Value of monitoring circulating donor‐reactive memory B cells to characterize antibody‐mediated rejection after kidney transplantation

Antibody‐mediated rejection (ABMR) is defined by specific histopathological lesions and evidence of circulating donor‐specific antibodies (DSA). Although DSA are not always detectable, monitoring donor‐reactive memory B cells (mBC) could identify patients at risk of developing ABMR. Peripheral donor‐reactive mBC using a novel HLA B cell ELISpot assay, serum DSA, and numbers of different B cell subsets were assessed in 175 consecutive kidney transplants undergoing either for‐cause or 6‐ and 24‐month surveillance biopsies for their association with main histological lesions of ABMR and impact on allograft outcome. In 85 incident for‐cause biopsies, high frequencies of donor‐reactive mBC were detected in all 16 (100%) acute ABMR/DSA+ and most chronic ABMR, with or without DSA (24/30[80%] and 21/29[72.4%], respectively). In a longitudinal cohort of 90 nonsensitized patients, a progressively higher expansion of donor‐reactive mBC than de novo DSA was observed at 6 and 24 months (8.8% vs 7.7% and 15.5% vs 11.1%, respectively) and accurately identified patients with ongoing subclinical ABMR (area under the curve = 0.917 and area under the curve = 0.809, respectively). An unsupervised hierarchical cluster analysis revealed a strong association between donor‐reactive mBC with main fundamental allograft lesions associated with ABMR and conferred a significant deleterious impact on graft outcome. Monitoring donor‐reactive mBC may be useful to further characterize humoral rejection after kidney transplantation.     

Histological picture of antibody‐mediated rejection without donor‐specific anti‐HLA antibodies: Clinical presentation and implications for outcome

In this cohort study (n = 935 transplantations), we investigated the phenotype and risk of graft failure in patients with histological criteria for antibody‐mediated rejection (ABMR) in the absence of circulating donor‐specific anti‐human leukocyte antigen (HLA) antibodies (DSA), and compared this to patients with definite ABMR and HLA‐DSA‐positivity. The histological picture did not differ between HLA‐DSA‐positive (n = 85) and HLA‐DSA‐negative (n = 123) cases of ABMR histology, apart from increased complement split product 4d (C4d) deposition in the peritubular capillaries in HLA‐DSA‐positive cases. Histology of ABMR without HLA‐DSA was more transient than DSA‐positive ABMR, and patients with ABMR histology without HLA‐DSA had graft survival superior to that of HLA‐DSA‐positive patients, independent of concomitant T cell–mediated rejection (38.2%) or borderline changes (17.9%). Multivariate analysis showed that the risk of graft failure was not higher in patients with histological picture of ABMR (ABMR_h) in the absence of HLA‐DSA, compared to patients without ABMR_h. Despite an association between C4d deposition and HLA‐DSA‐positivity, using C4d deposition as alternative for the DSA criterion in the diagnosis of ABMR, as proposed in Banff 2017, did not contribute to the prognosis of graft function and graft failure. We concluded that biopsies with ABMR_h but without detectable HLA‐DSA represent a distinct, often transient phenotype with superior allograft survival.     

Lymphoid neogenesis in skin of human hand,nonhuman primate,and rat vascularized composite allografts

The mechanisms of skin rejection in vascularized composite allotransplantation (VCA) remain incompletely understood. The formation of tertiary lymphoid organs (TLO) in hand transplantation has been recently described. We assess this phenomenon in experimental and clinical VCA rejection. Skin biopsies of human (n = 187), nonhuman primate (n = 11), and rat (n = 15) VCAs were analyzed for presence of TLO. A comprehensive immunohistochemical assessment (characterization of the cell infiltrate, expression of adhesion molecules) including staining for peripheral node addressin (PNAd) was performed and correlated with rejection and time post‐transplantation. TLO were identified in human, nonhuman primate, and rat skin samples. Expression of PNAd was increased in the endothelium of vessels upon rejection in human skin (P = 0.003) and correlated with B‐ and T‐lymphocyte numbers and LFA‐1 expression. PNAd expression was observed at all time‐points after transplantation and increased significantly after year 5. In nonhuman primate skin, PNAd expression was found during inflammatory conditions early and late after transplantation. In rat skin, PNAd expression was strongly associated with acute rejection and time post‐transplantation. Lymphoid neogenesis and TLO formation can be uniformly found in experimental and human VCA. PNAd expression in vascular endothelium correlates with skin rejection and T‐ and B‐cell infiltration.     

