Renal tubular function of patients with classical menkes disease

Kodama, Hiroko; Okabe, Ichiro; Kihara, Atsushi; Mori, Yuhko; Okaniwa, M.

doi:10.1007/bf01800360

Cited by 9 publications

(11 citation statements)

References 2 publications

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“…Long-term copper injection has a risk of causing copper accumulation to toxic levels in the kidneys, leading to severe renal damage (15)(16)(17). The present study confirmed that, without disulfiram pretreatment, systemically administered copper was preferentially taken up by the kidneys of living MD model mice.…”

Section: Discussionsupporting

confidence: 82%

“…In MD patients, primary renal dysfunction is caused by copper accumulation mainly in the medulla (renal tubule) (15); therefore, the finding that disulfiram was able to reduce copper uptake in the medulla was significant. Our ex vivo autoradiography analysis of the kidneys with 2 types of chelators revealed different copper distribution patterns in renal tissue: disulfiram-mediated reduction of copper uptake in the medulla and D-penicillamine-mediated reduction of copper uptake in the cortex.…”

Section: Discussionmentioning

confidence: 99%

“…Another important aspect of parenteral copper administration is that copper treatment is sometimes associated with excess copper accumulation in the kidneys, leading to renal dysfunction in patients and macular mice with MD (6,15). Previous reports demonstrated that copper administration lengthened the life-span of MD model mice but that copper accumulation to toxic levels in the kidneys led to severe renal damage (16,17).…”

mentioning

confidence: 99%

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PET Imaging Analysis with ⁶⁴Cu in Disulfiram Treatment for Aberrant Copper Biodistribution in Menkes Disease Mouse Model

Nomura

Nozaki²,

Hamazaki

et al. 2014

J Nucl Med

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Menkes disease (MD), an X-linked recessive disorder of copper metabolism caused by mutations in the copper-transporting ATP7A gene, results in growth failure and severe neurodegeneration in early childhood. Subcutaneous copper-histidine injection is the standard treatment for MD, but it has limited clinical efficacy. Furthermore, long-term copper injection causes excess copper accumulation in the kidneys, resulting in renal dysfunction. To attempt to resolve this issue, we used PET imaging with 64 Cu to investigate the effects of disulfiram on copper biodistribution in living mice serving as an animal model for MD (MD model mice). Methods: Macular mice were used as MD model mice, and C3H/He mice were used as wild-type mice. Mice were pretreated with 2 types of chelators (disulfiram, a lipophilic chelator, and D-penicillamine, a hydrophilic chelator) 30 min before 64 CuCl 2 injection. After 64 CuCl 2 injection, emission scans covering the whole body were performed for 4 h. After the PET scans, the brain and kidneys were analyzed for radioactivity with γ counting and autoradiography. Results: After copper injection alone, marked accumulation of radioactivity ( 64 Cu) in the liver was demonstrated in wild-type mice, whereas in MD model mice, copper was preferentially accumulated in the kidneys (25.56 ± 3.01 percentage injected dose per gram [%ID/g]) and was detected to a lesser extent in the liver (13.83 ± 0.26 %ID/g) and brain (0.96 ± 0.08 %ID/g). Copper injection with disulfiram reduced excess copper accumulation in the kidneys (14.54 ± 2.68 %ID/g) and increased copper transport into the liver (29.42 ± 0.98 %ID/g) and brain (5.12 ± 0.95 %ID/g) of MD model mice. Copper injection with D-penicillamine enhanced urinary copper excretion and reduced copper accumulation in most organs in both mouse groups. Autoradiography demonstrated that disulfiram pretreatment induced copper transport into the brain parenchyma and reduced copper accumulation in the renal medulla. Conclusion: PET studies with 64 Cu revealed that disulfiram had significant effects on the copper biodistribution of MD. Disulfiram increased copper transport into the brain and reduced copper uptake in the kidneys of MD model mice. The application of 64 Cu PET for the treatment of MD and other copperrelated disorders may be useful in clinical settings.

