Kidney Week

Abstract: FR-PO0103

Transferrinuria Promotes Iron-Mediated Tubular Remodeling During CKD Progression in a Murine Alport Model

Session Information

• Hereditary Glomerular and Tubulointerstitial Kidney Diseases
  October 23, 2026 | Location: Exhibit Hall A, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Genetic Diseases of the Kidneys

• 1202 Genetic Diseases of the Kidneys: Non-Cystic (Complex and Non-Cystic Monogenic)

Authors

• Tavris, Bengi Su, UniversitatsKlinikum Heidelberg Institut fur Humangenetik, Heidelberg, BW, Germany

Bengi Su Tavris, MD

• Ramakrishnan, Suresh K, UniversitatsKlinikum Heidelberg Institut fur Humangenetik, Heidelberg, BW, Germany

Suresh K Ramakrishnan, PhD

• Loza Valdes, Angel, UniversitatsKlinikum Heidelberg Institut fur Humangenetik, Heidelberg, BW, Germany

Angel Loza Valdes, PhD

• Rickert-Zacharias, Verena, UniversitatsKlinikum Heidelberg Institut fur Humangenetik, Heidelberg, BW, Germany

Verena Rickert-Zacharias, PhD, ScM

• Miner, Jeffrey H., Washington University in St Louis, St. Louis, Missouri, United States

Jeffrey H. Miner, PhD, FASN

• Simons, Matias, UniversitatsKlinikum Heidelberg Institut fur Humangenetik, Heidelberg, BW, Germany

Matias Simons, MD

Background

Although proteinuria is an established prognostic factor in CKD, whether it causally contributes to pathophysiology remains unclear. Transferrin is an 81 kDa iron-transport protein that is normally not filtered, but during glomerular proteinuria, transferrinuria could occur. We hypothesized that transferrinuria may lead to iron overload, altered metabolic conditions and damage in proximal tubules (PT) in a murine model of Alport syndrome.

Methods

Kidney and urine samples were collected from 8-week-old Col4a3 Wildtype (WT) and knockout (KO) mice. Urine was analyzed for transferrin content. Kidneys were analyzed for iron-related proteins, oxidative stress, and mitochondrial function. Ex vivo assays were performed on isolated tubules from 8-10-week-old mice.

Results

Transferrinuria and increased iron content of the kidney were observed in KO. Multiple iron-related proteins were altered in KO kidneys: Iron regulatory protein 1 and transferrin receptor 1 were significantly decreased, whilst ferritin was increased significantly. Oxidative stress and lipid peroxidation markers acyl-coA-synthetase long-chain family member 4 (ACSL4), 4-hydroxynonenal (4-HNE), malondialdehyde (MDA) were not increased, whilst the antiferroptotic enzyme glutathione peroxidase 4 (GPX4) was depleted in KO kidneys. Gene and protein expression analyses demonstrated a metabolic shift in KO kidneys with downregulation of β-oxidation and mitochondrial biogenesis. Mitochondria showed fragmented morphology, and the iron-sulfur cluster (ISC)-associated mitochondrial complexes were significantly decreased in KO.

Conclusion

Our findings build a framework of iron-driven cellular adaptations in PT under chronic transferrinuria. Our results do not suggest active ferroptosis despite iron overload, but mitochondrial dysfunction from impaired ISC formation under reduced iron bioavailability at later disease stages. These findings highlight the nonuniform pathophysiology across disease stages during CKD progression.

Funding

• Government Support – Non-U.S.