Inhibition of PCSK9 potentiates immune checkpoint therapy for cancer.

Despite its success in achieving the long-term survival of 10-30% of treated individuals, immune therapy is still ineffective for most patients with cancer1,2. Many efforts are therefore underway to identify new approaches that enhance such immune 'checkpoint' therapy3-5 (so called because its aim is to block proteins that inhibit checkpoint signalling pathways in T cells, thereby freeing those immune cells to target cancer cells). Here we show that inhibiting PCSK9-a key protein in the regulation of cholesterol metabolism6-8-can boost the response of tumours to immune checkpoint therapy, through a mechanism that is independent of PCSK9's cholesterol-regulating functions. Deleting the PCSK9 gene in mouse cancer cells substantially attenuates or prevents their growth in mice in a manner that depends on cytotoxic T cells. It also enhances the efficacy of immune therapy that is targeted at the checkpoint protein PD1. Furthermore, clinically approved PCSK9-neutralizing antibodies synergize with anti-PD1 therapy in suppressing tumour growth in mouse models of cancer. Inhibiting PCSK9-either through genetic deletion or using PCSK9 antibodies-increases the expression of major histocompatibility protein class I (MHC I) proteins on the tumour cell surface, promoting robust intratumoral infiltration of cytotoxic T cells. Mechanistically, we find that PCSK9 can disrupt the recycling of MHC I to the cell surface by associating with it physically and promoting its relocation and degradation in the lysosome. Together, these results suggest that inhibiting PCSK9 is a promising way to enhance immune checkpoint therapy for cancer.

Hyperactivation of p53 contributes to mitotic catastrophe in podocytes through regulation of the Wee1/CDK1/cyclin B1 axis.

Podocyte loss in glomeruli is a fundamental event in the pathogenesis of chronic kidney diseases. Currently, mitotic catastrophe (MC) has emerged as the main cause of podocyte loss. However, the regulation of MC in podocytes has yet to be elucidated. The current work aimed to study the role and mechanism of p53 in regulating the MC of podocytes using adriamycin (ADR)-induced nephropathy. In vitro podocyte stimulation with ADR triggered the occurrence of MC, which was accompanied by hyperactivation of p53 and cyclin-dependent kinase (CDK1)/cyclin B1. The inhibition of p53 reversed ADR-evoked MC in podocytes and protected against podocyte injury and loss. Further investigation showed that p53 mediated the activation of CDK1/cyclin B1 by regulating the expression of Wee1. Restraining Wee1 abolished the regulatory effect of p53 inhibition on CDK1/cyclin B1 and rebooted MC in ADR-stimulated podocytes via p53 inhibition. In a mouse model of ADR nephropathy, the inhibition of p53 ameliorated proteinuria and podocyte injury. Moreover, the inhibition of p53 blocked the progression of MC in podocytes in ADR nephropathy mice through the regulation of the Wee1/CDK1/cyclin B1 axis. Our findings confirm that p53 contributes to MC in podocytes through regulation of the Wee1/CDK1/Cyclin B1 axis, which may represent a novel mechanism underlying podocyte injury and loss during the progression of chronic kidney disorder.

Bone marrow mesenchymal stem cell-derived exosomal miR-30e-5p ameliorates high-glucose induced renal proximal tubular cell pyroptosis by inhibiting ELAVL1.

BACKGROUND: The rapid increase in the prevalence of diabetes has resulted in more cases of diabetic kidney disease (DKD). Treatment with bone marrow mesenchymal stem cells (BMSCs) may represent an alternative strategy to manage DKD. METHODS: HK-2 cells were treated with 30 mM high glucose (HG). Bone marrow MSC-derived exosomes (BMSC-exos) were isolated and internalized into HK-2 cells. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide (MTT) and lactate dehydrogenase (LDH) assays were used to measure viability and cytotoxicity. The secretion of IL-1ß and IL-18 was measured by ELISA. Pyroptosis was assessed by flow cytometry. Quantitative RT-PCR was used to measure the levels of miR-30e-5p, ELAV like RNA binding protein 1 (ELAVL1), IL-1ß, and IL-18. The expression of ELAVL1 and pyroptosis-associated cytokine proteins was determined by western blot analysis. A dual-luciferase reporter gene assay was conducted to confirm the relationship between miR-30e-5p and ELAVL1. RESULTS: BMSC-exos decreased LDH, IL-1ß, and IL-18 secretion and inhibited the expression of the pyroptosis-related factors (IL-1ß, caspase-1, GSDMD-N, and NLRP3) in HG-induced HK-2 cells. Moreover, miR-30e-5p depletion derived from BMSC-exos promoted HK-2 cell pyroptosis. Besides, miR-30e-5p over-expression or ELVAL1 knockdown could directly inhibit pyroptosis. ELAVL1 was a target of miR-30e-5p and knocking down ELAVL1 reversed the effect of miR-30e-5p inhibition in BMSC-exos-treated HK-2 cells. CONCLUSIONS: BMSC-derived exosomal miR-30e-5p inhibits caspase-1-mediated pyroptosis by targeting ELAVL1 in HG-induced HK-2 cells, which might provide a new strategy for treating DKD.

