Kidney Week Educational Symposia-Diagnostic Controversies in Transplantation: Of Biomarkers and Biopsies

Video Transcription

Video Summary

This session on “Diagnostic Controversies in Transplantation: Biomarkers and Biopsies” reviews how donor-derived cell-free DNA (dd-cfDNA) and related molecular tools may complement—or sometimes reduce reliance on—kidney transplant biopsy for diagnosing graft injury.<br /><br />Moderator Melissa Maniego frames the central challenge: balancing immunosuppression to prevent immune-mediated injury while avoiding infection and toxicity. Traditional monitoring (drug troughs, creatinine, proteinuria) is late and nonspecific, while biopsy remains the gold standard. She highlights the ideal surrogate biomarker: accessible, accurate, able to detect early injury, monitor treatment response, and distinguish overlapping clinical phenotypes. Donor-specific antibodies (DSA) are presented as a long-standing immune marker with prognostic value, especially for antibody-mediated rejection (ABMR).<br /><br />Alex Wiseman discusses dd-cfDNA as a dynamic injury signal with short half-life. He reviews the DART validation of AlloSure, where a 1% dd-cfDNA threshold performed best for ABMR (high specificity and ~96% negative predictive value, but modest positive predictive value). Performance was weaker for low-grade T-cell–mediated rejection (TCMR), prompting studies suggesting lower cutoffs (e.g., 0.5%) may better risk-stratify borderline/TCMR1A and predict worse outcomes (DSA association, eGFR decline, recurrent rejection). He notes limited head-to-head comparisons between AlloSure and Prospera and emphasizes dd-cfDNA should be additive rather than standalone. Combining dd-cfDNA with DSA can markedly improve ABMR positive predictive value (reported up to ~81%).<br /><br />Darshana Dadania focuses on infections, a major cause of post-transplant mortality. She reviews limitations of cultures and targeted PCR (variability, thresholds, slow/limited detection) and highlights metagenomic next-generation sequencing (e.g., Karius) to detect diverse pathogens rapidly. Her group’s urine cfDNA work uses methods optimized for highly fragmented microbial DNA, enabling organism detection, estimating bacterial replication activity, identifying resistance genes, and pairing pathogen signals with host-injury readouts (e.g., donor/kidney-origin cfDNA via sex mismatch or methylation). She concludes that future diagnostics will integrate pathogen detection, host injury, and immune response, alongside needed standardization and clinical validation.

Asset Subtitle

Milagros Samaniego-Picota, Alexander Wiseman, Darshana Dadhania
Support is provided by an educational grant from CareDx.

Keywords

kidney transplant biopsy

donor-derived cell-free DNA (dd-cfDNA)

AlloSure DART study

antibody-mediated rejection (ABMR)

T-cell–mediated rejection (TCMR)

donor-specific antibodies (DSA)

dd-cfDNA cutoff thresholds (1% vs 0.5%)

metagenomic next-generation sequencing (mNGS)

Karius pathogen detection

urine cell-free DNA microbial diagnostics