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443

Brief Reviews

Lipids and the KidneyBertram L. Kasiske, Michael P. O'Donnell, William Cowardin, and William F. Keane

Epidemiological studies have shown that hyper-tension and hypercholesterolemia are bothrisk factors for the development of cardio-

vascular disease.1-5 Although most investigationshave focused on the independent nature of the risksresulting from hypertension and hypercholesterol-emia, the data have also indicated a possible syner-gism in the combined influences of these and otherrisk factors on vascular disease.6 In addition, severalstudies have found a more frequent than expectedoccurrence of hypertension and hypercholesterol-emia in the same individuals.7-9 It is unlikely that thisassociation is the result of hypertension causingabnormalities in lipid metabolism. On the other hand,lipid abnormalities could participate in the pathogen-esis of hypertension in a number of ways. The elevatedsystemic vascular resistance resulting from advancedatherosclerotic vascular disease, for example, maycontribute to the development of hypertension in theelderly. However, recent experimental data have alsosuggested that lipid abnormalities associated withhypercholesterolemia may be involved in the patho-genesis of essential hypertension through mechanismsnot dependent on the presence of overt vasculardisease.10-13 This intriguing possibility casts a new lighton what is already known about the synergistic effectsof hypercholesterolemia and elevated blood pressureon atherosclerosis.

The kidney may be an important link in ourunderstanding of the interactions between abnormal-ities in lipid metabolism, blood pressure, and vascu-lar disease (Figure 1). There is now abundant evi-dence demonstrating that the kidney is a major targetorgan for both hypertension and lipid-induced injury.In addition, the kidney may have an important role inthe pathogenesis of essential hypertension, and it ispossible that lipid-induced renal alterations couldcontribute to the development and maintenance ofelevated blood pressure. Although it is well knownthat advanced renal vascular disease may causehypertension, it is also possible that earlier, more

From the Department of Medicine, Hennepin County MedicalCenter, University of Minnesota, Minneapolis, Minnesota.

Supported by United States Public Health Service grants RO1AM37396, R23 AM37112, and KO8 DK01628. M.P.O. is therecipient of a New Investigator Award. B.L.K. is the recipient of aClinical Investigator Award from the National Institutes of Health.

Address for correspondence: Bertram L. Kasiske, MD, Depart-ment of Medicine, Hennepin County Medical Center, 701 ParkAvenue, Minneapolis, MN 55415.

subtle, lipid-induced alterations could influence renalresistance, sodium chloride handling, or the release ofvasoactive mediators from the kidney. These earlylipid-associated alterations could be important in thepathogenesis of essential hypertension. Moreover,recent evidence has suggested that the kidney mayplay a role in lipoprotein metabolism. Thus, sufficientrenal damage caused by hypertension and abnormal-ities in lipid metabolism could result in additionaldeleterious effects on circulating lipoproteins.

A clue to the potential importance of the kidney inthe complex interrelation between cholesterol, bloodpressure, and vascular disease is to be found inseveral recent epidemiological studies. In theseinvestigations, the presence of urinary protein excre-tion, even in amounts not detectable by the usualclinical methods, was found to be an importantpredictor of cardiovascular disease mortality.14-16

Moreover, in at least one study, the relation betweenproteinuria and vascular disease was found to bestatistically independent of hypertension andhypercholesterolemia.16 Several different mecha-nisms could explain the. independent associationbetween urinary protein excretion and cardiovasculardisease. Indeed, the kidney could be both a targetorgan for, and a cause of, increased blood pressureand lipid abnormalities. Regardless of the underlyingmechanisms, the relative strength of the associationbetween proteinuria and vascular disease indicatesthe potential importance of the kidney in the patho-genesis or consequences, or both, of hypercholester-olemia and hypertension.

Histological studies have also pointed to a strongrelation between systemic atherosclerosis and renaldamage. When two groups of otherwise normal indi-viduals with different degrees of systemic atheroscle-rosis were compared (patients with renal artery ste-nosis were excluded), the group with more severeatherosclerosis was found to have a higher incidenceof nephron obsolescence and intrarenal vasculardisease.17 Although it is possible that the glomerularsclerosis and nephron destruction were caused by theintrarenal vascular disease, it is also possible that thesame factors causing systemic atherosclerosis (e.g.,hypertension and hyperlipidemia) resulted in thegreater degree of nephron destruction. In addition,differences in the amount of renal damage may havecaused differences in the incidence and severity ofsystemic hypertension that, in turn, could also help

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444 Hypertension Vol 15, No 5, May 1990

^Systemic Atherosclerosisj-

FIGURE 1. Schematic diagram showing possible relationsbetween hyp'ercholesterolemia, hypertension, vascular disease,and renal injury. Lipid abnormalities associated with hyper-cholesterolemia may contribute to both atherosclerosis andrenal damage. Decreased renal function may lead to lipidabnormalities directly, or indirectly through the effects ofproteinuria. Lipid abnormalities and renal injury may also beinvolved in the pathogenesis of hypertension. Elevated bloodpressure may, in turn, cause further renal damage and athero-sclerosis. PVR, peripheral vascular resistance; RVR, renalvascular resistance.

explain the observed association between renal dam-age and systemic atherosclerosis.

