Dysregulated lipid metabolism is associated with kidney allograft fibrosis.

BACKGROUND: Interstitial fibrosis and tubular atrophy (IF/TA), a histologic feature of kidney allograft destruction, is linked to decreased allograft survival. The role of lipid metabolism is well-acknowledged in the area of chronic kidney diseases; however, its role in kidney allograft fibrosis is still unclarified. In this study, how lipid metabolism contributes to kidney allografts fibrosis was examined. METHODS: A comprehensive bioinformatic comparison between IF/TA and normal kidney allograft in the Gene Expression Omnibus (GEO) database was conducted. Further validations through transcriptome profiling or pathological staining of human recipient biopsy samples and in rat models of kidney transplantation were performed. Additionally, the effects of enhanced lipid metabolism on changes in the fibrotic phenotype induced by TGF-ß1 were examined in HK-2 cell. RESULTS: In-depth analysis of the GEO dataset revealed a notable downregulation of lipid metabolism pathways in human kidney allografts with IF/TA. This decrease was associated with increased level of allograft rejection, inflammatory responses, and epithelial mesenchymal transition (EMT). Pathway enrichment analysis showed the downregulation in mitochondrial LC-fatty acid beta-oxidation, fatty acid beta-oxidation (FAO), and fatty acid biosynthesis. Dysregulated fatty acid metabolism was also observed in biopsy samples from human kidney transplants and in fibrotic rat kidney allografts. Notably, the areas affected by IF/TA had increased immune cell infiltration, during which increased EMT biomarkers and reduced CPT1A expression, a key FAO enzyme, were shown by immunohistochemistry. Moreover, under TGF-ß1 induction, activating CPT1A with the compound C75 effectively inhibited migration and EMT process in HK-2 cells. CONCLUSIONS: This study reveal a critical correlation between dysregulated lipid metabolism and kidney allograft fibrosis. Enhancing lipid metabolism with CPT1A agonists could be a therapeutic approach to mitigate kidney allografts fibrosis.

Enhanced super-mini-PCNL (eSMP): low renal pelvic pressure and high stone removal efficiency in a prospective randomized controlled trial.

OBJECTIVE: In the present prospective randomized controlled trial (RCT), enhanced-SMP (eSMP) and conventional Chinese mini-PCNL (mPCNL) were compared to test the low renal pelvic pressure (RPP) and high stone removal efficiency in eSMP. MATERIALS AND METHODS: Hundred patients with 2-5 cm renal calculus were enrolled. Renal pelvic pressure, operation time, lithotripsy time, removed stone volume, and complications were compared between eSMP and mPCNL statistically. RESULTS: There was no significant difference in removed stone volume between mPCNL and eSMP (8.09 ± 3.36 vs. 7.88 ± 3.07 mm3, t = 0.320, p = 0.750), lithotripsy time in mPCNL was longer than eSMP (49.6 ± 19.5 vs. 34.9 ± 14.2 min, t = 4.152, p < 0.001), thus stone removal efficiency was higher in eSMP (13.71 ± 1.18 vs. 9.82 ± 1.24 mm3/h, t = 15.499, p < 0.001). Intra-operative RPP in mPCNL was higher than eSMP (17.72 ± 3.33 vs. 12.03 ± 2.37 mmHg, t = 9.524, p < 0.001); accumulated time of backflow status (RPP > 30 mmHg) in mPCNL was longer than eSMP (23.3 ± 16.9 vs. 3.7 ± 4.2 s, t = 7.710, p < 0.001). There was no significant difference in postoperative fever rate between mPCNL and eSMP (12.77% vs. 4.34%, χ2 = 2.095, p = 0.148), nor final stone-free rate (87.2% vs. 91.3%, χ2 = 0.401, p = 0.526). Hospital stay in eSMP was shorter than mPCNL (2.54 ± 0.72 vs. 3.00 ± 0.88, t = 2.724, p = 0.008). CONCLUSION: Enhanced SMP (eSMP) was safe and effective in the management of 2-5 cm renal calculus. It can keep a lower renal pelvic pressure and a higher stone removal efficiency when compared to conventional Chinese mini-PCNL. CLINICAL TRIAL REGISTRATION: NC03206515.

