Renal disease in MIDs may be classified as primary or secondary. Secondary kidney disease may result from primary involvement of organs other than the kidneys in the MID. In the case of cardiac involvement in MID, there may be renal infarction from atrial fibrillation or heart failure, or hypertensive kidney disease from mitochondrial arterial hypertension. In the case of mitochondrial diabetes, renal insufficiency may be a consequence of the primary involvement of the pancreas in the MID. Another secondary renal disorder due to a primary mitochondrial defect may be renal insufficiency from rhabdomyolysis due to mitochondrial myopathy or mitochondrial epilepsy (8). Primary renal manifestations of MIDs include acute or chronic renal failure, nephrolithiasis, nephrotic syndrome, renal cysts, renal tubular acidosis (RTA), Bartter-like syndrome, Toni-Debré-Fanconi syndrome (TDFS), focal segmental glomerulosclerosis (FSGS), tubulointerstitial nephritis (TIN), nephrocalcinosis, and benign or malignant neoplasms (9). Renal involvement in MIDs may be classified according to the number of organs that are affected in addition to the kidney. If no other organs are additionally involved (absence of MIMODS) the mitochondrial nature of renal disease is often difficult to detect (10). However, when more organs are affected, it is more suggestive of a MID. Additionally, renal involvement may be classified according to the priority within the phenotype. In certain cases, renal involvement may dominate the phenotype whereas in other cases, renal disease may be a non-dominant feature. A further differentiation of renal involvement in MIDs relies on whether the underlying genotype manifests clinically or remains subclinical. Subclinical involvement may be detected upon observation of morphological abnormalities of mitochondria and a high quantity of heteroplasmy of mutated mtDNA during kidney biopsy or autopsy (11,12).

Renal involvement has been reported in a number of syndromic MIDs, which predominantly include mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS), Kearns Sayre syndrome (KSS; Table II) (13,14) and mitochondrial depletion syndromes (MDSs). On rare occasions, renal disease may be found in other rarer types of syndromic MIDs.

MELAS is one of the syndromic MIDs in which renal disease is fairly frequent. In a 14-year-old female with MELAS syndrome, the initial manifestation of the MID was an FSGS, which occurred 3 years prior to diagnosis of the MID (15). In a 35-year-old female with MELAS syndrome resulting from the m.13513G>A mutation, renal failure was the initial manifestation of the MID 9 years before diagnosis of the MID (10). In a 50-year-old male with MELAS syndrome, chronic renal failure requiring hemodialysis was one of the clinical manifestations (16). Chronic renal failure was the indication for renal transplantation in a 58-year-old male with MELAS syndrome (17). In a 13-year-old Asian female with MELAS syndrome, renal involvement manifested as FSGS (18). In another MELAS patient acute renal failure occurred and was associated with severe hyponatriemia due to renal sodium loss (19). Furthermore, in a female MELAS syndrome patient, severe kidney involvement with changes of FSGS was reported (20). Acute or chronic renal failure has been also reported in a number of MELAS patients with or without diabetes, suggesting that renal dysfunction is primary or secondary (21). In a series of 5 MELAS patients, FSGS was a phenotypic feature in all of them; thus, the authors concluded that renal involvement in MELAS may be underestimated (7). Chronic renal failure appears to be a typical manifestation of MELAS (22) and FSGS may be the dominant feature in these patients (23). Kidney cancer was reported in a 41-year-old male who was exhibiting MELAS syndrome (24). A histological work-up additionally revealed arteriolonephrosclerosis (24) and renal cell carcinoma was reported in a 2-year-old male with MELAS syndrome (25).

Renal abnormalities so far described in KSS include renal failure, RTA, Bartter-like syndrome and TDFS (Table II). In an 11-year-old female with KSS, TDFS was diagnosed 8 years prior to the diagnosis of the MID (15). TDFS was also reported in a 13-year-old female with KSS who additionally manifested with anhidrosis (26), as well as other patients (14,27–31). In a 5-year-old male with KSS, the MID manifested with RTA (Table II) (32), which was also described in an 18-year-old female (Table II) (33). In a 10-year-old male with KSS, the MID manifested in the kidneys as renal tubular dysfunction with isosthenuria, decreased urine-concentrating ability, and excessive excretion of potassium and magnesium (34). In addition, hyperreninemia and hyperaldosteronism were present in the absence of arterial hypertension, resulting in a diagnosis of Bartter-like syndrome (34). Furthermore, Bartter-like syndrome has been described in two other patients with KSS, in a 14-year-old male (13) and a 7-year-old female (Table II) (35). In addition, nephrocalcinosis has been identified as a rare feature of KSS (13).