Effects of Hypertension on the KidneyIt has long been appreciated that hypertension

causes renal injury. Early histological investigationsemphasized the deleterious effects of elevated sys-temic blood pressure on small intrarenal arteries andarterioles.18'19 In contrast, larger, interlobar arteriesappeared to be affected by age-related, atheroscle-rotic vascular disease that was not solely the result ofhypertension.18 In these early investigations, it wasnoted that the number of histologically intact neph-rons appeared to be diminished in kidneys withvascular disease.1820 This loss of functioning neph-rons to glomerulosclerosis was generally attributed toischemia caused by vascular occlusion.20-21 Morerecent studies have challenged the notion that glo-merular obsolescence is entirely the result of occlu-sive intrarenal vascular changes and have suggested,as an alternative explanation, that there may be otherfactors common to the pathogenesis of both.17

Recent investigations have also attempted to moreprecisely define the pathogenesis of hypertension-induced renal injury. The capillaries within the renalglomerulus are unique because they have both pre-glomerular and postglomerular arterioles. Increasesin preglomerular resistance tend to decrease intra-glomerular pressure and the rate of glomerular fil-tration. Conversely, unopposed increases in post-glomerular resistance raise glomerular capillarypressure and the filtration rate. A number of micro-puncture experiments have been carried out in ani-mal models of hypertension, and these experimentshave demonstrated that the amount of nephrondamage is largely dependent on the extent to which

systemic arterial pressure is transmitted to glomeru-lar capillaries.2223 Thus, in hypertensive rats withhigh preglomerular vascular resistance and normalintraglomerular pressures, little glomerular injuryoccurred.22-24 However, in hypertensive rats withlower preglomerular resistance and high glomerularcapillary pressure, a large amount of glomerularsclerosis resulted.22-23-25 Moreover, in the rat two-kidney, one clip model of hypertension, elevatedsystemic pressure is transmitted to the glomeruli ofthe undipped, but not the clipped kidney.26 As aresult, hypertensive renal injury is confined to theundipped kidney.23

It should also be recognized that the effects ofsystemic blood pressure and glomerular capillarypressure can be dissociated, and the importance ofintraglomerular pressure in the pathogenesis of renalinjury may explain why similar pharmacologicalreductions in systemic blood pressure may not yieldequivalent decreases in renal damage. Indeed, it hasbeen found that treatment of hypertensive rats withconverting enzyme inhibitors, which reduce bothsystemic and intraglomerular pressure, amelioratesthe amount of renal injury.27 However, an equivalentreduction in blood pressure using pharmacologicalagents that lowered systemic pressure without reduc-ing intraglomerular pressure left a substantiallygreater amount of renal injury.27

Despite the recent advances in our understandingof the pathogenesis of renal injury in experimentalmodels of hypertension, a number of questionsremain unanswered. Because micropuncture experi-ments cannot be carried out in humans, the impor-tance of intraglomerular pressure in the pathogenesisof hypertensive renal injury is still a matter of spec-ulation. Short-term studies in diabetic patients withnephropathy have suggested that converting enzymeinhibitors may reduce urine protein excretion andretard the progression of renal disease.2829 However,carefully controlled trials comparing convertingenzyme inhibitors with other antihypertensive agentshave not been carried out, and the long-term effectsof these agents on renal injury are unknown.

The mechanism whereby increased glomerularpressure may cause renal injury is also unknown. It ispossible that increased glomerular capillary pressuremay damage endothelial cells directly. Alternatively,an increased flux of plasma proteins across basementmembranes subjected to elevated glomerular pres-sure could result in cell injury through direct orindirect mechanisms. In this regard, it is important tonote that, in animal models of hypertension, renaldamage was often accompanied by both proteinuriaand plasma lipid abnormalities. In the two-kidneyGoldblatt model, in the remnant kidney model, and inthe Dahl salt-sensitive rat, the development of protein-uria is accompanied by increasing plasma lipid levels(see below).30-31 It is important, therefore, to examinethe possible independent, additive, or synergistic effectsof abnormal lipid metabolism on the renal injury asso-ciated with hypertension and proteinuria.



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Kasiske et al Lipids and the Kidney 445

Effects of Hypercholesterolemia on the Kidney

Many patients with renal disease who have apronounced reduction in functional renal massrecover enough function through compensatorymechanisms to survive a number of years. However, aslow, progressive deterioration in renal function thateventuates in end-stage renal failure frequentlydevelops in these patients.32"34 A number of mecha-nisms have been proposed to explain this chronic,progressive renal destruction.35-37 Because patientswith renal disease almost invariably have alterationsin lipid metabolism, it is important to determinewhether lipid abnormalities could participate in thepathogenesis of chronic renal injury.

Recent experimental data have suggested thatlipid abnormalities may indeed influence the devel-opment and progression of renal injury. Studiescarried out in several animal models of endogenoushyperlipidemia demonstrated that the pharmacolog-ical reduction of serum lipid levels was associatedwith a reduction in the amount of glomerular injury.Rats subjected to a surgical reduction in the numberof functioning nephrons, the so-called remnant kid-ney model of chronic renal failure, developed pro-teinuria, hypercholesterolemia, systemic hyperten-sion, and progressive renal injury.27-30'38 Whenremnant kidney rats were treated with either of twostructurally unrelated antilipemic agents (clofibricacid and lovastatin), serum cholesterol was reducedand the amount of renal injury diminished.39 More-over, micropuncture experiments demonstrated thatthe reduction in renal injury resulting from theantilipemic agents could not be explained by reducedglomerular pressures.39 Similar investigations werecarried out in the obese Zucker rat, which is a modelof hyperlipidemia, type II diabetes, and progressiverenal injury.40 Treatment of obese Zucker rats withclofibric acid or lovastatin effectively reduced serumlipids and ameliorated the proteinuria and renalinjury.41 Thus, these investigations indicated thatendogenous hyperlipidemia may be important in thedevelopment and progression of chronic, progressiverenal injury.

