Empagliflozin improves renal ischemia-reperfusion injury by reducing inflammation and enhancing mitochondrial fusion through AMPK-OPA1 pathway promotion.

BACKGROUND: Renal ischemia-reperfusion injury (IRI) is one reason for renal transplantation failure. Recent studies have shown that mitochondrial dynamics is closely related to IRI, and that inhibition or reversal of mitochondrial division protects organs against IRI. Optic atrophy protein 1 (OPA1), an important factor in mitochondrial fusion, has been shown to be upregulated by sodium-glucose cotransporter 2 inhibitor (SGLT2i). Also, the antiinflammatory effects of SGLT2i have been demonstrated in renal cells. Thus, we hypothesized that empagliflozin could prevent IRI through inhibiting mitochondrial division and reducing inflammation. METHODS: Using hematoxylin-eosin staining, enzyme linked immunosorbent assay (ELISA), flow cytometry, immunofluorescent staining, terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end labeling (TUNEL) staining, real-time PCR, RNA-sequencing, and western blot, we analyzed renal tubular tissue from in vivo and in vitro experiments. RESULTS: Through animal experiments and sequencing analysis, we first confirmed the protection against IRI and the regulation of mitochondrial dynamics-related factors and inflammatory factors by empagliflozin pretreatment. Then, through hypoxia/reoxygenation (H/R) cellular experiments, we confirmed that empagliflozin could inhibit mitochondrial shortening and division and upregulate OPA1 in human renal tubular epithelial cell line (HK-2) cells. Subsequently, we knocked down OPA1, and mitochondrial division and shortening were observed, which could be alleviated by empagliflozin treatment. Combined with the previous results, we concluded that OPA1 downregulation leads to mitochondrial division and shortening, and empagliflozin can alleviate the condition by upregulating OPA1. We further explored the pathway through which empagliflozin functions. Related studies have shown the activation of AMPK pathway by empagliflozin and the close correlation between the AMPK pathway and OPA1. In our study, we blocked the AMPK pathway, and OPA1 upregulation by empagliflozin was not observed, thus demonstrating the dependence of empagliflozin on the AMPK pathway. CONCLUSION: The results indicated that empagliflozin could prevent or alleviate renal IRI through antiinflammatory effects and the AMPK-OPA1 pathway. Ischemia-reperfusion injury is an inevitable challenge in organ transplantation. It is necessary to develop a new therapeutic strategy for IRI prevention in addition to refining the transplantation process. In this study, we confirmed the preventive and protective effects of empagliflozin in renal ischemia-reperfusion injury. Based on these findings, empagliflozin is promising to be a preventive agent for renal ischemia-reperfusion injury and can be applied for preemptive administration in kidney transplantation.

Could Metabolic Syndrome Be a Predictor of Survival Outcomes in Upper Tract Urothelial Carcinoma? A Propensity Score Matching Study in a Large Chinese Center.

Purpose: To evaluate the prognostic value of metabolic syndrome (MetS) in upper tract urothelial carcinoma (UTUC) patients based on propensity score matching (PSM) analysis. Patients and Methods: A total of 573 patients with UTUC after radical nephroureterectomy were included at Peking University People's Hospital from January 2007 to April 2021. MetS was diagnosed according to the criteria of Chinese Diabetes Society and was defined as the presence of 3 or more of the following 4 conditions (obesity, hyperglycemia, hypertension, high triglycerides and/or low high-density lipoprotein-cholesterol). Patients were divided into two groups based on whether they had MetS, whose variables were adjusted using 1:1 PSM analysis with a caliber of 0.02 to minimize selection bias. Univariate and multivariate Cox regression analysis were used to evaluate the association of MetS and its components with pathological outcomes after adjusting preoperative confounders by propensity score matching. The Kaplan-Meier method was used to estimate overall survival (OS), cancer-specific survival (CSS), and intravesical recurrence-free survival (IVRFS) after surgery. Results: MetS was significantly correlated with older age, a history of coronary heart disease, high Charlson Comorbidity Index, low estimated Glomerular filtration rate, and low aspartate/alanine aminotransferase ratio (all P<0.05). Multivariate Cox regression analysis and Kaplan-Meier curves demonstrated that MetS showed no statistical correlation with lower OS or IVRFS and approaching significance with lower CSS (P=0.063) before PSM. After PSM, the 5-year OS, CSS, and IVRFS were 64.1%, 74.7%, and 77.2%, respectively, in the MetS group, compared with 67.4%, 78.8%, and 77.2%, respectively, in non-MetS group. Univariate Cox regression analyses showed that MetS and its components were not associated with decreased OS, CSS, or IVRFS (all P>0.05). Conclusion: In our study, no statistical difference was found between MetS and survival outcomes in UTUC, except a marginal association with lower CSS. Further studies are needed to evaluate the role of MetS and its each single component on UTUC.