A quick stone component analysis matters in postoperative fever: a propensity score matching study of 1493 retrograde intrarenal surgery.

OBJECTIVE: To evaluate the role of stone components in postoperative fever following RIRS, and to investigate the role of quick stone component analysis during RIRS procedure. PATIENTS AND METHODS: 1493 patients with RIRS were retrospectively reviewed. Propensity score matching (PSM) analysis was performed as infection stones (IS) vs. calcium-containing stones (CS) and IS vs. other compositions (OS). Independent risk factors of postoperative fever were identified by logistic analysis and nomogram was constructed. RESULTS: A total of 73 patients suffered postoperative fever (4.9%), 8 patients with sepsis (0.5%), 4 patients with septic shock (0.3%). In IS vs. CS, the incidence of positive urine test (28.4% vs. 14.7%, p = 0.001), residual stone (48.2% vs. 37.6%, p = 0.04), and postoperative fever (9.1% vs. 2.0%, p = 0.004) was significantly higher in IS. In IS vs. OS, IS had a higher incidence of positive urine test (30.9% vs. 9.3%, p < 0.001) and residual stone (47.4% vs. 18.6%, p < 0.001), while there was no significant difference in postoperative fever (10.3% vs. 4.1%, p = 0.17). Multivariate regression analysis revealed that gender (OR 1.82, CI 1.09-3.07, p < 0.001), stone components (OR 0.6, CI 0.37-0.97, p = 0.038), urine test (OR 3.72, CI 2.23-6.20, p < 0.001), and neutrophil ratio > 75% (OR 5.17, CI 3.03-9.16, p < 0.001) were independent risk factors for postoperative fever. A nomogram with moderate discriminative ability (c-index: 0.813) was constructed to predict postoperative fever. CONCLUSION: Infection stones were closely associated with postoperative fever following RIRS, as well as female gender, preoperative positive urine test, and postoperative neutrophil ratio > 75%. A quick stone component analysis would help in prevention of infectious complications. Early and longer duration of antimicrobial therapy was recommended for patients with infection stones.

Is physical therapy effective following extracorporeal shockwave lithotripsy and retrograde intrarenal surgery: a meta-analysis and systematic review.

BACKGROUND: Physical therapy, including percussion, inversion, vibration and combinations, was clinically performed to improve the stone free rate (SFR) following lithotripsy procedures. However, physical therapy is not widely accepted in clinical practice owing to lack of high level evidence support and a standard protocol. The present meta-analysis aimed to evaluate the efficacy and safety of physical therapy in improving SFR following extracorporeal shockwave lithotripsy (ESWL) and retrograde intrarenal surgery (RIRS). METHODS: Systematic review of literature from PubMed, Scopus, Cochrane library and Embase was performed in March 2019. The efficacy and safety of physical therapy after ESWL and RIRS were assessed by meta-analysis of SFR and complication rate. RESULTS: A total of 8 prospective studies with 1065 patients were enrolled. When compared to non-intervention, physical therapy provided a higher SFR (OR:3.38, 95% CI: 2.45-4.66, p < 0.0001) at all time points (week 1, week 2 and month 1), while there was no significant difference in complications such as hematuria, lumbago, dizziness and urinary tract infection (OR: 0.84; 95%CI: 0.62-1.13; p = 0.237). In subgroup analysis of different stone locations, lower calyx stone (OR: 3.51; 95%CI: 2.21-5.55; p < 0.0001), upper ureter and renal pelvic stones (OR:2.79; 95%CI:1.62-4.81; p = 0.0002) had a higher SFR after physical therapy, while there was no significant improvement in SFR in upper and middle calyx stones. In subgroup analysis of different techniques, EPVL (external physical vibration lithecbole, OR:3.47; 95%CI:2.24-5.37; p < 0.0001) and PDI (percussion, diuresis and inversion, OR:3.24; 95%CI:2.01-5.21; p < 0.0001) were both effective in improving SFR when compared to non-intervention. CONCLUSIONS: Physical therapy is effective in improving the SFR after ESWL and RIRS, especially for lower calyx stones, upper ureter and renal pelvic stones, while without significant side effects. External physical vibration lithecbole (EPVL) might provide a relative uniformed and repeatable protocol for clinical practice of physical therapy. TRIAL REGISTRATION: PROSPERO 2019 CRD42019130228 .

