Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Iron metabolism in the pathogenesis of iron-induced kidney injury

Nature Reviews Nephrology volume 9, pages 385–398 (2013)Cite this article

Subjects

Abstract

In the past 8 years, there has been renewed interest in the role of iron in both acute kidney injury (AKI) and chronic kidney disease (CKD). In patients with kidney diseases, renal tubules are exposed to a high concentration of iron owing to increased glomerular filtration of iron and iron-containing proteins, including haemoglobin, transferrin and neutrophil gelatinase-associated lipocalin (NGAL). Levels of intracellular catalytic iron may increase when glomerular and renal tubular cells are injured. Reducing the excessive luminal or intracellular levels of iron in the kidney could be a promising approach to treat AKI and CKD. Understanding the role of iron in kidney injury and as a therapeutic target requires insight into the mechanisms of iron metabolism in the kidney, the role of endogenous proteins involved in iron chelation and transport, including hepcidin, NGAL, the NGAL receptor and divalent metal transporter 1, and iron-induced toxic effects. This Review summarizes emerging knowledge, which suggests that complex mechanisms of iron metabolism exist in the kidney, modulated directly or indirectly by cellular iron content, inflammation, ischaemia and oxidative stress. The potential exists for prevention and treatment of iron-induced kidney injury by customized iron removal or relocation, aided by detailed insight into the underlying pathological mechanisms.

Key Points

  • Iron content in the kidneys is increased in patients with chronic kidney disease or acute kidney injury, and is associated with proteinuria, haematuria or haemoglobinuria

  • Increased local exposure to iron in the kidney may have a role in causing acute kidney injury, development and progression of kidney disease and in causing end-stage renal disease

  • Decreasing the excessive iron in the kidneys may be a novel approach to treat acute kidney injury and chronic kidney disease

  • The kidneys express many proteins that are involved in iron metabolism and transport

  • The precise role and regulation of many proteins involved in renal iron metabolism and iron-induced kidney injury is poorly understood

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Kidney iron transport.
Figure 2: Iron filtration under physiological or disease conditions.
Figure 3: The effects of systemic iron overload.
Figure 4: Iron metabolism in glomerulopathy.
Figure 5: Iron metabolism in ischaemia–reperfusion injury.

Similar content being viewed by others

References

  1. Al-Ismaili, Z., Piccioni, M. & Zappitelli, M. Rhabdomyolysis: pathogenesis of renal injury and management. Pediatr. Nephrol. 26, 1781–1788 (2011).

    Article  PubMed  Google Scholar 

  2. Hentze, M. W., Muckenthaler, M. U., Galy, B. & Camaschella, C. Two to tango: regulation of mammalian iron metabolism. Cell 142, 24–38 (2010).

    Article  CAS  PubMed  Google Scholar 

  3. Shah, S. V., Baliga, R., Rajapurkar, M. & Fonseca, V. A. Oxidants in chronic kidney disease. J. Am. Soc. Nephrol. 18, 16–28 (2007).

    Article  CAS  PubMed  Google Scholar 

  4. Kell, D. B. Iron behaving badly: inappropriate iron chelation as a major contributor to the aetiology of vascular and other progressive inflammatory and degenerative diseases. BMC Med. Genomics 2, 2 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Kroot, J. J. C., Tjalsma, H., Fleming, R. E. & Swinkels, D. W. Hepcidin in human iron disorders: diagnostic implications. Clin. Chem. 57, 1650–1669 (2011).

    Article  CAS  PubMed  Google Scholar 

  6. Veuthey, T., D'Anna, M. C. & Roque, M. E. Role of the kidney in iron homeostasis: renal expression of prohepcidin, ferroportin, and DMT1 in anemic mice. Am. J. Physiol. Renal Physiol. 295, F1213–F1221 (2008).

    Article  CAS  PubMed  Google Scholar 

  7. Haase, M., Mertens, P. R. & Haase-Fielitz, A. Renal stress in vivo in real-time–visualised by the NGAL reporter mouse. Nephrol. Dial. Transplant. 26, 2109–2111 (2011).

    Article  PubMed  Google Scholar 

  8. Haase-Fielitz, A. et al. Urine hepcidin has additive value in ruling out cardiopulmonary bypass-associated acute kidney injury: an observational cohort study. Crit. Care 15, R186 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  9. Ho, J. et al. mass spectrometry-based proteomic analysis of urine in acute kidney injury following cardiopulmonary bypass: a nested case-control study. Am. J. Kidney Dis. 53, 584–595 (2009).

