Clinical and genetic analysis of a case of Gitelman syndrome accompanied with Graves disease and adrenocortical adenoma: A case report.

RATIONALE: Gitelman syndrome (GS), also known as familial hypokalemia and hypomagnesemia, is a rare autosomal recessive inherited disease caused by primary renal desalinization caused by impaired reabsorption of sodium and chloride ions in the distal renal tubules. We report a case of clinical and genetic characteristics of GS accompanied with Graves disease and adrenocorticotrophic hormone (ACTH)-independent adrenocortical adenoma. PATIENT CONCERNS: The patient is a 45 year old female, was admitted to our hospital, due to a left adrenal gland occupying lesion as the chief complaint. DIAGNOSIS: The patient was finally diagnosed as GS with Graves disease and adrenocortical adenoma. INTERVENTIONS: Potassium magnesium aspartate (1788 mg/d, taken orally 3 times a day (supplement a few times a day, intake method, treatment duration). Contains 217.2 mg of potassium and 70.8 mg of magnesium, and potassium chloride (4.5 g/d, taken orally 3 times a day (supplement a few times a day, intake method, and treatment duration); Potassium 2356 mg), spironolactone (20 mg/d, taken orally once a day (supplement a few times a day, intake method, treatment duration). After 3 months of treatment, the patient's blood potassium fluctuated between 3.3-3.6 mmol/L, and blood magnesium fluctuated between 0.5-0.7 mmol/L, indicating a relief of fatigue symptoms. OUTCOMES: On the day 6 of hospitalization, the symptoms of dizziness, limb fatigue, fatigue and pain were completely relieved on patient. In the follow-up of the following year, no recurrence of the condition was found. LESSONS: The novel c.1444-10(IVS11)G > A variation may be a splicing mutation. The compound heterozygous mutations of the SLC12A3 gene may be the pathogenic cause of this GS pedigree.

Cut-off values of haemoglobin and clinical outcomes in incident peritoneal dialysis: the PDTAP study.

BACKGROUND: To explore the cut-off values of haemoglobin (Hb) on adverse clinical outcomes in incident peritoneal dialysis (PD) patients based on a national-level database. METHODS: The observational cohort study was from the Peritoneal Dialysis Telemedicine-assisted Platform (PDTAP) dataset. The primary outcomes were all-cause mortality, major adverse cardiovascular events (MACE) and modified MACE (MACE+). The secondary outcomes were the occurrences of hospitalization, first-episode peritonitis and permanent transfer to haemodialysis (HD). RESULTS: A total of 2591 PD patients were enrolled between June 2016 and April 2019 and followed up until December 2020. Baseline and time-averaged Hb <100 g/l were associated with all-cause mortality, MACE, MACE+ and hospitalizations. After multivariable adjustments, only time-averaged Hb <100 g/l significantly predicted a higher risk for all-cause mortality {hazard ratio [HR] 1.83 [95% confidence interval (CI) 1.19-281], P = .006}, MACE [HR 1.99 (95% CI 1.16-3.40), P = .012] and MACE+ [HR 1.77 (95% CI 1.15-2.73), P = .010] in the total cohort. No associations between Hb and hospitalizations, transfer to HD and first-episode peritonitis were observed. Among patients with Hb ≥100 g/l at baseline, younger age, female, use of iron supplementation, lower values of serum albumin and renal Kt/V independently predicted the incidence of Hb <100 g/l during the follow-up. CONCLUSION: This study provided real-world evidence on the cut-off value of Hb for predicting poorer outcomes through a nation-level prospective PD cohort.

Selenium nanoparticles alleviate ischemia reperfusion injury-induced acute kidney injury by modulating GPx-1/NLRP3/Caspase-1 pathway.

