Exogenous BMP7 administration attenuated vascular calcification and improved bone disorders in chronic uremic rats.

Vascular calcification is commonly observed in chronic kidney disease (CKD) and is associated with increased morbidity and mortality. This study examined whether exogenous BMP7 administration can modulate disturbed CKD-MBD in adenine-induced chronic uremic rats. After an adenine diet for 4 weeks, the animals were injected with BMP7 for 2 weeks. Biochemical data, kidney tissue, bony structure, and vascular calcification of the thoracic aorta were examined and compared. Reduced renal function, hyperphosphatemia, and hyperparathyroidism with low 1,25(OH)2 vitamin D levels were observed in the adenine group. MicroCT revealed reduced bone mineral density (BMD), decreased bone and tissue volume ratio (BV/TV), and decreased trabecular number with increased separation. Marked vascular calcification was observed in adenine-fed animals, and immunohistochemical analysis showed increased expression of BMP2, RUNX2, vitamin D receptor (VDR), and Pit1 in aortic tissue. Treatment with BMP7 was associated with reduced serum phosphate, intact parathyroid hormone, FGF23, sclerostin, and DKK1 levels. BMP7 administration was accompanied with improvements in BMD and BV/TV. The increase in BMP2, RUNX2, VDR, and Pit1 was reversed by BMP7. In conclusion, exogenous BMP7 administration improved hyperphosphatemia and hyperparathyroidism in adenine-induced CKD. This treatment also attenuated vascular calcification and modulated structural abnormalities in the skeletal system.

Long-term safety and efficacy of ferric citrate in phosphate-lowering and iron-repletion effects among patients with on hemodialysis: A multicenter, open-label, Phase IV trial.

BACKGROUND: We explored the long-term safety and efficacy of ferric citrate in hemodialysis patients in Taiwan, and further evaluated the iron repletion effect and change of iron parameters by different baseline groups. METHODS: This was a 12-month, Phase IV, multicenter, open-label study. The initial dose of ferric citrate was administered by patients' clinical condition and further adjusted to maintain serum phosphorus at 3.5-5.5 mg/dL. The primary endpoint was to assess the safety profiles of ferric citrate. The secondary endpoints were to evaluate the efficacy by the time-course changes and the number of subjects who achieved the target range of serum phosphorus. RESULTS: A total of 202 patients were enrolled. No apparent or unexpected safety concerns were observed. The most common treatment-emergent adverse events were gastrointestinal-related with discolored feces (41.6%). Serum phosphorus was well controlled, with a mean dose of 3.35±1.49 g/day, ranging from 1.5 to 6.0 g/day. Iron parameters were significantly improved. The change from baseline of ferritin and TSAT were 227.17 ng/mL and 7.53%, respectively (p-trend<0.001), and the increase started to slow down after 3-6 months of treatment. In addition, the increase trend was found only in patients with lower baseline level of ferritin (≤500 ng/mL) and TSAT (<30%). CONCLUSIONS: Ferric citrate is an effective phosphate binder with favorable safety profile in ESRD patients. The iron-repletion by ferric citrate is effective, and the increase is limited in patients with a higher baseline. In addition to controlling hyperphosphatemia, ferric citrate also shows additional benefits in the treatment of renal anemia. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT03256838; 12/04/2017.

The Risk Factors of Blood Cadmium Elevation in Chronic Kidney Disease.

Low-level cadmium exposure has adverse effects on chronic kidney disease (CKD); however, the risk factors for elevated blood cadmium levels (BCLs) have not been studied in CKD. We conducted a cross-sectional investigation in 200 CKD patients and stratified them by the tertiles of BCL to compare their demographic, environmental, and biochemical data. The factors associated with BCL were identified, and their effects were examined in subgroups. In the analyses, female sex, smoking, and CKD stage 5D were associated with high BCL, and statin was inversely correlated with BCL (odds ratio [95% confidence interval, CI], 6.858 [2.381-19.746], p < 0.001, 11.719 [2.843-48.296], p = 0.001, 30.333 [2.252-408.520], p = 0.010, and 0.326 [0.122-0.873], p = 0.026; deviations of BCL [nmol/L, 95% CI], 2.66 [1.33-4.00], p < 0.001, 3.68 [1.81-5.56], p < 0.001, 3.38 [0.95-5.82], p = 0.007, and -2.07 [-3.35--0.78], p = 0.002). These factors were also independently correlated with BCL in subgroups, including non-dialysis CKD, hypertensive patients, non-smokers, and male patients. In conclusion, female sex, smoking, and CKD stage 5D were the major risk factors for elevated BCL; additionally, statins were negatively associated with BCL in CKD.

