EMX2 inhibits clear cell renal cell carcinoma progress via modulating Akt/FOXO3a pathway.

Empty spiracles homeobox 2 (EMX2) is initially identified as a key transcription factor that plays an essential role in the regulation of neuronal development and some brain disorders. Recently, several studies emphasized that EMX2 could as a tumor suppressor, but its role in human clear cell renal cell carcinoma (ccRCC) remains unclear. In the present study, we investigated the role and underlying mechanism of EMX2 in the regulation of ccRCC progress. Our results demonstrated that EMX2 expression was markedly decreased in ccRCC tissues and cell lines, and low EMX2 expression predicted the poor prognosis of ccRCC patients. In addition, forced expression of EMX2 significantly inhibited the cell growth, migration, and invasion in vitro, as well as ccRCC tumor growth in nude mice, via, at least in part, regulating Akt/FOXO3a pathway. In detail, EMX2 could attenuate the phosphorylation levels of Akt and FOXO3a, and increase FOXO3a expression without affecting total Akt expression in vivo and in vitro. Meanwhile, shRNA-mediated knockdown of FOXO3a expression could obviously attenuate the effects of EMX2 on cell growth, migration, invasion, and tumor growth. Furthermore, EMX2 could significantly attenuate the interaction between Akt and FOXO3a. Taken together, our results demonstrated that EMX2 could inhibit ccRCC progress through, at least in part, modulating Akt/FOXO3a signaling pathway, thus representing a novel role and underlying mechanism of EMX2 in the regulation of ccRCC progress.

Fc Fragment of IgE Receptor Ig (FCER1G) acts as a key gene involved in cancer immune infiltration and tumour microenvironment.

Although recent studies have revealed the relationship between Fc Fragment of IgE Receptor Ig (FCER1G) and human tumours, there is still a lack of a more comprehensive pan-cancer analysis of FCER1G as an immune-related gene. In this study, we investigated the expression pattern and prognostic value of FCER1G based on multiple databases. Subsequently, we further explored the role of FCER1G in tumour proliferation and metastasis, as well as its genomic alterations and DNA methylation levels, we next assessed the association between FCER1G and the immune infiltrating cells of the tumour microenvironment in different cancers and verified it by immunohistochemical staining. The correlation between FCER1G and immune checkpoint genes expression and its predictive power in the immune checkpoint blockade treatment cohorts were used to evaluate the importance of FCER1G in immunotherapy. Enrichment analysis of FCER1G-associated partners was also performed. In addition, we substantiated the expression of FCER1G in specific cell types of different tumours using single-cell RNA sequencing data from different databases. Our research results showed that FCER1G is up-regulated in most tumour. Positive associations were found between FCER1G expression and tumour prognosis, proliferation, and metastasis, we also found that FCER1G is closely related to the tumour microenvironment and tumour immunity. Moreover, FCER1G-associated partners were enriched in pathways associated with neutrophils activation. Finally, we confirmed that FCER1G was mainly expressed in monocyte/macrophages of the tumour microenvironment. In conclusion, our findings provided a comprehensive understanding of FCER1G in oncogenesis and tumour immunology among various tumours and demonstrated its potential value in prognosis prediction and tumour immunotherapy.

Extracellular vesicle-circEHD2 promotes the progression of renal cell carcinoma by activating cancer-associated fibroblasts.

