high, yet the elevations in choles- term; with those patients, I see no advantage in delaying terol are really not so striking. How closely is the lipid abnor- antihyperlipidemic therapy. As long as you know that the

you consider it worthwhile to carry out a clinical trial of therapy. If the patient goes into remission, you can always stop the treatment. DR. MADIAS: In the experimental studies showing that a decrease in dietary lipids protected renal function, were total calories and amount of protein controlled in the diet? DR. APPEL: The studies were controlled for the percentage of but I also said that contrasting studies have shown that the vascular changes seen at pathologic examination may be due to protein in the diet. Animal data demonstrate that when one hypertension and calciumlphosphorus abnormalities. There is lowers the lipid level and succeeds in decreasing albuminuria, also controversy regarding the mortality rates of this popula- the percentage of glomerulosclerosis in these models lessens. In tion. Some studies could not find an increase in the mortality all the (admittedly short-term) studies of lipid-lowering agents rate attributed to atherosclerosis in the study populations when in nephrotic patients, there's been no change in proteinuria or in they controlled smoking, hypertension, and other factors such serum albumin or creatinine levels [63, 66—69]. Perhaps the as age, male gender, etc. The significance of the risk of the lipid studies need to be longer. But we've used the HMG CoA abnormalities in patients on hemodialysis has been soundly reductase inhibitors in nephrotic patients for several years, and triglyceride-reducing diets and agents to reduce the incidence of atherosclerosis-related clinical events? DR. APPEL: When I spoke about the atherosclerotic risk in uremic and dialyzed patients, I presented the supporting data,

debated. One of the confounding variables that one cannot

I haven't noticed any change in their proteinuna or their

easily sort out is the background these patients bring to dialysis, albumin levels; in fact, some of them are developing progresincluding metabolic problems related to renal failure, hypertensive renal failure. Thus, whether lowering lipids will have a sion, and hyperlipidemia from the nephrotic syndrome. That's beneficial effect on the progression of renal disease in humans is probably been the larger debate: whether these patients are not clear. DR. GEETHA NARAYAN (Division of Nephrology, St. Elizaentering dialysis with a high risk for atherosclerosis. Perhaps

that's why the first year of dialysis is so devastating and why

beth's Hospital, Brighton, Massachusetts): Should we treat

180


dialysis patients who have high triglycerides and low HDL? What would you treat them with to raise the HDL? Da. APPEL: The first approach is dietary therapy: low satu-

1389, 1980 13. CARLSON LA, BOTTIGER LE: Ischaemic heart disease in relation

rated fat, low total fat (in terms of the percentage of intake), and low cholesterol. All these factors have been shown to alter the lipid abnormalities in uremic and dialyzed patients. In terms of

1:865—868, 1972 14. ROSENMAN RH, BRAND RJ, JENKINS CD, FRIEDMAN M, STRAUS

other approaches, low-dose clofibrate, which is not recommended for this usage, has been successful in ameliorating hypertriglyceridemia and altering the lipid pattern. This drug is

not recommended for use because it accumulates in patients with renal failure and can cause toxicity. I don't know whether another fibric acid derivative that is not excreted by the kidney would be beneficial. I don't think these agents have been used in dialyzed patients. Because we don't have good long-term data on medications, I would suggest dietary manipulation and other maneuvers that can raise HDL, such as exercise and the avoidance of other risk factors, such as cessation of smoking and control of hypertension. DR. KLEMENS MEYER (Fellow, Division of Clinical Decision Making, New England Medical Center): Just a point on gemfibrozil. The package insert lists renal failure as a contraindication to its use. But one European study found that gemfibrozil

lowers triglyceride levels and improves other parameters of lipoprotein metabolism in patients with chronic renal insufliciency [1651. The authors noted no adverse side effects. DR. APPEL: Gemfibrozil has been used successfully in nephrotic patients to gain improvement of the lipid profile, but I have not used it myself on any dialysis patients, nor do I know of anybody in New York who has used it. Reprint requests to Dr. G. Appel, Director of Clinical Nephrology, Columbia-Presbyterian Medical Center, New York, New York 100323784, USA

triglyceride and coronary heart disease. N Engi J Med 302:1383—

to fasting values of plasma triglycerides and cholesterol. Lancet R, WURM M: Coronary heart disease in the Western Collaborative Group study: JAMA 233:872—877, 1975 15. GRUNDY SM: Management of hyperlipidemia of kidney disease. Kidney Jut 37:847—853, 1990 16. LIPID RESEARCH CLINICS PROGRAM: The lipid research clinics coronary primary prevention trial results I and II. The relationship

of reduction in incidence of coronary heart disease. JAMA 251: 351—364, 365—372, 1984

