Lipids and Renal Disease

Roberto Trevisan, Alessandro R. Dodesini, and Giuseppe Lepore Unit of Diabetology, Ospedali Riuniti di Bergamo, Bergamo, Italy

Chronic renal disease is accompanied by characteristic abnormalities of lipid metabolism, which appear as a consequence of nephrotic syndrome or renal insufficiency and are reflected in an altered apolipoprotein profile as well as elevated plasma lipid levels. Experimental and clinical studies have suggested a correlation between the progression of renal disease and dyslipidemia. High and triglyceride plasma levels have been demonstrated to be independent risk factors for progression of renal disease in humans. The underlying pathophysiologic mechanisms for the relationship between lipid levels and progression of renal disease are not yet fully understood, although there are data that oxidative stress and insulin resistance may mediate the lipid-induced renal damage. In the animal model, lipid-lowering agents seem to ameliorate glomerular damage, preventing glomerulosclerosis and interstitial fibrosis. Although evidence from clinical studies indicates that statin therapy is associated with significant benefit in individuals with established chronic renal failure, whether lipid reduction can slow the renal functional decline awaits a primary renal outcome lipid-lowering therapy study. J Am Soc Nephrol 17: S145–S147, 2006. doi: 10.1681/ASN.2005121320

iabetes and are the leading cause of triglycerides concentrations (8). HDL levels also tend to be re- ESRD in the United States. In both individuals with duced with a disadvantageous alteration in their composition. D and without diabetes, microalbuminuria is predictive Similarly, in the nondiabetic population, those with microalbu- of future proteinuria, progressive decline in renal function, minuria have similar lipid abnormalities (9). accelerated , and increased cardiovascular mor- tality (1,2). One study showed that the combination of mi- Lipids as Progression Promoters croalbuminuria and mild renal insufficiency confers a risk for Studies in a variety of animal models have shown that hy- cardiovascular events even higher than that observed in pa- percholesterolemia accelerates the rate of progression of kidney tients with a coronary heart disease and a normal renal function disease (10). A high- diet causes infiltration and (3). Although several factors may explain this association be- foam cell formation in rats, leading to glomerulosclerosis (11). tween renal and , there is growing evi- In humans more than a decade ago, a relationship between dence that contributes not only to cardiovascu- serum cholesterol levels and GFR decline was shown in 31 pa- lar disease but also to renal disease progression. tients with type 1 diabetes and established overt nephropathy (12). In those with a total cholesterol level Ͼ7 mmol/L, the rate of Epidemiologic Evidence decline in GFR was at least three times higher than in those with All patients with chronic disease experience a secondary a level Ͻ7 mmol/L. The power of serum cholesterol levels in form of dyslipidemia that mimics the atherogenic dyslipidemia predicting the progression of diabetic nephropathy in type 1 dia- of insulin-resistant patients. This is characterized by an increase betes was confirmed by a Danish group in a study of 301 patients in serum triglycerides with elevated VLDL, small dense LDL who had diabetes and overt nephropathy and were followed up particles, and low HDL cholesterol. All of these particles are for 7 yr (13). characterized by triglyceride-rich (apoB)-con- A similar finding also was found in patients with type 2 diabe- taining complex , which have a significant athero- tes and overt nephropathy. A post hoc analysis of the Reduction of genic potential (4). Endpoints in NIDDM with the Angiotensin II Antagonist Losar- That dyslipidemia is not just secondary to renal disease was tan study showed in a large group of patients with type 2 diabetes shown clearly in diabetes: In both type 1 and type 2 diabetes, an that both total cholesterol and LDL cholesterol measured at base- unfavorable lipid profile is present at a very early stage of albu- line were independent risk factors for ESRD (14). minuria, when GFR is normal or elevated (5–7). The concentration The predictive power for renal disease progression also has of total cholesterol, VLDL, LDL cholesterol, and triglycerides rises been observed before the appearance of microalbuminuria, at least with increasing albumin excretion rate in patients with type 1 in diabetes. Ravid et al. (15) demonstrated in a prospective study diabetes. In addition, there is an increase in LDL mass and athero- of 574 patients with type 2 diabetes and normal renal function at genic small dense LDL particles, which correlates with the plasma baseline that a high cholesterol level was associated with a signif- icantly higher incidence of microalbuminuria as well as of cardio- vascular events. Samuelsson et al. (16) demonstrated a strong correlation be- Address correspondence to: Dr. Roberto Trevisan, Unit of Diabetology, Ospedali Riuniti di Bergamo, Largo Barozzi 1, 24100 Bergamo, Italy. Phone: ϩ39-35-220390; tween triglyceride-rich apoB-containing lipoproteins and the rate Fax: ϩ39-35-266889; E-mail: [email protected] of progression in nondiabetic patients with chronic kidney dis-

