Serum nitric oxide level correlates with serum brain natriuretic peptide and whole blood viscosity in hemodialysis patients.

BACKGROUND: Nitric oxide (NO) is tonically synthesized by the vascular endothelium and known as a marker of vasodilatation and blood flow. As NO has a critical role in hemodynamics, NO may be associated with other hemodynamics-related factors including atrial natriuretic peptide (ANP), B-type natriuretic peptide (BNP) and whole blood viscosity (WBV). It has been reported that serum NO level increased in patients undergoing hemodialysis. However, there are few reports about the relationship between NO and hemodynamic parameters in hemodialysis patients. OBJECTIVE: We investigated the associations between serum levels of NO and other hemodynamics-related factors such as ANP, BNP and WBV in patients with hemodialysis. METHODS: NO, ANP, and BNP levels before hemodialysis were measured using ELISA method. We measured WBV in pre- and post-dialysis. RESULTS: Mean serum levels of NO, ANP, and BNP were 13.97 ±â€¯10.34 µg/mL, 198.85 ±â€¯61.56 pg/mL, and 1233.32 ±â€¯280.81 pg/mL, respectively in patients with hemodialysis. The mean WBV values at shear rates of 1, 5, and 300 s-1 for pre-dialyses were 168.5 ±â€¯62.5, 76.9 ±â€¯20.6, and 33.3 ±â€¯3.8 mP, respectively. Serum NO level was positively correlated with WBV at shear rates of 1, 5, and 300 s-1 at pre- and post-hemodialysis. There is a correlation between serum nitrite levels and the change of SBV during hemodialysis. Serum nitrite levels correlated with the serum BNP levels. ANP levels have a negative correlation with pre-dialytic WBV. However, BNP levels did not correlate with WBV during hemodialysis. CONCLUSIONS: WBV is linked to an imbalance in serum vasoactive substances in hemodialysis patients and can cause significant hemodynamic disturbance.

Serum VEGF-D level is correlated with renal dysfunction and proteinuria in patients with diabetic chronic kidney disease.

ABSTRACT: Biomarkers associated with chronic kidney disease (CKD) may play a crucial role in the early diagnosis of diabetic kidney disease. However, there have been few reports published on serum vascular endothelial cell growth factor (VEGF)-D in patients with diabetic CKD. We divided patients with diabetic CKD into two groups: CKD 3-4 and CKD 5. In total, 42 patients with diabetic kidney disease and seven healthy controls without diabetes mellitus were enrolled in this study. An observational study was conducted to evaluate the serum VEGF-D levels and other clinical parameters in each group and to assess the relationship among these factors. The serum levels of VEGF-D were higher in the CKD 3-4 group and CKD 5 group than in the control group. However, there was no significant difference in serum levels of VEGF-D between CKD stage 3-4 group and CKD stage 5 group. Correlation analysis showed that serum VEGF-D was negatively correlated with estimated glomerular filtration rate but positively correlated with serum creatinine, urine albumin-to-creatinine ratio, and urine protein-to-creatinine ratio. Serum VEGF-D was a good biomarker in receiver operating characteristic analysis and independently associated with CKD stages in multiple linear regression analysis. Circulating VEGF-D was positively correlated with blood growth/differentiation factor-15, endostatin, and chemokine (C-X-C motif) ligand 16 levels. Serum VEGF-D levels were correlated with renal dysfunction, albuminuria, and proteinuria in patients with diabetic kidney disease. Elucidation of the role of VEGF-D as a biomarker requires further study.

Accumulation of P-bodies in Candida albicans under different stress and filamentous growth conditions.

