Kidney International, Vol. 57, Suppl. 75 (2000), pp. S-27–S-31

The role of lipids in renal disease: Future challenges

WILLIAM F. KEANE

Department of Medicine, Division of Nephrology, Hennepin County Medical Center, Minneapolis, Minnesota, USA

The role of lipids in renal disease: future challenges. Experi- lipids will have an added beneficial effect on reducingmental studies have provided in vivo and in vitro data to sup- the rate of loss of renal function in human renal diseases.port the notion that dyslipidemia contributes to glomerular Analysis of existing studies suggest that the use of theseand interstitial injury of the renal parenchyma. The 3-hydroxy-

agents, particularly the HMG-CoA reductase inhibitors,3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitorswill have additive effects to antihypertensive therapies.are a new class of lipid-lowering agents that have been exten-

sively studied during the past decade. These agents have sig- Since cardiovascular disease is intricately connected tonificant effects on circulating lipids and both renal and vascular the presence of proteinuria/albuminuria and renal dis-injury. New insights into the mechanisms of action of these ease, future attempts to modify dyslipidemia may haveagents have revealed an important effect on a variety of in-

substantial clinical benefits by reducing mortality ratesflammatory and fibrogenic processes that appear to have majorassociated with renal as well as cardiovascular disease.implications for human renal and cardiovascular diseases.

DYSLIPIDEMIA AND RENAL DISEASERecent clinical data have suggested that dyslipidemia

Microalbuminuriais an important clinical abnormality seen in patients withUrinary excretion of albumin above 30 mg/24 h or andiabetes mellitus and patients with essential hyperten-

albumin-to-creatinine ratio greater than 30, by conven-sion with microalbuminuria. It has been demonstratedtion, has been termed microalbuminuria. It has long beenthat microalbuminuria in both of these groups of patientsrecognized that excretion of increased amounts of albu-predicts the presence of a number of additional high riskmin is a highly significant predictor of those diabeticmetabolic abnormalities. The mechanisms involved inpatients that will develop progressive nephropathy [1–4].these abnormalities remain incompletely understood al-Similarly, diabetic patients with microalbuminuria alsothough insulin resistance may have a central role. Thesehave increased risk for cardiovascular disease [5–7]. Re-individuals are at increased risk for cardiovascular dis-cently, a similar association between microalbuminuriaease and increased cardiovascular mortality. There isand cardiovascular disease has been described in individ-also a growing body of data that support the notion thatuals with essential hypertension [7–12]. A number ofthese same groups of patients have an increased risk forcross sectional studies of microalbuminuric patients withdevelopment of progressive renal injury and that lipidsessential hypertension have also suggested that theseare an independent risk factor for this event. Unfortu-patients may be at greatest risk for more rapid loss ofnately, pharmacological interventional studies designedrenal function over time [13–15]. In both diabetic andto reduce the risk of dyslipidemia on cardiovascular andessential hypertension patients with microalbuminuria,renal diseases are only now being developed.the presence of multiple metabolic abnormalities hasDuring the past decade, considerable progress hasbeen recently identified. Paramount among these is thebeen made in the clinical and experimental understand-presence of insulin resistance and dyslipidemia in con-ing of the mechanisms of progressive renal disease. Hy-junction with abnormalities of the coagulation system.pertension, proteinuria and dyslipidemia have been iden-

tified as independent risk factors for progressive loss ofEssential hypertension and microalbuminuriarenal function. In humans, pharmacological treatments

In a study of 11,343 nondiabetic hypertensive subjects,to modify blood pressure or proteinuria have now beenmicroalbuminuria was present in approximately 30%. Ashown to have beneficial effects on rates of loss of renalconstellation of abnormalities has been seen in thesefunction. It remains unclear if reduction in circulatingpatients including loss of normal diurnal variation in bloodpressure, loss of salt sensitivity, reduced Na1/Li1 counter-

Key words: microalbuminuria, cardiovascular disease, diabetes transporter activity, increased insulin levels and periph-eral insulin resistance, increased fibrinogen, increased 2000 by the International Society of Nephrology

S-27

Keane: Lipids in renal diseaseS-28

von Willebrand factor, reduced plasminogen activating short duration to feel confident about the results. None-theless, these studies support the notion that use of lipid-factor and increased renin levels [8–12, 16–19]. In addi-lowering treatments have an additive effect to antihyper-tion, dyslipidemia manifest by increased apolipoproteintensive therapy in preserving renal function [26].B-containing lipids and reduced high density lipopro-

teins are frequently observed. Triglyceride levels areChronic renal insufficiencymost frequently elevated and recently, increased lipopro-

