Hyperlipidemia In Nephrotic Syndrome Research Articles

Relationship Between FKBP5 Polymorphisms at Rs1334894, Rs9394309, and Rs6912833 Loci, and Dyslipidemia in Pediatric Nephrotic Syndrome

Background: This study aimed to investigate the relationship between rs1334894, rs9394309, and rs6912833 polymorphisms in <I>FKBP5</I> and hyperlipidemia in nephrotic syndrome (NS). Methods: The case group included 74 children with primary NS, while the control group included 76 healthy children. Polymerase chain reaction and gene sequencing were used to detect polymorphisms at the rs1334894, rs9394309, and rs6912833 loci of <I>FKBP5,</I> in children with NS. Clinical data of total cholesterol (CHOL), triglycerides (TG), high-density lipoprotein (HDL), low-density lipoprotein (LDL), and plasma albumin were collected. Correlations between <I>FKBP5</I> polymorphisms and serum lipid levels were analyzed during the active period of the disease. Results: A significant difference in LDL levels between the AA and TA genotypes was observed at the rs6912833 locus of <I>FKBP5</I> in the case group, but no statistical difference in CHOL, TG, and HDL levels between these genotypes was found. No statistically significant differences in LDL levels between the AA and TA genotypes, and among the steroid-sensitive, -dependent, and -resistant groups were noted. Moreover, no statistically significant differences in the CHOL, TG, HDL, and LDL levels were observed between TT and TC genotypes at the rs1334894 locus. Conclusion: The AA genotype at the rs6912833 locus of <I>FKBP5</I> may be correlated with plasma lipid levels (LDL) in PNS patients.

Use of Lipid-Modifying Agents for the Treatment of Glomerular Diseases

Although dyslipidemia is associated with chronic kidney disease (CKD), it is more common in nephrotic syndrome (NS), and guidelines for the management of hyperlipidemia in NS are largely opinion-based. In addition to the role of circulating lipids, an increasing number of studies suggest that intrarenal lipids contribute to the progression of glomerular diseases, indicating that proteinuric kidney diseases may be a form of “fatty kidney disease” and that reducing intracellular lipids could represent a new therapeutic approach to slow the progression of CKD. In this review, we summarize recent progress made in the utilization of lipid-modifying agents to lower renal parenchymal lipid accumulation and to prevent or reduce kidney injury. The agents mentioned in this review are categorized according to their specific targets, but they may also regulate other lipid-relevant pathways.

Serum and urine ANGPTL8 expression levels are associated with hyperlipidemia and proteinuria in primary nephrotic syndrome

BackgroundThis study aimed to investigate the expression characteristics of ANGPTL8 in patients with primary nephrotic syndrome and its possible correlation with hyperlipidemia and proteinuria.MethodsANGPTL8 levels were determined using an enzyme-linked immunosorbent assay in 133 subjects with PNS and 60 healthy controls.ResultsCompared with healthy controls, subjects with primary nephrotic syndrome had higher levels of serum and urine ANGPTL8 (P < 0.001). In primary nephrotic syndrome patients, serum ANGPTL8 was positively correlated with cholesterol (r = 0.209, P < 0.05) and triglycerides (r = 0.412, P < 0.001), while there was no correlation with 24 hUTP. Urine ANGPTL8 was positively correlated with high-density lipoprotein cholesterol (r = 0.181, P < 0.05) and was significantly negatively correlated with creatinine (r = − 0.323, P < 0.001), eGFR (r = − 0, P < 0.001) and 24 hUTP (r = − 0.268, P = 0.002). Interestingly, the urine ANGPTL8 concentrations in membranous nephropathy and mesangial proliferative glomerulonephritis pathological types were different.ConclusionsSerum and urine ANGPTL8 levels in primary nephrotic syndrome patients were correlated with blood lipid levels and proteinuria, respectively, suggesting that ANGPTL8 may play a role in the development of primary nephrotic syndrome hyperlipidemia and proteinuria.

Kidney-derived PCSK9—a new driver of hyperlipidemia in nephrotic syndrome?