    Article  CAS  PubMed  Google Scholar 

  10. Ho, J. et al. Urinary hepcidin-25 and risk of acute kidney injury following cardiopulmonary bypass. Clin. J. Am. Nephrol. 6, 2340–2346 (2011).

    Article  CAS  Google Scholar 

  11. Smith, C. P. & Thévenod, F. Iron transport and the kidney. Biochim. Biophys. Acta 1790, 724–730 (2009).

    Article  CAS  PubMed  Google Scholar 

  12. Brittenham, G. M. Iron-chelating therapy for transfusional iron overload. N. Engl. J. Med. 364, 146–156 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Swinkels, D. W., Janssen, M. C. H., Bergmans, J. & Marx, J. J. M. Hereditary hemochromatosis: genetic complexity and new diagnostic approaches. Clin. Chem. 52, 950–968 (2006).

    Article  CAS  PubMed  Google Scholar 

  14. Alfrey, A. C. & Hammond, W. S. Renal iron handling in the nephrotic syndrome. Kidney Int. 37, 1409–1413 (1990).

    Article  CAS  PubMed  Google Scholar 

  15. Paller, M. S. & Hedlund, B. O. Role of iron in postischemic renal injury in the rat. Kidney Int. 34, 474–480 (1988).

    Article  CAS  PubMed  Google Scholar 

  16. Moreno, J. A. et al. Haematuria: the forgotten CKD factor? Nephrol. Dial. Transplant. 27, 28–34 (2012).

    Article  PubMed  Google Scholar 

  17. Moreno, J. A. et al. AkI associated with macroscopic glomerular hematuria: clinical and pathophysiologic consequences. Clin. J. Am. Soc. Nephrol. 7, 175–184 (2012).

    Article  CAS  PubMed  Google Scholar 

  18. Garrick, M. D. & Garrick, L. M. Cellular iron transport. Biochim. Biophys. Acta 1790, 309–325 (2009).

    Article  CAS  PubMed  Google Scholar 

  19. Mori, K. et al. Endocytic delivery of lipocalin-siderophore-iron complex rescues the kidney from ischemia-reperfusion injury. J. Clin. Invest. 115, 610–621 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Paragas, N. et al. NGAL-siderocalin in kidney disease. Biochim. Biophys. Acta 1823, 1451–1458 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Chakraborty, S., Kaur, S., Guha, S. & Batra, S. K. The multifaceted roles of neutrophil gelatinase associated lipocalin (NGAL) in inflammation and cancer. Biochim. Biophys. Acta 1826, 129–169 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Pawar, R. D. et al. Neutrophil gelatinase-associated lipocalin is instrumental in the pathogenesis of antibody-mediated nephritis in mice. Arthritis Rheum. 64, 1620–1631 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Barasch, J. & Qiu, A. Mutant NGAL proteins and uses thereof. International patent application WO/2011/149962 (2011).

  24. Rajapurkar, M. M., Hegde, U., Bhattacharya, A., Alam, M. G. & Shah, S. V. Effect of deferiprone, an oral iron chelator, in diabetic and non-diabetic glomerular disease. Toxicol. Mech. Methods 23, 5–10 (2013).

    Article  CAS  PubMed  Google Scholar 

  25. Goraya, N., Simoni, J., Jo, C. & Wesson, D. E. Dietary acid reduction with fruits and vegetables or bicarbonate attenuates kidney injury in patients with a moderately reduced glomerular filtration rate due to hypertensive nephropathy. Kidney Int. 81, 86–93 (2012).

    Article  CAS  PubMed  Google Scholar 

  26. Zhang, D., Meyron-Holtz, E. & Rouault, T. A. Renal iron metabolism: transferrin iron delivery and the role of iron regulatory proteins. J. Am. Soc. Nephrol. 18, 401–406 (2007).

    Article  CAS  PubMed  Google Scholar 

  27. García-Montoya, I. A., Cendón, T. S., Arévalo-Gallegos, S. & Rascón-Cruz, Q. Lactoferrin a multiple bioactive protein: an overview. Biochim. Biophys. Acta 1820, 226–236 (2012).

    Article  CAS  PubMed  Google Scholar 

  28. Adlerova, L., Bartoskova, A. & Faldyna, M. Lactoferrin: a review. Vet. Med. (Praha). 53, 457–468 (2008).

    Article  CAS  Google Scholar 

  29. Åbrink, M., Larsson, E., Gobl, A. & Hellman, L. Expression of lactoferrin in the kidney: Implications for innate immunity and iron metabolism. Kidney Int. 57, 2004–2010 (2000).

