Dyslipidemia in pediatric nephrotic syndrome: causes revisited

Clinical Biochemistry 36 (2003) 95–101

Review

Dyslipidemia in pediatric nephrotic syndrome: causes revisited Edgard E. Delvina,b,*, Aicha Merouanic, Emile Levyb,d a

Department of Clinical Biochemistry, bResearch Centre, Ste-Justine Hospital, University of Montreal, Montreal, Canada c Division of Nephrology, Department of Pediatrics, d Department of Nutrition, University of Montreal, Montreal, Canada

Keywords: Nephrotic syndrome; Lipids; Lipoproteins; Cytokines; MCNS

1. Introduction The nephrotic syndrome represents a collection of renal diseases involving the glomeruli, and in which hypoalbuminemia, proteinuria, edema and hyperlipidemia are the hallmarks [1]. It extends, in increasing order of severity, from the minimal change nephrotic syndrome (MCNS) with few long-standing complications, to syndromes leading to end-stage renal disease (ESDR) such as focal segmental glomerulosclerosis (FSGS) and membranous nephropathy. In children, MCNS is the most common form of idiopathic nephrotic syndrome accounting for more than 90% of cases [1,2]. The incidence of the nephrotic syndrome, in the pediatric population, varies between 2 and 7 cases per 100,000 patients per year [2]. According to the North American Renal Transplant Registry, primary renal disorders and systemic diseases associated with glomerulonephritis, including FSGS, account for 30% of the pediatric patients with end-stage renal failure, while the congenital nephrotic syndrome alone accounts for 3% [3]. It must be emphasized that virtually any glomerular lesion, even temporary, may be associated with proteinuria of a magnitude and length of time sufficient to induce the cluster of pathophysiological events leading to the nephrotic syndrome and to its potential cardiovascular complications. In this brief review we will focus on mechanisms involved in the dyslipidemia of the MCNS in the pediatric population. In order to set the stage, a short outline of the lipid metabolism follows. 1.1. Lipid metabolism Fig. 1 summarizes the metabolic pathway of exogenous and endogenous lipids. Following absorption from the gastrointestinal tract, dietary lipids are packaged in chylomi-

* Corresponding author. E-mail address: [email protected] (E. Delvin).

crons (CM), which are synthesized by intestinal cells by a series of co-ordinated events [4]. CMs represent a heterogeneous group of particles that can differ substantially in size and composition as they are constantly synthesized even in the absence of dietary lipids [5]. When collected during a fat-rich meal, they typically contain an average of 80% triglycerides, which acyl chains represent the fat composition of the meal, 10 to 20% phospholipids, 2% protein as well as 0.5 to 2% cholesterol esters and 0.5 to 2% free cholesterol coming from either the diet and or from the de novo synthesis [5]. Apolipoprotein B-48 (apo B-48) is the only structural protein of the CM required for their intracellular assembly and extrusion into the lymph ducts. Following the addition of 2 protein adducts, apolipoprotein C-II (apo C-II), and apolipoprotein E (apo E), CMs are converted to CM remnants by the action of lipoprotein lipase, activated by apo C-II. CM remnants are smaller in size, contain less triglycerides and are taken-up by hepatic cells through CM remnant receptors (CRR) that recognize the apo E moiety, that is now in an adequate quaternary conformation [5]. Very Low Density Lipoproteins (VLDL), endogenously produced by the liver, have a similar lipid composition to CMs but differ in that apolipoprotein B-100 is the main structural apolipoprotein. Once secreted into the circulation, VLDLs are first converted to intermediate density lipoproteins (IDL) by hepatic lipase. Some IDLs are metabolized by the liver. Those remaining in circulation are further converted to LDL through hydrolysis by hepatic lipase. In the course of the conversion of IDL to LDL, the particles not only loose triglycerides but also apo E and apo C-II moeities [6]. The LDLs are “oxidized” by peripheral tissues and macrophages, and cholesterol transported into cells via the scavenger receptor family [7,8] to join the intracellular pools. Upon efflux through the ATP-binding cassette A-1 (ABC-1), cholesterol enters the reverse cholesterol transport pathway that