BACKGROUND: The encapsulation of circular RNAs (circRNAs) into extracellular vesicles (EVs) enables their involvement in intercellular communication and exerts an influence on the malignant advancement of various tumors. However, the regulatory role of EVs-circRNA in renal cell carcinoma (RCC) remains elusive. METHODS: The in vitro and in vivo functional experiments were implemented to measure the effects of circEHD2 on the phenotype of RCC. The functional role of EVs-circEHD2 on the activation of fibroblasts was assessed by collagen contraction assay, western blotting, and enzyme-linked immunosorbent assay (ELISA). The mechanism was investigated by RNA pull-down assay, RNA immunoprecipitation, chromatin isolation by RNA purification, luciferase assay, and co-immunoprecipitation assay. RESULTS: We demonstrated that circEHD2 was upregulated in RCC tissues and serum EVs of RCC patients with metastasis. Silencing circEHD2 inhibited tumor growth in vitro and in vivo. Mechanistic studies indicated that FUS RNA -binding protein (FUS) accelerated the cyclization of circEHD2, then circEHD2 interacts with tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein eta (YWHAH), which acts as a bridge to recruit circEHD2 and Yes1-associated transcriptional regulator (YAP) to the promoter of SRY-box transcription factor 9 (SOX9); this results in the sustained activation of SOX9. Heterogeneous nuclear ribonucleoprotein A2/B1 (hnRNPA2B1) regulates the package of circEHD2 into EVs, then EVs-circEHD2 transmits to fibroblasts, converting fibroblasts to cancer-associated fibroblasts (CAFs). Activated CAFs promote the metastasis of RCC by secreting pro-inflammatory cytokines such as IL-6. Furthermore, antisense oligonucleotides (ASOs) targeting circEHD2 exhibited a strong inhibition of tumor growth in vivo. CONCLUSIONS: The circEHD2/YWHAH/YAP/SOX9 signaling pathway accelerates the growth of RCC. EVs-circEHD2 facilitates the metastasis of RCC by converting fibroblasts to CAFs. Our results suggest that EVs-circEHD2 may be a useful biomarker and therapeutic target for RCC.

PET Imaging of Bromodomain and Extra-Terminal Domain Inhibitors for the Noninvasive Assessment of Metabolic Changes in the Liver and Brain of Early-Stage Alcoholic Liver Disease.

Alcoholic liver disease (ALD) has a significant impact on human health and is one of the leading causes of liver disease mortality. The early and exact diagnosis of ALD is very important since the early stage of disease progression can be reversible. Although ALD can be evaluated by ultrasound, CT, or MRI, there is still no imaging technique sufficient in the diagnosis of early-stage ALD. Of the current studies, epigenetic modulation plays a significant role in the development and progression of ALD. In this work, we evaluate whether BRDs play a vital role in the early-stage ALD using our new PET imaging probe of BET proteins, [11C]CW22. PET/CT imaging of [11C]CW22 and [18F]FDG was used to identify early-stage lesions of livers and brains in the mice model. We found that the average uptake values of livers and brains in early-stage ALD were significantly increased for [11C]CW22 PET/CT imaging but only slightly changed in [18F]FDG PET/CT imaging. Consistently, we also found that BRD 3, 4 protein expression levels were significantly higher in the liver and brain tissues of early-stage ALD. Furthermore, through Pmod software, we found that [11C]CW22 PET/CT uptakes in the brain stem, cerebellum, and midbrain were significantly up-regulated in the early-stage ALD. In conclusion, BRDs were important mediators of damage in early-stage ALD. [11C]CW22 PET/CT imaging can detect the early-phase alcohol-induced damage of livers and brains, which will likely lead to human trials in the future.

Cerium oxide-based nanozyme suppresses kidney calcium oxalate crystal depositions via reversing hyperoxaluria-induced oxidative stress damage.

