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The multifaceted role of iron in renal health and disease

Nature Reviews Nephrology volume 16, pages 77–98 (2020)Cite this article

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Abstract

Iron is an essential element that is indispensable for life. The delicate physiological body iron balance is maintained by both systemic and cellular regulatory mechanisms. The iron-regulatory hormone hepcidin assures maintenance of adequate systemic iron levels and is regulated by circulating and stored iron levels, inflammation and erythropoiesis. The kidney has an important role in preventing iron loss from the body by means of reabsorption. Cellular iron levels are dependent on iron import, storage, utilization and export, which are mainly regulated by the iron response element–iron regulatory protein (IRE–IRP) system. In the kidney, iron transport mechanisms independent of the IRE–IRP system have been identified, suggesting additional mechanisms for iron handling in this organ. Yet, knowledge gaps on renal iron handling remain in terms of redundancy in transport mechanisms, the roles of the different tubular segments and related regulatory processes. Disturbances in cellular and systemic iron balance are recognized as causes and consequences of kidney injury. Consequently, iron metabolism has become a focus for novel therapeutic interventions for acute kidney injury and chronic kidney disease, which has fuelled interest in the molecular mechanisms of renal iron handling and renal injury, as well as the complex dynamics between systemic and local cellular iron regulation.

Key points

  • The mechanisms of renal iron handling differ between nephron segments, and iron transporters have a polarized organization in renal epithelial cells.

  • Renal disorders can reduce systemic iron levels as a result of enhanced urinary iron excretion and hepcidin-mediated reduction of iron transport and can decrease erythropoiesis-mediated iron utilization through increased urinary loss and reduced synthesis of erythropoietin.

  • Acquired and inherited disturbances in systemic iron homeostasis are associated with reduced kidney function and/or kidney injury.

  • Iron has an important role in acute kidney injury and chronic kidney disease, either as a critical initiator of oxidative stress and mitochondrial dysfunction or as a potent modulator of inflammation.

  • Targeting mechanisms of local and systemic iron homeostasis may provide novel therapies for kidney disease and its complications, including anaemia; however, such approaches will require close monitoring of iron balance and potential adverse effects.

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Fig. 1: Systemic and cellular iron handling and regulation.
Fig. 2: Kidney iron handling.
Fig. 3: Effects of kidney diseases on systemic iron homeostasis.
Fig. 4: Effects of systemic iron disorders on kidney injury.
Fig. 5: Mechanisms of iron-mediated kidney injury and cell death.

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Authors and Affiliations

  1. Department of Laboratory Medicine, Radboud Institute of Molecular Life Sciences, Radboud University Medical Center, Nijmegen, Netherlands

    Rachel P. L. van Swelm & Dorine. W. Swinkels

  2. Department of Nephrology, Radboud Institute of Health Sciences, Radboud University Medical Center, Nijmegen, Netherlands

    Jack F. M. Wetzels

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R.P.L van Swelm and D.W. Swinkels researched the data for the article and wrote the manuscript. J.F.M. Wetzels contributed substantially to discussions on the content and editing of the manuscript before submission.

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Glossary

Fenton reaction

The reaction in which Fe2+ catalyses the generation of highly reactive hydroxyl radicals via its reaction with hydrogen peroxide (H2O2), which is a product of mitochondrial oxidative respiration.

Reticuloendothelial system

Also known as the mononuclear phagocytic system. The reticuloendothelial system comprises the phagocytic cells (primarily monocytes and macrophages) that are located in reticular connective tissue.

Fanconi syndrome

A syndrome that results in inadequate reabsorption of filtered substrates, particularly low-molecular-weight proteins and peptides, in the renal proximal tubules. The syndrome can be caused by various congenital or acquired diseases.

Dent disease

A rare X-linked recessive disorder that affects the renal proximal tubules and is characterized by proteinuria, hypercalciuria, formation of calcium kidney stones, nephrocalcinosis and chronic kidney disease. Dent disease is a cause of Fanconi syndrome.

Lowe syndrome

Also known as oculocerebrorenal syndrome. A rare X-linked recessive disorder characterized by congenital cataracts, hypotonia, intellectual disability, proximal tubular acidosis, aminoaciduria and low-molecular-weight proteinuria. Lowe syndrome is a cause of Fanconi syndrome.

Mendelian randomization study

A study that uses measured variation in genes of known function to examine the causal effect of modifiable exposure on disease in observational studies.

Endoplasmic reticulum (ER) stress

Endoplasmic reticulum (ER) stress results in impairment in protein folding in the ER and the accumulation of misfolded proteins. It can be caused by disturbances in cellular processes including redox regulation and calcium regulation, glucose deprivation and viral infection.

Damage-associated molecular patterns

(DAMPs). Also known as danger-associated molecular patterns, danger signals and alarmins. Endogenous molecules that are released from damaged or dying cells and can initiate and perpetuate a non-infectious inflammatory response.

Haemoproteins

Proteins that are conjugated to haem. Examples include catalase, cytochrome, haemoglobin and myoglobin.

Iron-loading anaemias

Anaemias that are characterized by high serum iron, transferrin saturation and ferritin levels, as well as iron deposits in parenchymal cells and reticuloendothelial tissue with or without organ dysfunction.

Anticalins

Artificial proteins that can bind to antigens (either proteins or small molecules).

Aptamers

Oligonucleotide or peptide molecules that bind to specific target molecules.

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van Swelm, R.P.L., Wetzels, J.F.M. & Swinkels, D.W. The multifaceted role of iron in renal health and disease. Nat Rev Nephrol 16, 77–98 (2020). https://doi.org/10.1038/s41581-019-0197-5

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