Triangular prismatic JJ stent does not cause more discomfort than tubular ones: a randomised controlled trial comparison.

OBJECTIVE: To compare the stent-related symptoms (SRS) of three commonly used, readily accessible ureteric JJ stents after uncomplicated flexible ureteroscopic lithotripsy (FURL), in a prospective randomised controlled single-blind parallel-group study, in order to see whether structural difference might influence SRS. PATIENTS AND METHODS: Patients undergoing FURL were randomised into three groups: the Cook Group received conventional 6 F Cook Universa Soft JJ stents as control, the Kang Yi Bo (KYB) Group received 6 F KYB anti-reflux JJ stents, and the Urovision Group received 7 F Urovision Visiostar ESWL JJ stents. The ureteric stent symptom questionnaire (USSQ) was administered at 1 week, 4 weeks (before stent removal), and 5 weeks (one week after stent removal as baseline evaluation) after stent insertion. Both raw and baseline-adjusted USSQ domain subscores at 1 week and 4 weeks were compared. RESULTS: A total of 146 patients were included in the analysis. The KYB Group showed significantly lower P6&7 subscore yet higher urinary symptoms score 1 week and 4 weeks after stents insertion than both Cook and Urovision, whilst the Urovision Group achieved similar scores in most domains with Cook. CONCLUSIONS: Although the KYB anti-reflux JJ stent might prevent vesicoureteral reflux, it induces significantly stronger urinary symptoms, both at 1 week or 4 weeks after stent insertion, with or without baseline correction. Despite the unique triangular prismatic shape, the Urovision Visiostar stent does not cause heavier urinary symptoms or pain compared to the conventional cylinder shape counterparts.

Partial inhibition of activin receptor-like kinase 4 alleviates bladder fibrosis caused by bladder outlet obstruction.

The bladder undergoes profound structural alterations after bladder outlet obstruction (BOO), characterized by hypertrophy of the bladder wall and accumulation of extracellular matrix (ECM). Transforming growth factor-ß (TGF-ß) has been found to promote fibrosis of the bladder induced by partial bladder outlet obstruction (pBOO). Activin receptor-like kinase 4 (ALK4) is a downstream receptor of the TGF-ß superfamily. However, the role of the ALK4-Smad2/3 pathway in the pathogenesis of bladder fibrosis caused by pBOO remains unknown. This study focused on learning the role of ALK4 in the process of bladder fibrosis caused by pBOO. The pBOO mice models showed that ALK4 expression was found to upregulate in the wild-type bladder 6 weeks after pBOO compared to control group. Then, mice with heterozygous knockout of the ALK4 gene (ALK4+/-) were generated. Histological analysis and Western blot (WB) results showed significant suppression of collagen expression in the bladders of ALK4+/- mice after pBOO compared with WT mice. WB also showed that ALK4+/- mice demonstrated significant suppression of phosphorylated Smad2/3 (p-Smad2/3) expression in the bladder 6 weeks after pBOO but not of phosphorylated extracellular signal-regulated kinase, c-Jun N-terminal kinase or protein 38 (p-ERK, p-JNK, p-P38) expression. This effect might have occurred through partial inactivation of the Smad2/3 signaling pathway. In vitro, ALK4 overexpression promoted collagen production in cultured BSMCs and activated the Smad2/3 signaling pathway. Taken together, our results demonstrated that ALK4 insufficiency alleviated bladder fibrosis in a mouse model of pBOO partly by suppressing Smad2/3 activity.

Urine Macrophages Polarization Predicts Renal Function Recovery after Nephron-Sparing Surgery in Patients with Renal Cell Carcinoma.