Advantages of Small Bone-Window Craniotomy Under Microscope Combined Postoperative Intracranial Pressure Monitoring in the Treatment of Hypertensive Intracerebral Hemorrhage.

OBJECTIVE: The aim of this study is to analyze the clinical effect of small bone-window craniotomy with microscope combined postoperative ICP monitoring, and further explore an appropriate treatment for HICH patients. METHODS: One hundred fifty patients with HICH were selected according to inclusion and exclusion criteria and divided into 3 groups at random, 50 each group. Patients in 3 groups were treated with conventional craniotomy, small bone-window craniotomy and small bone-window craniotomy combined ICP monitoring respectively. The surgical efficiency, treatment effect and outcomes were recorded and analyzed. RESULTS: The intraoperative blood loss and operation time of small window groups were significantly less than that of conventional group, and the hematoma clearance rate in small window groups were significantly higher than in conventional group (P < 0.05). Compared with conventional group, the hospital stays and mannitol dose used were less in small window groups and least in small window combined ICP monitoring group (P < 0.05). The complication rate in small window combined ICP monitoring group was 10%, which was significantly lower than in conventional group (26%, P < 0.05), while no significant difference was found between small window group (18%) compared with the other 2 groups respectively (P > 0.05). The difference of morality rate between 3 groups wasn't significant (P > 0.05). Three treatment significantly increased the Barthel index score, and the improvement of small window combined ICP monitoring group was significantly higher than in other 2 groups respectively (P < 0.05), while the difference between this two groups wasn't significant (P > 0.05). CONCLUSION: Small bone-window craniotomy is more efficient and convenient than conventional craniotomy in the treatment of HICH. In the meantime, small bone-window craniotomy simultaneous with ICP monitoring significantly improved clinical effect and treatment outcomes of HICH patients.

Suspensory ligament release combined with acellular dermal matrix filler in infrapubic space: A new method for penile length augmentation.

Until now, no reliable method is recognised in treating buried penis. This study explored a new method of penile length augmentation using acellular dermal matrix filler in infrapubic space combined with liposuction and penile suspensory release. Patients with "small-sized penis" received penile length augmentation procedure including suprapubic liposuction, penile suspensory ligament release and insertion of folded acellular dermal matrix between corpora cavernosa and pubis symphysis. Their penile length from tip to skin was measured pre-operatively and post-operatively. The post-operative complications and patients' satisfaction were also recorded. Fifteen adult male patients were included with the mean age of 33.2 ± 4.6 years old and BMI of 28.9 ± 5.3 kg/m2 . The average amount of liposuction was 430 ± 90.0 ml. The average penile length measured pre-operatively and post-operatively (on table and 3 months afterwards) was 3.0 ± 1.3 cm, 7.3 ± 2.1 cm and 5.4 ± 1.8 cm. The penile length has significantly increased by 4.3 ± 1.6 cm (on table) and 2.4 ± 0.8 cm (3 months post-operatively; p < 0.05). The post-operative complications included oedema of penis, ecchymosis of lower abdomen and poor wound healing. No patient was dissatisfied with the appearance and function. The new method using acellular dermal matrix combined with liposuction and penile suspensory ligament release is safe and effective. The method could be applied to selected patients with buried penis.

Clear cell renal cell carcinoma bone metastasis: What should be considered in prognostic evaluation.

INTRODUCTION: Knowledge of clear cell renal cell carcinoma bone metastasis (ccRCC-BM) remains scarce. This study depicts clinical, pathological and outcome features of the disease and provides suggestions to establish prognosis prediction system more appropriate for ccRCC-BM. MATERIALS AND METHODS: Patients with ccRCC-BM had clinical, pathological data collected. Kaplan-Meier survival analysis was used for outcome profiles. Prognostic risks were evaluated using MSKCC/Motzer score. Univariate and multivariate logistic regression were performed to investigate association between clinical, pathological features and prognosis. RESULTS: In the series containing 106 ccRCC-BM patients with 4:1 male predominance, 44.3% of them had synchronous bone metastasis and 28.3% had multi-organ metastasis. Axial bone was prone to bone metastasis and the incidence of severe skeletal-related events was 54.7%. Curative bone lesion resection was performed in 70.7% patients. The median overall survival (mOS) time was 45 months for all and 32 months for those in unfavorable risk stratification. Shorter time to bone metastasis (TTBM) [OR 1.019, 95% CI (1.007, 1.031)], elderly age [OR 1.040, 95% CI (1.001, 1.080)], concomitant multi-organ metastasis [OR 3.883, 95% CI (1.375, 10.967)] and carbonic anhydrase (CA)-IX expression loss [OR 58.824, 95% CI (2.653, 1000)] were associated with poor prognosis. CONCLUSION: The outcome of ccRCC-BM remained poor in unfavorable risk stratification. Bone lesion resection accompanied by systematic therapy for selected patient could improve prognosis. Shorter TTBM, elderly age, concomitant multi-organ metastasis and the expression loss of CA-IX along with gender-bias, feasibility for surgical treatment are suggested to be incorporated in modified ccRCC-BM-specific prognosis prediction system.

