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Acute antibody-mediated rejection (AMR) is mediated by the activation of the classical complement system in addition to noncomplement-dependent inflammatory pathways. Complement fixation by donor-specific antibodies leads to cleavage of the complement proteins C4, C3, and C5 to produce multiple complement split-products (CSP) and the end-effector membrane attack complex, C5b-9. In this study, we investigate CSP as potential biomarkers for AMR.In an Institutional Review Board-approved, prospective, controlled study, CSP levels were measured in blood and urine samples from consecutive kidney transplant recipients with biopsy-proven AMR (n = 10), acute cellular rejection (ACR) (n = 5), or no rejection (n = 5). After obtaining informed consent, samples were collected at the time of biopsy (day 0) and days 15 (end of rejection treatment) and 30 postbiopsy for AMR and ACR patients. ELISA was used to measure C5a, C4d, and soluble C5b-9 concentrations in blood and urine, in addition to factor Bb (Bb) concentration in blood only. Kidney transplant histopathology was evaluated using the Banff 2013 classification. Rejection treatment and follow-up were performed per standard of care.Blood and urine CSP levels adjusted to urine creatinine were not elevated in AMR compared to no rejection and ACR arms. There was significant variability in CSP concentration within each of the study groups.Our study does not support the utility of CSP as surrogate biomarkers of AMR; however, it is limited by the small sample size and larger studies may be warranted.

Acute kidney injury (AKI) is common in kidney transplant recipients. In addition to the usual causes of AKI in native kidneys, certain features and risk factors are unique to kidney allografts. In this article, we will present an overview of the common transplant-specific AKI etiologies that include increased susceptibility to hemodynamic-mediated AKI, acute rejection, medication-induced AKI, recurrence of native kidney disease, infections, urinary tract obstruction, vascular thrombosis and post-transplant lymphoproliferative disorder. AKI is independently associated with allograft loss and patient mortality. It is, therefore, prudent for transplant centers to address it as a major quality measure.

Reduction in donor-specific antibody (DSA) has been associated with improved renal allograft survival after antibody-mediated rejection (AMR). These observations have not been separately analyzed for early and late AMR and mixed acute rejection (MAR). The purpose of this study was to evaluate long-term responses to proteasome inhibitor-based therapy for 4 rejection phenotypes and to determine factors that predict allograft survival.Retrospective cohort study evaluating renal transplant recipients with first AMR episodes treated with proteasome inhibitor-based therapy from January 2005 to July 2015.A total of 108 patients were included in the analysis. Immunodominant DSA reduction at 14 days differed significantly (early AMR 79.6%, early MAR 54.7%, late AMR 23.4%, late MAR 21.1%, P0.001). Death-censored graft survival (DCGS) differed at 3 years postrejection (early AMR 88.3% versus early MAR 77.8% versus late AMR 56.7% versus late MAR 54.9%, P = 0.02). Multivariate analysis revealed that immunodominant DSA reduction50% at 14 days was associated with improved DCGS (odds ratio, 0.12, 95% CI, 0.02-0.52, P = 0.01).In summary, significant differences exist across rejection phenotypes with respect to histological and DSA responses. The data suggest that DSA reduction may be associated with improved DCGS in both early and late AMR.

Background Classification of acute rejection (AR) based on etiology and timing may provide a means for enhancing therapeutic results and allograft survival. This study evaluated graft and patient survival after the first AR episodes among kidney transplant recipients with an early or late antibody-mediated rejection (AMR), acute cellular rejection (ACR) or mixed AR (MAR). Methods A prospective institutional review board-approved database was queried to identify biopsy-proven first AR episodes occurring from January 2005 to October 2012. The ACR was defined by Banff criteria; borderline AR was excluded. The AMR was defined as 3 of 4 criteria: renal dysfunction, donor specific antibody, C4d positivity on biopsy, and histological changes. The MAR met criteria for both ACR and AMR. Early AR occurred within six months post-transplant. AR episodes were then assigned to 1 of the 6 categories--early AMR, early ACR, early MAR, late AMR, late ACR, and late MAR. Results One hundred eighty-two kidney transplant recipients identified with a first AR episode. Mean follow-up was 773 days (± 715 days). No difference was observed in patient survival. Death-censored graft survival was 84%. Death-censored graft loss was higher with late versus early AMR (P = 0.01) and late versus early ACR (P = 0.03), but not late versus early MAR (P = 0.3). Conclusions The AR type demonstrated a hierarchy for graft survival with ACR better than MAR better than AMR, which persisted for both early and late AR. Improvement in long-term results of AR may require development of specific treatment for individual AR types.

Background Although several strategies for treating early antibody-mediated rejection (AMR) in kidney transplants have been investigated, evidence on treatment of late AMR manifesting after 6 months is sparse. In this single-center series, we present data on 23 consecutive patients treated for late AMR. Methods Late AMR was diagnosed using Banff 2007 criteria along with presence of donor-specific antibodies (DSA) and acute rise in serum creatinine (SCr). Response to therapy was assessed by improvement in SCr, histologic improvement, and decline in DSA strength. Results Overall, 17% (4/23) had documented nonadherence while 69% (16/23) had physician-recommended reduction in immunosuppression before AMR. Eighteen patients (78%) were treated with plasmapheresis or low-dose IVIg+rituximab; 11 (49%) with refractory AMR also received one to three cycles of bortezomib. While there was an improvement (P=0.02) in mean SCr (2.4 mg/dL) at the end of therapy compared with SCr at the time of diagnosis (2.9 mg/dL), this improvement was not sustained at most recent follow-up. Eleven (48%) patients had no histologic resolution on follow-up biopsy. Lack of histologic response was associated with older patients (odds ratio [OR]=3.17; P=0.04), presence of cytotoxic DSA at time of diagnosis (OR=200; P=0.04), and severe chronic vasculopathy (cv≥2) on index biopsy (OR=50; P=0.06). Conclusions A major setting in which late AMR occurred in our cohort was reduction or change in immunosuppression. Our data demonstrate an inadequate response of late AMR to current and novel (bortezomib) therapies. The benefits of therapy need to be counterweighed with potential adverse effects especially in older patients, large antibody loads, and chronic allograft vasculopathy.