Copyright © 2006 by the American Society of Nephrology ISSN: 1046-6673/1704-0145 S146 Journal of the American Society of Nephrology J Am Soc Nephrol 17: S145–S147, 2006 ease. Muntner et al. (17) then showed that people with low HDL The existence of a link between dyslipidemia and oxidative cholesterol and hypertriglyceridemia at baseline have a higher stress in the pathogenesis of renal damage was shown in unine- risk for having a loss of renal function. That all of the participants phrectomized rats, in which hyperlipidemia increased glomerular in this study (12,728 participants in the Atherosclerosis Risk in and tubulointerstitial infiltration and aggravated glomerulosclero- Communities) had a baseline creatinine Ͻ2 mg/dl in men and sis (23). Oxidative stress, with the resultant increased reactive Ͻ1.8 mg/dl in women suggests hypertriglyceridemia in the initi- oxygen species generation, contributed significantly to these ation of mild renal insufficiency. That high triglycerides levels are chronic degenerative processes. an independent predictor of renal disease also was confirmed in a It also is possible that some of the deleterious effects of lipids on prospective study of 297 patients with type 1 diabetes (18). kidney are mediated by other mechanisms that are responsible for the adverse lipid profile that is present in patients who are sus- Mechanisms ceptible to renal damage. As stated earlier, all patients with Progressive renal failure, especially that associated with pro- chronic disease experience a secondary form of dyslipidemia that teinuria, is accompanied by abnormalities of trans- mimics the atherogenic dyslipidemia of insulin-resistant patients port. Typically, the dyslipidemia is reflected predominantly in (24). This observation raises the possibility that the insulin resis- increased serum levels of triglycerides with high levels of tance syndrome may underlie or mediate the association between VLDL, apoB and pre-␤ HDL, and low levels of HDL and of lipids and a loss of renal function. apoA. Cholesterol levels may be very high in proteinuric pa- Recently a strong, positive, and significant relationship between tients (4). the metabolic syndrome and risk for chronic renal disease and This pattern of abnormalities is due to several pathogenetic microalbuminuria was found in a large nondiabetic general pop- mechanisms. First, urinary protein loss stimulates an increased ulation (25). Insulin resistance characterizes type 1 diabetes in LDL synthesis by the liver. It is likely that proteinuria with the patients with albuminuria and their first-degree relatives without resultant hypoalbuminemia leads to an upregulation of 3-hy- diabetes (26,27) and underlies many of the alterations of diabetic droxy-3-methylglutaryl CoA reductase with a consequent hyper- nephropathy, including high BP, lipid abnormalities, increased cholesterolemia (19). Conversely, low HDL with a poor matura- left ventricular mass, and a family history of hypertension and tion of HDL-3 to cholesterol-rich HDL-2 is due to acquired cardiovascular disease (24). These observations and a recent study lecithin-cholesterol acyltransferase deficiency secondary to abnor- by Orchard et al. (28) suggest that insulin resistance is likely to mal urinary losses of this enzyme (20). Impaired clearance of precede and play a role in the vascular damage of diabetic ne- chylomicrons and VLDL has emerged as the dominant factor for phropathy. the increased serum triglyceride concentration. Lipoprotein lipase (LPL) is the rate-limiting step in lipolysis of chylomicrons and Evidence of Lipid Involvement in Renal VLDL. LPL binds to heparan sulfate proteoglycans on the cell Damage: Effect of Statins surface of . In proteinuric renal diseases, a downregu- In recent years, the inhibition of 3-hydroxy-3-methylglutaryl lation of LPL protein abundance and enzymatic activity was CoA reductase by statins has demonstrated beneficial effects in found (4). These events are largely responsible for profound ab- different models of progressive renal failure (29). It is interest- normalities in lipoprotein metabolism in nephrotic syndrome and ing that some of the beneficial effects of statins can be seen chronic renal failure’s rendering these lipoproteins more athero- independent of the cholesterol reduction. In an elegant study genic. by Zoja et al. (30), it was shown that a combined angiotensin- Regarding the mechanisms by which abnormal serum lipid converting enzyme inhibitor and statin therapy had a remark- levels may contribute to renal disease progression, there is evi- able antiproteinuric effect with a significant improvement in dence that circulating lipids bind to and become trapped by ex- renal function. Drug combination limited glomerulosclerosis, tracellular matrix molecules (10), where they undergo oxidation tubular damage, and interstitial , compared with increasing the formation of such as super- placebo or drugs alone. oxide anion and hydrogen peroxide (21). The resultant reduction In vitro studies have established clearly that statins influence in the actions of endothelium-derived vasodilators/growth inhib- important intracellular pathways that are involved in the inflam- itors, such as prostacyclin and nitric oxide, with maintenance or matory and fibrogenic responses, which are common components increased formation of endothelium-derived vasoconstrictors/ of many forms of progressive renal injury (29). Statins also inhibit growth promoters, such as angiotensin II, endothelin-1, and plas- proliferation of cultured mesangial cells and renal epithelial tubu- minogen activator inhibitor-1, has significant vascular and renal lar cells through their capability to suppress the formation of pathophysiologic consequences. phagocytize oxi- intermediate metabolites of the mevalonate pathway, particularly dized lipids and undergo a transition to foam cells. Macrophage- the nonsterol isoprenoids, which seem to be essential in cell rep- derived foam cells release cytokines that recruit more macro- lication (31). phages to the lesion and influence lipid deposition, endothelial cell Although there is not yet a large intervention study on the effect function, and cell proliferation. Glomer- of statin therapy in the progression of renal damage, there is ular cells mimic some of these characteristics of cells in the ath- evidence from post hoc analyses to suggest that statins are likely to erosclerotic vessel wall (22); therefore, similar pathogenetic mech- be effective in the treatment of renal disease. This topic is devel- anisms may contribute to the progression of atherosclerosis and oped elsewhere in this issue. 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