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Fig. 1. CM: Chylomicrons; nCM: nascent CM; CMr: Chylomicron remnants; CMRR: Chylomicron remnant receptors; eHPL: endothelial lipoprotein lipase; hLPL: hepatic lipase; B-48: apolipoprotein B-48; C-II: apolipoprotein C-II; A-1: apolipoprotein A-1; E: apolipoprotein E; VLDL: very low density lipoproteins; LDL: low density lipoproteins; SRB: scavenger receptor B; ABC-1: ATP-binding cassette A-1; LCAT: lecithin-cholesterol acyltransferase; CETP: cholesterol ester transfer-protein; LDLR: LDL receptors. Stars: sites of metabolic disturbances.

involves the coordinated addition of lecithin by lecithincholesterol acyltransferase (LCAT) and of cholesterol esters by cholesterol ester transfer-protein (CETP). These reactions give rise first to small and relatively cholesterol-poor nascent HDL3 particles that then mature into anti-atherogenic HDL2 particles [9 –11]. The mechanisms underlying these abnormalities are not yet entirely understood.

Table 1 Summary of proposed mechanisms for hyperlipidemia in the minimal change nephrotic syndrome Synthetic pathway Increased availability of mevalonate Decreased kidney clearance of mevalonate Enhanced HMG-CoA-reductase Increased cholesterol synthesis Catabolic pathway Decreased LPL activity Impairment of VLDL clearance Recycling pathway Decreased LCAT activity Decreased reverse cholesterol transport

1.2. Hyperlipidemia and hypoalbuminemia in the nephrotic syndrome Early descriptions of the nephrotic syndrome have stressed the precocious deterioration of lipid metabolism and its progression with the severity of MCNS [12]. The hyperlipidemic profiles classically reported in MCNS consist of increased plasma total cholesterol, LDL-cholesterol, phospholipids, VLDL and LDL particles [13–15]. The mechanisms underlying these abnormalities are not yet entirely understood. Investigations have mostly been focused on the hepatic metabolism, leaving the absorptive aspect aside. The inverse relationship between plasma albumin and cholesterol in the nephrotic syndrome, described more than 40 years ago [12], was later strengthened by the observation that remission of the syndrome or acute increase of plasma albumin resulted in a lowering of plasma cholesterol levels [16]. However, the picture is more complex than initially anticipated. Kaysen et al. [17], have measured albumin turnover at steady state in 13 adult nephrotic patients under 2 protein regimens and have shown that, while the rate of albumin synthesis was within normal values with either diet, that of catabolism was below the normal reported range [18]. They further reported that circulating cholesterol and triglyceride levels were elevated regardless of the dietary

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protein content and thus excluded the absolute rate of albumin synthesis as a cause for the hyperlipidemia. However, changes both in serum cholesterol and triglyceride concentrations were more tightly related to renal albumin clearance. Taken together these data thus inferred that a causal link between albumin synthesis and circulating lipid concentrations was questionable. No further studies have clearly established a clear causal relationship between the rate of albumin synthesis and dyslipidemia in nephrotic patients. 1.3. Hyperlipidemia and oncotic pressure in the nephrotic syndrome Other investigators have claimed that the oncotic pressure was a key determinant in triggering dyslipidemia in the nephrotic syndrome. This concept came from in vitro experiments aimed at studying the expression of the apolipoprotein B (apoB) gene in HepG2 cells cultured in either normal or low oncotic pressure media [19]. The results indicated that cellular apolipoprotein B (apoB) mRNA content, at steady state, was increased when the cells were cultured in the presence of a hypo-oncotic medium and reduced when either dextrans or albumin were added. Since oncotic pressure, in vivo, is intimately linked to albumin concentration, the aforementioned in vitro experiments do not rule out other mechanisms, such as the release of vasoactive factors or electrolytic imbalance. 1.4.Cholesterol synthesis in the nephrotic syndrome Diverse metabolic causes of abnormal lipid profiles have been invoked by a number of researchers who studied the cholesterol synthetic pathway in experimental nephrosis. It is well established that hepatic cholesterol synthesis strictly depends on the availability of mevalonate. While, in normal circumstances, the kidney would metabolize this cholesterol precursor, its conversion and excretion are impaired in the nephrotic state [20]. This metabolic impairment thus allows a greater cholesterol availability that, coupled to an enhanced HMG-CoA reductase activity, leads to increased hepatic cholesterol synthesis [21] and unbalanced lipid homeostasis. 1.5. Lipoprotein catabolism and clearance in the nephrotic syndrome Other data point to the impairment of VLDL to LDL conversion by lipoprotein lipase (LPL) as a possible cause of dyslipidemia. The underlying hypothesis is that, in the nephrotic syndrome, LPL activity is reduced by as much as 50%, thereby potentially retarding VLDL removal from the circulation [22,23]. A variety of mechanisms have, in turn, been invoked to explain the decline in LPL activity. Early findings have stressed that, in uremic rats, increased concentrations of circulating free fatty acids lead to enhance-