Alterations in the levels and composition of lipids intein(a) levels have been described. The linkage betweenpatients with reduced renal function are common [27].dyslipidemia and microalbuminuria is not completely un-Characteristically, they demonstrate a moderate increasederstood and is not explained by obesity or increasedin apolipoprotein B-containing lipoproteins of very lowbody mass. A more likely explanation is that this meta-and low densities, and reduced levels and abnormal com-bolic derangement is related to the insulin resistanceposition of apolipoprotein A-containing lipoproteins ofand consequent hyperinsulinemia seen in this uniquehigh densities. In addition, triglyceride enrichment ofsubpopulation of patients with essential hypertension.the apolipoprotein B-containing lipids has been recentlyThe clinical ramifications of microalbuminuria haveidentified as an important abnormality that correlatesindicated a significant increase in the cardiovascularwith progression of renal disease. The presence of smallevent rate and mortality in these patients [7–12]. In adense, triglyceride-enriched particles is also a major risksecondary analysis of the Multiple Risk Factor Interven-factor involved in cardiovascular disease. This coupledtion Trial, the presence of minimal proteinuria conferredwith reduced high density lipoprotein is a highly athero-nearly a 2.5-fold greater risk for cardiovascular morbidgenic duet. The mechanisms for development of theseevents, even after adjustment for the usual risks for car-abnormalities are complex and incompletely understood.diovascular disease such as age, cholesterol, blood pres-Clearly, proteinuria is an important factor that is in-sure, smoking and degree of renal insufficiency [12]. Re-volved in stimulating hepatic production of various lipo-cent studies in an older Caucasian population haveproteins, particularly apolipoprotein B-containing lipids.demonstrated that the presence of microalbuminuriaIn addition, insulin resistance, which develops early inalso predicts the extent and severity of angiographicallythe course of renal insufficiency, may have importantdemonstrable coronary artery disease [19].effects on lipid metabolism possibly similar to that ob-served in diabetes and in certain patients with essentialDiabetes mellitus and microalbuminuriahypertension. A number of large trials have demon-The presence of microalbuminuria in patients withstrated that these lipid abnormalities are independent

type 1 and type 2 diabetes mellitus is a useful marker variables for the rate of loss of renal function [28]. Unfor-for those patients at greatest risk for the development tunately, no lipid interventional trials have been per-of microvascular and macrovascular disease [1, 2, 5, 6, formed in this population to see if either cardiovascular20, 21]. As discussed above, these individuals display a or renal death can be reduced.constellation of metabolic abnormalities including dys-lipidemia, hypertension, abnormalities in coagulation, Congenital abnormalities of lipids associated withand insulin resistance. The finding of an increased extent renal diseaseand severity of angiographically demonstrable coronary At least two primary lipid disorders have been associ-artery disease in older, microalbuminuric, type 2 diabetic ated with renal disease. Patients with a deficiency inindividuals is consistent with the notion of a dramatic lecithin-cholesterol acyltransferase develop large lipid-clustering of risk factors for vascular disease [19]. Unfor- laden lipoproteins, glomerular lipid deposits and eventu-tunately, few interventional studies designed to modify ally renal failure associated with glomerulosclerosis.cardiovascular risks in the diabetic patient have been More recently, abnormalities in apolipoprotein E haveperformed. In the Scandinavian Simvastatin Survival been described, mostly in Japanese patients, with a dis-Study, type 2 diabetic subjects were shown to have a 2.5- tinct form of progressive renal disease. Since the majorfold greater risk for coronary artery disease than the function of apolipoprotein E is to remove apolipoproteinnondiabetic study participants [22]. Treatment of the B containing particles by receptor-mediated endocytosis,dyslipidemia significantly reduced the risk of coronary genetic or acquired mutations leading to impairment ofheart disease events [22, 23]. this important function would be expected to be associ-

With regard to microvascular disease, a number of ated with extensive macrovascular and microvascularcross-sectional and prospective longitudinal studies have disease [29–32]. Indeed, this appears to be the case indemonstrated that dyslipidemia, particularly elevated the reports to date. A better understanding of thesecholesterol levels, is an identifiable risk factor for loss abnormalities will hopefully provide a more targetedof renal function on both univariate and multivariate approach to the treatment of these patients, as well asanalyzes [24, 25]. However, few interventional trials have a broader understanding of the factors that contribute

to progressive vascular and renal disease.been performed and are usually under-powered or of

Keane: Lipids in renal disease S-29

MECHANISMS OF LIPID INJURY: increase release of renin from juxtaglomerular cells [37].Reduction in endothelial-derived relaxing factor or nitricEXPERIMENTAL INSIGHTSoxide also has been reported. These alterations in thePre-clinical databalance of vasoactive substances favors enhanced vaso-

