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Hypertension, Hyperlipidemia, and Renal Damage
Hypertension, Hyperlipidemia, and Renal Damage William F. Keane, MD, Bertram L. Kasiske, MD, Michael P. O'Donnell, PhD, Youngki Kim, MD • Experimental studies have demonstrated that a number of factors participate in the progression of renal disease. Systemic and glomerular hypertension have been shown to be critical factors in renal injury. Hyperlipidemia that frequently coexists with renal disease also has been suggested as an important partiCipatory factor in nephron damage. Interestingly, both hypertension and hyperlipidemia seem to evoke glomerular growth, a factor that has also been postulated to be involved in glomerular and tubular destruction. Recently, experimental and clinical data suggest that an important interaction occurs between hyperlipidemia and hypertension. Not only do they frequently coexist, but hypertension dramatically exaggerates hyperlipidemic injury, and hyperlipidemia alters systemic and glomerular vascular production of vasoactive substances which maintain basal vascular tone. Thus, these recent observations underscore the interactive potential of the various risk factors that participate in progression of renal disease. They also suggest that multiple interventional strategies may be needed to optimally prevent progressive nephron loss. © 1993 by the National Kidney Foundation, Inc. INDEX WORDS: Hypertension; hyperlipidemia; glomerulosclerosis; progression; antilipemic agents; modified low-density lipoproteins.
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XPERIMENTAL STUDIES have suggested that hyperlipidemia which frequently accompanies progressive renal disease contributes to glomerular injury. Two main lines of evidence support this hypothesis. First, a variety of pharmacologic agents have reduced circulating lipids in these models and this has been associated with a reduction in glomerular injury and improvement in renal function. 1In most of these studies, therapy was administered prior to the development of glomerular injury and prevention of glomerulosclerosis was uniformly observed. 1On the other hand, when studies were performed after injury was established, lipid-lowering therapies were also shown to have a beneficial effect. 1 Additional support for a role oflipids in progressive renal injury has developed from studies of dietary-induced hypercholesterolemia. Dietary hypercholesterolemia alone is associated with only modest glomerular injury.2,3 However, in the presence of glomerular disease, hypertension, or reduced nephron population, nephron injury can be markedly aggravated by a high cholesterol intake. 3-5 The mechanisms whereby renal disease progresses have been intensely investigated during the past decade. Both hemodynamic and metabolic factors have been considered to be important in this process (Fig 1). Experimental studies have also suggested that compensatory hypertrophic and hyperplastic growth that occurs in remaining nephrons in response to progressive nephron loss may also modulate nephron injury.6 Although the effects of hyperlipidemia and hypertension on glomerular damage have been considered to be independent of each other, re-
cent experimental data suggest that there may be an important linkage between hyperlipidemia and hypertension (Fig 1). Data now indicate that hyperlipidemia may modify production and/or secretion of vasoactive substances. Specifically, hypercholesterolemia reduced vascular production of vasodilatory factors, while vascular production of vasoconstrictive factors was increased. 7 - 11 PHARMACOLOGIC MODIFICATION OF PROGRESSIVE GLOMERULAR INJURY WITH ANTILIPEMIC AGENTS
In a model of progressive renal failure induced by surgical removal of 80% to 90% of renal mass, hypertension, proteinuria, glomerulosclerosis, and progressive loss of renal function occurred. 12 Hypertrophy of the remaining nephrons occurred. Abnormal circulating lipids were found soon after ablation, and secondary hypercholesterolemia developed as albuminuria progressed. To determine whether abnormal lipid metabolism in this model might influence the development of focal, segmental glomerulosclerosis
From the Division ofNephrology, Department ofMedicine, Hennepin County Medical Center, Minneapolis, MN; and the Department of Pediatrics, University Hospital, University of Minnesota Medical School, Minneapolis, MN. This work was supported in part from grants received from the Baxter Extramural Grant Program and the American Heart Association. Address reprint requests to William F. Keane, MD, Division of Nephrology, Department of Medicine, Hennepin County Medical Center, 701 Park Ave S, Minneapolis, MN 55415. © 1993 by the National Kidney Foundation, Inc. 0272-6386/93/2105-2008$3.00/0
American Journal of Kidney Diseases, Vol 21, No 5, Suppl 2 (May), 1993: pp 43-50
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KEANE ET AL Reduced Nephron Population Diabetes Mellitus HypertrophicJHyperplastic Growth
Glomerulosclerosis
Fig 1. Schematic representation of factors that participate in progressive nephron injury. Both dyslipidemia and vasoactive factors that regulate blood pressure have been shown to influence glomerular cell growth. While it has been shown that hypertension can aggravate hyperlipidemic injury, recent data also suggest that hyperlipidemia may influence vascular production of vasoactive factors involved in maintaining vascular tone.
(FGS), 5/6 nephrectomy rats were treated with lovastatin or clofibric acid. 13 Both agents reduced serum lipid levels, diminished albuminuria, and significantly reduced the incidence of FGS. 13 Neither clofibric acid nor lovastatin appeared to reduce systemic blood pressure and thus, the effects of these agents were independent of blood pressure reduction. Similarly, short-term intervention with these lipid-lowering agents did not affect glomerular pressures and flows in the 5/6 nephrectomy rats.13 In addition, these agents reduced mesangial cellularity and expansion of mesangial matrix (Table 1). Thus, these results suggested that antilipemic therapies ameliorated glomerular injury by a mechanism not related to glomerular hemodynamic function. Probucol, a class of cholesterol-lowering agents with antioxidant properties, has also been shown to decrease proteinuria and attenuate the degree of histologic damage that occurred in rats with
subtotal nephrectomy.14 Preservation of renal function and a beneficial effect on glomerular and tubulointerstitial injury was shown. 14 This study provided additional support for the effect of antilipemic agents in progressive glomerular injury. It also raises a potentially important role for oxidative lipid injury in this experimental model. 14 Preliminary reports have suggested that lovastatin therapy is effective in this experimental model even when therapy is begun after the renal disease is established. IS Importantly, in the 5/6 nephrectomy model with established injury, combination therapy with lovastatin and the angiotensin-converting enzyme inhibitor, enalapril, almost completely prevented glomerulosclerosis, and significantly reduced mesangial expansion, systemic blood pressure, serum cholesterol, and proteinuria. IS Combination therapy was significantly more effective than either agent used alone. IS The Dahl salt-sensitive ("S") rat is a model of systemic hypertension in which albuminuria and progressive glomerular damage develop when these rats are fed a high-salt diet. 16 Hyperlipidemia was observed in these rats antecedent to glomerular injury, and was aggravated by increasing proteinuria. 17 Interestingly, lovastatin therapy in "s" rats for 4 months reduced serum cholesterol and urine albumin excretion by 38% and 76%, respectively. This was associated with one sixth the incidence of FGS as that in untreated "s" rats. 18 Perhaps the most unique finding of this study was that lovastatin reduced the degree of hypertension in Dahl "s" rats.18 One could postulate that this was primarily a result of less glomerular structural injury in the lovastatin-treated rats. However, the effect on blood
Table 1. Experimental Models of Progressive Renal Diseases That Have Been Shown to be Influenced by Antilipemic Agents Effect of Lipid-Lowering Agents Model
Systemic Pressure
Glomerular Pressure
FGS
Mesangial Expansion
Chronic PAN Obese Zucker rat 5/6 Nx Rat Dahl "8" Rat
Normal Normal Increased Increased
Increased Normal Increased Increased
Decreased Decreased Decreased Decreased
Unknown Decreased Decreased Decreased
Abbreviations: FG8, focal glomerulosclerosis; PAN, aminonucleoside of puromycin; Nx, nephrectomy; Dahl "8" , Dahl saltsensitive rat.
