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Background Carnitine deficiency may contribute to cardiovascular disease (CVD) in patients with hemodialysis (HD). Dyslipidemia plays a role in CVD and its prevalence is also high in HD patients. We examined here the effects of switching from oral administration (PO) to intravenous (IV) injection of l-carnitine on lipid metabolism in patients with HD. Methods Nine HD patients who had received l-carnitine orally (900 mg/day) for 1 year were enrolled in this study. We examined whether lipid parameters were improved by switching to IV injection therapy of 1000 mg l-carnitine. Results IV injection of l-carnitine for 1 week significantly increased total, free and acyl carnitine levels both before and after HD. Switching to IV injection therapy for 1 and 4 weeks decreased serum free fatty acid (FFA) (322 ± 104 versus 261 ± 124 µmol/L) and increased high-density lipoprotein-cholesterol levels (1.46 ± 0.49 versus 1.63 ± 0.62 mmol/L), respectively. Change in FFA values from the baseline (ΔFFA) was positively correlated with the Δacyl/free carnitine ratio (r2 = 0.553, P = 0.022). Conclusion This study demonstrated that switching to IV l-carnitine therapy from oral supplementation improved lipid profiles, thus supporting the clinical utility of IV administration of l-carnitine for the treatment of patients on HD. [ABSTRACT FROM AUTHOR]

Peritoneal protein loss due to high peritoneal permeability may contribute to hypoalbuminemia and early withdrawal from peritoneal dialysis ( PD) therapy in end stage renal disease ( ESRD) patients. We have found that pigment epithelium-derived factor ( PEDF) has anti-vasopermeability properties both in cell culture and animal models by counteracting the biological actions of vascular endothelial growth factor ( VEGF). However, it remains unknown which clinical variables, including dialysate VEGF and PEDF, are associated with decreased serum albumin levels and could predict early withdrawal from the PD in ESRD patients. We address these issues. Twenty-seven ESRD patients undergoing PD were enrolled. Clinical variables were measured at 6 months after commencing PD. We examined the independent correlates of serum albumin in PD patients and then prospectively investigated the predictors of withdrawal from the PD therapy over 4 years. Dialysate VEGF was associated with peritoneal solute transport rate ( P = 0.002), serum albumin (inversely, P < 0.001) and dialysate PEDF levels ( P < 0.001). In multiple stepwise regression analysis, age ( P = 0.002) and dialysate VEGF levels ( P < 0.001) were independent determinants of serum albumin levels. High VEGF (>27 pg/mL), low serum albumin (≤3.31 g/dL) and low hemoglobin (≤11.2 g/dL) were correlated with withdrawal from the PD therapy during the 4 years. The odds ratio of dialysate VEGF for early withdrawal from the PD was 6.310 ( P = 0.035). The present study demonstrated that increased dialysate VEGF was associated with decreased serum albumin and early withdrawal from the PD therapy. Inhibition of peritoneal VEGF production may be a therapeutic target in PD patients. [ABSTRACT FROM AUTHOR]

Although impaired synthesis and/or bioavailability of nitric oxide are considered to contribute to insulin resistance and the progression of liver disease in nonalcoholic fatty liver disease, role of asymmetric dimethylarginine, an endogenous inhibitor of nitric oxide synthase, has not been examined. We examined retrospectively which anthropometric and metabolic parameters were independently associated with serum levels of asymmetric dimethylarginine in nonalcoholic fatty liver disease. A total of 194 consecutive biopsy-proven nonalcoholic fatty liver disease patients with or without type 2 diabetes were enrolled. Serum asymmetric dimethylarginine levels in nonalcoholic fatty liver disease patients were significantly higher, irrespective of the presence or absence of diabetes, than those in healthy control. Multiple stepwise regression analysis showed that decreased total protein and procollagen N-terminal peptide levels, markers of advanced liver disease and hepatic fibrosis, respectively, were independently associated with asymmetric dimethylarginine levels in nonalcoholic fatty liver disease subjects without diabetes, whereas soluble form of receptor for advanced glycation end products and density ratio of liver to spleen in computed tomography were independent correlates of asymmetric dimethylarginine in diabetic patients. The present study suggests that asymmetric dimethylarginine may be associated with nonalcoholic fatty liver disease, especially subjects without diabetes. [ABSTRACT FROM AUTHOR]

