Prognostic value of neutrophil-to-lymphocyte ratio dynamics in patients with septic acute kidney injury: a cohort study.

BACKGROUND: Neutrophil-to-lymphocyte ratio (NLR) has been suggested to be a prognostic marker for various diseases, but whether NLR dynamics (ΔNLR) is related to mortality and disease severity in patients with septic acute kidney injury (AKI) has not been determined. METHODS: Between August 2013 and August 2021, septic AKI patients at our center were retrospectively enrolled. ΔNLR was defined as the difference between the NLR at septic AKI diagnosis and at hospital admission. The relationship between the ΔNLR and mortality was evaluated by Kaplan-Meier curves, Cox proportional hazards, and cubic spline analyses. The prediction values were compared by area under the receiver-operating characteristic curve (AUROC), net reclassification improvement (NRI), and integrated discrimination improvement (IDI) analyses. RESULTS: Of the 413 participants, the mean age was 63 ± 17 years, and 134 were female (32.4%). According to the median value, patients in the high-ΔNLR group had significantly greater 90-d mortality (74.4% vs. 46.6%, p < 0.001). After adjustment for potential confounders, high ΔNLR remained an independent predictor of 90-d mortality (HR = 2.80; 95% CI = 1.74-4.49, p < 0.001). Furthermore, ΔNLR had the highest AUROC for 90-d mortality (0.685) among the various biomarkers and exhibited an improved NRI (0.314) and IDI (0.027) when incorporated with PCT and CRP. For secondary outcomes, patients with high ΔNLR had increased risk of 30-d mortality (p = 0.004), need for renal replacement therapy (p = 0.011), and developing stage-3 AKI (p = 0.040) according to the adjusted models. CONCLUSIONS: High ΔNLR is independently associated with increased risk of patient mortality and adverse outcomes. ΔNLR might be utilized to facilitate risk stratification and optimize septic AKI management.

Stents migration into right atrium from severely calcified superior vena cava in a hemodialysis patient.

Vascular calcification is common among hemodialysis patients. In this report, we presented a case of superior vena cava (SVC) stent migration during endovascular angioplasty in a 50-year-old female hemodialysis patient with severe SVC calcification. The stent migration was refractory to the deployment of a second anchor stent, which shortly resulted in pericardium tamponade and was successfully rescued by emergent thoracotomy. The potential role of vascular calcification as a risk factor to stent migration was discussed. Patients with severe vascular calcification receiving endovascular angioplasty might need a careful risk screening for stent migration.

Fisetin ameliorates fibrotic kidney disease in mice via inhibiting ACSL4-mediated tubular ferroptosis.

Kidney fibrosis is the hallmark of chronic kidney disease (CKD) progression, whereas no effective anti-fibrotic therapies exist. Recent evidence has shown that tubular ferroptosis contributes to the pathogenesis of CKD with persistent proinflammatory and profibrotic responses. We previously reported that natural flavonol fisetin alleviated septic acute kidney injury and protected against hyperuricemic nephropathy in mice. In this study, we investigated the therapeutic effects of fisetin against fibrotic kidney disease and the underlying mechanisms. We established adenine diet-induced and unilateral ureteral obstruction (UUO)-induced CKD models in adult male mice. The two types of mice were administered fisetin (50 or 100 mg·kg-1·d-1, i.g.) for 3 weeks or 7 days, respectively. At the end of the experiments, the mice were euthanized, and blood and kidneys were gathered for analyzes. We showed that fisetin administration significantly ameliorated tubular injury, inflammation, and tubulointerstitial fibrosis in the two types of CKD mice. In mouse renal tubular epithelial (TCMK-1) cells, treatment with fisetin (20 µM) significantly suppressed adenine- or TGF-ß1-induced inflammatory responses and fibrogenesis, and improved cell viability. By quantitative real-time PCR analysis of ferroptosis-related genes, we demonstrated that fisetin treatment inhibited ferroptosis in the kidneys of CKD mice as well as in injured TCMK-1 cells, as evidenced by decreased ACSL4, COX2, and HMGB1, and increased GPX4. Fisetin treatment effectively restored ultrastructural abnormalities of mitochondrial morphology and restored the elevated iron, the reduced GSH and GSH/GSSG as well as the increased lipid peroxide MDA in the kidneys of CKD mice. Notably, abnormally high expression of the ferroptosis key marker ACSL4 was verified in the renal tubules of CKD patients (IgAN, MN, FSGS, LN, and DN) as well as adenine- or UUO-induced CKD mice, and in injured TCMK-1 cells. In adenine- and TGF-ß1-treated TCMK-1 cells, ACSL4 knockdown inhibited tubular ferroptosis, while ACSL4 overexpression blocked the anti-ferroptotic effect of fisetin and reversed the cytoprotective, anti-inflammatory, and anti-fibrotic effects of fisetin. In summary, we reveal a novel aspect of the nephroprotective effect of fisetin, i.e. inhibiting ACSL4-mediated tubular ferroptosis against fibrotic kidney diseases.