17. FRICK MH, ELO 0, HAAPA K, ET AL: Helsinki Heart Study. N Engi J Med 317:1237—1246, 1987

18. RIFKIND BM: Gemfibrozil, lipids, and coronary risk. N Engl J Med 317:1279—1282, 1987

19. BERNARD DB: Nephrology Forum: Extrarenal complications of the nephrotic syndrome. Kidney Jut 33:1184—1202, 1988 20. MALLICK NP, SHORT CD: The nephrotic syndrome and ischaemic

heart disease. Nephron 27:54-57, 1981 21. WASS V, CAMERON JS: Cardiovascular disease and the nephrotic syndrome: the other side of the coin. Nephron 27:58—61, 1981 22. WASS VJ, JARRETT RJ, CHILVERS C, CAMERON JS: Does the

nephrotic syndrome increase the risk of cardiovascular disease? Lancet 2:664—667, 1979 23. ORDONEZ JD, HIATT R, KILLEBREW F, FIREMAN B: The risk of

coronary artery disease among patients with the nephrotic syndrome. Kidney mt 37:243A, 1990 24. GILBOA N: Incidence of coronary heart disease associated with nephrotic syndrome. Med J Aust 1:207—208, 1976 25. ALEXANDER JH, SCHAPEL GJ, EDWARDS KDG: Increased inci-

dence of coronary heart disease associated with combined elevation of serum triglycerides and cholesterol in the nephrotic syndrome in man. Med fAust 2:119—122, 1974 26. BERLYNE GM, MALLICK NP: Ischaemic heart disease as a complication of nephrotic syndrome. Lancet 2:399—400, 1969 27. VOSNIDES G, CAMERON JS: Hyperlipidemia in renal disease. Med

JAust2:1985, 1974

References 1. CAMERON iS: The nephrotic syndrome and its complications. Am

JKidneyDis

10:157—171, 1987

2. CUTLER RE: Lipid disorders in renal disease: Prevalence, pathogenesis and diagnosis. Dial Transplant 17:533—536, 1988 3. RIESEN WF, MORDASINI R: Hyperlipidemia in renal failure: Phenotypes and pathogenic mechanisms. Contrib Nephrol 41:312— 320, 1984 4. MANSKE CL: Lipid abnormalities and renal disease. Kidney (NatI Kidney Fndtn) 20:25—30, 1988 5. CHAN MK, VARGHESE Z, MOORHEAD iF: Lipid abnormalities in

uremia, dialysis, and transplantation. Kidney Jut 19:625—637, 1981 6. EDEN HA: Lipoproteins and coronary artery disease. Hosp Pract, May 1983, pp 215—222 7. KANNEL WB, CASTELLI WP, GORDON T: Cholesterol in the prediction of atherosclerotic disease: new perspectives based on the Framingham Study. Ann Intern Med 90:85—91, 1979 8. LEES RS, LEES AM: High-density lipoproteins and the risk of atherosclerosis. N Engl J Med 306:1546—1548, 1982

9. LIPINSKA I, Gu!awlcH V: The value of measuring percent high-density lipoprotein in assessing risk of cardiovascular dis-

28. HOPPER J, RYAN P, LEE JC, ROSENMAN W: Lipoid nephrosis in 31 adult patients. Medicine 49:32 1—341, 1970

29. CURRY RC, ROBERTS WC: Status of the coronary arteries in the nephrotic syndrome. Am J Med 63:183—192, 1977 30. APPEL GB, BLUM CB, CHIEN S, KUNIS CL, APPEL AS: The

hyperlipidemia of the nephrotic syndrome. N Engl J Med 312: 1544—1548, 1985

31. BAXTER JH, GOODMAN HC, HAVEL FJ: Serum lipid and lipopro-

tein alterations in nephrosis. J Cliii Invest 39:455—465, 1960 32. MICHAEL! J, BAR-ON H, SHAFIR E: Lipoprotein profiles in a heterogenous group of patients with nephrotic syndrome. Isr J

Med Sci 17:1001—1008, 1981 33. OETLIKER OH, MORDASINI R, LUTSCHAG J, RIESEN W: Lipoprotein metabolism in nephrotic syndrome in childhood. Pediatr Res 14:64—66,

1983

34. OHTA T, MATSUDA I: Lipid and apolipoprotein levels in patients with nephrotic syndrome. Clin Chim Acta 117:133—143, 1981 35. CHAN MK, PERSAUD JW, RANDIAL L: Hyperlipidemia in un-

treated nephrotic syndrome, increased production or decreased removal. Clin Chim Acta 117:317—323, 1981 36. GHERARDI F, ROTA E, CALANDRA 5, GENOVA R, TAMBORINO A:

Relationship among the concentrations of serum lipoproteins and changes in their chemical composition in patients with untreated nephrotic syndrome. Eur J Clin Invest 7:563—570, 1977

ease. Arch Intern Med 142:469—472, 1982 10. MILLER GJ, MILLER NE: Plasma high-density lipoprotein concen-

37. SKOKOLOVSKAYA IV, NIKIFOROVA NV: High-density lipoprotein

tration and the development of ischaemic heart disease. Lancet

cholesterol in patients with untreated and treated nephrotic syn-

1:16—19, 1975

drome. Nephron 37:49—53, 1984

11. GORDON T, CASTELLI WP, HJORTLAND MC: High-density lipo-

38. SHORT CD, DURRINGTON PN, MALLICK NP, HUNT LP, TETLOW

protein as a protective factor against coronary artery disease: the

L, I5HOLA M: Serum and urinary high-density lipoproteins in glomerular disease with proteinuria. Kidney Jut 29:1224—1228,