Evaluation of ultrastructural alterations of glomerular basement membrane and podocytes in glomeruli by low-vacuum scanning electron microscopy.

BACKGROUND: Low-vacuum scanning electron microscopy (LV-SEM) is applied to diagnostic renal pathology. METHODS: To demonstrate the usefulness of LV-SEM and to clarify the optimal conditions of pathology samples, we investigated the alterations of glomerular basement membrane (GBM) and podocytes in control and experimental active Heymann nephritis (AHN) rats by LV-SEM. RESULTS: On week 15 following induction of AHN, spike formation on GBM with diffuse deposition of IgG and C3 developed. Using LV-SEM, diffuse crater-like protrusions were clearly noted three-dimensionally (3D) on surface of GBM in the same specimens of light microscopy (LM) and immunofluorescence (IF) studies only after removal coverslips or further adding periodic acid-silver methenamine (PAM) staining. These 3D ultrastructural findings of GBM surface could be detected in PAM-stained specimens by LV-SEM, although true GBM surface findings could not be obtained in acellular glomeruli, because some subepithelial deposits remained on surface of GBM. Adequate thickness was 1.5-5 µm for 10% formalin-fixed paraffin-embedded (FFPE) and 5-10 µm for the unfixed frozen sections. The foot processes and their effacement of podocytes could be observed by LV-SEM using 10%FFPE specimens with platinum blue (Pt-blue) staining or double staining of PAM and Pt-blue. These findings were obtained more large areas in 2.5% glutaraldehyde-fixed paraffin-embedded (2.5%GFPE) specimens. CONCLUSION: Our findings suggest that LV-SEM is a useful assessment tool for evaluating the alterations of GBM and podocytes in renal pathology using routine LM and IF specimens, as well as 2.5%GFPE specimens.

Serum albumin at 1 year after peritoneal dialysis predicts long-term outcomes on continuous ambulatory peritoneal dialysis.

BACKGROUND: Hypoalbuminemia at baseline is a powerful predictor of long-term outcomes in peritoneal dialysis patients. However, the levels of serum albumin are dynamically changed during PD. The present study investigated whether the improvement of hypoalbuminemia during PD can affect the patients' outcomes. METHODS: 436 consecutive incidents continuous ambulatory peritoneal dialysis patients were involved in this study. Demographic, hematologic, biochemical, and dialysis-related data at baseline as well as 1 year after PD were collected. All patients were followed for at least 1 year for mortality. RESULTS: Among the 436 patients, the mean age was 48.44 ± 14.98 years, with 58.26% males and 18.12% prevalence of diabetes. The mean follow-up time was 48.25 ± 24.05 months. During the follow-up period, a total of 68 patients died. Serum albumin was 34.35 ± 5.65 g/L at baseline, which increased to 37.39 ± 5.05 g/L at 1 year after PD. Multivariate linear regression analysis showed that sex, age, BMI, diabetic nephropathy, as well as albumin at baseline were independently associated with albumin at 1 year. Every 1 year of age rise would result in a 3.9% increase in the risk of mortality (HR = 1.039, 95%CI 1.016-1.061, p = 0.001). Every 1 g/L increase in albumin at 1 year after PD confers an 8.7% decrease in the risk of mortality (HR = 0.913, 95%CI 0.856-0.973, p = 0.005). CONCLUSION: The level of serum albumin was increased in the first year of PD. Serum albumin after 1 year of PD predicted mortality in peritoneal dialysis.

