Renal Phenotype in Mitochondrial Diseases: A Multicenter Study

Maria Parasyri; Per Brandström; Johanna Uusimaa; Elsebet Ostergaard; Omar Hikmat; Pirjo Isohanni; Karin Naess; I F M de Coo; Andrés Nascimento Osorio; Matti Nuutinen; Christopher Lindberg; Laurence A Bindoff; Már Tulinius; Niklas Darin; Kalliopi Sofou

doi:10.1159/000521148

Renal Phenotype in Mitochondrial Diseases: A Multicenter Study

Kidney Dis (Basel). 2022 Jan 24;8(2):148-159. doi: 10.1159/000521148. eCollection 2022 Mar.

Authors

Maria Parasyri¹, Per Brandström^{1

2}, Johanna Uusimaa^{3

4}, Elsebet Ostergaard⁵, Omar Hikmat^{6

7}, Pirjo Isohanni^{8

9}, Karin Naess¹⁰, I F M de Coo¹¹, Andrés Nascimento Osorio¹², Matti Nuutinen^{3

4}, Christopher Lindberg¹³, Laurence A Bindoff^{7

14}, Már Tulinius^{1

2}, Niklas Darin^{1

2}, Kalliopi Sofou^{1

2}

Affiliations

¹ Department of Paediatrics, Region Västra Götaland, Sahlgrenska University Hospital, Gothenburg, Sweden.
² Department of Paediatrics, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
³ Department of Children and Adolescents, Oulu University Hospital, Oulu, Finland.
⁴ PEDEGO Research Unit, Research Unit for Pediatrics, Pediatric Neurology, Pediatric Surgery, Child Psychiatry, Dermatology, Clinical Genetics, Obstetrics and Gynecology, Ophthalmology, Otorhinolaryngology, Medical Research Center Oulu (MRC Oulu), University of Oulu, Oulu, Finland.
⁵ Department of Clinical Genetics, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark.
⁶ Department of Pediatrics and Adolescent Medicine, Haukeland University Hospital, Bergen, Norway.
⁷ Department of Clinical Medicine (K1), University of Bergen, Bergen, Norway.
⁸ Department of Pediatric Neurology, Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
⁹ Research Programs Unit, Stem Cells and Metabolism, University of Helsinki, Helsinki, Finland.
¹⁰ Centre for Inherited Metabolic Diseases, Karolinska University Hospital, Stockholm, Sweden.
¹¹ Department Toxicogenomics, Faculty of Health, Medicine and Life Sciences, Graduate School MHeNS, Maastricht University, Maastricht, The Netherlands.
¹² Neuromuscular Diseases Unit, Hospital Sant Joan de Déu, Barcelona, Spain.
¹³ Department of Neurology, Neuromuscular Centre, Sahlgrenska University Hospital, Gothenburg, Sweden.
¹⁴ Neuro-SysMed, Center of Excellence for Clinical Research in Neurological Diseases, Haukeland University Hospital, Bergen, Norway.

Abstract

Aims: This study aimed to investigate associations between renal and extrarenal manifestations of mitochondrial diseases and their natural history as well as predictors of renal disease severity and overall disease outcome. The secondary aim was to generate a protocol of presymptomatic assessment and monitoring of renal function in patients with a defined mitochondrial disease.

Methods: A multicenter, retrospective cohort study was performed by the Mitochondrial Clinical and Research Network (MCRN). Patients of any age with renal manifestations associated with a genetically verified mitochondrial disease were included from 8 expert European centers specializing in mitochondrial diseases: Gothenburg, Oulu, Copenhagen, Bergen, Helsinki, Stockholm, Rotterdam, and Barcelona.

Results: Of the 36 patients included, two-thirds had mitochondrial DNA-associated disease. Renal manifestations were the first sign of mitochondrial disease in 19%, and renal involvement was first identified by laboratory tests in 57% of patients. Acute kidney injury occurred in 19% of patients and was the first sign of renal disease in the majority of these. The most common renal manifestation was chronic kidney disease (75% with stage 2 or greater), followed by tubulopathy (44.4%), the latter seen mostly among patients with single large-scale mitochondrial DNA deletions. Acute kidney injury and tubulopathy correlated with worse survival outcome. The most common findings on renal imaging were increased echogenicity and renal dysplasia/hypoplasia. Renal histology revealed focal segmental glomerulosclerosis, nephrocalcinosis, and nephronophthisis.

Conclusion: Acute kidney injury is a distinct renal phenotype in patients with mitochondrial disease. Our results highlight the importance to recognize renal disease as a sign of an underlying mitochondrial disease. Acute kidney injury and tubulopathy are 2 distinct indicators of poor survival in patients with mitochondrial diseases.

Keywords: Acute kidney injury; Mitochondrial DNA; Mitochondrial disease; Renal manifestations.