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Background: Chronic kidney disease (CKD) impairs intestinal barrier function which leads to endotoxemia and systemic inflammation. We have found depletion of intestinal epithelial tight junction (TJ) proteins in animals with CKD. We further showed that addition of end-stage renal disease patients’ plasma to the culture medium provokes a marked drop in transepithelial electrical resistance (TER) and depletion of TJ proteins in cultured human enterocytes. These effects were less severe with post- than with prehemodialysis plasma, suggesting a role of dialyzable agent(s). This study tested the hypothesis that intestinal barrier dysfunction in uremia may be due to diffusion of urea into the gut and its conversion to ammonia by microbial urease. Methods: Human enterocytes (T84 cells) were seeded on Transwell plates and utilized when TER exceeded 1,000 mΩ·cm 2 to ensure full polarization and TJ formation. Confluent cells were then incubated for 24 h in media containing 0, 42 or 74 mg/dl urea or urea plus urease to simulate presence of microbial flora. Results: At clinically relevant concentrations, urea caused a concentration-dependent fall in TER and the key TJ proteins claudin-1, occludin and zonula occludens 1. The effects of urea were dramatically amplified by urease causing cell detachment, dissipation of TER, and massive loss of TJ proteins. Conclusions: Uremia-induced disruption of intestinal TJ and barrier function is, in part, mediated by urea which is generally considered to be a nontoxic retained metabolite. These findings reveal a novel mechanism for a salutary effect of urea-lowering strategies, e.g. low-protein diet and longer and more frequent dialysis regimens in advanced CKD.

Background: Integrity of the tight junction (TJ) which seals the gap between the epithelial cells of the gastrointestinal tract is critical in preventing the entry of the microbial toxins, antigens, and other harmful products in the subepithelial tissues and the internal milieu. By enabling the absorption of these products, impairment of the intestinal epithelial barrier leads to local and systemic inflammation. We have recently found depletion of the key protein constituents of colonic epithelial TJ in animals with chronic kidney disease (CKD). Postmortem studies have revealed the presence of inflammation throughout the gastrointestinal tract in uremic humans. This observation suggests that uremia may cause disruption of the epithelial barrier in all segments of the gastrointestinal tract including the stomach, jejunum, and ileum. The present study was undertaken to explore this possibility. Methods: Sprague-Dawley rats were randomized to CKD or control groups. The CKD group was subjected to 5/6 nephrectomy while the control group underwent a sham operation. The animals were observed for 10 weeks at which time they were euthanized and their stomachs, jejunums, and ileums were removed and processed for measurement of TJ proteins. Results: The CKD rats showed marked azotemia, systemic oxidative stress, and marked depletion of the key protein constituents of the epithelial TJ (claudin-1, occludin, and ZO1) in the stomach, jejunum, and ileum. Conclusions: The present study extends the earlier finding of uremia-induced disruption of colonic epithelial TJ by documenting the involvement of the stomach, jejunum, and ileum as well.

Background: Despite standardized definitions of acute kidney injury (AKI), there is wide variation in the reported rates of AKI and hospital mortality for patients with AKI. Variation could be due to actual differences in disease incidence, clinical course, or a function of data ascertainment and application of diagnostic criteria. Using standard criteria may help determine and compare the risk and outcomes of AKI across centers. Methods: In this cohort study of critically ill patients admitted to the intensive care units at six hospitals in four countries, we used KDIGO criteria to define AKI. The main outcomes were the occurrence of AKI and hospital mortality. Results: Of the 15,132 critically ill patients, 32% developed AKI based on serum creatinine criteria. After adjusting for differences in age, sex, and severity of illness, the odds ratio for AKI continued to vary across centers (odds ratio (OR), 2.57-6.04, p < 0.001). The overall, crude hospital mortality of patients with AKI was 27%, which also varied across centers after adjusting for KDIGO stage, differences in age, sex, and severity of illness (OR, 1.13-2.20, p < 0.001). The severity of AKI was associated with incremental mortality risk across centers. Conclusions: In this study, the absolute and severity-adjusted rates of AKI and hospital mortality rates for AKI varied across centers. Future studies should examine whether variation in the risk of AKI among centers is due to differences in clinical practice or process of care or residual confounding due to unmeasured factors.