Analysis of glomerular PLA2R efficacy in evaluating the prognosis of idiopathic membranous nephropathy in the background of different serum anti-PLA2R levels.

OBJECTIVE: To verify glomerular PLA2R antigen and serum PLA2R antibody expression in membranous nephropathy as well as to explore glomerular PLA2R efficacy in evaluating the prognosis of idiopathic membranous nephropathy (IMN) in the background of different serum anti-PLA2R levels. METHODS: We retrospectively analyzed 155 patients who were diagnosed with IMN by kidney biopsy. Patients were divided into six groups according to their serum PLA2R antibody or glomerular PLA2R antigen positiveness and the level of serum anti-PLA2R titer. Both clinical features and pathological characteristics were recorded, and the remission time was compared among groups. Correlation between clinical figures and the anti-PLA2R titer or semi-quantity of glomerular PLA2R antigen was detected. RESULTS: A positive correlation between time to partial remission and serum anti-PLA2R titer was found. Among patients with serum anti-PLA2R titer <150 RU/ml, there were shorter remission time in negative glomerular PLA2R antigen group compared with positive glomerular PLA2R antigen, and a positive correlation between time to complete remission and semi-quantity of glomerular PLA2R antigen was found. CONCLUSION: Both glomerular PLA2R antigen and serum anti-PLA2R play a role in disease presentation and prognosis in primary membranous nephropathy. Glomerular PLA2R antigen has a major role on disease prognosis when serum anti-PLA2R titer is less than 150RU/ml, while serum anti-PLA2R has predominant role in IMN prognosis when serum anti-PLA2R titer is above 150RU/ml.

Low expression of HIV genes in podocytes accelerates the progression of diabetic kidney disease in mice.

With the widespread use combination antiretroviral therapy, there has been a dramatic decrease in HIV-associated nephropathy. However, although the patients living with HIV have low or undetectable viral load, the prevalence of chronic kidney disease (CKD) in this population remains high. Additionally, improved survival is associated with aging-related comorbidities such as diabetes and cardiovascular disease. A faster progression of CKD is associated with concurrent HIV infection and diabetes than with HIV infection or diabetes alone. To explore the potential pathogenic mechanisms that synergistically drive CKD progression by diabetes and HIV infection, we generated a new mouse model with a relatively low expression of HIV-1 proviral genes specifically in podocytes (pod-HIV mice) to better mimic the setting of kidney injury in patients living with HIV. While no apparent kidney phenotypes were observed at baseline in pod-HIV mice, the induction of mild diabetic kidney disease with streptozotocin led to significant worsening of albuminuria, glomerular injury, podocyte loss, and kidney dysfunction as compared to the mice with diabetes alone. Mechanistically, diabetes and HIV-1 synergistically increased the glomerular expression of microRNA-34a (miR-34a), thereby reducing the expression of Sirtuin-1 (SIRT1) deacetylase. These changes were also associated with increased acetylation and activation of p53 and p65 NF-κB and with enhanced expression of senescence and inflammatory markers. The treatment of diabetic pod-HIV mice with the specific Sirtuin-1 agonist BF175 significantly attenuated albuminuria and glomerulopathy. Thus, our study highlights the reduction in Sirtuin-1 as a major basis of CKD progression in diabetic patients living with HIV and suggests Sirtuin-1 agonists as a potential therapy.

Perilipin 5 ameliorates high-glucose-induced podocyte injury via Akt/GSK-3ß/Nrf2-mediated suppression of apoptosis, oxidative stress, and inflammation.