Increased plasma concentrations of proprotein convertase subtilisin/kexin type 9 or PCSK9, which reduces hepatic uptake of low-density lipoprotein by downregulation of the low-density lipoprotein receptor, have been reported in nephrotic patients and might contribute to hyperlipidemia in nephrotic syndrome. The results of the study by Molina-Jijon etal. found that renal PCSK9 expression was upregulated in the collecting duct of nephrotic patients and animals, suggesting that the kidney might be a major source for plasma PCSK9 in nephrotic syndrome.

Urine and serum ghrelin, sCD80 and sCTLA-4 levels in doxorubicin-induced experimental nephrotic syndrome.

Nephrotic syndrome (NS) is an immune-mediated disorder associated with hyperlipidemia. NS has been proposed to be mediated through CD80-related T cell immune response, which could be blocked using soluble cytotoxic T lymphocyte-associated s(CTLA)-4. Although ghrelin is a hormone-modulating lipid metabolism and suppressing immune system, the precise role of ghrelin in NS is not well established. We evaluated the levels of ghrelin, soluble CD80 (sCD80) and sCTLA4 in serum and urine in doxorubicin-induced NS in rats. We also investigated the relation between their levels and the levels of serum total cholesterol (TC), triglyceride, albumin and urine protein. While urinary ghrelin levels were significantly lower in the nephrotic rats compared to the control group, serum ghrelin levels were comparable in the nephrotic and control rats. In contrast, serum and urinary sCD80 and sCTLA4 levels were higher in the nephrotic rats than the controls. The urinary ghrelin levels were negatively correlated with the levels of serum triglyceride, TC and urine protein, sCD80 and sCTLA4. The urine sCD80 levels were positively correlated with the TC, urine protein and urine sCTLA4 levels, and negatively correlated with the serum albumin. The urine sCTLA4 levels were positively correlated with the TC and urine protein levels and negatively correlated with the serum albumin levels. In regression analysis, the urine ghrelin levels significantly relate to urine sCD80 levels. Besides, hyperlipidemia in NS did not appear to be related to serum ghrelin levels. Low urine ghrelin levels might be relevant to pathogenesis of doxorubicin-induced NS. The reduction in urine ghrelin levels might also be associated with increased levels of urine sCTLA4 and sCD80 which reflect proteinuria.

Circulating angiopoietin-like 4 links proteinuria with hypertriglyceridemia in nephrotic syndrome

The molecular link between proteinuria and hyperlipidemia in nephrotic syndrome is not known. We show in the present study that plasma angiopoietin-like 4 (Angptl4) links proteinuria with hypertriglyceridemia through two negative feedback loops. In previous studies in a rat model that mimics human minimal change disease, we observed localized secretion by podocytes of hyposialylated Angptl4, a pro-proteinuric form of the protein. But in this study we noted high serum levels of Angptl4 (presumably normosialylated based on a neutral isoelectric point) in other glomerular diseases as well. Circulating Angptl4 was secreted by extrarenal organs in response to an elevated plasma ratio of free fatty acids (FFAs) to albumin when proteinuria reached nephrotic range. In a systemic feedback loop, these circulating pools of Angptl4 reduced proteinuria by interacting with glomerular endothelial αvβ5 integrin. Blocking the Angptl4-β5 integrin interaction or global knockout of Angptl4 or β5 integrin delayed recovery from peak proteinuria in animal models. But at the same time, in a local feedback loop, the elevated extrarenal pools of Angptl4 reduced tissue FFA uptake in skeletal muscle, heart and adipose tissue, subsequently resulting in hypertriglyceridemia, by inhibiting lipoprotein lipase (LPL)-mediated hydrolysis of plasma triglycerides to FFAs. Injecting recombinant human ANGPTL4 modified at a key LPL interacting site into nephrotic Buffalo Mna and Zucker Diabetic Fatty rats reduced proteinuria through the systemic loop but, by bypassing the local loop, without increasing plasma triglyceride levels. These data show that increases in circulating Angptl4 in response to nephrotic-range proteinuria reduces the degree of this pathology, but at the cost of inducing hypertriglyceridemia, while also suggesting a possible therapy to treat these linked pathologies.

