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Kidney Biomarkers

Tuesday March 29, 2022 - 14:00 to 15:10

Room: VIRTUAL

406.6 Eplet mismatching and subclinical inflammation in a pediatric kidney transplant population

Maiya Rasheed, Canada

University of British Columbia

Abstract

Eplet mismatching and subclinical inflammation in a pediatric kidney transplant population

Maiya Rasheed1, Julie Ho2,3, Chris Wiebe2,4, Atul Sharma5, Ian Gibson6, Tom Blydt-Hansen7,8.

1Faculty of Science, University of British Columbia, Vancouver, BC, Canada; 2Nephrology, University of Manitoba, Winnipeg, MB, Canada; 3Manitoba Centre for Proteomics & Systems Biology, Winnipeg, MB, Canada; 4Transplant/Immunology Lab, University of Manitoba, Winnipeg, MB, Canada; 5Biostatistical Consulting Unit, George, Fay Yee Center for Healthcare Innovation, University of Manitoba, Winnipeg, MB, Canada; 6Pathology, University of Manitoba, Winnipeg, MB, Canada; 7Nephrology, Department of Pediatrics, BC Children's Hospital, Vancouver, BC, Canada; 8University of British Columbia, Vancouver, BC, Canada

While kidney transplants represent a life-saving measure for many, graft rejection due to donor recipient mismatch is still a concern. Donor HLA eplet mismatch in pediatric kidney transplant is associated with adverse risk HLA antibodies and allograft loss. Since early rejection/inflammation may initiate alloimmune programs of humoral sensitization, we sought to identify whether higher levels of inflammatory marker CXCL10 are associated with eplet mismatch in a pediatric cohort.

This is a secondary analysis of the PROBE study, a prospective biomarker validation cohort that included measurement of urinary CXCL10 and high-resolution HLA typing. Time-averaged urinary CXCL10 expression was log transformed (logCXCL10/Cr AUC) and modeled to test for association with DRB1 and totalDQ eplet mismatch (HLA matchmaker) and other peri-transplant covariates.

The cohort had a mean age of 11.4 ± 5.5 years with a predominance of males (61.9%), non-glomerular kidney disease (52.6%), and low immunological risk. At the antigen level, HLA-DRB1  and -totalDQ mismatch was 1.0±0.7 and 1.6±1.2, respectively; and at the eplet level the mismatch was  7.1±5.3 and 15.6±13.6, respectively. HLA-DR and -totalDQ antigen mismatch was strongly associated with HLA-DRB1 and -totalDQ eplet mismatch (r=0.69, p<0.001 and r=0.83, p<0.001, respectively, Figure 1). LogCXCL10/Cr AUC in the first year was significantly associated with HLA-DRB1 eplet mismatch (r=0.23, p=0.025) (Figure 1), but not with HLA-totalDQ eplet mismatch (r=0.087, p=0.40). Other peri-transplant characteristics associated with logCXCL10/Cr AUC were pre-emptive transplant (p=0.03), patient age ( p=0.007), and non-glomerular diagnosis (p=0.002). Exploratory analysis identified an informative range of threshold cut-off between 3-10 DRB1 mismatch that discriminated risk of elevated logCXCL10/Cr AUC in recipient, with the greatest discrimination at ≥3 mismatches representing a 4.5-fold increase (p=0.025). No similar threshold was identified for totalDQ mismatch. The model of mean log transformed CXCL10/Cr AUC in the first year after transplant included significant independent association with age at transplant (p=0.010) and glomerular diagnosis (p=0.058), while the HLA-DRB1 high risk category (3 or greater eplet mismatches) was not an independent predictor (p=0.26).The adjusted model of logCXCL10/Cr AUC in the first year after transplant identified independent association with pre-emptive transplant (p=0.033) and age at transplant (p=0.007), and a trend for HLA-DRB1 eplet mismatch (p=0.088).

In conclusion, greater HLA-DRB1 eplet mismatch is associated with increased allograft inflammation measured as elevated urinary CXCL10 expression in the first post-transplant year, with the highest risk differential seen at the level of 3 mismatches of more.

Presentations by Maiya Rasheed