Efficacy of Rituximab for Minimal Change Disease and Focal Segmental Glomerulosclerosis with Frequently Relapsing or Steroid-Dependent Nephrotic Syndrome in Adults: A Chinese Multicenter Retrospective Study.

INTRODUCTION: Rituximab has been proven effective and safe in pediatric patients with frequently relapsing or steroid-dependent nephrotic syndrome (FR/SDNS). We aimed to analyze the efficacy and safety of rituximab in adult FR/SDNS patients with minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS). METHODS: A retrospective cohort study at three nephrology centers in China included adult FR/SDNS patients with biopsy-proven MCD or FSGS. Primary outcomes were relapse frequency and first relapse-free survival time. Adverse events were well recorded, and logistic regression analyses were used to investigate the risk factors of relapse. RESULTS: Eighty-one patients (age, 25.0 years; interquartile range, 20.0-40.5; 67% males; 82.7% MCD) received an average rituximab dose of 1,393.8 ± 618.7 mg/2 years during the 2-year follow-up period. The relapse frequency, calculated as the ratio of relapse times to follow-up years, significantly decreased after rituximab treatment (0.04 [0.00, 0.08] vs. 1.71 [1.00, 2.45], p < 0.001). The first relapse-free survival time was 16.7 ± 8.0 months. Fifty-seven patients (70.4%) achieved cessation of corticosteroids and immunosuppressants within 3 months after the first rituximab infusion. Adverse events were mostly mild, and no severe treatment-related adverse events were observed. Low serum albumin level before rituximab and high CD56+CD16+ natural killer cell count after rituximab were independent risk factors of relapse within 2 years after rituximab treatment. CONCLUSION: Rituximab was proven an effective and safe treatment option for adult FR/SDNS patients with MCD or FSGS in maintaining disease remission and minimizing corticosteroid exposure.

Development of a risk prediction nomogram for sarcopenia in hemodialysis patients.

BACKGROUND: Sarcopenia is associated with various adverse outcomes in hemodialysis patients. However, current tools for assessing and diagnosing sarcopenia have limited applicability. In this study, we aimed to develop a simple and reliable nomogram to predict the risk of sarcopenia in hemodialysis patients that could assist physicians identify high-risk patients early. METHODS: A total of 615 patients undergoing hemodialysis at the First Affiliated Hospital College of Medicine Zhejiang University between March to June 2021 were included. They were randomly divided into either the development cohort (n = 369) or the validation cohort (n = 246). Multivariable logistic regression analysis was used to screen statistically significant variables for constructing the risk prediction nomogram for Sarcopenia. The line plots were drawn to evaluate the effectiveness of the nomogram in three aspects, namely differentiation, calibration, and clinical net benefit, and were further validated by the Bootstrap method. RESULTS: The study finally included five clinical factors to construct the nomogram, including age, C-reactive protein, serum phosphorus, body mass index, and mid-upper arm muscle circumference, and constructed a nomogram. The area under the ROC curve of the line chart model was 0.869, with a sensitivity and specificity of 77% sensitivity and 83%, the Youden index was 0.60, and the internal verification C-statistic was 0.783. CONCLUSIONS: This study developed and validated a nomogram model to predict the risk of sarcopenia in hemodialysis patients, which can be used for early identification and timely intervention in high-risk groups.

Comparison of Three Methods Estimating Baseline Creatinine For Acute Kidney Injury in Hospitalized Patients: a Multicentre Survey in Third-Level Urban Hospitals of China.

BACKGROUND/AIMS: A lack of baseline serum creatinine (SCr) data leads to underestimation of the burden caused by acute kidney injury (AKI) in developing countries. The goal of this study was to investigate the effects of various baseline SCr analysis methods on the current diagnosis of AKI in hospitalized patients. METHODS: Patients with at least one SCr value during their hospital stay between January 1, 2011 and December 31, 2012 were retrospectively included in the study. The baseline SCr was determined either by the minimum SCr (SCrMIN) or the estimated SCr using the MDRD formula (SCrGFR-75). We also used the dynamic baseline SCr (SCrdynamic) in accordance with the 7 day/48 hour time window. AKI was defined based on the KDIGO SCr criteria. RESULTS: Of 562,733 hospitalized patients, 350,458 (62.3%) had at least one SCr determination, and 146,185 (26.0%) had repeat SCr tests. AKI was diagnosed in 13,883 (2.5%) patients using the SCrMIN, 21,281 (3.8%) using the SCrGFR-75 and 9,288 (1.7%) using the SCrdynamic. Compared with the non-AKI patients, AKI patients had a higher in-hospital mortality rate regardless of the baseline SCr analysis method. CONCLUSIONS: Because of the scarcity of SCr data, imputation of the baseline SCr is necessary to remedy the missing data. The detection rate of AKI varies depending on the different imputation methods. SCrGFR-75 can identify more AKI cases than the other two methods.

