Urinary copper excretion is associated with long-term graft failure in kidney transplant recipients

IntroductionIn chronic kidney disease, proteinuria increases urinary copper excretion, inducing oxidative tubular damage and worsening kidney function. We investigated whether this phenomenon occurred in kidney transplant recipients (KTR). In addition, we studied the associations of urinary copper excretion with the biomarker of oxidative tubular damage urinary liver-type fatty-acid binding protein (u-LFABP) and death-censored graft failure. MethodsThis prospective cohort study was performed in the Netherlands between 2008 and 2017, including outpatient KTR with a functioning graft for longer than 1 year, who were extensively phenotyped at baseline. Twenty-four-hour urinary copper excretion was measured by inductively coupled plasma mass spectrometry. Multivariable linear and Cox regression analyses were performed. ResultsIn 693 KTR (57% men, 53 +/- 13 years, eGFR 52 +/- 20 mL/min/1.73 m2), baseline median urinary copper excretion was 23.6 (interquartile range 11.3-15.9) mu g/24-hour. Urinary protein excretion was positively associated with urinary copper excretion (standardized beta=0.39, P<0.001), and urinary copper excretion was positively associated with u-LFABP (standardized beta=0.29, P<0.001). During a median follow-up of 8 years, 109 (16%) KTR developed graft failure. KTR with relatively high copper excretion were at higher risk of long-term graft failure (HR 1.57, 95% CI 1.32-1.86 per log2, P<0.001), independent of multiple potential confounders like eGFR, urinary protein excretion, and time after transplantation. A dose-response relationship was observed over increasing tertiles of copper excretion (HR 5.03, 95% CI 2.75-9.19, tertile 3 vs 1, P<0.001). u-LFABP was a significant mediator of this association (74% of indirect effect, P<0.001). Conclusion In KTR, urinary protein excretion is positively correlated with urinary copper excretion. In turn, higher urinary copper excretion is associated with an independent increased risk of kidney graft failure, with a substantial mediating effect through oxidative tubular damage. Further studies are warranted to investigate whether copper excretion-targeted interventions could improve kidney graft survival.