Determinants of Poor Graft Outcome in Patients with Antibody-Mediated Acute Rejection

This study analyzes the incidence and course of antibody-mediated rejection (AMR) in a cohort of 237 renal transplant patients followed for 30 +/- 20 months. Among these, 32 patients were considered to be at risk for AMR and received intravenous immunoglobulin (IVIg), either as preconditioning (Group A, n = 18) or at the time of transplant (Group B, n = 14). The prevalence of AMR was 27.8% in Group A, 57.1% in Group B and 3.9% in the remainder of the population. Although graft loss remains greater among AMR than for acute cellular rejection (ACR) or the overall transplant population, we have identified a good outcome group (GFR > 15 mL/min/1.73 m(2)) (n = 13), whose renal function at the end of follow-up was comparable to that of the general transplant population. The factors associated with bad outcome are: (1) immunologic: presence and/or persistence of donor-specific anti-HLA antibodies post-transplantation and (2) histologic: neutrophilic glomerulitis, peritubular capillary dilatation with neutrophil infiltrates and interstitial edema at the time of first biopsy; and at the time of late biopsy (3-6 months): lesions of vascular rejection, and monocyte/macrophage infiltrates in glomeruli and dilated peritubular capillaries. Persistence of C4d does not predict outcome. This study outlines for the first time the immunologic and histologic profiles of AMR patients with poor prognosis.     

Subclinical Acute Antibody-Mediated Rejection in Positive Crossmatch Renal Allografts

Subclinical antibody-mediated rejection (AMR) has been described in renal allograft recipients with stable serum creatinine (SCr), however whether this leads to development of chronic allograft nephropathy (CAN) remains unknown. We retrospectively reviewed data from 83 patients who received HLA-incompatible renal allografts following desensitization to remove donor-specific antibodies (DSA). Ten patients had an allograft biopsy showing subclinical AMR [stable SCr, neutrophil margination in peritubular capillaries (PTC), diffuse PTC C4d, positive DSA] during the first year post-transplantation; 3 patients were treated with plasmapheresis and intravenous immunoglobulin. Three patients had a subsequent rise in SCr and an associated biopsy with AMR; 5 others showed diagnostic or possible subclinical AMR on a later protocol biopsy. One graft was lost, while remaining patients have normal or mildly elevated SCr 8-45 months post-transplantation. However, the mean increase in CAN score (cg + ci + ct + cv) from those biopsies showing subclinical AMR to follow-up biopsies 335 +/- 248 (SD) days later was significantly greater (3.5 +/- 2.5 versus 1.0 +/- 2.0, p = 0.01) than that in 24 recipients of HLA-incompatible grafts with no AMR over a similar interval (360 +/- 117 days), suggesting that subclinical AMR may contribute to development of CAN.     

Acute Tubular Injury Is an Important Component in Type I Acute Antibody-Mediated Rejection

Background

“Acute tubular necrosis (ATN)-like” changes in type I acute antibody- mediated rejection (AAMR) have been proposed since 2005, but the presence of “ATN-like” injury in AAMR has not well been established. The aim of this study was to confirm the presence of acute tubular injury in type I AAMR, using the specific proximal tubular injury marker, kidney injury molecule-1 (KIM-1).

Design

The study included 3 groups of cases, namely, a negative control group (normal nontransplantation renal parenchyma as group 1, n = 11), a positive control group (transplant ATN with negative C4d staining as group 2, n = 12), and study cases (type 1 AAMR as group 3, n = 19). Biopsy specimens from all groups were stained immunohistochemically for KIM-1 (monoclonal antibody) and KIM-1 staining intensity in proximal tubules was graded from 0.5 to 3+. Clinical indices were also correlated and analyzed.

Results

Group 1 demonstrated significantly lower serum creatinine levels (1.02 ± 0.10 mg/dL) when compared with both group 2 and group 3. Both groups 2 and 3 showed similar serum creatinine levels (4.02 ± 0.59 mg/dL in group 2 and 3.24 ± 0.34 mg/dL in group 3). The negative control group demonstrated negative proximal tubule staining for KIM-1, whereas both groups 2 and 3 showed positive KIM-1 staining in proximal tubules (intensity ranging from 1+ to 3+ in group 2 and from 0.5 to 3+ in group 3).

Conclusion

Our results, using KIM-1 immunohistochemistry, demonstrated that acute tubular injury is an important component of type I AAMR.     

