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In Journal of the American Society of Nephrology : JASN

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 that are 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 ( 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 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 vs. 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<2E-16). In biopsies with no molecular or histologic rejection, increased DSAProb or ABMR probability scores were associated with increased risk of kidney failure over three 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.

Madill-Thomsen Katelynn, Boehmig Georg, Bromberg Jonathan, Einecke Gunilla, Eskandary Farsad, Gupta Gaurav, Hidalgo Luis, Myslak Marek, Viklicky Ondrej, Perkowska-Ptasinska Agnieszka, Halloran Philip