Other animal models of endogenous hyperlipid-emia have also been shown to develop progressiverenal injury.4243 An interesting exception is theWatanabe heritable hyperlipidemic rabbit. TheWatanabe rabbit lacks the normal number of lowdensity lipoprotein receptors, and as a result, devel-ops pronounced hyperlipidemia. Renal injury wasnot found in this model.44 Understanding the uniqueresistance of the Watanabe rabbit to progressiverenal damage may ultimately help unravel the patho-genesis of lipid-induced renal injury.

In a number of experimental investigations, diet-induced hypercholesterolemia has also been shownto cause renal injury. Rats, rabbits, and guinea pigsfed diets containing cholesterol or increased amountsof saturated fat, or both, developed hypercholester-olemia.45-49 The lipid abnormalities in these experi-

ments were accompanied by proteinuria and progres-sive renal injury. Although blood pressure was notsystematically evaluated in these studies, others haveshown that high fat, high cholesterol diets mayincrease systemic blood pressure.12-50'51

The possible mechanisms whereby lipid abnormal-ities cause renal injury have recently been reviewedin detail.52-53 Many of these mechanisms may beanalogous to those believed important in the patho-genesis of atherosclerosis. Investigations have shownthat renal injury in models of hyperlipidemia isaccompanied by glomerular lipid deposition and theappearance of foam cells.41-45'47-49-54 In addition, lipidanalysis has indicated that cholesterol-induced injuryis associated with increased amounts of cholesteroland cholesteryl esters in renal tissue.45-49-55 Pro-nounced changes in renal fatty acids, similar to therelative essential fatty acid deficiency profile associ-ated with the development of atherosclerosis, havealso been described in models of lipid-induced renalinjury.55 These fatty acid changes could lead toalterations in the renal production of vasoactive andinflammatory mediators that could be important inthe pathogenesis of injury. Finally, investigationshave also shown that renal lipid deposition is accom-panied by the infiltration of the kidney with mono-cytes and macrophages.45-56 Research into the patho-genesis of atherosclerosis has demonstrated thepivotal role that macrophages play in this process,and similar mechanisms could be important in lipid-induced renal injury.

There are also clinical data pointing to an associ-ation between abnormalities in lipid metabolism andrenal injury. Indeed, renal lipid deposition has longbeen known to accompany glomerular injury in anumber of different kidney diseases.57-60 Glomerularand interstitial foam cells have also been found inpatients with renal disease.61-62 Moreover, the spon-taneous development of renal disease has beenreported in patients with uncommon forms ofdyslipoproteinemias.62-65 On the other hand, theprevalence of renal abnormalities in patients with themore common types of hyperlipidemias, althoughunknown, is probably not very high. Overt renaldisease does not develop in most patients with hyper-cholesterolemia, which suggests that other predispos-ing factors (e.g., immune-mediated glomerular injuryor glomerular hypertension) may have to be presentfor significant renal damage to occur.

Possible Interactive Effects of Lipid Abnormalitiesand Glomerular Hypertension on Renal InjuryThe experimental evidence suggests that both

increased intraglomerular pressures and hyperlipid-emia may independently cause renal injury. How-ever, these two risk factors are often seen together.Thus, it is important to determine how abnormalitiesin lipid metabolism could interact with alterations inglomerular pressures to cause renal injury. Althoughexperiments have shown that lipid abnormalities cancause renal injury in the absence of alterations in



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TABLE 1. Effects of Cholesterol Feeding on Rats With Two-Kidney, One Clip Hypertension

Variable and experimental group

Body weight (g)

Hypertension

Hypertension and cholesterol

Blood pressure

Hypertension


Serum cholesterol (mg/dl)

Hypertension


Serum triglycerides (mg/dl)

Hypertension


Urine albumin (mg/24 hr)

Hypertension


14 weeks

397 ±29

352±52*

161 + 15

166±14

51±8

230±102*

76±16

68±13

3±4

26 ±22*

Weeks of age

20 weeks

475 ±50

445±61

190±35

183±27

68 ±39

280±130*

94±52

80±16

37±59

68±34*

26 weeks

516±69

485 ±76

198±30

192±30

87+38

340±131*

101±45

78±13

58 ±70

107±65*

Values are mean±SD.*p<0.05 compared with hypertension group (urine albumins were analyzed after logarithmic normalization).

intraglomerular pressure, it is also possible thatpronounced changes in serum lipids can causeincreased glomerular pressure. To investigate thispossibility, micropuncture experiments were carriedout in Sprague-Dawley rats fed a high cholesteroldiet. Rats were studied at a time when there wasproteinuria and mild expansion of the glomerularmesangium but before there was evidence of glomer-ular sclerosis. Preliminary results have shown a pro-nounced increase in serum cholesterol levels after 4weeks of diet.66 Glomerular filtration and plasmaflow rates were not significantly affected by the diet.However, glomerular capillary pressure was in-creased by 10-20% in rats fed the high cholesteroldiet compared with control rats fed standard chow.66

Thus, although lipid abnormalities may cause renalinjury without elevating glomerular pressure, pro-nounced hypercholesterolemia may cause glomerularhypertension that could exaggerate the amount ofinjury.

