Factors at de novo donorâ specific antibody initial detection associated with allograft loss: a multicenter study

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/149234/1/tri13395-sup-0001-FigS1.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/149234/2/tri13395_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/149234/3/tri13395.pd

Agent Orange and long-term outcomes after radical prostatectomy

PurposeTo investigate the association between Agent Orange (AO) exposure and long-term prostate cancer (PC) outcomes.Material and methodsData from 1,882 men undergoing radical prostatectomy for PC between 1988 and 2011 at Veterans Affairs Health Care Facilities were analyzed from the Shared Equal Access Regional Cancer Hospital database. Men were stratified by AO exposure (binary). Associations between AO exposure and biopsy and pathologic Gleason sum (GS) and pathologic stage were determined by logistic regression models adjusted for preoperative characteristics. Hazard ratios for biochemical recurrence (BCR), secondary treatment, metastases, and PC-specific mortality were determined by Cox models adjusted for preoperative characteristics.ResultsThere were 333 (17.7%) men with AO exposure. AO-exposed men were younger (median 59 vs. 62 y), had lower preoperative prostate-specific antigen levels (5.8 vs. 6.7 ng/ml), lower clinical category (25% vs. 38% palpable), and higher body mass index (28.2 vs. 27.6 kg/m(2)), all P<0.01. Biopsy GS, pathologic GS, positive surgical margins, lymph node positivity, and extracapsular extension did not differ with AO exposure. At a median follow-up of 85 months, 702 (37.4%) patients had BCR, 603 (32.2%) patients received secondary treatment, 78 (4.1%) had metastases, and 39 (2.1%) died of PC. On multivariable analysis, AO exposure was not associated with BCR, secondary treatment, metastases, or PC mortality.ConclusionsAO exposure was not associated with worse preoperative characteristics such as elevated prostate-specific antigen levels or biopsy GS nor with BCR, secondary treatment, metastases, or PC death. Thus, as data on AO-exposed men mature, possible differences in PC outcomes observed previously are no longer apparent

The Potential of MicroRNAs as Novel Biomarkers for Transplant Rejection

The control of gene expression by microRNAs (miRNAs, miR) influences many cellular functions, including cellular differentiation, cell proliferation, cell development, and functional regulation of the immune system. Recently, miRNAs have been detected in serum, plasma, and urine and circulating miR profiles have been associated with a variety of diseases. Rejection is one of the major causes of allograft failure and preventing and treating acute rejection are the central task for clinicians working with transplant patients. Invasive biopsies used in monitoring rejection are burdensome and risky to transplant patients. Novel and easily accessible biomarkers of acute rejection could make it possible to detect rejection earlier and make more fine-tuned calibration of immunosuppressive or new target treatment possible. In this review, we discuss whether circulating miRNA can serve as an early noninvasive diagnostic biomarker and an expression fingerprint of allograft rejection and transplant failure. Understanding the regulatory interplay of relevant miRNAs and the rejecting allograft will result in a better understanding of the molecular pathophysiology of alloimmune injury

The Potential of MicroRNAs as Novel Biomarkers for Transplant Rejection

The control of gene expression by microRNAs (miRNAs, miR) influences many cellular functions, including cellular differentiation, cell proliferation, cell development, and functional regulation of the immune system. Recently, miRNAs have been detected in serum, plasma, and urine and circulating miR profiles have been associated with a variety of diseases. Rejection is one of the major causes of allograft failure and preventing and treating acute rejection are the central task for clinicians working with transplant patients. Invasive biopsies used in monitoring rejection are burdensome and risky to transplant patients. Novel and easily accessible biomarkers of acute rejection could make it possible to detect rejection earlier and make more fine-tuned calibration of immunosuppressive or new target treatment possible. In this review, we discuss whether circulating miRNA can serve as an early noninvasive diagnostic biomarker and an expression fingerprint of allograft rejection and transplant failure. Understanding the regulatory interplay of relevant miRNAs and the rejecting allograft will result in a better understanding of the molecular pathophysiology of alloimmune injury

Factors at de novo donor-specific antibody initial detection associated with allograft loss: a multicenter study

We aimed to evaluate patient factors including nonadherence and viral infection and de novo donor-specific antibody (dnDSA) characteristics [total immunoglobulin G (IgG), C1q, IgG3, and IgG4] as predictors of renal allograft failure in a multicenter cohort with dnDSA. We performed a retrospective observational study of 113 kidney transplant recipients with dnDSA and stored sera for analysis. Predictors of death-censored allograft loss were assessed by Cox proportional modeling. Death-censored allograft survival was 77.0% (87/113) during a median follow-up of 2.2 (IQR 1.2-3.7) years after dnDSA detection. Predictors of allograft failure included medication nonadherence [HR 6.5 (95% CI 2.6-15.9)], prior viral infection requiring immunosuppression reduction [HR 5.3 (95% CI 2.1-13.5)], IgG3 positivity [HR 3.8 (95% CI 1.5, 9.3)], and time post-transplant (years) until donor-specific antibody (DSA) detection [HR 1.2 (95% CI 1.0, 1.3)]. In the 67 patients who were biopsied at dnDSA detection, chronic antibody-mediated rejection [HR 11.4 (95% CI 2.3, 56.0)] and mixed rejection [HR 7.4 (95% CI 2.2, 24.8)] were associated with allograft failure. We conclude that patient factors, including a history of viral infection requiring immunosuppression reduction or medication nonadherence, combined with DSA and histologic parameters must be considered to understand the risk of allograft failure in patients with dnDSA

