Risk Of Allograft Loss Research Articles

Access to Waitlisting and Posttransplant Outcomes in Patients With Failed Kidney Allografts Secondary to Recurrent Glomerulonephritis.

Recurrent glomerulonephritis (GN) is an important cause of allograft loss after transplantation when GN is the primary cause of kidney failure. Retransplantation after allograft loss from recurrent disease requires careful consideration. We aimed to determine the probability of relisting and the risk of allograft loss after retransplantation in recipients with prior allograft loss from recurrent GN. Using data from the Australia and New Zealand Dialysis and Transplant Registry and multivariable Cox modeling, we compared the probability of waitlisting and allograft loss after second transplantation between those with and without prior allograft loss from recurrent disease. Of 3276 patients who received a second kidney transplant, 179 (5%) lost their first allograft from recurrent GN. Between 2006 and 2021, 1524 patients with failed first allografts (6% with recurrent GN, 45% with primary GN but no disease recurrence) were relisted for transplantation. Compared with patients without primary GN, the adjusted hazard ratios (95% confidence intervals) for relisting in patients with primary GN, with and without disease recurrence, were 1.09 (0.88-1.34) and 1.16 (1.05-1.29), respectively. The respective adjusted hazard ratios for allograft loss after repeat transplantation were 0.77 (0.59-1) and 1.02 (0.9-1.16). Of the 81 patients who received a second allograft after losing their first allograft to GN recurrence, 18 patients (22%) also lost their second allograft because of recurrent GN. Patients with prior allograft loss from GN recurrence were not disadvantaged, with comparable waitlist potential and allograft outcome after repeat transplantation. However, >20% of those with prior allograft loss from disease recurrence also lost their second allografts from recurrent disease.

Plasma NGAL levels in stable kidney transplant recipients and the risk of allograft loss.

The objective of this study was to investigate the utility of neutrophil gelatinase-associated lipocalin (NGAL) and calprotectin (CPT) to predict long-term graft survival in stable kidney transplant recipients (KTR). A total of 709 stable outpatient KTR were enrolled >2 months post-transplant. The utility of plasma and urinary NGAL (pNGAL, uNGAL) and plasma and urinary CPT at enrollment to predict death-censored graft loss was evaluated during a 58-month follow-up. Among biomarkers, pNGAL showed the best predictive ability for graft loss and was the only biomarker with an area under the curve (AUC)>0.7 for graft loss within 5 years. Patients with graft loss within 5 years (n=49) had a median pNGAL of 304 [interquartile range (IQR) 235-358] versus 182 (IQR 128-246) ng/mL with surviving grafts (P<.001). Time-dependent receiver operating characteristic analyses at 58 months indicated an AUC for pNGAL of 0.795, serum creatinine-based Chronic Kidney Disease Epidemiology Collaboration estimated glomerular filtration rate (eGFR) had an AUC of 0.866. pNGAL added to a model based on conventional risk factors for graft loss with death as competing risk (age, transplant age, presence of donor-specific antibodies, presence of proteinuria, history of delayed graft function) had a strong independent association with graft loss {subdistribution hazard ratio (sHR) for binary log-transformed pNGAL [log2(pNGAL)] 3.4, 95% confidence interval (CI) 2.24-5.15, P<.0001}. This association was substantially attenuated when eGFR was added to the model [sHR for log2(pNGAL) 1.63, 95% CI 0.92-2.88, P=.095]. Category-free net reclassification improvement of a risk model including log2(pNGAL) in addition to conventional risk factors and eGFR was 54.3% (95% CI 9.2%-99.3%) but C-statistic did not improve significantly. pNGAL was an independent predictor of renal allograft loss in stable KTR from one transplant center but did not show consistent added value when compared with baseline predictors including the conventional marker eGFR. Future studies in larger cohorts are warranted.

Programmed cell death ligand 1 expression associated with subtypes of post-transplant lymphoproliferative disorder among pediatric kidney transplant recipients.

