Urinary C5b-9 is an Independent Predictor of Graft Failure in Renal Transplant Recipients

R.G.M. Lammerts, M.F. Eisenga, M. Alyami, M.A.J. Seelen, M.R. Daha, J. van den Born, S.J.L. Bakker, S.P. Berger, On behalf of COMBAT Consortium

Thursday 15 march 2018

11:50 - 12:00h at Van Weelde Zaal

Categories: Basic / translational research, Session (parallel)

Parallel session: Parallel session 2: Basic / translational research

Introduction

Chronic antibody-mediated rejection is thought to be the main cause of late kidney-allograft loss, involving donor-specific antibody–mediated activation of the complement system. Activation of filtered or locally produced complement may contribute to the progression of renal failure via tubular formation of the terminal C5b-9 complement complex. The aim of this study was to determine the urinary C5b-9 excretion and to assess its association with long-term outcome in renal transplant recipients (RTRs).

Methods

We measured urinary C5b-9 in a well-defined cross-sectional cohort of RTRs. Urinary specimens were taken from the morning urine portion and terminal complement component C5b-9 was measured using an enzyme-linked-immunosorbent assay (ELISA). Cox regression analyses were used to investigate prospective associations with death censored graft failure.

Results

We included 639 RTRs (age 53±13 years; 58% males at 5.3 (1.8-12.2) years after transplantation). Mean eGFR was 52.2±20.1 ml/min/1.73m², urinary C5b-9 excretion was detectable in 102 (16%) RTRs with median [interquartile range] C5b-9 levels of 5.1 (2.8-12.8) ng/mL. During follow-up of 4.9±1.6 years, 75 RTRs developed death censored graft failure. In univariable analysis, detectable C5b-9 was associated with increased risk of graft failure (HR 4.17 [95%CI 2.63-6.63], P<0.001) compared to undetectable C5b-9. The association of detectable C5b-9 with graft failure remained (HR 4.19 [95%CI 2.62-6.70], P<0.001) independent of adjustment for age, sex, eGFR, and hs-CRP. Further adjustment for proteinuria>0.5 g/24h, did not materially alter the association of detectable C5b-9 with graft failure (HR 2.31 [95%CI 1.41-3.78], P=0.001).

Conclusion

Our results indicate that urinary C5b-9 is associated with graft failure, independently of potential confounders, including proteinuria. The results also suggest that urinary C5b-9 might be a useful biomarker for ongoing immunological injury and chronic kidney allograft deterioration. Our findings point towards a potential role for urinary complement activation in the pathogenesis of chronic allograft failure.