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Section: Discussionsupporting

confidence: 82%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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PET Imaging Analysis with ⁶⁴Cu in Disulfiram Treatment for Aberrant Copper Biodistribution in Menkes Disease Mouse Model

Nomura

Nozaki²,

Hamazaki

et al. 2014

J Nucl Med

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“…In animal models for WND and MNK, copper accumulation occurs in the proximal tubules but not in the distal tubules or the glomeruli [7]. In humans, the increased copper levels in the kidney of MNK patients are similar to or higher than that of WND patients [8]. In WND patients, this accumulation is believed to be the cause of tubular dysfunction [9].…”

Section: Introductionmentioning

confidence: 99%

Expression in Mouse Kidney of Membrane Copper Transporters Atp7a and Atp7b

Moore¹,

Cox²

2002

Nephron

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Copper is essential for activity of many enzymes, but is toxic in excess. Several copper proteins are required for copper homeostasis. ATP7A and ATP7B are genes encoding membrane copper transporters. ATP7A, defective in Menkes disease (MNK), is expressed in many tissues involved primarily in copper uptake from dietary sources. ATP7B, defective in Wilson disease (WND), is essential for copper excretion. Although MNK patients have a copper deficiency in most tissues, copper accumulates in proximal tubules in the kidney. WND patients also have copper accumulation in the proximal tubules. In some WND patients this copper accumulation may result in tubular dysfunction, resulting in the increased excretion of low molecular weight substances (e.g. amino acids and calcium). In mouse, we have demonstrated, by in situ hybridization, the expression pattern in the kidney of mouse orthologues, Atp7a and Atp7b, and have confirmed Atp7b expression by immunohistochemistry. Both Atp7a and Atp7b are expressed in glomeruli; however, Atp7b is also seen in the kidney medulla. This suggests that glomeruli are responsible for regulating copper levels in the filtrate. In WND patients, urinary copper levels are extremely high suggesting Atp7b in the loops of Henle may have a role in copper reabsorption.

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“…Mild renal tubular dysfunction can occur in a subset of patients with MD; urinary β2-microglobulin, a low-molecular-weight protein absorbed at the proximal tubule, increases with age, whereas other biochemical indicators of renal function remain normal (31,32). Dysfunction is caused by significant copper accumulation in the renal tubule.…”

Section: Munakata Et Almentioning

confidence: 99%

Copper-trafficking efficacy of copper-pyruvaldehyde bis(N4-methylthiosemicarbazone) on the macular mouse, an animal model of Menkes disease

et al. 2012

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Renal tubular function of patients with classical menkes disease

Cited by 9 publications

References 2 publications

PET Imaging Analysis with ⁶⁴Cu in Disulfiram Treatment for Aberrant Copper Biodistribution in Menkes Disease Mouse Model

PET Imaging Analysis with ⁶⁴Cu in Disulfiram Treatment for Aberrant Copper Biodistribution in Menkes Disease Mouse Model

Expression in Mouse Kidney of Membrane Copper Transporters Atp7a and Atp7b

Copper-trafficking efficacy of copper-pyruvaldehyde bis(N4-methylthiosemicarbazone) on the macular mouse, an animal model of Menkes disease

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Renal tubular function of patients with classical menkes disease

Cited by 9 publications

References 2 publications

PET Imaging Analysis with 64Cu in Disulfiram Treatment for Aberrant Copper Biodistribution in Menkes Disease Mouse Model

PET Imaging Analysis with 64Cu in Disulfiram Treatment for Aberrant Copper Biodistribution in Menkes Disease Mouse Model

Expression in Mouse Kidney of Membrane Copper Transporters Atp7a and Atp7b

Copper-trafficking efficacy of copper-pyruvaldehyde bis(N4-methylthiosemicarbazone) on the macular mouse, an animal model of Menkes disease

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PET Imaging Analysis with ⁶⁴Cu in Disulfiram Treatment for Aberrant Copper Biodistribution in Menkes Disease Mouse Model

PET Imaging Analysis with ⁶⁴Cu in Disulfiram Treatment for Aberrant Copper Biodistribution in Menkes Disease Mouse Model