Programmed cell death ligand 1 (PD-L1) expression on tumor cells engages the PD-1 receptor on T cells, inhibiting anti-tumor responses. PD-L1 has been detected in cases of post-transplant lymphoproliferative disorder (PTLD) but reports are limited. Here we examine PD-L1 expression and evaluate for clinical correlations. Twenty-one cases of PTLD were identified among pediatric kidney transplant recipients at our institution from February 1996 to April 2017. Using paraffin-embedded tissue biopsies, we examined 21 primary tumors for expression using PD-L1 monoclonal antibody performed with PAX5 as a double stain. We scored expression of PD-L1 on lesional B-cells as a percentage of positive cells. Clinical course and outcome were obtained from retrospective chart review. Applying revised 2017 WHO PTLD classification showed five non-destructive, nine polymorphic, and seven monomorphic cases. Average PD-L1 expression based upon PTLD subtype was: non-destructive 11%, polymorphic 43%, and monomorphic 73% (p=.01). Two patients transferred shortly after diagnosis, five received chemotherapy, and three died from PTLD. Among the fatalities, all showed monomorphic PTLD and 90% of lesional B-cells expressed PD-L1. In this case series, significant differences in PD-L1 expression were seen among different subtypes, and monomorphic PTLD demonstrated the highest expression. Study of a larger cohort is needed, and if the correlation of PD-L1 expression and PTLD subtype is confirmed, this may highlight the potential utility of checkpoint inhibitor therapy in cases of severe or refractory disease among kidney transplant recipient in whom the risk of allograft loss is acceptable given the option of chronic dialysis.

The Benefits of Preemptive Transplantation Using High-Kidney Donor Profile Index Kidneys.

The Kidney Donor Profile Index (KDPI) is a percentile score summarizing the likelihood of allograft failure: A KDPI ≥85% is associated with shorter allograft survival, and 50% of these donated kidneys are not currently used for transplantation. Preemptive transplantation (transplantation without prior maintenance dialysis) is associated with longer allograft survival than transplantation after dialysis; however, it is unknown whether this benefit extends to high-KDPI transplants. The objective of this analysis was to determine whether the benefit of preemptive transplantation extends to recipients of transplants with a KDPI ≥85%. This retrospective cohort study compared the post-transplant outcomes of preemptive and nonpreemptive deceased donor kidney transplants using data from the Scientific Registry of Transplant Recipients. 120,091 patients who received their first, kidney-only transplant between January 1, 2005, and December 31, 2017, were studied, including 23,211 with KDPI ≥85%. Of this cohort, 12,331 patients received a transplant preemptively. Time-to-event models for the outcomes of allograft loss from any cause, death-censored graft loss, and death with a functioning transplant were performed. Compared with recipients of nonpreemptive transplants with a KDPI of 0%-20% as the reference group, the risk of allograft loss from any cause in recipients of a preemptive transplant with KDPI ≥85% (hazard ratio [HR], 1.51; 95% confidence interval [CI], 1.39 to 1.64) was lower than that in recipients of nonpreemptive transplant with a KDPI ≥85% (HR, 2.39; 95% CI, 2.21 to 2.58) and similar to that of recipients of a nonpreemptive transplant with a KDPI of 51%-84% (HR, 1.61; 95% CI, 1.52 to 1.70). Preemptive transplantation is associated with a lower risk of allograft failure, irrespective of KDPI, and preemptive transplants with KDPI ≥85% have comparable outcomes with nonpreemptive transplants with KDPI 51%-84%.

Impact of donor hypertension on graft survival and function in living and deceased donor kidney transplantation: a nationwide prospective cohort study.