Oxidative stress damage to renal epithelial cells is the main pathological factor of calcium oxalate calculi formation. The development of medicine that could alleviate oxidative damage has become the key to the prevention and treatment of urolithiasis. Herein, porous nanorods CeO2 nanoparticles (CNPs) were selected from CeO2 with different morphologies as an antioxidant reagent to suppress kidney calcium oxalate crystal depositions with excellent oxidation resistance due to its larger specific surface area. The reversible transformation from Ce3+ to Ce4+ could catalyze the decomposition of excess free radicals and act as a biological antioxidant enzyme basing on its strong ability to scavenge free radicals. The protection capability of CNPS against oxalate-induced damage and the effect of CNPS on calcium oxalate crystallization were studied. CNPS could effectively reduce reactive oxygen species production, restore mitochondrial membrane potential polarity, recover cell cycle progression, reduce cell death, and inhibit the formation of calcium oxalate crystals on the cell surface in vitro. The results of high-throughput sequencing of mRNA showed that CNPs could protect renal epithelial cells from oxidative stress damage caused by high oxalate by suppressing the expression gene of cell surface adhesion proteins. In addition, CNPS can significantly reduce the pathological damage of renal tubules and inhibit the deposition of calcium oxalate crystals in rat kidneys while having no significant side effect on other organs and physiological indicators in vivo. Our results provide a new strategy for CNPS as a potential for clinical prevention of crystalline kidney injury and crystal deposition.

ATR Contributes More Than ATM in Intra-S-Phase Checkpoint Activation after IR, and DNA-PKcs Facilitates Recovery: Evidence for Modular Integration of ATM/ATR/DNA-PKcs Functions.

The intra-S-phase checkpoint was among the first reported cell cycle checkpoints in mammalian cells. It transiently slows down the rate of DNA replication after DNA damage to facilitate repair and thus prevents genomic instability. The ionizing radiation (IR)-induced intra-S-phase checkpoint in mammalian cells is thought to be mainly dependent upon the kinase activity of ATM. Defects in the intra-S-phase checkpoint result in radio-resistant DNA synthesis (RDS), which promotes genomic instability. ATM belongs to the PI3K kinase family along with ATR and DNA-PKcs. ATR has been shown to be the key kinase for intra-S-phase checkpoint signaling in yeast and has also been implicated in this checkpoint in higher eukaryotes. Recently, contributions of DNA-PKcs to IR-induced G2-checkpoint could also be established. Whether and how ATR and DNA-PKcs are involved in the IR-induced intra-S-phase checkpoint in mammalian cells is incompletely characterized. Here, we investigated the contributions of ATM, ATR, and DNA-PKcs to intra-S-phase checkpoint activation after exposure to IR of human and hamster cells. The results suggest that the activities of both ATM and ATR are essential for efficient intra-S-phase checkpoint activation. Indeed, in a wild-type genetic background, ATR inhibition generates stronger checkpoint defects than ATM inhibition. Similar to G2 checkpoint, DNA-PKcs contributes to the recovery from the intra-S-phase checkpoint. DNA-PKcs-deficient cells show persistent, mainly ATR-dependent intra-S-phase checkpoints. A correlation between the degree of DSB end resection and the strength of the intra-S-phase checkpoint is observed, which again compares well to the G2 checkpoint response. We conclude that the organization of the intra-S-phase checkpoint has a similar mechanistic organization to that of the G2 checkpoint in cells irradiated in the G2 phase.

Glycine suppresses kidney calcium oxalate crystal depositions via regulating urinary excretions of oxalate and citrate.

An abnormal urine composition is a key reason for kidney stone formation, but little is known about the roles of small metabolites in the urine during kidney stone formation. Here, we found urine glycine in patients with kidney calcium oxalate (CaOx) stone was significantly lower than that in healthy people via 1 H NMR spectra detection, and investigated the role and underlying mechanism of glycine in the regulation of CaOx stone formation. Our results showed that glycine could significantly attenuate ethylene glycol-induced CaOx crystal depositions in rat kidney via decreasing urine oxalate and increasing urine citrate. Mechanism studies revealed that glycine could decrease urine oxalate through downregulating Slc26a6 expression, whereas increase urine citrate via inhibiting Nadc1 expression. Moreover, glycine decreased the protein expression of both Slc26a6 and Nadc1 via increasing the expression of miRNA-411-3p, which directly bound to the 3'-untranslated regions of Slc26a6 and Nadc1 messenger RNAs, in vitro and in vivo. Together, our results revealed a novel role of glycine in the regulation of kidney CaOx crystal formation and provided a potential target for the treatment of kidney CaOx stone.