[Epidemiology of acute kidney injury in hospitalized patients in China].

Acute kidney injury (AKI) is a disease spectrum ranging from minimal elevation of serum creatinine to complete renal failure. It is significantly associated with increased mortality, length of hospital stay and medical care cost. With the increasing awareness of the importance of AKI, several high quality and multicenter epidemiological studies have been published recently in China. However, the results differ a lot due to the differences in regional economic development, the selection of target population and testing indicators, the disease definition and study strategies. The reported incidence of AKI in China is much lower than that in the developed countries. This article will analyze the current status and the problems facing AKI epidemiological studies of hospitalized patients with our own data and those from literature. The article intends to clarify the burden of AKI,to increase the awareness of AKI among clinicians and policy makers for achieving the goal of "zero by 2025" in China.

Remote ischemic preconditioning for prevention of acute kidney injury: a meta-analysis of randomized controlled trials.

BACKGROUND: Remote ischemic preconditioning (RIPC) to prevent acute kidney injury (AKI) following cardiac and vascular interventions is a controversial practice. STUDY DESIGN: We conducted a systematic review and meta-analysis using the MEDLINE database (1966 through November 2013), EMBASE (1988 through November 2013), and Cochrane Library database. SETTING & POPULATION: Patients undergoing cardiac and vascular interventions. SELECTION CRITERIA FOR STUDIES: Randomized controlled trials comparing patient outcome with or without RIPC for prevention of AKI following cardiac and vascular interventions. INTERVENTION: RIPC using an inflatable tourniquet around the limb or cross-clamping the iliac arteries versus non-RIPC. OUTCOMES: AKI, need for renal replacement therapy, postoperative kidney biomarkers, in-hospital mortality, and length of intensive care unit and hospital stay. RESULTS: 13 trials (1,334 participants) were included. RIPC decreased the risk of AKI for patients undergoing cardiac and vascular interventions compared with the control group (11 trials; 1,216 participants; risk ratio [RR], 0.70; 95% CI, 0.48-1.02; P = 0.06; I(2) = 45%) with marginal statistical significance. There were no differences in levels of postoperative kidney biomarkers (serum creatinine and glomerular filtration rate), incidence of renal replacement therapy, in-hospital mortality, hospital stay, or intensive care unit stay between the 2 groups. Metaregression analysis indicated that contrast intervention was not a covariate contributing significantly to heterogeneity on the risk estimate for AKI incidence; also, there was no dose effect of RIPC using tourniquet cuff around the limb on AKI prevention based on different ischemia duration. LIMITATIONS: Different AKI definitions adopted in the trials included. CONCLUSIONS: RIPC might be beneficial for the prevention of AKI following cardiac and vascular interventions, but the current evidence is not robust enough to make a recommendation. Adequately powered trials are needed to provide more evidence in the future.

Characterization and Function of the Interaction of Angiogenin With Alpha-Actinin 2.

