***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
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    Input: Complement inhibitors have not been thoroughly evaluated in the treatment of acute antibody‐mediated rejection ( ABMR ) . We performed a prospect i ve , single‐arm pilot study to investigate the potential effects and safety of C1 inhibitor ( C1‐INH ) Berinert added to high‐dose intravenous immunoglobulin ( IVIG ) for the treatment of acute ABMR that is nonresponsive to conventional therapy . Kidney recipients with nonresponsive active ABMR and acute allograft dysfunction were enrolled between April 2013 and July 2014 and received C1‐INH and IVIG for 6 months ( six patients ) . The primary end point was the change in eGFR at 6 months after inclusion ( M+6 ) . Secondary end points included the changes in histology and DSA characteristics and adverse events as evaluated at M+6 . All patients showed an improvement in eGFR between inclusion and M+6 : from 38.7 ± 17.9 to 45.2 ± 21.3 mL/min/1.73 m2 ( p = 0.0277 ) . There was no change in histological features , except a decrease in the C4d deposition rate from 5/6 to 1/6 ( p = 0.0455 ) . There was a change in DSA C1q status from 6/6 to 1/6 positive ( p = 0.0253 ) . One deep venous thrombosis was observed . In a secondary analysis , C1‐INH patients were compared with a similar historical control group ( 21 patients ) . C1‐INH added to IVIG is safe and may improve allograft function in kidney recipients with nonresponsive acute ABMR Background Despite major advances in transplant medicine , improvements in long-term kidney allograft survival have not been commensurate with those observed shortly after transplantation . The formation of donor-specific antibodies ( DSA ) and ongoing antibody-mediated rejection ( AMR ) processes may critically contribute to late graft loss . However , appropriate treatment for late AMR has not yet been defined . There is accumulating evidence that the proteasome inhibitor bortezomib may substantially affect the function and integrity of alloantibody-secreting plasma cells . The impact of this agent on the course of late AMR has not so far been systematic ally investigated . Methods / design The BORTEJECT Study is a r and omized controlled trial design ed to clarify the impact of intravenous bortezomib on the course of late AMR . In this single-center study ( nephrological outpatient service , Medical University Vienna ) we plan an initial cross-sectional DSA screening of 1,000 kidney transplant recipients ( functioning graft at ≥180 days ; estimated glomerular filtration rate ( eGFR ) > 20 ml/minute/1.73 m2 ) . DSA-positive recipients will be subjected to kidney allograft biopsy to detect morphological features consistent with AMR . Forty-four patients with biopsy-proven AMR will then be included in a double-blind placebo-controlled intervention trial ( 1:1 r and omization stratified for eGFR and the presence of T-cell-mediated rejection ) . Patients in the active group will receive two cycles of bortezomib ( 4 × 1.3 mg/m2 over 2 weeks ; 3-month interval between cycles ) . The primary end point will be the course of eGFR over 24 months ( intention-to-treat analysis ) . The sample size was calculated according to the assumption of a 5 ml/minute/1.73 m2 difference in eGFR slope ( per year ) between the two groups ( alpha : 0.05 ; power : 0.8 ) . Secondary endpoints will be DSA levels , protein excretion , measured glomerular filtration rate , transplant and patient survival , and the development of acute and chronic morphological lesions in 24-month protocol biopsies . Discussion The impact of anti-humoral treatment on the course of late AMR has not yet been systematic ally investigated . Based on the hypothesis that proteasome inhibition improves the outcome of DSA-positive late AMR , we suggest that our trial has the potential to provide solid evidence towards the treatment of this type of rejection . Trial registration Clinical trials.gov : NCT01873157 Kidney allograft rejection can occur in clinical ly stable patients , but long-term significance is unknown . We determined whether early recognition of sub clinical rejection has long-term consequences for kidney allograft survival in an observational prospect i ve cohort study of 1307 consecutive nonselected patients who underwent ABO-compatible , complement-dependent cytotoxicity-negative crossmatch kidney transplantation in Paris ( 2000 - 2010 ) . Participants underwent