Association between hypertension and 24-h urine composition in adults without urolithiasis in China.

PURPOSE: To explore the association between hypertension and 24-h urine composition in adults without urolithiasis in China. MATERIALS AND METHODS: Blood test and 24-h urine analysis were performed on 958 non-stone formers in six cities to select eligible participants. Eligible participants were divided into hypertension group and non-hypertension group according to WHO guidelines. The 24-h urine compositions between two groups were compared using univariate and multivariate logistic regressions. RESULTS: A total of 584 adults without urolithiasis were included in this analysis. Compared with non-hypertension group, hypertension group had significantly older age, higher BMI, higher prevalence of diabetes mellitus and higher levels of total cholesterol and LDL, but lower eCCr value, lower levels of serum creatinine and serum sodium (all P value < 0.05). In univariable comparisons, hypertension patients had significantly higher level of urine potassium (mean difference [MD] = - 3.89 mmol, 95% confidence interval [CI] - 7.37 to - 0.42, P = 0.014) but lower levels of urine creatinine (MD = 0.80 mmol, 95% CI 0.21-1.39, P = 0.004) and pH (MD = 0.12, 95% CI - 0.01 to 0.25, P = 0.033) than non-hypertension adults. However, no significant difference was found in all 24-h urinary components between two groups (all P value > 0.05) in multivariate Logistic regression analyses. CONCLUSIONS: Our study demonstrated that hypertension did not independently influence the 24-h urine composition in adults without urolithiasis in China; however, we cannot make such an arbitrary conclusion that hypertension was not a risk factor for urolithiasis.

Phosphofructokinase-M inhibits cell growth via modulating the FOXO3 pathway in renal cell carcinoma cells.

Phosphofructokinase-M (PFKM) is a key enzyme in glycolysis. The expression and activity of PFKM is closely related to the occurrence and development of malignant tumors, but its role in the regulation of renal cell carcinoma (RCC) is still unknown. We found that the expression of PFKM was lower in RCC tumor tissue than in adjacent normal tissues, and that low expression of PFKM was related to the poor overall survival of RCC patients. In addition, our results showed that FOXO3 mediated PFKM inhibited the growth, migration and invasion of RCC cells, suggesting that PFKM is a protective factor for RCC.

Identifying the novel key genes in renal cell carcinoma by bioinformatics analysis and cell experiments.

BACKGROUND: Although major driver gene have been identified, the complex molecular heterogeneity of renal cell cancer (RCC) remains unclear. Therefore, more relevant genes need to be identified to explain the pathogenesis of renal cancer. METHODS: Microarray datasets GSE781, GSE6344, GSE53000 and GSE68417 were downloaded from Gene Expression Omnibus (GEO) database. The differentially expressed genes (DEGs) were identified by employing GEO2R tool, and function enrichment analyses were performed by using DAVID. The protein-protein interaction network (PPI) was constructed and the module analysis was performed using STRING and Cytoscape. Survival analysis was performed using GEPIA. Differential expression was verified in Oncomine. Cell experiments (cell viability assays, transwell migration and invasion assays, wound healing assay, flow cytometry) were utilized to verify the roles of the hub genes on the proliferation of kidney cancer cells (A498 and OSRC-2 cell lines). RESULTS: A total of 215 DEGs were identified from four datasets. Six hub gene (SUCLG1, PCK2, GLDC, SLC12A1, ATP1A1, PDHA1) were identified and the overall survival time of patients with RCC were significantly shorter. The expression levels of these six genes were significantly decreased in six RCC cell lines(A498, OSRC-2, 786- O, Caki-1, ACHN, 769-P) compared to 293t cell line. The expression level of both mRNA and protein of these genes were downregulated in RCC samples compared to those in paracancerous normal tissues. Cell viability assays showed that overexpressions of SUCLG1, PCK2, GLDC significantly decreased proliferation of RCC. Transwell migration, invasion, wound healing assay showed overexpression of three genes(SUCLG1, PCK2, GLDC) significantly inhibited the migration, invasion of RCC. Flow cytometry analysis showed that overexpression of three genes(SUCLG1, PCK2, GLDC) induced G1/S/G2 phase arrest of RCC cells. CONCLUSION: Based on our current findings, it is concluded that SUCLG1, PCK2, GLDC may serve as a potential prognostic marker of RCC.