    Article  PubMed  Google Scholar 

  30. Norden, A. G. W. et al. Glomerular protein sieving and implications for renal failure in Fanconi syndrome. Kidney Int. 60, 1885–1892 (2001).

    Article  CAS  PubMed  Google Scholar 

  31. Itzhaki, R. F. & Belcher, E. H. Studies on plasma iron in the rat. II. Plasma iron concentration and plasma iron-binding capacity. Arch. Biochem. Biophys. 92, 74–80 (1961).

    Article  CAS  PubMed  Google Scholar 

  32. Tanner, G. A. Glomerular sieving coefficient of serum albumin in the rat: a two-photon microscopy study. Am. J. Physiol. Renal Physiol. 296, F1258–F1265 (2009).

    Article  CAS  PubMed  Google Scholar 

  33. Cohen, L. A. et al. Serum ferritin is derived primarily from macrophages through a nonclassical secretory pathway. Blood 116, 1574–1584 (2010).

    Article  CAS  PubMed  Google Scholar 

  34. Marzolo, M. P. & Farfán, P. New insights into the roles of megalin/LRP2 and the regulation of its functional expression. Biol. Res. 44, 89–105 (2011).

    Article  CAS  PubMed  Google Scholar 

  35. Le Blanc, S., Garrick, M. D. & Arredondo, M. Heme carrier protein 1 transports heme and is involved in heme-Fe metabolism. Am. J. Physiol Cell Physiol. 302, C1780–C1785 (2012).

    Article  CAS  PubMed  Google Scholar 

  36. Nath, K. A. Heme oxygenase-1: a provenance for cytoprotective pathways in the kidney and other tissues. Kidney Int. 70, 432–443 (2006).

    Article  CAS  PubMed  Google Scholar 

  37. Zarjou, A. et al. proximal tubule H-ferritin mediates renal iron trafficking and confers protection in acute kidney injury. J. Am. Soc. Nephrol. 23, 96A (2012).

    Google Scholar 

  38. Langelueddecke, C. et al. Lipocalin-2 (24p3/neutrophil gelatinase-associated lipocalin (NGAL)) receptor is expressed in distal nephron and mediates protein endocytosis. J. Biol. Chem. 287, 159–169 (2012).

    Article  CAS  PubMed  Google Scholar 

  39. Khan, A. A. & Quigley, J. G. Control of intracellular heme levels: heme transporters and heme oxygenases. Biochim. Biophys. Acta 1813, 668–682 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Cheng, X., Shen, D., Samie, M. & Xu, H. Mucolipins: intracellular TRPML1–3 channels. FEBS Lett. 584, 2013–2021 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Jenkitkasemwong, S., Wang, C. Y., Mackenzie, B. & Knutson, M. D. Physiologic implications of metal-ion transport by ZIP14 and ZIP8. Biometals 25, 643–655 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Yanatori, I. et al. Heme and non-heme iron transporters in non-polarized and polarized cells. BMC Cell Biol. 11, 39 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Vesey, D. A. Transport pathways for cadmium in the intestine and kidney proximal tubule: focus on the interaction with essential metals. Toxicol. Lett. 198, 13–19 (2010).

    Article  CAS  PubMed  Google Scholar 

  44. Wolff, N. A. et al. Ferroportin 1 is expressed basolaterally in rat kidney proximal tubule cells and iron excess increases its membrane trafficking. J. Cell. Mol. Med. 15, 209–219 (2011).

    Article  CAS  PubMed  Google Scholar 

  45. Yang, Z. et al. Kinetics and specificity of feline leukemia virus subgroup C receptor (FLVCR) export function and its dependence on hemopexin. J. Biol. Chem. 285, 28874–28882 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Camborieux, L., Julia, V., Pipy, B. & Swerts, J. P. Respective roles of inflammation and axonal breakdown in the regulation of peripheral nerve hemopexin: an analysis in rats and in C57BL/Wlds mice. J. Neuroimmunol. 107, 29–41 (2000).

    Article  CAS  PubMed  Google Scholar 

  47. Tolosano, E., Fagoonee, S., Morello, N., Vinchi, F. & Fiorito, V. Heme scavenging and the other facets of hemopexin. Antioxid. Redox Signal. 12, 305–320 (2010).