Hyperglycemia-induced podocyte damage contributes to the onset of diabetic nephropathy, a severe complication of diabetes. Perilipin 5 (Plin5) exerts a vital role in numerous pathological conditions via affecting cell apoptosis, oxidative stress, and inflammation. However, whether Plin5 plays a role in regulating podocyte damage of diabetic nephropathy has not been fully determined. This work aimed to explore the role of Plin5 in mediating high glucose (HG)-induced injury of podocytes in vitro. Our results demonstrated that Plin5 expression was markedly decreased in mouse podocytes challenged with HG. Plin5 overexpression markedly suppressed HG-induced apoptosis, reactive oxygen species (ROS) production, and the pro-inflammatory response in podocytes. On the contrary, Plin5 silencing produced the opposite effects. Further mechanistic analysis demonstrated that Plin5 upregulation remarkably increased the levels of phospho-Akt and phospho-glycogen synthase kinase-3ß (GSK-3ß) in HG-exposed podocytes. Moreover, Plin5 overexpression increased the levels of nuclear factor erythroid 2-related factor 2 (Nrf2) and enhanced the activation of Nrf2 signaling. Akt inhibition markedly blocked Plin5-mediated activation of Nrf2, while GSK-3ß inhibition reversed Plin5-silencing-induced suppressive effects on Nrf2 activation. Notably, Nrf2 suppression significantly blocked Plin5-mediated protective effects against HG-induced podocyte injury. In summary, our work indicates a vital role for Plin5 in protecting against HG-induced apoptosis, oxidative stress, and inflammation in podocytes via modulation of Akt/GSK-3ß/Nrf2 signaling. This study suggests that Plin5 may participate in modulating podocyte damage in diabetic nephropathy.

LncRNA MIAT enhances systemic lupus erythematosus by upregulating CFHR5 expression via miR-222 degradation.

Systemic lupus erythematosus (SLE), a complex polygenic autoimmune disease, is associated with increased complement activation. Complement factor H related protein 5 (CFHR5) may contribute to dysfunctional complement activation, thus predisposing to SLE. The expression levels of anti-dsDNA, C3 and CFHR5 in blood samples from 50 SLE patients and 50 healthy individuals were evaluated, and also their expression levels were measured in an MRL/lpr mouse model and control MRL/MPJ mice. The results showed that CFHR5 expression increased in SLE patients together with the increase of anti-dsDNA in comparison with the healthy control. Furthermore, CFHR5 expression was inversely correlated with C3, down-regulation of which was associated with worse SLE. Previous studies indicated that long noncoding RNA (lncRNA) regulates mRNA synthesis via microRNA (miRNA) inhibition. The present bioinformatics analysis revealed that the target miRNA (miR-222) was combined with both lncRNA MIAT and mRNA CFHR5. H&E staining of the kidney tissues of the MRL/lpr mice revealed that lncRNA MIAT, as a competitive inhibitor of miR-222, enhanced SLE by upregulating CFHR5 expression through the degradation of miR-222 in vivo. Thus, our study revealed for the first time the role of lncRNA MIAT in regulating CFHR5 expression in SLE in vivo and provided new insights into the role of lncRNA in regulation and complement function of SLE pathogenesis.

Clemaichinenoside protects renal tubular epithelial cells from hypoxia/reoxygenation injury in vitro through activating the Nrf2/HO-1 signalling pathway.

Renal ischaemia/reperfusion (I/R) is a major cause of acute renal failure with increased morbidity, mortality, and prolonged hospitalizations. Clematichinenoside (AR), a triterpenoid saponin isolated from the roots of Clematis chinensis, was reported to possess a protective effect against I/R injury. However, the effect of AR on renal I/R injury has not been evaluated. This study aims to examine the effect of AR on an in vitro I/R model in human proximal tubular epithelial cells HK-2. HK-2 cells were subjected to hypoxia/reoxygenation (H/R) stimulation to mimic I/R in vitro. The results showed that AR improved cell viability of H/R-stimulated HK-2 cells. AR pretreatment resulted in decreased production of reactive oxygen species (ROS) and malondialdehyde (MDA), as well as increased in superoxide dismutase (SOD) activity in H/R-stimulated HK-2 cells. In addition, AR also presented an anti-inflammatory activity, as evidenced by decreased secretion of pro-inflammatory cytokines including IL-6, IL-1ß, and TNF-α. Moreover, apoptotic rate was markedly decreased in HK-2 cells pretreated with AR. The bax expression was decreased, while bcl-2 expression was increased by AR pretreatment. Furthermore, AR enhanced the H/R-stimulated activation of the Nrf2/HO-1 signalling pathway in HK-2 cells. In conclusion, these findings indicated that AR protected HK-2 cells from H/R-induced cell injury via regulating the Nrf2/HO-1 signalling pathway.

MiR-325-3p inhibits renal inflammation and fibrosis by targeting CCL19 in diabetic nephropathy.