More than half of the kidney transplant candidates awaiting transplantation are sensitized to human leukocyte antigens (HLAs). Desensitization to HLAs involves treatment with immunomodulating therapies designed to reduce levels of anti-HLA antibodies in order to make kidney transplantation possible. Over the last two decades, desensitization therapies have been limited to plasmapheresis (PP), immunoadsorption (IA), intravenous immunoglobulins (IVIg), and rituximab. Review of reported experiences with desensitization in kidney transplant candidates revealed that PP or IA alone is inadequate to achieve durable reductions in HLA antibodies. Increasing evidence has accumulated indicating that high-dose IVIg has limited ability to reduce HLA antibodies, but a few centers have reported success with high-dose IVIg+rituximab in non-randomized trials. Overall experience in multiple centers, however, has shown high antibody-mediated rejection (AMR) rates, particularly in patients with the highest degrees of HLA sensitization. Low-dose IVIg combined with alternate day PP in living donor transplant candidates has been shown to provide enhanced survival over dialysis. However, low-dose IVIg/PP regimens also continue to be associated with unacceptable AMR rates. Recent experiences with plasma cell-targeted therapies based on the proteasome inhibitor bortezomib are relatively small but may represent an important alternative to non-deletional strategies with IVIg.

Background Histology remains a cornerstone for antibody-mediated rejection (AMR) diagnosis. Little data exist supporting histology for assessing therapeutic responses. This study evaluates histologic components in assessing AMR therapeutic responses. Methods Antibody-mediated rejection was diagnosed using Antibody Working Group criteria and Banff component scoring, and C4d staining data were analyzed. Statistics included independent and paired samples t test, χ(2), Fisher exact, or the Wilcoxon-signed rank test. Fifty-five AMR patients were analyzed. Early AMR was defined as occurring within 6 months after transplantation and treated with a single rituximab dose and 4 bortezomib doses preceded by plasmapheresis. Allograft biopsies were performed within 48 hours of treatment; repeat biopsy was performed 14 to 21 days later. Results Early AMR demonstrated histologic improvement in mean scores for acute Banff components glomerulitis (g), C4d, g+ peritubular capillaritis (ptc) and acute composite score, but showed deterioration in chronic Banff components tubular atrophy and interstitial fibrosis. Late AMR showed improved mean scores for acute Banff components tubulitis, interstitial inflammation, g, ptc, g + ptc, C4d, and acute composite score, but chronic scores did not change. Significant changes in distribution of Banff scores after treatment were observed for g, C4d, tubular atrophy, and interstitial fibrosis scores in early AMR patients and tubulitis, interstitial inflammation, g, ptc, and C4d in late AMR. Conclusions These results show that: (1) Banff component scoring provides insights into histologic responses to AMR therapy and may provide a potential endpoint for clinical AMR trials. (2) Early and late AMR demonstrate differences in acute and chronic Banff components at the time of the AMR diagnostic biopsy, as well as differential responses to AMR therapy.

BK polyomavirus mostly manifests as polyomavirus-associated nephropathy (PyVAN) in kidney transplant patients and polyoma virus-associated hemorrhagic cystitis (PyVHC) in bone marrow transplant patients. PyVHC in kidney transplant patients is only reported in four cases in the literature. Our patient had severe hemorrhagic cystitis without renal involvement. We postulate that our patient's exposure to ifosfamide and radiation 8 years prior transplantation might predispose him to this disease.

The endeavor to study desensitization in kidney transplantation hasn't been matched by an effort to investigate strategies to prevent sensitization. In this study (NCT02437422), we investigated the safety, impact on sensitization and pharmacokinetics of SANGUINATE (SG), a hemoglobin-based oxygen carrier, as a potential alternative to packed red blood cells (PRBC) in transplant candidates with end-stage renal disease (ESRD). Ten ESRD subjects meeting inclusion/exclusion (I/E) criteria were planned to receive 3 weekly infusions of SG (320mg/Kg). The study was stopped after 5 subjects were enrolled and their data was analyzed after completing a follow up period of 90 days. Two subjects had elevated troponin I levels in setting of SG infusion, one of which was interpreted as a non-ST elevation myocardial infarction. All other adverse events were transient. SG pharmacokinetic analysis showed mean(sd) Cmax, Tmax, AUC and half-life of 4.39(0.69)mg/ml, 2.42(0.91)hours, 171.86(52.35)mg.hour/ml and 40.60(11.96)hours respectively. None of the subjects developed new anti-HLA antibodies following SG infusion and throughout the study period. In conclusion, SG is a potential alternative to PRBCs in ESRD patients considered for kidney transplantation as it was not associated with humoral sensitization. Larger studies in highly sensitized patients are required to further evaluate for potential safety signals. This article is protected by copyright. All rights reserved.