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Open Access Highly Accessed Research article

Tubular reabsorption and local production of urine hepcidin-25

Hilde PE Peters1*, Coby MM Laarakkers2, Peter Pickkers3, Rosalinde Masereeuw4, Otto C Boerman5, Annemarie Eek5, Elisabeth AM Cornelissen6, Dorine W Swinkels2 and Jack FM Wetzels1

Author Affiliations

1 Nephrology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands

2 Laboratory Medicine, Laboratory of Genetic, Endocrine and Metabolic Diseases, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands

3 Intensive Care Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands

4 Pharmacology and Toxicology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands

5 Nuclear Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands

6 Pediatric Nephrology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands

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BMC Nephrology 2013, 14:70  doi:10.1186/1471-2369-14-70

Published: 25 March 2013

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 (β2m) 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 β2m in 19 patients who underwent cardiopulmonary bypass surgery. Hepcidin was measured by a mass spectrometry assay (MS), whereas β2m was measured by ELISA.

Results

In patients with chronic renal disease, FE of hepcidin-25 was strongly correlated with FE of β2m (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 β2m, 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 β2m in cardiac surgery patients suggests local production.

Keywords:
AKI; β2-microglobulin; Hepcidin; Megalin; Kidney tubules