Deletion of mitochondrial DNA in patient with chronic tubulointerstitial nephritis

doi:10.1016/S0022-3476(95)70359-4

The Journal of Pediatrics

Volume 126, Issue 4, April 1995, Pages 597-601

https://doi.org/10.1016/S0022-3476(95)70359-4 Get rights and content

Abstract

We report a mitochondrial DNA deletion (2.6 kb) in a boy with tubulointerstitial nephritis in whom chronic renal failure and leukodystrophy subsequently developed. Elevated lactate values in plasma and cerebrospinal fluid were suggestive of a defect in the mitochondrial respiratory chain. High amounts of deleted mitochondrial DNA were present in muscle and cerebral white matter. On the basis of this observation, we suggest giving consideration to genetic defects of oxidative phosphorylation in any attempt to determine the origin of unexplained chronic tubulointerstitial nephritis, especially when seemingly unrelated organs are involved. (J PEDIATR 1995;126:597-601)

Section snippets

CASE REPORT

A boy born to unrelated healthy parents (birth weight 3 kg) did well during the first years of life except for persistent intestinal obstruction after appendectomy at 5 years of age. At 11 years of age he had anemia and polyuria (height 131 cm [-2 SD], weight 27 kg [-2 SD]). Blood pressure was 130/60 mm Hg. Moderate proteinuria (0.5 gm/day) with no sign of proximal tubulopathy or renal failure was noted; the serum creatinine concentration was 206 μmol/L (2.3 mg/dl), and creatinine clearance was

METHODS

Plasma lactate-pyruvate and ketone body molar ratios (3-hydroxybutyrate/acetoacetate) were determined in the patient and in control subjects as indexes of the oxidation-reduction status in cytoplasm and mitochondria, respectively.² A needle biopsy of the kidney and an open biopsy of the deltoid were performed with local anesthesia and the specimens were processed for histologic studies and for spectrophotometric and polarographic analyses of mitochondrial respiratory enzymes. Enzyme activities

RESULTS

Histopathologic examination of the kidney showed prominent tubulointerstitial changes characterized by marked, and nearly diffuse, interstitial fibrosis with tubular lesions consisting of obstructions of the tubular lumen by hyaline casts. Moderate thickening of the tubular basement membrane around atrophic tubules was seen focally. Within these areas, glomeruli were totally sclerosed or had irregular thickening and wrinkling of the basement membrane and retraction of the tuft within thickened

DISCUSSION

We report here an mtDNA deletion in a patient with tubulointerstitial nephritis that resulted in a concentrating defect and chronic renal failure. Nephronophthisis was initially considered because it is the most frequent cause of tubulointerstitial nephritis in childhood, but this diagnosis remained questionable because specific thickening of the basement membrane in the tubules was not observed. The disease remained unexplained, and only when it progressed to involvement of the central nervous