Hypertensive living donors are potential candidates to expand the kidney donor pool. However, the impact of donor hypertension on graft survival and function remains to be clarified. We analyzed 3907 kidney transplant recipients registered in a nationwide prospective cohort from 2014 to 2018. Patients were divided by donor types and the presence of donor hypertension. The primary and secondary outcome was the occurrence of death-censored graft failure and renal allograft function, respectively. The prevalence of hypertension was 9.4% (258/2740) and 19.9% (232/1167) in living and deceased donors, respectively. During a median follow-up of 21.8 months, death-censored graft survival rate was significantly worse in recipients of hypertensive living donors than in those of normotensive living donors ( P = 0.008). In multivariable analysis, recipients of hypertensive living donors had a significantly increased risk of graft loss (adjusted hazard ratio 2.91; P = 0.009). The risk of allograft loss was not different between recipients of hypertensive living and normotensive deceased donors. Propensity score-matched analyses had consistent worse graft survival rate in recipients of hypertensive living donors compared to those of normotensive living donors ( P = 0.027), while it was not different between recipients of hypertensive living and normotensive deceased donors. Hypertension in living donors had a significant negative impact on one-year graft function (adjusted unstandardized β -3.64; P = 0.011). Hypertensive living donor recipients have significantly higher risks of renal allograft loss than normotensive living donor recipients, and showed similar outcomes compared to recipients of normotensive deceased donors.

Evolution of humoral lesions on follow-up biopsy stratifies the risk for renal graft loss after antibody-mediated rejection treatment.

The standard-of-care protocol, based on plasma exchanges, high-dose intravenous immunoglobulin and optimization of maintenance immunosuppression, can slow down the evolution of antibody-mediated rejection (AMR), but with high interindividual variability. Identification of a reliable predictive tool of the response to AMR treatment is a mandatory step for personalization of the follow-up strategy and to guide second-line therapies. Interrogation of the electronic databases of 2 French university hospitals (Lyon and Strasbourg) retrospectively identified 81 renal transplant recipients diagnosed with AMR without chronic lesions (cg score≤1) at diagnosis and for whom a follow-up biopsy had been performed 3-6 months after initiation of therapy. The evolution of humoral lesions on follow-up biopsy (disappearance versus persistence versus progression) correlated with the risk for allograft loss (logrank test, P=.001). Patients with disappearance of humoral lesions had ∼80% graft survival at 10 years. The hazard ratio for graft loss in multivariate analysis was 3.91 (P=.04) and 5.15 (P=.02) for patients with persistence and progression of lesions, respectively. The non-invasive parameters classically used to follow the intensity of humoral alloimmune response (evolution of immunodominant DSA mean fluorescence intensity) and the decline of renal graft function (estimated glomerular filtration rate decrease and persistent proteinuria) showed little clinical value to predict the histological response to AMR therapy. We conclude that invasive monitoring of the evolution of humoral lesions by the mean of follow-up biopsy performed 3-6 months after the initiation of therapy is an interesting tool to predict long-term outcome after AMR treatment.

Nivolumab (NIVO) + tacrolimus (TACRO) + prednisone (PRED) +/- ipilimumab (IPI) for kidney transplant recipients (KTR) with advanced cutaneous cancers.