Background: Recombinant erythropoietin has become a routine component of care of patients with chronic kidney disease reducing the need for blood transfusions but raising the risks for cardiovascular events. We undertook this secondary analysis of subjects enrolled in the Correction of Hemoglobin and Outcomes in Renal Insufficiency (CHOIR) trial to examine the interrelationships between epoetin-alfa maintenance doses utilized and achieved hemoglobin (Hb) irrespective of treatment target and randomized allocation. Methods: We performed a post hoc analysis from the CHOIR trial. Inclusion criteria were Hb <11.0 g/dl and estimated glomerular filtration rates of 15-50 ml/min/1.73 m 2 . To be included in the present analysis, subjects needed to be free of the composite event at 4 months, receive epoetin-alfa, and have ≥1 postbaseline Hb measurement. The mean weekly dose of epoetin-alfa received up to the time of first event or censure was the main exposure variable, while the achieved Hb at month 4 was the confounder representing the subject's underlying response to treatment. The primary outcome was the composite of death, heart failure hospitalization, stroke, or myocardial infarction. A Cox proportional hazard regression model was used in time-to-event analysis. Results: Among 1,244 subjects with complete data, the average weekly dose of epoetin-alfa ranged 143.3-fold from 133 to 19,106 units/week at the time of first event or censure. Cox proportional hazard analysis found that those in the middle tertile of Hb achieved (>11.5 to <12.7 g/dl) and the lowest tertile of epoetin-alfa dose exposure level (<5,164 units/week) had the lowest risk. Irrespective of Hb achieved, the relative risk in the highest tertile (>10,095 units/week) of epoetin-alfa dose exposure level was significantly escalated (hazard ratios ranged from 2.536 to 3.572, p < 0.05, when compared to the group of middle Hb tertile and lowered dose tertile). In a multivariable model that adjusted for achieved Hb, albumin, cholesterol, age, prior heart failure, prior stroke, prior deep venous thrombosis, atrial fibrillation or malignancy, the average weekly dose had a significant (p = 0.005) relative risk of 1.067 per 1,000 units of epoetin-alfa for the primary end point. Conclusions: In the CHOIR trial, average epoetin-alfa doses >10,095 units/week were associated with increased risks for cardiovascular events irrespective of the Hb achieved within the first 4 months of treatment. These data suggest the weekly epoetin-alfa dose and not the Hb achieved was a principal determinant in the primary outcome observed implicating a cardiovascular toxicity of this erythrocyte-stimulating agent.

Background/Aims: Hypovitaminosis D has been associated with an increased cardiovascular mortality in the general population and in patients with chronic kidney disease (CKD). Still, whether prescribing vitamin D reduces the risk of mortality in renal patients remains controversial. Methods: We searched PubMed, ClinicalTrials.gov and the Cochrane Library for long-term longitudinal studies comparing vitamin D compounds (25-hydroxyvitamin D, 1,25-dihydroxyvitamin D and synthetic derivatives) to placebo or no treatment in renal patients, and which evaluated mortality, to perform a meta-analysis. Data concerning study quality, population and effect size were extracted independently by two investigators using predefined forms. Results: Fourteen observational studies (194,932 patients) met all eligibility criteria. Most studies were performed in hemodialysis patients and all used calcitriol or synthetic analogues. In a random effects meta-analysis, receiving any vitamin D therapy significantly reduced the risk of all-cause mortality (relative risk 0.73, 95% CI 0.65-0.82). The relative risk of death was 0.72 (95% CI 0.65-0.80) after 3 years of therapy and 0.67 (95% CI 0.45-0.98) after 5 years. In meta-regression, the risk reduction was shown to be greater in patients with higher parathyroid hormone serum levels (p = 0.01). The risk of cardiovascular mortality was also significantly reduced in patients receiving any vitamin D derivative (relative risk 0.63, 95% CI 0.44-0.92). Conclusion: Therapies with 1,25-dihydroxyvitamin D and analogues are associated with reduced mortality in CKD patients, and particularly in those suffering from secondary hyperparathyroidism. These results, based on observational evidence, are supportive of prescribing vitamin D therapies to CKD patients, while respecting good practice guidelines.