INTRODUCTION: This study was conducted to investigate the underlying associations between urine macrophages polarization and renal function recovery after nephron-sparing surgery (NSS) in patients with renal cell carcinoma (RCC) and to explore the potential application values of urine macrophages polarization in predicting the severity of renal ischemia/reperfusion injury (RIRI). METHODS: Sixty-two patients with unilateral RCC who underwent NSS in our departments were prospectively recorded and followed up for long-term renal function to assess the onset of acute kidney injury (AKI) and chronic kidney disease (CKD). Urine samples of patients were collected 72 h after surgery for analyzing pro-inflammatory (classically activated/M1) and pro-reparative (alternatively activated/M2) macrophages polarization by flow cytometry. The detailed correlations between urine macrophages polarization and renal function recovery after NSS were explored by statistical analyses. RESULTS: The cumulative incidence of postoperative AKI was 27.4% (17/62), and 47.0% (8/17) of those eventually developed to CKD during the follow-up. The mean urine M1/M2 ratio was 10.54 ± 8.13 in the AKI group and 3.93 ± 3.10 in the non-AKI group, presenting a significant statistical difference (p < 0.0001). Meanwhile, the urine M1/M2 ratio presented amazing potential in predicting postoperative CKD as well, with a mean ratio of 12.54 ± 9.41 in the CKD group and 4.28 ± 3.21 in the non-CKD group (p < 0.0001). Though univariate analysis implied that urine M1/M2 ratio was a relevant factor of both postoperative AKI and CKD in NSS surgical patients, multivariate analysis did not show satisfying predicting potential in postoperative CKD, mainly due to the very limited candidates enrolled in this study. CONCLUSION: Urine macrophages polarization could predict renal function recovery after NSS in patients with RCC. The urine M1/M2 ratio might a potential biomarker of RIRI but needs to be further verified in clinical settings.

Correlation of prostatic morphological parameters and clinical progression in aging Chinese men with benign prostatic hyperplasia: Results from a cross-sectional study.

OBJECTIVES: Our study aimed to investigate the correlation of prostatic morphological parameters and benign prostatic hyperplasia (BPH) clinical progression in aging Chinese men. METHODS: In this retrospective study, a total of 1038 patients were reviewed. Prostatic morphology was measured by transrectal ultrasound (TRUS). Detailed medical history of all candidates was recorded and analyzed after being classified by specific prostatic measurements. Univariate and multivariate logistic regression analyses were used to estimate the correlation between variables. RESULTS: The cumulative incidence of BPH clinical progression was 63.68% (661/1038) in the study population. Prostate volume (PV), transitional zone volume (TZV), transitional zone index (TZI), and intravesical prostatic protrusion (IPP) were all positively associated with BPH progression (all p < .001). Patients with a PV > 60 ml, TZV > 15 ml, TZI > 0.5, or IPP > 5 mm had a significantly higher possibility of overall BPH clinical progression (adjusted odds ratio (OR): 2.485, 1.678, 1.886, and 1.924, respectively; 95% confidence interval (CI): 1.559-3.960, 1.131-2.489, 1.379-2.579, and 1.357-2.728, correspondingly). CONCLUSION: Prostatic morphological parameters are significantly associated with BPH clinical progression. Patients with larger prostatic morphological parameters are more easily prone to clinical progress. As a result, reasonable managements should be timely considered for those patients before clinical progression occurs.

Preoperative hydronephrosis predicts adverse pathological features and postoperative survival in patients with high-grade upper tract urothelial carcinoma.

PURPOSE: Epidemiological studies reported conflicting results about preoperative hydronephrosis in upper tract urothelial carcinoma (UTUC). This study aimed to investigate the association between preoperative hydronephrosis and pathologic features and oncologic outcomes in patients with UTUC treated by radical nephroureterectomy (RNU). MATERIALS AND METHODS: This was a retrospective, single-center cohort study of 377 patients treated by RNU without perioperative chemotherapy between January 2001 and December 2014. Logistic regression, Cox regression, and survival analyses were performed. RESULTS: Among the 226 patients with high-grade UTUC, 132 (58%) had preoperative hydronephrosis. Multivariable logistic regression revealed that hydronephrosis was independently associated with advanced pT stage (P=0.017) and lymph node or lymphovascular invasion (P=0.002). Median follow-up was 36 months (interquartile range: 20-48 months). The 3- and 5-year overall survival (OS) rates in patients with hydronephrosis were significantly lower than in those without hydronephrosis (both P <0.001). The 3- and 5-year cancer-specific survival (CSS) rates in patients with hydronephrosis were significantly lower than in those without hydronephrosis (both P=0.001). Hydronephrosis was independently associated with OS and CSS (P=0.001 and P=0.004, respectively). Among the 151 patients with low-grade UTUC, hydronephrosis was not associated with pathologic features and postoperative survival. CONCLUSIONS: Preoperative hydronephrosis was significantly associated with adverse pathologic features and postoperative survival in patients with high-grade UTUC.

