Introduction

Maternally inherited diabetes and deafness (MIDD) is a mitochondrial genetic disorder characterized by type 2 diabetes mellitus (DM) and hearing impairment. Abnormality in the mitochondrial (mt) DNA causes MIDD caused by defects in oxidative energy production. MIDD has variable clinical presentations, which can delay its diagnosis [1]. The m.3243A > G mutation in the mt tRNALeu(UUR) gene is the most common mutation found in MIDD, but this mutation is also found in mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) syndrome [2].

Mitochondria are abundant in the kidney, especially in proximal tubules and glomerular epithelial cells [3]; mitochondrial dysfunction can cause renal damage. Renal diseases associated with mitochondrial cytopathy include focal segmental glomerulosclerosis (FSGS) and tubulointerstitial nephropathy [4, 5]. Such complications lead to the progression of chronic kidney disease (CKD) and end-stage kidney disease, which require renal replacement therapy [6, 7]. However, the mechanisms that underlie kidney heterogeneity and CKD progression in patients with mitochondrial disease are not well understood.

Here we report a case of MIDD in a 57-year-old man with a m.3243 A > G mutation, who developed CKD. For this patient, two renal biopsies were conducted 20 years apart to confirm the progression of renal damage. A muscle biopsy also showed subclinical myopathy.

Case report

A 57-year-old Japanese man was referred to our Nephrology Department by his primary physician with gradually progressive renal dysfunction and proteinuria. He was born at the term of a normal pregnancy from nonconsanguineous parents. Since age 22, mild urine protein from ± to 1 + (dipstick test) had been noted in his general health checkups. His first renal biopsy was performed at 36 years of age. Light microscopy of that specimen revealed 12 glomeruli, with no global sclerosis; two showed mildly increased mesangial matrix, and the others were almost intact (Fig. 1a). In the interstitium, fibrosis comprised less than 5% of the area and no infiltration cells were seen. IgG, IgA, IgM, C3, C4, and C1q were not detected with immunofluorescence. Electron microscopy showed that some mitochondria in the distal tubular epithelial cells had cristae that had lost their normal structures (Fig. 1b). Diagnosis of mitochondrial disease was difficult at this point. Treatment with angiotensin-converting-enzyme inhibitor was initiated.

Fig. 1
figure 1

Initial renal biopsy findings taken at 36 years of age. a Light microscopy shows most glomeruli were intact (periodic acid-Schiff stain, × 200). b Electron microscopy shows some mitochondria in distal tubular epithelial cells had cristae that had lost normal structures

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The patient’s primary physician followed the man’s progress over the next two decades (Fig. 2). In a medical checkup at 40 years of age, he was found to have type 2 DM and bilateral sensorineural hearing loss. Five years later, medication for DM was started and he was using a hearing aid. Thereafter, serum hemoglobin A1c (HbA1c) levels remained in the range of 6–8%. Urine protein had increased from − to 2 + , and renal function gradually decreased. He had no symptoms of myopathy or encephalopathy and no history of stroke-like episodes. His mother had received hemodialysis for end-stage renal disease (etiology unknown) and his younger brother was suffering from hearing loss and renal dysfunction (Fig. 3), although no family member had undergone genetic examination. His current medications were glimepiride, saxagliptin, metformin, enalapril, and pravastatin. He had a history of smoking 20 cigarettes per day for 10 years before quitting at the age of 27.

Fig. 2
figure 2

Clinical course. Serum HbA1c levels remained in the 6–8% range; however, urine protein was 1 + –2 + , and renal function gradually decreased. eGFR estimated glomerular filtration rate, HbA1c hemoglobin A1c

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Fig. 3
figure 3

Family tree. Arrow indicates the patient described in this report. His mother had received hemodialysis for the end-stage renal disease of unknown etiology, while his younger brother exhibited hearing loss and renal dysfunction

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On physical examination, his height was 160 cm, weight 47.8 kg, and BMI 18.6 kg/m2. His blood pressure was 136/85 mmHg. He showed no peripheral edema or muscle weakness in his extremities. An ophthalmologic examination detected neither diabetic retinopathy nor hypertensive retinopathy. Electrocardiogram and echocardiogram were within normal limits. Laboratory data obtained from the patient on admission (Table 1) showed elevated serum creatinine levels (1.10 mg/dL) with an estimated glomerular filtration rate of 55 ml/min/1.73 m2. Proteinuria was observed at 0.64 g per gram of creatinine (g/gCre); no hematuria was detected (1–4 red blood cells/high-power field). Notable serum levels were HbA1c: 7.2%; lactic acid: 18.0 mg/dL (normal, 3.7–16.3 mg/dL); pyruvic acid: 0.93 mg/dL (normal, 0.3–0.9 mg/dL), and lactic acid/pyruvic acid ratio: 19 (normal, < 10).

Table 1 Laboratory data for blood and urine on admission
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A second renal biopsy was performed because hereditary kidney disease was suspected from his family history. Light microscopy revealed 4 glomeruli, all of which showed global glomerulosclerosis. In the interstitium, chronic fibrosis was observed over almost 40% of the area. Local chronic inflammatory cell infiltration and dilated tubules that contained proteinaceous material were also observed (Fig. 4a, b). The artery and arterioles showed moderate fibrous intimal thickening and hyalinization with enlarged vascular smooth muscle cells (Fig. 4c). Granular swollen epithelial cells (GSEC)—which are reportedly a specific change associated with mitochondrial cytopathy [8]—were found in the medullary collecting duct epithelium (Fig. 4d). As with his first renal biopsy, IgG, IgA, IgM, C3, C4, and C1q were not detected with immunofluorescence. Electron microscopy showed moderate foot process effacement. Accumulating mitochondria were observed in the cytoplasm of some podocytes (Fig. 4e) and proximal tubular cells (Fig. 4f), a portion of which were enlarged.

