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Background: Current treatments for antibody-mediated rejection (AMR) in kidney transplantation are based on low-quality data from a small number of controlled trials. Novel agents targeting B cells, plasma cells, and the complement system have featured in recent studies of AMR., Methods: We conducted a systematic review and meta-analysis of controlled trials in kidney transplant recipients using Medline, EMBASE, and CENTRAL from inception to February 2017., Results: Of 14 380 citations, we identified 21 studies, including 10 randomized controlled trials, involving 751 participants. Since the last systematic review conducted in 2011, we found nine additional studies evaluating plasmapheresis + intravenous immunoglobulin (IVIG) (two), rituximab (two), bortezomib (two), C1 inhibitor (two), and eculizumab (one). Risk of bias was serious or unclear overall and evidence quality was low for the majority of treatment strategies. Sufficient RCTs for pooled analysis were available only for antibody removal, and here there was no significant difference between groups for graft survival (HR 0.76; 95% CI 0.35-1.63; P = 0.475). Studies showed important heterogeneity in treatments, definition of AMR, quality, and follow-up. Plasmapheresis and IVIG were used as standard-of-care in recent studies, and to this combination, rituximab seemed to add little or no benefit. Insufficient data are available to assess the efficacy of bortezomib and complement inhibitors., 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 standard-of-care for the treatment of acute AMR.

Encapsulating peritoneal sclerosis (EPS) is a rare complication of peritoneal dialysis (PD) that carries a high morbidity and mortality. The 'two hit theory' suggests that long term deterioration of the peritoneum combined with intraperitoneal inflammation is needed in the pathogenesis of EPS. For unclear reasons, post transplantation EPS is being increasingly reported in patients previously on PD. To date, there is no proven effective therapy with an absence of randomised controlled trials. Individual case reports and small case series have reported on the use of tamoxifen and corticosteroids for medical management of EPS. The use of everolimus has been reported in a single case, and never in the setting of renal transplantation. Here, we present the first case of post-transplant encapsulating peritoneal sclerosis treated successfully with a combination of everolimus, tamoxifen, low dose corticosteroid and surgery., (© 2014 Asian Pacific Society of Nephrology.)

Background: Use of the mTOR inhibitor (mTORi) sirolimus to replace calcineurin inhibitors in kidney transplantation has been associated with improved renal function but, in a proportion of cases, also with de novo or exacerbated proteinuria. Experimental deficiency of vascular endothelial growth factor (VEGF) induces proteinuria and mTOR is required for VEGF production and signalling. We therefore explored the impact of sirolimus on the development of chronic allograft dysfunction (CAD) in the rat, with a focus on VEGF biology., Methods: Lewis rats received F344 kidney allografts and were treated with 24 weeks of cyclosporine or sirolimus. Controls included allografts treated with cyclosporine for 10 days only and isografts treated with cyclosporine or sirolimus for 24 weeks. Kidney injury (proteinuria and histology) and expression of VEGF and VEGF-receptor (VEGFR; immunohistochemistry, laser capture micro-dissection and quantitative RT-PCR) were assessed., Results: Allograft controls developed proteinuria, tubulointerstitial fibrosis and atrophy, glomerulosclerosis, vasculopathy and leucocyte accumulation. Proteinuria was significantly reduced in both treatment groups but significantly more in cyclosporine treated animals. Tubulointerstitial damage, glomerulosclerosis and leucocyte accumulation were significantly attenuated in both treatment groups; however, vasculopathy was reduced only by sirolimus. Significantly diminished expression of VEGF and VEGFR mRNA and protein was evident in the sirolimus group. In vitro, sirolimus reduced VEGF production by podocytes (P < 0.05) and inhibited VEGF-induced proliferation of podocytes, endothelial and mesangial cells., Conclusions: Cyclosporine and sirolimus retard development of CAD in this rat model. Sirolimus exhibits greater protection against vasculopathy but induces proteinuria; effects are likely to be related to inhibition of VEGF signalling.

Interleukin-18 (IL-18), a product of dendritic cells (DC), is a pro-inflammatory cytokine involved in the pathogenesis of allograft rejection, vascular disease, arthritis and diabetes. Rapamycin (Rapa) is an immunosuppressant that inhibits T cell mTOR kinase activation. In contrast, Sanglifehrin A (SFA), is a cyclophilin-binding immunosuppressant that does not act on calcineurin phosphatases but appears to inhibit IL-2-dependent T cell proliferation. Rapa and SFA exert some immunosuppressive effects on DC by inhibiting IL-12 production, although their effects on DC have not been investigated as comprehensively as those on T cells. We aimed to determine the impact of these drugs on DC IL-18 synthesis in vivo and in vitro. We found in vivo that LPS-stimulated OX62(+) DC produced significantly more IL-18 mRNA, compared to OX62(+) DC depleted splenocytes (p<0.01) and non-LPS-stimulated OX62(+) DC (p<0.01). OX62(+)CD4(+) and OX62(+)CD4(-) cells produced similar amounts of IL-18 mRNA. Rapa and SFA, but not CsA, significantly inhibited IL-18 production from OX62(+) DC in vitro, in a dose-dependent manner (p<0.05). In vivo IL-18 production was also inhibited by Rapa and SFA in splenic OX62(+) DC (p<0.01). Finally, inhibition of IL-18 production by Rapa and SFA was independent of the FK506 or cyclophilin pathways, respectively. In conclusion, Rapa and SFA, but not CsA, block IL-18 production and this novel Rapa blockade effect on IL-18 may contribute to the ability of Rapa to inhibit chronic allograft nephropathy and restenosis.