Relocation of lower pole renal stones helps improve the stone-free rate during flexible ureteroscopy with a low complication rate.

OBJECTIVE: To compare the efficacy and safety of relocating the lower pole stones to a favorable pole during flexible ureteroscopy with in situ lithotripsy for the treatment of 10-20 mm lower pole stone (LPS). METHODS: This study was a prospective analysis of patient outcomes who underwent an FURS procedure for the treatment of 10-20 mm lower pole renal stones from January 2020 to November 2022. The patients were randomized into a relocation group or in situ group. The LPSs were relocated into a calyx, during lithotripsy in the relocation group was performed, whereas the in situ group underwent FURS without relocation. All the procedures were performed by the same surgeon. The patients' demographic data, stone characteristics, perioperative parameters and outcomes, stone-free rate (SFR), complications, and overall costs were assessed retrospectively. RESULTS: A total of 90 patients were enrolled and analyzed in this study (45 per group) with no significant differences between the two groups in terms of age, gender, BMI, diabetes, hypertension, stone size, number, laterality, composition, and density. The mean operation time, total energy consumption, postoperative stay, and complications were similar between the groups. Both groups had similar SFR at 1 day postoperative follow-up (p = 0.091), while the relocation group achieved significantly higher SFR 3 months later (97.8% vs 84.4%, p = 0.026). The relocation group also had a significantly higher WisQol score than the in situ group (126.98 vs 110.18, p < 0.001). CONCLUSION: A satisfactory SFR with a relatively low complication rate was achieved by the relocation technique during the FURS procedure.

The Role of the EGF Receptor in Sex Differences in Kidney Injury.

BACKGROUND: Sex differences mediating predisposition to kidney injury are well known, with evidence indicating lower CKD incidence rates and slower decline in renal function in nondiabetic CKD for premenopausal women compared with men. However, signaling pathways involved have not been elucidated to date. The EGF receptor (EGFR) is widely expressed in the kidney in glomeruli and tubules, and persistent and dysregulated EGFR activation mediates progressive renal injury. METHODS: To investigate the sex differences in response to renal injury, we examined EGFR expression in mice, in human kidney tissue, and in cultured cell lines. RESULTS: In wild type mice, renal mRNA and protein EGFR levels were comparable in males and females at postnatal day 7 but were significantly lower in age-matched adult females than in adult males. Similar gender differences in renal EGFR expression were detected in normal adult human kidneys. In Dsk5 mutant mice with a gain-of-function allele that increases basal EGFR kinase activity, males had progressive glomerulopathy, albuminuria, loss of podocytes, and tubulointerstitial fibrosis, but female Dsk5 mice had minimal kidney injury. Oophorectomy had no effect on renal EGFR levels in female Dsk5 mice, while castration protected against the kidney injury in male Dsk5 mice, in association with a reduction in EGFR expression to levels seen in females. Conversely, testosterone increased EGFR expression and renal injury in female Dsk5 mice. Testosterone directly stimulated EGFR expression in cultured kidney cells. CONCLUSIONS: These studies indicate that differential renal EGFR expression plays a role in the sex differences in susceptibility to progressive kidney injury that may be mediated at least in part by testosterone.

Novel κ-opioid receptor agonist MB-1C-OH produces potent analgesia with less depression and sedation.

AIM: To characterize the pharmacological profiles of a novel κ-opioid receptor agonist MB-1C-OH. METHODS: [(3)H]diprenorphine binding and [(35)S]GTPγS binding assays were performed to determine the agonistic properties of MB-1C-OH. Hot plate, tail flick, acetic acid-induced writhing, and formalin tests were conducted in mice to evaluate the antinociceptive actions. Forced swimming and rotarod tests of mice were used to assess the sedation and depression actions. RESULTS: In [(3)H]diprenorphine binding assay, MB-1C-OH did not bind to µ- and δ-opioid receptors at the concentration of 100 µmol/L, but showed a high affinity for κ-opioid receptor (Ki=35 nmol/L). In [(35)S]GTPγS binding assay, the compound had an Emax of 98% and an EC50 of 16.7 nmol/L for κ-opioid receptor. Subcutaneous injection of MB-1C-OH had no effects in both hot plate and tail flick tests, but produced potent antinociception in the acetic acid-induced writhing test (ED50=0.39 mg/kg), which was antagonized by pretreatment with a selective κ-opioid receptor antagonist Nor-BNI. In the formalin test, subcutaneous injection of MB-1C-OH did not affect the flinching behavior in the first phase, but significantly inhibited that in the second phase (ED50=0.87 mg/kg). In addition, the sedation or depression actions of MB-1C-OH were about 3-fold weaker than those of the classical κ agonist (-)U50,488H. CONCLUSION: MB-1C-OH is a novel κ-opioid receptor agonist that produces potent antinociception causing less sedation and depression.