Candida albicans is an opportunistic fungal pathogen that grows as budding yeast, pseudohyphal, and hyphal forms. In response to external signals, C. albicans switches rapidly among these forms. mRNA-containing cytoplasmic granules, termed processing bodies (P-bodies), have been reported to accumulate under various environmental stress conditions in diverse species from yeast to mammals. Here, we provide the first microscopic and genetic characterization of P-bodies in C. albicans. The core components of P-bodies, including the decapping machinery (Dcp2 and Dhh1), 5'-3' exoribonuclease (Kem1/Xrn1), and the P-body scaffolding protein (Edc3), were identified and their localizations with respect to P-bodies were demonstrated. Various growth conditions, including glucose deprivation, hyperosmotic stress, and heat stress, stimulated the accumulation of P-bodies. In addition, we observed P-body aggregation during hyphal development. The deletion mutant strain edc3/edc3 had a defect in filamentation and exhibited a dramatic reduction in the number of P-bodies. These results suggest that Edc3 plays an essential role in the assembly and maintenance of P-bodies in C. albicans, and that the switch to filamentous growth appears to accompany P-body accumulation.

Changes in plasma sclerostin level associated with use of a medium cut-off dialyzer in end-stage renal disease.

BACKGROUND: Larger middle molecules are important substances associated with cardiovascular complications in end- stage renal disease. Unfortunately, larger middle molecules are not reliably removed by a high-flux dialyzer. A medium cut-off (MCO) membrane could effectively remove larger middle molecules. This study aimed to identify the long -term effect of the MCO membrane for changes of larger middle molecules. METHODS: Thirty-four patients were prospectively analyzed for 12 months. The enrolled patients were divided into control and MCO groups. We measured the plasma levels of growth differentiation factor 15, sclerostin, and fibroblast growth factor 23 in larger middle molecules and those of biomarkers including small solutes. Single-pool Kt/V (spKt/V) and reduction ratios also were evaluated. RESULTS: Plasma sclerostin did not increase significantly in patients using the MCO dialyzer (135.3 [-637.7 to 908.3], p = 0.715). And there was a significant difference in change of plasma sclerostin level between the two groups (-1,646.9 [-3,015.2 to -278.7], p = 0.033). Furthermore, a negative association between calcium and sclerostin was not observed in the MCO group (r = -0.142, p = 0.587). Solute clearance of larger middle molecules in the MCO group was significantly higher. Moreover, spKt/V values for patients in the MCO group were significantly increased without albumin loss. Values are presented as mean (95% confidence interval [CI]) or adjusted mean (95% CI). CONCLUSION: The MCO dialyzer can increase dialytic adequacy and suppress the increase in plasma sclerostin level without significant albumin loss in patients with end-stage renal disease.

Characterization of Medication Trends for Chronic Kidney Disease: Mineral and Bone Disorder Treatment Using Electronic Health Record-Based Common Data Model.

Chronic kidney disease-mineral bone disorder (CKD-MBD) is the most common complication in CKD patients. Although there is a consensus on treatment guidelines for CKD-MBD, it remains uncertain whether these treatment recommendations reflect actual practice. Therefore, the aim of this study was to investigate the CKD-MBD medication trend in real-world practice. This was a retrospective and observational study using a 12-year period database transformed into a common data model from three tertiary university hospitals. Study populations were subjects initially diagnosed as CKD. The date of diagnosis was designated as the index date. New patients were categorized year to year from 2008 to 2019 with a fixed observation period of 365 days to check the prescription of CKD-MBD medications including calcium-containing phosphate binder, noncalcium-containing phosphate binder, aluminium hydroxide, vitamin D receptor activator (VDRA), and cinacalcet. The numbers of CKD patients in the three hospitals were 7555, 2424, and 5351, respectively. The proportion for patients with CKD-MBD medication prescription decreased yearly regardless of hospital and CKD stage (p for trend < 0.05). The use of aluminium hydroxide disappeared steadily while the use of VDRA increased annually in all settings. Despite these changes in prescription patterns, the mean value for CKD-MBD-related serologic markers was almost within target range. The proportion of the population within the target value was not significantly changed. Irrespective of hospital and CKD stage, similar trends of prescription for CKD-MBD medications were observed in real-world practice. Further research with a distributed network study may be helpful to understand medication trends in CKD-MBD treatment.