Diabetic nephropathy (DN), a common cardiovascular disease, has been a global health threat. MicroRNAs (miRNAs) have been proposed to frequently participate in the occurrence and development of DN, however, the role of miR-325-3p in DN remains uncharacterized. Our research aimed to explore the function and mechanism of miR-325-3p in DN. Bioinformatics analysis (Targetscan, http://www.targetscan.org) and a wide range of experiments including RT-qPCR, CCK-8 assay, western blot, luciferase reporter assay, RNA immunoprecipitation (RIP) assays, urine protein and blood glucose assays, histology analysis and morphometric analysis were used to explore the function and mechanism of miR-325-3p and C-C motif chemokine ligand 19 (CCL19). CCL19 could facilitate the progression of DN by inhibiting cell viability and promoting inflammation and fibrosis in HK-2 and HMC cells. In addition, CCL19 was confirmed to be targeted and negatively regulated by miR-325-3p. Rescue assays validated that the impacts of miR-325-3p mimics on the viability, inflammation and fibrosis of HK-2 and HMC cells were recovered by CCL19 overexpression. To sum up, miR-325-3p inhibits renal inflammation and fibrosis by targeting CCL19 in a DN cell model and mice model, implying miR-325-3p as a possible therapeutic target for DN treatment.

Inhibitor of growth 4 inhibits cell proliferation, migration, and induces apoptosis of renal cell carcinoma cells.

The inhibitor of growth 4 (ING4) is known as a tumor suppressor. The expressions of ING4 were markedly reduced in human renal clear cell carcinoma (ccRCC) tissues. However, the role of ING4 in renal cell carcinoma (RCC) remains unknown. The aim of the current study was to detect the ING4 expression level and its potential role in human RCC cell lines. Our results showed that ING4 was lowly expressed in human RCC cell lines compared with that in proximal tubular cell line. Ectopic overexpression of ING4 inhibited the proliferation, migration, and invasion properties, and as well as prevented epithelial-mesenchymal transition (EMT) phenotype of RCC cells. In addition, ING4 overexpression induced cell apoptosis and autophagy in RCC cells. Furthermore, ING4 overexpression suppressed the activation of PI3K/Akt pathway in RCC cells. The activator of PI3K/Akt, insulin-like growth factor 1, abolished the effects of ING4 on RCC cells. These findings indicated that ING4 presented anticancer activity in RCC cells. The effects of ING4 on RCC cells were mediated by regulating the PI3K/Akt pathway. These findings suggested that ING4 could be used for gene therapy of RCC.

Expression of Vsig4 attenuates macrophage-mediated hepatic inflammation and fibrosis in high fat diet (HFD)-induced mice.

The innate immune response contributes to hepatic steatosis and nonalcoholic fatty liver disease (NAFLD). However, the pathogenic mechanism of NAFLD is still poorly understood. The costimulatory molecule V-set and immunoglobulin domain-containing protein-4 (Vsig4), which is exclusively expressed on macrophages, shows significant role in regulating macrophage-mediated inflammation. Here, we attempted to explore if Vsig4 expression was involved in high fat diet (HFD)-induced NAFLD. The results indicated that Vsig4 expression was markedly down-regulated in fatty livers of NAFLD patients and obese mice. Vsig4 knockout accelerated HFD-induced metabolic dysfunction. In addition, the loss of Vsig4 significantly promoted insulin resistance and lipid deposition in liver samples of HFD-challenged mice. Furthermore, HFD-induced inflammation was apparently accelerated in Vsig4 knockout mice by further activating nuclear factor-κB (NF-κB) signaling pathway. Also, Vsig4 deficient mice exhibited greater collagen accumulation in hepatic samples in HFD-challenged mice compared to the WT mice, which was through promoting transforming growth factor-ß1 (TGFß1) signaling. Importantly, we found that lipopolysaccharide (LPS)- or TGFß1-stimulated inflammation and fibrosis in primary hepatocytes and hepatic stellate cells, respectively, were markedly exacerbated by co-culture with condition medium from bone marrow-derived macrophages (BMDMs) with Vsig4 deficiency. Finally, transplantation of bone marrow cells from control mice to Vsig4-knockout mice restored the severity of steatosis, inflammation and fibrosis after HFD feeding. Therefore, loss of Vsig4 accelerated the severity of lipid deposition, fibrosis and the inflammatory response. Vsig4 could be a therapeutic target for NAFLD treatment.

