Yufeng Wang

MitoTEMPO Prevents Oxalate Induced Injury in NRK-52E Cells via Inhibiting Mitochondrial Dysfunction and Modulating Oxidative Stress.

As one of the major risks for urolithiasis, hyperoxaluria can be caused by genetic defect or dietary intake. And high oxalate induced renal epithelial cells injury is related to oxidative stress and mitochondrial dysfunction. Here, we investigated whether MitoTEMPO, a mitochondria-targeted antioxidant, could protect against oxalate mediated injury in NRK-52E cells via inhibiting mitochondrial dysfunction and modulating oxidative stress. MitoSOX Red was used to determine mitochondrial ROS (mtROS) production. Mitochondrial membrane potential (Δψm) and quantification of ATP synthesis were measured to evaluate mitochondrial function. The protein expression of Nox4, Nox2, and p22 was also detected to explore the effect of oxalate and MitoTEMPO on NADPH oxidase. Our results revealed that pretreatment with MitoTEMPO significantly inhibited oxalate induced lactate dehydrogenase (LDH) and malondialdehyde (MDA) release and decreased oxalate induced mtROS generation. Further, MitoTEMPO pretreatment restored disruption of Δψm and decreased ATP synthesis mediated by oxalate. In addition, MitoTEMPO altered the protein expression of Nox4 and p22 and decreased the protein expression of IL-6 and osteopontin (OPN) induced by oxalate. We concluded that MitoTEMPO may be a new candidate to protect against oxalate induced kidney injury as well as urolithiasis.

Comparison of minimally invasive percutaneous nephrolithotomy and flexible ureteroscopy for the treatment of intermediate proximal ureteral and renal stones in the elderly

The aim of this study is to compare the outcomes of flexible ureteroscopy (fURS) and minimally invasive percutaneous nephrolithotomy (mPNL) for the treatment of renal and/or proximal ureteral stones sized 1–2xa0cm in the elderly (≥60xa0years). Between January 2010 and March 2015, 184 consecutive mPNL and fURS were performed to treat intermediate renal and/or proximal ureteral stones in geriatric patients. The records were retrospectively reviewed and outcomes were compared. Although no significant difference was found in the complication rate between two groups, a statistical trend (pxa0=xa00.059) in favor of fURS was observed. In addition, multivariate analysis demonstrated that mPNL, preoperative positive urine culture and lower hemoglobin were independent risk factors for postoperative complication (pxa0=xa00.016, pxa0=xa00.021, pxa0=xa00.001, respectively). And fURS was significantly associated with less hemoglobin drop, red blood cell transfusion, analgesics requirement, postoperative hospital duration, and charges of laboratory tests, medical examinations and medications (pxa0=xa00.019, pxa0=xa00.037, pxa0=xa00.006, pxa0=xa00.000 and pxa0=xa00.007, pxa0=xa00.000, pxa0=xa00.000, pxa0=xa00.001, respectively), while higher costs of operations (pxa0=xa00.008). Receiver operating characteristic curve suggested a preoperative hemoglobin of 106.5xa0g/L as the threshold for predicting red blood cell transfusion after mPNL. The overall one-session stone-free rate of fURS at 1xa0month was lower (pxa0=xa00.006), while it was similar for solitary stone between two groups. Comorbidity and previous stone surgery did not affect postoperative complication and stone-free rate. This study shows that mPNL is more effective for multiple stones, but fURS is associated with potentially less complications and postoperative hospital stay. Furthermore, preoperative hemoglobin level and urine culture can be used to predict postoperative complication risk and they may be helpful in choosing treatment methods for the elderly.

Integrative microRNA-gene expression network analysis in genetic hypercalciuric stone-forming rat kidney

Background. MicroRNAs (miRNAs) influence a variety of biological functions by regulating gene expression post-transcriptionally. Aberrant miRNA expression has been associated with many human diseases. Urolithiasis is a common disease, and idiopathic hypercalciuria (IH) is an important risk factor for calcium urolithiasis. However, miRNA expression patterns and their biological functions in urolithiasis remain unknown. Methods and Results. A multi-step approach combining microarray miRNA and mRNA expression profile and bioinformatics analysis was adopted to analyze dysregulated miRNAs and genes in genetic hypercalciuric stone-forming (GHS) rat kidneys, using normal Sprague-Dawley (SD) rats as controls. We identified 2418 mRNAs and 19 miRNAs as significantly differentially expressed, over 700 gene ontology (GO) terms and 83 KEGG pathways that were significantly enriched in GHS rats. In addition, we constructed an miRNA-gene network that suggested that rno-miR-674-5p, rno-miR-672-5p, rno-miR-138-5p and rno-miR-21-3p may play important roles in the regulatory network. Furthermore, signal-net analysis suggested that NF-kappa B likely plays a crucial role in hypercalciuria urolithiasis. Conclusions. This study presents a global view of mRNA and miRNA expression in GHS rat kidneys, and suggests that miRNAs may be important in the regulation of hypercalciuria. The data provide valuable insights for future research, which should aim at validating the role of the genes featured here in the pathophysiology of hypercalciuria.

