title: Tubular reabsorption and local production of urine hepcidin-25.
abstract: BACKGROUND
  Hepcidin is a central regulator of iron metabolism. Serum hepcidin levels are increased in patients with renal insufficiency, which may contribute to anemia. Urine hepcidin was found to be increased in some patients after cardiac surgery, and these patients were less likely to develop acute kidney injury. It has been suggested that urine hepcidin may protect by attenuating heme-mediated injury, but processes involved in urine hepcidin excretion are unknown.
  
  
  METHODS
  To assess the role of tubular reabsorption we compared fractional excretion (FE) of hepcidin-25 with FE of β2-microglobulin (β(2)m) in 30 patients with various degrees of tubular impairment due to chronic renal disease. To prove that hepcidin is reabsorbed by the tubules in a megalin-dependent manner, we measured urine hepcidin-1 in wild-type and kidney specific megalin-deficient mice. Lastly, we evaluated FE of hepcidin-25 and β(2)m in 19 patients who underwent cardiopulmonary bypass surgery. Hepcidin was measured by a mass spectrometry assay (MS), whereas β(2)m was measured by ELISA.
  
  
  RESULTS
  In patients with chronic renal disease, FE of hepcidin-25 was strongly correlated with FE of β(2)m (r = 0.93, P <0.01). In megalin-deficient mice, urine hepcidin-1 was 7-fold increased compared to wild-type mice (p < 0.01) indicating that proximal tubular reabsorption occurs in a megalin- dependent manner. Following cardiac surgery, FE of hepcidin-25 increased despite a decline in FE of β(2)m, potentially indicating local production at 12-24 hours.
  
  
  CONCLUSIONS
  Hepcidin-25 is reabsorbed by the renal tubules and increased urine hepcidin-25 levels may reflect a reduction in tubular uptake. Uncoupling of FE of hepcidin-25 and β(2)m in cardiac surgery patients suggests local production.
authors.affiliation: Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. h.peters@nier.umcn.nl
authors.forename: Hilde P E
authors.initials: HP
authors.lastname: Peters
authors.forename: Coby M M
authors.initials: CM
authors.lastname: Laarakkers
authors.forename: Peter
authors.initials: P
authors.lastname: Pickkers
authors.forename: Rosalinde
authors.initials: R
authors.lastname: Masereeuw
authors.forename: Otto C
authors.initials: OC
authors.lastname: Boerman
authors.forename: Annemarie
authors.initials: A
authors.lastname: Eek
authors.forename: Elisabeth A M
authors.initials: EA
authors.lastname: Cornelissen
authors.forename: Dorine W
authors.initials: DW
authors.lastname: Swinkels
authors.forename: Jack F M
authors.initials: JF
authors.lastname: Wetzels
mesh_terms: D000042:Absorption / Q000502:physiology; D000328:Adult; D000368:Aged; D000818:Animals; D015415:Biomarkers / Q000097:blood / Q000652:urine; D005260:Female; D064451:Hepcidins / Q000097:blood / Q000652:urine*; D006801:Humans; D007684:Kidney Tubules / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D051436:Renal Insufficiency, Chronic / Q000097:blood / Q000652:urine*; D055815:Young Adult
chemical_list: D015415:Biomarkers; D064451:Hepcidins; C545475:hepcidin 25, human