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HYPERTENSION, HYPERLIPIDEMIA, AND RENAL DAMAGE
pressure also occurred early in the study when glomerular injury was minimal. Another lipid-lowering agent, clofibrate, has reduced blood pressure in Dahl "s" rats. 19 In this study, an enhanced production of vasodilatory cytochrome P450 products by the kidney was considered to be the mechanism by which this agent reduced blood pressure, suggesting a heretofore unrecognized relationship between antilipemic therapy and blood pressure regulation. 19 This effect of clofibrate may be unique in this model of hypertension, since reduction in blood pressure has not been reported with clofibrate in the renoprival model of hypertension. 13 The obese Zucker rat is a unique model of progressive glomerular injury. Obesity, which is a genetic recessive trait, insulin resistance, and hyperlipidemia are present at an early age and precede the development of glomerular injury. 20 At this early stage, blood pressure and glomerular hemodynamic function have been reported to be normal. 21 However, with the development of renal disease after 4 to 5 months of life, blood pressure gradually increases, and this is associated with the development of glomerular hypertension?2 Initiation of antilipemic therapy at an early age with either clofibric acid or lovastatin prevented the development of albuminuria and FGS in obese Zucker rats.23 In addition, amarked reduction in mesangial matrix and cellularity occurred (Table I). The beneficial effect of antilipemic therapy occurred independent of changes in systemic blood pressure or glomerular function. Initiation of lovastatin therapy after renal disease was established in obese Zucker rats also reduced the severity of glomerular and tubulointerstitial injury.24 Interestingly, blood pressure in the lovastatin-treated rats was lower than that in the control rats.24 In addition, lovastatin had modest effects on albuminuria, and reduced FGS. Although the effect of lovastatin on blood pressure in obese rats could be explained by less glomerular injury, lovastatin could have also directly influenced blood pressure, through an unknown mechanism. STUDIES OF DIETARY-INDUCED HYPERCHOLESTEROLEMIA IN NORMAL RATS
It has been demonstrated that feeding a high cholesterol diet to different animal species leads
to the development of FGS. I . 5 For example, Sprague Dawley rats fed a 4 %-cholesterol diet developed modest FGS over a 3-month period. 2,3 A number of features were associated with this relatively modest degree of glomerular injury. First, an influx of glomerular Ia + macrophages and ED-l + monocyte/macrophages occurred within days of initiating a high-cholesterol diet. 2,3 Second, glomerular enlargement occurred prior to the development of albuminuria or FGS and was evident after only 1 month of this diet. 2 Third, increased mesangial fractional area was also observed prior to FGS, and this was a result of increased mesangial matrix including laminin, fibronectin, and type IV collagen. 2,3 Fourth, after 1 to 3 months of cholesterol feeding, micropuncture studies showed changes in glomerular hemodynamic function. 2,25,26 Specifically, increased glomerular arteriolar resistances and glomerular hypertension occurred without evidence of systemic hypertension. 3,25,26 It is interesting that whole kidney vascular resistance after cholesterol feeding was also found to be increased in isolated rat kidneys perfused without red blood cells or plasma lipoproteins. 27 These data would suggest that factors intrinsic to the renal vasculature might participate in altered vascular resistance associated with hypercholesterolemia. In this regard, it is possible that the increased number of mesangial cells or glomerular macrophages associated with cholesterol feeding might alter the production of vasoactive substances, and thereby contribute to increased vascular resistance. It is also possible that hypercholesterolemia itself modifies production of vascular-derived vasoconstrictor and vasodilator substances. II HYPERLIPIDEMIA AGGRAVATES HYPERTENSIVE INJURY
Increased glomerular injury in Goldblatt hypertensive rats fed a high saturated fat diet has been observed. 28 In addition, in cholesterol-fed rats in which clip hypertension was induced, glomerular injury was nearly one and one halftimes greater in the unclipped kidney than in the clipped kidney.4 Recently, dietary-induced hypercholesterolemia was also shown to exaggerate glomerular injury in hypertensive Dahl "S" rats,z9 This exaggerated glomerular injury was characterized by a greater degree of proteinuria, larger glomerular volumes, and more extensive glo-
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merulosclerosis. 29 Interestingly, hypertensive, hypercholesterolemic Dahl "S" rats demonstrated a significant increase in renal vascular resistance with reduction in renal plasma flow although inulin clearance was maintained.29 Increased dietary cholesterol has also been shown to aggravate glomerular injury in a model of chronic nephrotic syndrome induced by aminonucleoside of puromycin (PAN).5 Although systemic hypertension is not observed in this experimental model of the nephrotic syndrome, glomerular hypertension has been found late in the course of this disease as proteinuria recurred. In PAN rats fed a high-cholesterol diet from the onset of glomerular injury, awake blood pressure was slightly but significantly higher than in control rats. 5 This increase in blood pressure in the nephrotic rats occurred before extensive glomerular injury was manifest. In addition, there was a trend towards higher renal vascular resistance and a reduction in renal blood flow. 5 Together, these experimental studies suggest that hyperlipidemia in the setting of underlying renal disease can aggravate renal injury; they also suggest that hyperlipidemia may cause altered vascular reactivity that can contribute to hypertension and altered glomerular hemodynamic function. HYPERLIPIDEMIA AND VASCULAR-DERIVED VASOACTIVE FACTORS
Hypercholesterolemia has been shown to increase glomerular production of thromboxane AiTxA 2) in the rat, and infusion of a TxA2 receptor antagonist reversed the increased vascular resistance seen in rats fed a 4% cholesterol diet. 25 ,26 Of note is that the antilipemic/antioxidant agent probucol prevented the hemodynamic alterations of high-cholesterol intake and reduced glomerular TxA2' suggesting a direct role for hypercholesterolemia and possibly oxidized lipoproteins in mediating these events.2 5 Moreover, the vasodilatory response to acetylcholine was blunted in hypercholesterolemia rats, related, in part, to the increased TxA2 production. 26 Recent studies of the renal microvasculature in cholesterol-fed rabbits also have indicated that prostacyclin production is reduced, lending support to the notion that hypercholesterolemia modifies renal vascular production of vasoactive eicosanoids. 3o
