Telitacicept Treatment Refractory Lupus Nephritis: A Case Report.

Introduction: Refractory lupus nephritis (LN) causes kidney disease progression and increases the risk of loss of renal function. Due to the high specificity and few side effects of biological agents, they are recommended for the treatment of systemic lupus erythematosus. There are few data on telitacicept for the treatment of refractory LN. Case Presentation: Here, we report the efficacy and safety of telitacicept in the treatment of refractory LN in a 25-year-old female patient. This patient with refractory lupus developed Pneumocystis jirovecii pneumonia while using multitargeted therapy, and the patient's urine protein was rapidly relieved after telitacicept combination with low-dose mycophenolate mofetil (MMF). Conclusion: This result suggests that telitacicept has a positive effect on refractory LN with no significant side effects. Further reports and a registry are necessary to confirm that telitacicept with low-dose MMF should be preferred in refractory LN.

Validation of metagenomic next-generation sequencing of bronchoalveolar lavage fluid for diagnosis of suspected pulmonary infections in patients with systemic autoimmune rheumatic diseases receiving immunosuppressant therapy.

Background: The accuracy and sensitivity of conventional microbiological tests (CMTs) are insufficient to identify opportunistic pathogens in patients with systemic autoimmune rheumatic diseases (SARDs). The study aimed to assess the usefulness of metagenomic next-generation sequencing (mNGS) vs. CMTs for the diagnosis of pulmonary infections in patients with SARDs receiving immunosuppressant therapy. Methods: The medical records of 40 patients with pulmonary infections and SARDs treated with immunosuppressants or corticosteroids were reviewed retrospectively. Bronchoalveolar lavage fluid (BALF) samples were collected from all patients and examined by mNGS and CMTs. Diagnostic values of the CMTs and mNGS were compared with the clinical composite diagnosis as the reference standard. Results: Of the 40 patients included for analysis, 37 (92.5%) were diagnosed with pulmonary infections and 3 (7.5%) with non-infectious diseases, of which two were considered primary diseases and one an asthma attack. In total, 15 pathogens (7 bacteria, 5 fungi, and 3 viruses) were detected by CMTs as compared to 58 (36 bacteria, 12 fungi, and 10 viruses) by mNGS. Diagnostic accuracy of mNGS was superior to that of the CMTs for the detection of co-infections with bacteria and fungi (95 vs. 53%, respectively, p < 0.01), and for the detection of single infections with fungi (97.5 vs. 55%, respectively, p < 0.01). Of the 31 patients diagnosed with co-infections, 4 (12.9%) were positive for two pathogens and 27 (87.1%) for three or more. The detection rate of co-infection was significantly higher for mNGS than CMTs (95 vs. 16%, respectively, p < 0.01). Conclusion: The accuracy of mNGS was superior to that of the CMTs for the diagnosis of pulmonary infections in patients with SARDs treated with immunosuppressants. The rapid diagnosis by mNGS can ensure timely adjustment of treatment regimens to improve diagnosis and outcomes.

A Case of Lupus Nephritis Preceded by Minimal Change Disease and Membranous Glomerulonephritis.

BACKGROUND Lupus nephritis (LN) is the most common and serious complication of systemic lupus erythematosus (SLE). Minimal change disease (MCD) and primary membranous nephropathy (PMN) are the 2 most common causes of primary nephrotic syndrome. Our purpose in publishing this case report is to introduce an unusual clinical course and initial renal biopsy revealed MCD and then PMN in second renal biopsy. Subsequently, a third renal biopsy resulted in a final diagnosis of LN. To the best of our knowledge, this is the first such report. CASE REPORT The 31-year-old male patient was initially diagnosed with MCD after the first renal biopsy in 2004. He improved with initial management and had a complete remission for 9 years. After 9 years, the patient again presented with heavy proteinuria without systemic lupus erythematous finding and he was diagnosed with MN following the second renal biopsy. Seven years later, he again developed proteinuria alone with concurrent systemic symptoms of systemic lupus erythematosus, and a third biopsy was performed, leading to final diagnosis as LN. He was well managed with the methylprednisolone and cyclophosphamide (CTX) regimen, which improved renal function and spared the patient from continuous hemodialysis. CONCLUSIONS In rare case, MCD may represent an early phase of lupus nephritis, which may subsequently develop into severe lupus nephritis.