9507 Background: Cancer is a leading cause of death among KTR, but these patients (pts) have been excluded from trials of immune checkpoint inhibitors due to immunosuppression and risk of allograft loss. We report findings from the first prospective clinical trial of NIVO + TACRO + PRED +/- IPI in KTR with selected advanced cutaneous cancers. Methods: The primary composite endpoint was lack of tumor progression per RECIST v1.1 without allograft loss at 16 weeks (W) on NIVO. Adult KTR with advanced melanoma, basal, cutaneous squamous, or Merkel cell carcinoma (MEL, BCC, CSCC, MCC), for whom non-immune therapies were insufficient were eligible. Immunosuppression was standardized to low-dose TACRO (goal trough 2-5 ng/mL) + PRED 5mg daily; pts then received NIVO 480mg IV q4W. Pts with progressive disease (PD) could receive NIVO 3mg/kg + IPI 1mg/kg IV q3W x 4 followed by NIVO 480mg IV q4W. Donor-derived cell-free DNA (dd-cfDNA) levels were measured q2W as a potential predictor of allograft rejection. Results: From 11/2019 - 4/2021, of 12 pts enrolled, 8 pts with CSCC, MCC or MEL were evaluable for response (Table). All pts experienced PD on NIVO; treatment-related allograft loss (TRAL) occurred in 1 pt. 6 pts then received IPI + NIVO. Responses: 2 (33%) with marked tumor regression at 6W and eventual complete response (CR; 1 with TRAL), and 4 (67%) with PD (1 with TRAL). 7/8 pre-NIVO tumor biopsies contained a paucity of infiltrating immune cells. Only 2/5 on-NIVO biopsies demonstrated moderate immune infiltrates; both of these pts later developed a CR to IPI + NIVO. Rejecting allografts contained dense immune responses (plasma cells, CD4+ &amp; CD8+ lymphocytes, PD-1+ lymphocytes, macrophages, PD-L1+ glomerular endothelium, and focal PD-1 &amp; PD-L1 positivity in renal tubules). In 2/3 pts with TRAL, elevations in dd-cfDNA levels occurred 10 and 15 days earlier than increases in weekly serum creatinine levels. TRAL #3 occurred after discontinuation of study therapy (including TACRO) and dd-cfDNA monitoring. Conclusions: In KTR receiving low-dose TACRO + PRED, NIVO augments tumor immune cell infiltration in some pts but is insufficient to mediate tumor regression. Adding IPI can enhance anti-tumor immunity and mediate tumor regression. TACRO + PRED was insufficient to prevent allograft rejection after PD-1 +/- CTLA-4 blockade in 2/8 pts. In pts with TRAL, increased dd-cfDNA levels preceded increased serum creatinine. Based on these findings, we are modifying the trial therapy regimen to augment anti-tumor immunity and preserve allograft function. Clinical trial information: NCT03816332. [Table: see text]

Interactions Between Donor Age and 12-Month Estimated Glomerular Filtration Rate on Allograft and Patient Outcomes After Kidney Transplantation

Reduced estimated glomerular filtration rate (eGFR) at 12-months after kidney transplantation is associated with increased risk of allograft loss, but it is uncertain whether donor age and types modify this relationship. Using Australia and New Zealand registry data, multivariable Cox proportional modelling was used to examine the interactive effects between donor age, types and 12-month eGFR on overall allograft loss. We included 11,095 recipients (4,423 received live-donors). Recipients with lowest 12-month eGFR (<30 ml/min/1.73 m2) experienced the greatest risk of allograft loss, with adjusted HR [95% CI) of 2.65 [2.38–2.95] compared to eGFR of 30–60 ml/min/1.73 m 2 ; whereas the adjusted HR for highest eGFR (>60 ml/min/1.73 m2) was 0.67 [0.62–0.74]. The association of 12-month eGFR and allograft loss was modified by donor age (but not donor types) where a higher risk of allograft loss in recipients with lower compared with higher 12-month eGFR being most pronounced in the younger donor age groups (p < 0.01). Recipients with eGFR <30 ml/min/1.73 m2 12-months after transplantation experienced ≥2.5-fold increased risk of overall allograft loss compared to those with eGFR of >60 ml/min/1.73 m2, and the magnitude of the increased risk is most marked among recipients with younger donors. Careful deliberation of other factors including donor age when considering eGFR as a surrogate for clinical endpoints is warranted.

P.131: Persistent Low Blood Pressure After Simultaneous Pancreas and Kidney Transplant Is not Associated With an Increased Risk of Allograft Loss

P.131: Persistent Low Blood Pressure After Simultaneous Pancreas and Kidney Transplant Is not Associated With an Increased Risk of Allograft Loss

Outcome of Husband-to-Wife Kidney Transplantation With Mutual Children: Single Center Experience Using T Cell-Depleting Induction and Review of the Literature.

