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Macro CK2 accumulation in tenofovir-treated HIV patients is facilitated by CK oligomer stabilization but is not predictive for pathology.
MedLine Citation:
PMID:  22894916     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
BACKGROUND: Ubiquitous mitochondrial creatine kinase (uMtCK) accumulates as Macroenzyme creatine kinase type 2 (Macro CK2) in the serum of HIV-infected patients under a tenofovir disoproxil fumarate (TDF) containing antiretroviral regimen. The genesis and clinical significance of this finding is unclear. METHODS: A prospective observational 5-year follow-up study was performed on those patients, in which Macro CK2 appearance was initially described ("TDF switch study" cohort). In addition, tenofovir (TFV), its prodrug TDF, and its active, intracellular derivative tenofovir diphosphate (TDP) were tested in vitro for their effects on different key properties of uMtCK to clarify possible interactions of uMtCK with TFV compounds. RESULTS: Under 5-years continuous TDF treatment only 4/12 (33%) patients remained Macro CK2 positive, whereas 8/12 originally positive patients were Macro CK2 negative at the end of follow-up. Prospective clinical follow-up data indicate that Macro CK2 appearance under TDF is not associated with a significant cell damage or occurrence of malignancies. A trend towards grade 1 hypophosphatemia suggests subclinical proximal tubular dysfunction in Macro CK2 positive patients, although it was not associated with a significant decline in estimated glomerular filtration rate. In vitro, TFV, TDF and TDP did not interfere with uMtCK enzyme activity as competitive inhibitors or pseudo-substrates, but TFV and TDF stabilized the native uMtCK octameric structure in dilute solutions. CONCLUSIONS: Appearance of octameric uMtCK as Macro CK2 in the serum of TDF treated patients is suggested to result from a combination of low level mitochondrial damage due to subclinical renal tubular dysfunction together with possible compensatory uMtCK overexpression and a putative concomitant stabilization of uMtCK octamers by higher levels of TFV in proximal tubules.
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-8-15
Journal Detail:
Title:  Antiviral therapy     Volume:  -     ISSN:  2040-2058     ISO Abbreviation:  Antivir. Ther. (Lond.)     Publication Date:  2012 Aug 
Date Detail:
Created Date:  2012-8-16     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9815705     Medline TA:  Antivir Ther     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
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