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Hypercholesterolemia has also been shown to increase renal vascular resistance of the Dahl "S" rae 9 and rats with PAN nephrosis. 5 These data suggest that hyperlipidemia may impair renal vascular endothelial function. In this regard, studies have suggested that endothelium-derived relaxing factor (EDRF) is involved in the normal regulation of vascular tone. Acute or chronic inhibition of endogenous nitric oxide synthesis in the rat resulted in systemic hypertension and renal vasoconstriction, associated with significant increased glomerular capillary pressure. 3I Hypercholesterolemia has been shown to alter production of a number of potent vascular vasoactive substances in the systemic arterial bed (Table 2). Specifically, in hypercholesterolemic rabbits, impaired endothelium-dependent vasodilatation involved not only large arteries but also arterioles, vessels not known to develop atheromatous lesions. 7 ,S,IO,11 Impaired endotheliumdependent arterial relaxation in hypercholesterolemic states has been demonstrated in monkeys, pigs, dogs, and humans. 7 Of particular interest are reports indicating that isolated normal arteries exposed to oxidized low-density lipoproteins (LDL) acquire vasomotor properties resembling those of atherosclerotic arteries and demonstrate a decreased responsiveness to agents that stimulate the release of EDRF. 9 Preliminary studies in hypercholesterolemic rodents have suggested a marked impairment in endothelial relaxation to acetylcholine; however, only in the setting of depletion of endogenous antioxidants, vitamin E, and selenium. 32 Increased levels of the potent vasoconstrictor endothelin have been observed in patients with atherosclerosis. 33 This increased level correlated closely with the extent of vascular atherosclerosis. Together these studies suggest that hyperlipidemia per se may modulate vascular production of vasoactive substances in both the systemic circulation and renal microcirculation. They also suggest that vascular deposition of oxidized liTable 2. The Influence of Hypercholesterolemia on Vascular Vasoactive Factors Vasodilators
Vasoconstrictors
Decreased prostacyclin Decreased EDRF
Increased thromboxane A2 Increased endothelin
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HYPERTENSION, HYPERLIPIDEMIA, AND RENAL DAMAGE
poproteins could be a factor that links hyperlipidemia to the development of altered vascular tone. DOES OXIDATIVE MODIFICATION OF LIPIDS PLAY A ROLE IN PROGRESSIVE RENAL DISEASE?
Although oxidized LOL has been recently proposed as a critical factor in the development of atherosclerosis,34 its role in progressive renal disease is only now being investigated. In this regard, mesangial cells have been shown to have receptors for native LOL as well as a scavenger receptors which recognize oxidized LOL. 35 .38 Oxidized LOL has been shown to be cytotoxic to mesangial cells and could, in this manner, contribute to glomerular damage. 35-38 Oxidized LOL also decreased mitogen-induced mesangial cell proliferation,35-38 and lysophosphatidylcholine has been identified as a major cytotoxic component of oxidized LOL.l Several cell types have been shown to oxidize LOL in vitro. Human monocytes, endothelial cells, smooth muscle cells, and human mesangial cells have the capacity to generate reactive oxygen molecules necessary to initiate lipid peroxidation. 39,40 Recent studies from our laboratory have indicated that in human mesangial cells this is an iron-catalyzed reaction involving superoxide. 38 The source of the reactive oxygen molecules involved in mesangial cell peroxidation of LOL appears to be arachidonic acid metabolism by the cytochrome P450 system. 38 In contrast, the lipoxygenase pathway of arachidonic acid metabolism appears to be responsible for the oxidative modification ofLOL by monocytes/macrophages. 34,40 Indirect evidence that oxidized LOL may participate in progressive glomerular injury leading to glomerulosclerosis has been reported (Table 3). Increased dietary cholesterol in rats has been associated with an increased influx of macrophages which ultimately form foam celts. 2,3 In cholesterol-fed rats and in obese Zucker rats, increased glomerular cholesterol esters and a relative reduction in polyunsaturated fatty acids have been reported. 2,41 These changes, which indirectly suggested oxidative modification of lipids, were associated with glomerulosclerosis. In vitro, increased binding of oxidized LOL to proteoglycans and collagen has been demonstrated,34 and in
Table 3. Experimental Findings Which Indirectly Suggest a Role for Modified Lipoproteins in Progessive Renal Injury Increased glomerular foam cells Increased mesangial matrix production by oxidized LDL Increased glomerular deposits of apolipoprotein B Altered lipid composition Increased cholesterol esters Decreased polyunsaturated fatty acids Increased glomerular binding of oxidized LDL
vivo, oxidized LDL preferentially bound to normal glomeruli. 42 Recently, lipid deposits and immunohistochemical detection of apolipoproteins have been reported in the mesangium and in areas of glomerulosclerosis.43-45 Whether these localized lipoproteins are modified and biochemically interact with mesangial matrix proteins, thereby contributing to mesangial injury, remains to be established. Expansion of mesangial matrix occurs prior to the development of glomerulosclerosis. 2,3.13,20,46 Preliminary reports indicate that native and oxidized LDL modify mRNA transcripts for al(IV) collagen in human mesangial cells.2,3 Collectively, these studies support the notion that oxidative modification of LDL in glomeruli could also contribute to a nonhemodynamic process that leads to glomerulosclerosis. CLINICAL RELATIONSHIP BETWEEN HYPERTENSION AND HYPERLIPIDEMIA
Early studies of the possible association between serum cholesterol and blood pressure levels have yielded conflicting results. However, in more recent epidemiologic studies, it was demonstrated that patients with essential hypertension had higher serum cholesterol and triglyceride levels and lower high-density lipoprotein cholestero1. 47 This association was observed in both men and women, and the level of blood pressure was directly associated with the level of total cholestero1. 47 In the Tecumseh Blood Pressure study, subjects with borderline hypertension had significantly higher cholesterol and triglyceride levels and lower high-density lipoprotein levels. 48 These lipid abnormalities were also associated with insulin resistance. Further insights into the relationship between carbohydrate and lipid metabolism and hyper-