Anti‐C1s monoclonal antibody BIVV009 in late antibody‐mediated kidney allograft rejection—results from a first‐in‐patient phase 1 trial

The classical pathway (CP) of complement may contribute to the pathogenesis of antibody‐mediated rejection (ABMR). Selective CP blockade may be a promising strategy to counteract rejection. The objective of this first‐in‐patient phase 1b trial was to evaluate the safety/tolerability and CP‐blocking potential of 4 weekly doses (60 mg/kg) of the anti‐C1s antibody BIVV009 in complement‐mediated disorders. Here we describe the results in a cohort of 10 stable kidney transplant recipients (median of 4.3 years posttransplantation) with late active ABMR and features of CP activation, such as capillary C4d or complement‐fixing donor‐specific antibodies (DSA). During 7 weeks follow‐up, no severe adverse events were reported, and BIVV009 profoundly inhibited overall and DSA‐triggered CP activation in serum. Five of 8 C4d‐positive recipients turned C4d‐negative in 5‐week follow‐up biopsies, while another 2 recipients showed a substantial decrease in C4d scores. There was, however, no change in microcirculation inflammation, gene expression patterns, DSA levels, or kidney function. In conclusion, we demonstrate that BIVV009 effectively blocks alloantibody‐triggered CP activation, even though short‐course treatment had no effect on indices of activity in late ABMR. This initial trial provides a valuable basis for future studies designed to clarify the therapeutic value of CP blockade in transplantation. ClinicalTrials.gov NCT#02502903.     

Impact of pretransplant donor‐specific antibodies on kidney allograft recipients with negative flow cytometry cross‐matches

The Luminex test can detect low levels of donor‐specific antibody (DSA) that cannot be detected by flow‐cytometric cross‐matching (FCXM) in kidney transplantation (KT). This study evaluated the impact of DSA on clinical outcomes in KT recipients negative on FCXM. Of 575 consecutive patients who underwent living donor KT between January 2013 and July 2016, 494 (85.9%) were DSA‐negative and 81 (14.1%) were DSA‐positive. Although rates of acute cellular rejection (ACR) at 1 year were similar in the 2 groups (P = .54), the incidence of antibody‐mediated rejection (ABMR) was significantly higher in the DSA‐positive group (P < .01). There was no statistically significant association between rejection‐free graft survival (RFGS) rates and pretransplant class I DSA. However, evaluation of pretransplant class II DSA showed that RFGS rates were significantly lower in patients with mean fluorescence intensity (MFI) >3000 than in patients with DSA‐negative (P < .01). On multivariate analyses, class II DSA MFI ≥5000 was a significant risk factor for acute rejection (hazard ratio, 7.48; P < .01). These findings suggested that pretransplant DSA alone did not affect graft survival in KT recipients without desensitization. However, class II DSA MFI >5000 was an independent predictor of acute rejection in DSA‐positive patients.     

What have we learned about how to prevent and treat antibody‐mediated rejection in kidney transplantation?