Energy output modalities of shockwave lithotripsy in the treatment of urinary stones: escalating or fixed voltage? A systematic review and meta-analysis.

PURPOSE: To compare the effectiveness and safety of escalating and fixed energy output modalities of shockwave lithotripsy (SWL) in the treatment of urinary stones. METHODS: A systematic literature search using PubMed, Embase, Cochrane Library and Web of Science was performed to obtain relevant studies up to December 2018. Summarized mean differences (MDs) and risk differences (RDs) with 95% confidence intervals (CIs) were used for comparing continuous and dichotomous variables, respectively. RESULTS: Six RCTs including 775 patients were identified. In the overall pooled outcomes, no significant difference was detected between escalating and fixed voltage group regarding initial and final success rate (SR) and stone-free status (SFS), auxiliary procedure and complication (hematoma, febrile episode, and pain) rate. However, when shockwave frequency ≥ 90 shocks/min, total shocks per session ≤ 3000, or 1-3 SWL sessions were performed, escalating group was associated with significantly higher SR1 (defined as SFS + fragments ≤ 4 mm); in addition, escalating group brought significantly less hematoma when total shocks per session ≤ 3000. CONCLUSIONS: Escalating voltage SWL offered comparable safety and effectiveness to that of fixed voltage SWL. However, escalating voltage SWL could be recommended in following conditions: (1) shockwave frequency ≥ 90 shocks/min, total shocks per session ≤ 3000, or 1-3 SWL sessions, for better stone removal; (2) total shocks per session ≤ 3000, for less hematoma formation.

Percutaneous nephrolithotomy versus flexible ureteroscopic lithotripsy in the treatment of upper urinary tract stones: a meta-analysis comparing clinical efficacy and safety.

BACKGROUND: Upper urinary tract stones is the most common diseases in urology. Percutaneous nephrolithotomy (PCNL) and ureteroscopic lithotripsy (fURL) are common treatment, but both their efficacy and safety are controversial. Thus we aim to evaluate the efficacy and safety of PCNL and fURL in the treatment of upper urinary tract stones, providing a reference for clinical work. METHODS: PubMed, Web of Science, Embase and CNKI were searched through Apr. 1, 2019 to identify eligible studies. Data were analyzed by using RevMan 5.3 and Stata 12.0 software. Pooled relative risks (RRs) or weighted mean difference (WMD) with 95% confidence intervals (CIs) were calculated using fixed or random effects methods. Publication bias and sensitivity analysis were performed. RESULTS: Four randomized controlled trials (RCTs), fifteen cohort studies involving 1822 patients were included. Stone-free rate of PCNL was significantly high than that of fURL (RR: 1.07; 95% CI: 1.03, 1.12; P = 0.0004). The decline of hemoglobin in PCNL was significantly high than that of fURL (WMD: 1.07; 95% CI: 0.54, 1.61; P < 0.0001). The number of blood transfusion was significantly greater in the PCNL compared to the fURL (RR: 5.04; 95% CI: 1.78, 14.24; P = 0.002). The incidence of postoperative bleeding or hematuria showed greater significantly difference in the PCNL compared to the fURL (RR: 2.72; 95% CI: 1.55, 4.75; P = 0.0005). Operation time, fever, infection, perforation, requiring drug analgesia was not significantly different between two surgical procedures. CONCLUSIONS: In the treatment of upper urinary tract stones, the stones clearance rate of PCNL is higher than fURL, and the safety of fURL is higher than PCNL.

