Clinicopathologic Features of Mitochondrial Nephropathy

Abstract

Introduction: The 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.

Methods: This nationwide survey included 757 nephrology sections throughout Japan, and consequently, data on 81 cases of mitochondrial nephropathy were collected.

Results: The most common renal manifestation observed during the disease course was proteinuria. Hearing loss was the most common comorbidity; a renal-limited phenotype was observed only in mitochondrial DNA (mtDNA) point mutation and COQ8B mutation cases. We found a median time delay of 6.0 years from onset of renal manifestations to diagnosis. Focal segmental glomerular sclerosis (FSGS) was the most common pathologic diagnosis. We then focused on 63 cases with the m.3243A>G mutation. The rate of cases with diabetes was significantly higher among adult-onset cases than among childhood-onset cases. Pathologic diagnoses were more variable in adult-onset cases, including diabetic nephropathy, nephrosclerosis, tubulointerstitial nephropathy, and minor glomerular abnormalities. During the median observation period of 11.0 years from the first onset of renal manifestations in patients with m.3243A>G, renal replacement therapy (RRT) was initiated in 50.8% of patients. Death occurred in 25.4% of the patients during the median observation period of 12.0 years. The median estimated glomerular filtration rate (eGFR) decline was 5.4 ml/min per 1.73 m²/yr in the cases, especially 8.3 ml/min per 1.73 m²/yr in FSGS cases, with m.3243A>G.

Conclusion: Here, we described the clinicopathologic features and prognosis of mitochondrial nephropathy using large-scale data.

Keywords: clinicopathologic feature; m.3243A>G; mitochondria; mitochondrial nephropathy; national survey; prognosis.

Graphical abstract

Figure 1

Diagram revealing information on the study participants and the summary of identified genes. (a) Diagram revealing the experimental results of the study participants. Cases without evidence of MD or nephropathy were excluded from the study. One case in which a worsening general metabolic status caused acute kidney injury was also excluded. Through genetic analysis, 81 cases were found to have gene mutation identified as the causative mutation of MDs. There were 20 cases without identified gene mutation that included 1 case with mtDNA mutation which has not been confirmed as the causative mutation of MDs. (b) Summary of identified causative gene mutations of MDs in this study. AKI, acute kidney injury; CoQ10, coenzyme Q10; MD, mitochondrial disease; mtDNA, mitochondrial DNA; nDNA, nuclear DNA; OXPHOS, oxidative phosphorylation; tRNA, transfer RNA.

Figure 2

Kaplan–Meier survival (a) without RRT and (b) without death after onset of renal manifestations. The dark line indicates childhood-onset cases, and the light line indicates adult-onset cases. RRT, renal replacement therapy.