Framingham Study. Am J Med 62:707—714, 1979 12. HULLY SB, ROSENMAN RH, BAWOL RD. BRAND RJ: Epidemiol-

ogy as a guide to clinical decisions: The association between

1986

39. ZILLERUELO 0, HSIA SL, FREUNDLICH M, GORMAN KM,

Nephrology Forum: Lipids in renal disease STRAUSE J: Persistence of serum lipid abnormalities in children with idiopathic nephrotic syndrome. J Pediatr 104:61—64, 1984 40. LUPES-VIRELLA M, VIRELLA G, DEBEUKELAER M, OWENS Ci,

COLWELL JA: Urinary high-density lipoproteins in minimal change glomerular disease and chronic glomerulopathy. C/in Chim Acta 94:73—81, 1979 41. APPEL GB, VALERI A, APPEL AS, BLUM C: The hyperlipidemia of

the nephrotic syndrome. Am J Med 87:5N, 45N—5lN, 1989 42. MARSH JB, SPARKS CE: Hepatic secretion of lipoproteins in the rat and the effect of experimental nephrosis. J C/in Invest 47:1685— 1695, 1968

43. SHAFIR E, BRENNER T: Lipoprotein synthesis in hypoproteinemia

of experimental nephrotic syndrome and plasmapheresis, in Plasma Protein Turnover, edited by BIANcHI R, MARINI G, MCFARLANE AS, Baltimore, University Park Press, 1976, pp 343—355

44. CALANDRA S, GHERARDI E, FAINARU M, GUAITANI A, BAR-

TOSEK I: Secretion of lipoproteins, apolipoproteins A-I and E by

isolated and perfused liver of rats with experimental nephrotic syndrome. Biochem Biophys Acta 665:331—338, 1981 45. GOLDBERG AC, OLIvERIRA HCF, QUINTAE ECR, MCNAMARA

DJ: Increased hepatic cholesterol production due to liver hypertrophy in rat experimental nephrosis. Biochim Biophys Acta 710:

181

61. EDWARDS KDG: Antilipaemic drugs and nephrotic hyperlipidemia, in Drugs Affecting Kidney Function and Metabolism. Progress in Biochem Pharmacol (vol 7), edited by EDWARDS KDG, Basel, Karger 1972, pp 370—426 62. ScHAEL Gi, EDWARDS KDG, NEALE FC: Factorial study of the efficacy of cholestyramine, L-tryptophan and clofibrate in human

nephrotic hyperlipidemia, in Drugs and the Kidney. Progress in Biochem Pharmacol (vol 9), edited by EDWARDS KDG, Basel, Karger, 1974, pp 82—98 63. VALERI A, GELFAND i, BLUM C, APPEL GB: Treatment of the hypenlipidemia of the nephrolic syndrome: a controlled trial. Am J Kidney Dis 8:388—396, 1986 64. PARTHASARATHY S, YOUNG SG, WITZTUM JL, PITTMAN RC,

STEINBERG D: Probucol inhibits oxidative modification of low density lipoprotein. J C/in invest 77:641—644, 1986 65. STEINBERG D, PARTHASARATHY 5, CAREW TE, KHoo JC, WIrz-

TUM JL: Beyond cholesterol. Modifications of low-density lipoprotein that increase atherogenicity. N Engi J Med 320:915—923, 1989

66. IIDA H, IzuMINO K, ASAKA M, FUJITA M, NI5HIN0 A, SASAYAMA S: Effect of probucol on hyperlipidemia in patients with nephrotic syndrome. Nephron 47:280—283, 1987 67. GOLPER TA, ILLINGWORTH DR, MORRIS CD, BENNETT WM:

syndrome in the rat induced by puromycin aminonucleoside. Exp

Lovastatin in the treatment of multifactonial hyperlipidemia associated with proteinuria. Am .1 Kidney Dis 8:312—320, 1989 68. RABELINK AJ, ERKELENS DW, HENE Ri, JOLES JA, KOOMANS

Mol Pathol 32:128—135, 1980 47. SCOTT Pi, WHITE BM, WINTERBOURN CC, HURLEY PJ: Low

profile in hyperlipidemia of nephrotic syndrome. Lancet 2:1335—

71—75, 1982

46. GHERARDI E, VECCHIA L, CALANDRA S: Experimental nephrotic

density lipoprotein peptide metabolism in nephrotic syndrome: a comparison with patterns observed in other syndromes characterized by hyperlipoproteinemia. Aust Ann Med 19:1—15, 1970 48. VEGA GL, GRUNDY SM: Lovastatin therapy in nephrotic hyperlipidemia: Effects on lipoprotein metabolism. Kidney mt 33:1160— 1168, 1988

49. MCKENZIE IFC, NESTEL PJ: Studies on the turnover of triglycer-

ides and esterified cholesterol in subjects with the nephrotic syndrome. J C/in invest 47:1685—1694, 1968 50. COHEN L, CRAMP DG, LEWIS AD, TICKNER JR: The mechanism

of hyperlipidemia in nephrotic syndrome—Role of low albumin and the LCAT reaction. C/in Chim Acta 104:393—400, 1980 51. FELTS JM, MAYERLE JA: Urinary loss of plasma high density lipoprotein—possible cause of the hyperlipidemia of the nephrotic syndrome. Circulation 49 & 50 (suppl 3):LII-263, 1974 52. SAKU K, MENDOZA SG, LAyER M, HYND BA, GARTSIDE PS, KASHYAP ML: High-density lipoprotein apolipoprotein Al and All