    Article  CAS  PubMed  Google Scholar 

  48. Moestrup, S. K., Gliemann, J. & Pallesen, G. Distribution of the α2-macroglobulin receptor/low density lipoprotein receptor-related protein in human tissues. Cell Tissue Res. 269, 375–382 (1992).

    Article  CAS  PubMed  Google Scholar 

  49. Zager, R. A., Vijayan, A. & Johnson, A. C. M. Proximal tubule haptoglobin gene activation is an integral component of the acute kidney injury “stress response”. Am. J. Physiol. Renal Physiol. 303, F139–F148 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Van Gorp, H., Delputte, P. L. & Nauwynck, H. J. Scavenger receptor CD163, a Jack-of-all-trades and potential target for cell-directed therapy. Mol. Immunol. 47, 1650–1660 (2010).

    Article  CAS  PubMed  Google Scholar 

  51. Sponsel, H. T. et al. Effect of iron on renal tubular epithelial cells. Kidney Int. 50, 436–444 (1996).

    Article  CAS  PubMed  Google Scholar 

  52. Sheerin, N. S., Sacks, S. H. & Fogazzi, G. B. In vitro erythrophagocytosis by renal tubular cells and tubular toxicity by haemoglobin and iron. Nephrol. Dial. Transplant. 14, 1391–1397 (1999).

    Article  CAS  PubMed  Google Scholar 

  53. Shvartsman, M. & Cabantchik, Z. I. Intracellular iron trafficking: role of cytosolic ligands. Biometals 25, 711–723 (2012).

    Article  CAS  PubMed  Google Scholar 

  54. Philpott, C. C. Coming into view: eukaryotic iron chaperones and intracellular iron delivery. J. Biol. Chem. 287, 13518–13523 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Johnson, A. C. M., Becker, K. & Zager, R. A. Parenteral iron formulations differentially affect MCP-1, HO-1, and NGAL gene expression and renal responses to injury. Am. J. Physiol. Renal Physiol 299, F426–F435 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Ludwiczek, S., Theurl, I., Bahram, S., Schümann, K. & Weiss, G. Regulatory networks for the control of body iron homeostasis and their dysregulation in HFE mediated hemochromatosis. J. Cell. Physiol. 204, 489–499 (2005).

    Article  CAS  PubMed  Google Scholar 

  57. Liu, Q. S., Nilsen-Hamilton, M. & Xiong, S. D. Synergistic regulation of the acute phase protein SIP24/24p3 by glucocorticoid and pro-inflammatory cytokines. Acta Physiologica Sinica 55, 525–529 (2003).

    CAS  PubMed  Google Scholar 

  58. Roudkenar, M. H. et al. Oxidative stress induced lipocalin 2 gene expression: addressing its expression under the harmful conditions. J. Radiat. Res. 48, 39–44 (2007).

    Article  CAS  PubMed  Google Scholar 

  59. Roudkenar, M. H. et al. Upregulation of neutrophil gelatinase-associated lipocalin, NGAL/Lcn2, in β-thalassemia patients. Arch. Med. Res. 39, 402–407 (2008).

    Article  CAS  PubMed  Google Scholar 

  60. Zager, R. A. & Burkhart, K. Myoglobin toxicity in proximal human kidney cells: roles of Fe, Ca2+, H2O2, and terminal mitochondrial electron transport. Kidney Int. 51, 728–738 (1997).

    Article  CAS  PubMed  Google Scholar 

  61. Paller, M. S. & Hedlund, B. E. Extracellular iron chelators protect kidney cells from hypoxia/reoxygenation. Free Radic. Biol. Med. 17, 597–603 (1994).

    Article  CAS  PubMed  Google Scholar 

  62. Kovtunovych, G., Eckhaus, M. A., Ghosh, M. C., Ollivierre-Wilson, H. & Rouault, T. A. Dysfunction of the heme recycling system in heme oxygenase 1-deficient mice: effects on macrophage viability and tissue iron distribution. Blood 116, 6054–6062 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Hashemieh, M., Azarkeivan, A., Akhlaghpoor, S., Shirkavand, A. & Sheibani, K. T2-star (T2*) magnetic resonance imaging for assessment of kidney iron overload in thalassemic patients. Arch. Iranian Med. 15, 91–94 (2012).

    Google Scholar 

  64. Sears, D. A., Anderson, P. R., Foy, A. L., Williams, H. L. & Crosby, W. H. Urinary iron excretion and renal metabolism of hemoglobin in hemolytic diseases. Blood 28, 708–725 (1966).