Costs of Treatment of Acute Antibody-Mediated Rejection in Kidney Transplant Recipients

BackgroundAntibody-mediated rejection (AMR) remains challenging in kidney transplant recipients. It may negatively impact the graft survival, and its treatment is associated to relatively high expenses. The aim of our study was to assess the costs of treatment of acute AMR in the Polish settings.MethodsA total of 11 kidney transplant recipients with acute AMR diagnosed between September 2016 and August 2019 and treated in our center were included. Direct costs of inpatient and outpatient care in the first year after AMR diagnosis from the perspective of a transplant center were retrospectively calculated.ResultsThe costs of treatment of acute AMR were considerably high, with a mean 1-month cost of treatment 12,718 PLN (～€2925; ～3307 US dollars). That means that costs of management of kidney transplant recipients with acute AMR are almost 2-fold higher than hemodialysis. Intravenous immunoglobulin was responsible for the majority (55%) of costs.ConclusionsTreatment of acute AMR increases the costs of post–kidney transplant care in involved patients. Therefore, efforts should be made to minimize the risk for acute AMR. Despite its potential clinical benefits, management of acute AMR is even more expensive than dialysis. Therefore, further cost-effectiveness analyses are needed to justify the spending and to establish the best treatment regimens.     

Treatment of Simultaneous Acute Antibody-Mediated Rejection and Acute Cellular Rejection With Alemtuzumab in Kidney Transplantation: A Case Report

This is a case report of a living related donor kidney transplantation using basiliximab induction and maintenance immunosuppression with cyclosporine, mycophenolate sodium, and steroid. On the second posttransplant day, the patient developed acute antibody-mediated rejection, which was treated with plasmapheresis and intravenous immunoglobulin (IVIG). Five days later, the graft had still not responded to the treatment. Another biopsy revealed additional acute cellular rejection (Banff IIA). As alemtuzumab can rapidly deplete T and B lymphocytes, monocytes, and natural killer cells, the patient was treated with alemtuzumab (30 mg subcutaneously) together with methylprednisolone (500 mg) and two more plasmaphereses. The kidney graft responded within 48 hours, producing more than 4 L of urine per day. The total lymphocyte decreased from 530/μL to 50/μL remaining in the 50 to 220/μL range. The patient received valgancyclovir and cotrimoxazole as infection prophylaxis. The kidney graft responded well to the rescue treatment and the patient was discharged with a serum creatinine of 1.1 mg/mL and has been uneventfully followed in the outpatient clinic for 8 months. Today, with the potent, effective, and selective immunosuppressive regimens, the rate and severity of acute cellular rejection in kidney transplantation has decreased in most centers. However, the rate of acute antibody-mediated rejection has increased to levels greater than those of acute cellular rejection in many centers. Acute antibody-mediated rejection is more difficult and expensive to treat successfully. The treatment of acute antibody-mediated rejection included plasmapheresis and IVIG. Herein we have reported a case of kidney transplantation simultaneously developing acute antibody-mediated and acute cellular rejection; the patient was successfully treated with alemtuzumab.     

Correlation of Donor-Specific Antibodies, Complement and Its Regulators with Graft Dysfunction in Cardiac Antibody-Mediated Rejection

Antibody-mediated rejection (AMR) is an immunopathologic process in which activation of complement often results in allograft injury. This study correlates C4d and C3d with HLA serology and graft function as diagnostic criteria for AMR. Immunofluorescence staining for C4d and C3d was performed on 1511 biopsies from 330 patients as part of routine diagnostic work-up of rejection. Donor-specific antibodies were detected in 95% of those with C4d+C3d+ biopsies versus 35% in the C4d+C3d– group (p = 0.002). Allograft dysfunction was present in 84% in the C4d+ C3d+ group versus 5% in the C4d+C3d− group (p < 0.0001). Combined C4d and C3d positivity had a sensitivity of 100% and specificity of 99% for the pathologic diagnosis of AMR and a mortality of 37%. Since activation of complement does not always result in allograft dysfunction, we correlated the expression pattern of the complement regulators CD55 and CD59 in patients with and without complement deposition. The proportion of patients with CD55 and/or CD59 staining was highest in C4d+C3d− patients without allograft dysfunction (p = 0.03). We conclude that a panel of C4d and C3d is diagnostically more useful than C4d alone in the evaluation of AMR. CD55 and CD59 may play a protective role in patients with evidence of complement activation.     