Proteinuria decreases tissue lipoprotein receptor levels resulting in altered lipoprotein structure and increasing lipid levels

Rats with nephrotic syndrome (NS) have a fivefold increase in lipids and a similar decrease in triglyceride-rich lipoprotein (TRL) clearance. Lipoprotein lipase (LPL) is reduced both in NS and in the Nagase analbuminemic rat. These rats have nearly normal triglyceride levels and TRL clearance, suggesting that reduction in LPL alone is insufficient to cause increased TRL levels. Apolipoprotein E (apoE) was decreased in lipoprotein fractions in NS, but not in analbuminemia. Here we tested whether decreased apoE binding to lipoproteins in NS contributes to hyperlipidemia by decreasing their affinity for lipoprotein receptors. Plasma apoE was increased 60% in both NS and analbuminemia compared with control (CTRL) as a result of a 60% decreased apoE clearance. Very-low-density lipoprotein and high-density lipoprotein in NS had significantly less apoE per mole of phospholipid compared with analbuminemia or CTRL and significantly greater lipid content; however, apoE binding did not differ by lipoprotein class or group. There was a significant reduction of receptors for lipoproteins in nearly all tissues in NS compared with CTRL and analbuminemia. Thus, apoE within lipoprotein fractions was reduced by dilution resulting from expansion of the lipid fraction due to decreased lipolysis and not to differing affinity for apoE. Decreased lipoprotein receptors result from proteinuria and contribute to hyperlipidemia in NS.

Decreased apoE within lipoprotein classes in the nephrotic syndrome is due to diluted apoE pool

Hyperlipidemia in nephrotic syndrome (NS) results from decreased clearance of triglyceride rich lipoproteins (TGLs). VLDL and HDL from NS rats have reduced apolipoprotein E (apoE) content despite increased plasma apoE levels. Lipoprotein lipase (LpL) is decreased in both NS and the Nagase Analbuminemic Rat (NAR). However, NAR have nearly normal lipid levels and TGLs clearance. ApoE, a ligand for the VLDL receptor, is depleted from NS VLDL rats, while normal or increased in NAR VLDL suggesting that the difference in VLDL apoE contributes to defective clearance. It is unknown whether decreased apoE was a consequence of decreased binding to VLDL. Plasma apoE was measured by ELISA. Apo E clearance was measured 7 Control, 7 NS and 9 NAR male rats using 125I labeled apoE. Apo E affinity was measured in 6 Control and 5 NS rats using spin labeled E4 binding with electron spin resonance and nonlinear regression. Apo E levels were significantly greater in plasma NS than in NAR and greater in both than in Control. However, VLDL and HDL from NS had significantly less apoE per mole of PL than those isolated from NAR or Control. ApoE clearance was significantly lower in NS than in NAR and Control, entirely accounting for the increased plasma levels of apoE. Binding of apoE did not differ by lipoprotein class or by group. Decreased apoE within lipoprotein classes in the nephrotic syndrome is due to diluted apoE pool. (Supported by the Department of Veteran's Affairs)

Decreased apolipoprotein E and VLDL receptors cause lipidemia in nephrotic syndrome

Hyperlipidemia in nephrotic syndrome (NS) is due to decreased clearance of triglyceride rich lipoproteins (TGLs). Lipoprotein lipase (LPL) hydrolyzes plasma TG, promotes the binding and catabolism of TGLs. Apolipoprotein E (apo E) facilitates binding by TGLs both to their receptor and LPL. A reduced plasma LpL level and reduced VLDL apo E were found in nephrotic rats. It is unknown whether low levels of LPL and/or VLDL apoE may contribute to the defective clearance. Lipoprotein particle size measured by Microtrac, showed no significant difference in nephrotic VLDL compared with control one. This finding indicated that the increased lipids in NS are due to increased particles accumulation in plasma instead of defective TGLs lipolysis via LpL. To study whether this accumulation is from decreased clearance and/or uptake by cells and organs, heart perfusion study demonstrated a significant decrease of VLDL uptake in NS heart. Endothelial cell VLDL uptake using fluorescent labeling technique showed a significant decreased cell uptake VLDL in NS compared with control. However, two groups had a similar increase when adding exogenous LpL. ApoE significantly increased VLDL cell uptake in NS compared with control at low concentration, but not at high concentration. Further, Western showed a significant decreased VLDL receptor in NS heart. These findings indicate that decreased LpL in nephrotic is not the major cause of defective VLDL clearance, decreased apoE and VLDL receptor contribute to the defect. The study was supported by the Department of Veteran's Affairs.