Angiogenin (ANG) is the first human tumor-derived angiogenic protein, which can promote angiogenesis and tumor growth. In a previous study, we identified alpha-actinin 2 (ACTN2), a cytoskeletal protein, as a direct interacting protein with angiogenin. However, the interaction between ANG and ACTN2 was not characterized in detail, which may provide information on the molecular mechanisms of ANG functions. In this study, we mapped the accurate binding domain and sites in ANG and ACTN2, respectively. In ANG, the residues from 83 to 105 are the smallest motif that can bind to ACTN2. We then use site mutation analysis to identify the precise binding sites of ANG in the interaction and found that the 101st residue arginine (R101) represents the critical residue involved in the ANG-ACTN2 interaction. In ACTN2, the residues from 383 to 632, containing two spectrin domains in the middle of the rod structure of ACTN2, play an important role in the interaction. Furthermore, we validated the interaction of ACTN2-383-632 to ANG by glutathione-S-transferase (GST) pull-down assay. In functional analysis, overexpressed ACTN2-383-632 could impair tumor cell motility observably, including cell migration and invasion. Meanwhile, ACTN2-383-632 overexpression inhibited tumor cell proliferation and survival as well. These data suggest that an excess expression of ACTN2 segment ACTN2-383-632 can inhibit tumor cell motility and proliferation by interfering with the interaction between ANG and ACTN2, which provides a potential mechanism of ANG action in tumor growth and metastasis.

Role of Age-Related Changes in DNA Methylation in the Disproportionate Susceptibility and Worse Outcomes of Sepsis in Older Adults.

Sepsis, a complex multisystem disorder, is among the top causes of hospitalization and mortality in older adults. However, the mechanisms underlying the disproportionate susceptibility to sepsis and worse outcomes in the elderly are not well understood. Recently, changes in DNA methylation have been shown to be linked to aging processes and age-related diseases. Thus, we postulated that age-related changes in DNA methylation may play a role in the onset and prognosis of sepsis in elderly patients. Here, we performed genome-wide methylation profiling of peripheral blood from patients with sepsis and controls. Among the CpG sites whose methylation changes may contribute to an increase in sepsis susceptibility or mortality, 241 sites that possessed age-related changes in DNA methylation in controls may partly explain the increased risk of sepsis in older adults, and 161 sites whose methylation significantly correlated with age in sepsis group may be the potential mechanisms underlying the worse outcomes of elderly septic patients. Finally, an independent cohort was used to validate our findings. Together, our study demonstrates that age-related changes in DNA methylation may explain in part the disproportionate susceptibility and worse outcomes of sepsis in older adults.

The clinicopathological features of drug-induced acute kidney injury-a single-center retrospective analysis.

BACKGROUND: This study aimed to analyze changes to the drug spectrum and clinicopathological features of drug-induced acute kidney injury (AKI) with recent medication habits changes. METHODS: A retrospective analysis of the characteristics of patients diagnosed with drug-induced AKI from January 2012 to October 2016 period at the First Affiliated Hospital of the Medical College of Zhejiang University was conducted. RESULTS: Between January 2012 and October 2016, 909 patients were diagnosed with AKI. Of these, 228 were diagnosed with drug-related AKI were engaged in this study, including 51 who underwent renal biopsies, 74 treated with antibacterial and antiviral drugs, and 63 who received nonsteroidal anti-inflammatory drugs (NSAIDs), and 17 who were treated with Chinese herbal medicine. AKI was most frequently associated with antibiotics and antiviral drugs, including cephalosporins, acyclovir, azithromycin, clindamycin, and levofloxacin. In those who underwent renal biopsy, 12 patients were diagnosed with allergic interstitial nephritis, 19 with interstitial nephritis, 8 with renal tubular epithelial cell injury, 2 with minimal change nephropathy, 2 with IgA nephropathy, and 2 with mild mesangial hyperplasia with glomerulosclerosis. The mean follow-up time was 437 days, ranging from 3 to 2,756 days. Among 228 patients, 165 recovered completely, 4 recovered partially, 8 did not recover, and 51 were lost to follow-up after discharge. CONCLUSIONS: The three main contributors to drug-induced AKI were antimicrobial agents, NSAIDs, and Chinese herbal medicines. The age distribution of the three different drug-induced AKI groups was significantly different. Allergic interstitial nephritis, interstitial nephritis, and tubular epithelial cell injury were the main pathological manifestations of drug-induced AKI. The novel predictive nomogram achieved a good performance of prediction recovery within 2 weeks in drug-induced AKI patients.

Inhibiting DNA Methylation Improves Survival in Severe Sepsis by Regulating NF-κB Pathway.