Flexible ureteroscopy for renal stone without preoperative ureteral stenting shows good prognosis

Purpose To clarify the outcome of flexible ureteroscopy (fURS) for management of renal calculi without preoperative stenting. Methods A total of 171 patients who received 176 fURS procedures for unilateral renal stones were reviewed. All procedures were divided into two groups depending on whether they received ureteral stenting preoperatively. Baseline characteristics of patients, stone burden, operation time, stone-free rates, and complications were compared between both groups. Results Successful primary access to the renal pelvis was achieved in 104 of 114 (91.2%) patients without preoperative stenting, while all procedures with preoperative stenting (n = 62) were successfully performed. A total of 156 procedures were included for further data analysis (56 procedures in stenting group and 100 in non-stenting group). No significant differences was found regardless of a preoperative stent placement in terms of stone-free rate (73.2% with stenting vs. 71.0% without, P = 0.854), operative time (70.4 ± 32.8 with stenting vs. 70.2 ± 32.1 without, P = 0.969). Conclusions fURS for management of renal stone without preoperative ureteral stenting are associated with well outcome in short term follow-up. Our study may help patients and doctors to decide if an optional stent is placed or not.

Regional versus General Anesthesia for Percutaneous Nephrolithotomy: A Meta-Analysis

Objective To compare the effectiveness and safety of regional anesthesia (RA) and general anesthesia (GA) for percutaneous nephrolithotomy (PNL). Patients and Methods PubMed, EMBASE, The Cochrane Library, and the Web of Knowledge databases were systematically searched to identify relevant studies. After literature screening and data extraction, a meta-analysis was performed using the RevMan 5.3 software. Results Eight randomized controlled trials (RCTs) and six non-randomized controlled trials (nRCTs) involving 2270 patients were included. Patients receiving RA were associated with shorter operative time (−6.22 min; 95%CI, −9.70 to −2.75; p = 0.0005), lower visual analgesic score on the first and third postoperative day (WMD, −2.62; 95%CI, −3.04 to −2.19; p < 0.00001 WMD, −0.38; 95%CI, −0.58 to −0.18; p = 0.0002), less analgesic requirements (WMD, −59.40 mg; 95%CI, −78.39 to −40.40; p<0.00001), shorter hospitalization (WMD, −0.36d; 95%CI, −0.66 to −0.05; p = 0.02), less blood transfusion (RR, 0.61; 95%CI, 0.41 to 0.93; p = 0.02), fewer modified Clavion-Dindo Grade II (RR, 0.56; 95%CI, 0.37 to 0.83; p = 0.005), Grade III or above postoperative complications (RR, 0.51; 95%CI, 0.33 to 0.77; p = 0.001), and potential benefits of less fever (RR, 0.79; 95%CI, 0.61 to 1.02; p = 0.07), nausea or vomiting (RR, 0.54; 95%CI, 0.20 to 1.46; p = 0.23), whereas more intraoperative hypotension (RR, 3.13; 95%CI, 1.76 to 5.59; p = 0.0001) when compared with patients receiving GA. When nRCTs were excluded, most of the results were stable but the significant differences were no longer detectable in blood transfusion, Grade II and more severe complications. No significant difference in the total postoperative complications and stone-free rate were found. Conclusions Current evidence suggests that both RA and GA can provide safe and effective anesthesia for PNL in carefully evaluated and selected patients. Each anesthesia technique has its own advantages but some aspects still remain unclear and need to be explored in future studies.