Fig. 4
figure 4

Renal biopsy findings at 57 years of age. a, b Light microscopy shows global glomerulosclerosis (arrows), local chronic inflammatory cell infiltration and dilated tubules that contain proteinaceous material (arrowheads, periodic-acid-Schiff stain, a: × 40, b: × 200). c Vascular smooth muscle cells are enlarged (periodic acid silver-methenamine stain, × 400). d Granular swollen epithelial cells in medulla collecting duct epithelium (arrows, Masson-trichrome stain, × 400). Electron microscopy shows accumulated mitochondria in cytoplasm of some podocytes (e) and proximal tubular cells (f), some of which were enlarged (arrow)

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Based on these findings, the mitochondrial disease was suspected, and a muscle biopsy was performed from his bicep. Modified Gomori trichrome stain showed ragged-red fibers (Fig. 5a). Ragged-red fibers that are positive for succinate dehydrogenase (SDH) stain indicate deficient fiber activity on cytochrome c oxidase stain; strongly SDH-reactive blood vessels were observed (Fig. 5b). These findings were consistent with mitochondrial dysfunction. A subsequent genetic test from the muscle specimen revealed a mitochondrial gene with a m.3243A > G mutation, with 69.9% heteroplasmy. Thus, the diagnosis of MIDD was considered to be unequivocal. Oral taurine supplementation (12 g/day) was initiated. One year later, his renal function has remained unchanged with no apparent side effects.

Fig. 5
figure 5

Light microscopy of muscle biopsy. a Ragged-red fibers on modified Gomori trichrome stain (arrows, × 100). b Ragged-red fibers positive for succinate dehydrogenase (SDH) stain (blue) showed deficient fiber activity on cytochrome c oxidase stain (brown) (arrows, × 100). Strongly SDH-reactive blood vessel was highlighted (upper panel)

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Discussion

In this patient, proteinuria appeared prior to diabetes or deafness, making an early diagnosis of MIDD difficult. Pathological findings progressed to nephrosclerosis with interstitial fibrosis and arteriolar hyaline thickening over 20 years, despite the absence of hypertension or diabetic retinopathy, and relatively good glycemic control. Although we could not find any FSGS lesions in the glomeruli, accumulating mitochondria were seen in podocytes and tubular cells by electron microscopy. GSECs were found in the medulla collecting duct epithelium, which indicated mitochondrial cytopathy. In contrast, no pathological manifestations typical of diabetic nephropathy (e.g., glomeruli with nodules or hyalinotic lesions) were found. These observations implied that mitochondrial cytopathy is mainly associated with CKD progression, rather than diabetic nephropathy.

CKD has been reported previously in patients with MIDD [4, 5]. Although the long course of DM appears to have a major impact on renal damage, renal manifestations in patients with MIDD are not always the consequences of diabetic nephropathy [9]. Acquired mitochondrial dysfunction is reportedly associated with progression of CKD [10, 11] and atherosclerosis [12]. The extent to which mitochondrial cytopathy is associated with the development of CKD in patients with MIDD is unclear. However, impairment of oxidative phosphorylation in podocytes and tubular cells can result in overgeneration of reactive oxygen species and in functional and structural alterations, resulting in proteinuria, tubular dysfunction and ultimately, development of glomerular sclerosis and interstitial impairment [3, 13, 14].

Clinical characteristics related to MIDD include early-onset DM with short stature, a normal or low BMI, and hearing loss that occurs at about the same time as the onset of DM [9, 15], as seen in this case. As the clinical manifestation depends on threshold levels of the mitochondrial mutation in each organ [2], patients with MIDD develop other mitochondria-related complications [15]. Our patient had no symptoms of a cardiac disorder or the neurological phenotype of MELAS syndrome, but his muscle biopsy showed ragged-red fibers despite the absence of muscle weakness. Although the clinical manifestations of mitochondrial diseases differ among individuals, histological changes due to mitochondrial abnormality may occur in some organs, even if no subjective symptoms are seen.

Treatment to prevent MIDD complications has not been established. Coenzyme Q10 therapy was reported to prevent progressive hearing loss and improve insulin secretory defect in patients with MIDD [16]. However, taurine modifies the first anticodon nucleotide mt tRNALeu(UUR) [17] in normal humans, and taurine modification was absent in mt tRNALeu(UUR) of cells derived from MELAS patients with the m.3243A > G mutation [18]. A recent multicenter, open-label trial in Japan showed that oral taurine supplementation can effectively reduce the recurrence of stroke-like episodes and increase taurine modification in mt tRNALeu(UUR) in MERAS [19]. Taurine is expected to serve as a therapeutic drug for various organ disorders caused by mitochondrial diseases with m.3243A > G mutations. In this case, we initiated oral taurine supplementation in addition to renin-angiotensin system blockade therapy, to prevent exacerbating MIDD-related symptoms and CKD progression. Careful follow-up is required.

In conclusion, the findings from the present case suggest that mitochondrial cytopathy due to MIDD may be associated with progressive CKD. If kidney disease associated with mitochondrial cytopathy is suspected from the clinical course, a proactive renal biopsy may lead to satisfactory diagnosis and treatment.