Peroxisome proliferator-activated receptor γ modulates renal crystal retention associated with high oxalate concentration by regulating tubular epithelial cellular transdifferentiation.

The differentiated phenotype of renal tubular epithelial cell exerts significant effect on crystal adherence. Peroxisome proliferator-activated receptor γ (PPARγ) has been shown to be critical for the regulation of cell transdifferentiation in many physiological and pathological conditions; however, little is known about its role in kidney stone formation. In the current study, we found that temporarily high oxalate concentration significantly decreased PPARγ expression, induced Madin Darby Canine Kidney cell dedifferentiation, and prompted subsequent calcium oxalate (CaOx) crystal adhesion in vitro. Furthermore, cell redifferentiation after the removal of the high oxalate concentration, along with a decreasing affinity to crystals, was an endogenic PPARγ-dependent process. In addition, the PPARγ antagonist GW9662, which can depress total-PPARγ expression and activity, enhanced cell dedifferentiation induced by high oxalate concentration and inhibited cell redifferentiation after removal of the high oxalate concentration. These effects were partially reversed by the PPARγ agonist 15d-PGJ2. Similar results were observed in animals that suffered from temporary hyperoxaluria followed by a recovery period. The active crystal-clearing process occurs through the transphenotypical morphology of renal tubular epithelial cells, reflecting cell transdifferentiation during the recovery period. However, GW9662 delayed cell redifferentiation and increased the secondary temporary crystalluria-induced crystal retention. This detrimental effect was partially reversed by 15d-PGJ2. Taken together, our results revealed that endogenic PPARγ activity plays a vital regulatory role in crystal clearance, subsequent crystal adherence, and CaOx stone formation via manipulating the transdifferentiation of renal tubular epithelial cells.

Allicin attenuates calcium oxalate crystal deposition in the rat kidney by regulating gap junction function.

Renal calculus is a global common urological disease that is closely related to crystal adhesion and renal tubular epithelial cell impairment. Gap junctions (GJs) and their components (connexins and Cxs) are involved in various pathophysiology processes, but their roles in renal calculi progression are not well defined. Our previous RNA microarray analysis suggests that GJs are one of the key predicted pathways involved in the renal calcium oxalate (CaOx) crystal rat model. In the current study, we found that the Cx43 and Cx32 expression and the GJ function decreased significantly after stimulation with CaOx or sodium oxalate (NaOx) in NRK-52E, MDCK, and HK-2 cells, and Cx43 expression also decreased in renal tissues in renal CaOx crystal model rats. Inhibition of Cx43 in NRK-52E cells by small interference RNA significantly increased the CD44 and androgen receptor expression, and the adhesion between CaOx crystals and cells, which were consistent with the function of GJ inhibitors. On the other hand, after GJ function and Cx43 expression were increased by allicin, diallyl disulfide, or diallyl trisulfide, the impairment of NRK-52E cells by NaOx or other GJ inhibitors and the adhesion between CaOx crystals and renal cells decreased significantly. Furthermore, allicin also increased Cx43 expression and inhibited crystal deposition in rat kidneys. Taken together, our results provide a basis that GJs and Cx43 may participate in renal CaOx stone progression and that allicin, together with its analogues, could be potential drugs for renal calculus precaution.

SPTLC1 inhibits cell growth via modulating Akt/FOXO1 pathway in renal cell carcinoma cells.

Serine palmitoyltransferase long chain-1 (SPTLC1), which is the rate-limiting enzyme for sphingolipid biosynthesis, has been indicated to be essential for carcinoma cell survival and proliferation in recent, but its role in the regulation of renal cell carcinoma (RCC) remains unknown. In the present study, we found that SPTLC1 expression was significantly decreased in RCC tissues compared to non-tumor tissues, and low SPTLC1 expression was associated with poor overall survival of RCC patients. In addition, our results revealed that forced expression of SPTLC1 could significantly inhibit cell growth in vitro and in vivo via, at least in part, modulating Akt/FOXO1 signaling pathway, thus representing a novel role of SPTLC1 in the regulation of tumor growth in RCC for the first time.