Organ dysfunction caused by sepsis is life-threatening and results in high mortality. Therapeutic options for sepsis are limited. Pathogenic factors are considered as components of environmental pressure that modify DNA methylation patterns thereby enhancing disease progression. Here, we found that sepsis patients exhibited higher levels of genomic DNA methylation patterns and hypermethylated genes associated with the NF-kB signaling pathway. Therefore, we hypothesized that a DNA methyl transferase inhibitor, Decitabine, may mitigate inflammation and improve survival by inhibiting the NF-κB signaling pathway. To test the hypothesis, mice challenged with caecal ligation and puncture (CLP) were subcutaneously injected with Decitabine solution (0.5, 1, and 1.5 mg/kg) 2 h following operation. Our results indicated that Decitabine reduces DNA methyltransferases (DNMTs), attenuates NF-κB activation, downregulates inflammatory cytokine levels, and inhibits the progression of sepsis. Thus, DNA methylation may be indispensable for sepsis and serve as a predicting factor. The use of Decitabine could represent a novel strategy in the treatment of sepsis.

Association between Blood Potassium Level and Recovery of Postoperative Gastrointestinal Motility during Continuous Renal Replacement Therapy in Patient Undergoing Open Abdominal Surgery.

BACKGROUND: The aim of this study was to identify the blood potassium level beneficial to the postoperative recovery of gastrointestinal motility during continuous renal replacement therapy (CRRT) in patient undergoing open abdominal surgery. MATERIALS AND METHODS: 538 critically ill patients after open abdominal surgery and receiving CRRT were retrospectively recruited as the study cohort. Demographic and clinical data were recorded along with an evaluation of the postoperative gastrointestinal motility. RESULTS: Correlation analysis was used to assess the correlation coefficient, and then the variables with correlation coefficient value less than 0.5 were included in the binary logistic regression model. Binary logistic regression model indicated that the postoperative blood potassium level was independently associated with the recovery of gastrointestinal motility (OR=0.109, 95% CI= 0.063 to 0.190, p<0.001). Based on the normal range of blood potassium level, we selected the cut-off point of blood potassium level via Weight of Evidence analysis, which was 4.00 mmol/L. Compared with the patients with insufficient blood potassium levels (plasma potassium concentration < 4.00 mmol/L), those with sufficient blood potassium levels (plasma potassium concentration≥ 4.00 mmol/L) conferred an increase in the rate of 4-day postoperative recovery of gastrointestinal motility (OR= 4.425, 95% CI = 2.933 to 6.667, p<0.001). CONCLUSIONS: Maintaining the blood potassium concentrations at a relatively high level of the normal blood potassium range during CRRT would be beneficial to postoperative recovery of gastrointestinal motility.

Effect of remote ischemic preconditioning on postoperative acute kidney injury among patients undergoing cardiac and vascular interventions: a meta-analysis.

It is currently controversial whether remote ischemic preconditioning (RIPC) reduces the incidence of acute kidney injury (AKI) in patients undergoing cardiovascular interventions. The main objective of this meta-analysis was to investigate whether RIPC provides renal protection for patients undergoing cardiac or vascular surgery. We searched the PubMed database (1966-Oct 2015), Embase database (1966-Oct 2015), Google Scholar, Cochrane Library, ClinicalTrials Database and Open Grey. Then we conducted a meta-analysis of the randomized controlled trials that met the inclusion criteria of our study. The interventions included use of an inflatable tourniquet around the limbs or cross-clamping of the iliac arteries before surgery (RIPC groups) and general cardiovascular intervention (control groups). The main outcomes examined included the incidence of AKI; changes in acute kidney injury biomarkers; and use of renal replacement therapy. Other outcomes examined included in-hospital mortality and the lengths of hospital stay and intensive care unit (ICU) stay. Finally, we screened 26 eligible studies containing 6699 patients who underwent cardiac or vascular interventions with RIPC (n = 3343) or without RIPC (n = 3356). The AKI incidence was decreased in the RIPC group as was the length of ICU stay. There were no differences in the changes in AKI biomarkers, use of renal replacement therapy or in-hospital mortality between the two groups. Remote ischemic preconditioning may decrease the occurrence of AKI in cardiovascular surgery patients. Since studies included have a significant heterogeneity, meta-analyses using a stricter inclusion criteria are needed to clarify the renoprotection effect of RIPC.

Monocyte Chemotactic Protein-1, Fractalkine, and Receptor for Advanced Glycation End Products in Different Pathological Types of Lupus Nephritis and Their Value in Different Treatment Prognoses.

