Kidney Week

Abstract: SA-PO0199

Pathogenic Mitochondrial DNA Variants in Inherited Tubulointerstitial Kidney Disease

Session Information

• Tubular, Metabolic, and Systemic Noncystic Genetic Kidney Diseases
  October 24, 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

• Zivna, Martina, Research Unit for Rare Diseases, Department of Pediatrics and Inherited Metabolic Disorders, First faculty of Medicine, Charles University, Prague, Czechia

Martina Zivna, MS, MSc, PhD

• Svojsova, Klara, Research Unit for Rare Diseases, Department of Pediatrics and Inherited Metabolic Disorders, First faculty of Medicine, Charles University, Prague, Czechia

Klara Svojsova, MSc

• Baresova, Veronika, Research Unit for Rare Diseases, Department of Pediatrics and Inherited Metabolic Disorders, First faculty of Medicine, Charles University, Prague, Czechia

Veronika Baresova, MS, MSc, PhD

• Hodanova, Katerina, Research Unit for Rare Diseases, Department of Pediatrics and Inherited Metabolic Disorders, First faculty of Medicine, Charles University, Prague, Czechia

Katerina Hodanova, PhD

• Hartmannova, Hana, Research Unit for Rare Diseases, Department of Pediatrics and Inherited Metabolic Disorders, First faculty of Medicine, Charles University, Prague, Czechia

Hana Hartmannova, PhD

• Kmochova, Tereza, Research Unit for Rare Diseases, Department of Pediatrics and Inherited Metabolic Disorders, First faculty of Medicine, Charles University, Prague, Czechia

Tereza Kmochova, MSc

• Musalkova, Dita, Research Unit for Rare Diseases, Department of Pediatrics and Inherited Metabolic Disorders, First faculty of Medicine, Charles University, Prague, Czechia

Dita Musalkova, PhD

• Sikora, Jakub, Research Unit for Rare Diseases, Department of Pediatrics and Inherited Metabolic Disorders, First faculty of Medicine, Charles University, Prague, Czechia

Jakub Sikora, MD, PhD

• Pavlovicova, Lea, Research Unit for Rare Diseases, Department of Pediatrics and Inherited Metabolic Disorders, First faculty of Medicine, Charles University, Prague, Czechia

Lea Pavlovicova, MD

• Stranecky, Viktor, Research Unit for Rare Diseases, Department of Pediatrics and Inherited Metabolic Disorders, First faculty of Medicine, Charles University, Prague, Czechia

Viktor Stranecky, MSc, PhD

• Kidd, Kendrah O., Wake Forest School of Medicine, Section on Nephrology, Winston Salem, United States

Kendrah O. Kidd, PhD

• Bleyer, Anthony J., Wake Forest School of Medicine, Section on Nephrology, Winston Salem, United States

Anthony J. Bleyer, MD, MS, FASN

• Kmoch, Stanislav, Research Unit for Rare Diseases, Department of Pediatrics and Inherited Metabolic Disorders, First faculty of Medicine, Charles University, Prague, Czechia

Stanislav Kmoch, MS, MSc, PhD

Background

Pathogenic variants in mitochondrial DNA (mtDNA) are increasingly recognized as a cause of Mitochondrially Inherited Tubulointerstitial Kidney Disease (MITKD) and often mimic autosomal dominant tubulointerstitial kidney disease (ADTKD).

Methods

In the Wake Forest Registry of hereditary TKD, we identified eight families negative for mutations in ADTKD-associated genes who carried variants in mitochondrial DNA. To assess the pathogenicity of the identified variants, we characterized the clinical, biochemical, genetic, cellular, and histopathological features of these families.

Results

In the Wake Forest TKD registry, we identified three families carrying novel mutations localized in the anticodon loop of mt-tRNA^Trp and in the anticodon stem of mt-tRNA^Leu(CUN) with blood heteroplasmy ranging from 59% to 100%. Additionally, we identified five families carrying mutations in MT-TF and MT-ND5 that had been previously reported. Clinical findings in these families include chronic kidney disease, bland urinary sediment, hyperuricemia, and kidney failure between the ages of 20 and 68 (graph). Notably, there are few other symptoms of mitochondrial disorders, such as seizures, encephalopathy, or lactic acidosis.
Patient-derived fibroblasts carrying MT-TF and MT-TW mutations showed decreased OXPHOS capacity to ~56% and significantly reduced mitochondrial translation compared to control fibroblasts.

Conclusion

Our study demonstrates that pathogenic mtDNA variants represent a significant and underdiagnosed cause of TKD. Therefore, mtDNA analysis should be included in cases of TKD with unknown genetic diagnosis and maternal type of inheritance.

Acknowledgment

This work was supported by grant NW26-07-00090 from the Agency for Health Research of the Czech Republic and projects LUAUS24087 by the Ministry of Education, Youth and Sports of the Czech Republic; the MULTIOMICS_CZ (ID Project CZ.02.01.01/00/23_020/0008540) – Co-funded by the European Union; and the National Center for Medical Genomics (LM2023067). Institutional support was provided through programs of Charles University in Prague (UNCE/24/MED/022 and Cooperation).

Table of eGFR and genotype.

Funding

• Government Support – Non-U.S.