Isolated v‐lesion in kidney transplant recipients: Characteristics,association with DSA,and histological follow‐up

Isolated v‐lesion (IvL) represents a rare and challenging situation in renal allograft biopsies because it is unknown whether IvL truly represents rejection, antibody‐ or T cell–mediated, or not. This multicentric retrospective study describes the clinicopathological features of IvL with an emphasis on the donor‐specific antibody (DSA) status, histological follow‐up, and graft survival. Inclusion criteria were the presence of v‐lesion with minimal interstitial (i ≤ 1) and microvascular inflammation (g + ptc≤1). C4d‐positive biopsies were excluded. We retrospectively found 33 IvL biopsies in 33 patients, mainly performed in the early posttransplantation period (median time 27 days) and clinically indicated in 66.7%. A minority of recipients (5/33, 15.2%) had DSA at the time of biopsy. IvL was treated by anti‐rejection therapy in 21 cases (63.6%), whereas 12 (36.4%) were untreated. Seventy percent of untreated patients and 66% of treated patients showed favorable histological evolution on subsequent biopsy. Kidney graft survival in IvL was significantly higher than in a matched cohort of antibody‐mediated rejection with arteritis. In conclusion, IvL is not primarily antibody‐mediated and may show a favorable evolution. The heterogeneity of IvL pathophysiology on early biopsies should prompt DSA testing as well as close clinical and histological follow‐up in all patients with IvL.     

Compartment‐specific expression of natural killer cell markers in renal transplantation: immune profile in acute rejection

Natural killer (NK) cells have been implicated in graft dysfunction. Here, we formulated hypothesis that distinct patterns of expression NK cells markers correlated with acute rejection in kidney transplantation. Therefore, we studied the pattern of NK cell markers CD56, CD57, and CD16 in different compartments of biopsies obtained from recipients diagnosed with acute graft rejection, with or without donor‐specific antibodies (DSA). DSA‐negative biopsies‐from patients with acute T‐cell mediated rejection (aTCMR) had an increased expression of CD56+ and CD57+ cells (P = 0.004 and P = 0.001) in the interstitial compartment in comparison with DSA‐positive biopsies from patients acute antibody‐mediated rejection (aABMR) with (aABMR C4d+) and without C4d deposition (aABMR C4d‐). CD16+ cells was increased (P = 0.03) in the glomerular compartment in DSA‐positive biopsies. We assume that CD16+ expression and antibody‐dependent cellular cytotoxicity (ADCC) in microvascular injury can be associated with aABMR. IFN‐γ release from cytoplasmic granules of NK cell could be associated with aTCMR. Our findings suggest that NK cells need to be carefully evaluated because variations in NK cell marker expression might imply the involvement of different immune system pathways in graft rejection.     

Early Ultrastructural Changes in Renal Allografts: Correlation With Antibody‐Mediated Rejection and Transplant Glomerulopathy

Transplant glomerulopathy (TG) is associated with antibody‐mediated renal allograft rejection (AMR) and reduced graft survival. Histologically, TG is typically seen >1 year posttransplantation. However, ultrastructural changes including glomerular endothelial swelling, subendothelial widening and early glomerular basement membrane duplication are associated with development of TG but appear much earlier. We examined the specificity of these changes for AMR, and whether these are inevitably associated with development of TG. Of 98 for cause renal allograft biopsies carried out within 3 months of transplantation with available serologic data, 17 showed C4d‐positive AMR and 16 had histologic changes of AMR and donor‐specific antibodies (DSA), but no C4d. All three ultrastructural changes were seen in 11 of 17 biopsies with C4d‐positive AMR, 8 of 16 with histologic changes of AMR and DSA but no C4d, and 0 of 65 without histologic changes of AMR and/or DSA (p < 0.0001 for both of the former groups vs. the latter). Twenty patients with positive DSA (18 with histologic changes of AMR and 11 C4d‐positive) had ≥1 follow‐up biopsy; eight developed overt TG 3.5–30 months posttransplantation. Among the 18 patients with DSA and histologic changes of AMR, 11 C4d‐positive and 7 C4d‐negative, treatment for AMR after the early biopsy significantly reduced subsequent development of overt TG.     