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tension were reported by Ferrari and colleagues. 49 Young normotensive humans with at least one essential hypertensive parent tended to have insulin resistance and dyslipidemia. 49 Thus, a familial trait for essential hypertension may coexist with defects in carbohydrate and lipoprotein metabolism that can be detected before, or at a very early stage in, the development of high blood pressure. An association has been found between abnormal red blood cell (sodium-lithium) countertransport activity, considered to be a genetic marker for essential hypertension, and the presence of hypercholesterolemia,50 lending further support to the notion that lipid abnormalities frequently coexist in subjects at greatest risk for hypertension. Increased circulating insulin levels and peripheral insulin resistance have recently been shown to be associated with increased central nervous system sympathetic activity in patients with essential hypertension. 5I Although much of our thinking regarding the mechanism of essential hypertension has focused on the role of insulin resistance, the possibility that the dyslipidemia frequently associated with insulin resistance might also contribute to the development of hypertension is particularly intriguing. In this regard, the recently described effects of hyperlipidemia on endothelial vasoactive substances (Table 2) may be particularly germain. In patients with type I and type II diabetes mellitus and early evidence of nephropathy as evidenced by microalbuminuria, abnormalities of lipid metabolism have been reported. 52-55 Specifically, increased LDL cholesterol and decreased high-density lipoprotein as well as an increased lipoprotein (a) have been demonstrated. 52-55 Similarly, a trend towards increased blood pressure and increased red blood cell sodium-lithium countertransport activity in patients with incipient type I diabetic nephropathy is also of note. 52-55 These data also raise the possibility that dyslipidemia may contribute to the development ofhypertension, possibly through an effect of modified lipoproteins on vascular wall reactivity. CLINICAL RELATIONSHIP BETWEEN HYPERLIPIDEMIA AND THE PROGRESSION OF RENAL DISEASE
Primary hyperlipidemia does not ostensibly lead to de novo glomerular disease, although there
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are a number of unique and genetically determined dyslipidemias that are associated with renal disease. I Nonetheless, a number of clinical studies have demonstrated that apolipoprotein B and E are frequently found in glomeruli of patients with various renal diseases. 43-45 It is well established that hyperlipidemic agents can improve the lipid profile in nephrotic patients. 56 Moreover, recent clinical studies in patients with the nephrotic syndrome have suggested that reduction of hyperlipidemia may be associated with a decreased proteinuria and improvement in renal function. 57-59 Intriguingly, in one study, decreased glomerular foam cells and lipid deposits were associated with reduction in LDL. 59 In patients with type I diabetic nephropathy, Mulec and colleagues suggested that the rate of decline in renal function in diabetic patients was in part correlated with serum cholesterollevels. 6o In patients with total serum cholesterol levels above 270 mg/dL, the rate of decline in glomerular filtration rate over 18 months was 0.7 mL/ min per month. For those patients with total serum cholesterol below 270 mg/dL, the rate of decline of renal function was significantly lower at only 0.2 mL/min per month. The level of albuminuria was not different between the groups and mean arterial pressure was only 3 mm Hg higher in the high-cholesterol group. Recently, Bazzato and colleagues reported that the combination of a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor with an angiotensinconverting enzyme inhibitor had an additional beneficial effect in reducing the rate of loss of renal function in both diabetic and nondiabetic patients. 61 While these and other studies are suggestive of the importance of hyperlipidemia in modulating progressive renal disease, prospective and controlled trials with clinically relevant functional and morphologic endpoints will be needed to answer this important issue. ACKNOWLEDGMENT The authors express their gratitude to Deanna Gunderson for help in preparing the manuscript.
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HYPERTENSION, HYPERLIPIDEMIA, AND RENAL DAMAGE
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50 cells: Mechanisms and consequences. Am J Pathol 1992 (in press) 39. Morel DW, DiCorleto PE, Chisolm GM: Endothelial and smooth muscle cells alter low density lipoprotein in vitro by free radical oxidation. Arteriosclerosis 4:357-364, 1984 40. Parthasarathy S, Wieland E, Steinberg D: A role for endothelial celllipoxygenase in the oxidative modification of low density lipoprotein. Proc Nat! Acad Sci USA 86: 10461050, 1989 41. Kasiske BL, O'Donnell MP, Cleary MP, Keane WF: Effects of reduced renal mass on tissue lipids and renal injury in hyperlipidemic rats. Kidney Int 35:40-47, 1989 42. Coritsidis G , Rifici V, Gupta S, Rie J, Shan Z, Neugarten J, Schlondorff D: Preferential binding of oxidized LDL to rat glomeruli in vivo and cultured mesangial cells in vitro. Kidney Int 39:858-866, 1991 43. Lee HS, Lee JS, Koh HI, Ko KW: Intraglomerular lipid deposition in routine biopsies. Clin Nephrol 36:67-75, 1991 44. Watanabe Y, Ozaki I, Yoshida F, Fukatsu A, Itoh Y, Matsuo S, Sakamoto N: A case of nephrotic syndrome with glomerular lipoprotein deposition with capillary ballooning and mesangiolysis. Nephron 51 :265-270, 1989 45. Sato H, Suzuki S, Kobayashi H, Ogino S, Inomata A, Arakawa M: Immunohistological localization of apolipoproteins in the glomeruli in renal disease: Specifically apoB and apoE. Clin Nephrol 36: 127-133, 1991 46. Adler S, Striker U, StrikerGE, Perkinson DT, Hibbert J, Couser WG: Studies of progressive glomerular sclerosis in the rat. Am J Pathol 123:553-562, 1986 47. Bnaa KH, Theile DS: Association between blood pressure and serum lipids in a population. The Troms Study. Circulation 83: 1305-13 I 4 , 1991 48. Julius S, Jamerson K, Mejia A, Krause L, Schork N, Jones K: The association of borderline hypertension with target organ changes and higher coronary risk: Tecumseh blood pressure study. JAMA 264:354-358, 1990 49. Ferrari P, Weidmann P, Shaw S, Giachino D, Riesen W, Allemann Y, Heynen G: Altered insulin sensitivity, hyperinsulinemia, and dyslipidemia in individuals with a hypertensive parent. Am J Med 91 :589-596, 1991 50. Yap L, Arrazola A, Soria F, Diez J: Is there increased cardiovascular risk in essential hypertensive patients with ab-