Variation of prostatic morphology in Chinese benign prostatic hyperplasia patients of different age decades.

OBJECTIVE: Our study aimed to investigate the age-related growth in prostatic morphological parameters in Chinese benign prostatic hyperplasia (BPH) patients, and to find out the regularity of how these parameters change with aging. METHODS: Medical records of 1038 BPH patients were obtained from a retrospective database of first-visit men with BPH. Change regularity of prostatic anatomical factors with aging was analyzed. RESULTS: Patients were classified into four groups according to different age decades. All prostatic anatomical factors assessed in this research increased with age growth (p < .0001). However, these anatomical factors sustained stably when older than 70 years. By analyzing the detailed correlation between age and prostatic morphological parameters, transitional zone index (TZI) (Pearson r = 0.358, r2 = 0.128, p < .0001) and transitional zone width (TZW) (Pearson r = 0.344, r 2= 0.118, p < .0001) showed the best correlation coefficient with age. After adjusted the influence of cardiovascular disease (CVD) and diabetes mellitus (DM), the result remained still similarly. CONCLUSION: Prostatic morphological parameters increase progressively with age growth when patients were younger than 70 years, indicating reasonable interventions to be provided to BPH patients before 70 years. In addition, TZI and TZW are two practical, easy-to-measure prostatic parameters that are significantly associated with the growth of age compared to others.

High serum concentration of estradiol may be a risk factor of prostate enlargement in aging male in China.

Objective: Assess the association between serum sex hormone level and prostate volume in men with benign prostatic hyperplasia (BPH).Material and methods: The study involved 239 BPH patients from January 2013 to June 2015 in our hospital. Each patient collected age, medical history, height, weight, body mass index, as well as a full examination of sex hormones, and transrectal ultrasound results.Results: Estradiol (E2) was significantly associated with prostate volume (r = 0.151, p = .02) and transitional zone volume (r = 0.136, p = .035). The association was more significant after adjusting age and BMI (r = 0.253 and 0.250, p <.001). Patients were divided into two groups according to prostate volume and E2, respectively. E2 in patients with prostate volume ≤50 ml was significantly lower than those with prostate volume >50 ml. Prostate volume, transitional zone volume and age were all significantly higher in the patients with E2 ≥ 160 umol/l than those in the patients with E2 < 160 umol/l. Through logistics regression, E2 (p = .012, OR = 1.004) are the only independent risk factor for prostate volume.Conclusions: E2 is significantly associated with prostate volume. High concentrations of E2 may be a risk factor for the large volume of prostate.

The association between body mass index and testosterone deficiency in aging Chinese men with benign prostatic hyperplasia: results from a cross-sectional study.

BACKGROUND AND OBJECTIVES: Evidence has supported obesity as a risk factor for both benign prostate hyperplasia (BPH) and hypogonadism. In this paper, we performed a retrospective study and discussed the prevalence of testosterone deficiency (TD) and its relationship to body mass index (BMI) in aging Chinese men with BPH who have surgical intervention. MATERIAL AND METHODS: We reviewed the clinical data by age, BMI, medical history, serum prostate-specific antigen (PSA) levels, serum total testosterone (TT) levels, biochemical analysis, and transrectal ultrasound. BMI and other variables were considered to be independent variables in an effort to evaluate any potential associations between these factors and TD status using non-adjusted and multivariate-adjusted regression models. RESULTS: Of the 795 BPH participants, 27.2% (216) patients had TD. After adjusting for all potential covariates, there was a similar J-shaped relationship between BMI and TD, with an inflection point of 19.2 kg/m2. The effect sizes and the confidence intervals on the left and right sides of this inflection point were 0.6 (0.4-1.0) (p = .043) and 1.2 (1.1-1.3) (p < .001), respectively. CONCLUSION: Nearly one-third of the aging Chinese BPH patients had TD in this study. The association between BMI and TD is not simple. A J-shaped curve correlation was detected. BMI was positively correlated with TD when it was over 19.2 kg/m2 and inversely correlated with TD when it was below 19.2 kg/m2. Long-term prospective studies are needed to confirm these findings.

Protein Disulfide Isomerase 4 Drives Docetaxel Resistance in Prostate Cancer.