Antibody‐mediated rejection in hand transplantation

Clinical relevance of antibody‐mediated rejection (ABMR) in vascularized composite allotransplantation (VCA) has not been defined. We herein describe a novel type of donor‐specific antibody (DSA) and B‐cell‐associated rejection in hand transplantation. In 2003, a bilateral forearm transplantation was performed on a 42‐year‐old male patient. In 2012, the patient presented with edematous hands and forearms without skin lesions. Punch skin biopsies revealed rejection grade Banff II. Immunohistochemical analysis identified large aggregates of CD20 +  lymphocytes with an architecture resembling lymph nodes. De novo DSA was found at a high level. Steroid treatment was ineffective, but administration of rituximab resulted in complete remission of clinical symptoms, evaporation of B‐cell aggregates, and disappearance of DSA. We herein report the first case of what we suggest is an ABMR in VCA occurring at 9 years after forearm transplantation. Rituximab therapy successfully reversed the event.     

Plasma cell densities and glomerular filtration rates predict renal allograft outcomes following acute rejection

The contribution of T cells and graft‐reactive antibodies to acute allograft rejection is widely accepted, but the role of graft‐infiltrating B and plasma cells is controversial. We examined 56 consecutive human renal transplant biopsies classified by Banff schema into T‐cell‐mediated (N = 21), antibody‐mediated (N = 18), and mixed (N = 17) acute rejection, using standard immunohistochemistry for CD3, CD20, CD138, and CD45. In a predominantly African‐American population (75%), neither Banff classification nor C4d deposition predicted the return to dialysis. Immunohistochemical analysis revealed CD3⁺ T cells as the dominant cell type, followed by CD20⁺ B cells and CD138⁺ plasma cells in all acute rejection types. Using univariate Cox Proportional Hazard analysis, plasma cell density significantly predicted graft failure while B‐cell density trended toward significance. Surprisingly T‐cell density did not predict graft failure. The estimated glomerular filtration rate (eGFR) at diagnosis of acute rejection also predicted graft failure, while baseline eGFR ≥6 months prior to biopsy did not. Using multivariate analysis, a model including eGFR at biopsy and plasma cell density was most predictive of graft loss. These observations suggest that plasma cells may be a critical mediator and/or an independently sensitive marker of steroid‐resistant acute rejection.     

Patterns of De Novo Allo B Cells and Antibody Formation in Chronic Cardiac Allograft Rejection After Alemtuzumab Treatment

Even though the etiology of chronic rejection (CR) is multifactorial, donor specific antibody (DSA) is considered to have a causal effect on CR development. Currently the antibody‐mediated mechanisms during CR are poorly understood due to lack of proper animal models and tools. In a clinical setting, we previously demonstrated that induction therapy by lymphocyte depletion, using alemtuzumab (anti‐human CD52), is associated with an increased incidence of serum alloantibody, C4d deposition and antibody‐mediated rejection in human patients. In this study, the effects of T cell depletion in the development of antibody‐mediated rejection were examined using human CD52 transgenic (CD52Tg) mice treated with alemtuzumab. Fully mismatched cardiac allografts were transplanted into alemtuzumab treated CD52Tg mice and showed no acute rejection while untreated recipients acutely rejected their grafts. However, approximately half of long‐term recipients showed increased degree of vasculopathy, fibrosis and perivascular C3d depositions at posttransplant day 100. The development of CR correlated with DSA and C3d deposition in the graft. Using novel tracking tools to monitor donor‐specific B cells, alloreactive B cells were shown to increase in accordance with DSA detection. The current animal model could provide a means of testing strategies to understand mechanisms and developing therapeutic approaches to prevent chronic rejection.     

