Protective effect of Cyclo(His-Pro) on peritoneal fibrosis through regulation of HDAC3 expression.

Peritoneal dialysis is a common treatment for end-stage renal disease, but complications often force its discontinuation. Preventive treatments for peritoneal inflammation and fibrosis are currently lacking. Cyclo(His-Pro) (CHP), a naturally occurring cyclic dipeptide, has demonstrated protective effects in various fibrotic diseases, yet its potential role in peritoneal fibrosis (PF) remains uncertain. In a mouse model of induced PF, CHP was administered, and quantitative proteomic analysis using liquid chromatography-tandem mass spectrometry was employed to identify PF-related protein signaling pathways. The results were further validated using human primary cultured mesothelial cells. This analysis revealed the involvement of histone deacetylase 3 (HDAC3) in the PF signaling pathway. CHP administration effectively mitigated PF in both peritoneal tissue and human primary cultured mesothelial cells, concurrently regulating fibrosis-related markers and HDAC3 expression. Moreover, CHP enhanced the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) while suppressing forkhead box protein M1 (FOXM1), known to inhibit Nrf2 transcription through its interaction with HDAC3. CHP also displayed an impact on spleen myeloid-derived suppressor cells, suggesting an immunomodulatory effect. Notably, CHP improved mitochondrial function in peritoneal tissue, resulting in increased mitochondrial membrane potential and adenosine triphosphate production. This study suggests that CHP can significantly prevent PF in peritoneal dialysis patients by modulating HDAC3 expression and associated signaling pathways, reducing fibrosis and inflammation markers, and improving mitochondrial function.

Multisample Mass Spectrometry-Based Approach for Discovering Injury Markers in Chronic Kidney Disease.

Urinary proteomics studies have primarily focused on identifying markers of chronic kidney disease (CKD) progression. Here, we aimed to determine urinary markers of CKD renal parenchymal injury through proteomics analysis in animal kidney tissues and cells and in the urine of patients with CKD. Label-free quantitative proteomics analysis based on liquid chromatography-tandem mass spectrometry was performed on urine samples obtained from 6 normal controls and 9, 11, and 10 patients with CKD stages 1, 3, and 5, respectively, and on kidney tissue samples from a rat CKD model by 5/6 nephrectomy. Tandem mass tag-based quantitative proteomics analysis was performed for glomerular endothelial cells (GECs) and proximal tubular epithelial cells (PTECs) before and after inducing 24-h hypoxia injury. Upon hierarchical clustering, out of 858 differentially expressed proteins (DEPs) in the urine of CKD patients, the levels of 416 decreased and 403 increased sequentially according to the disease stage, respectively. Among 2965 DEPs across 5/6 nephrectomized and sham-operated rat kidney tissues, 86 DEPs showed same expression patterns in the urine and kidney tissue. After cross-validation with two external animal proteome data sets, 38 DEPs were organized; only ten DEPs, including serotransferrin, gelsolin, poly ADP-ribose polymerase 1, neuroblast differentiation-associated protein AHNAK, microtubule-associated protein 4, galectin-1, protein S, thymosin beta-4, myristoylated alanine-rich C-kinase substrate, and vimentin, were finalized by screening human GECs and PTECs data. Among these ten potential candidates for universal CKD marker, validation analyses for protein S and galectin-1 were conducted. Galectin-1 was observed to have a significant inverse correlation with renal function as well as higher expression in glomerulus with chronic injury than protein S. This constitutes the first multisample proteomics study for identifying key renal-expressed proteins associated with CKD progression. The discovered proteins represent potential markers of chronic renal cell and tissue damage and candidate contributors to CKD pathophysiology.

A case of vasculitis triggered by infective endocarditis in a patient undergoing maintenance hemodialysis: a case report.

BACKGROUND: Immunoglobulin A vasculitis (IgA vasculitis) is one of the most common forms of vasculitis in children. It rarely occurs in adults. It is a systemic vasculitis with IgA deposition and is characterized by the classical tetrad of purpura, arthritis/arthralgia, gastrointestinal and renal involvement. Certain types of infections, and pharmacological agents have been reported to be associated with IgA vasculitis. Here, we describe a case of IgA vasculitis triggered by infective endocarditis in a patient undergoing maintenance hemodialysis. CASE PRESENTATION: A 70-year-old man undergoing hemodialysis was admitted because of skin purpura, abdominal pain, diarrhea, and lower back pain. We suspected him as IgA vasculitis based on the clinical features and skin biopsy findings. Transesophageal echocardiography revealed infective endocarditis, which predisposed him to IgA vasculitis. He was treated with antibiotics and low-dose corticosteroids, which led to resolution of vasculitis. CONCLUSIONS: This is the first case of IgA vasculitis triggered by infective endocarditis in a patient undergoing hemodialysis. Patients undergoing hemodialysis are at a high risk of infection because of immune dysfunction and frequent venipuncture. The incidence of infective endocarditis associated with IgA vasculitis is very low, but it has been repeatedly reported. Therefore, it is necessary to consider infective endocarditis in patients with clinical features that indicate IgA vasculitis.