Early and rapid prediction of postoperative infections following percutaneous nephrolithotomy in patients with complex kidney stones.

OBJECTIVES: To obtain more accurate and rapid predictors of postoperative infections following percutaneous nephrolithotomy (PCNL) in patients with complex kidney stones, and provide evidence for early prevention and treatment of postoperative infections. PATIENTS AND METHODS: A total of 802 patients with complex kidney stones who underwent PCNL, from September 2016 to September 2017, were recruited. Urine tests, urine cultures (UCs) and stone cultures (SCs) were performed, and the perioperative data were prospectively recorded. RESULTS: In all, 19 (2.4%) patients developed postoperative urosepsis. A multivariate logistic regression analysis revealed that an operating time of ≥100 min, urine test results with both positive urine white blood cells (WBC+) and positive urine nitrite (WBC+NIT+), positive UCs (UC+), and positive SCs (SC+) were independent risk factors of urosepsis. The incidence of postoperative urosepsis was higher in patients with WBC+NIT+ (10%) or patients with both UC+ and SC+ (UC+SC+; 8.3%) than in patients with negative urine test results or negative cultures (P < 0.01). Preoperative WBC+NIT+ was predictive of UC+SC+, with an accuracy of >90%. The main pathogens found in kidney stones were Escherichia coli (44%), Proteus mirabilis (14%) and Staphylococcus (7.4%); whilst the main pathogens found in urine were E. coli (54%), Enterococcus (9.4%) and P. mirabilis (7.6%). The incidence of E. coli was more frequent in the group with urosepsis than in the group without urosepsis (P < 0.05). CONCLUSIONS: WBC+NIT+ in preoperative urine tests could be considered as an early and rapid predictor of UC+SC+ and postoperative urosepsis. Urosepsis following PCNL was strongly associated with E. coli infections in patients with complex kidney stones.

Systematic review and cumulative analysis of the managements for proximal impacted ureteral stones.

PURPOSE: To compare the efficacy and safety of different treatment options for the management of proximal impacted ureteral stones (PIUS). METHODS: A systematic literature search using Pubmed, Medline, Embase and Cochrane Library was conducted to obtain studies concerning different managements for PIUS up to Jan 2018. Summary odds ratios (ORs), standard mean differences (SMDs) or weighted mean differences with their 95% confidence intervals (CIs) were calculated to compare the efficacy and safety of all included treatment methods, registered in PROSPERO under number CRD42018092745. RESULTS: A total of 15 comparative studies with 1780 patients were included. Meta-analyses of final stone-free rate (SFR) favored percutaneous nephrolithotomy (PCNL) over ureteroscopic lithotripsy (URL) (OR 10.35; 95% CI 5.26-20.35; P < 0.00001), laparoscopic ureterolithotomy over URL (OR 0.11; 95% CI 0.05-0.25; P < 0.00001) and URL over extracorporeal shockwave lithotripsy (OR 0.47; 95% CI 0.28-0.77; P = 0.003). As to complications, PCNL had a significantly higher blood transfusion rate (OR 7.47; 95% CI 1.3-42.85; P = 0.02) and a lower ureteral injury rate (OR 0.15; 95% CI 0.04-0.52; P = 0.003) compared with URL. It also shared a significantly lower stone-retropulsion rate (OR 0.03; 95% CI 0.01-0.15; P < 0.0001) and higher treatment costs (SMD = 2.71; 95% CI 0.71-4.70; P = 0.008) than URL. CONCLUSIONS: Our meta-analysis suggested that PCNL might be the best option for PIUS owing to its higher successful rate. Complications such as hemorrhage could be decreased by the application on mini-PCNL.