HA: Effects of simvastatin and cholestyramine on lipoprotein 1338, 1988 69. KASI5KE BL, VELOSA JA, MALSTENSON CE, LABELLE P, LANGENDORFER A, KEANE WF: The effects of lovastatin in hyperlip-

idemic patients with the nephrotic syndrome. Am J Kidney Dis 15:8—15, 1990

70. BRIDGEMAN iF, ROSEN SM, THORP JM: Complications during clofibrate treatment of nephrotic syndrome hyperlipoproteinemia. Lancet 2:506, 1972 71. GROGGEL GC, CHEUNG AK, ELLIS-BENIGN! K, WILSON DE: Safe

and effective treatment of the hyperlipidemia of nephrotic syndrome with gemfibrozil. Kidney mt 36:266—271, 1989 72. LINDNER A, CHARRA B, SHERRARD D, SCRIBNER BH: Acceler-

ated atherosclerosis in prolonged maintenance hemodialysis. N Engi J Med 290:697—701, 1974 73. ROSTAND SG, GRETES JC, KIRK KA, RUTSKY EA, ANDREOLI TE

Ischemic heart disease in patients with uremia undergoing maintenance hemodialysis. Kidney mt 16:600—611, 1979

turnover in moderate and severe proteinuria. Nephron 50:112—

74. PONTICELLI C, BARBI G, CATALUPPI A, DONATI C, ANNONI G,

115, 1988

BRANCACCI D: Lipid abnormalities in maintenance dialysis patients and renal transplant recipients. Kidney mt 13:572—578, 1978 75. IBELS LS, SIMONS LA, KING JO, WILLIAMS PF, NEALE FC, STEWART JH: Studies on the nature and causes of hyperlipidemia

53. MARSH JB, DRABKIN DL: Experimental reconstruction of meta-

bolic patterns of lipid nephrosis: key role of hepatic protein synthesis in hyperlipidemia. Metabolism 9:946—955, 1960 54. BAXTER iH, GOODMAN HC, ALLEN JC: Effects of infusions of

serum albumin on serum lipids and lipoproteins in nephrosis. J Clin invest 40:490—498, 1961

55. ALLEN JC, BAXTER JH, GOODMAN HC: Effects of dextran, polyvinylpyrrolidine and gamma globulin on the hyperlipidemia of experimental nephrosis. J C/in invest 40:499—508, 1961 56. YEDGAR S, WEINSTEIN DB, PATSCH W, SCHONFELD G, CASANDA

FE, STEINBERG D: Viscosity of culture medium as a regulator of

synthesis and secretion of very low density lipoproteins by cultured hepatocytes. J Biol Chem 257:2188—2192, 1982 57. YEDGAR S, EILAM 0, SHAFRIR E: Regulation of plasma lipid

levels by plasma viscosity in nephrotic rats. Am J Physiol 248: ElO—E14, 1985

58. KAYSEN GA, GAMBERTAGLIO J, FELTS J, HUTCHINSON FN:

Albumin synthesis, albuminuria and hyperlipidemia in nephrotic patients. Kidney mt 3 1:1368—1376, 1987 59. GOLPER TA, SWARTZ SH: Impaired renal mevalonate metabolism

in nephrotic syndrome: a stimulus for increased hepatic cholesterogenesis independent of GFR and hypoalbuminemia. Metabolism 31:471—476, 1982

60. EDWARDS KDG, SCHAPEL Gi: Nephrotic hyperlipidemia and its control by halofenate, clofibrate, and oxandrolone in a multifactonal trial in the rat (abstract). Aust NZ J Med 2:437. 1972

in uremia, maintenance dialysis and renal transplantation. Q J

Med 44:601—614, 1975 76. RITZ E, AUGUSTIN J, BOMMER J, GRASSO A, HABERBOSCH W:

Should hyperlipidemia of renal failure be treated? Kidney mt 28(Sl7):584—587, 1985 77. VINCENT! F, AMEND WJ, ABELE J, FEDUSKA NJ, SALVATIERRA

0: The role of hypertension in hemodialysis associated atherosclerosis. Am J Med 68:363—369, 1980 78. IBELS LS, ALFREY AC, HUFFER WE, CRAS WELL PW, ANDERSON

JJ, WEIL R: Arterial calcification and pathology in uremic patients undergoing dialysis. Am J Med 66:790—796, 1979 79. HAIRE HM, SHERRARD DJ, SCARDAPANE D, CURTIS FK, BRUZELL JD: Smoking, hypertension and mortality in a maintenance dialysis population. Cardiovasc Med 7:1163—1168, 1978 80. GREEN D, STONE NJ, KRUMLOVSKY FA: Putative atherogenic factors in patients with chronic renal failure. Frog Cardiovasc Dis 26:133—144, 1983

81. HAHN R, OETTE K, M0Nr0RF H, FINKE K, SIEBERTH HG: Analysis of cardiovascular risk factors in chronic hemodialysis patients with special attention to the hyperlipoproteinemias. Atherosclerosis 48:279—288, 1983 82. AVRAM MM, FEIN PA, ANIGNANI A, MITTMAN N, MUSHNICK RA, LUSTIG AR, LAPUZ MG, GOLDWASSER P: Cholesterol and