Peritoneal Dialysis Treatment in Small Children with Acute Kidney Injury: Experience in Northwest China.

BACKGROUND: Peritoneal dialysis (PD) is a kind of renal replacement therapy (RRT), which can be employed to treat pediatric acute kidney injury (AKI) as it is safe, simple, and cost-effective. The studies of PD treatment in pediatric AKI in China have rarely been reported in English literature. OBJECTIVE: To investigate the efficacy and the outcome of PD in pediatric patients with AKI. METHODS: We performed a retrospective study of children who received PD as RRT for AKI in a teaching hospital in northwest China from 2003 to 2013. Demographic characteristics and laboratory data were collected, and the prognostic factors of renal recovery were identified. RESULTS: There were 24 children (62.5% male) identified, with the mean age of 22.4 ± 18.7 months (3 months to 5 years old). The most common causes of AKI were drug induced (25.0%), glomerulonephritis (20.9%), and obstructive nephropathy (16.7%). The mean duration of PD was 11.3 ± 7.8 days (2-39 days). PD treatment was highly effective in attenuation of toxics, improvement of fluid overload, and correction of electrolyte disturbances (p < 0.001). One catheter outflow obstruction was noted, and no major complication was identified. In total, 18 children (75.0%) recovered and had the catheter successfully removed, 2 (8.3%) needed further PD treatment, and 4 (16.7%) died. The albumin level was significantly higher in patients who recovered with PD treatment (33.7 ± 6.2 vs. 21.5 ± 4.8 g/L, p = 0.002). CONCLUSIONS: PD can be performed safely and efficiently for the treatment of pediatric AKI. Low albumin level may be associated with poor prognosis of pediatric AKI.

Association between CCDC132, FDX1 and TNFSF13 gene polymorphisms and the risk of IgA nephropathy.

AIM: Previous genome-wide association studies have identified multiple susceptibility loci for IgA nephropathy (IgAN); however, validation of these findings is still needed. METHODS: We performed a case-control study among 347 Chinese Han IgAN patients and 310 ethnicity-matched controls. Twenty-two single nucleotide polymorphisms (SNPs) were genotyped and association analysis was performed. RESULTS: We found three alleles for IgAN in patients: the allele "C" of rs2188404 in the CCDC132 gene by recessive model (odds ratio (OR), 1.65; 95% confidence interval (CI), 1.10-2.48; P = 0.014) and additive model (OR, 1.29; 95% CI, 1.03-1.61; P = 0.024) analysis, respectively, the allele "A" of rs10488764 in FDX1 gene by additive model (OR, 1.27; 95% CI, 1.00-1.61; P = 0.048) analysis, the allele "A" of rs3803800 in TNFSF13 gene by recessive model (OR, 2.05; 95% CI, 1.16-3.62; P = 0.010) and additive model (OR, 1.35; 95% CI, 1.06-1.72; P = 0.013) analysis, respectively. However, the associations between these SNPs and the risk of IgAN were not significant when adjusted for age and sex. Additionally, we found polymorphisms of rs2188404, rs10488764 and rs3803800 were correlated with urine protein (UPRO), human serum albumin (HSA), total cholesterol (TC) and Lee's pathological grades. CONCLUSION: We did not find any positive association between these SNPs and the risk of IgAN after adjustment by age and sex, but did find a significant and strong correlation with relevant clinical pathological parameters. Our study may provide a new perspective to understanding the aetiology of IgAN.