SCAF4 variants are associated with epilepsy with neurodevelopmental disorders.

AIMS: The genetic causes of epilepsy with unknown etiology in most patients remain unknown. The aim of this study was to elucidate the phenotype of SCAF4-related epilepsy. METHODS: Trio-based whole-exome sequencing was performed in patients with epilepsy. Silico programs and protein modeling were employed to predict the damaging of variants. Previously reported SCAF4 variants were systematically reviewed to analyze the genotype-phenotype correlations. RESULTS: Three heterozygous variants in the SCAF4 were detected in three cases, including one missense variant and two frameshift variants. All variants were de novo. None of these variants is present in gnomAD controls. The missense variant was predicted to be damaging in silico tools. Protein modeling showed that two frameshift variants resulted in loss of domains, and the missense variant may disrupt a nearby phosphorylation site and alter the hydrogen bonds around 54C and the stability of the SCAF4 protein. Intellectual development was mildly delayed for all patients except for one with whom contact was lost. All probands experienced epilepsy as infrequent seizures, responded well to antiseizure drugs, and had a median [IQR] seizure onset age of 4 [1.75, 7.5] years. The variants in the domain-encoding exons and upstream exons exhibited a strong association with epilepsy. CONCLUSIONS: SCAF4 is a potential causative gene of epilepsy with neurodevelopmental disorders.

Serum total protein-to-albumin ratio predicts risk of death in septic acute kidney injury patients: A cohort study.

OBJECTIVE: Sepsis is the leading cause of acute kidney injury (AKI). Increasing evidence shows that serum total protein-to-albumin ratio (TAR) could serve as an inflammation- and nutrition-based prognostic marker in various diseases. The purpose of this study was to assess the prognostic value of TAR in predicting the clinical outcomes of septic AKI patients. METHODS: We retrospectively enrolled septic AKI patients between August 2015 and August 2022 at West China Hospital of Sichuan University. Patients admitted between August 2015 and August 2021 were defined as the original cohort. The primary outcomes were 30-day and 90-day all-cause mortality of septic AKI patients. The secondary outcomes were septic shock, transfer to the intensive care unit, mechanical ventilation, requirement for renal replacement therapy, and stage 3 AKI. The utility of TAR was further verified in a validation cohort of septic AKI patients admitted between September 2021 and August 2022. RESULTS: In the original cohort, a total of 309 eligible patients with a median age of 58 years were enrolled, of which 70.2 % were males. In multivariate Cox analysis, after adjustments for age, sex, and other confounding factors, higher TAR at admission was associated with an increased risk of 30-day and 90-day all-cause mortality in septic AKI patients (HR 1.91, 95 % CI 1.18-3.09, P = 0.008; HR 1.54, 95 % CI 1.01-2.34, P = 0.043, respectively). Subgroup analysis revealed no significant interactions in most strata. TAR at AKI diagnosis or discharge was not significantly related to 30-day (P = 0.120 and 0.153, respectively) or 90-day mortality (P = 0.147 and 0.124, respectively). We found no relationship between baseline TAR and septic shock, transfer to the intensive care unit, mechanical ventilation, requirement for renal replacement therapy, or stage 3 AKI (all P > 0.05). In the validation cohort of 81 septic AKI patients, TAR at admission remained a significant prognosticator for 30-day and 90-day mortality (HR 4.367, 95 % CI 1.20-15.87, P = 0.025; HR 4.237, 95 % CI 1.59-11.27, P = 0.004). CONCLUSIONS: TAR at admission is an independent risk factor for 30-day and 90-day mortality in septic AKI patients and could be used as a convenient and economic septic AKI prognostic indicator.

Massive Hemorrhage Following Acupuncture Treatment in a Neurofibromatosis Type 1 Patient.

Neurofibromatosis type 1 (NF1) is a genetic disorder involving multiple organs. Vascular involvement is a rare complication among NF1 patients. We report a case of a 59-year-old female NF1 patient who presented with a massive hematoma over the scapular area after undergoing acupuncture treatment. Contrast-enhanced CT and MRI demonstrated a slightly hyperdense mass measuring 24.2 × 10.3 cm in size, and multiple enlarged and tortuous malformed vessels were seen arising from the left subclavian artery. Arterial embolization and subsequent surgical mass resection were successfully performed. This case indicates that minor injuries such as acupuncture-related ones could cause severe hemorrhage in patients with vascular malformation related to NF1. Endovascular angiography and embolization proved to be effective in localizing the culprit vessel and stopping active bleeding in our patient.