COMMD5 is involved in the mechanisms of hypotension after parathyroidectomy in patients receiving hemodialysis.

BACKGROUND: Secondary hyperparathyroidism (SHPT) is a common complication of end-stage renal disease. Parathyroidectomy (PTx) is often employed for treatment of severe SHPT. However, PTx may cause hypotension via unknown mechanisms. COMM domain-containing protein 5 (COMMD5) in the parathyroid glands has been linked to blood pressure regulation of spontaneously hypertensive rats. OBJECTIVE: To explore the relationship between COMMD5 levels and reduced BP after PTx in patients receiving hemodialysis (HD). METHODS AND RESULTS: (1) The study cohort included 31 patients receiving HD who underwent PTx. Serum COMMD5 levels were higher post-PTx vs. pre-PTx. (2) Sprague-Dawley rats (n = 22) were assigned to a 5/6 nephrectomy group or sham surgery group, vascular rings of the thoracic aorta from rats with CKD were incubated with COMMD5, and changes in vascular tension were compared. COMMD5 inhibited vasoconstriction of vascular rings with intact endothelium, but had no effect on vascular rings without the endothelium. (3) Human umbilical vein endothelial cells were stimulated with COMMD5 or small interfering RNA (siRNA). The expression levels of atrial natriuretic peptide (ANP) and endothelial nitric oxide synthase (eNOS) were up-regulated and down-regulated, respectively. CONCLUSIONS: Serum COMMD5 levels were increased after PTx in SHPT patients. COMMD5 promoted high expression of ANP and eNOS in endothelial cells, leading to vasodilation and resulting in hypotension.

Impact of the COVID-19 pandemic on patients with chronic kidney disease: A narrative review.

ABSTRACT: Severe acute respiratory disease coronavirus 2 is currently causing the coronavirus disease 2019 (COVID-19) pandemic, placing extreme strain on the global health system. Vaccination is the main measure for preventing the COVID-19 epidemic, especially for high-risk groups including patients with chronic kidney disease (CKD). However, CKD patients receiving dialysis or kidney transplant may be characterized by decreased renal function and immune disorders, which may have uncertainties in their health. This overview aims to introduce the possible impact of the COVID-19 vaccine on kidney disease and its application in patients with CKD to provide evidence for the COVID-19 vaccine in patients with CKD. The data for this study were collected from PubMed, Cochrane Library, Embase, ClinicalTrials.gov, and the China Knowledge Resource Integrated Database (CNKI). The following keywords were used: "COVID-19", "COVID-19 vaccine," and "CKD". The publication time of the papers was set from the establishment of the databases to September 2021. A total of 47 studies were included, and patients with CKD are a high-risk group for COVID-19 infection and severe illness. Vaccination is a powerful tool for preventing CKD patients from COVID-19. Because of possible side effects, the recurrence or deterioration of kidney disease may occur in CKD patients after vaccination. Although vaccination for patients with CKD remains a problem, with the advantages outweighing the disadvantages, stable CKD patients should complete a vaccination plan, and doctors should be aware of the recurrence or deterioration of kidney disease and close monitoring. DATA ACCESS STATEMENT: Research data supporting this publication are available from the electronic databases of PubMed, Cochrane Library, Embase, ClinicalTrials.gov, and the China Knowledge Resource Integrated Database (CNKI).

Hydroxyapatite nanoparticles promote mitochondrial-based pyroptosis via activating calcium homeostasis and redox imbalance in vascular smooth muscle cells.

Hydroxyapatite nanoparticles (HAP) have been widely used in various fields because of their natural biological origin and functional properties. The emerging evidence on their toxicities has attracted research interest. HAP-induced vascular smooth muscle cell (VSMC) damage is a key step in vascular calcification (VC), particularly in patients with chronic kidney disease. However, the injury effects and mechanism of action of HAP on VSMCs have not been extensively investigated. This study comprehensively characterized commercially available HAP and investigated its adverse biological effects in cultured A7R5 cells.In vitroexperiments revealed that internalized HAP was localized in lysosomes, followed by the release of Ca2+owing to the low pH microenvironment. Upon Ca2+homeostasis, Ca2+enters the mitochondria, leading to the simultaneous generation of reactive oxygen species (ROS). ROS subsequently attack mitochondrial transmembrane potentials, promote mitochondrial ROS production, and oxidize mitochondrial DNA (Ox-mtDNA). Mitochondrial permeability-transition pores open, followed by the release of more Ox-mtDNA from the mitochondria into the cytosol due to the redox imbalance. This activates NLRP3/caspase-1/gasdermin D-dependent pyroptosis and finally excretes inflammatory factors to induce VC; an antioxidant could rescue this process. It has been suggested that HAP could induce an imbalance in intracellular Ca2+homeostasis in A7R5 cells, followed by the promotion of mitochondrial dysfunction and cell pyroptosis, finally enhancing VC. To detect thein vivotoxicity of HAP, mice were treated with Cy7-labelled HAP NPs for 24 h.In vivoresults also demonstrated that HAP accumulated in the kidneys, accompined with increased Ca concentration, upregulated oxidative stress-related factor and kidney damage. Overall, our research elucidates the mechanism of calcium homeostasis and redox imbalance, providing insights into the prevention of HAP-induced cell death.

RAGE mediates airway inflammation via the HDAC1 pathway in a toluene diisocyanate-induced murine asthma model.

BACKGROUND: Exposure to toluene diisocyanate (TDI) is a significant pathogenic factor for asthma. We previously reported that the receptor for advanced glycation end products (RAGE) plays a key role in TDI-induced asthma. Histone deacetylase (HDAC) has been reported to be important in asthmatic pathogenesis. However, its effect on TDI-induced asthma is not known. The aim of this study was to determine the role of RAGE and HDAC in regulating airway inflammation using a TDI-induced murine asthma model. METHODS: BALB/c mice were sensitized and challenged with TDI to establish an asthma model. FPS-ZM1 (RAGE inhibitor), JNJ-26482585 and romidepsin (HDAC inhibitors) were administered intraperitoneally before each challenge. In vitro, the human bronchial epithelial cell line 16HBE was stimulated with TDI-human serum albumin (TDI-HSA). RAGE knockdown cells were constructed and evaluated, and MK2006 (AKT inhibitor) was also used in the experiments. RESULTS: In TDI-induced asthmatic mice, the expression of RAGE, HDAC1, and p-AKT/t-AKT was upregulated, and these expressions were attenuated by FPS-ZM1. Airway reactivity, Th2 cytokine levels in lymph supernatant, IgE, airway inflammation, and goblet cell metaplasia were significantly increased in the TDI-induced asthmatic mice. These increases were suppressed by JNJ-26482585 and romidepsin. In addition, JNJ-26482585 and romidepsin ameliorated the redistribution of E-cadherin and ß-catenin in TDI-induced asthma. In TDI-HSA-stimulated 16HBE cells, knockdown of RAGE attenuated the upregulation of HDAC1 and phospho-AKT (p-AKT). Treatment with the AKT inhibitor MK2006 suppressed TDI-induced HDAC1 expression. CONCLUSIONS: These findings indicate that RAGE modulates HDAC1 expression via the PI3K/AKT pathway, and that inhibition of HDAC prevents TDI-induced airway inflammation.

Roxadustat Improves Erythropoietin Antibody-Mediated Pure Red Cell Aplasia in a Patient with Hemodialysis.

Anemia is a common complication of chronic kidney disease (CKD). Recombinant human erythropoietin (rHu-EPO) is used extensively in patients with CKD. However, anti-erythropoietin (anti-EPO) antibody has been reported during rHu-EPO treatment, which causes pure red cell aplasia (PRCA). We presented a case of 75-year-old man, who underwent hemodialysis for 2 years. He developed PRCA during rHu-EPO treatment. The rHu-EPO was immediately discontinued, and the patient was given roxadustat treatment. After 6 months of roxadustat treatment, the anti-EPO antibody was disappeared, and hemoglobin recovered normal range. The results suggest that roxadustat can be used to treat patients with anti-EPO antibody-mediated PRCA without immunosuppressive therapy.

Comparison of 6 equations for estimating glomerular filtration rate in a Chinese benign hypertensive nephrosclerosis population.

ABSTRACT: Equations to estimate glomerular filtration rate (eGFR) are useful for monitoring tje renal status of benign hypertensive nephrosclerosis (BHN). This study aimed to compare the applicability of 6 equations (Cockcroft-Gault [CG] adjusted for body surface area, original modification of diet in renal disease [MDRD], American abbreviated MDRD, Chinese modified MDRD, Chinese abbreviated MDRD, and Chronic Kidney Disease Epidemiology [CKD-EPI]) to estimate GFR in a Chinese BHN population. A total of 179 patients diagnosed with BHN were enrolled. The GFR estimated by each equation was compared to the reference GFR (rGFR) measured using the dual plasma sampling technetium-labeled diethylenetriaminepentaacetic acid method. The Chinese modified and Chinese abbreviated MDRD equations overestimated the rGFR, while the CG, CG adjusted for body surface area, original MDRD, American abbreviated MDRD, and CKD-EPI equations underestimated the rGFR. The difference in performance between estimated GFR (eGFR) based on the American abbreviated MDRD equation and the rGFR was not statistically significant (P = .191), while differences in the others were statistically significant (P < .05). Furthermore, the advantages in deviation, absolute deviation, deviation degree, precision, and accuracy were also significantly different from those of the other equations. Our findings suggest that eGFR based on the American abbreviated MDRD equation is suitable for the Chinese BHN population.

GAP-43 ameliorates Podocyte injury by decreasing nuclear NFATc1 expression.

Podocyte injury is sufficient to cause glomerulosclerosis and proteinuria, eventually leading to kidney failure. Previous studies found that podocytes and neurons had similar biological characteristics. Growth-associated protein-43 (GAP-43) is a growth cone protein in neurons, and a marker of axonal and synaptic growth. However, it is not known whether GAP-43 is expressed in podocytes. Compared with normal glomerular podocytes, GAP-43 was significantly reduced in patients with glomerular diseases. GAP-43 also significantly reduced in lipopolysaccharide (LPS)-treated podocytes. We found that the decreased expression of nephrin, the cell marker of the podocyte, was significantly recovered with GAP-43 overexpression. In contrast, the migration ability in LPS-treated podocyte was reduction after GAP-43 overexpressing. Moreover, overexpression of GAP-43 attenuated podocyte apoptosis by up-regulating the ratio of Bcl-2/Bax with LPS treatment. Finally, Plaue and Rcan1 which are downstream target gene of NFATc1 decreased with overexpression of GAP-43 podocytes. We concluded that GAP-43 attenuated podocyte injury by inhibiting calcineurin/NFATc1 signaling. The findings may provide a promising treatment for podocyte injury-related diseases.

PPBP as a marker of diabetic nephropathy podocyte injury via Bioinformatics Analysis.

Diabetic nephropathy (DN) is a type of kidney injuries associated with diabetes mellitus and the prevalence of DN has increased dramatically. However, DN still pose problems in therapy, and prognosis. Identifying new DN biomarkers would be helpful in reducing morbidity and mortality from DN and developing novel preventive approaches. In the study, from GSE36336 dataset with DN glomeruli samples, we screened for 238 differentially expressed genes. Enrichment analysis were performed to find out biological function and diseases of DEGs. Next, depended on protein-protein interaction network, We identified top 10 hub genes (Serpine1, Cxcl10, Cfd, Ppbp, Retn, Socs2, Ccr5, Mmp8, Pf4, Cxcl9) may played potential roles in DN. Meanwhile, transcriptome sequencing on podocyte were performed to reconfirm the reliability of Ppbp. To verify the efficiency of the selected genes as biomarkers, several experiments like qRT-PCR, renal histologic analysis and immunofluorescence were conducted to validate. Our results showed that PPBP have the potential to become a novel biomarker for DN podocyte injury.

Receptor activator of NF-κB mediates podocyte injury in diabetic nephropathy.

Receptor activator of NF-κB (RANK) expression is increased in podocytes of patients with diabetic nephropathy. However, the relevance of RANK to diabetic nephropathy pathobiology remains unclear. Here, to evaluate the role of podocyte RANK in the development of diabetic nephropathy, we generated a mouse model of podocyte-specific RANK depletion (RANK-/-Cre T), and a model of podocyte-specific RANK overexpression (RANK TG), and induced diabetes in these mice with streptozotocin. We found that podocyte RANK depletion alleviated albuminuria, mesangial matrix expansion, and basement membrane thickening, while RANK overexpression aggravated these indices in streptozotocin-treated mice. Moreover, streptozotocin-triggered oxidative stress was increased in RANK overexpression but decreased in the RANK depleted mice. Particularly, the expression of NADPH oxidase 4, and its obligate partner, P22phox, were enhanced in RANK overexpression, but reduced in RANK depleted mice. In parallel, the transcription factor p65 was increased in the podocyte nuclei of RANK overexpressing mice but decreased in the RANK depleted mice. The relevant findings were largely replicated with high glucose-treated podocytes in vitro. Mechanistically, p65 could bind to the promoter regions of NADPH oxidase 4 and P22phox, and increased their respective gene promoter activity in podocytes, dependent on the levels of RANK. Taken together, these findings suggested that high glucose induced RANK in podocytes and caused the increase of NADPH oxidase 4 and P22phox via p65, possibly together with the cytokines TNF- α, MAC-2 and IL-1 ß, resulting in podocyte injury. Thus, we found that podocyte RANK was induced in the diabetic milieu and RANK mediated the development of diabetic nephropathy, likely by promoting glomerular oxidative stress and proinflammatory cytokine production.

[Lung sounds can be used as an indicator for assessing severity of chronic obstructive pulmonary disease at the initial diagnosis].

OBJECTIVE: To assess the value of pulmonary auscultation for evaluating the severity of chronic obstructive pulmonary disease (COPD) at the initial diagnosis. METHODS: The patients with newly diagnosed COPD in our hospital between May, 2016 and May, 2019 were enrolled in this study. According to the findings of pulmonary auscultation, the lung sounds were classified into 5 groups: normal breathing sounds, weakened breathing sounds, weakened breathing sounds with wheezing, obviously weakened breathing sounds, and obviously weakened breathing sounds with wheezing. The pulmonary function of the patients was graded according to GOLD guidelines, and the differential diagnosis of COPD from asthmatic asthma COPD overlap (ACO) was made based on the GOLD guidelines and the European Respiratory Criteria. RESULTS: A total of 1046 newly diagnosed COPD patients were enrolled, including 949 male and 97 female patients with a mean age of 62.6± 8.71. According to the GOLD criteria, 88.1% of the patients were identified to have moderate or above COPD, 50.0% to have severe or above COPD; a further diagnosis of ACO was made in 347 (33.2%) of the patients. ANOVA analysis showed significant differences in disease course, FEV1, FEV1%, FEV1/FVC, FVC, FVC% and mMRC among the 5 auscultation groups (P < 0.001), but FENO did not differ significantly among them (P=0.097). The percentage of patients with wheezing in auscultation was significantly greater in ACO group than in COPD group (P < 0.001). Spearman correlation analysis showed that lung sounds was significantly correlated with disease severity, FEV1, FEV1%, FVC and FVC% of the patients (P < 0.001); Multiple linear regression analysis showed that a longer disease course, a history of smoking and lung sounds were all associated with poorer lung functions and a greater disease severity. CONCLUSIONS: Lung sounds can be used as an indicator for assessing the severity of COPD at the initial diagnosis.

Prediction of clinical response to omalizumab in moderate-to-severe asthma patients using the change in total serum IgE level.

BACKGROUND: Omalizumab (OMA) is an effective anti-immunoglobulin E (IgE) treatment for moderate-to-severe asthma. However, predicting an individual's response is difficult. Monitoring change of total serum IgE may be useful for predicting the response to OMA. The purpose of this study was to determine if measuring the change in total IgE level could predict the response to OMA in patients with moderate-to-severe asthma. METHODS: This study included 25 patients (11 females and 14 males; mean age =46.1 years; mean pre-bronchodilator FEV1% =67.8%) with moderate-to-severe asthma. All patients were treated with OMA, and total IgE serum concentrations were measured at baseline before treatment (median baseline total serum IgE =210 IU/mL) and at 4 weeks after beginning treatment. Patients were divided into responders (i.e., excellent or good response) and non-responders (i.e., moderate or poor response) using the global treatment effectiveness (GETE) response method after 16 weeks of treatment. The characteristics of responders and non-responders were compared, and receiver operating characteristic (ROC) curve analysis was used to determine the ability of change in IgE level to predict treatment response. RESULTS: There were 20 responders (80%) and 5 non-responders (20%), and responders demonstrated better improvements of asthma control test (ACT) and asthma control questionnaire (ACQ) scores, and reduction of oral corticosteroid use as compared with non-responders. Twenty-one patients had a total serum IgE 4-week-to-baseline ratio ≥2, and 20 of the patients responded to OMA. The area under the ROC curve (AUC) for baseline IgE level for predicting treatment response was 0.53 (95% CI: 0.18-0.88), and that of the week 4 IgE level was 0.69 (95% CI: 0.42-0.96). Using a cutoff value of 2, the 4-week: baseline IgE ratio achieved the highest AUC of 0.87 (95% CI: 0.64-1), with a sensitivity and specificity of 100% and 80%, respectively, for predicting treatment response. CONCLUSIONS: A total week 4 serum IgE level:baseline level ratio ≥2 can predict the response to OMA in patients with moderate-to-severe asthma after 16 weeks of treatment with high likelihood. Monitoring changes of total IgE level in asthma patients treated OMA may be useful for predicting clinical response.

Fractional exhaled nitric oxide was not associated with the future risk of exacerbations in Chinese asthmatics: a non-interventional 1-year real-world study.

BACKGROUND: Exacerbations are recognized as the most relevant predictor of future risk in asthmatics. We aimed to evaluate the association between asthma exacerbations, fractional exhaled nitric oxide (FENO), spirometry indices, and other potential risk factors in a non-interventional, real-world study performed in Guangzhou, China. METHODS: We performed a prospective 12 months follow-up of Chinese asthmatics. Spirometry and FENO measurements were performed at baseline. Adherence to inhaled corticosteroids (ICS) use was divided into two categories (>80% and <80%). Patients were seen 4 times after the initial baseline visit. RESULTS: A total of 222 patients with asthma (49.1% males) completed the study, of which 51 (23.0%) experienced exacerbations during the study period. Of the patients, 117 (52.7%) had good compliance. We compared lung function indices between the patients with and without exacerbations. There was no difference of forced expiratory volume in 1 s (FEV1) predicted, forced vital capacity (FVC) predicted, and FEVI/FVC (all, P>0.05) between the groups. There was also no significant difference in FENO level between the two groups. Compared to those that had exacerbations, patients without exacerbations had better treatment compliance (P<0.001). Logistic regression analysis identified an association between asthma exacerbations, poor control of symptom [odds ratio (OR) =2.295; 95% confidence interval (CI): 1.130-4.663; P=0.022], and nonadherence to asthma medications (OR =4.718; 95% CI: 2.149-10.359; P<0.001). CONCLUSIONS: Poor adherence rather than baseline FENO and FEV1% predicted was associated with the future risk of exacerbations in Chinese asthmatics in real world.

[Delayed diagnosis is associated with greater disease severity of chronic obstructive pulmonary disease].

OBJECTIVE: To investigate the association of the time of initial diagnosis with the severity of chronic obstructive pulmonary disease (COPD). METHODS: A total of 803 patients who were diagnosed to have COPD for the first time in our hospital between May 2015 to February 2018 were enrolled in this study.The diagnoses of COPD and asthma COPD overlap (ACO) were made according GOLD guidelines and european consensus definition.Lung function of the patients was graded according to the GOLD guidelines. RESULTS: The patients with COPD had a mean age of 61.8±9.9 years,including 726 male and 77 female patients.The course of the patients (defined as the time from symptom onset to the establishment of a diagnosis) was 3(0.5,8) years.Among these patients,85.2% had a moderate disease severity (FEV1%<80%),and 48.3% had severe or very severe conditions (FEV1%<50%);47.0% of them were positive for bronchial dilation test.In the overall patients,295(36.7%) were also diagnosed to have ACO,and the mean disease course of ACO[3(1,9) years]was similar to that of COPD[3(0.5,8) years](P>0.05).A significant correlation was found between the disease course and the lung function of the patients.Multiple linear regression analysis showed that an older age and a longer disease course were associated with poorer lung functions and a greater disease severity. CONCLUSIONS: The delay of the initial diagnosis is significantly related to the severity of COPD.