prospect i ve screening biopsies at 1 year post-transplant , with concurrent evaluations of graft complement deposition and circulating anti-HLA antibodies . The main analysis included 1001 patients . Three distinct groups of patients were identified at the 1-year screening : 727 ( 73 % ) patients without rejection , 132 ( 13 % ) patients with sub clinical T cell-mediated rejection ( TCMR ) , and 142 ( 14 % ) patients with sub clinical antibody-mediated rejection ( ABMR ) . Patients with sub clinical ABMR had the poorest graft survival at 8 years post-transplant ( 56 % ) compared with sub clinical TCMR ( 88 % ) and nonrejection ( 90 % ) groups ( P<0.001 ) . In a multivariate Cox model , sub clinical ABMR at 1 year was independently associated with a 3.5-fold increase in graft loss ( 95 % confidence interval , 2.1 to 5.7 ) along with eGFR and proteinuria ( P<0.001 ) . Sub clinical ABMR was associated with more rapid progression to transplant glomerulopathy . Of patients with sub clinical TCMR at 1 year , only those who further developed de novo donor-specific antibodies and transplant glomerulopathy showed higher risk of graft loss compared with patients without rejection . Our findings suggest that sub clinical TCMR and sub clinical ABMR have distinct effects on long-term graft loss . Sub clinical ABMR detected at the 1-year screening biopsy carries a prognostic value independent of initial donor-specific antibody status , previous immunologic events , current eGFR , and proteinuria Non-r and omised studies of the effects of interventions are critical to many areas of healthcare evaluation , but their results may be biased . It is therefore important to underst and and appraise their strengths and weaknesses . We developed ROBINS-I ( “ Risk Of Bias In Non-r and omised Studies - of Interventions ” ) , a new tool for evaluating risk of bias in estimates of the comparative effectiveness ( harm or benefit ) of interventions from studies that did not use r and omisation  to allocate units ( individuals or clusters of individuals ) to comparison groups . The tool will be particularly useful to those undertaking systematic review s that include non-r and omised studies A controlled trial was carried out to assess the value of intensive plasma exchange in 27 renal transplant recipients with clinical and histological evidence of acute vascular rejection . In addition to st and ard immunosuppression , 13 patients received  plasma exchange on six consecutive days at a mean exchange volume of 40.6 ml/kg of body weight each day using an intermittent cell separator . A further 14 patients received st and ard immunosuppression only . In addition , 10 patients exchanged prior to the controlled trial have been studied . Analysis of short-term benefit , as evidence d by a reduction in serum creatinine , and by subsequent graft survival revealed no significant difference in these parameters between the two groups in the controlled trial . This regimen of plasma exchange has not , therefore , been shown to modify acute renal allograft rejection Antibody‐mediated rejection ( AMR ) is typically treated with plasmapheresis ( PP ) and intravenous immunoglobulin ( st and ard of care ; SOC ) ; however , there is an unmet need for more effective therapy . We report a phase 2b , multicenter double‐blind r and omized placebo‐controlled pilot study to evaluate the use of human plasma‐derived C1 esterase inhibitor ( C1 INH ) as add‐on therapy to SOC for AMR . Eighteen patients received 20 000 units of C1 INH or placebo ( C1 INH n = 9 , placebo n = 9 ) in divided doses every other day for 2 weeks . No discontinuations , graft losses , deaths , or study drug‐related serious adverse events occurred . While the study 's primary end point , a difference between groups in day 20 pathology or graft survival , was not achieved , the C1 INH group demonstrated a trend toward sustained improvement in renal function . Six‐month biopsies performed in 14 subjects ( C1 INH = 7 , placebo = 7 ) showed no transplant glomerulopathy ( TG ) ( PTC+cg≥1b ) in the C1 INH group , whereas 3 of 7 placebo subjects had TG . Endogenous C1 INH measured before and after PP demonstrated decreased functional C1 INH serum concentration by 43.3 % ( p < 0.05 ) for both cohorts ( C1 INH and placebo ) associated with PP , although exogenous C1 INH – treated patients achieved supraphysiological levels throughout . This new finding suggests that C1 INH replacement may be useful in the