Clonal Hematopoiesis of Indeterminate Potential is Associated with Acute Kidney Injury.

Age is a predominant risk factor for acute kidney injury (AKI), yet the biological mechanisms underlying this risk are largely unknown and to date no genetic mechanisms for AKI have been established. Clonal hematopoiesis of indeterminate potential (CHIP) is a recently recognized biological mechanism conferring risk of several chronic aging diseases including cardiovascular disease, pulmonary disease and liver disease. In CHIP, blood stem cells acquire mutations in myeloid cancer driver genes such as DNMT3A, TET2, ASXL1 and JAK2 and the myeloid progeny of these mutated cells contribute to end-organ damage through inflammatory dysregulation. We sought to establish whether CHIP causes acute kidney injury (AKI). To address this question, we first evaluated associations with incident AKI events in three population-based epidemiology cohorts (N = 442,153). We found that CHIP was associated with a greater risk of AKI (adjusted HR 1.26, 95% CI: 1.19-1.34, p<0.0001), which was more pronounced in patients with AKI requiring dialysis (adjusted HR 1.65, 95% CI: 1.24-2.20, p=0.001). The risk was particularly high in the subset of individuals where CHIP was driven by mutations in genes other than DNMT3A (HR: 1.49, 95% CI: 1.37-1.61, p<0.0001). We then examined the association between CHIP and recovery from AKI in the ASSESS-AKI cohort and identified that non-DNMT3A CHIP was more common among those with a non-resolving pattern of injury (HR 2.3, 95% CI: 1.14-4.64, p = 0.03). To gain mechanistic insight, we evaluated the role of Tet2-CHIP to AKI in ischemia-reperfusion injury (IRI) and unilateral ureteral obstruction (UUO) mouse models. In both models, we observed more severe AKI and greater post-AKI kidney fibrosis in Tet2-CHIP mice. Kidney macrophage infiltration was markedly increased in Tet2-CHIP mice and Tet2-CHIP mutant renal macrophages displayed greater proinflammatory responses. In summary, this work establishes CHIP as a genetic mechanism conferring risk of AKI and impaired kidney function recovery following AKI via an aberrant inflammatory response in CHIP derived renal macrophages.

Mutation of Klotho rs3752472 protect the kidney from the renal epithelial cell injury caused by CaOx crystals through the Wnt/ß-catenin signaling pathway.

Calcium oxalate (CaOx) is a major contributor to urolithiasis, one of the most common urological diseases. Our previous study has shown that Klotho rs3752472 polymorphism correlates with an increased risk of CaOx-related urolithiasis in human cohorts. This study aims to identify the effect of Klotho rs3752472 polymorphism on the renal epithelium injury caused by CaOx. A rat urolithiasis model was established and validated. Renal function was assessed, and histological examination was performed. The distribution and expression of Klotho in the rat model were detected by immunohistochemical staining and western blotting analysis. A renal epithelial cell line (HK2) was used and intervened by COM crystals with several concentrations and time points. Expression of Klotho and key mediators in Wnt/ß-catenin pathway were assessed by Western blotting analysis. Wide-type and mutated plasmids of Klotho rs3752472 were added in the cell culture, and the activation of Wnt/ß-catenin signaling was tested. Finally, Wide-type and mutated plasmids of Klotho rs3752472 were adoptively transferred to the rat model, and the expression of Klotho was verified. In the rat model, Klotho was mainly distributed in the renal tubular area, which significantly declined in the urolithiasis group. In vitro, COM crystals significantly inhibited the expression of Klotho and induced remarkable renal epithelial cell injury. The mutation of Klotho rs3752472 can notably enhance the expression of Klotho, as well as the protection from renal epithelial cell injury and the inhibition of Wnt/ß-catenin signaling pathway. After adoptively transferred to the rat urolithiasis model, similar results were observed for the mutation of Klotho rs3752472. Klotho was significantly correlated with the renal epithelial cell injury induced by CaOx crystals. Furthermore, the mutation of Klotho rs3752472 can remarkably enhance the expression of Klotho in renal tissues and cells, and subsequently protect the renal epithelial cell from the formation of CaOx crystals through the inhibition of Wnt/ß-catenin signaling pathway.