Donor-specific Antibodies, Immunoglobulin-free Light Chains, and BAFF Levels in Relation to Risk of Late-onset PTLD in Liver Recipients

Posttransplant lymphoproliferative disorder (PTLD) is a neoplastic complication of transplantation, with early cases largely due to immunosuppression and primary Epstein-Barr virus infection. Etiology may differ for later-onset cases, but the contributions of immunosuppression, immune reactivity to the donor organ, and chronic B cell activation are uncertain. We conducted a case-control study of late-onset PTLD (diagnosed >1 year posttransplant) in a cohort of liver recipients. We assessed serum samples (obtained >6 months before diagnosis in cases) from N = 60 cases and N = 166 matched controls for donor-specific antibodies (DSAs, evaluable for N = 221 subjects), immunoglobulin kappa and lambda free light chains (FLCs, N = 137), and B cell activating factor (BAFF, N = 226). Conditional or unconditional logistic regression was used to calculate adjusted odds ratios (aORs). Circulating DSAs were less common in PTLD cases than controls (18% vs 30%), although this difference was borderline significant (aOR, 0.51; 95% confidence interval [CI], 0.24-1.10; = 0.09). Donor-specific antibodies against class II HLA antigens predominated and likewise showed a borderline inverse association with PTLD (aOR, 0.58; 95% CI, 0.27-1.24). The FLC levels were less frequently abnormal in cases than controls, but measurements were available for only a subset and confidence intervals were wide (elevated kappa: aOR, 0.57; 95% CI, 0.15-2.12; = 0.40; elevated lambda: aOR, 0.68; 95% CI, 0.30-1.50; = 0.34). B cell-activating factor levels were not associated with PTLD. Our results suggest that circulating DSAs are associated with decreased risk of late-onset PTLD. Because DSAs may develop in the setting of underimmunosuppression, the inverse association with DSAs supports a role for immunosuppression in the etiology of late-onset PTLD

Prevalence and Clinical Impact of Donor-Specific Alloantibody Among Intestinal Transplant Recipients

BackgroundRejection remains the leading cause of allograft loss, and a major barrier to improving long-term outcomes after intestinal transplantation. Our aim is to define the prevalence and investigate the role of donor-specific antibody (DSA) on intestinal graft outcomes.MethodsThe study includes 109 transplants performed in 95 recipients at a single center. Patients were screened for DSA pretransplant, monitored regularly posttransplant and when clinically indicated using the single-antigen bead Luminex assay. Standard induction immunosuppression was with interleukin-2 receptor antagonists, and antithymocyte globulin in high-risk recipients. Maintenance regimens were tacrolimus-based.ResultsPretransplant DSA was detected in 12 (11%) recipients with 50% continuing to have circulating antibodies posttransplant. An additional 24 (25%) patients developed de novo DSA, and of these, 71% had persistent antibodies. Recipients with preformed DSA demonstrated elevated risks of early graft failure, whereas those with de novo DSA experienced accelerated graft loss once DSA was detected, reaching a 28% failure rate within 2 years. HLA-DQ mismatch is a significant risk factor for de novo DSA emergence, whereas the persistence of antibodies is predicted by DSA strength and specificity. Although inclusion of the liver in the intestinal allograft imparts an immunological advantage against rejection-related graft loss, this protective effect was lost among recipients with persistent DSA.ConclusionsThe presence of DSA is associated with inferior graft outcomes among intestinal transplant recipients. An enhanced understanding of the mechanisms by which DSA causes allograft injury, and effective strategies targeting humoral immune reactivity are needed to improve long-term intestinal graft outcomes

Incidence and impact of de novo donor-specific alloantibody in primary renal allografts,”

Background. To date, limited information is available describing the incidence and impact of de novo donor-specific antiYhuman leukocyte antigen (HLA) antibodies (dnDSA) in the primary renal transplant patient. This report details the dnDSA incidence and actual 3-year post-dnDSA graft outcomes. Methods. The study includes 189 consecutive nonsensitized, non-HLA-identical patients who received a primary kidney transplant between March 1999 and March 2006. Protocol testing for DSA via LABScreen single antigen beads (One Lambda) was done before transplantation and at 1, 3, 6, 9, and 12 months after transplantation then annually and when clinically indicated. Results. Of 189 patients, 47 (25%) developed dnDSA within 10 years. The 5-year posttransplantation cumulative incidence was 20%, with the largest proportion of patients developing dnDSA in the first posttransplantation year (11%). Young patients (18Y35 years old at transplantation), deceased-donor transplant recipients, pretransplantation HLA (non-DSA)Ypositive patients, and patients with a DQ mismatch were the most likely to develop dnDSA. From DSA appearance, 9% of patients lost their graft at 1 year. Actual 3-year death-censored post-dnDSA graft loss was 24%. Conclusion. We conclude that 11% of the patients without detectable DSA at transplantation will have detectable DSA at 1 year, and over the next 4 years, the incidence of dnDSA will increase to 20%. After dnDSA development, 24% of the patients will fail within 3 years. Given these findings, future trials are warranted to determine if treatment of dnDSA-positive patients can prevent allograft failure