Targeting proprotein convertase subtilisin/kexin type 9 (PCSK9): from bench to bedside.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) has evolved as a pivotal enzyme in lipid metabolism and a revolutionary therapeutic target for hypercholesterolemia and its related cardiovascular diseases (CVD). This comprehensive review delineates the intricate roles and wide-ranging implications of PCSK9, extending beyond CVD to emphasize its significance in diverse physiological and pathological states, including liver diseases, infectious diseases, autoimmune disorders, and notably, cancer. Our exploration offers insights into the interaction between PCSK9 and low-density lipoprotein receptors (LDLRs), elucidating its substantial impact on cholesterol homeostasis and cardiovascular health. It also details the evolution of PCSK9-targeted therapies, translating foundational bench discoveries into bedside applications for optimized patient care. The advent and clinical approval of innovative PCSK9 inhibitory therapies (PCSK9-iTs), including three monoclonal antibodies (Evolocumab, Alirocumab, and Tafolecimab) and one small interfering RNA (siRNA, Inclisiran), have marked a significant breakthrough in cardiovascular medicine. These therapies have demonstrated unparalleled efficacy in mitigating hypercholesterolemia, reducing cardiovascular risks, and have showcased profound value in clinical applications, offering novel therapeutic avenues and a promising future in personalized medicine for cardiovascular disorders. Furthermore, emerging research, inclusive of our findings, unveils PCSK9's potential role as a pivotal indicator for cancer prognosis and its prospective application as a transformative target for cancer treatment. This review also highlights PCSK9's aberrant expression in various cancer forms, its association with cancer prognosis, and its crucial roles in carcinogenesis and cancer immunity. In conclusion, this synthesized review integrates existing knowledge and novel insights on PCSK9, providing a holistic perspective on its transformative impact in reshaping therapeutic paradigms across various disorders. It emphasizes the clinical value and effect of PCSK9-iT, underscoring its potential in advancing the landscape of biomedical research and its capabilities in heralding new eras in personalized medicine.

Leflunomide plus oral prednisone in treatment of idiopathic membranous nephropathy: a retrospective clinical study of efficacy and safety.

AIM: Treatment of idiopathic membranous nephropathy (IMN) remains a controversial issue. While clinical trials have shown that some immunosuppressants combined with glucocorticoid have a good efficacy on IMN patients. However, there is little data on leflunomide (LEF) in treatment of IMN. METHODS: Records of every patient with biopsy-proven IMN in Department of Nephrology, the First Affiliated Hospital, Xi'an Jiaotong University from January 2005 to December 2011 (n=194) were retrospectively analyzed. Patients with nephrotic IMN were treated with LEF plus oral prednisone (n=32) for at least 12 months, whereas 31 patients who did not receive any immunosuppressants were used as controls. RESULTS: Remission rates in the LEF group were 31.3%, 59.4%, 68.8% and 71.9% at 6, 9, 12 and 15 months, respectively, which were significantly higher than those in controls. In the LEF group, proteinuria decreased from 6.79 g/24 h at baseline to 5.63 g/24 h (P<0.01), 3.85 g/24 h (P<0.01) and 2.51 g/24 h (P<0.01) after treatment for 6, 9 and 12 months, respectively. Relapse occurred in five (21.7%) patients within a median of 14 months (range, 8-27) after cessation of LEF. No patients developed renal insufficiency during the therapeutic period. Multivariate analysis suggested that age negatively correlated with achievement of remission (odds ratio, 0.87; P<0.05). No serious adverse events were observed. CONCLUSION: LEF plus oral prednisone may be an alternative treatment option in Chinese patients with nephrotic IMN.

Open surgical insertion of Tenkchoff straight catheter without guide wire.

OBJECTIVE: To compare the clinical outcomes of open surgical peritoneal dialysis catheter (PDC) insertion with guide wire and the outcomes of PDC insertion without guide wire. METHODS: Data of the patients receiving open surgical Tenkchoff straight catheter insertion in our department from January 2005 to January 2011 were retrospectively analyzed. The 117 patients in whom PDC insertion was conducted with the guidance of guide wire were enrolled into group A, and the 121 cases receiving PDC insertion without guide wire were enrolled into group B. The incidences of post-operative complications (catheter obstruction, catheter displacement, bloody dialysate, and dialysate leakage), catheter survival, and patient survival rates were compared between the 2 groups. RESULTS: The baseline characteristics (gender, age, body mass index, prothrombin time, activated partial thromboplastin time, platelet count, serum creatinine, follow-up time, primary diseases, and outcomes) of the 2 groups were comparable (all P>0.05). In post-operative complications, only the incidence of early bloody dialysate showed significant difference, being 16.2% in group A and 7.4% in group B (P=0.04). Catheter and patient survival rates were not significantly different between the two groups. Overweight patients showed a higher incidence of catheter obstruction compared with normal weight patients [16.0% (4/25) vs.3.3% (7/213), P=0.02], but no differences in post-operative complications were found among overweight patients between the 2 groups. CONCLUSIONS: Open surgical Tenkchoff straight catheter insertion without guide wire does not lead to higher risk of post-operative complications and catheter removal. It may be an alternative option when guide wire is not available.