Vegetarian diets for treating nephrotic syndrome.

Vegetarian diets based on soy-protein appeared to be effective in treating the hyperlipidemia of nephrotic syndrome. Whether there is a unique effect of soy or whether all very low-fat, low-saturated-fat, low-cholesterol, and low-protein diets have similar effects remains unknown.

Expression profiling of hepatic genes associated with lipid metabolism in nephrotic rats

Hyperlipidemia is one of the major features of nephrotic syndrome (NS). Although many factors have been implicated in the pathogenesis of NS-related dyslipidemia, the underlying mechanisms remain largely uncharacterized. The present study was designed to examine the gene profile associated with lipid metabolism in the livers of nephrotic rats. NS was created in male Sprague-Dawley rats (n = 6) receiving sequential intraperitoneal injections of puromycin aminonucleoside. Analysis by Affymetrix assay, quantitative RT-PCR, and Northern and Western blotting revealed 21 genes associated with cholesterol and fatty acid metabolism. Eight genes involved in cholesterol metabolism, Apo A-I, Acly, Acat, Mpd, Fdps, Ss, Lss, and Nsdhl, were significantly upregulated under NS. Four genes involved in fatty acid biosynthesis, Acc, FAS, ELOVL 2, and ELOVL6, and three critical for triglyceride biosynthesis, Gpam, Agpat 3, and Dgat 1, were significantly upregulated, whereas two genes involved in fatty acid oxidation, Dci and MCAD, were downregulated. Expression of several genes in sterol-regulatory element-binding protein (SREBP)-1 activation was also aberrantly altered in nephrotic livers. The expression and transcriptional activity of SREBP-1 but not SREBP-2 were increased in nephrotic rats as assessed by real-time PCR, immunoblotting, and gel shift assays. The upregulation of hepatic genes involved in cholesterol biosynthesis may play an important role in the pathogenesis of hypercholesterolemia, whereas upregulation of genes participating in hepatic fatty acid and triglyceride biosynthesis and downregulation of genes involved in hepatic fatty acid oxidation may contribute to hypertriglyceridemia in nephrotic rats. Activation of SREBP-1 transcription factor may represent an underlying molecular mechanism of hyperlipidemia in NS.

Hypoalbuminemia and proteinuria contribute separately to reduced lipoprotein catabolism in the nephrotic syndrome

Hypertriglyceridemia is a result of reduced triglyceride (TG)-rich lipoprotein (TRL) catabolism and occurs in rats with nephrotic syndrome (NS) and in Nagase analbuminemic rats (NARs). While the heparin-releasable lipoprotein lipase (LpL) pool in NAR and in NS is similar, TG levels are significantly greater in NS, suggesting that factors other than reduced LpL alone act in NS but not in NARs. Furthermore, clearance of chylomicrons (CM) and very low-density lipoprotein (VLDL) is normal in vivo in NAR despite low LpL levels. We tested the hypotheses that impaired binding of VLDL and impaired VLDL-high density lipoprotein (HDL) interactions contribute to hyperlipidemia in NS. TG and apoB secretion was measured using Triton WR 1339. Clearance of CMs by perfused hearts from NS and NAR was determined. Binding of VLDL from control, NS and NAR to rat aortic endothelial cells (RAECs) was measured prior to and following incubation with HDL from NS, NARs, and control. ApoE, protein, and TG content was determined. TG levels were greatest in NS (516 +/- 95 mg/dL), intermediate in NAR (193 +/- 20), and least in control (97 +/- 16, P = 0.05), while in contrast, TG secretion was least in NS (178 +/- 33 mg/dL/hour) versus 212 +/- 17 in NAR and 294 +/- 15 in control (P < 0.001 vs. NS). Clearance of CMs by NS and NAR hearts was the same and significantly reduced versus control (P < 0.005). Binding of NS-VLDL to endothelial cells was reduced, while NAR-VLDL binding was increased versus control (P < 0.001). Incubation of NS-VLDL with control or NAR HDL increased VLDL binding compared with binding following incubation with NS HDL (P < 0.001). Increased TG levels in both NS and NAR are the result of decreased TRL clearance. TG levels are greater in NS because of the presence of a combined defect: (1) a decrease in endothelial-bound LpL that occurs as a consequence of reduced serum albumin concentration, and (2) a defect in VLDL binding to endothelial-bound LpL. This latter defect occurs only in the presence of proteinuria and is conferred by HDL.

