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Background:  Presence of macroenzyme creatine kinase (Macro CK) is a diagnostic pitfall in interpretation of elevated serum CK and CK-MB mass concentration and has to be further assessed by isoenzyme electrophoresis. Macro CK type 2 consists of polymeric mitochondrial CK complexes and has been reported predominantly in association with malignancy and liver disease. Its appearance is suggested as an indicator of cellular necrosis and cytotoxicity.

Methods:  We retrospectively and prospectively measured total CK, CK-MB isoenzyme activity and protein weight as well as CK isoenzyme distribution in sera from 468 ART-treated HIV-infected outpatients. Laboratory assays were performed in a blinded fashion. Medical charts were reviewed. Student’s t-test or Mann-Whitney test were performed, a p value of ≤ 0.05 was considered significant.

Results:  Analysis of CK-MB isoenzyme activity and mass concentration revealed evidence for Macro CK 2 in the sera of 32 of 408 (7.8%) patients. A regimen containing the nucleoside reverse transcriptase inhibitor (NRTI) tenofovir disoproxil fumarate (TDF) was the only significant common clinical finding in patients with Macro CK-2 appearance. To prove a possible relationship with TDF treatment, sera from an independent cohort of 41 patients collected before and during TDF exposure and control sera of 19 non-NRTI-treated patients were analyzed prospectively. Prior to TDF exposure, no serum showed Macro CK-2, but in 20 of the 41 (48%) TDF-treated patients a Macro CK-2 isoenzyme was detectable at an average of 3 months after TDF exposition. Atypical bands of Macro CK-2 in electrophoresis persisted for > 6 months. Control sera exhibited no Macro CK-2, whereas patients with detectable Macro CK-2 revealed in parallel a significant induction (p = 0.047) of b2-microglobulin levels, while glomerular filtration rates or markers of liver injury did not differ in TDF-treated patients with or without Macro CK-2 appearance.

Conclusions:  The finding of Macro CK-2 in HIV-infected patients pinpoints a strong association with TDF-containing ART. Accumulation of Macro CK-2 could result from a direct cytotoxic effect or insufficient Macro CK clearance capacity mediated by TDF and warrants further exploration. In addition, clinicians should be aware of the possibility that an increased rate of CK-MB in HIV-infected patients might not be an indicator of ischemic heart disease but Macro CK-2 appearance in TDF treatment.

Keywords: Tenofovir Disoproxil Fumarate ; creatine kinase; macroenzyme