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Hangzhou, China

Wu P.,Kidney Disease Center | Everly M.J.,Terasaki Foundation Laboratory | Rebellato L.M.,East Carolina University | Haisch C.E.,East Carolina University | And 7 more authors.
Transplantation | Year: 2013

Background. Approximately 7% to 9% of patients with donor-specific antiYhuman leukocyte antigen (HLA) antibodies (DSA) fail within 1 year post-DSA onset. However, little is known as to how this DSA-associated failure temporally progresses. This longitudinal study investigates DSA's temporal relationship to allograft dysfunction and identifies predictors of allograft function's progressive deterioration post-DSA. Methods. A cohort of 175 non-HLA identical patients receiving their first transplant between March 1999 and March 2006 were analyzed. Protocol testing for DSA via single antigen beads was done before transplantation and at 1, 3, 6, 9, and 12 months after transplantation then annually. Estimated glomerular filtration rate (eGFR) was analyzed before and after DSA onset. Results. Forty-two patients developed DSA and had adequate eGFR information for analysis. Before DSA onset, the 42 patients had stable eGFR. By 1 year post-DSA, the cohort's eGFR was significantly lower (PG0.001); however, 30 of 42 had stable function. Twelve patients had failure or early allograft dysfunction (eGFR decline 925% from DSA onset). Those who failed early (by 1 year post-DSA) had more antibody-mediated rejection than stable patients (P=0.03). Late failures (after 1 year post-DSA) were predictable with evidence of early allograft dysfunction (eGFR decline 925% by 1 year post-DSA; PG0.001). Early allograft dysfunction preceded late failure by nearly 1 year. Conclusions. DSA is temporally related to allograft function deterioration. However, in many cases, late allograft failures are preceded by early allograft dysfunction. Therefore, monitoring for early allograft dysfunction provides treating physicians with a window of opportunity for treatment or continued monitoring. © 2013 by Lippincott Williams & Wilkins. Source

Chahdi A.,Kidney Disease Center | Sorokin A.,Kidney Disease Center
Biochemical and Biophysical Research Communications | Year: 2010

Endothelin-1 (ET-1) is a potent mitogen that transmits signals through its cognate G protein-coupled receptors to stimulate extracellular signal-regulated kinase Erk1/2. Endothelin-1 receptors (ET-Rs) are known to interact with caveolin-1 and co-localize in caveolae which integrate different receptor and signaling proteins. We have recently shown that β1Pix binds specifically to ET-Rs. Here, we show that β1Pix binding to caveolin-1 is dependent on heterotrimeric G proteins activation state. β1Pix interaction with different G proteins is increased in the presence of the G protein activator AMF. Moreover, extraction of cholesterol with methyl-β-cyclodextrin disrupts the binding of β1Pix to Gαq, Gα12 and phospho-Erk1/2 but not the binding of β1Pix to Gβ1. The disruption of β1Pix dimerization strongly reduced the binding of caveolin-1, Gαq and Gα12. Constitutively active mutants of Gαq and Gα12 increased Cdc42 activation when co-expressed with β1Pix but not in the presence of β1Pix dimerization deficient mutant β1PixΔ (602-611). ET-1 stimulation increased the binding of phosphorylated Erk1/2 to β1Pix but not to β1PixΔ (602-611). RGS3 decreased ET-1-induced Cdc42 activation. These results strongly suggest that the activation of ET-Rs leads to the compartmentalization and the binding of Gαq to β1Pix in caveolae, where dimeric β1Pix acts as platform to facilitate the binding and the activation of Erk1/2. © 2009 Elsevier Inc. All rights reserved. Source

Chen M.,Peking University | Li H.,Peking Union Medical College | Li X.-Y.,Kidney Disease Center | Lu F.-M.,Fudan University | And 5 more authors.
American Journal of the Medical Sciences | Year: 2010

