Urinary Properdin and sC5b-9 Are Independently Associated With Increased Risk for Graft Failure in Renal Transplant Recipients.

Rosa G M Lammerts,Jan-Stephan Sanders,Mohamed R Daha,Stephan J L Bakker,Marc A Seelen,Michele F Eisenga,Robert A Pol,Mohammed Alyami,Jacob Van Den Born,Stefan P Berger

doi:10.3389/fimmu.2019.02511

Abstract

The pathophysiology of late kidney-allograft failure remains complex and poorly understood. Activation of filtered or locally produced complement may contribute to the progression of renal failure through tubular C5b-9 formation. This study aimed to determine urinary properdin and sC5b-9 excretion and assess their association with long-term outcome in renal transplant recipients (RTR).Methods: We measured urinary properdin and soluble C5b-9 in a well-defined cross-sectional cohort of RTR. Urinary specimens were taken from a morning urine portion, and properdin and sC5b-9 were measured using an enzyme-linked-immunosorbent assay (ELISA). Cox proportional hazard regression analyses were used to investigate prospective associations with death-censored graft failure.Results: We included 639 stable RTR at a median [interquartile range] 5.3 (1.8–12.2) years after transplantation. Urinary properdin and sC5b-9 excretion were detectable in 161 (27%) and 102 (17%) RTR, respectively, with a median properdin level of 27.6 (8.6–68.1) ng/mL and a median sC5b-9 level of 5.1 (2.8–12.8) ng/mL. In multivariable-adjusted Cox regression analyses, including adjustment for proteinuria, urinary properdin (HR, 1.12; 95% CI 1.02–1.28; P = 0.008) and sC5b-9 excretion (HR, 1.34; 95% CI 1.10–1.63; P = 0.003) were associated with an increased risk of graft failure. If both urinary properdin and sC5b-9 were detectable, the risk of graft failure was further increased (HR, 3.12; 95% CI 1.69–5.77; P < 0.001).Conclusions: Our findings point toward a potential role for urinary complement activation in the pathogenesis of chronic allograft failure. Urinary properdin and sC5b-9 might be useful biomarkers for complement activation and chronic kidney allograft deterioration, suggesting a potential role for an alternative pathway blockade in RTR.

Highlights

Despite improvements in immunosuppressive therapy over the last decades, chronic and irreversible deterioration of a transplanted kidney graft remains a major problem and is responsible for disappointing outcomes in long-term graft survival [1]
No significant differences were found at baseline in HLA mismatches, primary renal disease, history of delayed graft function, and rejection between patients with and without detectable urinary properdin or sC5b-9
Since properdin is involved in sC5b-9 complex formation via the alternative complement pathway [9], we aimed to assess whether the association between properdin and graft failure was mediated by sC5b-9

Summary

Introduction

Despite improvements in immunosuppressive therapy over the last decades, chronic and irreversible deterioration of a transplanted kidney graft remains a major problem and is responsible for disappointing outcomes in long-term graft survival [1]. Interstitial fibrosis/tubular atrophy (IFTA), presents itself as renal allograft dysfunction (occurring at least 3 months post-transplant) in the absence of active acute rejection, drug toxicity, or other diseases. It is thought that proteinuria contributes to the progression of renal failure by various mechanisms. One of these mechanisms is suggested to be leakage of albumin-bound lipids across the damaged glomerular filtration barrier, leading to lipoapoptosis after reabsorption by the downstream proximal tubule [7, 8]. Activation of filtered or locally produced complement may be harmful to renal tubular cells and contribute to the progression of renal failure by initiating interstitial fibrosis [9, 10]. Complement activation leads to the formation of C5b-9 [11], which can be used as a clinical indicator of complement activation in native kidney diseases [12, 13]

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