Segmental Ureterectomy is Acceptable for High-risk Ureteral Carcinoma Comparing to Radical Nephroureterectomy.

Purpose: To determine if segmental ureterectomy (SU) could be chosen for wider oncological indications than low-risk ureteral carcinoma, given the difficulties in accurate preoperative risk stratification determination and kidney-sparing needs for successive therapy. Methods: Data from ureteral carcinoma patients who underwent open SU or laparoscopic radical nephroureterectomy (RNU) between 2011 and 2016 were retrospectively reviewed. Kaplan-Meier survival analysis and Cox regression model with patients' baseline characteristics (age, bladder cancer history, hydronephrosis), procedure type, and tumor characteristics (site, size, pathological features) as covariates were used to evaluate oncological outcomes. Life quality parameters including preoperative renal function, Karnofsky performance status, pain score, and surgical complications were set as second endpoints. Results: Sixty-three patients (24 in SU group, 39 in RNU group) who had at least one high-risk factor were enrolled. In the mean follow-up time of 24.67 months, no significant difference was found in recurrence-free survival (66.7% and 69.2%, p = 0.798), overall survival (79.2% and 84.6%, p = 0.453), and cancer-specific survival (83.3% and 89.7%, p = 0.405) between SU and RNU groups. The Cox regression demonstrated that procedure type was not associated with oncological outcomes. Patients in SU group experienced significant mean estimated glomerular filtration rate (eGFR) increase by 4.60 ml/(min·1.73 m2) (p < 0.001). Proportion of patients having poor eGFR also decreased postoperatively in SU group. Mere tendency in physical performance status improvement and serious complications reduction was detected in SU group. Conclusion: SU is acceptable for high-risk ureteral carcinoma comparing to RNU with satisfying tumor control efficacy and advantage in renal function preservation.

Determining optimal maintenance schedules for adjuvant intravesical bacillus Calmette-Guerin immunotherapy in non-muscle-invasive bladder cancer: a systematic review and network meta-analysis.

OBJECTIVES: To figure out optimal bacillus Calmette-Guerin (BCG) maintenance schedules for non-muscle-invasive bladder cancer (NMIBC) patients by comparing different schedules in a systematic review using conventional and network meta-analysis. MATERIALS AND METHODS: Literature was searched in the databases of Medline, Embase, Cochrane library, Clinicaltrials.gov, Wanfang, CNKI and SinoMed in April 2016 and 9 randomized clinical trials comparing intravesical BCG maintenance therapy with BCG induction-only therapy or comparing different BCG maintenance schedules (induction-only, 1 year, 1.5 year, 2 year, 3 year maintenance) in NMIBC patients were included. Conventional and network meta-analyses within a Bayesian framework were performed to calculate odds ratios of tumor recurrence, progression and side effects (cystitis, hematuria, general malaise and fever). The surface under the cumulative ranking curve (SUCRA) mean ranking was used to obtain schedule hierarchy. RESULTS: Data from 1951 patients showed that longer-term maintenance BCG therapy does not significantly decrease tumor recurrence and progression rate of NMIBC compared to shorter-term maintenance BCG therapy. However, longer-maintenance therapy does not increase side effect incidence compared to induction-only therapy. According to SUCRA results, induction-only therapy has the highest probability of recurrence and progression but least probability of side effects. CONCLUSIONS: Longer BCG maintenance therapy (such as 3 years) is not superior to shorter maintenance therapy (such as 1 year). But maintenance therapy overall is better than induction-only BCG therapy while not increasing side effects. Though further evidence and clinical practice with balanced confounding factors (risk stratification and BCG strain) are wished for, the current study suggests the common use of 1 year intravesical BCG instillation for NMIBC patients.