Hyperlipidemia in the Nephrotic Syndrome

VIGNETTES IN CLINICAL PATHOPHYSIOLOGY

Hyperlipidemia in the Nephrotic Syndrome George A. Kaysen, MD, PhD INDEX WORDS: Albumin synthesis; glomerular permselectivity; hyperlipidemia; cholesterol; triglycerides; lipoproteins; proteinuria.

H

YPERLIPIDEMIA may be a severe and refractory manifestation of the nephrotic syndrome, responsible for accelerated atherogenesis. Nephrotic hyperlipidemia results from both the increased hepatic synthesis of lipids and their decreased rate of removal from the circulation. This combined defect may be caused by both the urinary loss of substances necessary for normal lipid metabolism and decreased plasma oncotic pressure. The following case demonstrates both the severity of the hyperlipidemia and the fluctuations that occur in blood lipids in parallel with proteinuria (Fig 1). Questions

1. What is the character and cause of hyperlipidemia in nephrotic patients? 2. What, if any, clinical significance does disordered lipid metabolism have in nephrosis? 3. Is there any effective therapy for the disordered lipid metabolism? CASE PRESENTATION A 69-year-old man first presented to the hospital in April 1985 with pedal edema, shortness of breath, and a burning sensation in his extremities. A diagnosis of amyloidosis was made on renal biopsy. Melphelan, 0.2 mg/kg, and prednisone, 2 mg/ kg, were administered for six days every 6 weeks starting in May 1985, for a total of six cycles, in conjunction with dietary protein restriction to 0.8 g/kg. Urinary protein loss decreased, serum protein concentration increased, and edema improved by the end of the sixth cycle. Angiotensin-converting enzyme (ACE) inhibitors were not used in this patient because of persistently low BP (100170 to 110/80). Niacin, 1.5 g/d, was administered in March 1987, but was discontinued because of an increase in the burning sensation in his hands and feet. The From the Division of Nephrology, Department of Medicine. l-eterans Administration Medical Center, Martinez. CA, and the University of California Davis School of Medicine. Davis, CA. Supported in part by the research service of the US l-eterans Administration. Address reprint requests to George A. Kaysen. MD, PhD, Chief of Nephrology, l-eterans Administration Medical Center. 150 Muir Rd, Martinez. CA 94553. © 1988 by the National Kidney Foundation, Inc. 0272-6386/881I206-0014$3.00/0

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patient reported an episode of pressing substernal chest pain in June 1987. and although an acute myocardial infarction was ruled out at that time, his ECG was changed from one previously obtained, showed a new right bundle branch block, and was compatible with inferior wall infarction of indeterminate age. A gated wall motion study performed at that time revealed a left ventricular ejection fraction of 46 %, decreased from a value of 56% reported on a similar study performed in April 1986. A presumptive diagnosis was made of an acute myocardial infarction having occurred during the interval between studies. Chemotherapy was again instituted in November 1987, after edema worsened and urinary protein increased. Serial measurements appear in Table I. Analysis of serum lipoproteins in January 1988 revealed that cholesterol was reduced in the high-density lipoprotein (HDL), ex region, (cholesterol 29 mg/dL, normal value 30 to 70 mg/dL; triglycerides 22 mg/dL, normal value 5 to 20 mg/mL). Cholesterol was increased in the intermediate-density lipoprotein-low -density lipoprotein) (lDL-LDL, pre-~) region, lDL cholesterol and triglycerides were each 97 mg/dL, LDL cholesterol was 179 mg/dL and triglycerides were 45 mg/dL. Neither very-low-density lipoprotein (VLDL) cholesterol (50 mg/dL) nor VLDL triglycerides (112 mg/dL) was increased. Chylomicrons were not detectable. The dyslipoproteinemia was not classifiable but was characterized by low ex (HDL) and increased pre-~ (lDL) lipoproteins. The LDL-to-HDL cholesterol ratio of 9.52 was greatly increased.

DISCUSSION

Question 1

Both increased lipid synthesis and decreased removal of circulating lipids contribute to hyperlipidemia in the nephrotic syndrome. l The characteristic disorder in nephrotic patients is an increase in the VLDL and/or IDL fraction and a decrease in HDL, resulting in an increase in the LDL-to-HDL cholesterol ratio. In addition to this quantitative defect in lipoprotein distribution, a qualitative defect also occurs within the lipoprotein fractions of nephrotic patients. The proportion of cholesterol to triglycerides (as seen in this patient) and of cholesterol, cholesterol esters, and phospholipids to proteins is increased in each lipoprotein fraction compared with nonnephrotic hyperlipidemic control patients, who have only a quantitative abnormality in serum lipids. Lipoprotein particles rich in phospholipid and esterified and nonesterified