Background: Idiopathic membranous nephropathy (IMN), a common cause of nephrotic syndrome in adults, is usually treated with corticosteroids in combination with cyclophosphamide or cyclosporine. A recent placebo-controlled study suggested that tacrolimus monotherapy was effective in IMN. However, the effectiveness of tacrolimus versus classic regimen and its potential nephrotoxicity remain inconclusive. This study evaluated the efficacy and safety of tacrolimus plus prednisone in patients with nephrotic IMN. Methods: Seventy-three patients with nephrotic IMN were recruited in this multicenter randomized controlled trial, 39 receiving tacrolimus and prednisone, while 34 receiving cyclophosphamide and prednisone. Tacrolimus was given at 0.1 mg/kg/d initially and adjusted to a blood trough level at 5 to 10 ng/mL for 6 months and then reduced to 2 to 5 ng/mL in the subsequent 3 months. Results: Intention-to-treat analysis suggested that the remission rate at the end of the sixth month was significantly higher in tacrolimus group than that in cyclophosphamide group (85% versus 65%, P < 0.05). The decrease of proteinuria was significantly greater in tacrolimus group. At the end of the 12th month, the remission rates were comparable between these 2 groups. Patients treated with tacrolimus were more likely to develop glucose intolerance (or diabetes mellitus), infection, and hypertension. No obvious nephrotoxicity of calcineurin inhibitor was found in repeat renal biopsy. Conclusions: Tacrolimus plus corticosteroids is an alternative therapeutic regimen for nephrotic IMN. The short-term efficacy might be better than cyclophosphamide plus prednisone. © Copyright 2010 Southern Society for Clinical Investigation. Source

Chahdi A.,Kidney Disease Center | Sorokin A.,Kidney Disease Center
Cellular Signalling | Year: 2010

Endothelin-1 (ET-1) is a vasoconstrictor peptide known to be a potent mitogen for glomerular mesangial cells. We have shown that ET-1 stimulates the adaptor protein p66Shc through Rac/Cdc42 guanine nucleotide exchange factor β1Pix. In this study, we demonstrate that ET-1-induced serine phosphorylation of p66Shc is mediated through Gαi3. Pertussis toxin treatment of cells induced a significant decrease in the interaction between β1Pix and ETA-R, and an increase in the binding of Gαi3 and Gβ1 to β1Pix. Activation of heterotrimeric G proteins by AlF4 - resulted in an increase of Gαi3 binding to β1Pix, which was significantly disrupted in cells expressing β1Pix dimerization deficient mutant, β1PixΔ (602-611). In cells expressing β1PixΔ (602-611), ET-1-induced p66Shc activation was also significantly decreased. Specific inhibition of EGF receptor by AG1478 blocked ET-1-induced p66Shc activation and the binding of p66Shc and Gαi3 to β1Pix. Inhibition of Erk1/2 blocked p66Shc activation induced by ET-1. Altogether, our results indicate that ET-1 activates p66Shc through EGF receptor transactivation, leading to the activation of Gαi3, β1Pix and Erk1/2. © 2009 Elsevier Inc. All rights reserved. Source

Yang Y.,Kidney Disease Center | Zhang P.,Kidney Disease Center | Lv R.,Kidney Disease Center | He Q.,Kidney Disease Center | And 3 more authors.
Intensive Care Medicine | Year: 2011

Purpose: To determine whether the main mitochondrial DNA (mtDNA) haplogroups of the Han people are associated with neurological recovery from septic encephalopathy. Methods: We studied 137 individuals with septic encephalopathy who were sequentially admitted to the intensive care unit or the emergency intensive care unit at the First Affiliated Hospital, College of Medicine, Zhejiang University, and the Peoples Hospital of Zhejiang Province. Demographic and clinical data were recorded along with clinical outcome over 28 days. The Glasgow coma scale (GCS) score was calculated daily until it reached 15 or until the patient died during the 28-day period. Follow-up was completed for all study participants. We then determined the mtDNA haplogroups of the patients by analyzing sequences of hypervariable mtDNA segments and testing diagnostic polymorphisms in the mtDNA coding region with DNA probes. Results: MtDNA haplogroup R, one of the main mtDNA haplogroups of the Han people, was a strong independent predictor of outcome following septic encephalopathy, conferring a 4.053- fold (95% CI 1.803-9.110, p = 0.001) increased chance of neurological recovery within 28 days compared with those with a non-R mtDNA haplogroup. Conclusion: In the Han population, mtDNA haplogroup R is a strong independent predictor of the outcome of septic encephalopathy, conferring an increased chance of neurological recovery compared with individuals with a non-R haplogroup. Our results provide potential insights into the mechanisms involved in septic encephalopathy, and reveal that the mtDNA haplogroup R is an independent predictor of the outcome of septic encephalopathy. © jointly held by Springer and ESICM 2011. Source

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