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normal kinetics of red blood cell sodium-lithium countertransport? J Hypertens 7:667-673, 1989 51. Lembo G, Napoli R, Capaldo B, Rendina V, laccarino G, Volpe M, Trimarco B, Sacca L: Abnormal sympathetic overactivity evoked by insulin in the skeletal muscle of patients with essential hypertension. J Clin Invest 90:24-29, 1992 52. Jones SL, Close CF, Mattock MB, Jarrett RJ, Keen H, Viberti GC: Plasma lipid and coagulation factor concentrations in insulin dependent diabetics with microaibuminuria. Br Med J 298:487-490, 1989 53. Krolewski AS, Warram JH, Laffel LMB: Genetic susceptibility to diabetic nephropathy. In Advances in Nephrology. St Louis, MO, Mosby, 1992, pp 69-81 54. Earle K, Walker J, Hill C, Viberti GC: Familial clustering of cardiovascular disease in patients with insulin-dependent diabetes and nephropathy. N Engl J Med 326:673677, 1992 55. Mangili R, Bending JJ, Scott G, Lai K, Gupta A, Viberti GC: Increased sodium-lithium countertransport activity in red cells of patients with insulin-dependent diabetes and nephropathy. N Engl J Med 318: 146-150, 1988 56. Keane WF, St Peter JV, Kasiske BL: Is the aggressive management of hyperlipidemia in nephrotic syndrome mandatory? Kidney Int 42: 1992 57. Suzaki K, Kobori S, Ueno S, Uehara M, Kayashima T, Takeda H, Fukuda S, Takahaski K, Nakamura N, Uzawa H, Schichiri M: Effect of plasmapheresis on familial type III hyperlipoproteinemia associated with glomerular lipidosis, nephrotic syndrome and diabetes mellitus. Atherosclerosis 80: 181-189, 1990 58. Reblink AJ, Hene RJ, Erkelens DW, Joles JA, Koomans HA: Partial remission of nephrotic syndrome in patients on long-term simvastatin. Lancet I: 1045-1046, 1990 59. Muso E, Yashiro M, Sawanishi K: Effect of LDLapheresis for steroid-resistant nephrotic syndromes. Nephrol Dial Transplant 7:693, 1992 (abstr) 60. Mulec H, Johnson SA, Bjorck S: Relationship between serum cholesterol and diabetic nephropathy. Lancet I: 15371538, 1990 61. Bazzato G, Fracasso A, Scan feria F: Risk factors on the progression of diabetic nephropathy. Role of hyperlipidemia and its correction. Nephrol Dial Transplant 7:710, 1992 (abstr)
E
XPERIMENTAL STUDIES have suggested that hyperlipidemia which frequently accompanies progressive renal disease contributes to glomerular injury. Two main lines of evidence support this hypothesis. First, a variety of pharmacologic agents have reduced circulating lipids in these models and this has been associated with a reduction in glomerular injury and improvement in renal function. 1In most of these studies, therapy was administered prior to the development of glomerular injury and prevention of glomerulosclerosis was uniformly observed. 1On the other hand, when studies were performed after injury was established, lipid-lowering therapies were also shown to have a beneficial effect. 1 Additional support for a role oflipids in progressive renal injury has developed from studies of dietary-induced hypercholesterolemia. Dietary hypercholesterolemia alone is associated with only modest glomerular injury.2,3 However, in the presence of glomerular disease, hypertension, or reduced nephron population, nephron injury can be markedly aggravated by a high cholesterol intake. 3-5 The mechanisms whereby renal disease progresses have been intensely investigated during the past decade. Both hemodynamic and metabolic factors have been considered to be important in this process (Fig 1). Experimental studies have also suggested that compensatory hypertrophic and hyperplastic growth that occurs in remaining nephrons in response to progressive nephron loss may also modulate nephron injury.6 Although the effects of hyperlipidemia and hypertension on glomerular damage have been considered to be independent of each other, re-
cent experimental data suggest that there may be an important linkage between hyperlipidemia and hypertension (Fig 1). Data now indicate that hyperlipidemia may modify production and/or secretion of vasoactive substances. Specifically, hypercholesterolemia reduced vascular production of vasodilatory factors, while vascular production of vasoconstrictive factors was increased. 7 - 11 PHARMACOLOGIC MODIFICATION OF PROGRESSIVE GLOMERULAR INJURY WITH ANTILIPEMIC AGENTS
In a model of progressive renal failure induced by surgical removal of 80% to 90% of renal mass, hypertension, proteinuria, glomerulosclerosis, and progressive loss of renal function occurred. 12 Hypertrophy of the remaining nephrons occurred. Abnormal circulating lipids were found soon after ablation, and secondary hypercholesterolemia developed as albuminuria progressed. To determine whether abnormal lipid metabolism in this model might influence the development of focal, segmental glomerulosclerosis
From the Division ofNephrology, Department ofMedicine, Hennepin County Medical Center, Minneapolis, MN; and the Department of Pediatrics, University Hospital, University of Minnesota Medical School, Minneapolis, MN. This work was supported in part from grants received from the Baxter Extramural Grant Program and the American Heart Association. Address reprint requests to William F. Keane, MD, Division of Nephrology, Department of Medicine, Hennepin County Medical Center, 701 Park Ave S, Minneapolis, MN 55415. © 1993 by the National Kidney Foundation, Inc. 0272-6386/93/2105-2008$3.00/0
American Journal of Kidney Diseases, Vol 21, No 5, Suppl 2 (May), 1993: pp 43-50
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44
KEANE ET AL Reduced Nephron Population Diabetes Mellitus HypertrophicJHyperplastic Growth
Glomerulosclerosis
Fig 1. Schematic representation of factors that participate in progressive nephron injury. Both dyslipidemia and vasoactive factors that regulate blood pressure have been shown to influence glomerular cell growth. While it has been shown that hypertension can aggravate hyperlipidemic injury, recent data also suggest that hyperlipidemia may influence vascular production of vasoactive factors involved in maintaining vascular tone.