Association between Circulating Vitamin D Level and Urolithiasis: A Systematic Review and Meta-Analysis

Many studies compared the serum/plasma 1,25 dihydroxyvitamin D3 (1,25(OH)2D) and 25 hydroxyvitamin D3 (25(OH)D) between people with and without nephrolithiasis, and their results were conflicting. After systematically searching PubMed, Web of Science, The Cochrane Library, CNKI, and the Wanfang Database, we conducted a meta-analysis. Thirty-two observational studies involving 23,228 participants were included. Meta-analysis of these studies showed that of stone formers (SFs), calcium SFs had significantly higher concentrations of 1,25(OH)2D (weighted mean difference (WMD), 10.19 pg/mL; 95% confidence interval (CI), 4.31–16.07; p = 0.0007 and WMD, 11.28 pg/mL; 95% CI, 4.07–18.50; p = 0.002, respectively) than non-stone formers, while the levels of 25(OH)D (WMD, 0.88 ng/mL; 95% CI, −1.04–2.80; p = 0.37 and WMD, −0.63 ng/mL; 95% CI, −2.72–1.47; p = 0.56, respectively) are similar. Compared with controls and normocalciuria SFs, hypercalciuria SFs had increased circulating 1,25(OH)2D (WMD, 9.41 pg/mL; 95% CI, 0.15–18.67; p = 0.05 and WMD, 2.75 pg/mL; 95% CI, −0.20–5.69; p = 0.07, respectively) and markedly higher 25(OH)D (WMD, 5.02 ng/mL; 95% CI, 0.99–9.06; p = 0.01 and WMD, 5.02 ng/mL; 95% CI, 2.14–7.90; p = 0.0006, respectively). Normocalciuria SFs had elevated 1,25(OH)2D level (WMD, 6.85 pg/mL; 95% CI, −5.00–18.71; p = 0.26) and comparable 25(OH)D (WMD, 0.94 ng/mL; 95% CI, −3.55–5.43; p = 0.68). Sensitivity analysis generated similar results. Current evidence suggests that increased circulating 1,25(OH)2D is associated with urinary stones and a higher level of circulating 25(OH)D is significantly associated with hypercalciuria urolithiasis. Further studies are still needed to reconfirm and clarify the role of vitamin D in the pathogenesis of stones.

The Wnt11 Signaling Pathway in Potential Cellular EMT and Osteochondral Differentiation Progression in Nephrolithiasis Formation

The molecular events leading to nephrolithiasis are extremely complex. Previous studies demonstrated that calcium and transforming growth factor-β1 (TGF-β1) may participate in the pathogenesis of stone formation, but the explicit mechanism has not been defined. Using a self-created genetic hypercalciuric stone-forming (GHS) rat model, we observed that the increased level of serous/uric TGF-β1 and elevated intracellular calcium in primary renal tubular epithelial cells (PRECs) was associated with nephrolithiasis progression in vivo. In the setting of high calcium plus high TGF-β1 in vitro, PRECs showed great potential epithelial to mesenchymal transition (EMT) progression and osteochondral differentiation properties, representing the multifarious increased mesenchymal and osteochondral phenotypes (Zeb1, Snail1, Col2A1, OPN, Sox9, Runx2) and decreased epithelial phenotypes (E-cadherin, CK19) bythe detection of mRNAs and corresponding proteins. Moreover, TGF-β-dependent Wnt11 knockdown and L-type Ca2+ channel blocker could greatly reverse EMT progression and osteochondral differentiation in PRECs. TGF-β1 alone could effectively promote EMT, but it had no effect on osteochondral differentiation in NRK cells (Rat kidney epithelial cell line). Stimulation with Ca2+ alone did not accelerate differentiation of NRK. Co-incubation of extracellular Ca2+ and TGF-β1 synergistically promotes EMT and osteochondral differentiation in NRK control cells. Our data supplied a novel view that the pathogenesis of calcium stone development may be associated with synergic effects of TGF-β1 and Ca2+, which promote EMT and osteochondral differentiation via Wnt11 and the L-type calcium channel.

Rigid ureteroscopic lithotripsy versus percutaneous nephrolithotomy for large proximal ureteral stones: A meta-analysis

