Exogenous pancreatic kininogenase protects against tacrolimus-induced renal injury by inhibiting PI3K/AKT signaling: The role of bradykinin receptors.

BACKGROUND: Tissue kallikrein offers a wide spectrum of biological activity in the protection against various types of injury. However, information on its role in tacrolimus (TAC)-induced renal injury is limited. OBJECTIVES: This study aimed to assess the beneficial effects of pancreatic kininogenase (PK) in a rat model of chronic TAC nephrotoxicity and in vitro. METHODS: Sprague Dawley rats were treated daily with either TAC or PK or a combination of the two for four weeks. The influence of PK on renal injury was examined in terms of renal function, histopathology, cytokine expression, oxidative stress, intracellular organelles, programmed cell death, and PI3K/AKT signaling. Human kidney proximal tubular (HK-2) cells and mouse mesangial (SV40 MES13) cells treated with TAC and PK were also studied. RESULTS: PK treatment improved renal function and histopathology. This effect was paralleled by downregulation of proinflammatory and profibrotic cytokine expression. TAC-induced oxidative stress was closely associated with endoplasmic reticulum stress and mitochondrial dysfunction, resulting in excessive programmed cell death (apoptosis and autophagy) that was significantly abrogated by concurrent PK interference with PI3K/AKT signaling. PK also stimulated bradykinin receptor 1 (B1R) and B2R mRNA synthesis and increased bioactive nitric oxide (NO) and cAMP concentrations in TAC-treated kidneys. Blockade of either B1R or B2R eliminated the renoprotective effects of PK. In HK-2 and SV40 MES13 cells, PK decreased TAC-induced overproduction of intracellular reactive oxygen species and inhibited apoptotic cells, whereas cell viability was improved. Moreover, activated PI3K/AKT signaling in HK-2 cells was inhibited by PK and the PI3K inhibitor, LY294002. CONCLUSIONS: These findings indicate that PK treatment protects against chronic TAC nephrotoxicity via inhibition of PI3K/AKT signaling.

Comparison of Characteristics, Follow-up and Outcomes of Active Surveillance for Prostate Cancer According to Ethnicity in the GAP3 Global Consortium Database.

BACKGROUND: Studies of active surveillance (AS) for prostate cancer (PCa) have focussed predominantly on Caucasian populations. Little is known about the experience of Asian men, while suitability for men of African descent has been questioned. OBJECTIVE: To compare baseline characteristics, follow-up, and outcomes for men on AS for PCa, according to ethnicity. DESIGN SETTING AND PARTICIPANTS: The study cohort included 13 centres from the GAP3 consortium that record ethnicity (categorised broadly as Caucasian/white, African/Afro-Caribbean/black, Asian, mixed/other, and unknown). Men with biopsy grade group >2, prostate-specific antigen (PSA) >20 ng/ml, T stage ≥cT3, or age >80 yr were excluded. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Clinical characteristics, follow-up schedules, outcome status, and reasons for discontinuation were compared across ethnic groups. Risk of upgrading, potential disease progression (grade group ≥3 or T stage ≥3), suspicious indications (any upgrading, number of positive cores >3, T stage ≥cT3, PSA >20 ng/ml, or PSA density >0.2 ng/ml/cc2), and conversion to treatment were assessed using mixed-effect regression models. RESULTS AND LIMITATIONS: The eligible cohort (n = 9158) comprised 83% Caucasian men, 6% men of African descent, 5% Asian men, 2% men of mixed/other ethnicity, and 4% men of unknown ethnicity. Risks of suspicious indicators (hazard ratio = 1.27; 95% confidence interval [CI] 1.12-1.45), upgrading (odds ratio [OR] = 1.40; 95% CI 1.14-1.71), and potential progression (OR = 1.46; 95% CI 1.06-2.01) were higher among African/black than among Caucasian/white men. Risk of transitioning to treatment did not differ by ethnicity. More Asian than Caucasian men converted without progression (42% vs 26%, p < 0.001). Heterogeneity in surveillance protocols and racial makeup limit interpretation. CONCLUSIONS: This multinational study found differences in the risk of disease progression and transitioning to treatment without signs of progression between ethnic groups. Further research is required to determine whether differences are due to biology, sociocultural factors, and/or clinical practice. PATIENT SUMMARY: This international study compared prostate cancer active surveillance outcomes by ethnicity. Risks of upgrading and disease progression were higher among African than among Caucasian men. Transitioning to treatment without progression was highest among Asian men. Understanding of these differences requires further investigation.