The efficacy and safety of high-dose tranexamic acid in adolescent idiopathic scoliosis: a meta-analysis.

BACKGROUND: This study aimed to evaluate the efficacy and safety of using high-dose intravenous tranexamic acid (TXA) to reduce blood loss in idiopathic scoliosis surgery. METHODS: This study was a meta-analysis, which consisted of retrospective cohort studies (RCSs) and randomized control trials (RCTs) found by searching electronic databases, namely PubMed, Web of Science, The Cochrane Central Register of Controlled Trials (CENTRAL), and the Google Scholar Database, dating from 1960 to 2019. The points of interest included total blood loss, a need for transfusion and transfusion criteria, surgery time, and the evidence of intraoperative and postoperative complications, such as seizures or thromboembolic events. The weighted mean differences (WMD) and 95% confidence interval (CI) of blood loss in the TXA intervention group compared to the control or placebo group were extracted and combined using the random effects model. RESULTS: In this meta-analysis, there was a total of three RCSs and two RCTs, which involved 334 patients. The results showed that blood loss is significantly reduced, with a weighted mean difference in the TXA group (WMD = - 525.14, P = 0.0000, CI ranged from - 839.83, - 210.44, I2 = 82%). Heterogeneity was assessed using the random effects model. CONCLUSIONS: A high dose of intravenous TXA reduced blood loss during adolescent idiopathic scoliosis surgery and did not lead to any significant thromboembolic event. Therefore, a high dose appears to be effective and safe for adolescent idiopathic scoliosis surgery. However, more high-quality research based on larger randomized controlled trials is still needed.

pH-triggered charge-reversal and redox-sensitive drug-release polymer micelles codeliver doxorubicin and triptolide for prostate tumor therapy.

AIM: To significantly promote cancer cell uptake and to achieve combination therapy and on-demand drug release, a pH-triggered charge-switchable and redox-responsive drug-release nanovehicle was developed in this study. MATERIALS AND METHODS: The nanocarrier was constructed by conjugating 3,3'-dithiodipropionic acid-modified doxorubicin (DTPA-DOX) and 2,3-dimethylmaleic anhydride (DMA) to the side amino groups of poly(ethylene glycol)-b-poly(L-lysine) (PEG-b-PLL) and by encapsulating triptolide (TRI) into the hydrophobic core. The surface charge of the obtained nanocarriers (DA-ss-DT) can change from negative to positive in response to tumor extracellular acidity pH, and the nanocarriers capably release two drugs in response to intracellular high glutathione (GSH) environment. RESULTS: Compared to the control group, the in vitro cellular uptake of DA-ss-DT by human prostate cancer PC-3 cells was significantly promoted in slightly acidic conditions, and the drug could be rapidly released in the high concentration of GSH conditions. The in vitro and in vivo antitumor experiments exhibited that the DA-ss-DT nanoparticles have a great antitumor effect in comparison to the control group. CONCLUSION: These findings demonstrated that the DA-ss-DT nanoparticles supply a useful strategy for promoting cellular uptake and synergetic anticancer therapy.

Remifentanil Requirement for Inhibiting Responses to Tracheal Intubation and Skin Incision Is Reduced in Patients With Parkinson's Disease Undergoing Deep Brain Stimulator Implantation.

