A mitochondrial DNA deletion presenting with corneal clouding and severe Fanconi syndrome.

BACKGROUND: Mitochondrial cytopathies are a diverse group of disorders characterized by impaired mitochondrial energy production. Disease manifestations are protean and may include seemingly disparate findings. CASE DIAGNOSIS/TREATMENT: Here we report a 5-year-old girl with the uncommon pairing of bilateral corneal dystrophy requiring corneal transplantation and severe Fanconi syndrome recalcitrant to oral bicarbonate therapy necessitating intravenous supplementation. Etiological work-up included qualitative urine organic acid testing, which demonstrated abnormalities in lactate, pyruvate, and ketoacids suggestive of a mitochondrial etiology. Confirmatory genetic testing in blood leukocytes revealed a large, novel, heteroplasmic, de novo mitochondrial DNA deletion at nt 8648-16072. CONCLUSION: The finding of Fanconi syndrome with disease processes in other, seemingly unrelated, organ systems should raise clinical suspicion for mitochondrial disease. Early assessment of urine organic acids in the etiological work-up of Fanconi syndrome may assist in the identification of respiratory chain disorders.

Reduced phosphate transport in the renal proximal tubule cells in cystinosis is due to decreased expression of transporters rather than an energy defect.

Nephropathic cystinosis is an autosomal recessive disorder caused by mutations in the CTNS gene [1], which encodes for a transporter (cystinosin) responsible for cystine efflux from lysosomes. In cystinotic renal proximal tubules (RPTs), the defect in cystinosin function results in reduced reabsorption of solutes by apical Na(+)/solute cotransport systems, including the Na(+)/phosphate (Pi) cotransport system [2]. However the underlying molecular mechanisms are unknown, given the lack of an appropriate cellular model. To obtain such a model system, we have knocked down cystinosin with siRNA in primary RPT cell cultures. An 80% reduction in cystinosin strongly inhibited Na(+) dependent Pi uptake (70%). Although this finding could be explained by a direct effect on transporters as well as by altered energetics (the ATP level dropped by 52%), our results demonstrate a lack of involvement of Na, K-ATPase, and a reduction in the number of NaPi2a transporters.

Regulation of renal proximal tubule Na-K-ATPase by prostaglandins.

Prostaglandins (PGs) play a number of roles in the kidney, including regulation of salt and water reabsorption. In this report, evidence was obtained for stimulatory effects of PGs on Na-K-ATPase in primary cultures of rabbit renal proximal tubule (RPT) cells. The results of our real-time PCR studies indicate that in primary RPTs the effects of PGE(2), the major renal PG, are mediated by four classes of PGE (EP) receptors. The role of these EP receptors in the regulation of Na-K-ATPase was examined at the transcriptional level. Na-K-ATPase consists of a catalytic α-subunit encoded by the ATP1A1 gene, as well as a ß-subunit encoded by the ATP1B1 gene. Transient transfection studies conducted with pHß1-1141 Luc, a human ATP1B1 promoter/luciferase construct, indicate that both PGE(1) and PGE(2) are stimulatory. The evidence for the involvement of both the cAMP and Ca(2+) signaling pathways includes the inhibitory effects of the myristolylated PKA inhibitor PKI, the adenylate cyclase (AC) inhibitor SQ22536, and the PKC inhibitors Gö 6976 and Ro-32-0432 on the PGE(1) stimulation. Other effectors that similarly act through cAMP and PKC were also stimulatory to transcription, including norepinephrine and dopamine. In addition to its effects on transcription, a chronic incubation with PGE(1) was observed to result in an increase in Na-K-ATPase mRNA levels as well as an increase in Na-K-ATPase activity. An acute stimulatory effect of PGE(1) on Na-K-ATPase was observed and was associated with an increase in the level of Na-K-ATPase in the basolateral membrane.

Targeting of renal proximal tubule Na,K-ATPase by salt-inducible kinase.

The renal proximal tubule (RPT) is a central locale for Na+ reabsorption, and blood pressure regulation. Na+ reabsorption in the RPT depends upon the Na,K-ATPase, which is controlled by a complex regulatory network, including Salt-Inducible Protein Kinase (SIK). SIKs are recently discovered members of the AMP-activated Protein Kinase (AMPK) family, which regulate salt homeostasis and metabolism in a number of tissues. In the RPT, SIK interacts with the Na,K-ATPase in the basolateral membrane (BM), regulating both the activity and level of Na,K-ATPase in the BM. Thus, Na,K-ATPase activity can be rapidly adjusted in response to changes in Na+ balance. Long-term changes in Na+ intake affect the state of SIK phosphorylation, and as a consequence the phosphorylation of TORCs, Transducers of Regulated CREB (cAMP Regulatory Element Binding Protein). Once phosphorylated, TORCs enter the nucleus, and activate transcription of the ATP1B1 gene encoding for the Na,K-ATPase beta subunit.

Lithium-induced membranous glomerulonephropathy in a pediatric patient.

Lithium-induced glomerular toxicity is an infrequent occurrence in pediatric patients. We report a 13-year-old patient presenting with clinical and laboratory evidence of renal insufficiency after long-term lithium use. Biopsy revealed membranous glomerulonephropathy. Discontinuation of the lithium treatment resulted in resolution of the symptoms and laboratory abnormalities. Other alkali metals have been implicated as risk factors for membranous glomerulonephropathy. To the best of our knowledge, this is the first reported case of lithium-induced glomerulonephropathy in a pediatric patient.