Potential urinary extracellular vesicle protein biomarkers of chronic active antibody-mediated rejection in kidney transplant recipients.

The aim of this study was to identify potential proteomic biomarkers for chronic active antibody-mediated rejection (CAMR) in kidney transplant recipients (KTRs). Among 385 KTRs enrolled in a cross-sectional multicenter study, 26 KTRs with biopsy-proven CAMR, 57 KTRs with long-term graft survival (LGS), and 10 rejection-free matched KTRs were included. A proteomic approach was employed to measure urinary extracellular vesicle (EV) changes in the KTRs. The urinary EVs were trypsin-digested using a gel-assisted protocol and quantified by label-free liquid chromatography with tandem mass spectrometry, using a data-dependent acquisition (DDA) mode. Western blot analysis was performed to confirm the protein levels for each candidate biomarker. Analysis of the isolated EV proteins revealed 93 and 97 proteins in the CAMR and LGS patients, respectively. Proteins that were identical in both groups were excluded and only high-significance proteins with a fold change of at least 1.5 were selected as candidate biomarkers. Six proteins (APOA1, TTR, PIGR, HPX, AZGP1, and CP) that were distinguishable between CAMR and LGS were selected. The proteins were confirmed by immunoblot analyses using independently acquired urinary EV samples. AZGP1 in particular was found to be a CAMR-specific proteomic biomarker that was distinguishable from the rejection-free control group with matching kidney function, duration of transplantation, and age. We identified and validated six proteomic biomarkers for CAMR and clarified one CAMR-specific proteomic biomarker in KTRs. Further clinical trials are needed before these rejection-specific biomarkers can be applied for the early prediction, diagnosis, and monitoring of the clinical response of KTRs to the treatment of CAMR.

The incidence, mortality, and risk factors of prostate cancer in Asian men.

The objective of this review was to describe the epidemiology and risk factors of prostate cancer (PCa) in Asian populations. English language publications published over the last 10 years covering studies on the incidence, mortality, and risk factors of PCa in Asia were reviewed. The incidence of PCa in Asia is rising but is still significantly lower than that in Western countries. Studies in Asia indicated that the consumption of red meat, fat, dairy, and eggs was associated with a higher risk for PCa. Age and family history were also found to be risk factors. The emergence of genetic data indicates that different genetic backgrounds between Asian and Western populations play a role in the observed differences in PCa incidence. The lower incidence of PCa in Asian men than in Western men may in part be due to a lack of systematic prostate-specific antigen screening, but environmental and genetic factors also play a role.

Efficacy and safety of CKD-11101 (darbepoetin-alfa proposed biosimilar) compared with NESP in anaemic chronic kidney disease patients not on dialysis.

OBJECTIVE: To evaluate the efficacy and safety of CKD-11101 (biosimilar darbepoetin-alfa, Chong Kun Dang Pharm.) compared with NESP® in treatment of anaemia in patients with chronic kidney disease not on dialysis. CLINICAL TRIAL REGISTRATION: NCT03431623. METHOD: In this multi-centre, randomized, double-blind study, patients were treated with CKD-11101 and NESP. The efficacy evaluation period (EEP) was 24 weeks, during which patients were treated every 2 weeks. All patients who completed the EEP were treated with CKD-11101 every 2 weeks for the first 4 weeks and every 4 weeks for the safety evaluation period (SEP), which was from 24 weeks to 52 weeks. The primary efficacy endpoint was the change in mean haemoglobin (Hb) level from baseline to end of EEP and mean dose needed to achieve the target Hb. RESULTS: The mean Hb level was increased in both groups during the EEP (both p < 0.001). The difference in mean Hb level change between the two groups was 0.01 g/dL (95% CI = -0.213-0.242), indicating that CKD-11101 was equivalent to NESP. The difference in mean administration dose between groups was -1.40 mcg (95% CI = -6.859-4.059) included in the equivalent range. The incidence of AEs and ADRs was not different between the two groups, and the frequency of ADRs was favourable in both groups (1.2% in CKD-11101 vs 7.7% in the NESP to CKD-11101 conversion group). CONCLUSION: CKD-11101 has an equivalent therapeutic effect as NESP in chronic kidney disease patients with renal anaemia. CKD-11101 can be safely used for long-term treatment and in patients converted from NESP.