Pretransplantation Cellular Alloreactivity Is Predictive of Acute Graft Rejection and 1-Year Graft Function in Kidney Transplant Recipients

Objective

To study cellular alloimmunity in kidney allograft recipients using an interferon-γ enzyme-linked immunosorbent spot assay (ELISPOT).

Material and Methods

Donor splenocyte peripheral blood mononuclear cells were obtained during kidney recovery in 53 kidney recipients including 11 with positive panel-reactive antibodies pretransplantation. For ELISPOT data analysis, the spot number, size, and intensity were calculated, reflecting the volume of cytokine secretion at the single-cell level. Results were recalculated as the ratio of the values observed for donor-stimulated to unstimulated recipient cells corrected for residual donor activity.

Results

Significantly greater pretransplantation donor-stimulated activity was observed in recipients who experienced an acute rejection episode (ARE) within 1 year (P < .05). Mean change in spot number, size, and intensity in patients without or with AREs was 0.99 vs 3.33, 1.60 vs 6.05, and 1.40 vs 6.31, respectively. The assessed parameters were prognostic of high risk of ARE: 1.5-fold increase in spot number (ARE incidence, 52% vs 9%), 2.5-fold increase in spot size (ARE incidence, 53% vs 13%), and 2.7-fold increase in spot intensity (ARE incidence, 52% vs 9%). The 3 parameters correlated with 1-year serum creatinine concentration (P < .05). In 14 recipients, AREs could have been predicted in 11 using pretransplantation ELISPOT results, and in only 2 on the basis of panel-reactive antibodies.

Conclusion

The ELISPOT-determined capacity of donor-induced reactivity observed in recipient cells obtained just before transplantation is predictive of risk of graft rejection and 1-year allograft function.     

Time of Occurrence of Kidney Acute Antibody-Mediated Allograft Rejection/Acute Cellular Rejection and Cell Senescence: Implications for Function Outcome

Background

Late versus early acute antibody-mediated rejection (AAMR) or acute cellular rejection (ACR) episodes are associated with poorer kidney function and graft survival. We explored whether cell senescence upon detection of AAMR ± ACR contributes to these results.

Methods

We reviewed the renal transplant database of 2 Institutions. Biopsies performed for acute graft dysfunction from January 2000 to March 2007 were analyzed for morphological criteria of AAMR with or without ACR (n = 17 from 17 patients). Immunoperoxidase staining for p16^INK4B was performed on the remaining paraffin-embedded tissue in 9 of 17 cases. The average number of positive cells/high power field (HPF) was calculated in every case. Cases with rejection were grouped according to the time of presentation: early (<3 months n = 8) versus late (>3 months; n = 9). Graft function was obtained using the Modification of Diet in Renal Disease (mDRD) glomerular filtration rate estimate (eGFR) before, during rejection, and at the last visit, to calculate ΔeGFR.

Results

Nuclear expression of p16^INK4B was 12.2 ± 11.3 cells/HPF in 4 of 8 biopsies performed at a median of 23 (range = 4-80) days (early AAMR ± ACR), and 59.8 ± 51.3 cells/HPF in 5 of 9 biopsies performed at a median of 1171 (range = 279-3210) days (late AAMR ± ACR). eGFR before rejection was 48.5 ± 7.6 mL/min, and 43.7 ± 4.3 mL/min for early and late rejection episodes, respectively (P = not significant [NS]). ΔeGFR of 12.5 ± 25.9 mL/min (early rejection), and −13.7 ± −12.3 mL/min (late rejection), versus last follow-up visit (P = .02) occurred at a median of 143.9 ± 94.1 and 69.6 ± 35.1 weeks after the rejection episodes, respectively.

Conclusions

Even though the number of biopsies analyzed for p16^INK4a was small, it was evident that the number of cells expressing this marker of senescence was higher among biopsy specimens obtained with late rejection episodes. This finding suggests the presence of injuries prior to the rejection episode. The significantly lower eGFR at last follow-up in the late rejection group may translate to a reduced capacity of the repair process to sustain nephron function.     