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Güçer et al39 described 2 pediatric patients who were found to have focal segmental glomerular sclerosis owing to different mtDNA deletions. In addition, mitochondrial disease can show a pure tubulointerstitial nephritis without evidence of a proximal tubulopathy, as reported by Rötig et al.40 Characterization of these genetic disorders is made difficult by the lack of a consistent genotype–phenotype relationship.
Acute kidney injury (AKI) continues to be a significant contributor to morbidity, mortality, and health care expenditure. In the United States alone, it is estimated that more than $10 billion is spent on AKI every year. Currently, there are no available therapies to treat established AKI. The mitochondrion is positioned to be a critical player in AKI with its dual role as the primary source of energy for each cell and as a key regulator of cell death. This review aims to cover the current state of research on the role of mitochondria in AKI, while also proposing potential therapeutic targets and future therapies.
Mitochondrial diseases part I: Mouse models of OXPHOS deficiencies caused by defects in respiratory complex subunits or assembly factors
2015, Mitochondrion
Mitochondrial disorders are the most common inborn errors of metabolism affecting the oxidative phosphorylation system (OXPHOS). Because of the poor knowledge of the pathogenic mechanisms, a cure for these disorders is still unavailable and all the treatments currently in use are supportive more than curative. Therefore, in the past decade a great variety of mouse models have been developed to assess the in vivo function of several mitochondrial proteins involved in human diseases. Due to the genetic and physiological similarity to humans, mice represent reliable models to study the pathogenic mechanisms of mitochondrial disorders and are precious to test new therapeutic approaches. Here we summarize the features of several mouse models of mitochondrial diseases directly related to defects in subunits of the OXPHOS complexes or in assembly factors. We discuss how these models recapitulate many human conditions and how they have contributed to the understanding of mitochondrial function in health and disease.
Renal involvement in mitochondrial cytopathies
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Les cytopathies mitochondriales sont des maladies génétiques affectant la phosphorylation oxydative consistant en la production d’adénosine triphosphate (ATP), source de l’énergie dans les tissus et les organes. La chaîne respiratoire mitochondriale comprend plus de 100 polypeptides dont la majorité est codée par des gènes nucléaires tandis que 13 sont codés par l’acide désoxyribonucléique (ADN) mitochondrial. L’ADN mitochondrial est transmis par la mère et les mutations sont donc de transmission maternelle. Durant la division cellulaire, les mitochondries sont réparties au hasard dans les cellules filles et le pourcentage de molécules d’ADN mutées et de molécules d’ADN normales dans les cellules filles peut varier au cours du temps. L’atteinte rénale au cours des cytopathies mitochondriales est rare. La manifestation la plus fréquente est une tubulopathie proximale, responsable d’une forme plus ou moins complète et sévère de syndrome de de Toni-Debré-Fanconi. Certains patients présentent un syndrome néphrotique et d’autres une néphropathie tubulo-interstitielle. Les investigations comportent des études métaboliques de l’état d’oxydoréduction dans le plasma, des études spectrophotométriques et spectroscopiques de la chaîne respiratoire mitochondriale, des études histologiques et des études génétiques.
Mitochondrial disorders are genetic defects of oxidative phosphorylation. Oxidative phosphorylation takes place in the mitochondrial inner membrane and consists of the oxidation of fuel molecules by oxygen and the concomitant energy transduction into ATP. The mitochondrial respiratory chain is a complex metabolic pathway. It is made of approximately 100 polypeptides, most of which are encoded in the nucleus whereas 13 are encoded in the mitochondria. Mitochondrial DNA is maternally inherited and its mutations are transmitted by the mother. During cell division, mitochondria are randomly partitioned in daughter cells. Therefore, in case normal and mutant DNA are present in the mother's cells, some lineage may have only mutant mitochondrial DNA or normal mitochondrial DNA while others may have both mutant and normal DNA, a condition named heteroplasmy. Renal involvement in mitochondrial cytopathies is rare. Patients most often present with a more or less complete de Toni-Debré-Fanconi syndrome. A few patients present with a nephrotic syndrome or with chronic tubulointerstitial nephritis. The investigation of patients with mitochondrial disorders include metabolic screening for abnormal oxidoreduction status in plasma, investigation of the mitochondrial respiratory chain, including polarographic and spectrophotometric studies, histopathologic studies and genetic studies.
Solute Transport, Energy Consumption, and Production in the Kidney
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Novel large-range mitochondrial DNA deletions and fatal multisystemic disorder with prominent hepatopathy
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Hepatic involvement in mitochondrial cytopathies rarely manifests in adulthood, but is a common feature in children. Multiple OXPHOS enzyme defects in children with liver involvement are often associated with dramatically reduced amounts of mtDNA. We investigated two novel large scale deletions in two infants with a multisystem disorder and prominent hepatopathy. Amount of mtDNA deletions and protein content were measured in different post-mortem tissues. The highest levels of deleted mtDNA were in liver, kidney, pancreas of both patients. Moreover, mtDNA deletions were detected in cultured skin fibroblasts in both patients and in blood of one during life. Biochemical analysis showed impairment of mainly complex I enzyme activity. Patients manifesting multisystem disorders in childhood may harbour rare mtDNA deletions in multiple tissues. For these patients, less invasive blood specimens or cultured fibroblasts can be used for molecular diagnosis. Our data further expand the array of deletions in the mitochondrial genomes in association with liver failure. Thus analysis of mtDNA should be considered in the diagnosis of childhood-onset hepatopathies.

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^☆: From the Unité de Recherches sur les Handicaps Génétiques de l'Enfant INSERM U393, Unité de Recherches de Néphrologie Pédiatrique, INSERM U192 and Département de Pédiatrie, Hôpital des Enfants-Malades, Paris, France, and the Service d'Anatomopathologie, Hôpital Lariboisière, Paris, France

^☆☆: Reprint requests: Arnold Munnich, MD, INSERM U393, Hôpital des Enfants Malades, 149 rue de Sèvres, 75743 Paris-Cedex 15, France.

^★: 0022-3476/95/$3.00 + 0 9/22/61435

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Deletion of mitochondrial DNA in patient with chronic tubulointerstitial nephritis☆,☆☆,★

Abstract

Section snippets

CASE REPORT

METHODS

RESULTS

DISCUSSION

Clin Chim Acta

Clinical aspects of mitochondrial disorders

J Inher Metab Dis

Lactic acidemia