182

Nephrology Forum: Lipids in renal disease lipid disturbances in renal disease: The natural history of uremic dyslipidemia and the impact of hemodialysis and CAPD. Am J

treatment by hemodialysis or peritoneal dialysis. J C/in Invest

Med 87:(5N)55—61N, 1989 83. CATTRAN DC, FENTON SA, WILSON DR, STEINER G: Defective

104. GOKAL R, MANN ii, OLIVER DO, LEDINGHAM JGG: Dietary treatment of hyperlipidemia in chronic hemodialysis patients. Am JClinNutr3l:1915—1918, 1978 105. DORNAN TL, GOKAL R, PEARCE iS, OLIVER DO, LEDINGHAM JGG, MANN JI: Long-term dietary treatment of hyperlipidemia in patients treated with chronic hemodialysis. Br Med J 281:1044,

triglyceride removal in lipemia associated with pentoneal and hemodialysis. Ann Intern Med 85:29—33, 1976 84. BRUNZELL JD, ALBERS JJ, HAAS LB, GOLDBERG AP, AGADON L,

SHERRARD DJ: Prevalence of serum lipid abnormalities in chronic hemodialysis. Metabolism 26:903—910, 1977 85. BAGDADE JD, ALBERS JJ: Plasma high-density lipoprotein concen-

trations in chronic hemodialysis and renal transplant patients. N EnglJ Med 296:1436—1439, 1977 86. CHAN MK, PERSAUD J, VARGHESE Z, MOORHEAD J: Pathogenic roles of post-heparin lipases in lipid abnormalities in hemodialysis patients. Kidney mt 25:812—818, 1984 87. GRUTZMACHER P, Mz W, PESCHKE B, GROSS W, SCHOEPPE W:

Lipoproteins and apolipoproteins during progression of chronic renal disease. Nephron 50:103—111, 1988 88. NICHOLS J, CUMMING AM, CATTO GRD, EDWARD N, ENGESET

J: Lipid relationships in dialysis and renal transplant patients. Q J Med 198:149—160, 1981

89. FRANK WM, RAO TK, MANIS T, DELANO BG, AVRAM MM, SAXENA AK, CARTER AC,FRIEDMAN EA: Relationship of plasma lipids to renal function and length of time on maintenance hemodialysis. Am J C/in Nutr 3 1:1886-1892, 1978 90. PAPADOPOULUS NM, BORER WZ, ELIN RJ, DIAMOND LH: An abnormal lipoprotein in the serum of uremic patients maintained on chronic hemodialysis. Ann Intern Med 92:634—635. 1980 91. NORBECK HE, ORO L, CARLSON LA: Serum lipoprotein concentration in chronic uremia. Am J C/in Nutr 3 1:1881—1885, 1978 92. GUARNIERI GF, MORACCIELLO M, CAMPANACCI L, URSINI F, FERRI L, VALENTE M, GREGOLIA C: Lecithin-cholesterol acyltransferase (LCAT) activity in chronic uremia. Kidney ml 8:526— 530, 1978 93. RUBIES-PRAT J, ROMERO R, CHACON P, MASDEN S, GRIN0 J,

A: Apoprotein A and B in patients with chronic renal failure undergoing hemodialysis and in renal graft recipients. Nephron 35:171—174, 1983 CARALPS

94. GOLDBERG AP, HARTER HR, PATSCH W, SCHECHTMAN KB, PROVINCE M, WEERTS C, KUISK I, MCCRATE MM, SCHONFELD

G: Racial differences in plasma high-density lipoproteins in patients receiving hemodialysis. N Engi J Med 308:1245—1251, 1983 95. RAMOS JM, HEATON A, MCGURK JG, WARD MK, KERR DNS:

Sequential changes in serum lipids and their subfractions in patients receiving continuous ambulatory peritoneal dialysis. Nephron 35:20—23, 1983 96. LINDHOLM B, NORBECK HE: Serum lipids and lipoproteins during

continuous ambulatory peritoneal dialysis. Ada Med Scand 220: 143—151, 1986

97. SAKU K, SASAKI J, Nrro 5, AVAKAWA K: Lipoprotein and apolipoprotein losses during continuous ambulatory peritoneal dialysis. Nephron 51:220—224, 1989 98, BRECKINRIDGE WC, RONCARI DAK, KHANNA R, OREoPouLos DG: The influence of continuous ambulatory peritoneal dialysis on plasma lipoproteins. Atherosclerosis 45:249—258, 1982 99. SAVDIE E, GIBSON JC, CRAWFORD GA, SIM0N5 LA, MAHONEY

JF: Impaired plasma triglyceride clearance as a feature of both uremic and post-transplant triglyceridemia. Kidney ml 18:774— 782, 100.