Design, Synthesis, and Biological Evaluation of Novel P2X7 Receptor Antagonists for the Treatment of Septic Acute Kidney Injury.

Sepsis-associated acute kidney injury (AKI) is a serious clinical problem, without effective drugs. Abnormal activation of the purinergic P2X7 receptor (P2X7R) in septic kidneys makes its antagonist a promising therapeutic approach. Herein, a series of novel P2X7R antagonists were designed, synthesized, and structurally optimized. Based on in vitro potency in human/mouse P2X7R using HEK293 cells, hepatic microsomal stability, and pharmacokinetic and preliminary in vivo assessments, compound 14a was identified by respective human and mouse P2X7R IC50 values of 64.7 and 10.1 nM, together with favorable pharmacokinetic properties. Importantly, 14a dose-dependently alleviated kidney dysfunction and pathological injury in both lipopolysaccharide (LPS)- and cecal ligation/perforation (CLP)-induced septic AKI mice with a good safety profile. Mechanistically, 14a could suppress NLRP3 inflammasome activation to inhibit the expression of cleaved caspase-1, gasdermin D, IL-1ß, and IL-18 in the injured kidneys of septic mice. Collectively, these results highlighted that P2X7R antagonist 14a exerted a therapeutic potential against septic AKI.

Incidence and risk factors of acute kidney injury in cancer patients treated with immune checkpoint inhibitors: a systematic review and meta-analysis.

Background: The incidence and risk factors of acute kidney injury (AKI) in patients with malignancies receiving immune checkpoint inhibitors (ICIs) are being extensively reported with their widespread application. Objective: This study aimed to quantify the incidence and identify risk factors of AKI in cancer patients treated with ICIs. Methods: We searched the electronic databases of PubMed/Medline, Web of Science, Cochrane and Embase before 1 February 2023 on the incidence and risk factors of AKI in patients receiving ICIs and registered the protocol in PROSPERO (CRD42023391939). A random-effect meta-analysis was performed to quantify the pooled incidence estimate of AKI, identify risk factors with pooled odds ratios (ORs) and 95% confidence intervals (95% CIs) and investigate the median latency period of ICI-AKI in patients treated with ICIs. Assessment of study quality, meta-regression, and sensitivity and publication bias analyses were conducted. Results: In total, 27 studies consisting of 24048 participants were included in this systematic review and meta-analysis. The overall pooled incidence of AKI secondary to ICIs was 5.7% (95% CI: 3.7%-8.2%). Significant risk factors were older age (OR: 1.01, 95% CI: 1.00-1.03), preexisting chronic kidney disease (CKD) (OR: 2.90, 95% CI: 1.65-5.11), ipilimumab (OR: 2.66, 95% CI: 1.42-4.98), combination of ICIs (OR: 2.45, 95% CI: 1.40-4.31), extrarenal immune-related adverse events (irAEs) (OR: 2.34, 95% CI: 1.53-3.59), and proton pump inhibitor (PPI) (OR: 2.23, 95% CI: 1.88-2.64), nonsteroidal anti-inflammatory drug (NSAID) (OR: 2.61, 95% CI: 1.90-3.57), fluindione (OR: 6.48, 95% CI: 2.72-15.46), diuretic (OR: 1.78, 95% CI: 1.32-2.40) and angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin-receptor blockers (ARBs) (pooled OR: 1.76, 95% CI: 1.15-2.68) use. Median time from ICIs initiation to AKI was 108.07 days. Sensitivity and publication bias analyses indicated robust results for this study. Conclusion: The occurrence of AKI following ICIs was not uncommon, with an incidence of 5.7% and a median time interval of 108.07 days after ICIs initiation. Older age, preexisting chronic kidney disease (CKD), ipilimumab, combined use of ICIs, extrarenal irAEs, and PPI, NSAID, fluindione, diuretics and ACEI/ARB use are risk factors for AKI in patients receiving ICIs. Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42023391939.

Neutrophil-to-Lymphocyte ratio as a prognostic marker of mortality and disease severity in septic Acute kidney injury Patients: A retrospective study.