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ment of liver lipoprotein synthesis and decrease of LPL activity [24]. Other studies focusing on glycosaminoglycan excretion processes in nephrotic patients and nephrotic rats, proposed that the reduced LPL activity was due either to altered synthesis or increased losses of various factors such as heparan sulfate [25,26]. The delayed disappearance of radiolabeled chylomicron (CM) particles in the nephrotic animals, which could be reversed by the acute administration of small amounts of purified heparan sulfate strengthened this suggestion [26]. More recently, Shearer et al [27]. revisited the mechanisms involved in the impairment of lipoprotein catabolism in 2 distinct models. The first was the aminoglycoside-induced nephrotic rat and the second the Nagase analbuminemic rat. They concluded that decreased clearance of VLDL resulted both from decreased binding of LPL to endothelial surfaces in the presence of a reduced oncotic pressure and/or hypoalbuminemia, and from an alteration of VLDL binding to endothelium-bound LPL. These observations support the earlier data published by Levy et al [28], whom have shown that the clearance rates of 14C-labeled lymph chylomicrons and VLDL isolated from normal rats had different clearance kinetics than those obtained from nephrotic rats when injected in normal or nephrotic recipients. Furthermore, physicochemical analyses revealed that “nephrotic VLDLs” were enriched in triacylglycerol and cholesterol at the expense of phospholipids. Taken together these results thus indicated that impaired lipid removal in the experimental nephrotic syndrome could be due to changes in the composition of triacylglycerol-rich particles, to their abundance and their binding to endothelium-bound enzymes. 1.6. Cholesterol recycling In the course of physiological cell turnover, membraneassociated cholesterol is partly recycled through cholesterol re-esterification by circulating lecithin-cholesterol acyltransferase (LCAT) and then incorporated into HDL particles that are returned to the liver [10]. The decreased LCAT activity, reported in the nephrotic syndrome [29], could jeopardise this pathway and thus account for the several lipoprotein abnormalities observed in this syndrome. Although the underlying mechanisms are not entirely understood at the present time, Vaziri et al. [30] have recently provided evidence that, in puromycin-induced nephrotic syndrome in Sprague-Dawley rats, renal loss contributed to the marked reduction in plasma LCAT activity. The complexity of the interacting metabolic pathways involved in lipid handling could explain in part the different dyslipidemic profiles observed in patients with NS. 1.7. Is there a unifying cause to dyslipidemia? Could the above-mentioned mechanisms be epiphenomena secondary to a unifying cause? Analysis of the clinical presentation of this syndrome gives credibility to this hy-