Background: Anti-phospholipase A2 receptor antibody (PLA2R-Ab) is useful in diagnosing idiopathic membranous nephropathy (IMN). We investigated the clinical relevance of PLA2R-Ab enzyme-linked immunosorbent assay (ELISA) in patients with IMN. Methods: We measured PLA2R-Ab with an ELISA kit from the serum of 160 patients with IMN (n = 93), secondary MN (n = 14) and other glomerulonephritis (n = 41) as well as healthy controls (n = 12) at the time of renal biopsy and investigated the correlation of titers of PLA2R-Ab with clinical parameters. Results: PLA2R-Ab was positive in 41 of 93 patients (44.1%) with IMN. No samples from the patients with secondary MN and other glomerulonephritis or healthy controls were positive with the ELISA test. The PLA2R-Ab-positive patients showed severe disease activity and a low remission rate. The PLA2R-Ab titer positively correlated with proteinuria and was negatively associated with renal function and serum albumin. The patients with a high titer of PLA2R-Ab had significantly decreased remission rates. The cumulative probabilities of remission was significantly lower in patients with PLA2R-Ab (p = 0.01) and even so in patients with a high titer of PLA2R-Ab (p = 0.04). When we compared the ELISA titers with Western blot (WB) data of 43 patients who had been enrolled in our previous study, 18 and 30 patients were positive on ELISA (41.9%) and WB (69.8%), respectively. WB and ELISA had a concordance rate of 72.1% and were positively correlated (r = 0.590, p < 0.001). Conclusion: The presence, as well as a high titer, of PLA2R-Ab on ELISA was associated with poor prognosis of IMN. Assessment of PLA2R-Ab with ELISA is an easy and reliable tool for the diagnosis and guidance of therapeutic plans.

Background/Aims: Recent evidence has shown that an inflammatory process is involved in the development and progression of diabetic nephropathy. This study examined the impact of activated intrarenal lymphocytes in this inflammatory process. Methods: We studied T cell recruitment in mice with streptozotocin (STZ)-induced diabetes by flow cytometry and immunohistochemistry. The kidney biopsy specimens from patients with type 2 diabetes mellitus and diabetic nephropathy were evaluated by immunohistochemistry. Results: In flow cytometry, intrarenal CD3+ T cells were significantly increased in proteinuric mice at 20 weeks after STZ injection. However, the population of T cells and B cells in diabetic spleen was not different from that of control mice. Immunohistochemistry also showed a marked infiltration of interstitial CD4+, CD8+ T cells in diabetic kidney. Interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α) mRNA expression was significantly increased in diabetic mouse kidney compared with controls. Interestingly, flow cytometry analysis of kidney-derived mononuclear cells from diabetic mice showed significantly increased production of IFN-γ and TNF-α by CD3+ T cells. Type 2 diabetic patients also showed a marked increase in CD4+, CD8+ and CD20+ cells in interstitium, and the number of CD4+ and CD20+ cells correlated with the amount of proteinuria. Conclusion: Our results clearly showed that aberrant intrarenal infiltration and the activation of T cells in interstitium are the underlying immunopathological mechanisms of diabetic kidney injury.