    CAS  PubMed  Google Scholar 

  65. Schein, A., Enriquez, C., Coates, T. D. & Wood, J. C. Magnetic resonance detection of kidney iron deposition in sickle cell disease: a marker of chronic hemolysis. J. Magn. Reson. Imaging 28, 698–704 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  66. Ballarín, J. et al. Acute renal failure associated to paroxysmal nocturnal haemoglobinuria leads to intratubular haemosiderin accumulation and CD163 expression. Nephrol. Dial. Transplant. 26, 3408–3411 (2011).

    Article  CAS  PubMed  Google Scholar 

  67. Fervenza, F. C. et al. Induction of heme oxygenase-1 and ferritin in the kidney in warm antibody hemolytic anemia. Am. J. Kidney Dis. 52, 972–977 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  68. Rakow-Penner, R., Glader, B., Yu, H. & Vasanawala, S. Adrenal and renal corticomedullary junction iron deposition in red cell aplasia. Pediatr. Radiol. 40, 1955–1957 (2010).

    Article  PubMed  Google Scholar 

  69. Rous, P. Urinary siderosis: hemosiderin granules in the urine as an aid in the diagnosis of pernicious anemia, hemochromatosis, and other diseases causing siderosis of the kidney. J. Exp. Med. 28, 645–658 (1918).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Wang, H. et al. Iron deposition in renal biopsy specimens from patients with kidney diseases. Am. J. Kidney Dis. 38, 1038–1044 (2001).

    Article  CAS  PubMed  Google Scholar 

  71. Ueda, N., Baliga, R. & Shah, S. V. Role of 'catalytic' iron in an animal model of minimal change nephrotic syndrome. Kidney Int. 49, 370–373 (1996).

    Article  CAS  PubMed  Google Scholar 

  72. Zager, R. A., Foerder, C. & Bredl, C. The influence of mannitol on myoglobinuric acute renal failure: functional, biochemical, and morphological assessments. J. Am. Soc. Nephrol. 2, 848–855 (1991).

    CAS  PubMed  Google Scholar 

  73. Delaby, C. et al. Renal handling of iron in mouse models of iron overload: recent concept. Am. J. Hematol. 86, E42 (2011).

    Google Scholar 

  74. Baliga, R., Zhang, Z., Baliga, M. & Shah, S. V. Evidence for cytochrome P-450 as a source of catalytic iron in myoglobinuric acute renal failure. Kidney Int. 49, 362–369 (1996).

    Article  CAS  PubMed  Google Scholar 

  75. Gutiérrez, L., Vujic Spasic, M., Muckenthaler, M. U. & Lázaro, F. J. Quantitative magnetic analysis reveals ferritin-like iron as the most predominant iron-containing species in the murine Hfe-haemochromatosis. Biochim. Biophys. Acta 1822, 1147–1153 (2012).

    Article  CAS  PubMed  Google Scholar 

  76. Harris, D. C. H. & Tay, Y. C. Mitochondrial function in rat renal cortex in response to proteinuria and iron. Clin. Exp. Pharmacol. Physiol. 24, 916–922 (1997).

    Article  CAS  PubMed  Google Scholar 

  77. Harris, D. C. H., Tay, C. & Nankivell, B. J. Lysosomal iron accumulation and tubular damage in rat puromycin nephrosis and ageing. Clin. Exp. Pharmacol. Physiol. 21, 73–81 (1994).

    Article  CAS  PubMed  Google Scholar 

  78. Nankivell, B. J. & Harris, D. C. H. Iron depletion in the remnant kidney. Nephron 70, 340–347 (1995).

    Article  CAS  PubMed  Google Scholar 

  79. Nankivell, B. J., Chen, J., Boadle, R. A. & Harris, D. C. H. The role of tubular iron accumulation in the remnant kidney. J. Am. Soc. Nephrol. 4, 1598–1607 (1993).

    Google Scholar 

  80. Viau, A. et al. Lipocalin 2 is essential for chronic kidney disease progression in mice and humans. J. Clin. Invest. 120, 4065–4076 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Remuzzi, A., Puntorieri, S., Brugnetti, B., Bertani, T. & Remuzzi, G. Renoprotective effect of low iron diet and its consequence on glomerular hemodynamics. Kidney Int. 39, 647–652 (1991).

    Article  CAS  PubMed  Google Scholar 

  82. De Vries, B. et al. Reduction of circulating redox-active iron by apotransferrin protects against renal ischemia-reperfusion injury. Transplantation 77, 669–675 (2004).

