Macro CK2 accumulation in tenofovir-treated HIV patients is facilitated by CK oligomer stabilization but is not predictive for pathology.
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 TFV 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
In just under 5 years of continuous TDF treatment, only 4/12 (33%) patients remained macro CK2-positive, whereas 8/12 (66%) 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 significant cell damage or occurrence of malignancies. A trend towards grade 1 hypophosphataemia suggests subclinical proximal tubular dysfunction in macro-CK2-positive patients, although it was not associated with a significant decrease 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 caused by 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.
Section of Infectious Diseases, Clinic and Policlinic IV, University of Munich, Munich, Germany. holger.schmid@lrz.uni-muenchen.de
Holger
H
Schmid
Malgorzata
M
Tokarska-Schlattner
Birgit
B
Füeßl
Maximilian
M
Röder
Laurence
L
Kay
Stéphane
S
Attia
Stephan R
SR
Lederer
Frank D
FD
Goebel
Uwe
U
Schlattner
Johannes R
JR
Bogner
D000225:Adenine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D019380:Anti-HIV Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002384:Catalysis / Q000187:drug effects; D052281:Creatine Kinase, Mitochondrial Form / Q000097:blood / Q000737:chemistry / Q000378:metabolism*; D004795:Enzyme Stability; D005500:Follow-Up Studies; D005919:Glomerular Filtration Rate / Q000187:drug effects; D015658:HIV Infections / Q000097:blood / Q000188:drug therapy / Q000378:metabolism*; D006801:Humans; D017674:Hypophosphatemia / Q000097:blood; D063065:Organophosphonates / Q000494:pharmacology* / Q000627:therapeutic use; D055503:Protein Multimerization / Q000187:drug effects; D000068698:Tenofovir
D019380:Anti-HIV Agents; D063065:Organophosphonates; D000068698:Tenofovir; D052281:Creatine Kinase, Mitochondrial Form; D000225:Adenine