Mitochondrial DNA deletion: a cause of chronic tubulointerstitial nephropathy.

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.