Antibody‐mediated rejection (ABMR) in kidney transplantation is a major cause of late graft loss, and despite all efforts to date the “standard of care” remains plasmapheresis, IVIg, and steroids, which itself is based on low quality evidence. This review focuses on the risk factors leading to memory and de novo donor‐specific antibody (DSA)‐associated ABMR, the optimal prevention strategies for ABMR, and advances in  adjunctive and emerging therapies for ABMR. Because new agents require regulatory approval via a Phase 3 randomized control trial (RCT), an overview of progress in innovative trial design for ABMR is provided. Finally, based on the insights gained in the biology of ABMR, current knowledge gaps are identified for future research that could significantly affect our understanding of how to optimally treat ABMR.     

Outcome of the risk‐stratified desensitization protocol in donor‐specific antibody‐positive living kidney transplant recipients: a retrospective study

Acceptable outcomes of donor‐specific antibody (DSA)‐positive living kidney transplantation (LKT) have recently been reported. However, LKT in crossmatch (XM)‐positive patients remains at high‐risk and requires an optimal desensitization protocol. We report our intermediate‐term outcomes of XM‐positive LKT vs. XM‐negative LKT in patients who underwent LKT between January 2012 and June 2015 in our institution. The rate of acute antibody‐mediated rejection (ABMR) within 90 days postoperation, graft function, and patient, and graft survival rates at 4 years were investigated. Patients were divided into three groups: XM?DSA? (n = 229), XM?DSA+ (n = 36), and XM + DSA+ (n = 15). The XM + DSA+ group patients underwent desensitization with high‐dose intravenous immunoglobulin, plasmapheresis, and rituximab. The rates of ABMR within 90 days in the XM?DSA?, XM?DSA+, and XM + DSA+ groups were 1.3%, 9.4%, and 60.0%, respectively (P < 0.001). There were no significant differences in the graft function throughout the observational period, the 4‐year patient or graft survival rates among three groups. This study showed that intermediate‐term outcomes of XM‐positive LKT were comparable to XM‐negative LKT. However, our current desensitization protocol cannot avert ABMR within 90 days, and XM positivity is still a significant risk factor for ABMR. Further refinement of the current desensitization regimen is required.     

A Probabilistic Approach to Histologic Diagnosis of Antibody‐Mediated Rejection in Kidney Transplant Biopsies

Histologic diagnosis of antibody‐mediated rejection (ABMR) in kidney transplant biopsies uses lesion score cutoffs such as 0 versus >0 rather than actual scores and requires donor‐specific antibody (DSA); however, cutoffs lose information, and DSA is not always reliable. Using microarray‐derived molecular ABMR scores as a histology‐independent estimate of ABMR in 703 biopsies, we reassessed criteria for ABMR to determine relative importance of various lesions, the utility of equations using actual scores rather than cutoffs, and the potential for diagnosing ABMR when DSA is unknown or negative. We confirmed that the important features for ABMR diagnosis were peritubular capillaritis (ptc), glomerulitis (g), glomerular double contours, DSA and C4d staining, but we questioned some features: arterial fibrosis, vasculitis, acute tubular injury, and sum of ptc+g scores. Regression equations using lesion scores predicted molecular ABMR more accurately than score cutoffs (area under the curve 0.85–0.86 vs. 0.75). DSA positivity improved accuracy, but regression equations predicted ABMR with moderate accuracy when DSA was unknown. Some biopsies without detectable DSA had high probability of ABMR by regression, although most had HLA antibody. We concluded that regression equations using lesion scores plus DSA maximized diagnostic accuracy and can estimate probable ABMR when DSA is unknown or undetectable.     

