The international Banff classification for kidney transplant pathology discretizes the rejection continuum into distinct diagnostic categories, introducing artificial dichotomization and threshold effects. To better reflect the underlying disease spectrum, we developed, in this cohort study, two novel indices for quantifying antibody-mediated (AMR) and T-cell mediated rejection (TCMR) from histological lesion scores, and calculated indices for overall activity and chronicity. These indices were evaluated in one derivation cohort and two independent validation cohorts, totaling 19,500 biopsies from 8,873 kidney transplant patients across 10 centers worldwide. The AMR, TCMR, and activity indices demonstrated hierarchical ordering between No rejection, intermediate and complete rejection histology. The chronicity index showed limited association with the major diagnostic categories. In the derivation cohort, the AMR and TCMR indices discriminated AMR from absence of AMR, and TCMR from absence of TCMR, with an AUC of 0.98 (95% confidence interval 0.97 to 0.98) and 0.99 (0.99 to 1.00) respectively). This excellent discrimination was confirmed in the validation cohorts. Those indices strictly confined intermediate phenotypes to a range of low index values and related to graft failure rates even within the diagnostic categories, thus reflecting the underlying rejection continuum. The four continuous indices offer an implementable and interpretable global evaluation of kidney transplant biopsy histology while eliminating the need for intermediate diagnostic categories and enable more probabilistic reasoning in the diagnostic approach to the spectrum of kidney transplant rejection.
Conversion to a belatacept-based immunosuppression is currently used as a calcineurin inhibitor (CNI) avoidance strategy when the CNI-based standard-of-care immunosuppression is not tolerated after kidney transplantation. However, there is a lack of evidence on the long-term benefit and safety after conversion to belatacept.
Anti-thymocyte globulin (ATG) is currently the preferential induction treatment in kidney recipients at high risk for allograft rejection. However, no study has evaluated the benefits of this induction strategy in terms of patient survival. We conducted a multicentric prospective study including unselected kidney recipients from 4 referral centers (2004-2014). We assessed the type of induction therapy (IL2R inhibitors or ATG) and the dose of ATG (mg/kg). All donor, recipient and transplant baseline characteristics were recorded. Patients were systematically screened for anti-HLA DSAs at the time of transplantation, at any clinical event and yearly. We considered all allograft biopsies (N=10,293) performed at 1-year post-transplant and for clinical indication. 4,696 kidney recipients were included, among whom 2,246 (48%) patients received ATG at a mean dose of 7.2±3.1 mg/kg and 2,450 (52%) patients received IL2R inhibitors. During a median follow-up post-transplant of 7.0 (IQR, 4.4-9.6) years, 680 patients were diagnosed with biopsy-proven ABMR within the first year post-transplant (14%) and 869 within the first 5 years post-transplant (19%). ATG induction was the main protective factor for ABMR occurrence at 1 year (adjusted HR=0.69; 95%CI=0.58-0.81) and at 5 years (HR=0.76, 95%CI=0.66-0.88), when adjusted for clinical, histologic and immunologic factors, with a dose-effect relationship. The protective effect of ATG was observed in patients receiving between 4.5 and 6.5 mg/kg (1-year HR=0.60, 95%CI=0.46-0.79 and 5-year HR=0.74 0.66-0.96), whereas no effect was observed in patients receiving less than 4.5 mg/kg. We generated a propensity score to match patients according to the induction treatment (ATG vs IL2R) with similar risk factors (Anti-HLA DSA at day 0, HLA mismatches, graft rank, donor’s age, type of donor and cold ischemia time). The matched sample was composed of 2,418 patients (1,209 in the ATG group and 1,209 in the IL2R group). Patients with pre-transplant DSAs receiving ATG (N=177, 7%) showed better patient survival at 5 years compared to patients with pre-transplant DSAs receiving IL2R inhibitors (N=175, 7%): 92% vs 84%, p=0.008, while those without pre-transplant DSAs (N=2,066 (85.44%)) had similar survival according to induction therapy (ATG: 88% vs IL2R: 89%). ATG is the main protective factor for ABMR occurrence in kidney recipients and improves patient survival in recipients with pre-transplant anti-HLA DSAs, independent of patient age and comorbidities.