A variety of experimental studies have lent credence constriction. Of note is that the HMG-CoA reductaseto the notion that dyslipidemia contributes to kidney inhibitors appear, in man, to normalize this vascular reac-injury [32]. A high saturated fat diet or a diet enriched tivity abnormality. Thus, an intricate relationship existsin cholesterol has been shown to enhance the degree of between hemodynamic factors that govern vascular tonerenal injury in experimental models of renal disease. The and metabolic factors that govern circulating lipids.most compelling data come from a number of studiesutilizing different classes of lipid-lowering agents to re- Modification of inflammatory responses to renal injuryduce circulating lipids. In all of these investigations re- by lipid lowering agentsduction of lipids was associated with improvement in As suggested by the in vivo studies, it is now apparentstructural damage to glomeruli and to the interstitium. that the HMG-CoA reductase inhibitors have a numberThese effects were associated with improvement in renal of important effects on cell processes involved in thefunction and were observed to occur even after renal inflammatory response [37, 38]. It has also become evi-disease was present [32]. These effects were seen in a dent that HMG-CoA reductase inhibitors reduce pro-variety of different models of progressive renal disease duction of molecules involved in fibrogenesis [39].and in some studies, have been shown to have an additive HMG-CoA reductase inhibitors reversibly inhibit theeffect to blockade of the renin angiotensin system [33]. proliferation of mesangial, vascular smooth muscle cellsIn some of these studies in which cholesterol levels were and tubular epithelial cells to various mitogenic sub-not profoundly elevated, HMG-CoA reductase inhibi- stances such as platelet-derived growth factor and insu-tors reduced the degree of vascular and tubulointerstitial lin-like growth factor [37, 40–42]. Apoptosis also is aug-injury [32]. These studies suggested that this class of mented by HMG-CoA reductase inhibition, and thisagents might have biological effects on the response to effect is reversible in the presence of mevalonate [37,injury in addition to their lipid-lowering capabilities. 43]. This early metabolite of acetyl coenzyme A is an

important product of HMG-CoA reductase and is essen-Mechanisms of lipid injurytial for the progression of the cell cycle [44].

The mechanisms whereby lipids contribute to vascular Macrophages play an important role in the process ofand renal injury are incompletely understood. Nonethe- injury and repair in the kidney. Their recruitment de-less, a number of important effects of lipids on vascular, pends upon the expression and production of a numbermesangial and tubular cells have been identified. Foam of cytokines that allow for the adhesion, migration andcells, which are believed to result from nonreceptor- maturation of these inflammatory cells from the vascula-mediated uptake of modified lipoproteins by macro- ture to glomeruli or interstitium. Mesangial and vascularphages, are frequently found in segments of glomeruli smooth muscle cells produce various cytokines involvedundergoing sclerosis and in the interstitial compartment in macrophage biology. Recent studies have shown thatof diseased kidneys [34]. Both macrophages as well as HMG-CoA reductase inhibitors can reduce mesangialmesangial cells may oxidize lipoproteins, and these modi- and smooth muscle cell expression and production offied lipoproteins have been demonstrated to be present monocyte chemoattractant protein-1 and macrophage-in glomeruli and interstitial regions [35]. Mesangial and colony stimulating factor (M-CSF) as well as vasculartubular cells can produce reactive oxygen species, partic- cell adhesion molecule-1 and intracellular adhesion mol-ularly superoxide, when exposed to a variety of factors ecule-1, which are integrin adhesion molecules involvedincluding angiotensin II and platelet-derived growth fac- in monocyte adherence to endothelial and mesangialtor [36]. Oxidized low-density lipoproteins (LDLs) have cells [38, 45, 46]. These in vitro effects have in vivo conse-been shown to stimulate inflammatory and fibrogenic quences in that HMG-CoA reductase inhibitors reducedcytokine production and to cause increased cell apopto- glomerular influx of macrophages and this was associatedsis [37]. These modified lipoproteins also increase pro- with a reduction in indices of glomerular injury.duction of reactive oxygen species, thereby creating a In the process of intracellular cholesterol metabolismself-perpetuating mechanism for formation of these a variety of intermediate products are formed by a pro-highly reactive lipids. The consequences of these events gressive elongation of carbon fragments. These interme-are an increase in macrophage influx and increased pro- diates are called nonsterol isoprenoids and have beenduction of various matrix proteins and collagens as well shown to be critical in prenylation of small intracellularas increased cell loss. These oxidized LDL particles have proteins such as p21ras. Two isoprenoid metabolites de-been shown to also increase production of vasoactive rived from mevalonate, farnesyl pyrophosphate and ger-

anylgeranyl pyrophosphate, have been shown to be indis-substances such as endothelin and thromboxane, and to

Keane: Lipids in renal diseaseS-30

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