(FGS), 5/6 nephrectomy rats were treated with lovastatin or clofibric acid. 13 Both agents reduced serum lipid levels, diminished albuminuria, and significantly reduced the incidence of FGS. 13 Neither clofibric acid nor lovastatin appeared to reduce systemic blood pressure and thus, the effects of these agents were independent of blood pressure reduction. Similarly, short-term intervention with these lipid-lowering agents did not affect glomerular pressures and flows in the 5/6 nephrectomy rats.13 In addition, these agents reduced mesangial cellularity and expansion of mesangial matrix (Table 1). Thus, these results suggested that antilipemic therapies ameliorated glomerular injury by a mechanism not related to glomerular hemodynamic function. Probucol, a class of cholesterol-lowering agents with antioxidant properties, has also been shown to decrease proteinuria and attenuate the degree of histologic damage that occurred in rats with
subtotal nephrectomy.14 Preservation of renal function and a beneficial effect on glomerular and tubulointerstitial injury was shown. 14 This study provided additional support for the effect of antilipemic agents in progressive glomerular injury. It also raises a potentially important role for oxidative lipid injury in this experimental model. 14 Preliminary reports have suggested that lovastatin therapy is effective in this experimental model even when therapy is begun after the renal disease is established. IS Importantly, in the 5/6 nephrectomy model with established injury, combination therapy with lovastatin and the angiotensin-converting enzyme inhibitor, enalapril, almost completely prevented glomerulosclerosis, and significantly reduced mesangial expansion, systemic blood pressure, serum cholesterol, and proteinuria. IS Combination therapy was significantly more effective than either agent used alone. IS The Dahl salt-sensitive ("S") rat is a model of systemic hypertension in which albuminuria and progressive glomerular damage develop when these rats are fed a high-salt diet. 16 Hyperlipidemia was observed in these rats antecedent to glomerular injury, and was aggravated by increasing proteinuria. 17 Interestingly, lovastatin therapy in "s" rats for 4 months reduced serum cholesterol and urine albumin excretion by 38% and 76%, respectively. This was associated with one sixth the incidence of FGS as that in untreated "s" rats. 18 Perhaps the most unique finding of this study was that lovastatin reduced the degree of hypertension in Dahl "s" rats.18 One could postulate that this was primarily a result of less glomerular structural injury in the lovastatin-treated rats. However, the effect on blood
Table 1. Experimental Models of Progressive Renal Diseases That Have Been Shown to be Influenced by Antilipemic Agents Effect of Lipid-Lowering Agents Model
Systemic Pressure
Glomerular Pressure
FGS
Mesangial Expansion
Chronic PAN Obese Zucker rat 5/6 Nx Rat Dahl "8" Rat
Normal Normal Increased Increased
Increased Normal Increased Increased
Decreased Decreased Decreased Decreased
Unknown Decreased Decreased Decreased
Abbreviations: FG8, focal glomerulosclerosis; PAN, aminonucleoside of puromycin; Nx, nephrectomy; Dahl "8" , Dahl saltsensitive rat.
45
HYPERTENSION, HYPERLIPIDEMIA, AND RENAL DAMAGE
pressure also occurred early in the study when glomerular injury was minimal. Another lipid-lowering agent, clofibrate, has reduced blood pressure in Dahl "s" rats. 19 In this study, an enhanced production of vasodilatory cytochrome P450 products by the kidney was considered to be the mechanism by which this agent reduced blood pressure, suggesting a heretofore unrecognized relationship between antilipemic therapy and blood pressure regulation. 19 This effect of clofibrate may be unique in this model of hypertension, since reduction in blood pressure has not been reported with clofibrate in the renoprival model of hypertension. 13 The obese Zucker rat is a unique model of progressive glomerular injury. Obesity, which is a genetic recessive trait, insulin resistance, and hyperlipidemia are present at an early age and precede the development of glomerular injury. 20 At this early stage, blood pressure and glomerular hemodynamic function have been reported to be normal. 21 However, with the development of renal disease after 4 to 5 months of life, blood pressure gradually increases, and this is associated with the development of glomerular hypertension?2 Initiation of antilipemic therapy at an early age with either clofibric acid or lovastatin prevented the development of albuminuria and FGS in obese Zucker rats.23 In addition, amarked reduction in mesangial matrix and cellularity occurred (Table I). The beneficial effect of antilipemic therapy occurred independent of changes in systemic blood pressure or glomerular function. Initiation of lovastatin therapy after renal disease was established in obese Zucker rats also reduced the severity of glomerular and tubulointerstitial injury.24 Interestingly, blood pressure in the lovastatin-treated rats was lower than that in the control rats.24 In addition, lovastatin had modest effects on albuminuria, and reduced FGS. Although the effect of lovastatin on blood pressure in obese rats could be explained by less glomerular injury, lovastatin could have also directly influenced blood pressure, through an unknown mechanism. STUDIES OF DIETARY-INDUCED HYPERCHOLESTEROLEMIA IN NORMAL RATS
It has been demonstrated that feeding a high cholesterol diet to different animal species leads