Rationale: Acute kidney injury (AKI) is a common critical illness in the clinic and currently lacks effective treatment options. Ischemia reperfusion injury (IRI) is a major pathogenic factor for AKI. Due to the deficiency of selenium (Se) in AKI patients, we intended to treat IRI-induced AKI using a Se rebalancing strategy in the present study. Methods: Sodium selenate, ascorbic acid, and bovine serum albumin (BSA) were employed to prepare nanomaterials termed Se@BSA nanoparticles (NPs) using a simple method. Experiments with human renal tubular epithelial HK-2 cells exposed to hypoxia/reoxygenation (H/R) and IRI-AKI mice were used to evaluate the therapeutic efficiency of Se@BSA NPs. Transcriptome sequencing, further molecular biology experiments, and pathologic analysis were performed to investigate the underlying mechanisms. Results: Se@BSA NPs accumulated in mouse kidneys and could be endocytosed by renal tubular epithelial cells after intravenous administration. In vitro studies showed that Se@BSA NP treatment markedly increased the levels of glutathione peroxidase (GPx)-1 and suppressed NLRP3 inflammasome activation in H/R cells, which resulted in reductions in the proteolytic cleavage of pro-Caspase-1 into active Caspase-1 and the maturation of inflammatory factors. Mouse experiments confirmed these findings and demonstrated an inspiring mitigative effect of Se@BSA NPs on IRI-induced AKI. Owing to modulation of the GPx-1/NLRP3/Caspase-1 pathway, Se@BSA NPs dramatically inhibited fibrosis formation after AKI. Conclusion: This study provides an effective therapeutic option by applying easy-to-produce Se-containing nanomaterials to remedy Se imbalance and impede inflammatory responses in the kidney, which is a promising candidate for AKI treatment.

The Intestinal Microbiota and Metabolites in the Gut-Kidney-Heart Axis of Chronic Kidney Disease.

Emerging evidences demonstrate the involvement of gut microbiota in the progression of chronic kidney disease (CKD) and CKD-associated complications including cardiovascular disease (CVD) and intestinal dysfunction. In this review, we discuss the interactions between the gut, kidney and heart in CKD state, and elucidate the significant role of intestinal microbiota in the gut-kidney-heart axis hypothesis for the pathophysiological mechanisms of these diseases, during which process mitochondria may serve as a potential therapeutic target. Dysregulation of this axis will lead to a vicious circle, contributing to CKD progression. Recent studies suggest novel therapies targeting gut microbiota in the gut-kidney-heart axis, including dietary intervention, probiotics, prebiotics, genetically engineered bacteria, fecal microbiota transplantation, bacterial metabolites modulation, antibiotics, conventional drugs and traditional Chinese medicine. Further, the identification of specific microbial communities and their corresponding pathophysiological metabolites and the illumination of the gut-kidney-heart axis may contribute to innovative basic research, clinical trials and therapeutic strategies against CKD progression and uremic complications in CKD patients.

Discovery of a Natural Product with Potent Efficacy Against SARS-CoV-2 by Drug Screening.

The novel coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread worldwide for almost 2 years. It starts from viral adherence to host cells through an interaction between spike glycoprotein 1 (S1) containing a receptor-binding domain (RBD) and human angiotensin-converting enzyme-2 (ACE2). One of the useful strategies to prevent SARS-CoV-2 infection is to inhibit the attachment of RBD to ACE2. Therefore, the current work proposed potent peptides against SARS-CoV-2 infection by carrying out MM-PBSA calculation based on the binding of 52 antiviral peptides (AVPs) to RBD. Considering the binding free energies of AVPs to RBD, cyanovirin-N (CV-N) showed the strongest RBD binding affinity among 52 AVPs. Upon structural analysis of RBD complex with CV-N, it was observed that 12 of the 13 key residues of RBD binding to ACE2 were hijacked by CV-N. CV-N bound to RBD at a smaller affinity of 14.9 nM than that of ACE2 and inhibited the recruitment of S1 to human alveolar epithelial cells. Further analysis revealed that CV-N suppressed SARS-CoV-2 S pseudovirion infection with a half-maximal inhibitory concentration (IC50) of 18.52 µg/mL. This study demonstrated a drug screening for AVPs against SARS-CoV-2 and discovered a peptide with inspiring antiviral properties, which provided a promising strategy for the COVID-19 therapeutic approach.

Establishment of a Drug Screening Model for Cardiac Complications of Acute Renal Failure.

Acute renal failure (ARF) is a clinical critical syndrome with rapid and severe decline of renal function. Complications of ARF, especially its cardiac complications (cardiorenal syndrome type 3, CRS-3), are the main causes of death in patients with ARF. However, the shortage and limited efficacy of therapeutic drugs make it significant to establish new large-scale drug screening models. Based on the Nitroreductase/Metronidazole (NTR/MTZ) cell ablation system, we constructed a Tg(cdh17:Dendra2-NTR) transgenic zebrafish line, which can specifically ablate renal tubular epithelial cells. The absence of renal tubular epithelial cells can lead to ARF in zebrafish larvae. The ARF symptoms, such as heart enlargement, slow heart rate and blood stasis, are similar to the clinical manifestations of human CRS-3. Furthermore, two therapeutic drugs (digoxin and enalapril) commonly used in the clinical treatment of heart failure were also effective in alleviating the symptoms of CRS-3 in zebrafish, which proved the effectiveness of this model. Drug screening further discovered a potential drug candidate, α-lipoic acid, which can effectively alleviate the symptoms of CRS-3 through its antioxidant function. Accordingly, we established a new ARF model of zebrafish, which laid a foundation for large-scale screening of new therapeutic drugs for its complications.

Effectiveness of Chinese herbal medicine combined with Western medicine on deferring dialysis initiation for nondialysis chronic kidney disease stage 5 patients: a multicenter prospective nonrandomized controlled study.

BACKGROUND: In clinical practice, Chinese herbal medicine (CHM) purportedly has beneficial therapeutic effects for chronic kidney disease (CKD), which include delaying disease progression and dialysis initiation. However, there is a lack of high-quality evidence-based results to support this. Therefore, this study aimed to evaluate the efficacy of CHM combined with Western medicine in the treatment of stage 5 CKD. METHODS: This was a prospective nonrandomized controlled study. Stage 5 CKD (nondialysis) patients were recruited form 29 AAA class hospitals across China from July 2014 to April 2019. According to doctors' advice and the patients' wishes, patients were assigned to the CHM group (Western medicine + CHM) and the non-CHM group (Western medicine). Patient demographic data, primary disease, blood pressure, Chinese and Western medical drugs, clinical test results, and time of dialysis initiation were collected during follow-up. RESULTS: A total of 908 patients were recruited in this study, and 814 patients were finally included for further analysis, including 747 patients in the CHM group and 67 patients in the non-CHM group. 482 patients in the CHM group and 52 patients in the non-CHM group initiated dialysis. The median time of initiating dialysis was 9 (7.90, 10.10) and 3 (0.98,5.02) months in the CHM group and non-CHM group, respectively. The multivariate Cox regression analysis showed that patients in the CHM group had a significantly lower risk of dialysis [adjusted hazard ratio (aHR): 0.38; 95% confidence interval (CI): 0.28, 0.53] compared to those in the non-CHM group. After 1:2 matching, the outcomes of 160 patients were analyzed. The multivariate Cox regression analysis showed that patients in the CHM group had a significantly lower risk of dialysis (aHR: 0.32; 95% CI: 0.21, 0.48) compared to patients in the non-CHM group. Also, the Kaplan-Meier analysis demonstrated that the cumulative incidence of dialysis in the CHM group was significantly lower than that in the non-CHM group (log-rank test, P<0.001) before and after matching. CONCLUSIONS: This study suggest that the combination of CHM and Western medicine could effectively reduce the incidence of dialysis and delay the time of dialysis initiation in stage 5 CKD patients.

IgA nephropathy with anti-neutrophil cytoplasmic antibody seropositivity.

BACKGROUND: There are few reports of IgA nephropathy (IgAN) with antineutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis. METHODS: The authors report the clinical and pathological findings in 14 patients with IgAN and ANCA seropositivity. RESULTS: These retrospective cases consisted of 4 men and 10 women with a mean age of 44.4 ± 12.7 years. ANCA-positivity was documented by EUROBlot kits and indirect immunofluorescence in all patients. The results of EUROBlot kits were positive in 14 patients (12 MPO-ANCA, 2 PR3-ANCA). Indirect immunofluorescence was positive in 14 patients (12 P-ANCA, 2 C-ANCA). Three of 14 IgAN with ANCA-positive patients showed severe clinical manifestations with crescents involving a mean of 56% glomeruli, including heavy proteinuria (mean 24-hour urine protein: 3.8 g/d), hematuria and acute renal failure (mean creatinine: 4.5 ± 3.7 mg/dL). The remaining 11 patients with no crescents showed various degrees of proteinuria (mean 24-hour urine protein: 2.4 ± 2.4 g/d), hematuria and serum creatinine levels (median creatinine: 0.9 (IQR, 0.5 - 1.4) mg/dL). The follow-up period for 10 patients had an average length of 14.0 ± 11.2 months. Among the three patients with crescents who had been treated with steroids and cyclophosphamide, one patient became dialysis dependent at the time of biopsy and remained on dialysis after treatment, another died of acute heart failure, and the last one showed improvement in renal function after treatment and did not develop end-stage renal disease (ESRD) 26 months after renal biopsy. The remaining 7 patients with no crescents were treated with steroids, cyclophosphamide, renin-angiotensin system inhibitors, and/or Traditional Chinese Medicine; 6 had stabilized or improved renal function and one progressed to ESRD with worsening renal function. CONCLUSIONS: These findings suggest not all ANCAs are involved in the pathology of IgAN. In patients with IgAN and ANCAs, identification of pathogenic vs. non-pathogenic ANCAs is recommended.

Design of a potent antibiotic peptide based on the active region of human defensin 5.

Human defensin 5 (HD5) is a broad-spectrum antibacterial peptide with a C-terminal active region. To promote the development of this peptide into an antibiotic, we initially substituted Glu21 with Arg because it is an electronegative residue located around the active region. Although detrimental to dimer formation, the E21R substitution markedly enhanced the antibacterial activity of HD5 and increased its ability to penetrate cell membranes, demonstrating that increasing the electropositive charge compensated for the effect of dimer disruption. Subsequently, a partial Arg scanning mutagenesis was performed, and Thr7 was selected for replacement with Arg to further strengthen the antibacterial activity. The newly designed peptide, T7E21R-HD5, exhibited potent antibacterial activity, even in saline and serum solutions. In contrast to monomeric E21R-HD5, T7E21R-HD5 assembled into an atypical dimer with parallel ß strands, thus expanding the role of increasing electropositive charge in bactericidal activity and providing a useful guide for further defensin-derived antibiotic design.

Resveratrol prevents high glucose-induced epithelial-mesenchymal transition in renal tubular epithelial cells by inhibiting NADPH oxidase/ROS/ERK pathway.

Resveratrol (RSV) is reported to have renoprotective activity against diabetic nephropathy, while the mechanisms underlying its function have not been fully elucidated. In this study, we investigate the effect and related mechanism of RSV against high glucose-induced epithelial to mesenchymal transition (EMT) in human tubular epithelial cells (HK-2). A typical EMT is induced by high glucose in HK-2 cells, accompanied by increased levels of reactive oxygen species (ROS). RSV exhibits a strong ability to inhibit high glucose-induced EMT by decreasing intracellular ROS levels via down-regulation of NADPH oxidase subunits NOX1 and NOX4. The activation of extracellular signal-regulated kinase (ERK1/2) is found to be involved in high glucose-induced EMT in HK-2 cells. RSV, like NADPH oxidase inhibitor diphenyleneiodonium, can block ERK1/2 activation induced by high glucose. Our results demonstrate that RSV is a potent agent against high glucose-induced EMT in renal tubular cells via inhibition of NADPH oxidase/ROS/ERK1/2 pathway.

Determination of organophosphorus pesticides in cucumber and potato by stir bar sorptive extraction.

Organophosphorus pesticides (OPPs) in vegetables were determined by stir bar sorptive extraction (SBSE) and capillary gas chromatography with thermionic specific detection (TSD). Hydroxy-terminated polydimethylsioxane (PDMS) prepared by sol-gel method was used as extraction phase. The effects of extraction temperature, salting out, extraction time on extraction efficiency were studied. The detection limits of OPPs in water were < or = 1.2 ng/l. This method was also applied to the analysis of OPPs in vegetable samples and matrix effect was studied. Linear ranges of OPPs in vegetable samples were 0.05-50 ng/g with detection limits < or =0.15 ng/g and the repeatability of the method was less than 20% relative standard deviation.