Background and Aims: Advanced glycation end products (AGEs) contribute to cardiovascular disease in patients with hemodialysis (HD). We have recently found that carnitine levels are inversely associated with skin AGE levels in HD patients. We examined whether l-carnitine supplementation reduced skin AGE levels in HD patients with carnitine deficiency. Methods: This was a single-center study. One hundred and two HD patients (total carnitine levels <50 μmol/L) were enrolled and randomized to either oral administration of l-carnitine (900 mg/day) ( n=51) or control ( n=51). After 6 months, metabolic and inflammatory variables, including serum levels of carnitine, were measured. Skin AGE levels were determined by evaluating skin auto-fluorescence with an AGE-reader. Results: There were no significant differences of clinical variables at baseline between the control and l-carnitine therapy group. Thirty-two patients did not complete the assessment or treatment of the study. Oral l-carnitine supplementation for 6 months significantly increased low-density lipoprotein cholesterol (LDL-C), triglycerides, total, free, and acyl carnitine levels, while it decreased alanine transaminase, acyl/free carnitine ratio, β2-microglobulin, and skin AGE values. Change in total carnitine values from baseline (Δtotal carnitine) and Δfree carnitine were inversely associated with Δskin AGE levels in l-carnitine-treated patients ( p=0.036 and p=0.016, respectively). In multiple regression analysis, Δfree carnitine was a sole independent determinant of Δskin AGEs ( R2=0.178). Conclusions: The present study demonstrated that oral l-carnitine supplementation significantly decreased skin AGE levels in HD patients with carnitine deficiency. These observations suggest that supplementation of l-carnitine might be a novel therapeutic strategy for preventing the accumulation of tissue AGEs in carnitine-deficient patients with HD. [ABSTRACT FROM AUTHOR]

Advanced glycation end products (AGEs) and their receptor (RAGE) play a role in diabetic nephropathy. We screened DNA aptamer directed against AGEs (AGEs-aptamer) in vitro and examined its effects on renal injury in KKAy/Ta mice, an animal model of type 2 diabetes. Eight-week-old male KKAy/Ta or C57BL/6J mice received continuous intraperitoneal infusion of AGEs- or control-aptamer for 8 weeks. AGEs-aptamer was detected and its level was increased in the kidney for at least 7 days. The elimination half-lives of AGEs-aptamer in the kidney were about 7 days. Compared with those in C57BL/6J mice, glomerular AGEs levels were significantly increased in KKAy/Ta mice, which were blocked by AGEs-aptamer. Urinary albumin and 8-hydroxy-2'-deoxy-guanosine levels were increased, and glomerular hypertrophy and enhanced extracellular matrix accumulation were observed in KKAy/Ta mice, all of which were prevented by AGEs-aptamer. Moreover, AGEs-aptamer significantly reduced gene expression of RAGE, monocyte chemoattractant protein-1, connective tissue growth factor, and type IV collagen both in the kidney of KKAy/Ta mice and in AGE-exposed human cultured mesangial cells. Our present data suggest that continuous administration of AGEs-aptamer could protect against experimental diabetic nephropathy by blocking the AGEs-RAGE axis and may be a feasible and promising therapeutic strategy for the treatment of diabetic nephropathy. [ABSTRACT FROM AUTHOR]

