Schmid Holger, Tokarska-Schlattner Malgorzata, Füeßl Birgit, Röder Maximilian, Kay Laurence, Attia Stéphane, Lederer Stephan R, Goebel Frank D, Schlattner Uwe, Bogner Johannes R
Section of Infectious Diseases, Clinic and Policlinic IV, University of Munich, Munich, Germany.
Antivir Ther. 2013;18(2):193-204. doi: 10.3851/IMP2313. Epub 2012 Aug 16.
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.
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.
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.
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.
在接受含富马酸替诺福韦二吡呋酯（TDF）的抗逆转录病毒治疗方案的HIV感染患者血清中，普遍存在的线粒体肌酸激酶（uMtCK）会以2型肌酸激酶巨酶（巨CK2）的形式蓄积。这一发现的成因及临床意义尚不清楚。
对最初描述有巨CK2出现的患者进行了一项为期5年的前瞻性观察随访研究（“TDF转换研究”队列）。此外，在体外测试了替诺福韦（TFV）、其前体药物TDF及其活性细胞内衍生物替诺福韦二磷酸酯（TDP）对uMtCK不同关键特性的影响，以阐明uMtCK与TFV化合物之间可能的相互作用。
在持续TDF治疗不到5年的时间里，只有4/12（33%）的患者仍为巨CK2阳性，但在随访结束时，最初12例阳性患者中有8/12（66%）变为巨CK2阴性。前瞻性临床随访数据表明，TDF治疗下巨CK2的出现与显著的细胞损伤或恶性肿瘤的发生无关。1级低磷血症的趋势提示巨CK2阳性患者存在亚临床近端肾小管功能障碍，尽管这与估计肾小球滤过率的显著降低无关。在体外，TFV、TDF和TDP不会作为竞争性抑制剂或假底物干扰uMtCK酶活性，但TFV和TDF可在稀溶液中稳定天然uMtCK八聚体结构。
TDF治疗患者血清中八聚体uMtCK以巨CK2形式出现，推测是由亚临床肾小管功能障碍导致的低水平线粒体损伤、可能的uMtCK代偿性过表达以及近端小管中较高水平的TFV对uMtCK八聚体的假定稳定作用共同所致。