BACKGROUND: Protein disulfide isomerase 4 (PDIA4) has been reported to be closely associated with chemoresistance in several types of malignancies. But the pathogenic mechanisms of PDIA4 involved in docetaxel (DTX) resistance in prostate cancer (PCa) are still unknown. Hence, this study was conducted to evaluate the potential effect of PDIA4 on chemoresistance to DTX in PCa cells and to investigate the underlying mechanisms. METHODS: Two types of DTX-resistant PCa cells, that is, DTX-resistant PC-3 cells (PC-3/DTXR) and C4-2B cells (C4-2B/DTXR) were developed, as well as the parental PC-3 and C4-2B cells were obtained to investigate these issues. Short hairpin RNAs targeting human PDIA4 to knockdown the expression of PDIA4 or PDIA4-expressing adenoviral vectors to overexpress the PDIA4 were transfected into PCa cells to study the underlying mechanisms of PDIA4 involving in PCa DTX resistance. RESULTS: Results showed that PDIA4 exhibited a dramatic overexpression in PC-3/DTXR and C4-2B/DTXR cells. Down-regulation of PDIA4 by infecting PC-3/DTXR and C4-2B/DTXR cells with shPDIA4 lentivirus stimulated cell death by prompting apoptosis. Up-regulation of PDIA4 by infecting PC-3 and C4-2B cells with PDIA4-expressing adenovirus showed severer resistance to DTX. In addition, PDIA4 up-regulation induced phosphorylated protein kinase B (Akt) expression, while PDIA4 knockdown significantly inhibited the expression in PCa cells. CONCLUSIONS: Our study indicates that PDIA4 is a negative regulator of PCa cell apoptosis and plays a critical role in PCa DTX resistance by activating the Akt-signaling pathway. Thereby, it implies that targeting PDIA4 could be a potential adjuvant therapeutic approach against DTX resistance in PCa.

Optimized Anti-Prostate-Specific Membrane Antigen Single-Chain Variable Fragment-Loaded Nanobubbles as a Novel Targeted Ultrasound Contrast Agent for the Diagnosis of Prostate Cancer.

OBJECTIVES: To prepare optimized prostate-specific membrane antigen (PSMA) single-chain variable fragment (scFv)-loaded nanobubbles (NBs) as a novel targeted ultrasound (US) contrast agent for diagnosis and treatment of prostate cancer (PCa). METHODS: Prostate-specific membrane antigen scFv-loaded NBs were prepared by membrane hydration and biotin-streptavidin conjugation. Flow cytometry was used to observe the binding rate of the targeted NBs to PSMA-expressing cells. Contrast-enhanced US was used to monitor targeted and nontargeted NBs administered to nude mice with 22RV1, LNCaP, and PC-3 xenograft tumors. The specific binding ability of the targeted NBs was further examined by fluorescence imaging of tumor cryosections. RESULTS: Uniformly sized targeted NBs were successfully prepared (mean ± SD, 485.3 ± 28.4 nm). The NBs showed good stability and bound specifically to LNCaP and 22RV1 cells with high PSMA expression in vitro but did not bind to PC-3 cells without PSMA expression. The targeted NBs presented good US enhancement, and the results of the in vivo xenograft tumor nude mouse model showed that the peak contrast intensity in LNCaP and 22RV1 cells was significantly higher for the targeted NBs than the nontargeted NBs (P < .05), whereas there was no significant difference in PC-3 cells. Immunofluorescence results obtained from tumor sections confirmed that the targeted NBs were capable of targeting PSMA-expressing tumor cells. CONCLUSIONS: These novel PSMA scFv-loaded NBs have proven to be an excellent US contrast agent for imaging PSMA-expressing PCa and have the potential to not only enable efficient and safe molecular imaging but also to serve as a delivery system for targeted PCa therapies.

The possible association between serum interleukin 8 and acute urinary retention in Chinese patients with benign prostatic hyperplasia.