Development and outcomes of de novo donor‐specific antibodies in low,moderate, and high immunological risk kidney transplant recipients

De novo donor‐specific antibodies (dnDSA) play an important role in antibody‐mediated rejection (ABMR) and graft failure, yet their development in kidney transplant recipients (KTx) of higher immunological risk has not been characterized. We prospectively determined the incidence of dnDSA at 3 and 12 months posttransplant and assessed their associations with outcomes in recipients stratified by low, moderate, and high immunological risk. Adult KTx were screened for DSA pretransplant, months 3 and 12 posttransplant, and when clinically indicated. Outcomes included incidence of dnDSA, death‐censored graft survival (DCGS), and ABMR. Of 371 recipients, 154 (42%) were transplanted across a pretransplant DSA that became undetectable by 12 months posttransplant in 78% of cases. dnDSA were detected in 16% (95% confidence interval [CI]: 12‐20%) by 3 months and 23% (95% CI: 18‐29%) by 12 months posttransplant. Incidence at 12 months was higher in the moderate (30%) and high‐risk groups (29%) compared to the low‐risk group (16%). dnDSA were associated with an increased risk of ABMR (hazard ratio [HR] 2.2; 95% CI: 1.1‐4.4; P = .04) but were not an independent risk factor for DCGS. In conclusion, dnDSA were more frequent in transplant recipients of higher immune risk and associated with an increased risk of ABMR.     

Identifying Subphenotypes of Antibody‐Mediated Rejection in Kidney Transplants

The key lesions in antibody‐mediated kidney transplant rejection (ABMR) are microcirculation inflammation (peritubular capillaritis and/or glomerulitis lesions, abbreviated “pg”) and glomerular double contours (cg lesions). We used these features to explore subphenotypes in 164 indication biopsies with ABMR‐related diagnoses: 137 ABMR (109 pure and 28 mixed with T cell–mediated rejection [TCMR]) and 27 transplant glomerulopathy (TG), identified from prospective multicenter studies. The lesions indicated three ABMR subphenotypes: pgABMR, cgABMR, and pgcgABMR. Principal component analysis confirmed these subphenotypes and showed that TG can be reclassified as pgcgABMR (n = 17) or cgABMR (n = 10). ABMR‐related biopsies included 45 pgABMR, 90 pgcgABMR, and 25 cgABMR, with four unclassifiable. Dominating all time intervals was the subphenotype pgcgABMR. The pgABMR subphenotype presented earliest (median <2 years), frequently mixed with TCMR, and was most associated with nonadherence. The cgABMR subphenotype presented late (median 9 years). Subphenotypes differed in their molecular changes, with pgABMR having the most histologic–molecular discrepancies (i.e. potential errors). Donor‐specific antibody (DSA) was not identified in 29% of pgcgABMR and 46% of cgABMR, but failure rates and molecular findings were similar to cases where DSA was known to be positive. Thus, ABMR presents distinct subphenotypes, early pg‐dominant, late cg‐dominant, and combined pgcg phenotype, differing in time, molecular features, accompanying TCMR, HLA antibody, and probability of nonadherence.     

Benefits of a loading dose of tacrolimus on graft survival of kidney transplants in nonhuman primates

We examined the benefit of a loading dose of tacrolimus on the production of donor-specific antibodies (DSA), occurrence of acute rejection (AR) episodes, graft survival, and histological evidence of antibody-mediated rejection (ABMR) after kidney transplantation in nonhuman primates. Eight cynomolgus monkeys were assigned to two groups (n = 4 each): a maintenance dose-group, orally administered 1 mg/kg/day tacrolimus from the day of transplantation; and a loading-dose group, orally administered 2 mg/kg/day tacrolimus for 21 days after transplantation followed by 1 mg/kg/day. The monkeys were observed for up to 178 days after transplantation. Plasma creatinine was monitored over time. Recipients with increased plasma creatinine levels of >2 mg/dL received anti-acute rejection therapy. In the maintenance dose-group, DSA production, frequent AR episodes, and histological evidence of ABMR were observed in all recipients. Three of four recipients did not survive until the end of the observation period. In the loading-dose group, two recipients showed DSA production, frequent AR episodes and histological evidence of ABMR, while the remaining two had no DSA, AR episodes, or ABMR. Our findings indicate that a loading dose of tacrolimus may prevent DSA production, occurrence of AR events and ABMR, and prolong graft survival following kidney transplantation in monkeys.     