Roles of Zinc-responsive transcription factor Csr1 in filamentous growth of the pathogenic Yeast Candida albicans.

In the fungal pathogen Candida albicans, the yeast-to-hyphal transition occurs in response to a broad range of environmental stimuli and is considered to be a major virulence factor. To address whether the zinc homeostasis affects the growth or pathogenicity of C. albicans, we functionally characterized the zinc-finger protein Csr1 during filamentation. The deduced amino acid sequence of Csr1 showed a 49% similarity to the zinc-specific transcription factor, Zap1 of Saccharomyces cerevisiae. Sequential disruptions of CSR1 were carried out in diploid C. albicans. The csr1/csr1 mutant strain showed severe growth defects under zinc-limited growth conditions and the filamentation defect under hyphainducing media. The colony morphology and the germ-tube formation were significantly affected by the csr1 mutation. The expression of the hyphae-specific gene HWP1 was also impaired in csr1/csr1 cells. The C. albicans homologs of ZRT1 and ZRT2, which are zinc-transporter genes in S. cerevisiae, were isolated. High-copy number plasmids of these genes suppressed the filamentation defect of the csr1/csr1 mutant strain. We propose that the filamentation phenotype of C. albicans is closely associated with the zinc homeostasis in the cells and that Csr1 plays a critical role in this regulation.

Human CD36 overexpression in renal tubules accelerates the progression of renal diseases in a mouse model of folic acid-induced acute kidney injury.

BACKGROUND: Acute kidney injury (AKI) is a risk factor for progression to chronic kidney disease, with even subclinical AKI episodes progressing to chronic kidney disease. Several risk factors such as preexisting kidney disease, hyperglycemia, and hypertension may aggravate renal disease after AKI. However, mechanisms underlying the progression of AKI are still unclear. This study identified the effect of human cluster of differentiation 36 (CD36) overexpression on the progression of folic acid-induced AKI. METHODS: Pax8-rtTA/tetracycline response element-human CD36 transgenic mice were used to elucidate the effect of human CD36 overexpression in the proximal tubules on folic acid-induced AKI. RESULTS: Results of histological analysis showed severely dilated tubules with casts and albuminuria in folic acid-treated transgenic mice overexpressing human CD36 compared with folic acid-treated wild-type mice. In addition, analysis of mRNA expression showed a significant increase in the collagen 3a1 gene in folic acid-treated transgenic mice overexpressing human CD 36 compared with folic acid-treated wild type mice. CONCLUSION: Human CD36-overexpressing transgenic mice showed severe pathological changes and albuminuria compared with wild-type mice. Moreover, mRNA expression of the collagen 3a1 gene increased in folic acid-treated transgenic mice. These results suggest that human CD36 overexpression is a risk factor of AKI and its progression to chronic kidney disease.

Changes in whole blood viscosity during hemodialysis and mortality in patients with end-stage renal disease.