Donor Specificity but Not Broadness of Sensitization Is Associated With Antibody‐Mediated Rejection and Graft Loss in Renal Allograft Recipients

Panel‐reactive antibodies are widely regarded as an important immunological risk factor for rejection and graft loss. The broadness of sensitization against HLA is most appropriately measured by the “calculated population‐reactive antibodies” (cPRA) value. In this study, we investigated whether cPRA represent an immunological risk in times of sensitive and accurate determination of pretransplantation donor‐specific HLA antibodies (DSA). Five hundred twenty‐seven consecutive transplantations were divided into four groups: cPRA 0% (n = 250), cPRA 1–50% (n = 129), cPRA 51–100% (n = 43), and DSA (n = 105). Patients without DSA were considered as normal risk and received standard immunosuppression without T cell–depleting induction. Patients with DSA received an enhanced induction therapy and maintenance immunosuppression. Surveillance biopsies were performed at 3 and 6 months. Median follow‐up was 5.7 years. Among the three cPRA groups, there were no differences regarding the 1‐year incidence of ABMR (p = 0.16) and TCMR (p = 0.75). The 5‐year allograft survival rates were similar and around 87% (p = 0.28). The estimated glomerular filtration rate at last follow‐up was 50–53 mL/min (p = 0.45). On multivariable Cox proportional hazard analysis, the strongest independent predictor for ABMR and (death‐censored) graft survival was pretransplantation DSA. cPRA were not predictive for ABMR, TCMR, or (death‐censored) graft survival. We conclude that with current DSA assignment, the broadness of sensitization measured by cPRA does not imply an immunological risk.     

Utility of protocol kidney biopsies for de novo donor‐specific antibodies

There is limited information about the role of protocol kidney biopsies for de novo donor‐specific antibodies (dnDSA) in kidney transplant recipients, especially in those with stable graft function. We initiated a routine posttransplant DSA monitoring and surveillance biopsy program for dnDSA since 2014. We identified 45 kidney transplant recipients with dnDSA detected between January 2014 and February 2017 who underwent kidney biopsy within 60 days of detection of dnDSA. Twenty‐nine (64%) had stable graft function and 16 (36%) had impaired graft function at the time of dnDSA detection. Even in the group with stable graft function, we found a high rate of rejection (53%) on biopsy. Eighty‐eight percent of patients with impaired graft function had rejection. Those patients with impaired graft function had significantly lower estimated glomerular filtration rate at 12 months postbiopsy and at last follow‐up. Those with impaired graft function had more graft failures; however, this result was not statistically significant. The high rate of asymptomatic rejection, and the fact that outcomes in asymptomatic patients are poor, is in support of the utility of surveillance biopsies in patients with dnDSA.     

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.     

Pancreas Allograft Biopsies with Positive C4d Staining and Anti‐Donor Antibodies Related to Worse Outcome for Patients

C4d+ antibody‐mediated rejection following pancreas transplantation has not been well characterized. Therefore, we assessed the outcomes of 27 pancreas transplantation patients (28 biopsies), with both C4d staining and donor‐specific antibodies (DSA) determined, from a cohort of 257 patients. The median follow‐up was 50 (interquartile range [IQR] 8–118) months. Patients were categorized into 3 groups: group 1, patients with minimal or no C4d staining and no DSA (n = 13); group 2, patients with either DSA present but no C4d, diffuse C4d+ and no DSA or focal C4d+ and DSA (n = 6); group 3, patients with diffuse C4d+ staining and DSA (n = 9). Active septal inflammation, acinar inflammation and acinar cell injury/necrosis were significantly more abundant in group 3 than in group 2 (respective p‐values: 0.009; 0.033; 0.025) and in group 1 (respective p‐values: 0.034; 0.009; 0.002). The overall uncensored pancreas graft survival rate for groups 1, 2 and 3 were 53.3%, 66.7% and 34.6%, respectively (p = 0.044). In conclusion, recipients of pancreas transplants with no C4d or DSA had excellent long‐term graft survival in comparison with patients with both C4d+ and DSA present. Hence, C4d should be used as an additional marker in combination with DSA in the evaluation of pancreas transplant biopsies.     