Podocyte Disease Following Treatment with Intravenous Ibandronate in an Older Patient.

Bisphosphonates are commonly used to treat osteoporosis. While renal toxicity is common with pamidronate and zoledronate, few ibandronate-related cases are reported. We describe a rare case of ibandronate-associated nephrotoxicity. An 88-year-old woman was admitted for edema. She had been receiving intravenous ibandronate treatment for postmenopausal osteoporosis and had no other diagnosed diseases. She was presented with proteinuria, hypoalbuminemia (1.9 g/dL), and an elevated serum creatinine level (1.8 mg/dL). Renal biopsy revealed podocyte disease, favoring a diagnosis of focal segmental glomerulosclerosis. She was treated with diuretics, tacrolimus, and fimasartan. Steroids were avoided due to severe osteoporosis. Three months later, the edema had subsided and the laboratory findings had improved (serum albumin 3.5 g/dL, serum creatinine 0.97 mg/dL). This case emphasizes the importance of careful monitoring of proteinuria and renal function during ibandronate treatment. In older adult patients, kidney biopsy and immunosuppressive treatment may be considered based on physical activity and underlying diseases.

Predictive value of cardio-ankle vascular index for the risk of end-stage renal disease.

BACKGROUND: Arterial stiffness is associated with increased cardiovascular morbidity and mortality. However, the predictive value of the cardio-ankle vascular index (CAVI), one of the indicators for arterial stiffness, for the risk of end-stage renal disease (ESRD) remains unknown. METHODS: A total of 8701 patients with documented CAVI measurements by pulse wave velocity (PWV) were included in the study. Patients were divided according to the quartiles of CAVI. The hazard ratio (HR) of ESRD was calculated using the Cox model, after adjustment for multiple variables or death. RESULTS: During the median follow-up period of 7 years (maximum 12 years), ESRD and mortality occurred in 203 and 1071 patients, respectively. The median value of CAVI was 8.5 (interquartile range 7.7-9.3). The risk of ESRD was higher in the fourth-quartile group than the first-quartile group [adjusted HR 2.46 (IQR 1.62-3.71), P < 0.001]. When a death-adjusted risk analysis was performed, the fourth quartile of CAVI had a higher risk of ESRD than the first quartile [adjusted HR 2.35 (IQR 1.58-3.49), P < 0.001]. CONCLUSIONS: The measurement of CAVI by PWV may be needed to predict the risk of ESRD.

Blood Pressure-Related Risk Among Users Versus Nonusers of Antihypertensives: A Population-Based Cohort in Korea.

There have been few studies comparing blood pressure (BP)-related outcomes between users and nonusers of antihypertensive drugs. We constructed a population-based cohort of 492 540 Koreans aged 40 to 79 years, who had no preexisting cardiorenal diseases, from the National Health Insurance Service-Health Screening database. The primary composite outcome was death (or critical care unit admission) from cardiorenal causes, revascularization for myocardial infarction or stroke, and new-onset end-stage renal disease. Using time-dependent Cox models, we estimated hazard ratios according to BP and antihypertensive use, which were determined in each year of follow-up. Over 10 years of follow-up, the primary outcome occurred in 26 122 subjects, and 33 550 deaths were noted. Among nonusers of antihypertensives, the risk for the primary outcome increased linearly from a BP of 105/65 mm Hg, and the risk for all-cause mortality increased from a BP of 115/75 mm Hg. Among irregular users, the risk for the primary outcome increased as the BP increased >115/75 mm Hg. Among active users, the risk for the primary outcome increased in systolic BP <115 mm Hg and >135 mm Hg, and in diastolic BP <65 mm Hg and >85 mm Hg, and the risk for all-cause mortality increased in systolic BP <125 mm Hg and >135 or 145 mm Hg. In conclusion, this population-based study demonstrated that the associations between BP and adverse outcomes were J-shaped among active antihypertensive users, but linear or flat and then increasing among nonusers or irregular users.

Incidence of diabetes and its mortality according to body mass index in South Koreans aged 40-79 years.