Clinico-pathological features of diabetic and non-diabetic renal diseases in type 2 diabetic patients: a retrospective study from a 10-year experience in a single center.

AIM: To compare clinical and pathological characteristics as well as prognosis between diabetic nephropathy (DN) and non-diabetic renal disease (NDRD) so as to explore potential diagnostic criteria of DN and provide some guidance for the treatment of type 2 diabetes mellitus (T2DM) patients with kidney involvement. METHODS: T2DM patients with renal impairment who underwent kidney biopsy were included in this study, who were classified into 3 groups (DN, NDRD, DN with NDRD) based on their renal pathological diagnosis. Baseline clinical characteristics as well as follow-up data were collected and analyzed among 3 groups. Logistic regression was performed to determine the best predictors for DN diagnosis. Additional 34 MN patients without diabetes were enrolled by propensity score matching method to compare serum PLA2R antibody titer and kidney outcomes between diabetic MN patients and MN alone. RESULTS: Among 365 patients with type 2 diabetes who underwent kidney biopsy, 179 (49.0%) patients were diagnosed with NDRD alone and 37 (10.1%) patients with NDRD combined DN. Risk factors for DN development in T2DM patients were longer time since diabetes diagnosis, higher level of serum creatinine, absence of hematuria and presence of diabetic retinopathy by multivariate analysis. Lower rate of proteinuria remission and higher risk of renal progression were observed in DN group compared with NDRD group. Membranous nephropathy was the most common NDRD in diabetic patients. There was no difference in serum PLA2R antibody positiveness or titer between MN patients with or without T2DM. There was lower remission rate but similar renal progression in diabetic MN when age, gender, baseline eGFR, albuminuria and IFTA score were adjusted. CONCLUSIONS: Non-diabetic renal disease is not uncommon in T2DM patients with renal impairment, which has better prognosis with proper treatment. Coexisting diabetic status does not exert negative impact on renal progression in MN patients, and immunosuppressive agents should be administered when necessary.

Serum vancomycin levels predict the short-term adverse outcomes of peritoneal dialysis-associated peritonitis.

BACKGROUND: The role of monitoring serum vancomycin levels during treatment of peritoneal dialysis (PD)-associated peritonitis is controversial. Substantial inter-individual variability may result in suboptimal serum levels despite similar dosing of vancomycin. The published predictors of suboptimal serum vancomycin levels remain limited. METHODS: Data were retrospectively collected from 541 patients on continuous ambulatory peritoneal dialysis between 1 January 2018 and 31 December 312019. For gram-positive cocci and culture-negative peritonitis, we adopted a vancomycin administration and monitoring protocol. Short-term adverse outcomes of PD-associated peritonitis, including transfer to haemodialysis, death, persistent infection beyond planned therapy duration and relapse, were observed. The association between trough serum vancomycin levels and short-term adverse outcomes was evaluated. RESULTS: Intraperitoneal vancomycin was used in 61 gram-positive cocci or culture-negative peritonitis episodes in 56 patients. Fourteen episodes of short-term adverse outcomes occurred in 12 patients, whose average trough serum vancomycin levels on day 5 of treatment were significantly lower than those who didn't experience any adverse outcomes (8.4 ± 1.7 vs 12.5 ± 4.3 mg/L, p = 0.003). In gram-positive cocci or culture-negative peritonitis patients, those with higher day 5 trough serum vancomycin levels had a lower risk of short-term adverse outcomes (odds ratio: 0.6, 95% confidence interval: 0.4 to 0.9, p = 0.011). Receiver operating charecteristic curve (ROC) analyses showed that the day 5 trough serum vancomycin levels diagnostic threshold value for short-term adverse outcomes was 10.1 mg/L. After adjustments for gender, exchange volume and residual kidney function (RKF), baseline higher peritoneal transport was associated with a suboptimal (<10.1 mg/L) day 5 serum vancomycin level. CONCLUSIONS: Serum vancomycin levels are correlated with short-term adverse outcomes of PD-associated peritonitis, and higher peritoneal solute transport status is associated with suboptimal trough serum vancomycin levels on day 5.