Urine alpha1-microglobulin is a better marker for early tubular dysfunction than beta2-microglobulin among tenofovir-exposed human immunodeficiency virus-infected men who have sex with men

Objectives: Men who have sex with men are at risk of tenofovir nephrotoxicity due to its wide use in both treatment and prophylaxis for human immunodeficiency virus infection, but little is known about the urinary biomarkers of early renal dysfunction in this population. This study aims to identify useful biomarkers of early renal dysfunction among human immunodeficiency virus-infected men who have sex with men exposed to tenofovir.Methods: In a cross-sectional study urinary alpha1-microglobulin, beta2-microglobulin, N-acetyl-B-n-glucosaminidase and albumin were measured and expressed as the ratio-to-creatinine in 239 human immunodeficiency virus-infected men who have sex with men who were treatment naïve or receiving antiretroviral therapy with tenofovir-containing or non-tenofovir-containing regimens. Additionally, 56 patients in the non-antiretroviral therapy group started a tenofovir-containing regimen and were assessed after 3 and 6 months on antiretroviral therapy.Results: Both the frequency of alpha1-microglobulin proteinuria (alpha1-microglobulin-creatinine ratio >25.8 mg/g) and the median urinary alpha1-microglobulin-creatinine ratio were higher in the tenofovir disoproxil fumarate group than the other two groups (all p< 0.05). A higher frequency of beta2-microglobulin proteinuria (beta2-microglobulin-creatinine ratio >0.68 mg/g) was also observed in the tenofovir group (28.9%) compared to the non-tenofovir group (13.6%, p= 0.024). There were no significant differences between groups for N-acetyl-β-n-glucosaminidase and albumin. In the longitudinal study, the median urinary alphat-microglobulin-creatinine ratio after 3 and 6 months on tenofovir-containing therapy (16.8 and 17.3 mg/g) was higher than baseline (12.3 mg/g, p= 0.023 and 0.011, respectively), while no statistically important changes were observed in urinary beta2-microglobulin-creatinine ratio or in the other biomarkers after 3 and 6 months on antiretroviral therapy (all p> 0.05).Conclusion: Urinary alphat-microglobulin seems to be a more sensitive and stable indicator of tubular dysfunction than urinary beta2-microglobulin for assessing tenofovir-related nephrotoxicity and can be significantly altered after tenofovir exposure.

Decreased Expression of Vitamin K Epoxide Reductase Complex Subunit 1 in Kidney of Patients with Calcium Oxalate Urolithiasis / 华中科技大学学报（医学）（英德文版）

Urinary prothrombin fragment 1 (UPTF1) is a potent inhibitor of urinary stone formation.UPTF1 exerts such inhibitory effect by effective γ-carboxylation in which vitamin K epoxide reductase complex subunit 1 (VKORC1),the rate-limiting enzyme,is involved.This study examined the correlation between VKORC1 expression and calcium oxalate urolithiasis.The renal cortex samples were obtained from patients undergoing nephrectomy and then divided into 3 groups:urolithiasis group,control group A [hydronephrosis-without-stone (HWS) group],control group B (normal control group).The localization and expression of VKORC 1 in renal tissues were determined by using immunohistochemistry,immunofluorescence microscopy,Western blotting and SYBR Green Ⅰreal-time reverse-transcription PCR.The rapid amplification of cDNA ends (RACE) were conducted to obtain the 3'- and 5'-untranslated region (UTR) of VKORC1.The results showed that VKORC1was located in the cytoplasm of renal tubular epithelial cells.The expression of VKORC 1 in the urolithiasis group was significantly lower than that in the other two control groups (P＜0.05).Moreover,the 3'- and 5'-UTR sequence of the VKORC 1 gene was successfully cloned.No insertion or deletion was found in the 3'- and 5'-UTR.However,a 171-bp new base sequence was discovered in the upstream of 5'-UTR end in the urolithiasis group.It was concluded that the decreased expression of VKORC1 may contribute to the development of calcium oxalate urolithiasis in the kidney.

CD44 is involved in CXCL-12 induced acute myeloid leukemia HL-60 cell polarity

CXCL-12 and its receptor CXCR4 participate in breast cancer and melanoma cell metastasis to bone and lymphoid nodes. CD44, as a receptor for hyaluronic acid, is involved in lymphocyte recirculation, homing, adhesion and migration. But the role of CD44 in CXCL-12 induced leukemia cell migration still remains unclear. The present study showed that CXCL-12 stimulation induced the rapid internalization of CXCR4 and facilitated the formation of lamellipodia and uropod in acute leukemia cell line HL-60. CXCL-12 also induced CD44 translocation into the uropod, while CD44 remained evenly distributed on the untreated cell membranes. Results suggest that CD44 participates in CXCL-12 induced cell polarization and subsequent cell migration.

Genetic Mutation of Vitamin K-dependent Gamma-glutamyl Car-boxylase Domain in Patients with Calcium Oxalate Urolithiasis / 华中科技大学学报（医学）（英德文版）

To investigate the exon mutation of vitamin K-dependent gamma-glutamyl carboxylase (GGCX or VKDC) in patients with calcium oxalate urolithasis, renal cortex and peripheral blood sam-ples were obtained from severe hydronephrosis patients (with or without calculi), and renal tumor pa-tients undergoing nephrectomy. GGCX mutations in all 15 exons were examined in 44 patients with calcium oxalate urolithiasis (COU) by polymerase chain reaction (PCR) and denatured high pressure liquid chromatography (DHPLC), and confirmed by sequencing. Mutation was not found in all COU samples compared to the controls. These data demonstrated that functional GGCX mutations in all 15 exons do not occur in most COU patients. It was suggested that there may be no significant association between the low activity and mutation of GGCX in COU.