Few data on husband-to-wife transplantations with mutual children (H2W) exist in the current era. We investigated the outcome of H2W transplantations (n = 25) treated with T cell-depleting induction compared to women with prior pregnancies also receiving their first HLA-mismatched kidney transplant, but from a different donor source: (i) other living donor (n = 52) and (ii) deceased donor (n = 120). Seventy-four percent of the women had ≥2 pregnancies; median follow-up time was 5 years. Death-censored allograft survival was significantly lower in the H2W group compared to the other two groups (p = 0.03). Three of four graft losses in the H2W group were due to rejection. 5-year patient survival in the H2W group was high and similar compared to the other living donor group (100 vs. 98%; p = 0.28). The incidence of (sub)clinical antibody-mediated rejection was higher in the H2W group (36 vs. 20 vs. 18%) (p = 0.10). The frequency of infections was similar among the three groups. No immunological parameter was predictive for rejection or graft loss in H2W transplantations. In conclusion, H2W transplantation is a valuable option, but associated with a higher risk for allograft loss due to rejection despite T cell-depleting induction. Further research is required for better risk prediction on an individual patient level.

Delayed graft function predicts high risk of allograft loss following pediatric kidney transplantation

Delayed graft function predicts high risk of allograft loss following pediatric kidney transplantation

A Multicenter Application of the 2018 Banff Classification for BK Polyomavirus-associated Nephropathy in Renal Transplantation.

With current immunosuppressive regimens, BK polyomavirus-associated nephropathy (BKPyVAN) is still a matter of concern. Stratification of patients at risk for allograft loss is of uttermost importance to guide treatment choice and assess prognosis. In 2018, the Banff working group proposed a classification scheme for the prognosis of BKPyVAN, but external application on independent cohorts is yet to be performed. We investigated how the 2018 Banff classification would perform in a multicenter cohort comprising 50 cases of biopsy-proven BKPyVAN compared to previously published classification systems. We analyzed consecutive BKPyVAN cases from two Dutch university hospitals between 2002 and 2013, retrieved clinical data, and scored all biopsies according to the Banff 2018 classification, and as a comparison, 4 previously proposed BKPyVAN classification systems. We used estimated glomerular filtration rate trajectories and death-censored graft survival as primary endpoints. The 2018 Banff classification did not associate with estimated glomerular filtration rate decline or graft failure and performed only slightly better than the 4 previously proposed classifiers. Anti-human leukocyte antigen donor-specific antibodies (DSAs), especially in combination with ongoing biopsy-proven BKPyVAN on follow-up, did correlate with graft function and survival. Patients who were DSA+/BKPyVAN+ on follow-up had more inflammation at the baseline biopsy, which by itself was not associated with graft outcomes. Neither the 2018 Banff BKPyVAN classification nor previously published stratification systems could be applied to our multicenter patient cohort. Our data suggest that there might be a prognostic value for follow-up biopsies and DSA measurements to improve risk stratification after BKPyVAN, although prospective multicenter efforts with protocol measurements are needed to confirm this.

2082. Using a Commercially Available Assay Measuring Cytomegalovirus (CMV)-Specific CD4+ and CD8+ T-Cell Immunity by Intracellular Cytokine Staining to Predict Clinically Significant CMV Events