MDSs are characterised by a reduction in the quantity of mtDNA within a mitochondrion of a cell. MDSs are due to mutations in the ribonucleotide reductase regulatory TP53 inducible subunit M2B (RRM2B), MpV17 mitochondrial inner membrane protein (MPV17), DNA polymerase γ, catalytic subunit (POLG1), DNA polymerase γ 2, accessory subunit (POLG2), succinate-CoA ligase ADP-forming β subunit (SUCLA2), succinate-CoA ligase GDP-forming β subunit (SUCLG2), twinkle mtDNA helicase (C10orf2), deoxyguanosine kinase (DGUOK), thymidine kinase 2, mitochondrial (TK2), F-box and leucine rich repeat protein 4 (FBXL4), and transcription factor A, mitochondrial (TFAM) genes, In an infant with MDS due to a mutation in the RRM2B gene, the MID manifested along with proximal renal tubulopathy and nephrocalcinosis (36). In an infant with MDS, but without detection of the underlying genetic defect, RTA developed 1 year after liver transplantation and was attributed to tacrolimus toxicity and renal involvement in the MID (37). In three siblings with MDS due to a C10orf2 (twinkle) mutation, the MDS manifested as hepatocerebral syndrome and as proximal renal tubulopathy (Table III) (38). Renal tubulopathy was also reported in a female newborn with MDS carrying an mtDNA copy number of only 2% (39). In one of two males with MDS due to a mutation in the RRM2B gene, proximal renal tubulopathy was described (40). Tubulopathy was also present in a female infant with MDS carrying the RRM2B mutation c.368T>C (41). In addition, tubulopathy was detected in three patients during an investigation of 11 patients with MDS due to mutations in the DGUOK gene (42). Furthermore, MDS resulting from mutations in the MPV17 gene may be associated with tubulopathy (Table III) (43).

Single cases of renal involvement have been reported in other syndromic MIDs, such as chronic progressive external ophthalmoplegia (CPEO) (44), Pearson syndrome (45), Leber hereditary optic neuropathy (LHON) (46), coenzyme-Q deficiency, X-linked sideroblastic anemia (XLSA) (47), Leigh syndrome (48), or hyperuricemia, metabolic alkalosis, pulmonary hypertension, and progressive renal failure in infancy (HUPRA) syndrome (49). In a 44-year-old female with CPEO, the MID initially manifested initially with hearing loss at age 22 years, which was followed by renal failure at 30 years of age (44). In an infant with Pearson syndrome due to a single mtDNA deletion, the bone marrow, central nervous system, exocrine pancreas and the kidneys were involved. Renal involvement manifested as severe tubular dysfunction (45). In another patient with Pearson syndrome multiple renal cysts were reported (50). In a 1-year-old female with LHON, renal involvement manifested as nephronophthisis, also referred to as TIN (46). In an infant with primary coenzyme-Q deficiency due to a mutation in the COQ2 gene, the MID manifested with nephrotic syndrome due to FSGS (51). In an 81-year-old male with XLSA due to mutations in the ALAS2 gene, renal involvement manifested as severe renal failure requiring haemodialysis (47). In a study of four patients with Leigh syndrome due to a mutation in the SURF1 gene, three had significant proximal RTA (48). Hyperuricemia, pulmonary hypertension, renal failure in infancy and alkalosis (HUPRA) syndrome due to SARS2 gene mutations is, by definition, a rare MID that presents along with renal failure (52). In two Palestinian infants with HUPRA syndrome due to a SARS2 mutation, tubulopathy was a cardinal phenotypic feature of the disease (49). In a Turkish family with myopathy, lactic acidosis, and sideroblastic anaemia (MLASA) syndrome due to a YARS2 mutation, renal involvement manifested as tubulopathy (53). In a neonate with Leigh syndrome due to a mutation in the ACAD9 gene, autopsy revealed hyperplasia of mitochondria in renal tubular cells (54). In addition, in a patient with Leigh syndrome due to a mutation in the ND5 gene renal salt loss was deemed responsible for secondary hyponatriemia (55). Diffuse glomerulocystic kidneys were reported in a patient with Leigh syndrome, but without detecting the genetic defect (56). Growth retardation, aminoaciduria, cholestasis, iron overload, lactic acidosis and early death (GRACILE) syndrome is an early-onset, autosomal recessive multisystem MID due to mutations in the BCS1L gene. Clinically, GRACILE syndrome is characterised by fetal growth retardation, Fanconi-type aminoaciduria, cholestasis, iron overload, profound lactic acidosis, and early mortality (57). One of the clinical hallmarks of GRACILE syndrome is TDFS-type tubulopathy with aminoaciduria. In a mouse model of GRACILE syndrome, tubulopathy was one of various other phenotypic features (58). Late-onset nephrotic syndrome was described in Mpv17 knock-out mice (59). In single patients with multiple systemic lipomatosis, which may be due to the m.8344A>G mutation, RTA has been reported (60). In a male infant with pyruvate dehydrogenase deficiency (PDH), RTA was one of the clinical manifestations in addition to lactic acidosis, contributing to the death of this individual (61). Whether renal excretion of urinary phosphatidylethanolamine, cardiolipin, and phosphatidylserine in four patients with myoclonus epilepsy with ragged-red fibres (MERRF) (62) and in one patient with CPEO was truly attributable to renal involvement remains unknown, but they may be derived from sulfatides, which are specific to the kidneys (62).