Early interstitial macrophage infiltration with mild dysfunction is associated with subsequent kidney graft loss

Macrophage infiltration is associated with unfavorable kidney graft outcome in protocol biopsies, but few studies have evaluated its impact on clinical practice. We therefore prospectively evaluated 37 kidney transplant recipients (KTRs) who underwent kidney biopsy due to slight increases in serum creatinine, or mild proteinuria (>0.3 g/24 hr), in the first post‐transplant year. Banff score, CD68⁺ count (score 0‐3) by immunohistochemistry, and 1‐year DSA were assessed. DGF was reported in 10 (27%) patients, 6 (16%) had normal biopsy, 7 (19%) borderline lesions, 13 (35%) IFTA, and 11 (30%) other lesions. Fifteen KTRs had grade 3 CD68⁺ infiltration, and 47% developed de novo DSA. During a 6.2 ± 2.7 year follow‐up, four patients (11%) suffered from biopsy‐proven T‐cell rejection, 17 KTRs (46%) lost their graft (12 in the grade 3 CD68⁺ group). Graft survival was lower in KTRs with grade 3 CD68⁺ infiltration (P = 0.0074; log‐rank test). Grade 3 CD68⁺ infiltrate was an independent predictor of graft loss (HR 5.41, 95% CI 1.74‐16.8; P = 0.003), together with more severe graft dysfunction at biopsy (HR 6.41, 95% CI 2.57‐16; P < 0.001). We conclude that grade 3 CD68⁺ interstitial infiltration is associated with increased risk of subsequent graft loss independent of other factors.     

Interleukin‐17 positive cells accumulate in renal allografts during acute rejection and are independent predictors of worse graft outcome

Interleukin‐17 (IL‐17) plays an important role in the regulation of cellular and humoral immune responses. Recent studies suggest a role for IL‐17 in transplantation. Our study investigated whether quantifying IL‐17⁺ cells in renal transplant biopsies during acute rejection could have additional prognostic value for better stratifying patients at risk for nonresponsiveness to anti‐rejection therapy and future graft dysfunction. Forty‐nine renal biopsies with acute rejection were double immunostained and quantitatively analyzed for IL‐17 and CD3 (IL‐17⁺ T‐lymphocytes), tryptase (IL‐17⁺ mast cells) or CD15 (IL‐17⁺ neutrophils). Total IL‐17⁺ cell count correlated with total percentage of inflamed biopsy and estimated GFR during rejection. Most IL‐17⁺ cells were mast cells and neutrophils. We could hardly find any IL‐17⁺ T‐lymphocytes. IL‐17⁺ mast cells correlated with interstitial fibrosis/tubular atrophy (IF/TA). None of the IL‐17⁺ cell counts had an additional prognostic value for response to anti‐rejection treatment. Multivariate analysis correcting for C4d positivity and time from transplantation to biopsy showed that total IL‐17⁺ cell count independently predicts graft dysfunction at the last follow‐up, which was validated in an independent cohort of 48 renal biopsies with acute rejection. We conclude that intragraft IL‐17⁺ cell count during acute allograft rejection could have an additional value for predicting late graft dysfunction.     

Re‐evaluation of glomerulitis using occlusion criteria based on the Banff 2013 revision: a retrospective study

The presence of occlusion/near‐occlusion of glomerular capillaries was recently added to the existing definition of glomerulitis (g). We retrospectively re‐evaluated 135 renal allograft biopsies regarding g to ensure no antibody‐damaged grafts were missed. Previous and revised g scores (pg and rg, respectively) were compared for clinicopathologic correlations. The g score did not change in 100 (74.1%) biopsies. Thirty‐five (25.9%) biopsies were changed to a lower score. Sensitivity and specificity of pg and rg for the presence of donor‐specific antibodies (DSA) were 76% vs. 58% and 70% vs. 79%, respectively. Pg score indicated graft loss with 65% sensitivity and 63% specificity, whereas rg showed 46% sensitivity and 71% specificity. Area under the curve (AUC) values in ROC analysis for DSA and graft loss were as follows: pg, 0.773; rg, 0.693; and pg, 0.635; rg, 0.577, respectively. A comparison of the two AUC values revealed a significant difference between pg and rg only for DSA (P = 0.0076). Pg and post‐transplant time of biopsy independently predicted graft loss, whereas rg did not. In conclusion, revised g scores showed lesser sensitivity but higher specificity for DSA and graft loss. Recent definition of g missed antibody‐mediated rejection in few cases, and it was not an independent predictor for graft loss.     