BackgroundCytomegalovirus (CMV) infection is a common opportunistic infection associated with significant morbidity, mortality, and risk of allograft loss. Early detection of viremia and initiation of treatment prior to disease progression is paramount. Alternatively, in the absence of treatment, many patients also control CMV infection, including low-level viremia, without progressing to disease. Thus, many treatment decisions (e.g., viremia thresholds to initiate treatment) are not currently well-defined. Given the excessive toxicities and costs of antiviral therapy, there is growing interest in assays that measure CMV-specific T-cell immunity (TCI), which may predict protection against infection. The Viracor® CMV T-cell Immunity Panel (CMV-TCIP) uses flow cytometry and intracellular cytokine staining (ICS) to measure % of CMV-specific CD4+ and CD8+ T-cells. Other currently available TCI commercial assays measure only aggregate (CD4+ and CD8+) or CD8+ immune responses only.MethodsWe included patients who had CMV-TCIP results at Rhode Island Hospital (January 2016–February 2018) and who subsequently had at least one additional assessment for CMV viremia. CMV events were defined as rising viremia prompting initiation of treatment and were captured after the most recent CMV-TCIP result. We built CMV-protection relative-operating curves (ROC) for % of CD4+ and CD8+ CMV-specific T-cells.ResultsWe analyzed 17 samples from 13 patients: 10 were SOT (eight kidney, two heart) recipients (seven CMV R+, three D+/R−); two had hematologic malignancies; one other was immunosuppressed (prednisone, infliximab) for autoimmune colitis. Four additional samples were excluded because of CD4+ or CD8+ ICS background positivity. The CMV-protection ROC AUC was significant for % of CMV-specific CD4+ but not CD8+ T-cells (Figure 1). At a cut-off of 0.26% CMV-specific CD4+ T-cells, PPV was 90% (95% CI 71–100%), and NPV was 86% (95% CI 60–100%). In 14 of 17 cases (82%), the CMV-TCIP result was useful in guiding management.ConclusionIn this small, single-center, heterogeneous series, the % of CMV-specific CD4+ T-cells measured by ICS was predictive of protection against CMV. The CMV-TCIP can be a useful, cost-effective test, and merits further validation in larger prospective studies. Figure 1.Disclosures D. Farmakiotis, Viracor: Consultant and Invited speaker, Consulting fee.

Inflammation in Fibrotic Areas (i-IF/TA) Identifies a T cell-mediated Rejection Component of IF/TA with Poor Kidney Allograft Outcome

Addressing the etiological heterogeneity of interstitial fibrosis in kidney allografts represents an important challenge to improve long-term transplant outcomes. We investigated the determinants, clinical and histological phenotype, and outcome of i-IF/TA in a prospective cohort of kidney recipients. We prospectively enrolled 1539 kidney recipients transplanted between 2004 and 2010, with systematic assessment of i-IF/TA using the i-IF/TA Banff score and of tubulitis in atrophic tubules (t-IF/TA), on allograft biopsies performed at 1 year post-transplantation. We considered donor, recipient and transplant baseline characteristics, immunosuppression, infectious diseases (CMV, pyelonephritis, BK virus), presence of donor-specific anti-HLA antibodies (DSAs) and all the biopsy-proven diagnoses (T cell-mediated rejection [TCMR], antibody-mediated rejection [ABMR], recurrence, BK virus-associated nephropathy [BKVAN], calcineurin inhibithor [CNI] toxicity, acute tubular necrosis) recorded within the first year after transplantation. We identified 946 (61%) patients with IF/TA at one year post-transplant, among whom 394 (42%) patients showed i-IFTA, which was associated with t-IF/TA in 309 (78%) patients. Patients with i-IF/TA at 1 year post-transplant had significantly decreased allograft survival at 8 years compared with patients with non-inflammatory IF/TA (81% vs 87%, P=0.002). Independent risk factors for i-IF/TA included: TCMR (OR=2.7, p<0.001), BKVAN (OR=3.3, p=0.007) and HLA B (OR=1.3, p=0.012) and DR (OR=1.2, p=0.044) mismatching, while steroid therapy (OR=0.6, p=0.039), CNI therapy (OR=0.5, p=0.011) and inosine-5'-monophosphate dehydrogenase inhibitor therapy (OR=0.5, p=0.011) had protective effects on i-IF/TA occurrence. Unsupervised hierarchical clustering based on the whole spectrum of Banff elementary lesions assessed at 1 year post-transplant showed that i-IF/TA aggregated in the TCMR cluster (i, t, ti, t-IF/TA and i-IF/TA) and not in the ABMR (g, ptc, C4d, cg) and chronicity clusters (cv, ci, ct, ah). We observed a positive gradient between increasing level of i-IF/TA and t-IF/TA Banff scores and the risk of allograft loss (p<0.001). i-IFTA may reflect a TCMR subcomponent of IF/TA related to under-immunosuppression and is associated with poor kidney transplant outcome compared to non-inflammatory IF/TA.

