Abstract
Background and Aims
Mitochondrial diseases (MDs) are one of the most common inherited metabolic disorders caused by mutations of either mitochondrial or nuclear genes involved in the oxidative phosphorylation pathway.
Tissues with high energy demand (i.e. brain and skeletal muscle) are preferentially affected, and MDs are not rarely referred to as mitochondrial encephalomyopathies. However, one of the hallmarks of MDs is multisystemic involvement, with large clinical variability and severity due to different mitochondrial DNA heteroplasmy levels. Given the possibility of multisystemic phenotype of MDs, renal involvement has been suggested, based on renal cells vulnerability to poor energy supply. A specific mitochondrial kidney disease is thought to underlie renal manifestations, therefore theoretically every district of the nephron might be affected by MDs. Regarding tubular involvement, we suggested a possible association between nephrolithiasis and MDs, based on data of 3 related stone formers with reduced urinary citrate excretion and MELAS syndrome. The aim of this study is to provide a clinical description of the renal phenotypes of patients with MDs.
Method
In 2019, 6 patients with MDs routinely followed by the Neurology outpatient clinic of our Institution were randomly asked to perform renal screening. Genetic tests, blood and 24-hour urine analyses were assessed in the whole population. The main comorbidities were recorded. Glomerular filtration rate (GFR) was estimated using creatinine clearance.
Results
Half of the patients were female, the average age at renal evaluation was 48±15 years; diabetes, hypertension and neurosensorial hypoacusia occurred in 4, 1 and 2 subjects, respectively. Five patients had m.3243A>G mutation, responsible for more than 85% of maternal inherited diabetes and deafness (MIDD) and syndrome of mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS). The remaining patient carried the m.8363G>A variant, reported to be associated with a multisystem MDs known as Leigh syndrome (subacute necrotizing encephalomyelopathy). Median serum creatinine was 0.6 mg/dL (IQR: 0.5-1.1) with median GFR of 92 mL/min/1.73 m2 (IQR: 40-117). Three patients exhibited signs of kidney disease: one had both reduced GFR and proteinuria (eGFR 37 mL/min/1.73 m2 and 750 mg/day respectively), one had renal impairment (58 mL/min/1.7 3m2) and severe hypocitraturia (22 mg/day), one showed increased urinary calcium excretion (348 mg/day). In one patient, evaluation of the type of proteinuria has not been performed yet. Serum lactate was 3.1±1.9 mmol/L, urinary pH 5.8±0.3 and median urinary citrate excretion 593 mg/24h (IQR: 310-923). No relevant results were found on serum and/or urinary levels of sodium, potassium, magnesium, phosphorus, urate, chloride, oxalate, parathyroid hormone and 25-OH vitamin D.
Conclusion
These results confirmed the presence of renal disease and its heterogeneity in patients with MDs. A complete renal screening is necessary in these subjects in order to early recognize renal involvement and carefully select candidates for further diagnostic work-up including renal biopsy. A consensus on the optimal renal screening for these patients has yet to be established.
Mitochondrial Structure and Bioenergetics in Normal and Disease Conditions