to the development of FGS. I . 5 For example, Sprague Dawley rats fed a 4 %-cholesterol diet developed modest FGS over a 3-month period. 2,3 A number of features were associated with this relatively modest degree of glomerular injury. First, an influx of glomerular Ia + macrophages and ED-l + monocyte/macrophages occurred within days of initiating a high-cholesterol diet. 2,3 Second, glomerular enlargement occurred prior to the development of albuminuria or FGS and was evident after only 1 month of this diet. 2 Third, increased mesangial fractional area was also observed prior to FGS, and this was a result of increased mesangial matrix including laminin, fibronectin, and type IV collagen. 2,3 Fourth, after 1 to 3 months of cholesterol feeding, micropuncture studies showed changes in glomerular hemodynamic function. 2,25,26 Specifically, increased glomerular arteriolar resistances and glomerular hypertension occurred without evidence of systemic hypertension. 3,25,26 It is interesting that whole kidney vascular resistance after cholesterol feeding was also found to be increased in isolated rat kidneys perfused without red blood cells or plasma lipoproteins. 27 These data would suggest that factors intrinsic to the renal vasculature might participate in altered vascular resistance associated with hypercholesterolemia. In this regard, it is possible that the increased number of mesangial cells or glomerular macrophages associated with cholesterol feeding might alter the production of vasoactive substances, and thereby contribute to increased vascular resistance. It is also possible that hypercholesterolemia itself modifies production of vascular-derived vasoconstrictor and vasodilator substances. II HYPERLIPIDEMIA AGGRAVATES HYPERTENSIVE INJURY
Increased glomerular injury in Goldblatt hypertensive rats fed a high saturated fat diet has been observed. 28 In addition, in cholesterol-fed rats in which clip hypertension was induced, glomerular injury was nearly one and one halftimes greater in the unclipped kidney than in the clipped kidney.4 Recently, dietary-induced hypercholesterolemia was also shown to exaggerate glomerular injury in hypertensive Dahl "S" rats,z9 This exaggerated glomerular injury was characterized by a greater degree of proteinuria, larger glomerular volumes, and more extensive glo-
46
merulosclerosis. 29 Interestingly, hypertensive, hypercholesterolemic Dahl "S" rats demonstrated a significant increase in renal vascular resistance with reduction in renal plasma flow although inulin clearance was maintained.29 Increased dietary cholesterol has also been shown to aggravate glomerular injury in a model of chronic nephrotic syndrome induced by aminonucleoside of puromycin (PAN).5 Although systemic hypertension is not observed in this experimental model of the nephrotic syndrome, glomerular hypertension has been found late in the course of this disease as proteinuria recurred. In PAN rats fed a high-cholesterol diet from the onset of glomerular injury, awake blood pressure was slightly but significantly higher than in control rats. 5 This increase in blood pressure in the nephrotic rats occurred before extensive glomerular injury was manifest. In addition, there was a trend towards higher renal vascular resistance and a reduction in renal blood flow. 5 Together, these experimental studies suggest that hyperlipidemia in the setting of underlying renal disease can aggravate renal injury; they also suggest that hyperlipidemia may cause altered vascular reactivity that can contribute to hypertension and altered glomerular hemodynamic function. HYPERLIPIDEMIA AND VASCULAR-DERIVED VASOACTIVE FACTORS
Hypercholesterolemia has been shown to increase glomerular production of thromboxane AiTxA 2) in the rat, and infusion of a TxA2 receptor antagonist reversed the increased vascular resistance seen in rats fed a 4% cholesterol diet. 25 ,26 Of note is that the antilipemic/antioxidant agent probucol prevented the hemodynamic alterations of high-cholesterol intake and reduced glomerular TxA2' suggesting a direct role for hypercholesterolemia and possibly oxidized lipoproteins in mediating these events.2 5 Moreover, the vasodilatory response to acetylcholine was blunted in hypercholesterolemia rats, related, in part, to the increased TxA2 production. 26 Recent studies of the renal microvasculature in cholesterol-fed rabbits also have indicated that prostacyclin production is reduced, lending support to the notion that hypercholesterolemia modifies renal vascular production of vasoactive eicosanoids. 3o
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Hypercholesterolemia has also been shown to increase renal vascular resistance of the Dahl "S" rae 9 and rats with PAN nephrosis. 5 These data suggest that hyperlipidemia may impair renal vascular endothelial function. In this regard, studies have suggested that endothelium-derived relaxing factor (EDRF) is involved in the normal regulation of vascular tone. Acute or chronic inhibition of endogenous nitric oxide synthesis in the rat resulted in systemic hypertension and renal vasoconstriction, associated with significant increased glomerular capillary pressure. 3I Hypercholesterolemia has been shown to alter production of a number of potent vascular vasoactive substances in the systemic arterial bed (Table 2). Specifically, in hypercholesterolemic rabbits, impaired endothelium-dependent vasodilatation involved not only large arteries but also arterioles, vessels not known to develop atheromatous lesions. 7 ,S,IO,11 Impaired endotheliumdependent arterial relaxation in hypercholesterolemic states has been demonstrated in monkeys, pigs, dogs, and humans. 7 Of particular interest are reports indicating that isolated normal arteries exposed to oxidized low-density lipoproteins (LDL) acquire vasomotor properties resembling those of atherosclerotic arteries and demonstrate a decreased responsiveness to agents that stimulate the release of EDRF. 9 Preliminary studies in hypercholesterolemic rodents have suggested a marked impairment in endothelial relaxation to acetylcholine; however, only in the setting of depletion of endogenous antioxidants, vitamin E, and selenium. 32 Increased levels of the potent vasoconstrictor endothelin have been observed in patients with atherosclerosis. 33 This increased level correlated closely with the extent of vascular atherosclerosis. Together these studies suggest that hyperlipidemia per se may modulate vascular production of vasoactive substances in both the systemic circulation and renal microcirculation. They also suggest that vascular deposition of oxidized liTable 2. The Influence of Hypercholesterolemia on Vascular Vasoactive Factors Vasodilators
Vasoconstrictors
Decreased prostacyclin Decreased EDRF
Increased thromboxane A2 Increased endothelin
47
HYPERTENSION, HYPERLIPIDEMIA, AND RENAL DAMAGE
poproteins could be a factor that links hyperlipidemia to the development of altered vascular tone. DOES OXIDATIVE MODIFICATION OF LIPIDS PLAY A ROLE IN PROGRESSIVE RENAL DISEASE?