Abstract Background and Aims To assess the performances of the current eGFR equations, including the race-free CKD-EPI-2021, in the kidney transplant population, and compare these performances to a race-free kidney-recipient-specific (KRS) GFR equation. Method We included adult kidney recipients transplanted between 01/01/2000 and 01/01/2021 in 17 academic cohorts in Europe, the USA and Australia comprising 14 transplant centres and three clinical trials. Measured GFRs (mGFR) were assessed using 51Cr-EDTA, 99Tc-DTPA, inulin, iothalamate or iohexol clearance, according to the local practice. A KRS GFR equation was developed using additive and multiplicative stepwise linear regressions and its performance was compared to those of the current GFR equations. The performances were assessed with the P30 and the correct classification of chronic kidney disease (CKD) stage metrics. Results The study included 15 489 patients, having 50 464 GFR values both measured and estimated by creatinine-based equations. Among the current GFR equations, race-free CKD-EPI-2021 equation showed the lowest performance compared with MDRD and CKD-EPI-2009 equations. We then built a race-free KRS GFR equation based on an additive model including creatinine, age, and sex. We showed that using race did not increase the performance of the equation. We found that the race-free KRS GFR equation showed significantly improved performance compared with the race-free CKD-EPI-2021 equation and performed well in the external validation cohorts (P30 ranging from 73.0% to 91.3%). Finally, we showed that the race-free KRS GFR equation performed well in a series of kidney transplant recipient subpopulations stratified by race, sex, age, body mass index, donor type, therapeutics, creatinine and GFR measurement methods and timing. Based on these results we developed an online application that estimates GFR based on recipient age, sex and creatinine: https://transplant-prediction-system.shinyapps.io/eGFR_equation_KTX/ Conclusion Using multiple, international cohorts of kidney recipients, we developed and validated a new race-free KRS GFR equation that demonstrated high accuracy and outperformed the race-free CKD-EPI-2021 equation developed in individuals with native kidneys.
The use of an integrated approach, combining the characteristics of donor specific antibodies and flow crossmatch, improves the risk stratification in crossmatch-positive kidney transplant recipients. See the companion article from Schinstock et al on page 1671. The use of an integrated approach, combining the characteristics of donor specific antibodies and flow crossmatch, improves the risk stratification in crossmatch-positive kidney transplant recipients. See the companion article from Schinstock et al on page 1671. Anti-HLA sensitization is a barrier to transplantation with a growing number of sensitized patients. To overcome this barrier, a revised allocation system was introduced in the United States in 2014 in order to increase the access to transplantation.1Stewart DE Klassen DK Early experience with the new kidney allocation system: a perspective from UNOS.Clin J Am Soc Nephrol. 2017; 12: 2063-2065Crossref PubMed Scopus (24) Google Scholar Recent studies have shown promising results with an improved patient survival when compared to end-stage renal disease patients on waiting lists in the United States.2Montgomery RA Lonze BE King KE et al.Desensitization in HLA-incompatible kidney recipients and survival.N Engl J Med. 2011; 365: 318-326Crossref PubMed Scopus (502) Google Scholar,3Orandi BJ Luo X Massie AB et al.Survival benefit with kidney transplants from HLA-incompatible live donors.N Engl J Med. 2016; 374: 940-950Crossref PubMed Scopus (234) Google Scholar The main limitation remains the increased risk of allograft loss mainly due to antibody-mediated rejection (AMR). Several research teams have joined the quest to identify biomarkers that will allow a better assessment of the risk of rejection and allograft loss. Strategies based on crossmatch (XM) determination before transplantation are useful to avoid transplantation with a high risk of rejection but are a tool to allow the transplantation rather than a risk stratification tool at the time of transplantation or after transplantation. Anti-HLA donor-specific antibody (DSA) evaluation based on mean fluorescence intensity (MFI) using the single antigen bead assay has improved the capacity of predicting AMR and allograft loss but does not cover the complexity and the heterogeneity of the antibody. Numerous studies have shown the necessity to take into account the characteristics and the properties of anti-HLA DSA to improve the prediction. Indeed, de novo anti-HLA DSA or complement-activating anti-HLA DSA (C1q, C4d, C3d binding anti-HLA DSA and IgG3 subclass) are associated with a worse allograft survival beyond the simple MFI of the antibody.4Aubert O Loupy A Hidalgo L et al.Antibody-mediated rejection due to preexisting versus de novo donor-specific antibodies in kidney allograft recipients.J Am Soc Nephrol. 