Subclass analysis of donor HLA‐specific IgG in antibody‐incompatible renal transplantation reveals a significant association of IgG4 with rejection and graft failure

Donor HLA‐specific antibodies (DSAs) can cause rejection and graft loss after renal transplantation, but their levels measured by the current assays are not fully predictive of outcomes. We investigated whether IgG subclasses of DSA were associated with early rejection and graft failure. DSA levels were determined pretreatment, at the day of peak pan‐IgG level and at 30 days post‐transplantation in eighty HLA antibody‐incompatible kidney transplant recipients using a modified microbead assay. Pretreatment IgG₄ levels were predictive of acute antibody‐mediated rejection (P = 0.003) in the first 30 days post‐transplant. Pre‐treatment presence of IgG₄ DSA (P = 0.008) and day 30 IgG₃ DSA (P = 0.03) was associated with poor graft survival. Multivariate regression analysis showed that in addition to pan‐IgG levels, total IgG₄ levels were an independent risk factor for early rejection when measured pretreatment, and the presence of pretreatment IgG₄ DSA was also an independent risk factor for graft failure. Pretreatment IgG₄ DSA levels correlated independently with higher risk of early rejection episodes and medium‐term death‐censored graft survival. Thus, pretreatment IgG₄ DSA may be used as a biomarker to predict and risk stratify cases with higher levels of pan‐IgG DSA in HLA antibody‐incompatible transplantation. Further investigations are needed to confirm our results.     

Banff survey on antibody‐mediated rejection clinical practices in kidney transplantation: Diagnostic misinterpretation has potential therapeutic implications

The aim of this study was to determine how the Banff antibody‐mediated rejection (ABMR) classification for kidney transplantation is interpreted in practice and affects therapy. The Banff Antibody‐Mediated Injury Workgroup electronically surveyed clinicians and pathologists worldwide regarding diagnosis and treatment for 6 case‐based scenarios. The participants' (95 clinicians and 72 renal pathologists) assigned diagnoses were compared to the Banff intended diagnoses (reference standard). The assigned diagnoses and reference standard differed by 26.1% (SD 28.1%) for pathologists and 34.5% (SD 23.3%) for clinicians. The greatest discordance between the reference standard and clinicians' diagnosis was when histologic features of ABMR were present but donor‐specific antibody was undetected (49.4% [43/87]). For pathologists, the greatest discordance was in the case of acute/active ABMR C4d staining negative in a positive crossmatch transplant recipient (33.8% [23/68]). Treatment approaches were heterogeneous but linked to the assigned diagnosis. When acute/active ABMR was diagnosed by the clinician, treatment was recommended 95.3% (SD 18.4%) of the time vs only 77.7% (SD 39.2%) of the time when chronic active ABMR was diagnosed (P < .0001). In conclusion, the Banff ABMR classification is vulnerable to misinterpretation, which potentially has patient management implications. Continued efforts are needed to improve the understanding and standardized application of ABMR classification in the transplant community.     

Early clinical experience using donor‐derived cell‐free DNA to detect rejection in kidney transplant recipients

Donor‐derived cell‐free DNA (dd‐cfDNA) became Medicare reimbursable in the United States in October 2017 for the detection of rejection in kidney transplant recipients based on results from its pivotal validation trial, but it has not yet been externally validated. We assessed 63 adult kidney transplant recipients with suspicion of rejection with dd‐cfDNA and allograft biopsy. Of these, 27 (43%) patients had donor–specific antibodies and 34 (54%) were found to have rejection by biopsy. The percentage of dd‐cfDNA was higher among patients with antibody–mediated rejection (ABMR; median 1.35%; interquartile range [IQR]: 1.10%‐1.90%) compared to those with no rejection (median 0.38%, IQR: 0.26%‐1.10%; P < .001) and cell–mediated rejection (CMR; median: 0.27%, IQR: 0.19%‐1.30%; P = .01). The dd‐cfDNA test did not discriminate patients with CMR from those without rejection. The area under the ROC curve (AUC) for CMR was 0.42 (95% CI: 0.17‐0.66). For ABMR, the AUC was 0.82 (95% CI: 0.71‐0.93) and a dd‐cfDNA ≥0.74% yielded a sensitivity of 100%, specificity 71.8%, PPV 68.6%, and NPV 100%. The dd‐cfDNA test did not discriminate CMR from no rejection among kidney transplant recipients, although performance characteristics were stronger for the discrimination of ABMR.     