Background Matrix metalloproteinase-2 (MMP-2) is responsible for the degradation of various types of extracellular matrix (ECM) proteins such as type IV collagen. Decreased MMP-2 expression and activity has been generally thought to contribute to increased accumulation of ECM at the advanced stage of diabetic nephropathy. However, the kinetics and role of MMP-2 in the early phase of diabetic nephropathy remain unclear. To address this issue, we examined whether streptozotocin (STZ)-induced early diabetic nephropathy was accelerated in MMP-2 knockout (KO) mice. Methods Diabetes was induced by the injection of STZ in 6-week-old control and MMP-2 KO mice. Animals were killed after 16 weeks of diabetes of after observation alone. Results Compared with non-diabetic control mice, renal MMP-2 expression and activity were increased in 16-week old diabetic mice. Serum levels of blood urea nitrogen and creatinine and urinary excretion levels of albumin and N-acetyl-β-d-glucosaminidase were significantly elevated in diabetic MMP-2 KO mice when compared with wild-type diabetic littermates. Further, accumulation of ECM in the glomeruli and atrophy and fibrosis in the tubulointerstitium were exacerbated, and renal α-smooth muscle actin expression was enhanced in diabetic MMP-2 KO mice. Conclusions Our present study suggests that renal expression and activity of MMP-2 are increased as a compensatory mechanism in the early phase of diabetic nephropathy. Since MMP-2 could play a protective role against the progression of diabetic nephropathy, further enhancement of MMP-2 expression and/or activity in the kidney may be a therapeutic target for the treatment of early diabetic nephropathy. [ABSTRACT FROM PUBLISHER]

ABSTRACT: Aim: There is accumulating evidence that advanced glycation end products (AGE) play a role in cardiovascular disease (CVD) in patients with haemodialysis (HD). Carnitine deficiency is frequently observed in HD patients, which may also contribute to CVD. In this study, we examined whether carnitine deficiency was independently associated with increased tissue accumulation levels of AGE in HD patients. Methods: One hundred and twenty-nine HD patients underwent determinations of blood chemistries including serum level of carnitine. Tissue AGE levels were evaluated by measuring skin autofluorescence with an AGE-reader. Results: Serum carnitine levels were significantly lower, while skin AGE levels were significantly higher in HD patients compared with healthy controls ( P < 0.001). In univariate analysis, β2-microglobulin (β2-MG) and carnitine (inversely) were correlated with skin AGE levels. Multiple stepwise regression analysis revealed that carnitine levels were one of the independent determinants of skin AGE levels ( P = 0.024). When β2-MG-adjusted skin AGE levels were stratified by serum carnitine levels, a statistical significance and dose-response relationship were observed ( P = 0.043). Furthermore, skin AGE levels were one of the independent determinants of serum carnitine levels as well ( P = 0.012). Conclusion: The present study demonstrated that decreased carnitine levels were independently associated with increased skin AGE levels in HD patients. Since carnitine is reported to inhibit the formation of AGE in vitro, our study suggests that supplementation of carnitine may be a therapeutic target for preventing the accumulation of tissue AGE and subsequently reducing the risk of CVD in HD patients. [ABSTRACT FROM AUTHOR]

C-reactive protein (CRP) level predicts future cardiovascular events in patients on haemodialysis (HD). Advanced glycation end products (AGE) play a role in cardiovascular disease (CVD) in HD patients. However, which variables including tissue AGE levels are independently associated with CRP remains unknown. Therefore, whether tissue AGE and CRP levels were correlated with atherosclerosis in HD patients was examined. Fifty-four HD patients underwent determinations of blood chemistries and tissue AGE. Tissue AGE levels were evaluated by measuring skin autofluorescence. Pulsatility index (PI) in the carotid artery was measured using a Doppler ultrasonography. Univariate analyses showed that age, white blood cells, serum albumin (inversely), alkaline phosphatase (inversely), tartrate-resistant acid phosphatase 5b (TRAP5b) (inversely) and skin AGE levels were significantly correlated with high-sensitivity CRP (hsCRP). Multiple stepwise regression analysis revealed that serum albumin, TRAP5b and skin AGE levels were independent determinants of hsCRP. Further, PI was highest among HD patients with high skin AGE and high hsCRP levels. The present study suggests that tissue AGE level is one of the independent determinants of hsCRP in HD patients. Tissue AGE and hsCRP levels may be correlated with each other, which could in concert contribute to the progression of atherosclerosis in these subjects. This study demonstrates the association between tissue advanced glycation end products (AGE) level and high-sensitivity C-reactive protein (hsCRP) in haemodialysis patients. In addition, tissue AGE and hsCRP levels could in concert contribute to the progression of atherosclerosis in these subjects. [ABSTRACT FROM AUTHOR]

Background: Asymmetric dimethylarginine (ADMA) plays important roles in the pathogenesis of chronic kidney disease (CKD). We have recently found that ADMA is involved in glomerular sclerosis and tubulointerstitial fibrosis in an animal model of CKD. However, relationship between plasma ADMA levels and severity of renal damage in CKD patients remains unknown.Methods: Relatively young 109 biopsy-proven IgA nephropathy (IgAN) patients (age: 32.7 ± 13.2; estimated glomerular filtration rate, eGFR: 86.5 ± 28.8 ml/min/1.73 m²) were enrolled. We retrospectively investigated whether plasma levels of ADMA were associated with severity of the renal tissue damage and could be a predictor of the disease progression in our subjects.Results: ADMA levels were higher in IgAN patients than age-, sex- and mean eGFR-matched healthy volunteers (0.53 ± 0.14 vs. 0.43 ± 0.08 μM, p < 0.01). ADMA levels were associated with the severity of glomerular and tubulointerstitial injury. Multiple stepwise regression analysis revealed that ADMA, but not proteinuria was an independent determinant for the disease progression assessed by annual reduction rates of eGFR. In univariate analyses, ADMA levels were correlated with proteinuria, total cholesterol, triglycerides, and uric acid. Proteinuria was a sole independent correlate of ADMA in multiple stepwise regression analysis.Conclusion: The present study demonstrated that ADMA was correlated with the severity of the renal tissue damage and could be a predictor of disease progression in IgAN patients. [ABSTRACT FROM AUTHOR]

1. Regulatory T cells (Treg) and cytotoxic T cells (CTL) are involved in various immune diseases. However, the prognostic impact of Treg and CTL in patients with myeroperoxidase anti-neutrophil cytoplasmic antibody-associated glomerulonephritis (MPO-ANCA-GN) is not well known. Therefore, in the present study, we examined the relationship between expression of forkhead box P3 (Foxp3) and T cell intracytoplasmic antigen (TIA)-1, Treg and CTL markers and renal survival in patients with MPO-ANCA-GN. 2. Forty patients with MPO-ANCA-GN and 10 patients with minimal change nephrotic syndrome (MCNS) underwent physical examination, determination of blood chemistry and renal biopsy. Immunohistochemical staining for Foxp3 and TIA-1 was performed on paraffin-embedded renal sections. 3. Although almost all patients received standard immunosuppressive treatment for 6 months, seven MPO-ANCA-GN patients needed maintenance haemodialysis (HD), whereas 33 patients did not (non-HD). Both Foxp3- and TIA-1-positive cells were detected in the interstitium and glomeruli of MPO-ANCA-GN patients, whereas they were rarely detected in patients with MCNS. The total crescent rate was significantly higher in the HD group than in the non-HD group (35.9 ± 3.5 vs 65.8 ± 7.4, respectively). In the interstitium, the age-adjusted Foxp3/TIA-1 ratio was significantly higher in the non-HD group than in the HD group (0.016 ± 0.016 vs 0.004 ± 0.008, respectively; P < 0.05). The Foxp3/TIA-1 ratio, but not the Foxp3/CD3 ratio, remained significantly higher in the non-HD group than in the HD group even after adjustment for crescent rate. Age- and total crescent rate-adjusted renal survival rates were higher in patients with a Foxp3/TIA-1 ratio ≥ 0.06 than in patients with a Foxp3/TIA-1 ratio < 0.06 ( P = 0.02). 4. The results of the present study suggest that Treg could play a protective role against MPO-ANCA-GN and that a decreased Foxp3/TIA-1 ratio in interstitial areas may predict future renal failure in patients with MPO-ANCA-GN. [ABSTRACT FROM AUTHOR]