BACKGROUND: Acute kidney injury (AKI) is a frequent complication of sepsis associated with increased mortality and morbidity. The neutrophil-to-lymphocyte ratio (NLR) has been shown as a risk factor for septic AKI. In this study, we aimed to further evaluate NLR's prediction value on the prognosis of septic AKI patients. METHODS: Septic AKI patients at a tertiary university-affiliated medical center were retrospectively enrolled from August 2015 to August 2021. The primary outcomes were 30-day and 90-day mortality, and secondary outcomes were disease severity, length of stay, and rehospitalization in survivors. Kaplan-Meier curves, Cox proportional hazards, cubic spline and logistics regression analyses were performed for adverse outcomes basing on NLR. The predictive value of NLR on morality was also estimated by the area under the receiver operating characteristic curve (AUROC). RESULTS: A total of 309 septic AKI patients were included with a mean age of 57.8 ± 18.1 years and 92 (29.8 %) being female. The 30-day mortality was 43.4 % and 90-day morality was 61.8 %. When divided by the median of NLR at hospital admission, patients in the high NLR group were associated with an increased 30-day/90-day mortality. After adjusting for multiple covariates, the predictive value of NLR remained significant for 30-day mortality (HR: 2.96, 95 % CI: 1.48-5.92, p = 0.002) and 90-day mortality (HR: 1.88, 95 % CI: 1.11-3.16, p = 0.018). NLR at admission had the highest AUROC (0.618) for 30-day mortality compared with other parameters such as white blood cell (0.573), neutrophil (0.579), lymphocyte (0.567), platelet (0.546), BUN (0.580), albumin (0.545), C-reactive protein (0.571) and procalcitonin (0.534). A similar predictive value on mortality was also observed for NLR measured at septic AKI diagnosis. For secondary outcomes, high NLR was associated with increased risk of transfer to ICU, mechanical ventilation, stage-3 AKI and renal replacement therapy, but not with length of hospital/ICU stay or long-term rehospitalization. CONCLUSION: High NLR is independently associated with 30-day/90-day mortality and disease severity in septic AKI patients. NLR may serve as an economic and widely available biomarker of septic AKI prognosis.

Tight junctions and acute kidney injury.

Acute kidney injury (AKI) is characterized by a rapid reduction in kidney function caused by various etiologies. Tubular epithelial cell dysregulation plays a pivotal role in the pathogenesis of AKI. Tight junction (TJ) is the major molecular structure that connects adjacent epithelial cells and is critical in maintaining barrier function and determining the permeability of epithelia. TJ proteins are dysregulated in various types of AKI, and some reno-protective drugs can reverse TJ changes caused by insult. An in-depth understanding of TJ regulation and its causality with AKI will provide more insight to the disease pathogenesis and will shed light on the potential role of TJs to serve as novel therapeutic targets in AKI.

Blood Pressure Variability and the Progression of Chronic Kidney Disease: a Systematic Review and Meta-Analysis.

BACKGROUND: Blood pressure variability (BPV) is a risk factor for poor prognosis including cardiovascular events, chronic kidney disease, and mortality, independent of elevated BP. METHODS: We searched PubMed/Medline, EMBASE, and the Cochrane Central Register of Controlled Trials (CENTRAL) from inception to November 23, 2022. Cohort studies reporting the association between BPV and chronic kidney disease (CKD) progression were selected. Hazard ratios were pooled using a random-effects model. Meta-regression, subgroup analyses, and sensitivity analyses were conducted. RESULTS: A total of 23 studies were included in this systematic review and meta-analysis. Increased BPV was associated with progression of CKD (HR: 1.21, 95% CI: 1.09-1.33) and incidence of ESRD (HR: 1.08, 95% CI: 1.08-1.30). Among the different BPV metrics, high variation independent of mean (VIM), coefficient of variation (CV), standard deviation (SD), and average real variability (ARV) were indicated as predictors of CKD progression. DISCUSSION: Increased BPV was associated with CKD progression.

Percutaneous superior vena cava puncture for hemodialysis catheter placement.

