Higher Urinary Iron Levels are Associated with Kidney Dysfunction, Tubular Damage, and Increased Mortality in Kidney Transplant Recipients.

Abstract

Background: Increased urinary iron can result from (i) increased delivery of iron to the kidneys, (ii) increased glomerular passage of iron, and/or (iii) decreased tubular reuptake. Currently, the relevance of urinary iron levels is unknown. We investigated urinary iron with different pathways and clinical outcomes in kidney transplant recipients (KTRs).

Methods: We measured urinary iron in samples from the prospective TransplantLines Food & Nutrition Biobank and Cohort study. Multivariable linear and Cox regression models were applied.

Results: We included 693 stable KTRs (age 53±13 years, 43% female, estimated glomerular filtration rate [eGFR] 52±20 ml/min/1.73m2). Higher urinary iron was associated with lower eGFR and higher kidney damage markers, including albuminuria, 24h urinary liver-type fatty acid-binding protein excretion, urinary endothelial growth factor to creatinine ratio, and plasma neutrophil-gelatinase associated lipocalin (all P<0.001). In contrast, urinary iron was not associated with systemic iron status, but was increased with oral iron supplementation. During a follow-up of 5.3 years, 83 KTRs experienced graft failure, and 150 died. Prospectively, higher urinary iron was associated with graft failure, but the association was decreased after adjustment for proteinuria. In contrast, urinary iron was independently associated with increased mortality risk (HR per doubling: 1.29; 95% CI: 1.08-1.56).

Conclusions: Higher urinary iron levels are associated with worse kidney function, more proteinuria, increased tubular damage markers and higher mortality. Oral iron supplementation seems to be an important determinant of urinary iron levels. These findings raise the possibility that urinary iron acts as a tubulotoxic agent and mechanistic studies are warranted.