Complement C3F allotype synthesized by liver recipient modifies transplantation outcome independently from donor hepatic C3.

Complement component 3 (C3) presents both slow (C3S) and fast (C3F) variants, which can be locally produced and activated by immune system cells. We studied C3 recipient variants in 483 liver transplant patients by RT-PCR-HRM to determine their effect on graft outcome during the first year post-transplantation. Allograft survival was significantly decreased in C3FF recipients (C3SS 95% vs C3FS 91% vs C3FF 83%; P=.01) or C3F allele carriers (C3F absence 95% vs C3F presence 90%, P=.02). C3FF genotype or presence of C3F allele independently increased risk for allograft loss (OR: 2.38, P=.005 and OR: 2.66, P=.02, respectively). C3FF genotype was more frequent among patients whose first infection was of viral etiology (C3SS 13% vs C3FS 18% vs C3FF 32%; P=.04) and independently increased risk for post-transplant viral infections (OR: 3.60, P=.008). On the other hand, C3FF and C3F protected from rejection events (OR: 0.54, P=.03 and OR: 0.63, P=.047, respectively). Differences were not observed in hepatitis C virus recurrence or patient survival. In conclusion, we show that, independently from C3 variants produced by donor liver, C3F variant from recipient diminishes allograft survival, increases susceptibility to viral infections, and protects from rejection after transplantation. C3 genotyping of liver recipients may be useful to stratify risk.

Post-transplant lymphoproliferative disorders.

Post-transplant lymphoproliferative disorders (PTLDs) are a group of conditions that involve uncontrolled proliferation of lymphoid cells as a consequence of extrinsic immunosuppression after organ or haematopoietic stem cell transplant. PTLDs show some similarities to classic lymphomas in the non-immunosuppressed general population. The oncogenic Epstein-Barr virus (EBV) is a key pathogenic driver in many early-onset cases, through multiple mechanisms. The incidence of PTLD varies with the type of transplant; a clear distinction should therefore be made between the conditions after solid organ transplant and after haematopoietic stem cell transplant. Recipient EBV seronegativity and the intensity of immunosuppression are among key risk factors. Symptoms and signs depend on the localization of the lymphoid masses. Diagnosis requires histopathology, although imaging techniques can provide additional supportive evidence. Pre-emptive intervention based on monitoring EBV levels in blood has emerged as the preferred strategy for PTLD prevention. Treatment of established disease includes reduction of immunosuppression and/or administration of rituximab (a B cell-specific antibody against CD20), chemotherapy and EBV-specific cytotoxic T cells. Despite these strategies, the mortality and morbidity remains considerable. Patient outcome is influenced by the severity of presentation, treatment-related complications and risk of allograft loss. New innovative treatment options hold promise for changing the outlook in the future.

Detection of C3d-binding donor-specific anti-HLA antibodies at diagnosis of humoral rejection predicts renal graft loss.

Antibody-mediated rejection (AMR) is a major cause of kidney graft loss, yet assessment of individual risk at diagnosis is impeded by the lack of a reliable prognosis assay. Here, we tested whether the capacity of anti-HLA antibodies to bind complement components allows accurate risk stratification at the time of AMR diagnosis. Among 938 kidney transplant recipients for whom a graft biopsy was performed between 2004 and 2012 at the Lyon University Hospitals, 69 fulfilled the diagnosis criteria for AMR and were enrolled. Sera banked at the time of the biopsy were screened for the presence of donor-specific anti-HLA antibodies (DSAs) and their ability to bind C1q and C3d using flow bead assays. In contrast with C4d graft deposition, the presence of C3d-binding DSA was associated with a higher risk of graft loss (P<0.001). Despite similar trend, the difference did not reach significance with a C1q-binding assay (P=0.06). The prognostic value of a C3d-binding assay was further confirmed in an independent cohort of 39 patients with AMR (P=0.04). Patients with C3d-binding antibodies had worse eGFR and higher DSA mean fluorescence intensity. In a multivariate analysis, only eGFR <30 ml/min per 1.73 m(2) (hazard ratio [HR], 3.56; 95% confidence interval [CI], 1.46 to 8.70; P=0.005) and the presence of circulating C3d-binding DSA (HR, 2.80; 95% CI, 1.12 to 6.95; P=0.03) were independent predictors for allograft loss at AMR diagnosis. We conclude that assessment of the C3d-binding capacity of DSA at the time of AMR diagnosis allows for identification of patients at risk for allograft loss.