The reason for the increase in glomerular capillarypressure associated with hypercholesterolemia isunclear. The glomerular hemodynamic changescould have been the result of the altered plasmaviscosity or decreased red blood cell deformabilitythat is known to occur in hyperlipidemia.67-68 It isinteresting, however, that whole kidney vascularresistance after cholesterol feeding was found to beincreased in isolated kidneys perfused without redblood cells or plasma lipoproteins.69 This latterobservation suggested the possibility that factors inaddition to altered blood rheology could have playeda role in the glomerular hemodynamic changes. Inthis regard, it is possible that the increased number ofmesangial cells or glomerular macrophages that areassociated with cholesterol feeding could release

vasoactive mediators and contribute to increasedglomerular capillary pressures.

Additional experiments have been carried out todetermine the extent to which alterations in glomer-ular pressure and serum lipids could act additively, orsynergistically, to accelerate renal injury. The two-kidney Goldblatt model of systemic hypertensionoffers a unique opportunity to examine the possibleinteractive effects of alterations in intraglomerularpressure and lipid abnormalities on renal injury. Byplacing a single clip on the left renal artery of normalrats, a pronounced elevation in systemic blood pres-sure occurs. Compensatory vasodilation exposes theglomeruli in the undipped kidney to pressures thatare much higher than normal.26 In contrast, intra-glomerular pressure in the clipped kidney is actuallylower than normal.26 By comparing the renal histol-ogy in clipped and undipped kidneys from the samerats, the glomerular hemodynamic modulation ofcholesterol-induced renal injury can be examined.

Normal, 6-week-old male Sprague-Dawley ratswere fed standard chow (n=16) or standard chowsupplemented with 4% cholesterol and 2% sodiumcholate («=13). After 4 weeks of diet (i.e., at 10weeks of age) a single clip was placed on the rightrenal artery of all rats. Systolic blood pressures wereelevated in both diet groups and serum cholesterollevels were markedly increased in the cholesterol-fedrats (Table 1). In contrast, serum triglycerides werenot significantly different between the two groups(Table 1). Compared with normal Sprague-Dawleyrats (data not shown), albumin excretion wasincreased in both diet groups (Table 1). Moreover,the cholesterol-fed rats had a significantly higherurine albumin excretion rate (Table 1).

The glomerular areas of undipped kidneys, deter-mined by planar morphometry, were greater in



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g 30.0

u10

5 20.0

i 10.0

•Standard DietESJHigh Cholesterol

(8)

(13) (1«) <fl f ^ j

(13)

(18)

IClippedKidneys

NormalKidneys

UndippedKidneys

FIGURE 2. Bar graph showing relation between reduced,normal, or elevated perfusion pressure and glomerulosclerosisin rats fed a standard diet (open bars) or high cholesterol(hatched bars). Clipped kidneys of Goldblatt hypertensive ratswith low renal perfusion pressure are compared with kidneysfrom rats with normal renal perfusion pressure56 andundipped kidneys that have glomeruli exposed to systemichypertension.

cholesterol-fed rats (ll,200± 1,700 /xm2) comparedwith standard chow rats (8,440±898 ju,m2, p<0.01).The glomeruli in the clipped kidneys were smallercompared with undipped kidneys, but the glomeruliin the clipped kidneys were larger in cholesterol-fedrats (8,500±l,300 jam2) compared with those ofstandard chow controls (6,400±440 jam2, p<0.Ql).There was no glomerulosclerosis in clipped kidneysfrom rats fed standard chow. However, in the clippedkidneys from rats fed high cholesterol, 0.4±0.5% hadglomerulosclerosis (p<0.05 compared with those ofstandard chow rats). In the undipped kidneys, whereglomerular pressures have been reported to beelevated,26 the percent of glomeruli with sclerosis was19±19% in the standard chow group versus 32±20%in the cholesterol-fed group (/?<0.05).

It is interesting that the amount of glomerularinjury in the clipped kidneys of rats fed a highcholesterol diet was less than that previouslyobserved in normotensive Sprague-Dawley rats fedthe same high cholesterol diet for the same length oftime (Figure 2). Although glomerular hemodynamicmeasurements were not carried out in these experi-ments, others demonstrated that glomerular pres-sures were actually reduced in the clipped kidneys inthe rat, two-kidney Goldblatt model.26 Thus, thesedata suggest that a reduction in normal glomerularpressures may have resulted in a decrease in theamount of cholesterol-induced glomerular injury. Ofcourse, other changes in the clipped kidneys couldhave also caused the observed differences in injury. Itis also significant that the amount of glomerularinjury in the undipped kidneys was increased com-pared with clipped and normal kidneys in bothstandard chow and cholesterol-fed rats (Figure 2).Moreover, the injurious effects of combining theglomerular hemodynamic changes (i.e., increasedpressure) in the undipped Goldblatt hypertensive ratkidney with diet-induced hypercholesterolemiaappeared to be additive but not synergistic in thismodel (Figure 2).