2017; 28: 1912-1923Crossref PubMed Scopus (158) Google Scholar, 5Loupy A Lefaucheur C Vernerey D et al.Complement-binding anti-HLA antibodies and kidney-allograft survival.N Engl J Med. 2013; 369: 1215-1226Crossref PubMed Scopus (645) Google Scholar, 6Lefaucheur C Viglietti D Bentlejewski C et al.IgG donor-specific anti-human HLA antibody subclasses and kidney allograft antibody-mediated injury.J Am Soc Nephrol. 2016; 27: 293-304Crossref PubMed Scopus (200) Google Scholar In a large meta-analysis including 7936 solid organ transplant patients and 37 studies, Bouquegneau et al reported a significant deleterious impact on allograft survival of complement-activating anti-HLA DSAs (pooled hazard ratio: 3.09; 95% confidence interval: 2.55-3.74; P = .001; I2 = 29.3%), reinforcing the idea that characterization of anti-HLA DSA properties including C1q-, C3d-, C4d-binding anti-HLA DSA and IgG3 subclass may have an additive value at an individual scale for noninvasive biomarker-guided immunological risk stratification to better predict allograft survival.7Bouquegneau A Loheac C Aubert O et al.Complement-activating donor-specific anti-HLA antibodies and solid organ transplant survival: A systematic review and meta-analysis.PLoS Med. 2018; 15: e1002572Crossref PubMed Scopus (65) Google Scholar In a study including 851 kidney recipients transplanted between 2008 and 2010, Viglietti et al specifically studied the value of C1q binding anti-HLA DSA and IgG3 subclass to predict allograft loss compared to anti-HLA DSA MFI. In this study, addition of the C1q-binding capacity of DSA and IgG3 positivity increased discrimination performance of the traditional model at transplantation and posttransplant that includes anti-HLA DSA MFI, showing its additive value.8Viglietti D Loupy A Vernerey D et al.Value of donor-specific anti-HLA antibody monitoring and characterization for risk stratification of kidney allograft loss.J Am Soc Nephrol. 2017; 28: 702-715Crossref PubMed Scopus (89) Google Scholar Regarding those results, taking into account the properties of anti-HLA DSA may improve decision-making, risk prediction, but also therapeutic intervention. The study by Schnistock et al exemplifies the value of careful characterization and monitoring of DSA in the context of antibody-compatible transplantation. The authors conducted an observational retrospective study and examined long-term outcomes from kidney transplant recipients issued from 3 groups: +XM patients receiving eculizumab to prevent early active AMR; a historical cohort of +XM patients; and a group of -XM patients. Data were issued from a systemic follow-up of anti-HLA DSA tested at postoperative day 7, 14, 28, 90, 180, and 365 with IgG3 subclass and C1q-activating capacity analyzed in the +XM group of patients receiving eculizumab. B cell flow cytometric XM (BFXM) and allograft biopsies at 5 years posttransplantation were analyzed.9Schinstock CA, Bentall AJ, Smith BH, et al. Long-term outcomes of eculizumab-treated positive crossmatch recipients: allograft survival, histologic findings, and natural history of the donor-specific antibodies. Am J Transplant. 2018; https://doi.org/10.1111/ajt.15175.Google Scholar The authors have previously reported that, with a 2-year follow-up, patients with a +XM receiving eculizumab had a reduced rate of clinical early active AMR but with a similar rate of subsequent chronic AMR up to 5 years posttransplantation (57.9% [11/19] in the +XM with eculizumab patient group versus 71.4% [20/28] of the in the +XM control group; P = .36).9Schinstock CA, Bentall AJ, Smith BH, et al. Long-term outcomes of eculizumab-treated positive crossmatch recipients: allograft survival, histologic findings, and natural history of the donor-specific antibodies. Am J Transplant. 2018; https://doi.org/10.1111/ajt.15175.Google Scholar,10Stegall MD Diwan T Raghavaiah S et al.Terminal complement inhibition decreases antibody-mediated rejection in sensitized renal transplant recipients.Am J Transplant. 2011; 11: 2405-2413Abstract Full Text Full Text PDF PubMed Scopus (447) Google Scholar Subgroup analyses demonstrate that in +XM patients with eculizumab, patients with a BFXM channel shift <300 or negative IgG3 at the time of transplantation had 94.1% and 81.6% 5- and 7-year death-censored allograft survival rates, respectively. For the +XM patients treated with eculizumab, C1q-positive patients at baseline presented with a 35.7% (5/14) rate of death-censored allograft loss as compared with 0% (0/4) among the patients with C1q-negative DSA (P = .23). Of note, chronic AMR was observed in 57.9% (11/19) of +XM patients treated with eculizumab as compared with 71.4% (20/28) of the +XM control group (P = .36). Overall the authors found that characterization of the properties of DSA, in addition to BFXM, may help to improve risk stratification in HLA-incompatible kidney transplantation. Namely, +XM patients, with a BFXM channel shift <300 or negative IgG3 after treatment with eculizumab, had excellent long-term allograft survival. Several limitations should be acknowledged. Type 2 error (ie, failing to identify a true difference between groups) is very plausible with this small sample size (n = 30 patients +XM treated with eculizumab). Namely, a P > .05 does not exclude the possibility of a clinically meaningful difference between groups but instead might be explained by the small sample size. The study is also hampered by missing data, such as the missing 5-year biopsy results and/or anti-HLA DSA results (MFI, IgG3, C1q). As IgG4 has also been shown to significantly associate with subclinical AMR, the added value of other subclasses should also be evaluated.6Lefaucheur C Viglietti D Bentlejewski C et al.IgG donor-specific anti-human HLA antibody subclasses and kidney allograft antibody-mediated injury.J Am Soc Nephrol. 