American Journal of Kidney Diseases, Vol XII. No 6 (December). 1988: pp 548·551

HYPERLIPIDEMIA IN THE NEPHROTIC SYNDROME

549

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Fig 1. Normal pathways of lipoprotein metabolism and potential derangements occurring in the nephrotic syndrome. Cholesterol and cholesterol esters are represented by Chol, triglycerides as TG. Each lipoprotein particle is shown to be surrounded by a shell of apolipoproteins, but the specific apolipoproteins associated with each group of particles is not represented. Loss of heparan sulfate leads to inactivation of tissue lipoprotein lipase, causing potential blocks in lipolysis in peripheral tissues with a resultant block in lipid uptake by these tissues in nephrosis (shown). Reduced lipoprotein lipase activity causes both a reduced rate of catabolism of lipoproteins and the formation of abnormal remnant particles. These abnormal remnant particles are not adequately recognized by the liver and uptake of them by that tissue is therefore reduced in nephrosis. Cholesterol biiosynthesis is normally down-regulated by cholesterol transported to the liver. Because the hepatic uptake of lipids is reduced in nephrosis, this normal process of down-regulation of HMG CoA reductase by pinocytosed cholesterol is deranged in nephrosis. Both LDL and chylomicron remnants are shown to be taken up by the same LDL receptor, but in fact uptake of these particles may be partially mediated by separate receptors.

perm selectivity is severely disrupted. While phenotypic classification of the dyslipoproteinemias associated with the nephrotic syndrome is difficult, if not useless , the prevalence of all types of lipoprotein abnormalities except type I have

cholesterol, resembling VLDL and chylomicron remnants (IDL) , accumulate. These may result from an inability to convert VLDL and IDL to LDL. In addition , HDL, but not the larger lipoproteins , is lost in the urine when glomerular Table 1. Date

April 1985 May 1985 December 1986 November 1987 January 1988

Chemical Studies

Chol (mg/dL)

Trig (mg/dL)

Salb (g/dL)

Sprot (g/dL)

Uprot (g/d)

Clprot (I'Umin)

CICr (mUmin)

770 726 306 434 349

1780 1580 372 325 335

2.41 2.32 3.0 1.9 2.2

4.5 4.0 5.4 3.4 4.1

18.1 19.6 5.6 14.3 9.4

279 341 72 292 159

67.9 91.9 57.3 29 50

Abbreviations: Chol, serum cholesterol; Trig, serum triglycerides; Salb, serum albumin concentration; Sprot, serum total protein; Uprot, urinary protein excretion; Clprot, renal clearance of protein (urinary albumin measurements were not available so renal protein clearance is presented rather than renal albumin clearance); CICr, endogenous creatinine clearance.

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been reported to increase. The prevalence of type IV hyperlipidemia has been reported to be greatest in some series, while types lIb, III, and V have had the highest prevalence in others. Diabetes mellitus does not exert an independent effect on serum lipoprotein class nor on total serum cholesterol and triglyceride concentration when the nephrotic syndrome is present. Although hyperlipidemia is one of the hallmarks of the nephrotic syndrome, the precise cause of increased synthesis and decreased clearance of lipoproteins is controversial. That increased hepatic synthesis of lipids and lipoproteins occurs parallel with and as a result of increased albumin synthesis in nephrosis has been postulated. 2 However, increased lipid levels may occur in nephrotic patients without an increased rate of albumin synthesis. We found that although the rate of albumin synthesis was not increased in nephrotic patients eating a low-protein diet (12.61 ± 1.20 g/1.73 M2/d in nephrotic patients compared with a control value of 13.80 ± 0.77 g/1.73 M 2 /d), both serum cholesterol (325 ± 44 mg/dL) and triglycerides (265 ± 65 mg/dL) were elevated in the nephrotic patients. 3 Thus no clear link could be established between hyperlipidemia and the rate of albumin synthesis. Both serum cholesterol and triglyceride concentration correlated with the renal clearance of albumin rather than with its rate of synthesis. This observation supports the hypothesis that the urinary loss of a lipid regulatory substance may play a role in the pathogenesis of nephrotic hyperlipidemia. Garber et a1 4 found that lipoprotein lipase (LPL) activity was reduced in nephrotic rats and suggested that the reduction in LPL activity was responsible for the incomplete conversion of VLDL and remnant particles (IDL) to LDL and HDL. Staprans and Felts 5 then showed that when the ai-acid glycoprotein (aAG) fraction isolated from the urine of nephrotic patients was injected into nephrotic rats, the defect in removal of triglycerides and the decreased LPL activity were corrected. aAG is a 44-Kd highly negatively charged polymer that stimulates LPL in vitro and is likely to be lost in the urine in parallel with albumin. aAG carries with it an essential LPL cofactor, heparan sulfate. The urinary loss of heparan sulfate therefore causes depletion of this important cofactor in nephrosis. Decreased LPL activity, by reducing the rate of lipolysis in