Acute Antibody-Mediated Rejection in Living ABO-Incompatible Kidney Transplantation: Long-Term Impact and Risk Factors

The impact of acute antibody-mediated rejection (AAMR) on the long-term outcome on ABO-incompatible (ABOI) kidney transplantation is not well understood. We retrospectively analyzed the long-term impact of AAMR and risk factors for AAMR in 57 consecutive recipients performed between 1999 and 2004. Nineteen patients (33%) who developed AAMR within 3 months posttransplantation constituted of the AMR group. The graft survival rate was significantly lower in the AMR group (AMR vs. non-AMR, respectively; 5 years: 84% vs. 95%; 8 years: 45% vs. 95%; p = 0.009). The prevalence of transplant glomerulopathy at 1 year posttransplantation was significantly higher in the AMR group (AMR 64% vs. non-AMR 3%, p < 0.001). Multivariate analysis demonstrated that anti-blood group IgG antibody titers of 1:32 at the time of transplantation (OR, 9.52; p = 0.041) and donor-specific anti-HLA antibodies (DSHA) detected by Luminex single bead method (OR, 5.68; p = 0.015) were independent risk factors for AAMR regardless of baseline anti-blood group IgG antibody titers. Our results indicate that AAMR has a heavy impact on the long-term outcome and preoperative DSHA appears to have a more significant association with poor graft outcomes than anti-blood group antibodies, even in ABOI kidney transplantation.     

Platelets in Early Antibody-Mediated Rejection of Renal Transplants

Antibody-mediated rejection is a major complication in renal transplantation. The pathologic manifestations of acute antibody-mediated rejection that has progressed to functional impairment of a renal transplant have been defined in clinical biopsy specimens. However, the initial stages of the process are difficult to resolve with the unavoidable variables of clinical studies. We devised a model of renal transplantation to elucidate the initial stages of humoral rejection. Kidneys were orthotopically allografted to immunodeficient mice. After perioperative inflammation subsided, donor-specific alloantibodies were passively transferred to the recipient. Within 1 hour after a single transfer of antibodies, C4d was deposited diffusely on capillaries, and von Willebrand factor released from endothelial cells coated intravascular platelet aggregates. Platelet-transported inflammatory mediators platelet factor 4 and serotonin accumulated in the graft at 100- to 1000-fold higher concentrations compared with other platelet-transported chemokines. Activated platelets that expressed P-selectin attached to vascular endothelium and macrophages. These intragraft inflammatory changes were accompanied by evidence of acute endothelial injury. Repeated transfers of alloantibodies over 1 week sustained high levels of platelet factor 4 and serotonin. Platelet depletion decreased platelet mediators and altered the accumulation of macrophages. These data indicate that platelets augment early inflammation in response to donor-specific antibodies and that platelet-derived mediators may be markers of evolving alloantibody responses.     

Fractal Analysis of Heart Graft Acute Rejection Microscopic Images

Background

Endomyocardial biopsy to evaluate rejection in the transplanted heart is accepted at the “gold standard.” The complexity of microscopic images suggested using digital methods for precise evaluating of acute rejection episodes with numerical representation. The aim of the present was study to characterize digitally acute rejection of the transplanted heart using complexity/fractal image analysis.

Material and Methods

Biopsy samples harvested form 40 adult recipients after orthotropic heart transplantation were collected and rejection grade was evaluated according to the International Society for Heart and Lung Transplantation (0, 1a, 1b, or 3a) at transverse and longitudinal sections. Fifteen representative digital microscope images from each grade were collected and analyzed after Sobel edge detection and binarization.

Results

Only mean fractal dimension showed a progressive and significant increase and correlation based on rejection grade using longitudinal sections. Lacunarity and number of foreground pixels showed unequivocal results.

Conclusion

Mean fractal diameter could serve as auxiliary digital parameter for grading of acute rejection in the transplanted heart.     

