Purpose: Transplant vascular injury (TVI) is a major cause of renal allograft failure and is resistant to treatment. Non-invasive pathogenic biomarkers of TVI would provide new diagnostic and treatment options. We hypothesized that circulating Wnt pathway factors, which are pathogenic in native renal disease, would also be novel biomarkers of TVI.

Methods: Cross-sectional study of 120 kidney recipients with biopsy-proven TVI (n=66; with 33 antibody-mediated rejection and 33 transplant glomerulopathy) or no major transplant abnormality (NOMOA, n=54). We measured Wnt pathway factors in biopsy-correlated serum/plasma samples by ELISA, including activin-A, fibroblast growth factor-23 (FGF23) and sclerostin (SOST). Optimal diagnostic cutoffs were determined using the Youden index. We compared mean levels between TVI and NOMOA by the Mann-Whitney-U test. We evaluated diagnostic performance by ROC analysis and logistic regression.

Results: TVI and NOMOA had similar clinical/demographic data except that TVI had lower estimated GFR (32 vs. 40 mL/min/1.73 m², P=0.04). Mean serum Activin-A (530 ± 41 vs. 394 ± 27) and plasma FGF23 levels (427 ± 85 vs. 418 ± 113) were higher and serum SOST levels (137 ± 10 vs. 168 ± 11) were lower in TVI vs. NOMOA (all P<0.05). The best diagnostic index for TVI combined high FGF23 with low SOST levels (Table) and was robust to adjustment for eGFR [aOR (95% CI) = 7.5 (3.0, 19.0); P<0.0001].

Conclusions: High FGF23 and low SOST levels have better non-invasive diagnostic performance for TVI compared to eGFR. Once validated in an external cohort, circulating Wnt factors should be further explored as novel diagnostic and therapeutic targets.

CITATION INFORMATION: Seifert M., Malone A., Boohaker L., Gaut J., Jain S., Brennan D., Mannon R. Circulating Wnt Pathway Factors Are Non-Invasive Biomarkers of Transplant Vascular Injury Am J Transplant. 2017;17 (suppl 3).

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