In four adult patients with FSGS, kidney disease was attributed to an MID, as renal biopsy revealed the presence of the m.3243A>G mutation in the tRNA(Leu) gene (61). Notably, no other organs were affected in these four patients; thus, kidney disease was the initial manifestation and dominant feature of the MID and, therefore, the phenotype was not consistent with MELAS syndrome at the time of diagnosis (63). In a patient with sensorineural blindness, attributed to a non-genetically proven MID, Bartter-like syndrome was the second phenotypic feature (64). In a consanguineous family with isolated COX-deficiency due to a mutation in the COX10 gene, which encodes the heme A:farnesyltransferase, increased urinary amino acids suggested proximal renal tubulopathy (65). In a 54-year-old female, the homoplasmic m.7501T>A mutation in the tRNA(Ser) gene manifested as proteinurea due to sclerosis of one-quarter of the glomeruli observed during kidney biopsy (66). Almost one-third of the interstitium was fibrotic in this patient. Tubular granular swollen epithelial cells (GSECs), which have been demonstrated to indicate a MID (67), were present in the medulla collecting ducts (66). In a study of six patients with encephalopathy, hepatopathy, and proximal tubulopathy, the causative mutation was detected in the BCS1L gene resulting in respiratory chain complex III deficiency (68). In a study of 35 multi-ethnic patients carrying a TMEM70 mutation, 35% manifested with renal disease in the form of RTA, hydronephrosis and acute or chronic renal failure (69). In a newborn girl with MIMODS due to a mutation in the LARS2 gene, encoding for a mitochondrial amino-acyl-tRNA synthetase, progressive renal failure was responsible for mortality 5 days after birth (70). In three children from the same consanguineous parents, antenatal skin oedema, hypotonia, cardiomyopathy and tubulopathy were attributed to mutations in the MRPS22 gene (71). In a consanguineous Lebanese patient with respiratory chain complex III deficiency due to a UQCC2 gene mutation, renal tubulopathy was one of the phenotypic manifestations, in addition to severe intrauterine growth retardation and neonatal lactic acidosis (72). Chronic renal failure was also reported in an 11-month-old male who presented with truncal ataxia, sensorineural hearing loss, muscle hypotonia, delayed visual maturation, global developmental delay and dilated cardiomyopathy (73). Nuclear genetic studies identified a causative mutation in the RMND1 gene (73). End-stage renal disease due to TIF was reported in a 16-month-old girl with developmental regression, lactic acidosis, hypotonia, gastrointestinal dysmotility, adrenal insufficiency, arterial hypertension and haematological abnormalities carrying a tRNA(Phe) mutation (74). Isolated renal disease as the sole manifestation of a MID was reported in a 9-year-old female with steroid-resistant FSGS (75). The MID was due to a point mutation in the mtDNA located at the tRNA(Tyr) gene (75).

A diagnostic work-up of renal disease in MIDs is not different from a work-up of renal disease in patients without an MID. The diagnosis is based on blood tests, urine analysis, imaging, functional tests and biopsies. Biopsy is important, as it may show abnormalities, which have been reported in MID patients with renal involvement (Table I), as well as morphological abnormalities of mitochondria. A strong indicator for the mitochondrial nature of a kidney disease appears to be the presence of GSECs. MID patients with suspected renal involvement should, therefore, undergo kidney biopsy, to establish whether GSECs are present. In addition, a biopsy may show microvascular degeneration of the renal tubular epithelial cells, such as in Leigh syndrome. If additional biochemical investigations are performed, dysfunction of one or various respiratory chain complexes may be detected. If genetic studies are conducted, mutations in mtDNA- or nDNA-located genes may be detected (Table III) and, in the case of mtDNA mutations, the heteroplasmy rates may be determined. Notably, a single patient may present with more than one renal abnormality (Table I).

Treatment of mitochondrial nephropathy is the same as for non-mitochondrial nephropathy. However, drugs that are mitochondrion-toxic should generally be avoided in MID patients. Though not supported by evidence from appropriate clinical trials, mitochondrial nephropathy may respond to supportive treatment administered to MID patients, such as antioxidants, co-factors or vitamins (76). In patients with steroid resistant nephrotic syndrome due to mutations in the ADCK4 gene, which is involved in COQ10 biosynthesis, coenzyme-Q may be highly beneficial (77). Renal failure in MIDs may be of such a degree that haemodialysis may be required.

To the best of our knowledge, there are no available systematic studies regarding the outcome of renal disease in MIDs. The outcome of renal involvement in MIDs is dependent on the underlying mutation, as well as the type of renal disease. The outcome of renal disease in MIDs is also dependent on whether it is primary or secondary. In the case of mtDNA mutations, the heteroplasmy rate in the kidneys may be significant for the outcome of renal disease. Though not systematically investigated, it is speculated that the severity of renal disease increases and that the outcome of kidney disease becomes worse as the heteroplasmy rate increases.