1980

77:1071—1083, 1984

1980

106. SANFELIPPO ML, SWENSON RS, REAVEN GM: Response of

plasma triglycerides to dietary changes in patients on hemodialysis. Kindey mt 14:180—186, 1978 107. TSUKAMOTO Y, OKUBO M, YONEDA T, MARUMO F, NAKAMURA

H: Effects of a polyunsaturated fatty acid rich diet on serum lipids in patients with chronic renal failure. Nephron 31:236-241, 1982 108. CATFRAN DC, STEINER G, FENTON SSA, AMPIL M: Dialysis

hyperlipemia: response to dietary manipulation. Clin Nephrol 13:177—182, 1980

109. LANGER T, LEVY RI: Acute muscular syndrome associated with administration of clofibrate. N Engi J Med 279:856-858, 1968 110. SHERRARD DJ, GOLDBERG AB, HASS LB, BRUNZELL JD: Chronic

clofibrate therapy in maintenance hemodialysis patients. Nephron 25:219—221,

1980

111. HAMAZAKI T, NAKAZAWA R, TATENO 5, SHISHIDO H, ISODA K, HATTORI Y, YOSHIDA T, FUJITA T, YANO S, KUMAGAI A: Effects

of fish oil rich in eicosapentaenoic acid on serum lipids in hyperlipidemic hemodialysis patients. Kidney mt 26:81—84, 1984 112. SCHARSCHMIDT LA, GIBBONS NB, MCGARNY L, BERGER P,

AXELROD M, JANIS R, Ko YH: Effects of dietary fish oil on renal insufficiency in rats with subtotal nephrectomy. Kidney mt 32:700— 709, 1987 113. FRIEDMAN EA, FEINSTEIN El, BEYER MM, GALONSKY RS, HIRSCH SR: Charcoal induced lipid reduction in uremia, Kidney

Jut 13:S170—176, 1978 114. GUARNIERI G, TOIGO G, CRAPESI L, SITULIN R, DELBIANCO A, C0R5I M, LOGRECO P, PAVIOTTI G, MI0NI G, CAMPANACCI L: Carnitine metabolism in chronic renal failure. Kidney Int 32:S1 16— S127, 1987 115. WANNER C, WIELAND M, SCHOLLMEYER P, MORL WM: Effect of lovastatin on the lipoprotein system of hyperlipidemic hemodialysis patients. Kidney mt 37:323(A), 1990 116. EDITORIAL: Hyperlipidemia after renal transplantation. Lancel 1:919—920, 1988

117. MARKELL MS, FRIEDMAN EA: Hyperlipidemia after organ transplantation. Am J Med 87:5N:61N—67N, 1989 118. KASISKE BL, UMEN AJ: Persistent hyperlipidemia in renal transplant patients. Medicine 66:309—316, 1987 119. IBEL5 LS, ALFREY AC, WElL R: Hyperlipidemia in adult, pediatric, and diabetic renal transplant recipients. Am J Med 64:634-642, 1978

120. VATSALA A, WEINBERG RB, SCHOENBERG L, GREVEL J, GOLD-

STEIN RH, VAN BUREN CT, LEWIS RM, KAHAN BD: Lipid abnormalities in cyclosporine-prednisone treated renal transplant recipients. Transplantation 48:37—43, 1989 121. GHOSH P, EVANS DB, TOMLINSON SA, CALNE RY: Plasma lipids

following renal transplantation. Transplantation 15:521—523, 1973 122. GOKAL R, MANN JI, MOORE RA, MORRIS PJ: Hyperlipidemia following renal transplantation. Q J Med 48:507—517, 1979 123. PONTICELLI C, BARBI GL, CANTALUPPI A, DEVECCHI A, ANNONI G, DONNATI C, CECHETTIN M: Lipid disorders in renal

GOLDBERG AP, APPELBAUM-BOWDEN DM, BIERMAN EL, HAZtransplant recipients. Nephron 20:189-195, 1978 ZARD WR, HAAS LB, SHERRARD Di, BRUNZELL JD, HUTTUNEN124. CATTRAN DC, STEINER G, WILSON DR, FENTON SSA: Hyperlip-

JK, EINHOLM C, NIKKILA EA: Increase in lipoprotein lipase during clofibrate treatment of hypertriglyceridemia in patients on hemodialysis. N EnglJ Med 301:1073—1076, 1979 101. AKMAL M, KASIM SE, SOLIMAN AR, MASSRY SG: Excess para-

thyroid hormone adversely affects lipid metabolism in chronic

renal failure. Kidney mt 37:854—858, 1990 102. HUECK CC, LIERSCH M, RITZ E, STREGMEIER K, WIRTH A, MEHLS 0: Hyperlipoproteinemia in experimental chronic renal insufficiency in the rat. Kidney mt 14:142—150, 1978 103. DIEPLINGER H, SCHOENFELD PY, FIELDING CJ: Plasma choles-

terol metabolism in end-stage renal disease: Difference between

idemia after renal transplantation: Natural history and pathophysiology. Ann Intern Med 91 :554—559, 1979 125. CHAN MK, VARGHESE Z, PERSAUD JW, FERNANDO ON, MOORHEAD J: The role of multiple pharmaco-therapy in the pathogenesis of hyperlipidemia after renal transplantation. C/in Nephrol 15:309—313, 1981

126. LOWRY RP, SOLTYS G, MANGEL R, KWITEROVITCH P, SNIDERMAN AD: Type II hyperlipoproteinemia, hyperapobetalipopro-

teinemia, and hyperalphalipoproteinemia following renal transplantation. Transplant Proc 19:2229—2232, 1987 127. JUNG K, NEUMANN R, SCHOLZ D, NUGEL E: Abnormalities in the