2016; 27: 293-304Crossref PubMed Scopus (200) Google Scholar,11Khovanova N Daga S Shaikhina T et al.Subclass analysis of donor HLA-specific IgG in antibody-incompatible renal transplantation reveals a significant association of IgG4 with rejection and graft failure.Transpl Int. 2015; 28: 1405-1415Crossref PubMed Scopus (42) Google Scholar Moreover, the generalizability of these results is limited by the fact that this retrospective study focuses on living donors only. Last, this field lacks robust and well-conducted randomized controlled trials. But beyond the sole design of trials, a clear pathogenesis-based assessment of injuries occurring in HLA-incompatible patients depicting the biological processes operating in the allograft is lacking. This is of great importance considering the complexity of potential complement-dependent and complement-independent mechanisms of allograft injury that have been previously described.12Lefaucheur C Viglietti D Hidalgo LG et al.Complement-activating anti-HLA antibodies in kidney transplantation: allograft gene expression profiling and response to treatment.J Am Soc Nephrol. 2018; 29: 620-635Crossref PubMed Scopus (67) Google Scholar Studies evaluating complement-targeting drugs in kidney transplantation are listed in Table 1.TABLE 1List of published and registered studies on complement inhibition in kidney transplantationPublished studiesBerinertVo AA, Zeevi A, Choi J, et al. A phase I/II placebo-controlled trial of C1-inhibitor for prevention of antibody-mediated rejection in HLA sensitized patients. Transplantation. 2015 Feb;99(2):299-308N = 20C1 esterase inhibitor [human]Montgomery RA, Orandi BJ, Racusen L, et al. Plasma-derived C1 esterase inhibitor for acute antibody-mediated rejection following kidney transplantation: results of a randomized double-blind placebo- controlled pilot study. Am J Transplant. 2016;16(12):3468-3478N = 18Anti-C1s humanized antibodyWahrmann M, Mühlbacher J, Marinova L, et al. Effect of the anti-C1s humanized antibody TNT009 and its parental mouse variant TNT003 on HLA antibody-induced complement activation-a preclinical in vitro study. Am J Transplant. 2017;17(9):2300-2311N = 68 (in vitro)Eskandary F, Jilma B, Muhlbacher J, et al. Anti-C1s monoclonal antibody BIVV009 in late antibody-mediated kidney allograft rejection-results from a first-in-patient phase 1 trial. Am J Transplant. 2018;18(4):916-926N = 10Registered studiesEculizumabSafety & efficacy of eculizumab in the prevention of antibody mediated rejection in sensitized recipients of a kidney transplant from a deceased donor (NCT01567085)N = 80Safety & efficacy of eculizumab to prevent antibody mediated rejection in living donor kidney transplant recipients requiring desensitization (NCT01399593)N = 102 Open table in a new tab The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation.
The authors conducted a prospective trial to assess the feasibility of real time central molecular assessment of kidney transplant biopsy samples from 10 North American or European centers. Biopsy samples taken 1 day to 34 years posttransplantation were stabilized in RNAlater, sent via courier overnight at ambient temperature to the central laboratory, and processed (29 h workflow) using microarrays to assess T cell- and antibody-mediated rejection (TCMR and ABMR, respectively). Of 538 biopsy samples submitted, 519 (96%) were sufficient for microarray analysis (average length, 3 mm). Automated reports were generated without knowledge of histology and HLA antibody, with diagnoses assigned based on Molecular Microscope Diagnostic System (MMDx) classifier algorithms and signed out by one observer. Agreement between MMDx and histology (balanced accuracy) was 77% for TCMR, 77% for ABMR, and 76% for no rejection. A classification tree derived to provide automated sign-outs predicted the observer sign-outs with >90% accuracy. In 451 biopsy samples where feedback was obtained, clinicians indicated that MMDx more frequently agreed with clinical judgment (87%) than did histology (80%) (p = 0.0042). In 81% of feedback forms, clinicians reported that MMDx increased confidence in management compared with conventional assessment alone. The authors conclude that real time central molecular assessment is feasible and offers a useful new dimension in biopsy interpretation. ClinicalTrials.gov NCT#01299168.
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