BACKGROUND: Biopsy-based transcriptomics (BBT) was implemented in Central Europe in 2022 to improve kidney transplant diagnostics. Differences in diagnostic practices across transplant centers remain underexplored. METHODS: This retrospective multicenter study analyzed 474 kidney graft biopsies from 10 transplant centers between August 2022 and May 2024, where, besides routine histology, BBT using the Molecular Microscope Diagnostic System (MMDx) was performed. Differences in BBT indications and discrepancies between histology assessment by Banff 2022 and MMDx sign-outs among transplant centers were evaluated. RESULTS: Most centers used BBT in only 12%-31% of all performed biopsies, relying on histology alone for most diagnostic decisions. BBT indications varied across centers: 3 focused on histological no-rejection with clinical discrepancy (44%, 45%, and 70%), 2 on chronic or chronic-active antibody-mediated rejection (AMR; clinical discrepancy 44% and 48%), and 2 on borderline changes (clinical discrepancy 30% and 33%). BBT showed moderate agreement with histology (κ = 0.49), with similar discrepancy rates between high- and low-volume centers. Molecular AMR was found in 44% of probable AMR, 63% of active AMR, 63% of microvascular inflammation, C4d- and donor-specific antibody (DSA)-, 77% of chronic-active AMR, and 21% chronic AMR. Molecular T cell-mediated rejection (TCMR) was confirmed in 26% of histologically active TCMR, in 9% of chronic TCMR, and in 16% of borderline changes. In histologic no-rejection cases, molecular AMR was present in 10% of DSA- and 34% of DSA+ biopsies. CONCLUSIONS: A moderate discrepancy between histology and MMDx sign-outs was found regardless of the center volume. BBT indications notably varied among centers. Standardized indications should be defined to improve the integration of molecular diagnostics into routine care.

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• Journal Article MeSH

Antibody-mediated rejection (ABMR) is a major obstacle to the long-term success in kidney transplantation. Diagnosis of ABMR is determined according to the internationally recognized Banff criteria. However, a significant proportion of patients does not meet all the defined criteria, and the outcome of such cases remains poorly understood. The histology of ABMR frequently lacks sensitivity and specificity. More importantly, mixed forms of ABMR and T cell-mediated rejection as well as findings of nonspecific injury are common in clinical settings. Donor-specific anti-HLA antibodies (DSA) are detectable only in half of the ABMR cases by histology. Prognostic role of non-HLA antibodies against various endothelial proteins has been discussed. Antibody independent NK cell activation reflecting killer-cells' inhibitory receptor incompatibility is suggested in microvascular inflammation in DSA negative patients. Molecular assessment of ABMR has been prioritized to overcome high interobserver variability and improve diagnostics in mixed forms of rejections and in DSA negative cases. Finally, donor-derived cell-free DNA detected in a recipient's peripheral blood sample has been proposed as a noninvasive marker for diagnosis of graft rejection, and thus might serve as a liquid biopsy in the near future. Despite all achievements, diagnosing ABMR in kidney allografts remains to be a challenge in a significant number of cases.

• MeSH
• Allografts MeSH
• Isoantibodies MeSH
• Kidney pathology   MeSH
• Humans MeSH
• Graft Rejection diagnosis   MeSH
• Kidney Transplantation * adverse effects   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Names of Substances
• Isoantibodies MeSH

Background: The prognostic role of intimal arteritis of kidney allografts in donor-specific antibody negative (DSA-) antibody-mediated rejection (ABMR) remains unclear. Methods: Seventy-two out of 881 patients who had undergone kidney transplantation from 2014 to 2017 exhibited intimal arteritis in biopsies performed during the first 12 months. In 26 DSA negative cases, the intimal arteritis was accompanied by tubulointerstitial inflammation as part of T cell-mediated vascular rejection (TCMRV, N = 26); intimal arteritis along with microvascular inflammation occurred in 29 DSA negative (ABMRV/DSA-) and 19 DSA positive cases (ABMRV, DSA+, N = 17). In 60 (83%) patients with intimal arteritis, the surveillance biopsies after antirejection therapy were performed. Hundred and two patients with non-vascular ABMR with DSA (ABMR/DSA+, N = 55) and without DSA (ABMR/DSA-, N = 47) served as controls. Time to transplant glomerulopathy (TG) and graft failure were the study endpoints. Results: Transplant glomerulopathy -free survival at 36 months was 100% in TCMRV, 85% in ABMR/DSA-, 65% in ABMRV/DSA-, 54% in ABMR/DSA+ and 31% in ABMRV/DSA+ (log rank p < 0.001). Death-censored graft survival at 36 months was 98% in ABMR/DSA-, 96% in TCMRV, 86% in ABMRV/DSA-, 79% in ABMR/DSA+, and 64% in ABMRV/DSA+ group (log rank p = 0.001). In surveillance biopsies, the resolution of rejection was found in 19 (90%) TCMRV, 14 (58%) ABMRV/DSA-, and only 4 (27%) ABMRV/DSA+ patients (p = 0.006). In the multivariable model, intimal arteritis as part of ABMR represented a significant risk for TG development (HR 2.1, 95% CI 1.2-3.8; p = 0.012) regardless of DSA status but not for graft failure at 36 months. Conclusions: Intimal arteritis as part of ABMR represented a risk for early development of TG regardless of the presence or absence of DSA. Intimal arteritis in DSA positive ABMR represented the high-risk phenotype.

• Keywords
• antibody-mediated rejection, intimal arteritis, kidney transplantation, rejection diagnostics, vascular rejection,
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• Journal Article MeSH

BACKGROUND: Thrombotic microangiopathy (TMA) significantly affects kidney graft survival, but its pathophysiology remains poorly understood. METHODS: In this multicenter, retrospective, case-control paired study designed to control for donor-associated risks, we assessed the recipients' risk factors for de novo TMA development and its effects on graft survival. The study group consists of patients with TMA found in case biopsies from 2000 to 2019 (n = 93), and the control group consists of recipients of paired kidney grafts (n = 93). Graft follow-up was initiated at the time of TMA diagnosis and at the same time in the corresponding paired kidney graft. RESULTS: The TMA group displayed higher peak panel-reactive antibodies, more frequent retransplantation status, and longer cold ischemia time in univariable analysis. In the multivariable regression model, longer cold ischemia times (odds ratio, 1.18; 95% confidence interval [CI], 1.01-1.39; P = 0.043) and higher peak pretransplant panel-reactive antibodies (odds ratio, 1.03; 95% CI, 1.01-1.06; P = 0.005) were found to be associated with increased risk of de novo TMA. The risk of graft failure was higher in the TMA group at 5 y (hazard ratio [HR], 3.99; 95% CI, 2.04-7.84; P < 0.0001). Concomitant rejection significantly affected graft prognosis at 5 y (HR, 6.36; 95% CI, 2.92-13.87; P < 0.001). De novo TMA associated with the active antibody-mediated rejection was associated with higher risk of graft failure at 5 y (HR, 3.43; 95% CI, 1.69-6.98; P < 0.001) compared with other TMA. CONCLUSIONS: Longer cold ischemia and allosensitization play a role in de novo TMA development, whereas TMA as a part of active antibody-mediated rejection was associated with the highest risk for premature graft loss.

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• Journal Article MeSH