Faculty Bibliography

Purpose of Review/UNASSIGNED:Over the past two decades, significant strides made in our understanding of the etiology of antibody-mediated rejection (AMR) in transplantation have put the complement system in the spotlight. Here, we review recent progress made in the field of pharmacologic complement inhibition in clinical transplantation and aim to understand the impact of this therapeutic approach on outcomes in transplant recipients. Recent Findings/UNASSIGNED:Encouraged by the success of agents targeting the complement cascade in disorders of unrestrained complement activation like paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS), investigators are testing the safety and efficacy of pharmacologic complement blockade in mitigating allograft injury in conditions ranging from AMR to recurrent post-transplant aHUS, C3 glomerulopathies and antiphospholipid anti-body syndrome (APS). A recent prospective study demonstrated the efficacy of terminal complement inhibition with eculizumab in the prevention of acute AMR in human leukocyte antigen (HLA)-incompatible living donor renal transplant recipients. C1 esterase inhibitor (C1-INH) was well tolerated in two recent studies in the treatment of AMR and was associated with improved renal allograft function. Summary/UNASSIGNED:Pharmacologic complement inhibition is emerging as valuable therapeutic tool, especially in the management of highly sensitized renal transplant recipients. Novel and promising agents that target various elements in the complement cascade are in development. Graphical Abstractá…Ÿ.

Antibody-mediated rejection (AMR) is typically treated with plasmapheresis (PP) and intravenous immunoglobulin (standard of care; SOC); however, there is an unmet need for more effective therapy. We report a phase 2b, multicenter double-blind randomized 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.

BACKGROUND:Immunoglobulin (Ig)A nephropathy is the most common primary glomerulonephritis worldwide, with a high recurrence rate after kidney transplantation. The aim of this study was to assess allograft survival, impact of recurrence on allograft function, and risk factors for post-transplant IgA recurrence. METHODS:We identified 104 patients with IgA nephropathy who underwent kidney transplantation at our center between 1993 and 2014. Fourteen patients underwent more than one allograft. RESULTS:IgA recurrence was documented in 23 (19%) allografts. Median time to recurrence was 6.75 years (interquartile range, 1.4-9.2 years). Twelve of the 23 recurrences were from living related donors (P = .07), and those with younger age at transplantation (37.7 ± 2.3 vs 44 ± 1.3, P = .05) were at higher risk of recurrence. Mean allograft survival was reduced in those with recurrence (6.5 ± 5.1 years) compared with those without recurrence (10.4 ± 7.5 years). At 6 years after transplant, allograft failure was documented in 52% of the recurrence group compared with 10% in the non-recurrence group (P = .002). CONCLUSIONS:IgA recurrence after transplant is an important cause of allograft loss. Living related donors and younger age at transplantation are associated with high recurrence rate. Close monitoring and treatment of recurrence are crucial.

Patients requiring desensitization prior to renal transplantation are at risk for developing severe antibody-mediated rejection (AMR) refractory to treatment with plasmapheresis and intravenous immunoglobulin (PP/IVIg). We have previously reported success at graft salvage, long-term graft survival and protection against transplant glomerulopathy with the use of eculizumab and splenectomy in addition to PP/IVIg. Splenectomy may be an important component of this combination therapy and is itself associated with a marked reduction in donor-specific antibody (DSA) production. However, splenectomy represents a major operation, and some patients with severe AMR have comorbid conditions that substantially increase their risk of complications during and after surgery. In an effort to spare recipients the morbidity of a second operation, we used splenic irradiation in lieu of splenectomy in two incompatible live donor kidney transplant recipients with severe AMR in addition to PP/IVIg, rituximab and eculizumab. This novel approach to the treatment of severe AMR was associated with allograft salvage, excellent graft function and no short- or medium-term adverse effects of the radiation therapy. One-year surveillance biopsies did not show transplant glomerulopathy (tg) on light microscopy, but microcirculation inflammation and tg were present on electron microscopy.

Transplantation is now lifesaving therapy for patients with end stage organ failure but requires lifelong immunosuppression with resultant morbidity. Current immunosuppressive strategies inhibit T cell activation and prevent donor-recipient engagement. Therefore, it is not surprising that few host cells are demonstrated in donor grafts. However, our recent small animal studies found large numbers of recipient stem cells present after transplant and pharmacological mobilization resulting in a chimeric, repopulated organ. We now confirm these findings in a well characterized large animal preclinical model. Here we show that AMD3100 (A) and FK506 (F) mobilization of endogenous stem cells immediately post kidney transplant combined with repeat therapy at 1, 2, and 3 months led to drug free long term survival in maximally immunologically mismatched swine. Three long term recipients have stable chimeric transplants, preserved anti-donor skin graft responses, and normal serum creatinine despite withdrawal of all medication for 3 years

Transplant tolerance allowing the elimination of life long immunosuppression has been the goal of research for 60 years. The induction of mixed chimerism has shown promise and has been successfully extended to large animals and the clinic. However, it remains cumbersome and requires heavy early immunosuppression. Here, we report that 4 injections of AMD3100 (A), a CXCR-4 antagonist, plus 8 injections of low-dose FK506 (F, 0.05mg/kg/day) first week after kidney transplantation extended survival, but death from renal failure occurred at 30-90 days. Repeating the same course of A and F at 1, 2 and 3 months after transplant resulted in 92% allograft acceptance (n=12) at 7 months, normal kidney function and histology with no further treatment. Transplant acceptance was associated with the influx of host stem cells resulting in a hybrid kidney and a modulated host immune response. Confirmation of these results could initiate a paradigm shift in post-transplant therapy