Emergence of SGLT2 Inhibitors as Powerful Antioxidants in Human Diseases.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a new class of oral glucose-lowering agents. Apart from their glucose-lowering effects, large clinical trials assessing certain SGLT2 inhibitors have revealed cardiac and renal protective effects in non-diabetic patients. These excellent outcomes motivated scientists and clinical professionals to revisit their underlying mechanisms. In addition to the heart and kidney, redox homeostasis is crucial in several human diseases, including liver diseases, neural disorders, and cancers, with accumulating preclinical studies demonstrating the therapeutic benefits of SGLT2 inhibitors. In the present review, we aimed to update recent advances in the antioxidant roles of SGLT2 inhibitors in common but debilitating human diseases. We anticipate that this review will guide new research directions and novel therapeutic strategies for diabetes, cardiovascular diseases, nephropathies, liver diseases, neural disorders, and cancers in the era of SGLT2 inhibitors.

Combined Melatonin and Extracorporeal Shock Wave Therapy Enhances Podocyte Protection and Ameliorates Kidney Function in a Diabetic Nephropathy Rat Model.

(1) Background: Diabetic nephropathy (DN) is common complication of diabetes. Current therapy for DN does not include promotion of podocyte protection. Therefore, we investigated the therapeutic effect of melatonin (Mel) combined extracorporeal shock wave (SW) therapy on a DN rat model. (2) Methods: The DN rats were treated with Mel (5 mg/kg) twice a week for 6 weeks and SW treatment once a week (0.13 mJ/mm2) for 6 weeks. We assessed urine microalbumin, albumin to creatinine ratio (ACR), glomerular hypertrophy, glomerular fibrosis, podocyte markers (Wilm's tumor protein-1, synaptopodin and nephrin), cell proliferation, cell survival, cell apoptosis, renal inflammation and renal oxidative stress. (3) Results: The Mel combined SW therapy regimen significantly reduced urine microalbumin excretion (3.3 ± 0.5 mg/dL, p < 0.001), ACR (65.2 ± 8.3 mg/g, p < 0.001), glomerular hypertrophy (3.1 ± 0.1 × 106 µm3, p < 0.01) and glomerular fibrosis (0.9 ± 0.4 relative mRNA fold, p < 0.05). Moreover, the Mel combined SW therapy regimen significantly increased podocyte number (44.1 ± 5.0% area of synaptopodin, p < 0.001) in the Mel combined SW group. This is likely primarily because Mel combined with SW therapy significantly reduced renal inflammation (753 ± 46 pg/mg, p < 0.01), renal oxidative stress (0.6 ± 0.04 relative density, p < 0.05), and apoptosis (0.3 ± 0.03 relative density, p < 0.001), and also significantly increased cell proliferation (2.0 ± 0.2% area proliferating cell nuclear antigen (PCNA), p < 0.01), cell survival, and nephrin level (4.2 ± 0.4 ng/mL, p < 0.001). (4) Conclusions: Mel combined SW therapy enhances podocyte protection and ameliorates kidney function in a DN rat model. Mel combined SW therapy may serve as a novel noninvasive and effective treatment of DN.

Recent advances in lab-on-paper diagnostic devices using blood samples.

Lab-on-paper, or microfluidic paper-based analytical devices (µPADs), use paper as a substrate material, and are patterned with a system of microchannels, reaction zones and sensing elements to perform analysis and detection. The sample transfer in such devices is performed by capillary action. As a result, external driving forces are not required, and hence the size and cost of the device are significantly reduced. Lab-on-paper devices have thus attracted significant attention for point-of-care medical diagnostic purposes in recent years, particularly in less-developed regions of the world lacking medical resources and infrastructures. This review discusses the major advances in lab-on-paper technology for blood analysis and diagnosis in the past five years. The review focuses particularly on the many clinical applications of lab-on-paper devices, including diabetes diagnosis, acute myocardial infarction (AMI) detection, kidney function diagnosis, liver function diagnosis, cholesterol and triglyceride (TG) analysis, sickle-cell disease (SCD) and phenylketonuria (PKU) analysis, virus analysis, C-reactive protein (CRP) analysis, blood ion analysis, cancer factor analysis, and drug analysis. The review commences by introducing the basic transmission principles, fabrication methods, structural characteristics, detection techniques, and sample pretreatment process of modern lab-on-paper devices. A comprehensive review of the most recent applications of lab-on-paper devices to the diagnosis of common human diseases using blood samples is then presented. The review concludes with a brief summary of the main challenges and opportunities facing the lab-on-paper technology field in the coming years.