A simultaneous study of the metabolism of apolipoprotein B and albumin in nephrotic patients

The nephrotic syndrome is characterized by proteinuria, hypoalbuminemia and hyperlipidemia. Despite intensive research it is not clear at present what the causal links are between these pathological findings. Stable isotope labeled amino acid tracer kinetic analysis was used to simultaneously investigate the metabolism of four apolipoprotein B-containing lipoproteins (VLDL1, VLDL2, IDL and LDL) and albumin in seven patients with nephrotic syndrome and marked hypercholesterolemia, in two additional nephrotic patients with concomitant renal failure and mixed hyperlipidemia, and in a matched group of normolipidemic controls. Increased concentrations of VLDL2, IDL and LDL were due to (a) impaired VLDL2 and IDL delipidation, (b) reduced LDL catabolism, and (c) a trend towards an increased rate of total apolipoprotein B production. The rate of fractional albumin elimination was three times higher in patients than in controls and the rate of albumin synthesis was increased by 45%. No correlations were detectable between rates of apolipoprotein B production and the rate of albumin synthesis. The results of this study suggest that hyperlipidemia in nephrotic syndrome is predominantly the result of delayed lipoprotein delipidation and catabolism. There is no evidence that it is driven by a general increase of the rate of hepatic protein synthesis.

Alterations in the activity of reverse cholesterol transport: a contributing factor to the hyperlipidemia of nephrotic syndrome?

Alterations in the activity of reverse cholesterol transport: a contributing factor to the hyperlipidemia of nephrotic syndrome?

Effect of vegetarian soy diet on hyperlipidaemia in nephrotic syndrome

Nephrotic patients with persistent proteinuria also have various lipid abnormalities that may promote atherosclerosis and more rapid progression of renal disease. We aimed to find out whether dietary manipulation can correct the hyperlipidaemia found in these patients. After a baseline control period of 8 weeks on their usual diets, 20 untreated patients with chronic glomerular diseases, stable long-lasting severe proteinuria (5·9 [SD 3·4] g/24 h) and hyperlipidaemia (mean serum cholesterol 8·69 [3·34] mmol/l) ate a vegetarian soy diet for 8 weeks. The diet was low in fat (28% of total calories) and protein (0·71 [0·36] g/kg ideal body weight daily), cholesterol free, and rich in monounsaturated and polyunsaturated fatty acids (polyunsaturated/ saturated ratio 2·5) and in fibre (40 g/day). After the diet period the patients resumed their usual diets for 8 weeks (washout period). During the soy-diet period there were significant falls in serum cholesterol (total, low-density lipoprotein, and high-density lipoprotein) and apolipoproteins A and B, but serum triglyceride concentrations did not change. Urinary protein excretion fell significantly. The concentrations of all lipid fractions and the amount of proteinuria tended to return towards baseline values during the washout period. We do not know whether the favourable effect of this dietary manipulation on proteinuria was due to the qualitative or quantitative modifications of dietary protein intake or was a direct consequence of the manipulation of dietary lipid intake.

The mechanism of hyperlipidaemia in nephrotic syndrome — role of low albumin and the lcat reaction

Diminished autologous LCAT activity was found in patients with proteinuria. This was due to substrate limitation and albumin appeared the most likely limiting factor. It is suggested that low albumin can contribute to the hyperlipidaemia of nephrotic syndrome through its role on the LCAT reaction. Evidence of the ability of triglyceride to enhance homologous LCAT activity was also noted.