GEORGE A. KAYSEN

peripheral tissue, seems to be responsible for the decreased rate of removal and processing of circulating VLDL and IDL particles. Cholesterol and triglycerides taken up by the liver normally down-regulate the hepatic production of these lipids. Reduced hepatic uptake of cholesterol and triglycerides from the incompletely metabolized VLDL and IDL remnant particles may therefore lead to failed down-regulation of hepatic synthesis of these lipids, thus linking their reduced rate of clearance with their increased rate of synthesis. It is probable that reduced oncotic pressure also contributes to but is not the only cause of hyperlipidemia in nephrosis, a disorder characterized both by reduced serum oncotic pressure and by the urinary loss of macromolecules. However, reduced serum oncotic pressure may exert a direct effect on lipid homeostasis independent of any effect on albumin synthesis. Analburninernic humans and analbuminemic rats without kidney disease have increased serum concentrations of both cholesterol and triglycerides. Infusion of oncotically active macromolecules (albumin or dextran) reduces serum lipids in both animals with the nephrotic syndrome and in analbuminemic rats, further supporting a link between decreased serum oncotic pressure and hyperlipidemia. 6 .7 In some reports, increased serum lipid levels in nephrotics have been correlated with hypoproteinemia or hypoalbuminemia. However, in the case presented here, both serum cholesterol and triglycerides were significantly correlated with urinary protein excretion (r = 0.946, P < 0.01 and r = 0.846, P < 0.05, respectively) but did not vary in any predictable way with serum protein or albumin concentrations. Changes in blood lipids therefore appear to have occurred in this patient as a result of changes in glomerular permeability, as we have previously reported for other patients. 3 Question 2

Accelerated atherosclerosis occurs in patients with proteinuria and hyperlipidemia, resulting in a sharply increased incidence of cardiovascular disease and stroke. One study reported an 85-fold increase in the incidence of ischemic heart disease in such patients. 8 Indeed such an outcome would be expected from the reduced HDL cholesterol and massive increase in total cholestrerol.

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HYPERLIPIDEMIA IN THE NEPHROTIC SYNDROME

Question 3

Primary therapy should be directed at reducing the increased renal clearance of macromolecules. In the best of circumstances this therapy would be primary treatment of the underlying renal lesion, such as the use of corticosteroids in treatment of minimal-change nephrotic syndrome. Consumption of a diet rich in protein increases the renal clearance of albumin and does not lead to increased albumin pools. 9 Reduction in dietary protein intake to 0.8 to 1.0 g/kg may therefore also playa role in the conservative management of the nephrotic patient. 3,9 The use of ACE inhibitors has been found to reduce proteinuria in patients with a variety of renal lesions and may therefore prove effective in reducing serum lipids as a consequence of reduced proteinuria. In preliminary studies in our laboratory we found that when pro-

teinuria was reduced in nephrotic patients treated with the ACE inhibitor enalapril, serum cholesterol was also reduced even though albumin synthesis was not altered. The hepatic activity of HMG CoA reductase, the rate-limiting enzyme in the regulation of hepatic cholesterol synthesis, is increased in nephrosis. Lovastatin, a potent inhibitor of HMG CoA reductase, is available for treatment of hypercholesterolemia, but it remains to be demonstrated whether such therapy is indeed salutary in nephrotic patients. The ability of the aAG fraction of human urine to correct the defect in catabolism of circulating lipids in nephrotic rats suggests that a clinical armamentarium directed at each of the defects characteristic of nephrotic hyperlipidemia (increased synthesis and decreased removal of serum lipids) may one day be available.

REFERENCES 1, Chan MK, Persaud JW, Ramdial L, et al: Hyperlipidemia in untreated nephrotic syndrome, increased production of decreased removal? Clin Chern Acta 117:317-323, 1981 2, Marsh JB, Drabkin DK: Experimental reconstruction of metabolic patterns of lipoid nephrosis, Key role of hepatic protein synthesis in hyperlipidemia, Metabolism 9:946-955, 1960 3, Kaysen GA, Gambertoglio J, Felts JM, et al: Albumin synthesis, albuminuria and hyperlipidemia in nephrotic patients, Kidney Int 31:1368-1376, 1987 4, Garber DW, Gottlieb BA, Marsch JB, et al: Catabolism of very low density lipo-proteins in experimental nephrosis, J Clin Invest 74: 1375-1383, 1984 5, Staprans I, Felts JM: The effect of a-acid glycoprotein

(orosomucoid) on triglyceride metabolism in the nephrotic syndrome, Biochem Biophys Res Comm 79:1272-1278, 1977 6, Baxter JH, Goodman HC, Allen JC: Effects of infusions of serum albumin on serum lipids and lipoproteins in nephrosis, J Clin Invest 40:490-498, 1961 7, Allen JC, Baxter JH, Goodman HC: Effects of dextran, polyvinylpyrrolidone and gamma globulin on the hyperlipidemia of experimental nephrosis, J Clin Invest 40:499-508, 1961 8, Berlyne GM, Mallick NP: Ischemic heart disease as a complication of nephrotic syndrome, Lancet 2:399-400, 1969 9, Kaysen GA, Gambertoglio J, Jimenez I, et al: Effect of dietary protein intake on albumin homeostasis in nephrotic patients, Kidney Int 29:572-577, 1986