    Article  CAS  PubMed  Google Scholar 

  83. Mishra, J. et al. Amelioration of ischemic acute renal injury by neutrophil gelatinase-associated lipocalin. J. Am. Soc. Nephrol. 15, 3073–3082 (2004).

    Article  PubMed  Google Scholar 

  84. Michelakakis, H. et al. Iron overload and urinary lysosomal enzyme levels in β-thalassaemia major. Eur. J. Pediatr. 156, 602–604 (1997).

    Article  CAS  PubMed  Google Scholar 

  85. Lin, J. L., Lin-Tan, D. T., Hsu, K. H. & Yu, C. C. Environmental lead exposure and progression of chronic renal diseases in patients without diabetes. N. Engl. J. Med. 348, 277–286 (2003).

    Article  CAS  PubMed  Google Scholar 

  86. Aldudak, B. et al. Renal function in pediatric patients with β-thalassemia major. Pediatr. Nephrol. 15, 109–112 (2000).

    Article  CAS  PubMed  Google Scholar 

  87. Koliakos, G. et al. Urine biochemical markers of early renal dysfunction are associated with iron overload in β-thalassaemia. Clin. Lab. Haematol. 25, 105–109 (2003).

    Article  CAS  PubMed  Google Scholar 

  88. Nath, K. A. et al. Heme protein-induced chronic renal inflammation: suppressive effect of induced heme oxygenase-11. Kidney Int. 59, 106–117 (2001).

    Article  CAS  PubMed  Google Scholar 

  89. Boutaud, O. & Roberts II, L. J. Mechanism-based therapeutic approaches to rhabdomyolysis-induced renal failure. Free Radic. Biol. Med. 51, 1062–1067 (2011).

    Article  CAS  PubMed  Google Scholar 

  90. Hsiao, P. J., Wang, S. C., Wen, M. C., Diang, L. K. & Lin, S. H. Fanconi syndrome and CKD in a patient with paroxysmal nocturnal hemoglobinuria and hemosiderosis. Am. J. Kidney Dis. 55, e1–e5 (2010).

    Article  PubMed  Google Scholar 

  91. Leonardi, P. & Ruol, A. Renal hemosiderosis in the hemolytic anemias: diagnosis by means of needle biopsy. Blood 16, 1029–1038 (1960).

    CAS  PubMed  Google Scholar 

  92. Zager, R. A. Rhabdomyolysis and myohemoglobinuric acute renal failure. Kidney Int. 49, 314–326 (1996).

    Article  CAS  PubMed  Google Scholar 

  93. Zager, R. A., Johnson, A. C. M. & Becker, K. Renal cortical hemopexin accumulation in response to acute kidney injury. Am. J. Physiol. Renal Physiol. 303, F1460–F1472 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Tolosano, E. et al. Haptoglobin modifies the hemochromatosis phenotype in mice. Blood 105, 3353–3355 (2005).

    Article  CAS  PubMed  Google Scholar 

  95. Zhou, X. Y. et al. HFE gene knockout produces mouse model of hereditary hemochromatosis. Proc. Natl Acad. Sci. USA 95, 2492–2497 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Muncie, J. & Campbell, J. S. Alpha and beta thalassemia. Am. Fam. Physician 80, 339–344 (2009).

    PubMed  Google Scholar 

  97. Amer, J., Goldfarb, A. & Fibach, E. Flow cytometric analysis of the oxidative status of normal and thalassemic red blood cells. Cytometry A 60, 73–80 (2004).

    Article  PubMed  Google Scholar 

  98. Chiou, S. S. et al. Lipid peroxidation and antioxidative status in β-thalassemia major patients with or without hepatitis C virus infection. Clin. Chem. Lab. Med. 44, 1226–1233 (2006).

    Article  CAS  PubMed  Google Scholar 

  99. Livrea, M. A. et al. Oxidative stress and antioxidant status in β-thalassemia major: iron overload and depletion of lipid-soluble antioxidants. Blood 88, 3608–3614 (1996).

    CAS  PubMed  Google Scholar 

  100. Walter, P. B. et al. Oxidative stress and inflammation in iron-overloaded patients with β-thalassaemia or sickle cell disease. Br. J. Haematol. 135, 254–263 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Mackinnon, B. et al. Urinary transferrin, high molecular weight proteinuria and the progression of renal disease. Clin. Nephrol. 59, 252–258 (2003).