Tailored use of belatacept in adolescent kidney transplantation

Adolescent transplant recipients are at risk for nonadherence, development of de novo donor‐specific antibody (dnDSA), and allograft loss. Belatacept, a selective T cell costimulatory blocker, is associated with reduced dnDSA, improved renal function, and prolonged allograft survival when compared to calcineurin inhibitor‐based regimens in adults; however, its use in children is scant. Three adolescents were initiated on belatacept between August 2017 and September 2018 at the time of kidney transplantation. Selection criteria included age ≥ 14 and EBV IgG + serostatus. Intraoperative alemtuzumab and methylprednisolone were given as induction therapy. Tailored maintenance therapy included steroid‐free belatacept and sirolimus for two patients. One patient was initially maintained steroid‐free on belatacept and belimumab, an inhibitor of B cell activating factor to treat concurrent systemic lupus erythematous; steroids were added subsequently. Renal function, biopsy‐proven rejection, dnDSA, allograft survival, infection, nonadherence, and proteinuria were monitored. Renal function was 86, 73, 52 mL/min/1.73 m² at 20, 20, and 8 months, respectively. There was 100% adherence to therapy and no development of dnDSA. All patients had treatable infections. One developed steroid‐responsive acute cellular rejection. Belatacept‐based regimens can be tailored for adolescent recipients with good short‐term clinical outcomes.     

Belatacept in renal transplant recipient with mild immunologic risk factor: A pilot prospective study (BELACOR)

The benefit of belatacept on antibody‐mediated rejection (ABMR) incidence after kidney transplant with preformed donor‐specific antibodies (DSAs) has never been assessed. Between 2014 and 2016, we conducted a multicenter prospective clinical trial with 49 patients to determine kidney allograft outcome in recipients with preformed DSAs (maximal mean fluorescence intensity 500 to 3000) treated with belatacept (BELACOR trial). Immunosuppressive strategy included antithymocyte globulin, belatacept, mycophenolate mofetil, and steroids. An ancillary control group was designed retrospectively, including patients fulfilling the same inclusion criteria treated with calcineurin inhibitors. In BELACOR group, no patient exhibited acute ABMR, patient and allograft survival at 1 year was 100% and 95.4%, respectively, and the estimated glomerular filtration rate was 53.2 mL/min/1.73 m². However, the 12‐month incidence of acute T cell–mediated rejection was 25.4% (14.5% to 42.4%). Comparison with the control group showed significantly higher T cell–mediated rejection incidence only in the BELACOR group (P = .003). Considering the DSAs, the outcome was similar in the 2 groups except a significantly higher number of patients displayed a complete disappearance of class II DSAs in the BELACOR group (P = .001). Belatacept was not associated with an acute ABMR increased risk and may be considered as immunosuppressive strategy in transplant recipients with preformed DSAs (maximal mean fluorescence intensity 500 to 3000). Prospective randomized trials are needed to confirm these results.     