Acute urinary retention (AUR) is one of the progressive manifestations of benign prostatic hyperplasia (BPH). This cross-sectional study was conducted to analyse the possible association between serum interleukin 8 (sIL-8) and AUR in BPH patients to provide evidence of sIL-8 as a potential biomarker for the prediction of AUR. The relationship between sIL-8 levels and AUR was evaluated by logistic regressions in 245 ageing Chinese men with BPH. The discriminant validity of sIL-8 and the optimal cut-off value were determined by a receiver operating characteristic curve. The levels of sIL-8 increased significantly in BPH patients with AUR (p < 0.001). The sIL-8 concentration was positively correlated with AUR in BPH patients (OR = 1.024, 95% CI: 1.009-1.040, p = 0.002). The correlation with AUR in the group with a high sIL-8 level (≥43.05 pg/ml) was significantly enhanced (OR = 8.853, 95% CI: 2.433-32.205, p = 0.001). The sIL-8 level correlated with AUR in Chinese BPH patients independently. As a possible predictor, sIL-8 may contribute to the screening of high-risk populations for AUR to create opportunities for the early effective interventions to improve prognosis and enhance the quality of life. Prospective studies are needed to support all these results.

MicroRNA-101 protects bladder of BOO from hypoxia-induced fibrosis by attenuating TGF-ß-smad2/3 signaling.

Bladder outlet obstruction is a common disease, which always evokes urinary bladder wall remodeling significantly. It has been suggested that bladder outlet obstruction can make the bladder progression from inflammation to fibrosis, and hypoxia may play a vital role. It has been found the expression of microRNA-101 varied in bladder after BOO. But what role microRNA-101 and hypoxia play in bladder is not well known. This study is to investigate the mechanism of microRNA-101 and hypoxia in fibrosis of bladder after BOO. We found the expression of microRNA-101 and hif-1α increased in bladder after BOO. Hypoxia could promote the expression of extracellular matrix subtypes and microRNA-101 in BSMCs. When microRNA-101b was translated into BSMCs, the smad2/3 signaling pathway was found to repress. Dual luciferase reporter detected that microRNA-101b attenuated the TGF-ß signaling pathway by inhibiting the expression of TGFßR1. Then, we conclude microRNA-101b is induced by hypoxia and represses fibrosis of BSMCs by inhibiting the expression of TGFßR1 through TGF-ß signaling pathway, and it may be an anti-fibrotic miRNA for therapy. © 2018 IUBMB Life, 71(1):235-243, 2019.

Urinary neutrophil gelatinase-associated lipocalin as a biomarker to monitor renal function in patients with obstructive ureteral calculi.

PURPOSE: Our study aimed to investigate the clinical significance of urinary neutrophil gelatinase-associated lipocalin (NGAL) as an effective real-time monitoring biomarker of renal function in patients with obstructive ureteral calculi presenting renal colic. METHODS: A cohort of 89 first-visit patients with renal colic caused by unilateral ureteral calculi were retrospectively reviewed. 46 of which received double-J ureteral stent placement (group 1) and the remaining 43 treated conservatively with analgesics and hydration (group 2) when diagnosed. Urinary NGAL (uNGAL) values in the baseline, 2 h and 1 day after treatments were recorded. The variation of this parameter over time and the association with patients' characteristics were analyzed. RESULTS: uNGAL levels decreased as time went by for patients receiving double-J ureteral stent placement (47.23 ± 28.32 ng/mL for baseline, 40.73 ± 21.86 ng/mL for 2 h and 34.67 ± 18.00 ng/mL for 1 day after operation; p = 0.0363). Nevertheless, for those treating conservatively, the levels emerged a mild increase (50.63 ± 32.30 ng/mL, 56.00 ± 32.01 ng/mL and 60.63 ± 34.08 ng/mL, correspondingly; p = 0.3708). By analyzing the association between uNGAL variation and patients' characteristics of group 1, operation duration showed the best correlation coefficient (Pearson r = 0.6106, r2 = 0.3728, p < 0.0001). CONCLUSIONS: uNGAL can be used as a biomarker to monitor the renal function effectively when serum creatinine (sCr) was within normal limits. And double-J ureteral stent can be considered as a protective factor to renal function in patients with obstructive ureteral calculi presenting renal colic.

Integrative transcriptome analysis identifies genes and pathways associated with enzalutamide resistance of prostate cancer.

BACKGROUND: Enzalutamide, a novel androgen receptor (AR) signaling inhibitor, has been widely used to increase survival in patients with castration-resistant prostate cancer. However, resistance to enzalutamide invariably develops. METHODS: To understand the underlying mechanisms of resistance to enzalutamide, we performed integrative analysis on multiple transcriptome datasets to identify those genes constantly up- or down-regulated in response to enzalutamide treatment. RESULTS: There were 703 and 581 differentially expressed genes derived from enzalutamide-sensitive and -resistant cell lines, respectively. Functional enrichment analysis on these genes demonstrated that biological processes of cell proliferation and ubiquitin mediated proteolysis pathway are specifically disturbed in sensitive cell lines but not resistant ones. Such divergence explained why enzalutamide ineffective for resistant prostate cancer. CONCLUSIONS: Taken together, the present study revealed a set of critical genes, which can provide etiologic clues as to enzalutamide-resistant prostate cancer and guide novel therapeutic approaches.