    Article  CAS  PubMed  Google Scholar 

  102. Brown, E. A., Sampson, B., Muller, B. R. & Curtis, J. R. Urinary iron loss in the nephrotic syndrome–an unusual cause of iron deficiency with a note on urinary copper losses. Postgrad. Med. J. 60, 125–128 (1984).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Howard, R. L., Buddington, B. & Alfrey, A. C. Urinary albumin, transferrin and iron excretion in diabetic patients. Kidney Int. 40, 923–926 (1991).

    Article  CAS  PubMed  Google Scholar 

  104. Prinsen, B. H. C. M. et al. Transferrin synthesis is increased in nephrotic patients insufficiently to replace urinary losses. J. Am. Soc. Nephrol. 12, 1017–1025 (2001).

    CAS  PubMed  Google Scholar 

  105. Ellis, D. Anemia in the course of the nephrotic syndrome secondary to transferrin depletion. J. Pediatr. 90, 953–955 (1977).

    Article  CAS  PubMed  Google Scholar 

  106. Naito, Y. et al. Effect of iron restriction on renal damage and mineralocorticoid receptor signaling in a rat model of chronic kidney disease. J. Hypertens. 30, 2192–2201 (2012).

    Article  CAS  PubMed  Google Scholar 

  107. Mahmoodi, B. K. et al. Associations of kidney disease measures with mortality and end-stage renal disease in individuals with and without hypertension: a meta-analysis. Lancet 380, 1649–1661 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  108. Gutierrez, E. et al. Oxidative stress, macrophage infiltration and CD163 expression are determinants of long-term renal outcome in macrohematuria-induced acute kidney injury of IgA nephropathy. Nephron Clin. Pract. 121, C42–C53 (2012).

    Article  CAS  PubMed  Google Scholar 

  109. Eller, K., Banas, M. C., Kirsch, A. H. & Rosenkranz, A. R. Lipocalin-2 is an endogenous inhibitor of inflammation in murine nephrotoxic serum nephritis. J. Am. Soc. Nephrol. 23, 563A (2012).

    Article  CAS  Google Scholar 

  110. Lipton, P. Ischemic cell death in brain neurons. Physiol. Rev. 79, 1431–1568 (1999).

    Article  CAS  PubMed  Google Scholar 

  111. Sola, A., Ventayol, A. & Hotter, G. Lcn-2 over-expressing bone marrow-derived macrophages promote renal regeneration. J. Am. Soc. Nephrol. 23, 106A (2012).

    Google Scholar 

  112. Jung, M. et al. Infusion of IL-10-expressing cells protects against renal ischemia through induction of lipocalin-2. Kidney Int. 81, 969–982 (2012).

    Article  CAS  PubMed  Google Scholar 

  113. Kozyraki, R. et al. Megalin-dependent cubilin-mediated endocytosis is a major pathway for the apical uptake of transferrin in polarized epithelia. Proc. Natl Acad. Sci. USA 98, 12491–12496 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Peters, H. P. E. et al. Tubular reabsorption and local production of urine hepcidin-25. BMC Nephrology 14, 70 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Ludwiczek, S. et al. Ca2+ channel blockers reverse iron overload by a new mechanism via divalent metal transporter-1. Nat. Med. 13, 448–454 (2007).

    Article  CAS  PubMed  Google Scholar 

  116. Liu, C. B., Wu, B., Xiao, M. & Wang, L. Q. Effects of nifedipine on iron deposits and nutritional metabolism in chronic iron-overloaded rats. Chinese J. Pharmacol. Toxicol. 25, 77–82 (2011).

    Google Scholar 

  117. Huang, X. P., Thiessen, J. J., Spino, M. & Templeton, D. M. Transport of iron chelators and chelates across MDCK cell monolayers: Implications for iron excretion during chelation therapy. Int. J. Hematol. 91, 401–412 (2010).

    Article  CAS  PubMed  Google Scholar 

  118. Abbas, M. et al. Evaluation of urinary excretion and renal clearance of deferiprone, creatinine, iron and zinc in human. Asian J. Chem. 6, 4583–4592 (2009).

    Google Scholar 

  119. Baum, M. Renal Fanconi syndrome secondary to deferasirox: where there is smoke there is fire. J. Pediatr. Hematol. Oncol. 32, 525–526 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  120. Suzuki, Y. A. & Lönnerdal, B. Baculovirus expression of mouse lactoferrin receptor and tissue distribution in the mouse. Biometals 17, 301–309 (2004).