It is also interesting that the amount of injury wasproportional to the size of remaining intact glomer-uli, and that cholesterol was associated with anincrease in glomerular size in both clipped andundipped kidneys. The effects of the clip and of thecholesterol diet could reflect differences in glomeru-lar hemodynamic function (i.e., increased pressure)or could reflect differences in the compensatoryhypertrophic response to the different amounts ofglomerular injury in the experimental groups. Thelatter could be particularly important, as it hasrecently been suggested that the renal hypertrophicresponse per se may be important in the pathogenesisof renal injury.70-71

A similar investigation has been carried out by othersusing a diet that produced a much milder degree ofhypercholesterolemia.49 Indeed, normal rats fed a highcholesterol, high fat diet had serum total cholesterollevels that were not significantly different from rats feda control, high carbohydrate diet.49 In that investiga-tion, as in the present study, the greatest amount ofdamage was seen in undipped kidneys of rats fed thehigh cholesterol, high fat diet.49 Altogether these datasuggest that the relatively mild cholesterol-inducedinjury seen in normal kidneys may become severe whencombined with other injurious factors such as increasedglomerular pressure.

Possible Impact of Renal Abnormalities onHypertension and Hypercholesterolemia

Experimental and clinical evidence suggest thathypercholesterolemia and associated lipid abnormal-ities may be important in the pathogenesis of essen-tial hypertension. It has been postulated that alter-ations associated with hypercholesterolemia couldincrease smooth muscle cell contractility by alteringendothelial-dependent relaxing factors, changingmembrane cation transport, or affecting vasculareicosanoid production.10-13'72-73 Alterations insmooth muscle contractility could, in turn, affectperipheral vascular resistance and systemic arterialpressure. Because the kidney has a unique role in theregulation of systemic blood pressure, it is alsopossible that cholesterol-induced alterations in renalfunction could be important in the pathogenesis ofessential hypertension.

It is known that severe renal vascular diseasecaused by hypertension and hypercholesterolemiacan contribute to elevated systemic blood pressure.However, the results of studies carried out usingisolated kidneys from rats fed a high cholesterol dietfor only 4 weeks, indicated that cholesterol mayinduce changes in renal vascular resistance at atime when the only histological change apparent isa mild glomerular mesangial expansion.69 Renalvascular resistance was significantly elevated in theisolated, perfused kidneys from rats fed the highcholesterol diet, and the filtration fraction wasreduced.69 These hemodynamic changes were simi-lar to those reported in individuals with essentialhypertension.74-76 Because the kidneys in these



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experiments were isolated from lipoproteins andother possible systemic influences of the diet, thecholesterol was the apparent cause of intrinsic renalalterations that resulted in the increased resistance.Histologically, only a small amount of mesangialmatrix expansion and increased mesangial cellularitywere seen after 4 weeks of cholesterol feeding (per-sonal observations). There was no glomerulosclerosisevident at this time, and no vascular abnormalitieswere seen (personal observations). The mechanismfor these early alterations in renal resistance withcholesterol feeding is unknown. However, otherinvestigations have shown that cholesterol feedingmay directly, or indirectly, alter smooth muscle cellcontractility.11'73 These data suggested that hyper-cholesterolemia may cause early alterations in renalvascular resistance that could participate in thepathogenesis of essential hypertension.

Although patients with untreated essential hyper-tension are more likely to have hypercholesterol-emia,7-9 certainly not all hypercholesterolemicpatients have elevated blood pressure. Likewise,changes in serum cholesterol in experimental modelsof hyperlipidemia have not been uniformly associatedwith alterations in systemic blood pressure.39-41 Thesedata raise the possibility that hypercholesterolemiamay not cause increased blood pressure per se butmay be a marker for other associated abnormalitiesin lipoprotein or fatty acid metabolism. Alternatively,lipoprotein abnormalities associated with hypercho-lesterolemia may combine with other factors to causeincreased blood pressure.

It is also possible that renal alterations resultingfrom hypercholesterolemia and hypertension couldcontribute to elevated plasma lipoprotein levels.Although the mechanisms are still uncertain, it is wellknown that patients with large amounts of urinaryprotein excretion have pronounced hyperlipidemia.Whether low levels of urinary protein excretion alsocontribute to plasma lipid abnormalities is unknown.To the extent that urinary protein excretion mayreflect abnormal renal lipoprotein metabolism, it ispossible that even low levels of proteinuria couldcontribute to abnormalities in plasma lipids. More-over, it has also been shown that declines in glomerularfiltration rate are associated with abnormalities in lipidmetabolism. Indeed, individuals with glomerular filtra-tion rates less than 50-60 ml/min begin to manifestabnormalities in circulating lipoproteins.7778 The effectof this renal functional reduction on lipid metabolismsuggests that the normal, age-related decline in glomer-ular filtration rate could play a role in the propensity forcholesterol levels to increase with age.79

In summary, a substantial body of evidence pointsto the potentially important role of the kidney in thecomplex relation between hypercholesterolemia,hypertension, and mortality from vascular disease. Itis generally accepted that the kidney is a major targetorgan for the deleterious effects of hypertension.However, recent data suggest that lipid abnormalitiesassociated with hypercholesterolemia may also cause

renal damage. In addition, alterations in renal func-tion resulting from hypercholesterolemia or hyper-tension may contribute to the maintenance of ele-vated blood pressure and abnormal lipid metabolism.Taken all together, these data suggest that the treat-ment of both hypercholesterolemia and hypertensionmay best preserve renal function. Moreover, choles-terol and blood pressure reduction strategies that bestpreserve renal function may be the most effective inreducing the incidence of cardiovascular disease.