Whole blood viscosity (WBV) plays a role in hemorheology and is determined by many factors such as red blood cell factors, plasma protein and blood volume. As WBV changes during hemodialysis, mortality may be due to changes in WBV in patients on hemodialysis. However, there are few prospective data on the relationship between changes in WBV and overall mortality in dialysis patients. We tried to investigate the correlations between values of WBV at variable shear rates before and after hemodialysis and overall or atherosclerosis-related mortality in patients with end-stage kidney disease.Forty-three patients receiving hemodialysis were enrolled in this study. In this 5.8-year prospective observational study, analyses of the effects of WBV at shear rates of 300 s-1 (systolic WBV; SBV), 5 s-1 (diastolic WBV5; DBV5), and 1 s-1 (diastolic WBV1; DBV1) during dialysis on all-cause and atherosclerotic mortality was performed.Among a total of 43 patients, 27 (62.7%) died over the course of the study. Thirteen deaths were caused by atherosclerotic events. A high degree of change in WBV at shear rates of 300 s-1 and 5 s-1 during hemodialysis (ΔSBV, ΔDBV5) was positively correlated with overall mortality (HR = 4.688, 95% confidence interval [CI], 1.269-17.319, p = 0.020; HR = 3.941, 95% CI, 1.057-14.701, p = 0.041, respectively). A high degree of change in diastolic blood pressure (ΔDBP) during hemodialysis was also positively correlated with overall mortality (HR = 3.035, 95% CI, 1.039-8.867, p = 0.042). However, comparative analysis between WBV at shear rates of 300 s-1, 5 s-1, and 1 s-1 and overall mortality did not reveal any significant relationships. Kaplan-Meier analysis revealed that the all-cause mortality was significantly higher in patients from a high degree of change of WBV at shear rates of 300 s-1, compared to those from the moderate or low degree of changes of WBV at shear rates of 300 s-1 (p = 0.020, log-rank test). Survival rate in high ΔDBP was lower than that of moderate or low ΔDBP group in Kaplan-Meier survival analysis (p = 0.004, log-rank test).Our data showed that a high degree of change in WBV at variable shear rates during hemodialysis might impact overall survival in patients with end-stage kidney disease. However, large-scale studies to evaluate the relationship of WBV with overall mortality and atherosclerotic mortality will be needed.

Nonsteroidal antiinflammatory drug induced acute granulomatous interstitial nephritis.

BACKGROUND: Acute interstitial nephritis is a common cause of acute kidney injury (AKI). The granulomatous inflammation is rarely but often manifests as a form of a granulomatous interstitial nephritis (GIN) in the kidney. Acute granulomatous interstitial nephritis is mainly associated with drugs, infection and autoimmune diseases. CASE PRESENTATION: A 44-year-old-male visited our out-patient department with symptoms of nausea, vomiting, and general weakness that had developed over the previous 2 weeks. He had history of medication, nonsteroidal anti-inflammatory drugs. On admission to the general ward, his serum creatinine level was markedly elevated. GIN was confirmed by renal biopsy and 30 mg of corticosteroid per day was immediately initiated. Subsequently, his serum creatinine level and uremic symptoms dramatically decreased. CONCLUSION: Acute granulomatous interstitial nephritis is a rare but important disease on AKI. As long as we can carefully exclude infectious diseases as the cause of granulomatous lesion, acute granulomatous interstitial nephritis can be treated with steroid regardless of the etiologies. Since there is no proven treatment for the GIN yet, we can carefully suggest that moderate to high dosage corticosteroid can be helpful for prognosis in case of acute granulomatous interstitial nephritis of patients with AKI.

Roles of Edc3 in the oxidative stress response and CaMCA1-encoded metacaspase expression in Candida albicans.

The Edc3 protein is an enhancer of mRNA decapping, and acts as a scaffold protein for the mRNA granules that are known as processing bodies in yeast. In the pathogenic yeast Candida albicans, various stresses, such as glucose depletion, oxidative stress, and filamentation defects, induce the accumulation of processing bodies. Here, we report that the edc3/edc3 deletion strain showed increased resistance to various stresses, including hydrogen peroxide, acetic acid, and high temperature. Oxidative stress is known to induce the intracellular accumulation of reactive oxygen species (ROS) and apoptotic cell death in C. albicans. We found that the ROS level was lower in edc3/edc3 cells than in wild-type cells following oxidative stress. We also observed that expression of the metacaspase gene CaMCA1 was decreased in edc3/edc3 cells. Overexpression of CaMCA1 suppressed the decreased accumulation of ROS and the increased resistance to hydrogen peroxide in edc3/edc3 cells. The catalase Cat1 and the superoxide dismutase Sod1 were upregulated in edc3/edc3 cells as compared with wild-type cells. On the basis of these findings, we suggest that EDC3 plays a critical role in the expression of CaMCA1 and the oxidative stress response in C. albicans.