Renal late effects in patients treated for cancer in childhood: a report from the Children's Oncology Group.

Improvements in childhood cancer therapy have led to increasing numbers of long-term survivors. These survivors are at risk for a variety of late effects due to the disease itself, treatment exposures (surgery, chemotherapy, and radiotherapy), underlying medical problems, and health behaviors. The COG LTFU Guidelines are risk-based, exposure-related recommendations for the identification and management of late effects due to therapies utilized in the treatment of childhood cancer, and are designed for asymptomatic survivors presenting for routine medical follow-up 2 or more years after completion of cancer therapy. The COG Guidelines Task Force on Urinary Tract Complications conducted an extensive review of the medical literature via MEDLINE. Specific treatment exposures which were reviewed include nephrectomy, chemotherapy regimens known to be nephrotoxic (cisplatin, carboplatin, ifosfamide, and methotrexate), and renal irradiation. Literature sources were ranked according to the strength of evidence and are cited in the review. This review summarizes the literature that supported the recommendations for cancer survivors at risk for nephrotoxicity previously outlined in the Children's Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent and Young Adult Cancers (COG LTFU Guidelines).

Effect of glutathione depletion on Ifosfamide nephrotoxicity in rats.

Kidney injury is an important side effect of the chemotherapeutic agent ifosfamide in humans. Previous studies have shown that treatment with ifosfamide reduces kidney glutathione and that the toxicity of ifosfamide is enhanced in glutathione-depleted renal tubule cells in vitro. In this study, we examined the effect of glutathione depletion on ifosfamide nephrotoxicity in vivo using rats treated with the glutathione-depleting agent buthionine sulfoximine. Animals received 80 mg/kg ifosfamide intraperitoneally daily for three days with or without buthionine sulfoximine in drinking water. Buthionine sulfoximine produced a significant fall in renal glutathione content but did not affect kidney function. Ifosfamide-treated rats developed low-grade glucosuria, phosphaturia and proteinuria that worsened with concomitant buthionine sulfoximine therapy. These findings indicate that glutathione depletion exacerbates ifosfamide nephrotoxicity in rats and suggest that pharmacological methods for replenishing intracellular glutathione may be effective in ameliorating ifosfamide-induced renal injury.

Cancer and the kidney.

This article provides a summary of renal cancers that can affect adolescent patients. It encompasses both isolated and syndrome-associated cancers and the various renal complications associated with cancer therapy. Prompt recognition and appropriate referral and management, along with periodic long-term follow-up, will enhance both the survival and quality of life of young people afflicted with these serious diseases.

Interstitial nephritis from mesalazine: case report and literature review.

We report a new case of biopsy-confirmed mesalazine-induced interstitial nephritis in an 18-year-old male with ulcerative colitis. His renal function improved with drug discontinuation and corticosteroid treatment. An English literature review revealed an additional 22 cases of this complication that, taken together, showed (1) a male predominance, (2) an absence of specific symptoms or findings on urinalysis, (3) a 61% frequency of residual chronic renal insufficiency with 13% of patients developing end-stage renal disease, and (4) an apparent favorable response to steroid therapy. We conclude that patients receiving 5-aminosalicylates should be routinely monitored with serum creatinine measurements to prevent this uncommon but potentially serious adverse drug reaction.

Comparative toxicity of ifosfamide metabolites and protective effect of mesna and amifostine in cultured renal tubule cells.

Renal injury is a common side effect of the chemotherapeutic agent ifosfamide. Current evidence suggests that the ifosfamide metabolite chloroacetaldehyde contributes to this nephrotoxicity. The present study examined the effects of chloroacetaldehyde and acrolein, another ifosfamide metabolite, on rabbit proximal renal tubule cells in primary culture. The ability of the uroprotectant medications sodium 2-mercaptoethanesulfonate (mesna) and amifostine to prevent chloroacetaldehyde- and acrolein-induced renal cell injury was also assessed. Chloroacetaldehyde and acrolein (25-200 M) produced dose-dependent declines in neutral red dye uptake, glucose transport and glutathione content. Chloroacetaldehyde was a more potent toxin than acrolein. Pretreatment of cells with the glutathione-depleting agent buthionine sulfoximine enhanced the toxicity of both chloroacetaldehyde and acrolein while co-administration of mesna or amifostine prevented metabolite toxicity. These results support the hypothesis that chloroacetaldehyde is responsible for ifosfamide-induced nephrotoxicity. The protective effect of mesna and amifostine in vitro contrasts with clinical experience showing that these medications do not eliminate ifosfamide nephrotoxicity.

Renal injury from valproic acid: case report and literature review.

A child with developmental delay and epilepsy developed glucosuria approximately 16 months after starting valproic acid therapy. Laboratory evaluation revealed global defects in proximal tubule function consistent with the De Toni-Debré-Fanconi syndrome. Discontinuation of valproate led to complete recovery 5 months later. Review of previously reported cases indicates that this complication is unique to children and reversible when the medication is discontinued.