Mitochondrial Permeability Transition in Cardiomyocyte Apoptosis during Acute Graft Rejection

Evidence indicates that acute cardiac graft rejection is associated with cardiomyocyte apoptosis. Mitochondrial permeability transition (MPT) induces apoptotic cell death. We sought to determine whether MPT might play a role in cardiomyocyte apoptosis in the rat model of heterotopic cardiac transplantation. Syngenic and allogenic transplantations were performed, and both native and grafted hearts were harvested 3 or 5 d after transplantation for detection of acute rejection, assessment of Ca²⁺-induced MPT, and myocardial apoptosis by TUNEL staining and caspase 3 activity. Allogenic grafts developed severe acute rejection at day 5 with concomitant cardiomyocyte apoptosis (apoptotic index: 7.1 ± 1.0% vs. 1.0 ± 0.2% in syngenic hearts, and caspase 3 activity: 38 ± 25 vs. 5 ± 9 nmol/mg, in allogenic vs. syngenic grafts, respectively). At day 5, Ca²⁺-induced MPT was dramatically altered in allogenic when compared with syngenic grafts (mean Ca²⁺ overload averaged 0 ± 20 vs. 280 ± 30 μM in allogenic and syngenic grafts, respectively). NIM811, a nonimmunosuppressive derivative of cyclosporin A (CsA), that specifically inhibits the MPT pore, did not alter acute rejection, but significantly delayed Ca²⁺-induced MPT pore opening, attenuated caspase 3 activity and cardiomyocyte apoptosis in allogenic grafts. This suggests that mitochondrial permeability transition pore opening may play an important role in cardiomyocyte apoptosis associated with acute cardiac graft rejection.     

Effect of Rabbit Antithymocyte Globulin on Acute and Chronic Active Antibody-Mediated Rejection After Kidney Transplantation

BackgroundRabbit antithymocyte globulin (rATG) induction is associated with reduction in the occurrence of de novo donor-specific antibody (DSA) and antibody-mediated rejection (AMR). Therefore, rATG administration is considered as a treatment for AMR. However, only a few studies have investigated the treatment of AMR with rATG after kidney transplantation.MethodsBetween April 2013 and March 2018, 162 consecutive de novo kidney transplantations were performed with induction immunosuppressive therapy comprising tacrolimus, mycophenolate mofetil, methylprednisolone, and basiliximab. AMR was diagnosed on the basis of the presence of DSA and episode biopsy findings. For DSA-positive recipients, plasmapheresis was performed to remove DSA before rATG administration (1.5 mg/kg for 5 days). Patients treated with rATG against active AMR were retrospectively analyzed for graft function.ResultsA total of 13 kidney transplant recipients developed active AMR within 302 days after transplantation. After rATG administration, the mean serum creatinine and urine protein levels significantly declined from 3.03 mg/dL to 1.68 mg/dL (P = .002) within 46 days and from 3.01 g/gCr to 0.54 g/gCr (P = .006) within 106 days, respectively. The peripheral blood lymphocyte count rapidly decreased after rATG administration and remained low for 12 months. With regard to adverse events, fever (84.6%), cytomegaloviremia (84.6%), thrombocytopenia (61.5%), anemia (30.8%), and neutropenia (15.4%) occurred within 3 months after rATG administration.ConclusionsrATG improved graft function by suppressing peripheral blood lymphocytes in kidney transplant recipients with active AMR. The rATG administration as a treatment for active AMR may contribute to positive graft outcomes after kidney transplantation.     

Role of Major Histocompatibility Complex and Ethnicity in Acute Renal Graft Rejection

Background

The major histocompatibility complex (MHC) plays a main role in antigen presentation. Class I, II, and III genes form defined “blocks” of conserved DNA sequences (conserved extended haplotypes) that are useful to follow the ancestry of a population. Each variant encodes a specific peptide that determines a particular individual's immune response. In addition, differential expression of HLA antigens in certain physiological and pathological conditions may participate in the pathogenesis of allograft rejection versus tolerance.

Objectives

The aim of this study was to determine whether the specific HLA ancestry was associated with acute renal graft rejection among the Mexican mestizo population.

Materials and Methods

We studied 544 Mexican mestizo renal donors and their respective recipients for their serologically determined HLA and based on antigens haplotype assignments. The acute rejection group was compared with the nonrejection group among donors and recipients, correspondingly.

Results

Frequent Mexican alleles were observed in this study. Moreover, HLA-B*61/-DR*04, HLA-A*35/-DR*06 (Amerindian ancestry), HLA-A*68/-DR*01, HLA-A*28/-B*65/-DR*01 (African ancestry), and HLA-A*33/-B*65 (Caucasian ancestry) in donors were associated with acute renal graft rejection episodes.

Conclusion

Knowing the ancestry of a donor's HLA molecules may help to individualize immunosuppressive therapy for postransplant surveillance, because they may be more membrane-exposed in parenchymal cells, making them more susceptible of being recognized by the recipient's immune system.     