BACKGROUND: Parkinson's disease (PD) is a common neurodegenerative disease affecting the quality of life in the elderly. We speculated that PD patients might have abnormal pharmacodynamics due to the degenerative neural system, and the present study was performed to investigate the pharmacodynamics of remifentanil in PD patients. MATERIALS AND METHODS: Two arms of patients were recruited, including 31 PD patients undergoing pulse generator placement after deep brain stimulator implantation and 31 pair-controlled patients undergoing intracranial surgery without PD (NPD). Patients were anesthetized with target-controlled infusion of propofol and remifentanil. The effective concentration of remifentanil to inhibit responses to intubation and skin incision in 50% and 95% patients (EC50 and EC95) was determined by the up and down method. RESULTS: Demographic data, bispectral index, and hemodynamic values were similar between the PD and the NPD groups. The average remifentanil concentration used in the PD group for tracheal intubation is significantly lower than in the NPD group (P<0.001). The EC50 for inhibiting the response to tracheal intubation were 1.86 ng/mL (95% confidential interval [CI], 1.77-1.96 ng/mL) in the PD group and 3.20 ng/mL (95% CI, 3.13-3.27 ng/mL) in the NPD group. The average remifentanil concentration used in the PD group for skin incision is significantly lower than in the NPD group (P<0.001). EC50 for inhibiting the response to skin incision were 2.17 ng/mL (95% CI, 2.09-2.25 ng/mL) in the PD group and 3.09 ng/mL (95% CI, 3.02-3.17 ng/mL) in the NPD group. CONCLUSIONS: The remifentanil concentrations required for inhibiting responses to tracheal intubation and skin incision are reduced markedly in PD patients undergoing pulse generator placement (NCT01992692).

Propofol requirement for induction of unconsciousness is reduced in patients with Parkinson's disease: a case control study.

Parkinson's disease (PD) is the second most prevalent neurodegenerative disease, but whether the neurodegenerative process influences the pharmacodynamics of propofol remains unclear. We aimed to evaluate the effect of PD on pharmacodynamics of propofol. A total of 31 PD patients undergoing surgical treatment (PD group) and 31 pair-controlled non-PD patients undergoing intracranial surgery (NPD group) were recruited to investigate the propofol requirement for unconsciousness induction. Unconsciousness was induced in all patients with target-controlled infusion of propofol. The propofol concentration at which unconsciousness was induced was compared between the two groups. EC50 and EC95 were calculated as well. Demographic data, bispectral index, and hemodynamic values were comparable between PD and NPD groups. The mean target concentration of propofol when unconsciousness was achieved was 2.32 ± 0.38 µg/mL in PD group, which was significantly lower than that in NPD group (2.90 ± 0.35 µg/mL). The EC50 was 2.05 µg/mL (95% CI: 1.85-2.19 µg/mL) in PD group, much lower than the 2.72 µg/mL (95% CI: 2.53-2.88 µg/mL) in NPD group. In conclusion, the effective propofol concentration needed for induction of unconsciousness in 50% of patients is reduced in PD patients. (This trial is registered with NCT01998204.).

Androgens augment proximal tubule transport.

The proximal tubule contains an autonomous renin-angiotensin system that regulates transport independently of circulating angiotensin II. Androgens are known to increase expression of angiotensinogen, but the effect of androgens on proximal tubule transport is unknown. In this in vivo microperfusion study, we examined the effect of androgens on proximal tubule transport. The volume reabsorptive rate in Sprague-Dawley rats given dihydrotestosterone (DHT) injections was significantly higher than in control rats given vehicle injections (4.57 +/- 0.31 vs. 3.31 +/- 0.23 nl x min(-1) x mm(-1), P < 0.01). Luminally perfusing with either enalaprilat (10(-4) M) to inhibit production of angiotensin II or losartan (10(-8) M) to block the angiotensin receptor decreased the proximal tubule volume reabsorptive rate in DHT-treated rats to a significantly greater degree than in control vehicle-injected rats. The renal expression of angiotensinogen was shown to be higher in the DHT-treated animals, using Northern blot analysis. The expression of angiotensin receptors, determined by specific binding of angiotensin II, was not different in the two groups of animals. Brush-border membrane protein abundance of the Na/H exchanger, a membrane transport protein under angiotensin II regulation, was also higher in DHT-treated rats vs. control rats. Rats that received DHT had higher blood pressures than the control rats but had no change in their glomerular filtration rate. In addition, serum angiotensin II levels were lower in DHT-treated vs. control rats. These results suggest that androgens may directly upregulate the proximal tubule renin-angiotensin system, increase the volume reabsorptive rate, and thereby increase extracellular volume and blood pressure and secondarily decrease serum angiotensin II levels.