Kidney Week

Abstract: TH-PO886

Iron Sequestration in Kidney Macrophages Is Essential for Protecting Proximal Tubules from Iron Overload during Iron Therapy in CKD

Session Information

• Anemia and Iron Metabolism
  October 24, 2024 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Anemia and Iron Metabolism

• 200 Anemia and Iron Metabolism

Authors

• Federman, Hannah Glenn, Weill Cornell Medicine, New York, New York, United States

Hannah Glenn Federman, PhD

• Campbell, Chantalle A., Weill Cornell Medicine, New York, New York, United States

Chantalle A. Campbell

• Elsayed, Heba, Weill Cornell Medicine, New York, New York, United States

Heba Elsayed, MS

• Bhatia, Divya, Weill Cornell Medicine, New York, New York, United States

Divya Bhatia, PhD

• Choi, Mary E., Weill Cornell Medicine, New York, New York, United States

Mary E. Choi, MD

• Vinchi, Francesca, New York Blood Center, New York, New York, United States

Francesca Vinchi, PhD

• Akchurin, Oleh M., Weill Cornell Medicine, New York, New York, United States

Oleh M. Akchurin, MD, PhD

Background

Chronic kidney disease (CKD) affects 10-15% of the adult U.S. population. Iron supplementation is very common in patients with CKD, and may lead to organ iron overload, rising concerns about nephrotoxic effects of iron. However, intrarenal iron trafficking during iron supplementation in CKD has not been delineated, making it difficult to account for renal effects of iron in CKD patients.

Methods

CKD was induced in 8-week old wild type (WT) and myeloid-specific (LysM-Cre) ferritin heavy chain knockout mice (Fth1^Mφ-KO) by 8 weeks of adenine diet. Iron dextran was administered intraperitoneally once a week, 500 mg/kg/dose. Kidney tissues were assessed by histology as well as processed for single cell suspensions via collagenase digestion immediately upon harvest, and analyzed by flow cytometry. Furthermore, proximal tubular epithelial cells (pTEC) and kidney macrophages were isolated using CD133 and CD11b magnetic microbeads.

Results

In pTEC of untreated WT CKD mice, ferritin heavy and light chain proteins were induced while labile iron pool was reduced, compared to healthy WT mice. Expression of transferrin receptor 1 (TfR1), a major iron importer, was reduced in pTEC of untreated CKD mice compared to controls. Iron suppementation resulted in iron accumulation within kidney macrophages in WT CKD mice while sparing pTEC, as assessed by Perls iron stain of kidney tissues and sorted kidney macrophages. In Fth1^Mφ-KO CKD mice supplementaed with iron, the distribution of iron within the kidney was vastly different from the WT: iron was accumulating primarily in pTEC, with especially massive iron content seen within atrophic tubulues in the areas of fibrosis (Figure).

Conclusion

Kidney macrophages are indespensable for preventing tubular iron overload during iron supplementation in CKD. Modifying iron-scavenging ability of kidney macrophages may represent a novel renoprotective strategy in CKD.

Iron accumulation in wild type and myeloid-specific ferritin heavy chain knockout mice with adenine-induced CKD treated with iron dextran supplementation.

Funding

• NIDDK Support