Faculty Bibliography

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 & AIMS:Treatment of Crohn's disease (CD) may require multiple bowel resections that lead to short bowel syndrome. Intestinal transplantation is an effective treatment for short bowel syndrome, but limited data are available on long-term outcomes in CD. We aimed to characterize the long-term risk of rejection, graft failure, and death among patients with CD after intestinal transplantation, and compare their outcomes with those of patients without CD. METHODS:We performed a retrospective study of adults in the Scientific Registry of Transplant Recipients who received intestinal transplants in the United States from May 1990 through June 2014. Outcomes data were collected at 3 months, 6 months, 1 year, and every year after the procedure. We compared risks of rejection at 1 year after transplantation between patients with and without CD using the chi-square test and logistic regression. Longitudinal risks of graft failure and death were compared between patients with and without CD using the Kaplan-Meier method and Cox proportional hazards. Multivariable analyses adjusted for recipient, donor, and institutional characteristics. RESULTS:Of 1115 cases of intestinal transplantation, 142 were performed for CD and 973 for non-CD indications. One year after the procedure, the transplant was rejected in 36.9% of patients with CD and 33.3% of patients without CD (P = .48). For patients with CD, the actuarial risk of graft failure at 1, 5, and 10 years after intestinal transplantation was 18.6%, 38.7%, and 49.2%; the risk of death was 22.5%, 50.3%, and 59.7%, respectively. The risk of graft failure was greater for patients with CD (adjusted hazard ratio [aHR], 1.48; 95% CI, 1.03-2.13; P = .04), but patients with versus without CD had similar risks of death (aHR, 0.88; 95% CI, 0.64-1.20; P = .41). In subgroup analyses, the risk of graft failure was increased among patients with CD undergoing transplantation between 1990 and 2000 (aHR, 3.49; 95% CI, 1.23-9.92; P = .02), but not after 2000 (aHR, 1.37; 95% CI, 0.92-2.04; P = .12). CONCLUSIONS:In an analysis of patients who received intestinal transplants, the risks of graft rejection or death were similar between patients with versus without CD. Before year 2000, patients with CD had an increased risk of graft failure, but not thereafter. Changes in posttransplant immunosuppression around the same time might be analyzed to learn more about the mechanisms and management strategies to reduce graft failure in CD.

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.

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.

There is an increased risk of acute rejection (AR) in human immunodeficiency virus-positive (HIV+) kidney transplant (KT) recipients. Induction immunosuppression is standard of care for those at high risk of AR; however, use in HIV+ patients is controversial, given fears of increased infection rates. We sought to compare clinical outcomes between HIV+ KT recipients who were treated with (i) anti-thymocyte globulin (ATG), (ii) IL-2 receptor blocker, and (iii) no induction. We studied 830 HIV+ KT recipients between 2000 and 2014, as captured in the Scientific Registry of Transplant Recipients, and compared rates of delayed graft function (DGF), AR, graft loss and death. Infections and hospitalizations were ascertained by International Classification of Diseases, Ninth Revision codes in a subset of 308 patients with Medicare. Compared with no induction, neither induction agent was associated with an increased risk of infection (weighted hazard ratio [wHR] 0.80, 95% confidence interval [CI] 0.55-1.18). HIV+ recipients who received induction spent fewer days in the hospital (weighted relative risk [wRR] 0.70, 95% CI 0.52-0.95), had lower rates of DGF (wRR 0.66, 95% CI 0.51-0.84), less graft loss (wHR 0.47, 95% CI 0.24-0.89) and a trend toward lower mortality (wHR 0.60, 95% CI 0.24-1.28). Those who received induction with ATG had lower rates of AR (wRR 0.59, 95% CI 0.35-0.99). Induction in HIV+ KT recipients was not associated with increased infections; in fact, those receiving ATG, the most potent agent, had the lowest rates. In light of the high risk of AR in this population, induction therapy should be strongly considered.

BACKGROUND: Recent evidence suggests that living kidney donors are at an increased risk of end-stage renal disease. However, predicting which donors will have renal dysfunction remains challenging, particularly among those with no clinical evidence of disease at the time of donation. Although renal biopsies are not routinely performed as part of the donor evaluation process, they may yield valuable information that improves the ability to predict renal function in donors. METHODS: We used implantation protocol biopsies to evaluate the association between histological abnormalities in the donated kidney and postdonation renal function (estimated glomerular filtration rate, eGFR) of the remaining kidney in living kidney donors. Longitudinal analysis using mixed-effects linear regression was used to account for multiple eGFR measures per donor. RESULTS: Among 310 donors between 1997 and 2012, median (IQR) follow-up was 6.2 (2.5-8.7; maximum 14.0) years. In this cohort, the overall prevalence of histological abnormalities was 65.8% (19.7% abnormal glomerulosclerosis, 23.9% abnormal interstitial fibrosis and tubular atrophy (IFTA), 4.8% abnormal mesangial matrix increase, 32.0% abnormal arteriolar hyalinosis, and 32.9% abnormal vascular intimal thickening). IFTA was associated with a 5-mL/min/1.73 m decrease of postdonation eGFR after adjusting for donor age at donation, sex, race, preoperative systolic blood pressure, preoperative eGFR, and time since donation (P < 0.01). CONCLUSIONS: In this single-center study, among healthy individuals cleared for living donation, IFTA was associated with decreased postdonation eGFR, whereas no other subclinical histological abnormalities provided additional information.

The infrequent use of ABO-incompatible (ABOi) kidney transplantation in the United States may reflect concern about the costs of necessary preconditioning and posttransplant care. Medicare data for 26 500 live donor kidney transplant recipients (2000 to March 2011), including 271 ABOi and 62 A2-incompatible (A2i) recipients, were analyzed to assess the impact of pretransplant, transplant episode and 3-year posttransplant costs. The marginal costs of ABOi and A2i versus ABO-compatible (ABOc) transplants were quantified by multivariate linear regression including adjustment for recipient, donor and transplant factors. Compared with ABOc transplantation, patient survival (93.2% vs. 88.15%, p = 0.0009) and death-censored graft survival (85.4% vs. 76.1%, p < 0.05) at 3 years were lower after ABOi transplant. The average overall cost of the transplant episode was significantly higher for ABOi ($65 080) compared with A2i ($36 752) and ABOc ($32 039) transplantation (p < 0.001), excluding organ acquisition. ABOi transplant was associated with high adjusted posttransplant spending (marginal costs compared to ABOc - year 1: $25 044; year 2: $10 496; year 3: $7307; p < 0.01). ABOi transplantation provides a clinically effective method to expand access to transplantation. Although more expensive, the modest increases in total spending are easily justified by avoiding long-term dialysis and its associated morbidity and cost.