OBJECTIVE: Central venous occlusion (CVO) refractory to endovascular angioplasty is a critical challenge that threatens hemodialysis vascular access. In the present study, we evaluated the efficacy and safety of tunneled, cuffed central venous catheter (tCVC) placement via percutaneous superior vena cava (SVC) puncture in patients with refractory CVO. METHODS: Patients requiring maintenance hemodialysis with refractory CVO who had undergone percutaneous SVC puncture and tCVC insertion at a university-affiliated hospital from January 2016 to June 2020 were included. The patients were followed up until May 2021. The demographic information, complications, and catheter patency were analyzed. RESULTS: A total of 205 patients (105 women [51.2%]; mean age, 61 ± 15 years) were included. The SVC puncture and tCVC insertion were successfully performed in 194 patients, for a technical success rate of 94.6%. One patient had experienced a pleura injury and hemothorax and had required urgent thoracotomy. A total of 37 patients had presented with mild chest pain and were prescribed oral nonsteroidal anti-inflammatory drugs. During follow-up of the 194 patients with a successful procedure, catheter dysfunction due to thrombosis had occurred in 66 patients, catheter malposition had occurred in 5 patients, and catheter-related blood stream infection had developed in 6 patients. The 3-year primary patency rate was 64.2%, and the 3-year secondary patency rate was 76.3%. CONCLUSIONS: A tCVC placed through a percutaneous SVC puncture had a satisfactory technical success rate and long-term patency rate in patients requiring hemodialysis, providing an optional vascular access for those with exhausted central vein resources. SVC puncture also avoided the use of left-sided catheters and preserved central vein resources. Caution should be given to avoid potential complications such as pleura injury and hemothorax.

[Sichuan Dark Tea-Based Medicated Dietary Formula Improves Obesity-Induced Renal Lipid Metabolism Disorder in Mice by Remodeling Gut Microbiota and Short-Chain Fatty Acid Metabolism]. / å››å·é»‘èŒ¶è¯è†³é æ–¹é€šè¿‡é‡å¡‘è‚ é“èŒç¾¤å’ŒçŸ­é“¾è„‚è‚ªé ¸ä»£è°¢æ”¹å–„è‚¥èƒ–å°é¼ è‚¾è„è„‚è´¨ç´Šä¹±.

Objective: To investigate the renoprotective effects of a Sichuan dark tea-based medicated dietary formula (alternatively referred to as Qing, or clarity in Chinese) on mice with diet-induced obesity (DIO) and to explore the specific mechanisms involved. Methods: Male C57BL/6 mice were randomly assigned to three groups, a control group, a DIO group, and a Qing treatment group, or the Qing group, with 8 mice in each group. The mice in the control group were given normal maintenance feed and purified water, and the other two groups were fed a high-fat diet for 12 weeks to establish the DIO model. After that, high-fat diet continued in the DIO group, while the Qing group was given Qing at the same time for 12 weeks, during which period the weight of the mice was monitored and recorded every week. The mice were sacrificed after 12 weeks. Serum samples were collected and the levels of triglyceride (TG), total cholesterol (TC), alanine aminotransferase (ALT), aspartate aminotransferase (AST), and albumin were measured to evaluate liver function. In addition, renal lipids were extracted to determine the levels of TG and TC in the kidney and periodic acid-Schiff (PAS) and oil red O stainings were performed to evaluate kidney pathological injury. Western blot was performed to determine the phosphorylated AMPK (pAMPK)/AMPK ratio in the kidney tissue. RT-qPCR and Western blot were used to determine the expression of proteins related to fatty acid oxidation, including acetyl-CoA carboxylase 1 (ACC1), carnitine acyltransferase 1 (CTP1), peroxisome proliferators-activated receptor γ (PPARγ), peroxisome proliferators-activated receptor-1 α (PPAR1α), sterol-regulatory element binding proteins (SREBP-1), and key proteins related to lipid synthesis, including fatty acid synthase (FASN) and stearoyl-coenzyme A desaturase 1 (stearoyl-CoA desaturase) in the kidney tissue. 16SrRNA and metabolomics were applied to analyze the gut microbiota in the intestinal contents and its metabolites. Results: Compared with those of the control group, the levels of liver mass (P=0.0003), serum ALT (P<0.0001) and AST (P=0.0001), and kidney TC (P=0.0191) and TG (P=0.0101) of the DIO group were significantly increased and there was lipid deposition in the kidney. Compared with those of the DIO group, mice in the Qing group showed effective reduction in liver mass (P=0.0316) and improvements in the abnormal serum levels of AST (P=0.0012) and ALT (P=0.0027) and kidney TC (P=0.0200) and TG (P=0.0499). In addition, mice in the Qing group showed significant improvement in lipid deposition in the kidney. Qing group showed increased pAMPK/AMPK ratio in comparison with that of the DIO group. In comparison with those of the control group, mice in the DIO group had upregulated expression of lipid synthesis-related genes and proteins (SREBP-1, FASN, and SCD1). As for the fatty acid oxidation-related genes and proteins, DIO mice showed upregulated expression of ACC1 and downregulated expression of CPT1A, PPARγ, and PGC1α in comparison with those of the control group. In the Qing goup, improvements in regard to all these changes were observed. The Qing group demonstrated improvement in the disrupted homeostasis of the gut microbiota. Short-chain fatty acids in the cecal contents, especially isovaleric acid and propionic acid, were also restored. Conclusion: Sichuan dark tea-based medicated dietary formula may improve renal lipid metabolism by regulating gut microbiota and the levels of intestinal short-chain fatty acids, thereby protecting obesity-related kidney injury. Isovaleric acid and propionic acid may be the metabolites key to its regulation of gut microbiota.