183

Nephrology Forum: Lipids in renal disease composition of serum high density lipoprotein in renal transplant

sclerosis: Analogies to atherosclerosis. Kidney

mt 33:917—924,

1988

recipients. C/in Nephrol 17:191—194, 1982 128. JUNG K, SCHEIFLER A, BLANK W, SHOLZ D, SCHULZE BD,

147. KEANE WF, KASISKE BL, O'DONNELL MD, SCHMITZ PG: Ther-

HANSEN C: Changed composition of high-density lipoprotein subclasses HDL2 and HDL3 after renal transplantation. Trans-

apeutic implications of lipid lowering agents in the progression of renal disease. Am J Med 87:(5N)2l—24N, 1989

plantation 46:407—409, 1988 129. MARKELL MS, BROWN CD, FRIEDMAN EA: Risk of early posttransplant hyperlipidemia in cyclosporine treated renal transplant

148. KASISKE BL, O'DONNELL MD, CLEARY MP, KEANE WF: Treat-

1nt35:519, 1989 130. HARRIS KPG, RUSSEL GI, PARVIN SD, VEITCH PS, WALLS J:

ment of hyperlipidemia reduces glomerular injury in obese Zucker rats. Kidney mt 33:667—672, 1988 149. HARRIS KPG, PURKERSON ML, YATES J, KLAHR S: Lovastatin ameliorates the development of glomerulosclerosis and uremia in experimental nephrotic syndrome. Am J Kidney Dis 15:16—23,

Alterations in lipid and carbohydrate metabolism attributable to cyclosporine A in renal transplant recipients. Br Med J 292:16,

150. KASISKE BL, O'DONNELL MP, GARVIS WJ, KEANE WF: Pharma-

patients is related to pretransplant LDL level (abstract). Kidney

1990

cologic treatment of hyperlipidemia reduces glomerular injury in

1986

rat 5/6 nephrectomy model of chronic renal failure. Circ Res

131. RAINE AEG, CARTER R, MANN JI, CHAPMAN JR, MORRIS PJ:

Increased plasma LDL cholesterol after renal transplantation associated with cyclosporine immunosuppression. Transplant

62:367—374, 1988

151. WASSERMAN J, SANTIAGO A, RIFIcI V, MOLTHOFER H, SCHARSCHMIDT L, EPSTEIN M, SCHLONDORFF D: Interaction of

Proc 19:1820—1821, 1987

132. RAINE AEG, MORRIS PJ: Hyperlipidemia after renal transplantation. Lancet 2:391, 1988 133. CURTIS JJ, GALLA JH, WOODFORD SY, LUCAS BA, LUKE RG:

low density lipoprotein with rat mesangial cells. Kidney mt 35:1168—1174, 1989 152. CORITSIDIS G, RIFICI V, SCHLONDORFF D: The effects of oxidized

lipoproteins on cultured mesangial cells (MC) (abstract). Kidney tnt 37:502A, 1990

Effect of alternate-day prednisone on plasma lipids in renal transplant recipients. Kidney ml 22:42—47, 1982 134. IBELS LS, REARDON MF, NESTEL PJ: Plasma post-heparin lipolytic activity and triglyceride activity in uremic and hemodialysis patients and allograft recipients. J Lab C/in Med 87:648—658, 1976 135. CRAWFORD GA, SAVDIE E, STEWART JH: Heparin-released plasma lipases in chronic renal failure and after renal transplantation. C/in Sci 57:155—165, 1979 136.

VERSLIUS DJ, WENTING GJ, DERKX FHM, SCHALEKAMP MADH,

JEEKEL J, WEIMAR W: Who should be converted from cyclospo-

rine to conventional immunosuppression in kidney transplantation, and why. Transplantation 44:387—389, 1987 137. SHEN SY, LUKENS CW, ALONGI SV, SFEIR RE, DAGHER FJ,

SADLER JH: Patient profile and effect of dietary therapy on post-transplant hyperlipidemia. Kidney tnt 24:S147—l52, 1983

153. C0RITSIDI5 G, NEUGARTEN J, SCHLONDORFF D: In vivo glomer-

ular uptake of native and oxidized low density lipoprotein. Kidney tnt 37:501A, 1990 154. MULCAHY WS, SMITH JB, SELAK M, KRISHNA GG: Cytotoxicity of

low density lipoprotein (LDL) in cultured rat mesangial cells

(MC). Kidney tnt 37:514(A), 155.

1990

OSHSAWA H, YAMABE H, OZAWA K, FUKUSHI K, KUBOTA H, CHIBA N, SOHMA Y, KANAZAWA T, ONADERA K: Intraglomerular

lipid deposition in experimental focal glomerular sclerosis in the rat. Nephron 50:66, 1988 156. KASISKE BL, O'DONNELL MP, CLEARY MP, KEANE WF: Effects

of reduced renal mass or tissue lipids and renal injury in hyperlipidemic rats. Kidney ml 35:40—47, 1989 157. KASISKE BL, O'DONNELL MP, SCHMITZ PG. KIM Y, KEANE WF:

138. NELSON J, BEAUREGARD H, GELINAS M, ST. LOUIS G, DALOZE P,

Renal injury of diet-induced hypercholesterolemia in rats. Kidney

SMEESTER5 C, CORMAN J: Rapid improvement of hyperlipidemia

mnt37:880—891, 1990 158. AL-SHEBEB T, FROHLICH J, MAGIL AB: Glomerular disease in

in kidney transplant patients with a multifactorial hypolipidemic diet. Transplant Proc 20:1264—1270, 1988

hypercholesterolemic guinea pigs: A pathogenetic study. Kidney

139. DRUKKER A, TURNER C, START K, MUNIAN A, WASS V, HAY- tnt 33:498—507, 1988 159. ANDERSON S, KING AJ, BRENNER BM: Hyperlipidemia and COCK G, CHANTLER C: Hyperlipidemia after renal transplantation

140.

in children on alternate day corticosteroid therapy. Clin Nephrol

glomerular sclerosis: An alternative view point. Am J Med 87:

26: 140-145, 1986 EAST C, ALIVIZATOS PR, GRUNDY SM, JONES PH, FARMER JA:

(5N)34—38N, 1990 160. WEISINGER JR, KEMPSON RL, ELDRIDGE FL, SWENSON RS: The

Rhabdomyolysis in patients receiving lovastatin after cardiac transplantation. N Engi J Med 318:48, 1988 141. NORMAN DJ, ILLINGSWORTH DR, MUNSON J, HOSENPUD J:

Myolysis and acute renal failure in a heart transplant recipient receiving lovastatin. N Engi J Med 318:46—47, 1988 142. KUPIN V, VENKAT KK, OH HK, STALLAK , Mozs M: Treatment of hypercholesterolemia with lovastatin in renal transplant recipients. Am Soc Transplant Physicians 8th Annu Mtg, Chicago, 1989 143. KASISKE BL, TORTORICE KL, HEIM-DOTHOY KL, RAO KY:

nephrotic syndrome: A complication of massive obesity. Ann Intern Med 81:440—447, 1974 161. MOORHEAD JF, EL-NAHAS M, HANNY D, ET AL: Focal glomerular

and nephrotic syndrome with partial lecithin: cholesterol acyltransferase deficiency and high density lipoprotein. Lancet sclerosis

1:936—938, 1982

162. SAITO T, SATO K, KUDO K, ET AL: Lipoprotein glomerulopathy: Glomerular lipoprotein thrombi in a patient with hyperlipoprotein-

uria.AmJKidneyDis 13:148—153,1989

Cholesterol synthesis inhibition reduces total and low density lipoprotein cholesterol in renal transplant recipients. Am Soc

163. AVRAM MM:

Transplant Physicians 8th Annu Mtg, Chicago, 1989

glomerulopathy. Am J Med 87:(5N)39—41N, 1989 164. AVRAM MM (ED): Role of cholesterol and lipids in renal disease. Am J Med 87:(5N)l—75N, 1989

144. KEANE WF, KASISKE BL, O'DONNELL MD: Lipids and progressive glomerulosclerosis. Am J Nephrol 8:261—271, 1988 145. MOORHEAD JF, EL-NAHAS M, CHAN MK, VARGHESE Z: Lipid nephrotoxicity in chronic progressive glomerular and tubulointerstitial disease. Lancel 2:1309—1311, 1982 146. DIAMOND JR. KARNOVSKY MJ: Focal and segmental glomerulo-

Similarities between glomerular sclerosis and ather-

osclerosis in human renal biopsy specimens: A role for lipoprotein

165. PASTERNACK A, VANTINNEN T, SOLOVAKI T, KUUSI T, KORTE T:

Normalization of lipase and hepatic lipase by gemfibrozil results in

correction of lipoprotein abnormalities in chronic renal failure. Clin Nephrol 27:163—168, 1987

Lipid lowering in renal disease.

Basic data related to lipid abnormalities in peripheral vascular disease.

Lipid abnormalities in kidney disease and management strategies.

Comments on renal abnormalities of sickle cell disease.

Trace elements and lipid peroxidation abnormalities in patients with chronic renal failure.

Lipid abnormalities and lipid-based repair strategies in atopic dermatitis.

Stratum corneum lipid abnormalities in atopic dermatitis.

Lipid Abnormalities and Inflammation in HIV Inflection.

[Detection of lipid abnormalities in blood donors].

Lipid abnormalities in patients with Rheumatoid Arthritis.

Persistent lipid abnormalities in statin-treated coronary artery disease patients with and without diabetes in China.

Blunt renal trauma in children with pre-existing renal abnormalities.

Extrahepatic cell membrane lipid abnormalities and cellular dysfunction in liver disease.

An overview of lipid abnormalities in patients with inflammatory bowel disease.

Gaucher disease: plasmalogen levels in relation to primary lipid abnormalities and oxidative stress.

Association of serum testosterone with lipid abnormalities in patients with angiographically proven coronary artery disease.

Abnormalities of lipoprotein composition in renal insufficiency.

Cytogenetic abnormalities in renal oncocytic neoplasms.

Antenatal detection of renal abnormalities.

A grading index of serum lipid abnormalities.

Serum lipoprotein abnormalities in renal allograft recipients.

Lipid metabolism in renal failure.

Current Focuses in Serum Lipid Abnormalities in Dialysis Patients.

TLR9 Deficiency Leads to Accelerated Renal Disease and Myeloid Lineage Abnormalities in Pristane-Induced Murine Lupus.