Urinary Epidermal Growth Factor/Creatinine Ratio and Graft Failure in Renal Transplant Recipients: A Prospective Cohort Study.

Manuela Yepes-Calderón,Stefan P Berger,Rijk O B Gans,Gerjan J Navis,Camilo G Sotomayor,Stephan J L Bakker,Matthias Kretzler,Wenjun Ju

doi:10.3390/jcm8101673

Abstract

Graft failure (GF) remains a significant limitation to improve long-term outcomes in renal transplant recipients (RTR). Urinary epidermal growth factor (uEGF) is involved in kidney tissue integrity, with a reduction of its urinary excretion being associated with fibrotic processes and a wide range of renal pathologies. We aimed to investigate whether, in RTR, uEGF is prospectively associated with GF. In this prospective cohort study, RTR with a functioning allograft ≥1-year were recruited and followed-up for three years. uEGF was measured in 24-hours urine samples and normalized by urinary creatinine (Cr). Its association with risk of GF was assessed by Cox-regression analyses and its predictive ability by C-statistic. In 706 patients, uEGF/Cr at enrollment was 6.43 [IQR 4.07–10.77] ng/mg. During follow-up, 41(6%) RTR developed GF. uEGF/Cr was inversely associated with the risk of GF (HR 0.68 [95% CI 0.59–0.78]; P < 0.001), which remained significant after adjustment for immunosuppressive therapy, estimated Glomerular Filtration Rate, and proteinuria. C-statistic of uEGF/Cr for GF was 0.81 (P < 0.001). We concluded that uEGF/Cr is independently and inversely associated with the risk of GF and depicts strong prediction ability for this outcome. Further studies seem warranted to elucidate whether uEGF might be a promising marker for use in clinical practice.

Highlights

In recent decades short-term graft survival has seen great improvement, chronic graft failure remains a major clinical challenge for renal transplantation with no significant reduction achieved in the same time frame [1]
In crude linear regression analyses, there was no significant association between years after transplantation and Urinary epidermal growth factor (uEGF)/Cr (Std. β = −0.015; P = 0.71), the association became apparent after the adjustment for calcineurin inhibitors usage (Std. β = −0.81; P = 0.046)
In effect-modification analyses we found that none of the pre-specified variables we explored was a significant effect-modifier of the association between uEGF/Cr and the risk of graft failure (P > 0.10), we did not proceed with any subgroup analyses (Table S4)

Summary

Introduction

In recent decades short-term graft survival has seen great improvement, chronic graft failure remains a major clinical challenge for renal transplantation with no significant reduction achieved in the same time frame [1]. Finding non-invasive biomarkers that could reflect the pathophysiological changes in the renal tissue would be of remarkable utility as potential tools to monitor patients and timely identify those at high risk of graft failure [7], who could benefit from further interventions and stricter follow-up before structural damage is already present [8]. Epidermal growth factor (EGF) is a 53-amino acid peptide produced in the kidney at the ascending loop of Henle and the distal convoluted tubule [7,8]. It stimulates the proliferation and differenEtpiaidtieornmoaflegpriodwertmhaflaacntodre(pEiGthFe)liaisl cael5ls3,-aanmdinuondaecridnoprempatildceonpdroitdiouncsedit hinastahecrkitiidcanleryolaetinthe renasaclednedvienlgoplomoepnot f[7H],emnlaeinantednathnecedoisftarel ncaolntvuobluutleedinttuebguriltey[7a,n8d]. We aimed to evaluate the prediction ability of uEGF for graft failure

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Discussion

Conclusion