Long-Term Experience of Plasmapheresis in Antibody-Mediated Rejection in Renal Transplantation

Background

Antibody-mediated rejection (AMR) continues to pose a serious challenge in renal transplantation with potentially devastating consequences. Treatment options for this condition include plasmapheresis, high-dose intravenous immunoglobulin (IVIG), plasmapheresis with low-dose IVIG, and the use of rituximab (anti-CD20 chimeric antibody). We previously reported on the short-term outcome of plasmapheresis as a rescue therapy for AMR in our centre. We now report on the long-term follow up.

Methods

Over a 2.5-year study period, 440 cadaveric transplants were performed. AMR developed in 20 (4.5%) patients. Treatment included plasmapheresis and intensification of their immunosuppressive therapy.

Results

Excluding two patients who had infarcted their grafts at diagnosis, 18 patients received plasmapheresis treatment for AMR. Of the 18 patients treated, 14 recovered function, two developed graft infarction within a fortnight of starting plasmapheresis, and two patients were withdrawn from treatment. In the 14 who recovered renal function, graft survival was 86% at 12 months. In this study we report on the 5-year follow-up of these AMR-treatment responders. Eleven patients have a functioning graft at 5 years; graft function was stable with a mean serum creatinine of 130 μmol/L at 5 years compared to 123 μmol/L at 1 year. At 5-years follow-up; graft survival was 78% and patient survival 93%.

Conclusions

Little information is available in the literature regarding the long-term outcome of this therapy. This is the first report on the long-term (5-year) follow-up of plasmapheresis as a rescue therapy for AMR.     

Genome‐Wide Association Study of Acute Renal Graft Rejection

Acute renal rejection is a major risk factor for chronic allograft dysfunction and long‐term graft loss. We performed a genome‐wide association study to detect loci associated with biopsy‐proven acute T cell–mediated rejection occurring in the first year after renal transplantation. In a discovery cohort of 4127 European renal allograft recipients transplanted in eight European centers, we used a DNA pooling approach to compare 275 cases and 503 controls. In an independent replication cohort of 2765 patients transplanted in two European countries, we identified 313 cases and 531 controls, in whom we genotyped individually the most significant single nucleotide polymorphisms (SNPs) from the discovery cohort. In the discovery cohort, we found five candidate loci tagged by a number of contiguous SNPs (more than five) that was never reached in iterative in silico permutations of our experimental data. In the replication cohort, two loci remained significantly associated with acute rejection in both univariate and multivariate analysis. One locus encompasses PTPRO, coding for a receptor‐type tyrosine kinase essential for B cell receptor signaling. The other locus involves ciliary gene CCDC67, in line with the emerging concept of a shared building design between the immune synapse and the primary cilium.     

Disappearance of T Cell-Mediated Rejection Despite Continued Antibody-Mediated Rejection in Late Kidney Transplant Recipients

The prevalent renal transplant population presents an opportunity to observe the adaptive changes in the alloimmune response over time, but such studies have been limited by uncertainties in the conventional biopsy diagnosis of T cell-mediated rejection (TCMR) and antibody-mediated rejection (ABMR). To circumvent these limitations, we used microarrays and conventional methods to investigate rejection in 703 unselected biopsies taken 3 days to 35 years post-transplant from North American and European centers. Using conventional methods, we diagnosed rejection in 205 biopsy specimens (28%): 67 pure TCMR, 110 pure ABMR, and 28 mixed (89 designated borderline). Using microarrays, we diagnosed rejection in 228 biopsy specimens (32%): 76 pure TCMR, 124 pure ABMR, and 28 mixed (no borderline). Molecular assessment confirmed most conventional diagnoses (agreement was 90% for TCMR and 83% for ABMR) but revealed some errors, particularly in mixed rejection, and improved prediction of failure. ABMR was strongly associated with increased graft loss, but TCMR was not. ABMR became common in biopsy specimens obtained >1 year post-transplant and continued to appear in all subsequent intervals. TCMR was common early but progressively disappeared over time. In 108 biopsy specimens obtained 10.2–35 years post-transplant, TCMR defined by molecular and conventional features was never observed. We conclude that the main cause of kidney transplant failure is ABMR, which can present even decades after transplantation. In contrast, TCMR disappears by 10 years post-transplant, implying that a state of partial adaptive tolerance emerges over time in the kidney transplant population.