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pothesis. First, the nephrotic syndrome is expressed in a cyclical fashion with relapse and remission episodes of varying intensities. Second, it has been shown that proinflammatory cytokines are over-expressed during the relapse episodes, during which lipid disorders are concomitantly observed. For example, Matsumoto et al [31,32]. have reported increased spontaneous and lipopolysaccharide (LPS)-induced production of IL-18 in peripheral blood monocytes and elevated urinary IL-18 concentration in patients in the active phase of MCNS when compared to normal controls. They further observed that urinary IL-18 levels correlated with the degree of proteinuria and subsequently decreased as the patients entered into remission. Another set of data published by Yap et al. [33], support the involvement of cytokines in the onset of MCNS. They have shown increased IL-13 mRNA expression in CD4⫹ and CD8⫹ lymphocytes in patients with nephrotic relapse as compared to those in remission and normal subjects. This was associated with increased cytoplasmic IL-13 expression in phorbol myristate acetate/ionomycin-activated lymphocytes from patients with relapse compared to remission. They concluded that IL-13 might act on monocytes to produce vascular permeability factor(s) involved in the pathogenesis of proteinuria in patients with relapse nephrotic syndrome. Further to the above reports, Neuhaus et al [34]. have shown that the production and secretion of both IL-2 and IL-4 was significantly increased in stimulated peripheral blood monocytes obtained from relapsing children with steroid-sensitive MCNS when compared to cells obtained at remission. They concluded that relapse of the disease was associated with T-lymphocyte activation. The host response to pathogenic stimuli is often associated with several changes in lipid metabolism that could potentially modify lipoprotein production or structure, and thus establish a pro-atherogenic environment [33,35]. Indeed a number of studies conducted in animal models, have invariably shown that endotoxins and cytokines had deleterious effects on lipid metabolism. As early as 1989, Feingold et al [36] showed that administration of TNF␣, IL-1 and interferon alpha (IFN␣) to intact mice, all stimulated hepatic fatty acid and cholesterol synthesis. The same group has later shown that administration of IL-1 to rats, at doses similar to those that cause fever and anorexia and stimulate ACTH secretion, promoted long lasting increases in plasma triglyceride levels that was accounted for, in part, by increased triglyceride secretion [37]. More recently, Hardardottir et al [38,39] have shown that lipopolysacharride (LPS) endotoxin, administered to Syrian Hamsters markedly increased hepatic HMG-CoA reductase activity, protein mass and mRNA levels and decreased duodenal apolipoprotein A-1 mRNA levels. Finally, Khovidhunkit et al [40]. have shown that LPS, TNF␣ and IL-1 administration to Syrian hamsters significantly decreased liver scavenger receptor class B type I (SR-B1) mRNA. This observation is important since SR-B1 plays a pivotal role in the reverse cholesterol transport by promoting cholesterol efflux from

peripheral cells and by mediating selective uptake of cholesterol esters by the liver. To exert their effects, the above-cited cytokines stimulate a variety of downstream regulatory pathways that involve acute phase regulatory enzymes. The increased levels of these cytokines activate their respective receptors that stimulate complex protein kinase cascades that ultimately enhance NF-␬B DNA-binding activity [41]. Interestingly, Sahali et al [42]. have recently shown that peripheral blood mononuclear cells from patients with active steroid-sensitive MCNS displayed high levels of NF-␬B DNA-binding activity and abated expression of I␬B␣ proteins, inhibitors of NF-␬B. They have further shown, in the same cells, that inhibition of the proteasome activity resulted in a cytosolic accumulation of phosphorylated I␬B␣ proteins and a significant reduction in the NF-␬B binding activity. In addition, Mezzanno et al [43]. have recently shown a significant relationship between the intensity of proteinuria and tubular NF-␬B activation in MCNS and idiopathic membranous nephropathy (MN) patients. Taken together, these data thus suggest that alterations in the NF-␬B/I␬B␣ proteins regulatory feedback loop may contribute to the abnormalities that occur in steroid sensitive MCNS. Although the authors considered their results in the context of the immunologic response in MCNS, we propose that these perturbations influence other pathways such as lipid metabolism. Indeed, Gruber et al [44] have identified and characterized a NF-␬B responsive element located upstream from the transcriptional start site of the apolipoprotein C-III gene. This observation is topical, as this apolipoprotein plays a central role in controlling the metabolism of circulating remnant triglyceride-rich lipoproteins and is associated with hypertriglyceridemia in humans [45,46]. While beyond the scope of this short review, the modulation of inducible nitric oxide synthase (iNOS) by NF-kB [47,48] is also worth of notice, as this enzyme is intimately involved in lipid peroxidation, a well described marker of and contributor to oxidative damage of cell membranes of lipoproteins and other lipid-rich structures in a variety of conditions such as diabetes, atherosclerosis and rheumatoid arthritis [49 –51]. 1.8. Proposed scenario We, therefore, propose the following scenario (Fig. 2), to explain the transient dyslipidemic component observed during active MCNS. A pathologic stimulus triggers a first line inflammatory process that leads to dysregulated cytokine production and signaling mechanisms by epithelial cells, lymphocytes and macrophages. This translates into the enhanced phosphorylation of the NF-␬B inhibitor protein (I␬B␣) by I␬B kinase, its transfer to the ubiquitin-proteasome for degradation. This frees NF-␬B and enhances its translocation to the nucleus where it modulates the expression of a number of genes involved in lipid metabolism and in the metabolism of cell adhesion molecules (Fig. 2). Upon

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has been shown in puromycin-induced nephrotic syndrome [52].