treatment of AMR We report 1‐year outcomes of a r and omized study of Rituximab versus st and ard‐of‐care immunosuppression ( Thymoglobulin and /or pulse steroids ) for treatment of biopsy confirmed , acute transplant rejection with B‐cell infiltrates , in 20 consecutive recipients ( 2–23 years ) . Graft biopsies , with Banff and CADI scores , CD20 and C4d stains , were performed at rejection and 1 and 6 months later . Peripheral blood CMV , EBV and BK viral loads , graft function , DSA , immunoglobulins , serum humanized antichimeric antibody ( HACA ) and Rituximab , and lymphocyte counts were monitored until 1 year posttreatment . Rituximab infusions were given with a high index of safety without HACA development and increased infections complications  . Rituximab therapy result ed in complete tissue B‐cell depletion and rapid peripheral B‐cell depletion . Peripheral CD19 cells recovered at a mean time of ∼12 months . There were some benefits for the recovery of graft function ( p = 0.026 ) and improvement of biopsy rejection scores at both the 1‐ ( p = 0.0003 ) and 6‐month ( p < 0.0001 ) follow‐up biopsies . Reappearance of C4d deposition was not seen on follow‐up biopsies after Rituximab therapy , but was seen in 30 % of control patients . There was no change in DSA in either group , independent of rejection resolution . This study reports safety and suggests further investigation of Rituximab as an adjunctive treatment for B‐cell‐mediated graft rejection Antibody‐mediated rejection ( AMR ) frequently causes refractory graft dysfunction . This r and omized controlled trial was design ed to evaluate whether immunoadsorption ( IA ) is effective in the treatment of  severe C4d‐positive AMR . Ten out of 756 kidney allograft recipients were included . Patients were r and omly assigned to IA with protein A ( N = 5 ) or no such treatment ( N = 5 ) with the option of IA rescue after 3 weeks . Enrolled recipients were subjected to tacrolimus conversion and , if indicated , ‘ anti‐cellular ’ treatment . All IA‐treated patients responded to treatment . One death unrelated to IA occurred after successful reversal of rejection . Four control subjects remained dialysis‐dependent . With the exception of one patient who developed graft necrosis , non‐responders were subjected to rescue IA , however , without success . Because of a high graft loss rate in the control group the study was terminated after a first interim analysis . Even though limited by small patient numbers , this trial suggests efficiency of IA in reversing severe AMR Background Treatment of acute antibody-mediated rejection ( AMR ) is based on a combination of plasma exchange ( PE ) , IVIg , corticosteroids ( CS ) , and rituximab , but the place of rituximab is not clearly specified in the absence of r and omized trials . Methods In this phase III , multicenter , double-blind , placebo-controlled trial , we r and omly assigned patients with biopsy-proven AMR to receive rituximab ( 375 mg/m2 ) or placebo at day 5 . All patients received PE , IVIg , and CS . The primary endpoint was a composite of graft loss or no improvement in renal function at day 12 . Results Among the 38 patients included , at 1 year , no deaths occurred , but 1 graft loss occurred in each group . The primary endpoint frequency was 52.6 % ( 10/19 ) and 57.9 % ( 11/19 ) in the rituximab and placebo groups , respectively ( P = 0.744 ) . Renal function improved in both groups , as soon as day 12 with no difference in serum creatinine level and proteinuria at 1 , 3 , 6 , and 12 months . Supplementary administration of rituximab and total number of IVIg and PE treatments did not differ between the 2 groups . Both groups showed improved histological features of AMR and Banff scores at 1 and 6 months , with no significant difference between groups but with a trend in favor of the rituximab group . Both groups showed decreased mean fluorescence intensity of donor-specific antibodies as soon as day 12 , with no significant 
    Output:
    
Plasmapheresis and IVIG were used as st and ard-of-care in recent studies , and to this combination , rituximab seemed to add little or no benefit .
Conclusion Newer studies evaluating rituximab showed little or no difference to early graft survival , and the efficacy of bortezomib and complement inhibitors for the treatment of AMR remains unclear .
Despite the evidence uncertainty , plasmapheresis and IVIG have become st and ard-of-care for the treatment of acute AMR