Reassessing the Significance of Intimal Arteritis in Kidney Transplant Biopsy Specimens

Intimal arteritis (the presence of v-lesions) in kidney transplant biopsy specimens is believed to have major prognostic and diagnostic significance. We assessed the relationship of v-lesions to prognosis in 703 indication biopsy specimens and used microarray-based molecular tests to re-examine the relationship of v-lesions to rejection. v-Lesions were noted in 49 specimens (7%) and were usually mild (v1). The presence of v-lesions had no effect on graft survival compared with the absence of v-lesions. Pathologists using current conventions almost always interpreted v-lesions as reflecting T cell–mediated rejection (TCMR), either pure or mixed with antibody-mediated rejection (ABMR). The molecular scores questioned the conventional diagnoses in 29 of 49 specimens (59%), including ten that were conventional TCMR with no molecular rejection and nine that were conventional TCMR mixed with pure ABMR molecularly. The presence of tubulointerstitial inflammation (i-t) meeting TCMR criteria allowed subclassification of v-lesion specimens into 21 i-t-v-lesion specimens and 28 isolated v-lesion specimens. Molecular TCMR scores were positive in 95% of i-t-v-lesion specimens but only 21% of isolated v-lesion specimens. Molecular ABMR scores were often positive in isolated v-lesion biopsies (46%). Time of biopsy after transplantation was critical for understanding isolated v-lesions: most early isolated v-lesion specimens had no molecular rejection and were DSA negative, whereas most isolated >1 year after transplantation had positive DSA and ABMR scores. Therefore, v-lesions in indication biopsy specimens do not affect prognosis and can reflect TCMR, ABMR, or no rejection. Time after transplantation, DSA, and accompanying inflammation provide probabilistic basis for interpreting v-lesions.     

Pre‐existing donor‐specific antibodies are detrimental to kidney allograft only when persistent after transplantation

Donor‐specific antibodies (DSA) increase the risk of allograft rejection and graft failure. They may be present before transplant or develop de novo after transplantation. Here, we studied the evolution of preformed DSA and their impact on graft outcome in kidney transplant recipients. Using the Luminex Single Antigen assay, we analyzed the sera on the day of transplantation of 239 patients who received a kidney transplant. Thirty‐seven patients (15.5%) had pre‐existing DSA detected the day of transplantation. After 5 years, the pre‐existing DSA disappeared in 22 patients whereas they persisted in 12. Variables associated with DSA persistence were age <50 years (P = 0.009), a history of previous transplantation (P = 0.039), the presence of class II DSA (P = 0.009), an MFI of preformed DSA >3500 (P < 0.001), and the presence of two or more DSA (P < 0.001). DSA persistence was associated with a higher risk of graft loss and antibody‐mediated rejection. Previously undetected preformed DSA are deleterious to graft survival only when they persist after transplantation.     

Evaluation of C1q Status and Titer of De Novo Donor‐Specific Antibodies as Predictors of Allograft Survival

De novo donor‐specific antibodies (dnDSAs) that develop after renal transplantation are independent predictors of allograft loss. However, it is unknown if dnDSA C1q status or titer at the time of first detection can independently predict allograft loss. In a consecutive cohort of 508 renal transplant recipients, 70 developed dnDSAs. Histologic and clinical outcomes were correlated with the C1q assay or dnDSA titer. C1q positivity correlated with dnDSA titer (p < 0.01) and mean fluorescence intensity (p < 0.01) and was more common in class II versus class I dnDSAs (p < 0.01). C1q status correlated with tubulitis (p = 0.02) and C4d status (p = 0.03) in biopsies at the time of dnDSA development, but not T cell–mediated rejection (TCMR) or antibody‐mediated rejection (ABMR). De novo DSA titer correlated with Banff g, i, t, ptc, C4d scores, TCMR (p < 0.01) and ABMR (p < 0.01). Post‐dnDSA graft loss was observed more frequently in recipients with C1q‐positve dnDSA (p < 0.01) or dnDSA titer ≥ 1:1024 (p ≤ 0.01). However, after adjustment for clinical phenotype and nonadherence in multivariate models, neither C1q status nor dnDSA titer were independently associated with allograft loss, questioning the utility of these assays at the time of dnDSA development.