2. Conclusion

Fig. 2. An inflammatory process enhances the production of cytokines such as IL-1, IL-18 and TNF␣ by activated lymphocytes or macrophages, which then bind to their respective receptors (R), The activated receptors are phosphorylated and activate a battery of cellular proteins that will recruit and in turn phosphorylate the NF-␬B inhibitor protein (I␬fB␣) by I␬B kinase. This will activate its transfer to the ubiquitin-proteasome for degradation and free NF-␬B for its translocation to the nucleus where it will modulate the expression of a number of genes involved in lipid metabolism and in the metabolism of cell adhesion molecules.

remission, either spontaneously or following corticosteroid therapy, the offensive stimuli taper down with the restoration of normal kidney function and of normal metabolism. This set of events may also explain the decreased clearance of VLDL [27] or the acquired deficiency of LCAT [30] through modification of in renal tissue integrity and permeability. The latter could be achieved by modulating the expression of cell adhesion molecules 1 such as paxillin, a regulator of cell adhesion to extracellular matrix. Enhanced expression of this cytoskeletal-associated protein has been

Table 2 Cytokine activation in the minimal change nephrotic syndrome Increased spontaneous and lipopolysaccharide (LPS)-induced production of IL-18 in peripheral blood monocytes and elevated urinary IL-18 concentration in patients in the active phase of MCNS.

Some pediatric patients with MCNS enter remission either spontaneously or after a short-term treatment with corticosteroid; others will have a number of relapses of varying length of time during which they present with dyslipidemic profiles [53–55]. The ensuing question is whether the dyslipidemic component of the disease should or should not be treated. The causal relationship between hyperlipidemia and cardiovascular diseases is now well established [56 –58]. As early as 1969, Berlyne and Mallick [59] reported on the increased incidence of ischemic heart disease in adult patients with a nephrotic syndrome. Although other investigators questioned this observation [60,61], a number of later reports have made the case that hyperlipidemic profiles consisting of increased plasma cholesterol, phospholipids, VLDL and LDL particles [13–15] were significant deleterious components of the nephrotic syndrome in adults. Despite indications of a long-term increased risk of cardiovascular diseases in adults, evidence of myocardial infarction and of atherosclerosis in children are anecdotal [62]. As a result, no consensus has been reached as to the treatment of the dyslipidemic component in children with MCNS. Clearly prospective studies that involve pediatric patients with MCNS, with and without repeated relapse episodes, are needed to establish the need of treatment of the dyslipidemic component of the disease. As alluded to, NF-␬B plays a pivotal role in the production of pro-inflammatory molecules, some of which may be involved in the onset of MCNS. In this context, could the NF-␬B/I␬B␣ pathway be an important partner in the etiology of dyslipidemia in MCNS? May strategies aiming at inhibiting NF-␬B prove to be novel and efficient approaches for the treatment of patients with MCNS?

Matsumoto K, Kanmatsuse K. (2001): Elevated interleukin-18 levels in the urine of nephrotic patients. Nephron 88: 333–399. Matsumoto K, Kanmatsuse K. (2001) Augmented interleukin-18 production by peripheral bood monocytes in patients with minimalchange nephrotic syndrome. Am J Nephrol 21: 20–7. increased IL-13 mRNA expression in CD4⫹ and CD8⫹ lymphocytes in patients with nephrotic relapse. Yap HK, Cheung W, Murugasu B et al. (1999) Th1 and Th2 cytokine mRNA profiles in childhood nephrotic syndrome: evidence for increased IL-13 mRNA expression in relapse. J Am Soc Nephrol 10529–37. Increased production and secretion of both IL-2 and IL-4 in stimulated peripheral blood monocytes obtained from relapsing children with steroid-sensitive MCNS Neuhaus TJ, Wadhwa M, Callard R et al. (1995) Increased IL-2, IL-4 and interferongamma (IFN-gamma) in steroid-sensitive nephrotic syndrome. Clin Exp Immunol 100: 475–479.

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