AcknowledgmentWe thank Jan Lovick for her assistance in prepar-

ing this manuscript.

References1. Reed DM, MacLean CJ, Hayashi T: Predictors of atheroscle-

rosis in the Honolulu heart program. Am J Epidemiol 1987;126:214-225

2. Kromhout D, Bosschieter EB, Drijver M, Coulander CL:Serum cholesterol and 25-year incidence of and mortality frommyocardial infarction and cancer: The Zutphen study. ArchIntern Med 1988;148:1051-1055

3. Castelli WP: Epidemiology of coronary heart disease: TheFramingham study. Am J Med 1984;76:4-12

4. GifFord RW: Review of the long-term controlled trials ofusefulness of therapy for systemic hypertension. Am J Cardiol1989;63:8B-16B

5. Criqui MH: Epidemiology of atherosclerosis: An updatedoverview. Am J Cardiol 1986;57:18C-32C

6. Criqui MH, Barret-Connor E, Holdbrook MJ, Austin MA,Turner JD: Clustering of cardiovascular disease risk factors.Prev Med 1980;9:525-533

7. MacMahon SW, MacDonald GJ, Blacket RB: Plasma lipopro-tein levels in treated and untreated hypertensive men andwomen. Arteriosclerosis 1985;5:391-396

8. Lochen M-L: The Tromso heart study: Coronary risk factorlevels in treated and untreated hypertensives. Acta Med Scand1988;.224:515-521

9. Shieh SM, Shen M, Fuh MMT, Chen YDI," Reaven GM:Plasma lipid and lipoprotein concentrations in Chinese maleswith coronary artery disease, with and without hypertension.Atherosclerosis 1987;67:49-55

10. Hunt SC, Williams RR, Smith JB, Ash KO: Associations ofthree erythrocyte cation transport systems with plasma lipidsin Utah subjects. Hypertension 1986;8:30-36

11. Verbeuren TJ, Jordaens FH, Zonnekeyn LL, Van Hove CE,Coene MC, Hermann AG: Effect of hypercholesterolemia onvascular reactivity in the rabbit. Circ Res 1986;58:552-564

12. Smith-Barbaro P, Quinn MR, Fisher H, Hegsted DM: Theeffect of dietary fat and salt on blood pressure, renal and aorticprostaglandins. Nutr Res 1981;l:277-287

13. Locher R, Neyses L, Stimpel M, Kuffer B, Vetter W: Thecholesterol content of the human erythrocyte influences cal-cium influx through the channel. Biochem Biophys Res Com-mun 1984;124:822-828

14. Kannel WB, Stampfer MJ, Castelli WP, Verter J: The prog-nostic significance of proteinuria: The Framingham study. AmHeart J 1984;108:1347-1352

15. Bulpitt CJ, Beevers DG, Butler A, Coles EC, Hunt D,Munro-Faure AD, Newson RB, O'Riordan PW, Petrie JC,Rajagopalan B, et al: The survival of treated hypertensivepatients and their causes of death: A report from the DHSShypertensive care computing project (DHCCP). J Hypertens1986;4:93-99

16. Samuelsson O, Wilhelmsen L, Elmfeldt D, Pennert K, WedelH, Wikstrand J, Berglund G: Predictors of cardiovascularmorbidity in treated hypertension: Results from the primarypreventive trial in Goteborg, Sweden. / Hypertens 1985;3:167-176



ownloaded from



17. Kasiske BL: Relationship between vascular disease and age-associated changes in the human kidney. Kidney Int 1987;31:1153-1159

18. Williams RH, Harrison TR: A study of the renal arteries inrelation to age and to hypertension. Am Heart J 1937;14:645-658

19. Smith JP: Hyaline arteriolosclerosis in the kidney. J Pathol1955;64:147-168

20. Kimmelstiel P: Glomerular changes in arteriosclerotic con-traction of the kidney. Am J Pathol 1935; 11:483-495

21. McManus JFA, Lupton CH: Ischemic obsolescence of renalglomeruli: The natural history of the lesions and their relationto hypertension. Lab Invest 1960;9:413-434

22. Raij L, Azar S, Keane W: Role of hypertension in progressiveglomerular immune injury. Hypertension 1985;7:398-404

23. Olson JL, Wilson SK, Heptinstall RH: Relation of glomerularinjury to preglomerular resistance in experimental hyperten-sion. Kidney Int 1986;29:849-857

24. Arendhorst WJ, Beierwaltes WH: Renal and nephron hemo-dynamics in spontaneously hypertensive rats. Am J Physiol1979;236:F246-F251

25. Dworkin LD, Hostetter TH, Rennke HG, Brenner BM:Hemodynamic basis for glomerular injury in rats withdesoxycorticosterone-salt hypertension. J Clin Invest 1984;73:1448-1461

