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Focal segmental glomerulosclerosis (FSGS) accounts for about 40% of all nephrotic syndrome cases in adults. The presence of several potential circulating factors has been suggested in patients with primary FSGS and particularly in patients with recurrent disease after transplant. Irrespectively of the nature of the circulating factors, this study was aimed at identifying early glomerular/podocyte-specific pathways that are activated by the sera of patients affected by FSGS. Kidney biopsies were obtained from patients undergoing kidney transplantation due to primary FSGS. Donor kidneys were biopsied pre-reperfusion (PreR) and a subset 1–2 hours after reperfusion of the kidney (PostR). Thirty-one post reperfusion (PostR) and 36 PreR biopsy samples were analyzed by microarray and gene enrichment KEGG pathway analysis. Data were compared to those obtained from patients with incident primary FSGS enrolled in other cohorts as well as with another cohort to correct for pathways activated by ischemia reperfusion. Using an ex-vivo cell-based assay in which human podocytes were cultured in the presence of sera from patients with recurrent and non recurrent FSGS, the molecular signature of podocytes exposed to sera from patients with REC was compared to the one established from patients with NON REC. We demonstrate that inflammatory pathways, including the TNF pathway, are primarily activated immediately after exposure to the sera of patients with primary FSGS, while phagocytotic pathways are activated when proteinuria becomes clinically evident. The TNF pathway activation by one or more circulating factors present in the sera of patients with FSGS supports prior experimental findings from our group demonstrating a causative role of local TNF in podocyte injury in FSGS. Correlation analysis with clinical and histological parameters of disease was performed and further supported a possible role for TNF pathway activation in FSGS. Additionally, we identified a unique set of genes that is specifically activated in podocytes when cultured in the presence of serum of patients with REC FSGS. This clinical translational study supports our prior experimental findings describing a potential role of the TNF pathway in the pathogenesis of FSGS. Validation of these findings in larger cohorts may lay the ground for the implementation of integrated system biology approaches to risk stratify patients affected by FSGS and to identify novel pathways relevant to podocyte injury. [ABSTRACT FROM AUTHOR]

Our goal in using dual induction therapy is to bring the kidney transplant recipient closer (through more effectively timed lymphodepletion) to an optimally immunosuppressed state. Here, we report long-term results of a prospective randomized trial comparing (Group I, N = 100) rATG/Dac (3 rATG, 2 Dac doses) vs. (Group II, N = 100) rATG/Alemtuzumab(C1H) (1 dose each), using reduced tacrolimus dosing, EC-MPS, and early corticosteroid withdrawal. Lower EC-MPS dosing was targeted in Group II to avoid severe leukopenia. Median follow-up was 96 mo post-transplant. There were no differences in 1st BPAR (including borderline) rates: 10/100 vs. 9/100 in Groups I and II during the first 12mo( P = 0.54), and 20/100 vs. 20/100 throughout the study( P = 0.90). Equally favorable renal function was maintained in both treatment arms(N.S.). While not significant, more patients in Group II experienced graft loss, 25/100 vs. 18/100 in Group I( P = 0.23). Actuarial patient/graft survival at 96 mo was 92%/83% vs. 85%/73% in Groups I and II(N.S.). DWFG-due-to-infection(N.S.), EC-MPS withholding-due-to-leukopenia during the first 2mo( P = 0.03), and incidence of viral infections( P = 0.09) were higher in Group II, whereas EC-MPS withholding-due-to-GI symptoms was higher in Group I( P = 0.009). No other adverse event differences were observed. While long-term anti -rejection and renal function efficacy were demonstrated in both treatment arms, slight over-immunosuppression of Group II patients occurred. [ABSTRACT FROM AUTHOR]