One-Year Biopsy Data of Antibody-Incompatible Kidney Transplantation and Correlation with Medium-To-Long Term Risk of Allograft Loss - a Prospective Analysis

One-Year Biopsy Data of Antibody-Incompatible Kidney Transplantation and Correlation with Medium-To-Long Term Risk of Allograft Loss - a Prospective Analysis

Antibody testing for cardiac antibody-mediated rejection: Which panel correlates best with cardiovascular death?

Recent efforts are being undertaken to update and refine current diagnostic criteria for antibody-mediated rejection (AMR) in heart transplantation. We believe that the appropriate reactants are those that best predict the adverse consequences of AMR and therefore tested various models using different reactants to find the best predictors of cardiovascular mortality in pathologically defined AMR. The study group included only patients in whom all immunofluorescence antibodies of interest had been tested on biopsy specimens obtained after 2002 when C4d was routinely added. We analyzed our data using 3 Cox proportional hazard models with time-varying covariates using an end point of cardiovascular mortality, as previously defined. In 3,712 biopsy specimens from 422 patients, the 2-antibody model achieved a value of R(2) = 0.930 using C3d and C4d antibodies alone. A model that used 4 antibodies--C3d, C4d, human leukocyte antigen-D related (HLA-DR) and fibrin--was superior (R(2) = 0.988). The model that best predicted cardiovascular mortality included all 6 antibodies: HLA-DR, immunoglobulin (Ig) G, IgM, C3d, C4d, and fibrin (R(2) = 0.989). The models using 4 or 6 antibodies were significantly superior to the model using only C3d and C4d (for each interaction, p < 0.0001). The combination of complement components, HLA-DR and fibrin, is valuable in defining AMR in patients at risk for allograft loss from cardiovascular causes. Fibrin is particularly important for detecting the presence of severe AMR, with a high likelihood of poor long-term patient outcome.

New treatments for acute humoral rejection of kidney allografts

Acute antibody-mediated rejection (acute humoral rejection; AHR) of organ allografts usually presents as severe dysfunction with a high risk of allograft loss. Peritubular capillary complement C4d deposition with renal dysfunction, associated with circulating donor-specific anti-human leukocyte antigen alloantibodies, is diagnostic of AHR in kidney allografts. Removal of alloantibodies with suppression of antibody production and rejection reversal is now possible. Therapeutic strategies that include combinations of plasmapheresis (or immunoadsorption), tacrolimus, mycophenolate mofetil and/or intravenous immunoglobulins, as well as rituximab or splenectomy, have been recently used to successfully treat AHR. However, the optimal protocol to treat AHR still remains to be defined. Anti-CD20+ monoclonal antibody therapy (rituximab) aiming at depleting B cells and suppressing antibody production has been used as rescue therapy in some episodes of steroid- and antilymphocyte-resistant humoral rejection. Plasmapheresis and/or intravenous polyclonal immunoglobulin, as well as rituximab, have also been used to successfully desensitize selected high-immunological risk patients in anticipation of a previously cross-match positive (or ABO incompatible) kidney transplantation. In the near future, the possible role of new specific anti-B-cell approaches or, possibly, of new anti-T-cell activation approaches using selective agents such as belatacept should be assessed to further refine the present treatment of humoral rejection.