Anti‐HLA Donor‐Specific Antibodies Detected in Positive B‐Cell Crossmatches by Luminex® Predict Late Graft Loss

The significance of B‐cell crossmatching in kidney transplantation is controversial. Recipients (n = 471) transplanted in a single centre from 1987 to 2005 with complete T‐ and B‐cell crossmatch records were studied. Sera from 83 patients transplanted across a positive B‐cell crossmatch, with concomitant negative T‐cell crossmatch (T–B+) on either current and/or peak sera were studied using Luminex^® to determine presence of donor‐specific antibodies (DSA). Clinical outcomes of T–B+ patients were compared with 386 T–B? patients. T–B+ predicted vascular (p = 0.01), but not cellular (p = 0.82) or glomerular (p = 0.14) rejection. IgG HLA DSA were found in 33% (n = 27) of the T–B+ patients and were associated with higher risk of any (p = 0.047), vascular (p = 0.01) or glomerular (p < 0.001) rejection at 6 months. Of 27 patients with DSA, 18/21 (86%) were the complement‐fixing IgG₁ and/or IgG₃ subclass antibodies. DSA imposed a statistically significant higher risk of graft loss 5 years posttransplant (1.8 [1.0–3.3], p = 0.045). This study showed that only one‐third of positive B‐cell crossmatch (BXM) was caused by DSA and was associated with late graft loss. Thus, using BXM to preclude kidney transplantation may potentially disadvantage >60% of patients in whom BXM is not indicative of the presence of DSA.     

Refractory acute kidney transplant rejection with CD20 graft infiltrates and successful therapy with rituximab

Acute rejection is an expected event after transplantation and has been associated with poor long-term kidney transplant outcome. The presence of B cells in the kidney graft with acute rejection is thought to be an omnious sign, as it has been associated with poor graft outcome. There is no definitive treatment for acute rejection with B cells in the graft. Rituximab, a humanized monoclonal antibody against CD20, has been used in the treatment of B cell lymphoma. We present the case of a 49-yr-old Caucasian male with early acute kidney allograft rejection that was refractory to high doses of steroids and rabbit anti-thymocyte globulin (thymoglobulin). Repeat renal biopsy revealed T cell and B cells in the kidney graft and responded to the combination of rituximab and muromonab (a mouse monoclonal antibody to CD3 receptor). Over 9 months post-transplant, the patient remains rejection free with a serum creatinine of 1.7 mg/dL.     

Isolated vascular “v” lesions in liver allografts: How to approach this unusual finding

According to the Banff criteria for kidney allografts, isolated vascular or “v” lesions are defined as intimal inflammation, age‐inappropriate fibro‐intimal hyperplasia, or both, without the presence of associated interstitial T cell‐mediated rejection (TCMR). In general, these lesions portend a worse outcome for kidney allografts, particularly in those where the “v” lesions are identified in patients with coexistent donor specific antibodies (DSA) or later after transplantation. Although affected arteries are rarely sampled in liver allograft biopsies, we identified nine patients at a mean of 1805 days posttransplantation and compared these to matched controls. Almost half (4 of 9) of the study patient biopsies showed inflammatory arteritis associated with focal or diffuse C4d positivity, which was not observed in matched controls. One “v” lesion patient progressed to rejection‐related graft failure and two developed moderate/severe TCMR in subsequent biopsies, whereas only one rejection episode occurred in follow‐up biopsies, and no rejection‐related deaths or graft failures were detected in controls. In conclusion, patients with liver allograft isolated “v” lesions should undergo further evaluation and closer follow‐up for impending TCMR and/or underlying co‐existent chronic antibody‐mediated rejection (AMR).     