FFAR4 improves the senescence of tubular epithelial cells by AMPK/SirT3 signaling in acute kidney injury.

Acute kidney injury (AKI) is a serious clinical complication with high morbidity and mortality rates. Despite substantial progress in understanding the mechanism of AKI, no effective therapy is available for treatment or prevention. We previously found that G protein-coupled receptor (GPCR) family member free fatty acid receptor 4 (FFAR4) agonist TUG891 alleviated kidney dysfunction and tubular injury in AKI mice. However, the versatile role of FFAR4 in kidney has not been well characterized. In the study, the expression of FFAR4 was abnormally decreased in tubular epithelial cells (TECs) of cisplatin, cecal ligation/perforation and ischemia/reperfusion injury-induced AKI mice, respectively. Systemic and conditional TEC-specific knockout of FFAR4 aggravated renal function and pathological damage, whereas FFAR4 activation by TUG-891 alleviated the severity of disease in cisplatin-induced AKI mice. Notably, FFAR4, as a key determinant, was firstly explored to regulate cellular senescence both in injured kidneys of AKI mice and TECs, which was indicated by senescence-associated ß-galactosidase (SA-ß-gal) activity, marker protein p53, p21, Lamin B1, phospho-histone H2A.X, phospho-Rb expression, and secretory phenotype IL-6 level. Mechanistically, pharmacological activation and overexpression of FFAR4 reversed the decrease of aging-related SirT3 protein, where FFAR4 regulated SirT3 expression to exhibit anti-senescent effect via Gq subunit-mediated CaMKKß/AMPK signaling in cisplatin-induced mice and TECs. These findings highlight the original role of tubular FFAR4 in cellular senescence via AMPK/SirT3 signaling and identify FFAR4 as a potential drug target against AKI.

Kidney health in the COVID-19 pandemic: An umbrella review of meta-analyses and systematic reviews.

Background: This umbrella review aims to consolidate evidence from systematic reviews and meta-analyses investigating the impact of the coronavirus disease-2019 (COVID-19) on kidney health, and the associations between kidney diseases and clinical outcomes in COVID-19 patients. Methods: Five databases, namely, EMBASE, PubMed, Web of Science, the Cochrane Database of Systematic Reviews and Ovid Medline, were searched for meta-analyses and systematic reviews from January 1, 2020 to June 2, 2022. Two reviewers independently selected reviews, identified reviews for inclusion and extracted data. Disagreements were resolved by group discussions. Two reviewers independently assessed the methodological quality of all included reviews using ROBIS tool. A narrative synthesis was conducted. The characteristics and major findings of the included reviews are presented using tables and forest plots. The included meta-analyses were updated when necessary. The review protocol was prospectively registered in PROSPERO (CRD42021266300). Results: A total of 103 reviews were identified. Using ROBIS, 30 reviews were rated as low risk of bias. Data from these 30 reviews were included in the narrative synthesis. Ten meta-analyses were updated by incorporating 119 newly available cohort studies. Hospitalized COVID-19 patients had a notable acute kidney injury (AKI) incidence of 27.17%. AKI was significantly associated with mortality (pooled OR: 5.24) and severe conditions in COVID-19 patients (OR: 14.94). The pooled prevalence of CKD in COVID-19 patients was 5.7%. Pre-existing CKD was associated with a higher risk of death (pooled OR: 2.21) and disease severity (pooled OR: 1.87). Kidney transplant recipients were susceptible to SARS-CoV-2 infection (incidence: 23 per 10,000 person-weeks) with a pooled mortality of 18%. Conclusion: Kidney disease such as CKD or recipients of kidney transplants were at increased risk of contracting COVID-19. Persons with COVID-19 also had a notable AKI incidence. AKI, the need for RRT, pre-existing CKD and a history of kidney transplantation are associated with adverse outcomes in COVID-19. Systematic review registration: www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021266300, identifier: CRD42021266300.

Traditional Chinese herbs and natural products in hyperuricemia-induced chronic kidney disease.

