The Spectrum of Renal Abnormalities in Mitochondrial Disorders Is Broad

Abstract

We read with interest the article by Imasawa et al.1Imasawa T. Hirano D. Nozu K. et al.J-SMiN CollaboratorsClinicopathologic features of mitochondrial nephropathy.Kidney Int Rep. 2022; 7: 580-590https://doi.org/10.1016/j.ekir.2021.12.028Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar about a retrospective study of patients with a genetically confirmed mitochondrial disorder (MID) who also had proteinuria, reduced glomerular filtration rate, or Fanconi syndrome. The most common renal abnormality was proteinuria and the most common pathologic finding was focal segmental glomerular sclerosis.1Imasawa T. Hirano D. Nozu K. et al.J-SMiN CollaboratorsClinicopathologic features of mitochondrial nephropathy.Kidney Int Rep. 2022; 7: 580-590https://doi.org/10.1016/j.ekir.2021.12.028Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar Among 63 m.3243A>G carriers, diabetic nephropathy, nephrocalcinosis, and tubulo-interstitial nephropathy were the most frequent renal abnormalities.1Imasawa T. Hirano D. Nozu K. et al.J-SMiN CollaboratorsClinicopathologic features of mitochondrial nephropathy.Kidney Int Rep. 2022; 7: 580-590https://doi.org/10.1016/j.ekir.2021.12.028Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar The study is appealing but raises concerns that need to be discussed. A limitation of the study is that heteroplasmy rates of patients carrying mitochondrial DNA variants were not included.1Imasawa T. Hirano D. Nozu K. et al.J-SMiN CollaboratorsClinicopathologic features of mitochondrial nephropathy.Kidney Int Rep. 2022; 7: 580-590https://doi.org/10.1016/j.ekir.2021.12.028Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar Because phenotype, disease course, genetic counseling, and outcome strongly depend on heteroplasmy rates in affected tissues, it is crucial to know this parameter. Mitochondrial DNA copy number is another parameter determining the phenotypic expression of a mitochondrial DNA variant; this is why it is essential to relate phenotype, disease course, and outcome with this feature as well. Several renal manifestations of MIDs were not included in the discussion. These include, for example, nephrolithiasis, renal cysts, and neoplasms.2Finsterer J. Scorza F.A. Renal manifestations of primary mitochondrial disorders.Biomed Rep. 2017; 6: 487-494https://doi.org/10.3892/br.2017.892Crossref PubMed Google Scholar In various MIDs, nephrolithiasis has been reported as a phenotypic feature of the disease including patients carrying the variant m.3243A>G.3Bargagli M. Primiano G. Primiano A. et al.Recurrent kidney stones in a family with a mitochondrial disorder due to the m.3243A>G mutation.Urolithiasis. 2019; 47: 489-492https://doi.org/10.1007/s00240-018-1087-1Crossref PubMed Scopus (4) Google Scholar Cyst formation and neoplasms are generally more prevalent in MIDs than non-MID cohorts.4Finsterer J. Frank M. Prevalence of neoplasms in definite and probable mitochondrial disorders.Mitochondrion. 2016; 29: 31-34https://doi.org/10.1016/j.mito.2016.05.002Crossref PubMed Scopus (17) Google Scholar For didactic reasons, it is recommended to delineate primary from secondary renal involvement in MIDs. Primary mitochondrial dysfunction originates from the kidney itself, whereas secondary dysfunction results from manifestations of the MIDs in organs other than the kidneys. For example, in the case of cardiac involvement, intracardiac thrombus formation may ensue leading to cardioembolism including the kidneys. Because MIDs frequently manifest with diabetes,5Yeung R.O. Al Jundi M. Gubbi S. et al.Management of mitochondrial diabetes in the era of novel therapies.J Diabetes Complications. 2021; 35: 107584https://doi.org/10.1016/j.jdiacomp.2020.107584Crossref PubMed Scopus (14) Google Scholar diabetic nephropathy may ensue. MIDs are most often complicated by lactic acidosis, which may secondarily damage renal tissue. Not addressed was renal dysfunction due to the toxicity of drugs given to treat manifestations of the MID, particularly epilepsy, heart failure, arterial hypertension, psychosis, cognitive dysfunction, and depression. Overall, the interesting study has limitations that call the results and their interpretation into question. Clarifying these weaknesses would strengthen the conclusions and could enhance the study. Ethics approval was in accordance with ethical guidelines. The study was approved by the institutional review board. Consent to participate was obtained from the patient. Consent for publication: was obtained from the patient. All data are available from the corresponding author. JF: design, literature search, discussion, first draft, critical comments, and final approval. Clinicopathologic Features of Mitochondrial NephropathyKidney International ReportsVol. 7Issue 3PreviewThe clinicopathologic characteristics of nephropathy associated with mitochondrial disease (MD) remain unknown. We retrospectively analyzed a cohort of patients with proteinuria, decreased glomerular filtration rate, or Fanconi syndrome who had a genetic mutation confirmed as the cause of MD, defined as mitochondrial nephropathy. Full-Text PDF Open AccessIn Reply to “The Spectrum of Renal Abnormalities in Mitochondrial Disorders Is Broad”Kidney International ReportsVol. 7Issue 7PreviewWe sincerely thank Dr. Finsterer for his interest in our study of mitochondrial nephropathy and would like to comment on the points raised as follows. At first, as pointed out by him,1 heteroplasmy rates in mitochondrial DNA (mtDNA) is a key factor that affects clinicopathologic features and prognosis of mitochondrial diseases caused by mtDNA mutation. Therefore, we recognize that the lack of data on heteroplasmy rates is a limitation of our study and has already been mentioned likewise in the Discussion section of the original paper. Full-Text PDF Open Access