BACKGROUND: Early diagnosis is important for the outcome of lupus nephritis (LN). However, the pathological type of lupus nephritis closely related to the clinical manifestations; therefore, the treatment of lupus nephritis depends on the different pathological types. OBJECTIVE: To assess the level of monocyte chemotactic protein (MCP-1), fractalkine (Fkn), and receptor for advanced glycation end product (RAGE) in different pathological types of lupus nephritis and to explore the value of these biomarkers for predicting the prognosis of lupus nephritis. METHODS: Patients included in this study were assessed using renal biopsy. Class III and class IV were defined as the proliferative group, class V as non-proliferative group, and class V+III and class V+IV as the mixed group. During the follow-up, 40 of 178 enrolled patients had a poor response to the standard immunosuppressant therapy. The level of markers in the different response groups was tested. RESULTS: The levels of urine and serum MCP-1, urine and serum fractalkine, and serum RAGE were higher in the proliferative group, and lower in the non-proliferative group, and this difference was significant. The levels of urine and serum MCP-1 and serum RAGE were lower in the poor response group, and these differences were also significant. The relationship between urine MCP-1 and urine and serum fractalkine with the systemic lupus erythematosus disease activity index was evaluated. CONCLUSION: The concentration of cytokines MCP-1, fractalkine, and RAGE may be correlated with different pathology type of lupus nephtitis. Urine and serum MCP-1 and serum RAGE may help in predicting the prognosis prior to standard immunosuppressant therapy.

Effects of rapamycin against paraquat-induced pulmonary fibrosis in mice.

BACKGROUND AND AIMS: Ingestion of paraquat (PQ), a widely used herbicide, can cause severe toxicity in humans, leading to a poor survival rate and prognosis. One of the main causes of death by PQ is PQ-induced pulmonary fibrosis, for which there are no effective therapies. The aim of this study was to evaluate the effects of rapamycin (RAPA) on inhibiting PQ-induced pulmonary fibrosis in mice and to explore its possible mechanisms. METHODS: Male C57BL/6J mice were exposed to either saline (control group) or PQ (10 mg/kg body weight, intraperitoneally; test group). The test group was divided into four subgroups: a PQ group (PQ-exposed, non-treated), a PQ+RAPA group (PQ-exposed, treated with RAPA at 1 mg/kg intragastrically), a PQ+MP group (PQ-exposed, treated with methylprednisolone (MP) at 30 mg/kg intraperitoneally), and a PQ+MP+RAPA group (PQ-exposed, treated with MP at 30 mg/kg intraperitoneally and with RAPA at 1 mg/kg intragastrically). The survival rate and body weight of all the mice were recorded every day. Three mice in each group were sacrificed at 14 d and the rest at 28 d after intoxication. Lung tissues were excised and stained with hematoxylin-eosin (H&E) and Masson's trichrome stain for histopathological analysis. The hydroxyproline (HYP) content in lung tissues was detected using an enzyme-linked immunosorbent assay (ELISA) kit. The expression of transforming growth factor-ß1 (TGF-ß1) and α-smooth muscle actin (α-SMA) in lung tissues was detected by immunohistochemical staining and Western blotting. RESULTS: A mice model of PQ-induced pulmonary fibrosis was established. Histological examination of lung tissues showed that RAPA treatment moderated the pathological changes of pulmonary fibrosis, including alveolar collapse and interstitial collagen deposition. HYP content in lung tissues increased soon after PQ intoxication but had decreased significantly by the 28th day after RAPA treatment. Immunohistochemical staining and Western blotting showed that RAPA treatment significantly down-regulated the enhanced levels of TGF-ß1 and α-SMA in lung tissues caused by PQ exposure. However, RAPA treatment alone could not significantly ameliorate the lower survival rate and weight loss of treated mice. MP treatment enhanced the survival rate, but had no significant effects on attenuating PQ-induced pulmonary fibrosis or reducing the expression of TGF-ß1 and α-SMA. CONCLUSIONS: This study demonstrates that RAPA treatment effectively suppresses PQ-induced alveolar collapse and collagen deposition in lung tissues through reducing the expression of TGF-ß1 and α-SMA. Thus, RAPA has potential value in the treatment of PQ-induced pulmonary fibrosis.