Retrograde intrarenal surgery in lateral position for lower pole stone: an initial experience from Single Academic Hospital.

Retrograde intrarenal surgery (RIRS) was generally challenging in management of lower pole stone (LPS) since the unfavorable anatomy. Theoretically, LPS was prone to fall out and down to renal pelvis when patients turned to lateral position, thus to facilitate lithotripsy. The aim of the present study was to report our initial experience of RIRS in lateral position for LPS. From January 2020 to February 2021, 21 patients with LPS received RIRS in lateral position. The intraoperative finding, operation time, complications and stone-free rate (SFR) were recorded and analyzed. The mean stone size was 16.7 ± 2.4 mm, multiple stones in lower pole were noted in 38.1% (8/21) cases. The mean infundibular-pelvic angle (IPA) was 35.2 ± 6.9°, IPA less than 30° was noted in six cases (28.6%, 6/21). Mean operation time was 43.5 ± 6.3 min. Obvious stone fragments dropping from the lower calyx to renal pelvis during the lithotripsy were noted in 17 cases (81.0%). Only one case (4.8%) suffered postoperative fever (Clavien I), no severe complication (> Clavien II) was noted. Hospital stay was 1.1 ± 0.3 days, the SFR in postoperative 1 month was 85.7%. LPS was prone to fall out and down to renal pelvis when patients in lateral position, thus to facilitate the lithotripsy. RIRS in lateral position was feasible for the management of LPS; however, RCT with large sample was required to certify our initial finding.

A DNA Damage Repair Gene Signature Associated With Immunotherapy Response and Clinical Prognosis in Clear Cell Renal Cell Carcinoma.

Background: Clear cell renal cell carcinoma (ccRCC) is the most common subtype in renal cell carcinoma with relatively poor clinical outcomes DNA damage repair genes (DDRGs) as potential biomarkers are rarely reported in predicting immunotherapy response and clinical prognosis for ccRCC. Methods: RNA-seq and clinical data of ccRCC cohort were collected form TCGA database. Univariate Cox regression and LASSO analysis were performed to construct a DDRG risk signature. Functional enrichment analysis was performed to explore latently enriched pathways associated with DDRG signature. Immune cell infiltration level was estimated using gene set enrichment analysis, and immune response of ccRCC was predicted by tumor immune dysfunction and exclusion (TIDE) algorithm. To predict 1-, 3-, and 5-years overall survival (OS), a nomogram was constructed based on independent prognostic factors, whose performance would be evaluated by calibration curve. Results: A total of 47 DNA damage repair related genes (DDRGs) with significant prognostic value were identified in the ccRCC cohort (n = 519). A DDRG risk signature comprising six DRRGs (MSH3, RAD54L, RAD50, EME1, UNG, and NEIL3) were constructed by the LASSO analysis. ccRCC patients were then divided into low- and high-risk groups based on the risk score. Survival analysis revealed that patients in high-risk groups exhibited significantly poorer OS and progression-free survival (PFS), as was confirmed by the testing dataset. Functional enrichment analysis indicated that differentially expressed genes (DEGs) between high- and low-risk groups were mainly associated with immune-related biological processes in ccRCC, among which the immunodeficiency pathway was significantly enriched in the high-risk group. Though the risk signature was significantly correlated with the immune cell infiltration, PD-1 and PD-L1 were less expressed in the DDRG signature, which might indicate the poor response to immunotherapy in the high-risk group. Furthermore, the Cox regression analysis indicated that the DDRG signature can be served as an independent prognostic predictor when compared to clinical characteristics. Based on the independent prognostic predictors, we constructed a nomogram with excellent predictive ability in OS prediction for ccRCC patients. Conclusion: We developed a reliable DDRG risk signature that can independently predict the OS and PFS of ccRCC, which is also promising for predicting immunotherapeutic responses in ccRCC patients.