Object To compare the safety and efficacy of rigid ureteroscopic lithotripsy (rigid URSL) and percutaneous nephrolithotomy (PCNL) in treating large proximal ureteral stones. Methods A systematic search of PubMed, EMBASE, Cochrane Library, and Web of Science databases was performed to find out relevant studies. After literature screening according to the predetermined inclusion and exclusion criteria, data of eligible studies was extracted and then a meta-analysis was conducted via RevMan 5.3 software. Results Five randomized controlled trials (RCTs), one prospective and four retrospective cohort studies involving 837 patients were included. Patients underwent rigid URSL were associated with shorter operation time (WMD, -23.66min; 95%CI, −45.00 to -2.32; p = 0.03), shorter hospital stay (WMD, -2.76d; 95%CI, −3.51 to −2.02; p< 0.00001), lower 3rd-day (RR, 0.73; 95%CI, 0.66 to 0.82; p < 0.00001) and 1st-month (RR, 0.82; 95%CI, 0.77 to 0.87; p < 0.00001) stone-free rate, higher risk of conversion to other surgical procedures (RR, 4.28; 95%CI, 1.93 to 9.46; p = 0.0003), higher incidence of migration (RR, 28.49; 95%CI, 9.12 to 89.00; p < 0.00001) and ureteral perforation (RR, 6.06; 95%CI, 1.80 to 20.44; p = 0.004), lower risk of fever (RR, 0.64; 95%CI, 0.42 to 0.97; p = 0.04), transfusion (RR, 0.19; 95%CI, 0.04 to 0.85; p = 0.03) and hematuria (RR, 0.38; 95%CI, 0.25 to 0.57; p < 0.0001). No significant difference was observed in terms of incidence of embolization, pain and ureterostenosis. When cohort studies or studies in which flexible ureteroscopy was used as an intraoperative auxiliary procedure were excluded, we both found that most of the results kept stable. Conclusions Both PCNL and rigid URSL are safe for patients with large proximal ureteral stones while PCNL is more effective in stone clearance.

Losartan Ameliorates Calcium Oxalate-Induced Elevation of Stone-Related Proteins in Renal Tubular Cells by Inhibiting NADPH Oxidase and Oxidative Stress

Calcium oxalate (CaOx) is the most common type of urinary stone. Increase of ROS and NADPH oxidase gives rise to inflammation and injury of renal tubular cells, which promotes CaOx stone formation. Recent studies have revealed that the renin-angiotensin system might play a role in kidney crystallization and ROS production. Here, we investigated the involvement of Ang II/AT1R and losartan in CaOx stone formation. NRK-52E cells were incubated with CaOx crystals, and glyoxylic acid-induced hyperoxaluric rats were treated with losartan. Oxidative stress statuses were evaluated by detection of ROS, oxidative products (8-OHdG and MDA), and antioxidant enzymes (SOD and CAT). Expression of NADPH oxidase subunits (Nox2 and Nox4), NF-κB pathway subunits (p50 and p65), and stone-related proteins such as OPN, CD44, and MCP-1 was determined by Western blotting. The results revealed upregulation of Ang II/AT1R by CaOx treatment. CaOx-induced ROS and stone-related protein upregulation were mediated by the Ang II/AT1R signaling pathway. Losartan ameliorated renal tubular cell expression of stone-related proteins and renal crystallization by inhibiting NADPH oxidase and oxidative stress. We conclude that losartan might be a promising preventive and therapeutic candidate for hyperoxaluria nephrolithiasis.

Impact of previous open renal surgery on the outcomes of subsequent percutaneous nephrolithotomy: a meta-analysis

Objective The aim of this study was to systematically compare the perioperative outcomes of percutaneous nephrolithotomy in patients with or without previous ipsilateral open renal surgery (POS). Design Systematic searches of the PubMed, Web of Science and Cochrane Library databases were used to identify relevant studies, and, following literature screening and data extraction, a meta-analysis was performed. Results 17 retrospective cohort studies involving 4833 procedures (4784 patients) were included. No statistically significant differences were observed between patients with or without POS in terms of supracostal access; single/multiple tracts; metal dilator need; time required to access the collecting system; fluoroscopic duration; demand for analgesics; hospital stay; final stone-free rate; and risk of developing certain complications (eg, fever, haemorrhage, haemo/hydro/pneumothorax, blood transfusion, urinary tract infection and sepsis) as well as regarding the risk of total complications. Patients with POS, however, had a greater drop in haemoglobin (weighted mean difference (WMD), 1.78u2005g/L; 95% CI 1.09 to 2.47; p<0.00001) and higher risk of bleeding that required angiographic embolisation (relative risk (RR), 3.73; 95% CI 1.36 to 10.21; p=0.01). In addition, patients with POS also had a lower initial stone-free rate (RR, 0.96; 95% CI 0.92 to 0.99; p=0.007) and more secondary treatment (RR, 1.61; 95% CI 1.09 to 2.37; p=0.02). Sensitivity analysis produced comparable results except for differences in operative time and initial stone-free rate, which did, however, prove to be statistically insignificant (p=0.16 and 0.69, respectively). Conclusions Current evidence suggests that percutaneous nephrolithotomy in patients with POS is associated with a significantly greater drop in haemoglobin, higher risk of requiring angiographic embolisation and auxiliary procedures, potentially longer operative time, and lower initial stone-free rate than percutaneous nephrolithotomy in patients without POS.