Hyperuricemia is a common biochemical disorder, which resulted from both excessive uric acid (UA) production and/or absolute or relative impairment of urinary UA excretion. Growing evidence has indicated that hyperuricemia is an independent risk factor for the development and progression of chronic kidney disease (CKD), causing hyperuricemia-induced CKD (hyperuricemic nephropathy, HN). The therapeutic strategy of HN is managing hyperuricemia and protecting kidney function. Adverse effects of commercial drugs make persistent treatment of HN challenging. Traditional Chinese medicine (TCM) has exact efficacy in lowering serum UA without serious adverse effects. In addition, TCM is widely applied for the treatment of CKD. This review aimed to provide an overview of efficacy and mechanisms of traditional Chinese herbs and natural products in hyperuricemia-induced CKD.

Fatty acid-binding protein 4 is a therapeutic target for septic acute kidney injury by regulating inflammatory response and cell apoptosis.

Sepsis is a systemic inflammatory state in response to infection, and concomitant acute kidney injury (AKI) significantly increases morbidity and mortality. Growing evidence suggests that fatty acid-binding protein 4 (FABP4) is critically involved in kidney diseases, while its role in septic AKI remains unknown. Here, FABP4 was mainly upregulated in renal tubular epithelial cells (RTECs) following cecal ligation and puncture (CLP)- or lipopolysaccharide (LPS)-induced septic AKI. FABP4 inhibition by genetic deletion or BMS309403 treatment both attenuated kidney dysfunction and pathological injury in CLP- or LPS-treated mice. Notably, RTEC-specific deletion of FABP4 also showed similar renoprotective effects. Moreover, FABP4 inhibition alleviated inflammation and apoptosis in CLP-injured kidneys and LPS-stimulated mouse tubular epithelial cells. Mechanistically, TLR4 blockage improved sepsis-induced kidney injury, as well as suppressed c-Jun phosphorylation and FABP4 expression, where c-Jun knockdown also inhibited LPS-stimulated FABP4 level. Meanwhile, FABP4 inhibition reduced the elevated phosphorylated c-Jun, while the levels of TLR4 and MyD88 were uninfluenced. Collectively, the increased FABP4 in RTECs is dependent on TLR4/c-Jun signaling activation and contributes to kidney injury, by forming a positive feedback loop with c-Jun to aggravate inflammation and apoptosis in septic AKI. Thus, FABP4 may be a therapeutic target for septic AKI.

Blood Pressure Variability and Prognosis in Hemodialysis Patients: A Systematic Review and Meta-Analysis.

BACKGROUND: The prognostic value of blood pressure variability (BPV) in patients receiving hemodialysis is inconclusive. In this study, we aimed to assess the association between BPV and clinical outcomes in the hemodialysis population. METHODS: Pubmed/Medline, EMBASE, Ovid, the Cochrane Library, and the Web of Science databases were searched for relevant articles published until April 1, 2020. Studies on the association between BPV and prognosis in patients receiving hemodialysis were included. RESULTS: A total of 14 studies (37,976 patients) were included in the analysis. In patients receiving hemodialysis, systolic BPV was associated with higher all-cause (hazard ratio [HR]: 1.13; 95% confidence interval [CI]: 1.07-1.19; p < 0.001) and cardiovascular (HR: 1.16; 95% CI: 1.10-1.22; p < 0.001) mortality. In the stratified analysis of systolic BPV, interdialytic systolic BPV, rather than 44-h ambulatory systolic BPV or intradialytic systolic BPV, was identified to be related to both all-cause (HR: 1.11; 95% CI: 1.05-1.17; p = 0.001) and cardiovascular (HR: 1.14; 95% CI: 1.06-1.22; p < 0.001) mortality. Among the different BPV metrics, the coefficient of variation of systolic blood pressure was a predictor of both all-cause (p = 0.01) and cardiovascular (p = 0.002) mortality. Although diastolic BPV was associated with all-cause mortality (HR: 1.09; 95% CI: 1.01-1.17; p = 0.02) in patients receiving hemodialysis, it failed to predict cardiovascular mortality (HR: 0.86; 95% CI: 0.52-1.42; p = 0.56). CONCLUSIONS: This meta-analysis revealed that, in patients receiving hemodialysis, interdialytic systolic BPV was associated with both increased all-cause and cardiovascular mortality. Furthermore, the coefficient of variation of systolic blood pressure was identified as a potentially promising metric of BPV in predicting all-cause and cardiovascular mortality. The use of 44-h ambulatory systolic BPV, intradialytic systolic BPV, and metrics of diastolic BPV in the prognosis of the hemodialysis population require further investigation (PROSPERO registry number: CRD42019139215).

Natural flavonol fisetin attenuated hyperuricemic nephropathy via inhibiting IL-6/JAK2/STAT3 and TGF-ß/SMAD3 signaling.

BACKGROUND: The naturally occurring flavonol fisetin (3,3',4',7-tetrahydroxyflavone), widely dispersed in fruits, vegetables and nuts, has been reported to exert anti-inflammatory, antioxidant and anti-angiogenic effects. Our previous study indicated fisetin ameliorated inflammation and apoptosis in septic kidneys. However, the potential nephroprotective effect of fisetin in hyperuricemic mice remains unknown. PURPOSE: The current study was designed to investigate the effect of fisetin on hyperuricemic nephropathy (HN) and explore the underlying mechanisms. METHODS: The HN was induced in mice by mixing of potassium oxonate (2400 mg/kg) and adenine (160 mg/kg) in male C57BL/6J mice. Fisetin (50 or 100 mg/kg) was orally administrated either simultaneously with the establishment of HN or after HN was induced. As a positive control, allopurinol of 10 mg/kg was included. Uric acid levels in the serum and urine as well as renal function parameters were measured. Renal histological changes were measured by periodic acid-Schiff (PAS) and Masson's trichrome stainings. The expression of gene/protein in relation to inflammation, fibrosis, and uric acid excretion in the kidneys of HN mice or uric acid-treated mouse tubular epithelial (TCMK-1) cells were measured by RNA-seq, RT-PCR, western blot and immunohistochemical analysis. RESULTS: Treatment with fisetin, regardless of administration regimen, dose-dependently attenuated hyperuricemia-induced kidney injury as indicated by the improved renal function, preserved tissue architecture, and decreased urinary albumin-to-creatinine ratio. Additionally, fisetin lowered uricemia by modulating the expression of kidney urate transporters including urate transporter 1(URAT1), organic anion transporter 1 (OAT1), organic anion transporter 3 (OAT3) and ATP binding cassette subfamily G member 2 (ABCG2). Moreover, hyperuricemia-induced secretions of proinflammatory factors including tumor necrosis factor-alpha (TNF-α), interleukin 6 (IL-6) and monocyte chemoattractant protein-1(MCP-1) in HN mice and uric acid-stimulated TCMK-1 cells were mitigated by fisetin treatment. Meanwhile, fisetin attenuated kidney fibrosis in HN mice with restored expressions of alpha-smooth muscle actin (α-SMA), collagen I and fibronectin. Mechanistically, fisetin regulated the aberrant activation of signal transducer and activator of transcription-3 (STAT3) signaling and transforming growth factor-ß (TGF-ß) signaling in the HN kidneys and uric acid-stimulated TCMK-1 cells. CONCLUSION: Fisetin lowered uricemia, suppressed renal inflammatory response, and improved kidney fibrosis to protect against hyperuricemic nephropathy via modulation of STAT3 and TGF-ß signaling pathways. The results highlighted that fisetin might represent a potential therapeutic strategy against hyperuricemic nephropathy.

The diagnostic value of multi-detector CT angiography for catheter-related central venous stenosis in hemodialysis patients.

The objective is to compare Multi-detector CT angiography (MDCTA) and digital subtraction angiography (DSA) in diagnosing hemodialysis catheter related-central venous stenosis (CVS). During a period of 6 years, hemodialysis patients with suspected catheter related-CVS who received both MDCTA and DSA were retrospectively enrolled. We analyzed the sensitivity, specificity, accuracy, Cohen's kappa coefficient (κ) and other diagnostic parameters for MDCTA compared to DSA. A total of 1533 vascular segments in 219 patients were analyzed. Among the 280 lesions identified by DSA, 156 were correctly identified by MDCTA. There were 124 false negative and 41 false positive diagnoses. MDCTA had a high specificity (96.73%) but a low sensitivity (55.71%), with a moderate inter-test agreement (κ = 0.5930). In stratified analyses of vascular segments, the specificities of MDCTA were 89.93% (superior vena cava), 98.95% (left brachiocephalic vein), 95.33% (right brachiocephalic vein), 99.53% (left subclavian vein), 97.61% (right subclavian vein), 97.13% (left internal jugular vein), and 95.86% (right internal jugular vein), while the sensitivities were 90.00%, 65.52%, 66.67%, 87.50%, 40.00%, 20.00% and 8.11%, respectively. Good to excellent inter-test agreement was observed for the superior vena cava (κ = 0.7870), left brachiocephalic vein (κ = 0.7300), right brachiocephalic vein (κ = 0.6610), and left subclavian vein (κ = 0.8700) compared with poor to low agreement for the right subclavian vein (κ = 0.3950), left internal jugular vein (κ = 0.1890), and right internal jugular vein (κ = 0.0500). MDCTA had a high specificity in diagnosing hemodialysis catheter related-CVS. Its sensitivity varied by central venous segments, with better performance in superior vena cava and brachiocephalic veins.