Alkaloid Extract of Moringa oleifera Lam. Exerts Antitumor Activity in Human Non-Small-Cell Lung Cancer via Modulation of the JAK2/STAT3 Signaling Pathway.

Lung cancer is one of the most common malignant tumors diagnosed worldwide. Moringa oleifera Lam. is a valuable medicinal plant native to India and Pakistan. However, the antilung cancer activity of M. oleifera alkaloid extract (MOAE) is unknown. The present study aimed to evaluate the regulatory effect of MOAE on A549 cells by examination of the proliferation, apoptosis, cell cycle, and migration of cells and to elucidate the possible mechanism of action of MOAE. We tested five types of cancer cells and four types of lung cancer cells and found MOAE exerted the strongest growth inhibitory effect against A549 cells but had low toxicity to GES-1 cells (human gastric mucosal epithelial cells). Simultaneously, MOAE induced apoptosis and increased the expression of the apoptosis-related proteins caspase-3 and caspase-9 in A549 cells. Furthermore, MOAE induced cell cycle arrest in the S phase through a decrease in the expression of the proteins cyclin D1 and cyclin E and an increase in the expression of the protein p21. MOAE also inhibited the migratory ability of A549 cells and decreased the expression of the migration-related proteins, matrix metalloproteinase (MMP) 2 and MMP9. In addition, the phosphorylation level of JAK2 and STAT3 proteins was decreased in MOAE-treated A549 cells. Furthermore, AZD1480 (a JAK inhibitor) and MOAE inhibited the proliferation and migration of A549 cells and induced cell apoptosis, and the effects of MOAE and AZD1480 were not additive. These results indicated that MOAE inhibits the proliferation and migration of A549 cells and induces apoptosis and cell cycle arrest through a mechanism that is related to the inhibition of JAK2/STAT3 pathway activation. Thus, this extract has potential for preventing and treating lung cancer.

Isothiocyanate From Moringa oleifera Seeds Inhibits the Growth and Migration of Renal Cancer Cells by Regulating the PTP1B-dependent Src/Ras/Raf/ERK Signaling Pathway.

Moringa oleifera Lam. is a tropical and subtropical plant that has been used for centuries as both food and traditional medicine. 4-[(α-L-Rhamnosyloxy) benzyl] isothiocyanate (MIC-1) is an active substance in M. oleifera, with anti-cancer activity. However, whether MIC-1 exerts anti-renal cancer effects is unknown. Therefore, the aim of the present study was to evaluate the effects of MIC-1 on the growth and migration of renal cell carcinoma (RCC) cells and to identify the putative underlying mechanism. We found that, among 30 types of cancer cells, MIC-1 exerted the strongest growth inhibitory effects against 786-O RCC cells. In addition, MIC-1 (10 µM) significantly inhibited the growth of five RCC cell lines, including 786-O, OSRC-2, 769-P, SK-NEP-1, and ACHN cells, but was not toxic to normal renal (HK2) cells. Also, MIC-1 suppressed 786-O and 769-P cell migration and invasion abilities, and reduced the expression of matrix metalloproteinase (MMP)-2 and MMP-9. Furthermore, MIC-1 induced apoptosis and cell cycle arrest, increased Bax/Bcl-2 ratio, and decreased cell cycle-related protein expression in 786-O cells and 769-P cells. Molecular docking and small-molecule interaction analyses with PTP1B both showed that MIC-1 inhibited PTP1B activity by binding to its active site through hydrogen bonding and hydrophobic interactions. Additionally, MIC-1 could suppress the growth and migration of 786-O cells by inhibiting PTP1B-mediated activation of the Src/Ras/Raf/ERK signaling pathway. In vivo experiments further showed that MIC-1 markedly inhibited the growth of xenograft tumors in mice, and greatly increased Bax/Bcl-2 ratio in tumor tissues. In addition, MIC-1 had no effect on the PTP1B-dependent Src/Ras/Raf/ERK signaling pathway in HCT-116 cells, Hep-G2 cells, and A431 cells. Overall, our data showed that MIC-1 could be a promising, non-toxic, natural dietary supplement for the prevention and treatment of renal cancer.