PURPOSE: The purpose of this study was to assess diabetes incidence and all-cause mortality according to baseline body mass index (BMI) and to compare relative risks of mortality associated with incident diabetes across various BMI classes in a cohort of South Korean adults. PATIENTS AND METHODS: Based on data from the National Health Insurance database of Korean individuals aged 40-79 years without preexisting diabetes, we calculated BMI at the baseline health examination. We estimated the relative risk of mortality associated with incident diabetes using time-dependent Cox models and considering the time of diabetes diagnosis. RESULTS: We noted 29,307 incident diabetes cases and 22,940 deaths during an 8-year follow-up of the initial cohort (n=436,692) and 73,756 incident diabetes cases and 57,556 deaths during a 10-year follow-up of the replication cohort (n=850,282). Regarding all-cause mortality, time-dependent Cox models revealed statistically significant interactions between diabetes status and baseline BMI class (P=0.018 and P<0.001 in the initial and replication cohorts, respectively). In separately conducted analyses for each BMI class, diabetes-associated relative risks for BMI values of 16.0-18.4, 18.5-22.9, 23.0-24.9, 25.0-29.9, and 30.0-34.9 kg/m2 were 1.50 (95% confidence interval [CI], 1.09-2.07), 1.39 (95% CI, 1.26-1.54), 1.20 (95% CI, 1.08-1.35), 1.18 (95% CI, 1.07-1.30), and 0.97 (95% CI, 0.74-1.28) in the initial cohort, and 1.44 (95% CI, 1.18-1.74), 1.33 (95% CI, 1.26-1.41), 1.24 (95% CI, 1.16-1.31), 1.11 (95% CI, 1.05-1.17), and 0.99 (95% CI, 0.85-1.16) in the replication cohort. The increasing trend of relative risk with decreasing BMI persisted mostly among subgroups stratified according to age or sex and smoking status. CONCLUSION: Incident diabetes was associated with a greater increase in all-cause mortality risk in adults with lower BMI relative to those with higher BMI. This emphasizes the importance of treatment and prevention of type 2 diabetes among normal weight or underweight adults, particularly in Asia.

ACN9 Regulates the Inflammatory Responses in Human Bronchial Epithelial Cells.

BACKGROUND: Airway epithelial cells are the first line of defense, against pathogens and environmental pollutants, in the lungs. Cellular stress by cadmium (Cd), resulting in airway inflammation, is assumed to be directly involved in tissue injury, linked to the development of lung cancer, and chronic obstructive pulmonary disease (COPD). We had earlier shown that ACN9 (chromosome 7q21), is a potential candidate gene for COPD, and identified significant interaction with smoking, based on genetic studies. However, the role of ACN9 in the inflammatory response, in the airway cells, has not yet been reported. METHODS: We first checked the anatomical distribution of ACN9 in lung tissues, using mRNA in situ hybridization, and immunohistochemistry. Gene expression profiling in bronchial epithelial cells (BEAS-2B), was performed, after silencing ACN9. We further tested the roles of ACN9, in the intracellular mechanism, leading to Cd-induced production, of proinflammatory cytokines in BEAS-2B. RESULTS: ACN9 was localized in lymphoid, and epithelial cells, of human lung tissues. ACN9 silencing, led to differential expression of 216 genes. Pathways of sensory perception to chemical stimuli, and cell surface receptor-linked signal transduction, were significantly enriched. ACN9 silencing, further increased the expression of proinflammatory cytokines, in BEAS-2B after Cd exposure. CONCLUSION: Our findings suggest, that ACN9 may have a role, in the inflammatory response in the airway.

Recurrent renal cell carcinoma manifesting as a large intrathoracic fibrotic mass: A case report.

Renal cell carcinomas (RCCs) have a strong tendency to metastasize, and the most common sites are the lungs, bones and liver. Late recurrence is another feature of the RCC, with lesions appearing ≥10 years after surgical treatment. However, fibrosis has rarely been associated with the disease. The present study reports a case of recurrent RCC that manifested as a fibrotic mass within the thorax. A 48-year-old man presented with dyspnea that had persisted for 3 days. The patient had undergone a right radical nephrectomy for stage II clear cell carcinoma of the kidney 6 years previously. The patient was a current smoker, with a smoking history of 20 pack-years. Chest radiography showed pleural effusion in the right thorax with an egg-sized mass shadow within the right upper lung (RUL) field. Computed tomography (CT) showed a main mass, 7 cm in diameter, within the RUL, with heterogeneous enhancement and multiple nodules of various sizes in the lungs, suggestive of primary lung cancer or metastatic RCC. A CT-guided percutaneous needle aspiration biopsy was obtained from the main mass, but histology revealed dense fibrous tissue without any malignant cells. Positron emission tomography-CT demonstrated an irregular hypermetabolic RUL mass, with a standardized uptake value (SUV) of 5.0, along the right pleura, and small pulmonary nodules (SUV, 2.0). Ultrasound-guided biopsy was attempted for a smaller hypermetabolic pleural nodule and the result was clear cell adenocarcinoma, consistent with the previous renal histology. The present study describes the case, along with a review of the relevant literature.