    Article  CAS  PubMed  Google Scholar 

  121. Zhao, R., Diop-Bove, N., Visentin, M. & Goldman, I. D. Mechanisms of membrane transport of folates into cells and across epithelia. Annu. Rev. Nutr. 31, 177–201 (2011).

    Article  CAS  PubMed  Google Scholar 

  122. Shepard, M., Dhulipala, P., Kabaria, S., Abraham, N. G. & Lianos, E. A. Heme oxygenase-1 localization in the rat nephron. Nephron 92, 660–664 (2002).

    Article  CAS  PubMed  Google Scholar 

  123. Branten, A. J. W., Swinkels, D. W., Klasen, I. S. & Wetzels, J. F. M. Serum ferritin levels are increased in patients with glomerular diseases and proteinuria. Nephrol. Dial. Transplant. 19, 2754–2760 (2004).

    Article  CAS  PubMed  Google Scholar 

  124. Paragas, N. et al. The Ngal reporter mouse detects the response of the kidney to injury in real time. Nat. Med. 17, 216–223 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Haase, V. H. Hemoglobin in the kidney: breaking with traditional dogma. J. Am. Soc. Nephrol. 19, 1440–1441 (2008).

    Article  PubMed  Google Scholar 

  126. Rodríguez-Capote, K. et al. Utility of urine myoglobin for the prediction of acute renal failure in patients with suspected rhabdomyolysis: a systematic review. Clin. Chem. 55, 2190–2197 (2009).

    Article  CAS  PubMed  Google Scholar 

  127. Kulaksiz, H. et al. The iron-regulatory peptide hormone hepcidin: expression and cellular localization in the mammalian kidney. J. Endocrinol. 184, 361–370 (2005).

    Article  CAS  PubMed  Google Scholar 

  128. Kapojos, J. J. et al. Production of hemopexin by TNF-α stimulated human mesangial cells. Kidney Int. 63, 1681–1686 (2003).

    Article  CAS  PubMed  Google Scholar 

  129. Baliga, R., Ueda, N. & Shah, S. V. Increase in bleomycin-detectable iron in ischaemia/reperfusion injury to rat kidneys. Biochem. J. 291, 901–905 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors' research work is partly funded by an Innovation grant from the Dutch Kidney foundation (to R. Masereeuw, J. F. M. Wetzels and D. W. Swinkels; project number IP 12.81).

Author information

Authors and Affiliations

  1. Department of Laboratory Medicine, Laboratory of Genetic Endocrine and Metabolic diseases, Radboud University Medical Centre, Geert Grooteplein–Zuid 10, Nijmegen, 6525 GA, the Netherlands

    A. M. F. Martines, H. Tjalsma & D. W. Swinkels

  2. Department of Pharmacology and Toxicology, Radboud University Medical Centre, Geert Grooteplein–Zuid 10, Nijmegen, 6525 GA, the Netherlands

    R. Masereeuw

  3. Department of Physiology, Radboud University Medical Centre, Geert Grooteplein–Zuid 10, Nijmegen, 6525 GA, the Netherlands

    J. G. Hoenderop

  4. Department of Nephrology, Radboud University Medical Centre, Geert Grooteplein–Zuid 10, Nijmegen, 6525 GA, the Netherlands

    J. F. M. Wetzels

Authors
  1. A. M. F. Martines
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. R. Masereeuw
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. H. Tjalsma
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. J. G. Hoenderop
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. J. F. M. Wetzels
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. D. W. Swinkels
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

A. M. F. Martines researched data for the article and wrote the manuscript. A. M. F. Martines, R. Masereeuw, H. Tjalsma, J. G. Hoenderop, J. F. M. Wetzels and D. W. Swinkels contributed substantially to discussions of the content and/or editing of the manuscript before submission.

Corresponding author

Correspondence to D. W. Swinkels.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Table 1

Findings indicative of iron-related kidney injury in haem-related diseases (DOC 145 kb)

Supplementary Table 2

Findings indicative of iron-related kidney injury in systemic iron overload (DOC 84 kb)

Supplementary Table 3

Findings indicative of iron-related kidney injury in glomerulopathy (DOC 127 kb)

Supplementary Table 4

Findings indicative of iron-related kidney injury in ischaemia-reperfusion kidney injury (DOC 53 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Martines, A., Masereeuw, R., Tjalsma, H. et al. Iron metabolism in the pathogenesis of iron-induced kidney injury. Nat Rev Nephrol 9, 385–398 (2013). https://doi.org/10.1038/nrneph.2013.98

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrneph.2013.98

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing