BACKGROUND: Donor -specific HLA antibody (DSA) is present in many kidney transplant patients whose biopsies are classified as no rejection (NR). We explored whether in some NR kidneys DSA has subtle effects not currently being recognized. METHODS: We used microarrays to examine the relationship between standard-of-care DSA and rejection-related transcript increases in 1679 kidney transplant indication biopsies in the INTERCOMEX study (ClinicalTrials.gov NCT01299168), focusing on biopsies classified as NR by automatically assigned archetypal clustering. DSA testing results were available for 835 NR biopsies and were positive in 271 (32%). RESULTS: DSA positivity in NR biopsies was associated with mildly increased expression of antibody-mediated rejection (ABMR)-related transcripts, particularly IFNG-inducible and NK cell transcripts. We developed a machine learning DSA probability (DSAProb) classifier based on transcript expression in biopsies from DSA-positive versus DSA-negative patients, assigning scores using 10-fold cross-validation. This DSAProb classifier was very similar to a previously described "ABMR probability" classifier trained on histologic ABMR in transcript associations and prediction of molecular or histologic ABMR. Plotting the biopsies using Uniform Manifold Approximation and Projection revealed a gradient of increasing molecular ABMR-like transcript expression in NR biopsies, associated with increased DSA (P<2 × 10-16). In biopsies with no molecular or histologic rejection, increased DSAProb or ABMR probability scores were associated with increased risk of kidney failure over 3 years. CONCLUSIONS: Many biopsies currently considered to have no molecular or histologic rejection have mild increases in expression of ABMR-related transcripts, associated with increasing frequency of DSA. Thus, mild molecular ABMR-related pathology is more common than previously realized.

Alberta Transplant Applied Genomics Centre Edmonton Alberta Canada

Department of Medicine Division of Nephrology and Transplant Immunology University of Alberta Edmonton Alberta Canada

Department of Nephrology and Transplant Center Institute for Clinical and Experimental Medicine Prague Czech Republic

Department of Nephrology Hannover Medical School Hannover Germany

Department of Pathology Medical University of Warsaw Warsaw Poland

Department of Surgery University of Wisconsin Madison Wisconsin

Departments of Surgery and Microbiology and Immunology University of Maryland Baltimore Maryland

Division of Nephrology and Dialysis Department of Medicine 3 Medical University of Vienna Vienna Austria

Division of Nephrology Virginia Commonwealth University Richmond Virginia

Pomeranian Medical University Department of Clinical Interventions and Department of Nephrology and Kidney Transplantation Samodzielny Publiczny Wojewodzki Szpital Zespolony Szczecin Poland

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