Microvascular inflammation in renal allograft biopsies assessed by endothelial and leukocyte co‐immunostain: a retrospective study on reproducibility and clinical/prognostic correlates

The most prominent histologic lesion in antibody‐mediated rejection is microvascular inflammation (MVI); however, its recognition and scoring can be challenging and poorly reproducible between pathologists. We developed a dual immunohistochemical (IHC)‐stain (anti‐CD34/anti‐CD45 for endothelium/leukocytes) as ancillary tool to improve on the semi‐quantitative Banff scores and allow quantification of MVI. We examined the relationship between CD34–CD45 IHC‐based quantitative MVI score (the inflamed peritubular capillary ratio, iptcr) and renal‐graft failure or donor‐specific antibodies (DSA) strength at the time of biopsy. Quantitative iptcr score was significantly associated with renal graft failure (hazard ratio 1.81, per 1 SD‐unit [0.13 points] of iptcr‐increase; P = 0.026) and predicted the presence and strength of DSA (ordinal odds ratio: 2.42; P = 0.005; 75 biopsies/60 kidney transplant recipients; 30 HLA‐ and/or ABO‐incompatible). Next, we assessed inter‐pathologist agreement for ptc score and ptc extent (focal/diffuse) using CD34–CD45 IHC as compared to conventional stain. Compared to conventional stain, CD34–CD45 IHC significantly increased inter‐pathologist agreement on ptc score severity and extent (κ‐coefficient from 0.52–0.80 and 0.46–0.68, respectively, P < 0.001). Our findings show that CD34–CD45 IHC improves reproducibility of MVI scoring and facilitates MVI quantification and introduction of a dual anti‐CD34/CD45 has the potential to improve recognition of MVI ahead of DSA results.     

B‐Cell Depletion Extends the Survival of GTKO.hCD46Tg Pig Heart Xenografts in Baboons for up to 8 Months

Xenotransplantation of genetically modified pig organs offers great potential to address the shortage of human organs for allotransplantation. Rejection in Gal knockout (GTKO) pigs due to elicited non‐Gal antibody response required further genetic modifications of donor pigs and better control of the B‐cell response to xenoantigens. We report significant prolongation of heterotopic alpha Galactosyl transferase “knock‐out” and human CD46 transgenic (GTKO.hCD46Tg) pig cardiac xenografts survival in specific pathogen free baboons. Peritransplant B‐cell depletion using 4 weekly doses of anti‐CD20 antibody in the context of an established ATG, anti‐CD154 and MMF‐based immunosuppressive regimen prolonged GTKO.hCD46Tg graft survival for up to 236 days (n = 9, median survival 71 days and mean survival 94 days). B‐cell depletion persisted for over 2 months, and elicited anti‐non‐Gal antibody production remained suppressed for the duration of graft follow‐up. This result identifies a critical role for B cells in the mechanisms of elicited anti‐non‐Gal antibody and delayed xenograft rejection. Model‐related morbidity due to variety of causes was seen in these experiments, suggesting that further therapeutic interventions, including candidate genetic modifications of donor pigs, may be necessary to reduce late morbidity in this model to a clinically manageable level.     

Kidney Allograft Survival After Acute Rejection,the Value of Follow‐Up Biopsies

Kidney allografts are frequently lost due to alloimmunity. Still, the impact of early acute rejection (AR) on long‐term graft survival is debated. We examined this relationship focusing on graft histology post‐AR and assessing specific causes of graft loss. Included are 797 recipients without anti‐donor antibodies (DSA) at transplant who had 1 year protocol biopsies. 15.2% of recipients had AR diagnosed by protocol or clinical biopsies. Compared to no‐AR, all histologic types of AR led to abnormal histology in 1 and 2 years protocol biopsies, including more fibrosis + inflammation (6.3% vs. 21.9%), moderate/severe fibrosis (7.7% vs. 13.5%) and transplant glomerulopathy (1.4% vs. 8.3%, all p < 0.0001). AR were associated with reduced graft survival (HR = 3.07 (1.92–4.94), p < 0.0001). However, only those AR episodes followed by abnormal histology led to reduced graft survival. Early AR related to more late alloimmune‐mediated graft losses, particularly transplant glomerulopathy (31% of losses). Related to this outcome, recipients with AR were more likely to have new DSA class II 1 year posttransplant (no‐AR, 11.1%; AR, 21.2%, p = 0.039). In DSA negative recipients, early AR often leads to persistent graft inflammation and increases the risk of new DSA II production. Both of these post‐AR events are associated with increased risk of graft loss.