26. Schwietzer G, Gertz KH: Changes of hemodynamics andglomerular ultraflltration in renal hypertension of rats. KidneyInt 1979;15:134-143

27. Anderson S, Rennke HG, Brenner BM: Therapeutic advan-tage of converting enzyme inhibitors in arresting progressiverenal disease associated with systemic hypertension in the rat./ Clin Invest 1986;77:1993-2000

28. Parving HH, Hommel E, Smidt UM: Protection of kidneyfunction and decrease in albuminuria by captopril in insulindependent diabetics with nephropathy. Br Med J 1988;297:1086-1091

29. Marre M, Chatellier G, Leblanc H, Guyene YTT, Menard J,Passa P: Prevention of diabetic nephropathy with enalapril innormotensive diabetics with microalbuminuria. BrMedJ 1988;297:1092-1095

30. Heuck CC, Liersch M, Ritz R, Stegmeier K, Wirth A, MehlsO: Hyperlipoproteinemia in experimental chronic renal insuf-ficiency in the rat. Kidney Int 1978;14:142-150

31. O'Donnell MP, Kasiske BL, Keane WF: Risk factors forglomerular injury in rats with genetic hypertension. Am JHypertens 1989;2:9-13

32. Baldwin DS, Gluck MC, Schacht RG, Gallo G: The long-termcourse of poststreptococcal glomerulonephritis. Ann InternMed 1974;80:342-358

33. Schacht RG, Gluck MC, Gallo GR, Baldwin DS: Progressionto uremia after remission of acute poststreptococcal glomeru-lonephritis. N Engl J Med 1976;295:977-981

34. Kleinknecht D, Grunfeld JP, Gomez C, Moreau JF, Garcia-Torres R: Diagnostic procedures and long-term prognosis inbilateral renal cortical necrosis. Kidney Int 1973;4:390-400

35. Klahr S, Purkerson ML, Heifets M: Factors that may retardthe progression of renal disease. Kidney Int 1987;32:S35-S39

36. Olson JL, Heptinstall RH: Nonimmunologic mechanisms ofglomerular injury. Lab Invest 1988;59:564-578

37. Brenner BM: Hemodynamically mediated glomerular injuryand the progressive nature of kidney disease. Kidney Int1983;23:647-655

38. Shimamura T, Morrison AB: A progressive glomerulosclerosisoccurring in partial five-sixths nephrectomized rats. Am JPathol 1975;79:95-106

39. Kasiske BL, O'Donnell MP, Garvis WJ, Keane WF: Pharma-cologic treatment of hyperlipidemia reduces glomerular injuryin rat 5/6 nephrectomy model of chronic renal failure. Circ Res1988;62:367-374 .

40. Kasiske BL, O'Donnell MP, Keane WF: The obese Zucker ratmodel of glomerular injury in type II diabetes. / Diab Compl1987;l:26-29

41. Kasiske BL, O'Donnell MP, Cleary MP, Keane WF: Treat-ment of hyperlipidemia reduces glomerular injury in obeseZucker rats. Kidney Int 1988;33:667-672

42. Imai Y, Matsumura H, Miyajima H, Oka K: Serum and tissuelipids and glomerulosclerosis in the spontaneously hypercho-lesterolemic rat, with a note on the effects of gonadectomy.Atherosclerosis 1977;27:165-178

43. Michaelis OE, Carswell N, Valasquez MT, Hansen CT: Therole of obesity, hypertension and diet in diabetes and itscomplications in the spontaneous hypertensive/NIH-corpulentrat. Nutrition 1989;5:56-59

44. Raij L, Tollins JP, Luscher T: Hyperlipidemia and renal injury.Studies in atherosclerosis prone Watanabe rabbits with hered-itary hyperlipidemia (abstract). Kidney Int 1988;33:383

45. Al-Shebeb T, Frohlich J, Magil AB: Glomerular disease inhypercholesterolemic guinea pigs: A pathogenetic study. Kid-ney Int 1988;33:498-507

46. Peric-Golia L, Peric-Golia M: Aortic and renal lesions inhypercholesterolemic adult, male, virgin Sprague-Dawley rats.Atherosclerosis 1983;46:57-65

47. French SW, Yamanaka W, Ostwald R: Dietary induced glo-merulosclerosis in the guinea pig. Arch Pathol Lab Med1967;83:204-210

48. Wellmann KF, Volk BW: Renal lesions in experimentalhypercholesterolemia in normal and in subdiabetic rabbits: II.Long term studies. Lab Invest 1971;24:144-145

49. Groene HJ, Groene E, Luthe H, Weber MH, Helmchen U:Induction of glomerular sclerosis by a lipid-rich diet in malerats. Lab Invest 1989;60:433-446

50. Bronte-Stewart B, Hepinstall RH: The relationship betweenexperimental hypertension and cholesterol-induced atheromain rabbits. J Pathol 1954;68:407-417

51. Burstyn PG, Horrobin DF, Muiruri K: Effects of a high fat dietand of intravenous infusions of cholesterol on arterial pressurein rabbits. BrJExp Pathol 1972;53:258-264

52. Keane WF, Kasiske BL, O'Donnell MP: Lipids and progres-sive glomerulosclerosis. Am J Nephrol 1988;8:261-271

53. Diamond JR, Karnovsky MJ: Focal and segmental glomerulo-sclerosis: Analogies to atherosclerosis. Kidney Int 1988;33:917-924