Although oxidized LOL has been recently proposed as a critical factor in the development of atherosclerosis,34 its role in progressive renal disease is only now being investigated. In this regard, mesangial cells have been shown to have receptors for native LOL as well as a scavenger receptors which recognize oxidized LOL. 35 .38 Oxidized LOL has been shown to be cytotoxic to mesangial cells and could, in this manner, contribute to glomerular damage. 35-38 Oxidized LOL also decreased mitogen-induced mesangial cell proliferation,35-38 and lysophosphatidylcholine has been identified as a major cytotoxic component of oxidized LOL.l Several cell types have been shown to oxidize LOL in vitro. Human monocytes, endothelial cells, smooth muscle cells, and human mesangial cells have the capacity to generate reactive oxygen molecules necessary to initiate lipid peroxidation. 39,40 Recent studies from our laboratory have indicated that in human mesangial cells this is an iron-catalyzed reaction involving superoxide. 38 The source of the reactive oxygen molecules involved in mesangial cell peroxidation of LOL appears to be arachidonic acid metabolism by the cytochrome P450 system. 38 In contrast, the lipoxygenase pathway of arachidonic acid metabolism appears to be responsible for the oxidative modification ofLOL by monocytes/macrophages. 34,40 Indirect evidence that oxidized LOL may participate in progressive glomerular injury leading to glomerulosclerosis has been reported (Table 3). Increased dietary cholesterol in rats has been associated with an increased influx of macrophages which ultimately form foam celts. 2,3 In cholesterol-fed rats and in obese Zucker rats, increased glomerular cholesterol esters and a relative reduction in polyunsaturated fatty acids have been reported. 2,41 These changes, which indirectly suggested oxidative modification of lipids, were associated with glomerulosclerosis. In vitro, increased binding of oxidized LOL to proteoglycans and collagen has been demonstrated,34 and in
Table 3. Experimental Findings Which Indirectly Suggest a Role for Modified Lipoproteins in Progessive Renal Injury Increased glomerular foam cells Increased mesangial matrix production by oxidized LDL Increased glomerular deposits of apolipoprotein B Altered lipid composition Increased cholesterol esters Decreased polyunsaturated fatty acids Increased glomerular binding of oxidized LDL
vivo, oxidized LDL preferentially bound to normal glomeruli. 42 Recently, lipid deposits and immunohistochemical detection of apolipoproteins have been reported in the mesangium and in areas of glomerulosclerosis.43-45 Whether these localized lipoproteins are modified and biochemically interact with mesangial matrix proteins, thereby contributing to mesangial injury, remains to be established. Expansion of mesangial matrix occurs prior to the development of glomerulosclerosis. 2,3.13,20,46 Preliminary reports indicate that native and oxidized LDL modify mRNA transcripts for al(IV) collagen in human mesangial cells.2,3 Collectively, these studies support the notion that oxidative modification of LDL in glomeruli could also contribute to a nonhemodynamic process that leads to glomerulosclerosis. CLINICAL RELATIONSHIP BETWEEN HYPERTENSION AND HYPERLIPIDEMIA
Early studies of the possible association between serum cholesterol and blood pressure levels have yielded conflicting results. However, in more recent epidemiologic studies, it was demonstrated that patients with essential hypertension had higher serum cholesterol and triglyceride levels and lower high-density lipoprotein cholestero1. 47 This association was observed in both men and women, and the level of blood pressure was directly associated with the level of total cholestero1. 47 In the Tecumseh Blood Pressure study, subjects with borderline hypertension had significantly higher cholesterol and triglyceride levels and lower high-density lipoprotein levels. 48 These lipid abnormalities were also associated with insulin resistance. Further insights into the relationship between carbohydrate and lipid metabolism and hyper-
48
tension were reported by Ferrari and colleagues. 49 Young normotensive humans with at least one essential hypertensive parent tended to have insulin resistance and dyslipidemia. 49 Thus, a familial trait for essential hypertension may coexist with defects in carbohydrate and lipoprotein metabolism that can be detected before, or at a very early stage in, the development of high blood pressure. An association has been found between abnormal red blood cell (sodium-lithium) countertransport activity, considered to be a genetic marker for essential hypertension, and the presence of hypercholesterolemia,50 lending further support to the notion that lipid abnormalities frequently coexist in subjects at greatest risk for hypertension. Increased circulating insulin levels and peripheral insulin resistance have recently been shown to be associated with increased central nervous system sympathetic activity in patients with essential hypertension. 5I Although much of our thinking regarding the mechanism of essential hypertension has focused on the role of insulin resistance, the possibility that the dyslipidemia frequently associated with insulin resistance might also contribute to the development of hypertension is particularly intriguing. In this regard, the recently described effects of hyperlipidemia on endothelial vasoactive substances (Table 2) may be particularly germain. In patients with type I and type II diabetes mellitus and early evidence of nephropathy as evidenced by microalbuminuria, abnormalities of lipid metabolism have been reported. 52-55 Specifically, increased LDL cholesterol and decreased high-density lipoprotein as well as an increased lipoprotein (a) have been demonstrated. 52-55 Similarly, a trend towards increased blood pressure and increased red blood cell sodium-lithium countertransport activity in patients with incipient type I diabetic nephropathy is also of note. 52-55 These data also raise the possibility that dyslipidemia may contribute to the development ofhypertension, possibly through an effect of modified lipoproteins on vascular wall reactivity. CLINICAL RELATIONSHIP BETWEEN HYPERLIPIDEMIA AND THE PROGRESSION OF RENAL DISEASE
Primary hyperlipidemia does not ostensibly lead to de novo glomerular disease, although there
KEANE ET AL
are a number of unique and genetically determined dyslipidemias that are associated with renal disease. I Nonetheless, a number of clinical studies have demonstrated that apolipoprotein B and E are frequently found in glomeruli of patients with various renal diseases. 43-45 It is well established that hyperlipidemic agents can improve the lipid profile in nephrotic patients. 56 Moreover, recent clinical studies in patients with the nephrotic syndrome have suggested that reduction of hyperlipidemia may be associated with a decreased proteinuria and improvement in renal function. 57-59 Intriguingly, in one study, decreased glomerular foam cells and lipid deposits were associated with reduction in LDL. 59 In patients with type I diabetic nephropathy, Mulec and colleagues suggested that the rate of decline in renal function in diabetic patients was in part correlated with serum cholesterollevels. 6o In patients with total serum cholesterol levels above 270 mg/dL, the rate of decline in glomerular filtration rate over 18 months was 0.7 mL/ min per month. For those patients with total serum cholesterol below 270 mg/dL, the rate of decline of renal function was significantly lower at only 0.2 mL/min per month. The level of albuminuria was not different between the groups and mean arterial pressure was only 3 mm Hg higher in the high-cholesterol group. Recently, Bazzato and colleagues reported that the combination of a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor with an angiotensinconverting enzyme inhibitor had an additional beneficial effect in reducing the rate of loss of renal function in both diabetic and nondiabetic patients. 61 While these and other studies are suggestive of the importance of hyperlipidemia in modulating progressive renal disease, prospective and controlled trials with clinically relevant functional and morphologic endpoints will be needed to answer this important issue. ACKNOWLEDGMENT The authors express their gratitude to Deanna Gunderson for help in preparing the manuscript.
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HYPERTENSION, HYPERLIPIDEMIA, AND RENAL DAMAGE
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