Impact of habitual intake of glucosamine, fresh fruit, and tea on the risk of urolithiasis: A two-sample Mendelian randomization study.

Dietary patterns have a significant impact on the occurrence of urolithiasis. This study aimed to investigate the causal relationships between the consumption of glucosamine, fresh fruits, and tea, and the predisposition to urinary stones using a Mendelian randomization (MR) approach. Genetic proxies for these dietary factors were obtained from the UK Biobank, while the summary data for urolithiasis genome-wide association analyses were sourced from the FinnGen consortium. Five MR methodologies, namely inverse variance weighted (IVW), MR-Egger regression, weighted median, weighted mode, and simple mode, were employed in the analysis. To validate the findings, sensitivity evaluations such as the MR-PRESSO disruption test and Cochran Q test for heterogeneity were performed. The IVW method showed that glucosamine consumption had a strong inverse association with urolithiasis risk (Odds Ratio [OR] = 0.006, 95% Confidence Interval [CI] 0.0001-0.287, P = .009), surpassing the associations of fresh fruits (OR = 0.464, 95% CI 0.219-0.983, P = .045) and tea (OR = 0.550, 95% CI 0.345-0.878, P = .012). These findings were consistent when verified using alternative MR techniques, and the sensitivity analyses further supported their credibility. The results of this MR analysis demonstrate that regular consumption of glucosamine, fresh fruits, and tea is inversely correlated with the risk of developing urolithiasis.

Nephron sparing surgery for a patient with a complicated solitary functioning kidney and a giant pT3 renal cell carcinoma: A case report.

A solitary functioning kidney (SFK) with renal cell carcinoma (RCC) is an imperative indication for nephron-sparing surgery (NSS). Nevertheless, a giant pT3 RCC mass (maximum diameter >20 cm) on the functioning side of a patient with SFK is extremely rare. However, whether NSS is more beneficial than radical nephrectomy (RN) in such patients is controversial. Here, we present the case of a 71-year-old female patient with a 20 cm*16 cm RCC mass in the SFK, who initially presented with hematuria and acute urinary tract obstructive anuria caused by renal calculi. The patient underwent NSS treatment after our evaluation, and the 26-month follow-up revealed that her renal function recovered to the state before the tumor formation. In addition, no relapse or metastasis was detected.

Omnidirectional (Flexible) Ureteral Access Sheath: Safety, Efficacy, and Initial Experience Report.

Background: Recently a novel omnidirectional (OD) ureteral access sheath (UAS) has been developed. By retrospectively reviewing and comparing the flexible ureteroscopic lithotripsy (FURL) cases in our institution with either a conventional Cook UAS or an OD UAS in the past year, we shared our experience of the safety, efficacy, and relevant issues on the usage of OD UAS. Materials and Methods: The medical history and surgery details of 199 patients with kidney stones or ureterojunctional stones who underwent FURL in Xinhua Hospital, including 61 Cook UAS and 138 OD UAS, were reviewed and compared. The maximal deflection angle was measured by steering four different types of ureteroscopes to bend the OD UAS in different states. Result: The deflection angle of OD UAS was ∼110° to 130° free load, and 90° to 130° when loaded with different instruments. The stone burden and position were similar in two groups. Given a similar prestent ratio and operation time, the OD UAS group achieved a higher single-session stone-free rate (SFR) (63.9% vs 94.2%, p < 0.0001) at 1-month follow-up evaluated by a CT scan. Conclusion: OD UAS is a novel device with high safety and efficacy. The unique flexible design allows it to bend with the ureteroscope and enter renal calices and be set close to the stone. Combined with the suction port, OD UAS contributes greatly to dealing with large-burden kidney stones, shortens operation time, and improves single-session SFR.

LRRK2 aggravates kidney injury through promoting MFN2 degradation and abnormal mitochondrial integrity.

