INTER-CENTER VARIABILITY OF BIOPSY-BASED TRANSCRIPT DIAGNOSTICS – DO MOLECULAR CLASSIFIERS ADD THE SAME VALUE EVERYWHERE?

 

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INTER-CENTER VARIABILITY OF BIOPSY-BASED TRANSCRIPT DIAGNOSTICS – DO MOLECULAR CLASSIFIERS ADD THE SAME VALUE EVERYWHERE?

Please follow the instructions below to input your abstract title.

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Elena
Rho
Dusan Harmacek dusan.harmacek@usz.ch University Hospital Zurich Nephrology Zurich Switzerland -
David Kronthaler david.kronthaler@uzh.ch Epidemiology, Biostatistics and Prevention Institute Department of Biostatistics, University of Zurich Zurich Switzerland -
Lukas Weiidmann lukas.weidmann@usz.ch University Hospital Zurich Nephrology Zurich Switzerland -
Kai Castrezana-Lopez kai.castrezanalopez@usz.ch University Hospital Zurich Nephrology Zurich Switzerland -
Elena Rho elena.rho@usz.ch University Hospital Zurich Nephrology Zurich Switzerland *
Seraina von Moos seraina.vonmoos@usz.ch University Hospital Zurich Nephrology Zurich Switzerland -
Kerstin Hübel kerstin.huebel@usz.ch University Hospital Zurich Nephrology Zurich Switzerland -
Florian Westphal florian.westphal@usz.ch University Hospital Zurich Nephrology Zurich Switzerland -
Petra Hruba hrup@ikem.cz Institute for Clinical and Experimental Medicine Nephrology Prague Czech Republic -
Eva Girmanova eva.girmanova@ikem.cz Institute for Clinical and Experimental Medicine Nephrology Prague Czech Republic -
L. Voska l.voska@ikem.cz Institute for Clinical and Experimental Medicine Nephrology Prague Czech Republic -
K. Jaklova k.jaklova@ikem.ch Institute for Clinical and Experimental Medicine Nephrology Prague Czech Republic -
Ulrike Held ulrike.held@uzh.ch Epidemiology, Biostatistics and Prevention Institute Department of Biostatistics, University of Zurich Zurich Switzerland -
Ondrej Viklicky ondrej.viklicky@ikem.cz Institute for Clinical and Experimental Medicine Nephrology Prague Czech Republic -
Thomas Schachtner thomas.schachtner@usz.ch University Hospital Zurich Nephrology Zurich Switzerland -

Biopsy-based transcript diagnostics provide an objective approach to evaluating kidney allograft biopsies, complementing traditional histopathology. However, their diagnostic performance and clinical impact may vary across transplant centers due to center-specific factors. Recognizing this, the Banff 2022 Work Plan emphasizes the need to validate biopsy-based transcript assays in diverse clinical settings to ensure consistent interpretation across centers.

A total of 755 kidney allograft biopsies from two European transplant centers (Prague and Zurich) were analyzed using the Molecular Microscope® Diagnostic System (MMDx®) in two reference laboratories located in Portland, USA, and Prague, Czechia. Histopathological lesion scores were compared with MMDx molecular classifier categories and probability scores using a cumulative link proportional model. The study cohort included 145 cases of antibody-mediated rejection (AMR), 117 probable AMR, 64 cases of DSA-negative and C4d-negative microvascular inflammation (MVI), and 93 cases of T cell–mediated rejection (TCMR).

Histological lesions, including glomerulitis (g), peritubular capillaritis (ptc), interstitial inflammation (i), and tubulitis (t), were strongly associated with their corresponding molecular lesion and classifier scores across centers (p < 0.005). However, when adjusting for molecular lesion and classifier scores in a multivariate cumulative link proportional odds model, histological grading remained significantly influenced by the transplant center (p < 0.001). When holding the molecular AMR classifier score constant, the odds ratio (OR) for higher microvascular inflammation (MVI) in Zurich was 1.838 (95% CI 1.330–2.549; p < 0.001). Notably, MVI severity was not affected by donor-specific antibody (DSA) status (OR 0.983; 95% CI 0.729–1.326; p = 0.915). Similarly, when controlling for either the molecular AMR or TCMR classifier score, the odds of higher intimal arteritis (v-lesion) grading in Zurich were markedly increased (OR 5.027; 95% CI 3.129–8.355; p < 0.001 and OR 4.832; 95% CI 2.994–8.077; p < 0.001, respectively). Finally, glomerular basement membrane double contours (cg) were associated with a higher molecular cg > 0 probability only in the presence of MVI across centers (p < 0.05).

Histological lesions remain major drivers of molecular diagnostic readouts across centers. Yet, significant inter-center variability suggests that biopsy indication, timing, and local pathology practices impact the relationship between molecular and histological findings. Therefore, the added diagnostic value of MMDx should not be assumed universal but should be critically assessed within the center’s clinical and histopathological environment.

Kewords