Mitochondrial DNA deletion: A cause of chronic tubulointerstitial nephropathy

Abstract

We report the first case of a mitochondrial DNA (mtDNA) deletion diagnosed by renal biopsy. An eight-year-old girl with megaloblastic anemia and severe growth retardation developed progressive renal insufficiency accompanied by partial Fanconi syndrome. Histologic examination of the renal biopsy disclosed nonspecific chronic tubulointerstitial disease characterized by tubular atrophy and interstitial fibrosis. On ultrastructural examination, tubular cell mitochondria were extremely dysmorphic with prominent size variation, abnormal arborization, disorientation of the cristae and osmiophilic electron-dense inclusions. Functional histochemical stains for mitochondrial enzymes performed on cryostat renal sections revealed focal tubular absence of cytochrome C oxidase (COX), a respiratory chain enzyme partially encoded by mtDNA, with preservation of succinate dehydrogenase (SDH), a respiratory chain enzyme entirely encoded by nuclear DNA (nDNA). Immunoreactivity for COX subunit 2 (encoded by mtDNA) was weak to undetectable in most tubular cells, whereas reactivity for subunit 4 (encoded by nDNA) was intense in all cells. Molecular analysis of the mtDNA of kidney and peripheral blood leukocytes was performed using Southern blot and PCR. Both techniques disclosed a 2.7 kb mtDNA deletion located between nucleotide (nt) 9700 and nt 13700, a common site for mtDNA deletions associated with encephalomyopathies. Mitochondrial DNA deletions may be an under-recognized cause of idiopathic tubulointerstitial nephropathy in children lacking neurologic or myopathic manifestations.

Genetic Features of Mitochondrial Respiratory Chain Disorders

“…The most common manifestation is a proximal tubulopathy with de Toni-Debré-Fanconi syndrome (12,13). Other renal presentations have been reported, including glomerular disease with nephrotic syndrome and chronic tubulointerstitial nephropathy (14,15). Plasma lactate levels and lactate/pyruvate (L/P) ratios are consistently normal but, interestingly, abnormal urinary lactate and Krebs cycle intermediate levels indicate a RC deficiency.…”

Mitochondrial dysfunction in the pathophysiology of renal diseases

“…All the above-mentioned aspects make proximal tubules especially vulnerable to mitochondrial dysfunction, which leads to RTEC apoptosis/necrosis, EMT, and renal fibrosis. A case report showed that mtDNA deletion can lead to extremely dysmorphic mitochondria with defects in respiratory chain enzymes encoded by mtDNA in tubular cells, which clinically manifests as tubular atrophy and interstitial fibrosis (132).…”

Renal manifestations of genetic mitochondrial disease

“…(Figure 1), and one report describes an individual presenting with symptoms of Pearson Syndrome but developing features of Kearns-Sayre syndrome over time. 44 The renal tubular defects associated with mtDNA deletions may affect the proximal 40,[43][44][45][46][47] or distal renal tubular segments. 39 The rarity of reports that include mtDNA deletions and a kidney phenotype make it difficult to draw any genotype-phenotype correlations, and the factors that contribute to the variety and penetrance of clinical features associated with mtDNA deletions may be related to the inheritance and distribution of mtDNA, as discussed earlier.…”