Mitochondrial dysfunction is one of the key features of acute kidney injury (AKI) and associated fibrosis. Leucine-rich repeat kinase 2 (LRRK2) is highly expressed in kidneys and regulates mitochondrial homeostasis. How it functions in AKI is unclear. Herein we reported that LRRK2 was dramatically downregulated in AKI kidneys. Lrrk2-/- mice exhibited less severity of AKI when compared to wild-type counterparts with less mitochondrial fragmentation and decreased reactive oxygen species (ROS) production in proximal renal tubular cells (PTCs) due to mitofusin 2 (MFN2) accumulation. Overexpression of LRRK2 in human PTC cell lines promoted LRRK2-MKK4/JNK-dependent phosphorylation of MFN2Ser27 and subsequently ubiquitination-mediated MFN2 degradation, which in turn exaggerated mitochondrial damage upon ischemia/reperfusion (I/R) mimicry treatment. Lrrk2 deficiency also alleviated AKI-to-chronic kidney disease (CKD) transition with less fibrosis. In vivo pretreatment of LRRK2 inhibitors attenuated the severity of AKI as well as CKD, potentiating LRRK2 as a novel target to alleviate AKI and fibrosis.

Down-regulation of spinal D-amino acid oxidase expression blocks formalin-induced tonic pain.

A series of inhibitors of d-amino acid oxidase (DAAO) are specific in blocking chronic pain, including formalin-induced tonic pain, neuropathic pain and bone cancer pain. This study used RNA interference technology to further validate the notion that spinal DAAO mediates formalin-induced pain. To target DAAO, a siRNA/DAAO formulated in polyetherimide (PEI) complexation and a shRNA/DAAO (shDAAO, with the same sequence as siRNA/DAAO after intracellular processing) expressed in recombinant adenoviral vectors were designed. The siRNA/DAAO was effective in blocking DAAO expression in NRK-52E rat kidney tubule epithelial cells, compared to the nonspecific oligonucleotides. Furthermore, multiple-daily intrathecal injections of both siRNA/DAAO and Ad-shDAAO for 7 days significantly inhibited spinal DAAO expression by 50-80% as measured by real-time quantitative PCR and Western blot, and blocked spinal DAAO enzymatic activity by approximately 60%. Meanwhile, both siRNA/DAAO and Ad-shDAAO prevented formalin-induced tonic phase pain by approximately 60%. Multiple-daily intrathecal injections of siRNA/DAAO and Ad-shDAAO also blocked more than 30% spinal expression of GFAP, a biomarker for the activation of astrocytes. These results further suggest that down-regulation of spinal DAAO expression and enzymatic activity leads to analgesia with its mechanism potentially related to activation of astrocytes in the spinal cord.

Perioperative anemia predicts kidney injury after partial nephrectomy.

PURPOSE: Partial nephrectomy (PN) induced kidney injury is still a challenging clinical matter that has not been completely conquered. This study aimed to explore the influences of perioperative anemia on renal function after PN. MATERIALS AND METHODS: A total of 114 patients undergoing PN were retrospectively studied. Serum creatinine was tested preoperatively and 24 hours and 3 days after PN to evaluate the occurrence of acute kidney injury (AKI). Perioperative anemia was evaluated on the basis of the hemoglobin (Hb) value at 24 hours and 3 days postoperation. Patients were then followed up for the development of chronic kidney disease (CKD). Associations between perioperative anemia and postoperative AKI and CKD were determined. RESULTS: The cumulative incidence of perioperative anemia was 33.33% in the study. A total of 32.46% of patients suffered from postoperative AKI, and 16.67% of patients progressed to CKD. The incidences of AKI and CKD in perioperative anemia patients were dramatically exceeded in those without anemia. Further statistical analyses indicated that perioperative anemia was a relevant factor for postoperative kidney injury, presenting the highest odds ratio of 31.272 for postoperative AKI and 17.179 for postoperative CKD. Receiver operating characteristic curve analysis showed that ΔHb=(preoperative Hb)-(postoperative Hb nadir) was a meaningful predictor of postoperative kidney injury, with an area under the curve of 0.784 for predicting postoperative AKI and 0.805 for postoperative CKD. CONCLUSIONS: Perioperative anemia can predict kidney injury after PN, and ΔHb shows a meaningful predictive value for postoperative AKI and CKD.