54. Diamond JR, Karnovsky MJ: Exacerbation of chronic amino-nucleoside nephrosis by dietary cholesterol supplementation.Kidney Int 1987;32:671-677

55. Kasiske BL, O'Donnell MP, Cleary MP, Keane WF: Effects ofreduced renal mass on tissue lipids and renal injury inhyperlipidemic rats. Kidney Int 1989;35:40-47

56. Kasiske BL, Kim Y, O'Donnell MP, Keane WF: Renal injuryin hypercholesterolemia is associated with the accumulation ofglomerular macrophages (abstract). Clin Res 1989;37:493A

57. Munk F: Beriche iiber Krankheitsfalle und Behandlungsver-fahren. Med Klin 1916;12:1019-1076

58. Fahr T: Beitrage zur Frage der Nephrose. Virchows Arch [A]1922;239:32-40

59. Bell ET: Lipoid nephrosis. Am J Pathol 1929;5:587-62260. Kimmelstiel P, Wilson C: Intercapillary lesions in the glomer-

ulus of the kidney. Am J Pathol 1936;12:83-9861. McKenzie IFC, Kincaid-Smith P: Foam cells in the renal

glomerulus. J Pathol 1969;97:151-15462. Amatruda JM, Margolis S, Hutchins GM: Type 3 hyperli-

poproteinemia with mesangial foam cells in renal glomeruli.Arch Pathol 1974;98:51-54

63. Faraggiana T, Churg J: Renal lipidoses: A review. Hum Pathol1987;18:621-679

64. Saito T, Sato H, Kudo K, Oikawa S, Shibuta T, Hara Y,Yoshinaga K, Sakaguchi H: Lipoprotein glomerulopathy: Glo-merular lipoprotein thrombi in a patient with hyperlipopro-teinemia. AmJKidDis 1989;13:148-153

65. Gjone E, Blomhoff JP, Skarbevik AJ: Possible associationbetween an abnormal low density lipoprotein and nephrop-athy in lecithin Cholesterol acyltransferase deficiency. ClinChemActa 1974;54:11-18

66. Schmitz PG, O'Donnell MP, Kasiske BL, Keane WF: Diet-induced hypercholesterolemia elevates glomerular capillarypressure (abstract). Kidney Int 1989;35:473



ownloaded from



67. Seplowitz AH, Chien S, Smith FR: Effects of lipoproteins onplasma viscosity. Atherosclerosis 1981;38:89-95

68. Cooper RA, Arner EC, Wiley JS, Shattil SJ: Modification ofred cell membrane structure by cholesterol-rich lipid disper-sions: A model for the primary spur cell defect. / Clin Invest1975;55:115-126

69. Kasiske BL, O'Donnell MP, Keane WF: Diet-induced hyper-cholesterolemia increases the intrinsic renal vascular resis-tance of isolated perfused rat kidneys (abstract). Clin Res1987;35:444A

70. Yoshida Y, Fogo A, Ichikawa I: Glomerular hemodynamicchanges vs. hypertrophy in experimental global sclerosis. Kid-ney Int 1989;35:654-660

71. Harris DCH, Chan L, Schrier RW: Remnant kidney hyperme-tabolism and progression of chronic renal failure. Am JPhysioll988;254(Renal Fluid Electrolyte Physiol 23):F267-F276

72. Ortega A, Mas-Oliva J: Direct regulatory effect of cholesterolon the calmodulin stimulated calcium pump of cardiac sarco-lemma. Biochem Biophys Res Commun 1986;139:868-874

73. Aksulu HE, Cellek S, Turker RK: Cholesterol feeding atten-uates endothelium-dependent relaxation response to acetyl-

choline in the main pulmonary artery of chickens. Eur JPharmacol 1986;129:397-400

74. Hollenberg NK, Adams DF: The renal circulation in hyper-tensive disease. Am J Med 1976;60:773-784

75. London GM, Safar ME, Sassard JE, Levenson JA, Simon AC:Renal and systemic hemodynamics in sustained essentialhypertension. Hypertension 1984;6:743-754

76. Coruzzi P, Musiari L, Biggi A, Ravanetti C, Vallisa D,Montanari A, Novarini A: Role of renal hemodynamics in theexaggerated natriuresis of essential hypertension. Kidney Int1988;33:875-880

77. Frank WM, Sreepada Rao TK, Manis T, Delano BG, AvramMM, Saxena AK, Carter AC, Friedman EA: Relationship ofplasma lipids to renal function and length of time on mainte-nance hemodialysis. Am J Clin Nutr 1978;31:1886-1892

78. Grutzmacher P, Radtke HW, Schifferdecker E, Peschke B,Riepenhausen J, Fassbinder W, Schoeppe W: Early changes ofplasma lipid status and glucose tolerance during the course ofchronic renal failure. Contrib Nephrol 1984;41:332-336

79. Kritchevsky D: Diet, lipid metabolism, and aging. Fed Proc1979;38.2001-2006

KEY WORDSrenal function

hypercholesterolemiaglomerulonephritis

essential hypertension

(Hypertension 1990; 15:443-450)



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B L Kasiske, M P O'Donnell, W Cowardin and W F KeaneLipids and the kidney.

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