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Abstract: TH-PO135

Hepcidin Deficiency Exacerbates Renal Pathology in Disseminating Candidiasis

Session Information

  • AKI: Mechanisms - I
    November 03, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
    Abstract Time: 10:00 AM - 12:00 PM

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Kasem, Sadat, University of Florida, Gainesville, Florida, United States
  • Agarwal, Annanya, University of Florida, Gainesville, Florida, United States
  • Desai, Dhruv N., University of Florida, Gainesville, Florida, United States
  • Lionakis, Michail, National Institutes of Health, Bethesda, Maryland, United States
  • Mehrad, Borna, University of Florida, Gainesville, Florida, United States
  • Scindia, Yogesh M., University of Florida, Gainesville, Florida, United States
Background

Candida albicans is a human fungal pathogen and accounts for more than 50% of all invasive fungal infections. Fungal growth within the kidney and consequent kidney failure are the major cause of mortality during disseminating candidiasis. C. albicans utilizes a range of iron acquisition mechanisms that contribute to its virulence. Patients with fungal infection have substantially increased transferrin saturation and serum iron concentrations independent of underlying hematological disorder. Thus, host iron handling may be critical checkpoint to the outcome of the infection. Using a murine model of systemic iron overload, we investigated whether C.albicans-induced pathology is influenced by iron availability.

Methods

Iron overloaded hepcidin knockout (Hamp-/-) and wild type (WT) litter mates were infected with C. albicans SC5314 and outcomes of infection were evaluated.

Results

Compared to WT mice, Hamp-/- mice displayed increased kidney fungal burden, pathology and had higher mortality. C. albicans was in yeast form in the WT kidneys but had transformed into hyphae in the iron rich renal tubular region of Hamp-/- mice. The greater fungal burden was associated with loss of parenchyma and increased infiltration of p21 positive neutrophils in the kidneys of Hamp-/- mice, whereas the bone marrow neutrophil output in these mice had decreased.

Conclusion

Our data identify systemic iron overload as a susceptibility factor to C. albicans induced kidney failure. Hepcidin deficiency-induced kidney iron burden was associated transformation of yeast into hyphae, suggesting increased virulence. Increased p21 expression in neutrophils suggests impaired NETosis and may possibly explain increased fungal burden. Our data highlight importance of host iron metabolism in susceptibility to disseminating candidiasis.

Funding

  • Other NIH Support