Abstract: There is accumulating evidence that engagement of the receptor for advanced glycation end products (RAGE) with ligands such as advanced glycation end products (AGEs) and high mobility group box–1 (HMGB-1) elicits vascular inflammation, thus contributing to the increased risk for cardiovascular disease. Furthermore, enhanced accumulation of asymmetric dimethylarginine (ADMA) plays a role in cardiovascular disease in chronic kidney disease (CKD) patients. However, the relationships among serum levels of AGEs, HMGB-1, soluble form of RAGE (sRAGE), and ADMA are largely unknown. The aim of the present study is to determine their relationships in CKD patients. Twenty nondiabetic normotensive CKD patients with dyslipidemia and 20 age- and sex-matched healthy controls were enrolled. All subjects underwent determination of blood chemistries; urinary proteinuria; and serum levels of AGEs, HMGB-1, sRAGE, and ADMA. Serum AGE, HMGB-1, sRAGE, and ADMA levels in CKD patients were significantly higher than those in control subjects. Circulating levels of AGEs in CKD patients were positively associated with sRAGE and ADMA, and HMGB-1 with ADMA, but not sRAGE. There were no significant associations among these markers and serum creatinine, estimated glomerular filtration rate, proteinuria, and lipid levels. In multiple regression analyses, AGEs and HMGB-1 were independently correlated with ADMA. The present study demonstrated that AGE and sRAGE levels were correlated with each other and that AGEs and HMGB-1 were independently associated with ADMA in nondiabetic CKD patients. Elevation of the RAGE ligands may enhance ADMA levels, suggesting the active involvement of AGE/HMGB-1–RAGE–ADMA axis in CKD patients. [Copyright &y& Elsevier]

Background. IL-1β has the potential to promote progressive renal disease by effects on macrophage recruitment and activation or by effects mediated through tubular cell transforming growth factor (TGF)-β production, previously demonstrated in vitro. [ABSTRACT FROM PUBLISHER]

Background/Aim:Matrix metalloproteinase-2 (MMP-2) has been implicated in chronic kidney disease (CKD) and cardiovascular disease. However, there is no knowledge about the correlations between serum levels of MMP-2, proteinuria and atherosclerosis in patients with CKD. We investigated whether serum MMP-2 levels were associated with proteinuria, intima media thickness (IMT), and the presence of carotid atherosclerotic plaque in CKD patients. Methods: CKD patients without hemodialysis (n = 99) were enrolled. MMP-2 levels were measured by an ELISA system. IMT and carotid atherosclerotic plaque were evaluated by a high-resolution ultrasonography. Results: Multivariate analyses revealed that low-density lipoprotein (p < 0.001), MMP-2 (p = 0.001) and systolic blood pressure (p = 0.011) were independent correlates of proteinuria. Age- and serum creatinine-adjusted MMP-2 levels were significantly increased (p = 0.001) in proportion to the increasing levels of proteinuria. Further, age (p < 0.001), systolic blood pressure (p = 0.015) and MMP-2 levels (p = 0.042) were independent correlates of IMT. MMP-2 levels were significantly (p < 0.01) higher in patients with atherosclerotic plaque than those without it. Conclusions: The present study demonstrated that serum levels of MMP-2 were one of the independent correlates of proteinuria and IMT in patients with CKD. Our results suggest that serum MMP-2 levels may be one of the risk factors for renal damage and atherosclerosis in CKD patients. Copyright © 2008 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]