Background/Aims: Advanced glycation end products (AGEs) induce epithelial mesenchymal transition (EMT) in renal proximal tubular epithelial cells (PTECs) by promoting the two EMT regulators, transforming growth factor beta (TGF-β) and connective tissue growth factor (CTGF). However, the exact signaling mechanism remains largely unclear. Methods: We investigated the promotion to high mobility group box 1 (HMGB1) in renal tubular epithelial HK-2 cells by AGE-BSA with quantitative PCR and western blot assay, and then determined the regulatory role of HMGB1 in the AGE-BSA-induced CTGF and TGF-β. In addition, the dependence of the receptor of advanced glycation end products (RAGE) was also examined in the CTGF and TGF-β promotion by AGEs and HMGB1 in HK-2 cells using the RNAi method. Results: It was demonstrated that AGEs induced translocation and release of HMGB1 from tubular epithelial HK-2 cells, and the released HMGB1 enhanced the promotion to CTGF and TGF-β by AGEs in HK-2 cells. On the other side, the HMGB1 knockdown by siRNA attenuated the AGE-BSA-induced expression of TGF-β. Moreover, the CTGF and TGF-β promotion in HK-2 cells by AGEs and HMGB1 was RAGE-dependent. Conclusion: Our results indicated that AGEs induced HMGB-1 and promoted the CTGF and TGF-β in renal epithelial HK-2 cells RAGE-dependently. And there was a synergism between AGEs and HMGB1 in the RAGE signaling activation. The in vitro data suggested that the AGE-RAGE and HMGB-1-RAGE signaling might play an important role in the promotion of CTGF and TGF-β in the renal fibrosis process of diabetic nephropathy.

Background: Previous studies showed that connective tissue growth factor (CTGF)-induced proliferation of lung fibroblasts and production of chemokines in mesangial cells could be inhibited by lipoxin A 4 (LXA 4 ). It is speculated that LXA 4 could modulate the CTGF-induced epithelial to mesenchymal transition. Methods: The expressions of α-smooth muscle actin (α-SMA), E-cadherin, integrin-linked kinase (ILK), extracellular signal-regulated kinase 1/2 (ERK1/2), phosphatidylinositol 3-kinase (PI3-K), Akt and Smad signaling were assessed by Western blot and/or real-time RT-PCR, and activation of Ras or ILK by activity assay, expressions of α-SMA and zonula occludens-1 by immunofluorescence assay in proximal tubular epithelial cells (HK-2). Results: Pretreatment of HK-2 cells with LXA 4 inhibited the morphological fibroblast-like changes and α-SMA expression induced by CTGF but not by transforming growth factor-β 1 (TGF-β 1 ). The expressions of E-cadherin and zonula occludens-1 reduced by CTGF but not by TGF-β 1 were increased by LXA 4 . LXA 4 inhibited the expression and activity of ILK and activation of Ras, ERK1/2, PI3-K and Akt in HK-2 cells stimulated by CTGF. LXA 4 did not affect TGF-β 1 -induced expression of ILK, Smad-2/3 phosphorylation and Smad-2’s binding to Smad-4 and subsequent nuclear translocation. Conclusion: LXA 4 inhibits the tubular epithelial to mesenchymal transition, initiated by CTGF but not by TGF-β 1 , via downregulation of ILK, Ras/MEK/ERK1/2 and PI3-K/Akt-dependent signal pathway stimulated by CTGF.

Background: Acute kidney injury (AKI) is a frequent and serious complication of sepsis. A growing body of evidence now suggests that inflammatory reactions and tubular dysfunction induced by oxidative stress involved in the mechanisms of the disease. This study aimed to determine the role of anti-inflammatory and anti-oxidant activities of mangiferin (MA) in sepsis-induced AKI. Methods: We investigated the effects of MA on apoptosis of rat kidney proximal tubular cell (RPTC), together with renal function and morphological alterations of mice undergoing cecal-ligation and puncture (CLP). The levels of oxidative stress in kidney tissues were also determined. Moreover, we mainly focus on the effects of MA in regulating the production of NLRP3 and Nrf2 in the present study. Results: The exposure to LPS (5 Vg/ml) yielded a significant increase of apoptosis in RPTC cells, which was largely inhibited by MA pretreatment. MA attenuates renal dysfunction and ameliorates the morphological changes in the septic mice induced by CLP. MA inhibits oxidative stress, decreases serum levels of IL-1F and IL-18, and prevents tubular epithelial cells apoptosis in kidneys of CLP mice model. Data in this study also suggest that MA promotes Nrf2 expression and suppresses renal NLRP3 inflammasome activation. Conclusion: In summary, MA protects against sepsis-induced AKI through NLRP3 inflammasome inhibition and Nrf2 up-regulation. Thus, the mangiferin could thus be a promising candidate for development of a multi-potent drug. i 2014 S. Karger AG, Basel