Incidence, characteristics and outcomes among inpatient, outpatient and emergency department with reported high critical serum potassium values.

OBJECTIVES: Severe hyperkalemia can cause life-threatening arrhythmia, cardiac arrest, or death. This study aimed to investigate the incidence and the associated factors relevant to critical hyperkalemia (≥6 mmol/L) among inpatients, outpatients, and emergency department. Their clinical outcomes were also analyzed. METHODS: All patients whose high serum potassium values had been reported as critical laboratory values in 2016 were enrolled. Their demographic data, comorbidities, clinical symptoms, biochemical data, and outcomes were reviewed and collected. The Charlson comorbidity score (CCS) and glomerular filtration rate (GFR) were computed to assess the comorbidity burden and renal function. Patients were divided into groups according to different settings, potassium and GFR levels, and their survival. RESULTS: Of the 293,830 total serum potassium tests, 1,382 (0.47%) reports were listed as critical laboratory values. The average reply time was 6.3 min. Their mean age was 67.2 years, while the average GFR was 12.2 mL/min/1.73 m2. The overall mortality rate was 34%. Patients in the emergency department had the highest incidence (0.92%), while inpatients had the worst outcome (51% mortality). The leading cause of mortality was septic shock. The fatal group had higher rates of clinical symptoms, higher potassium values, CCS, and eGFR (all p<0.05). CONCLUSIONS: Most of the responses for the reports were obtained within a short period of time. Patients with reported high critical serum potassium values were characterized by high rates of comorbidity, reduced eGFR, and mortality. The incidence, clinical manifestations, and outcomes varied in the different clinical settings.

Association between Enzyme-Linked Immunosorbent Assay-Measured Kidney Injury Markers and Urinary Cadmium Levels in Chronic Kidney Disease.

Cadmium exposure is associated with chronic kidney disease (CKD), but the optimal biomarker for early cadmium-associated nephrotoxicity in low-level exposure has not yet been established. We conducted a cross-sectional investigation involving 167 CKD patients stratified according to tertiles of urinary cadmium levels (UCd), in which enzyme-linked immunosorbent assay (ELISA)-measured novel renal biomarkers were utilized to assess the extent of renal injury associated with cadmium burden. In the analyses, urinary kidney injury molecule-1 (KIM-1) levels and age were the independent factors positively correlated with UCd after adjusting for covariates in non-dialysis-dependent CKD patients (high vs. low UCd, odds ratio (95% confidence interval), 1.0016 (1.0001-1.0032), p = 0.043, and 1.0534 (1.0091-1.0997), p = 0.018). Other conventional and novel renal biomarkers, such as serum creatinine, estimated glomerular filtration rate, CKD staging, urinary protein/creatinine ratio, urinary 8-hydroxy-2-deoxyguanosine (8-OHdG), and urinary epidermal growth factor (EGF) were not independently correlated with UCd in the analyses. In conclusion, our study found that the ELISA-measured urinary KIM-1 level could serve as an early renal injury marker in low-level cadmium exposure for non-dialysis-dependent CKD patients. In addition, age was an independent factor positively associated with UCd in this population.

The TMPRSS6 variant (SNP rs855791) affects iron metabolism and oral iron absorption - a stable iron isotope study in Taiwanese women.

Genome wide studies have associated TMPRSS6 rs855791 (2321 C>T) with iron status and hepcidin. It is unclear whether this polymorphism affects iron absorption. In nonanemic Taiwanese women (n=79, 44 TT variant, 35 CC variant), we administered standardized rice-based test meals containing 4 mg of labeled 57Fe or 58Fe as FeSO4 on alternate days. Fractional iron absorption was measured by erythrocyte incorporation of the tracers 14 days after administration. Compared to the CC variant, in the TT variant serum iron and transferrin saturation were lower (P=0.001; P<0.001, respectively) and serum hepcidin/transferrin saturation and serum hepcidin/serum iron ratios were higher (P=0.042; P=0.088, respectively). Serum hepcidin did not differ between groups (P=0.862). Geometric mean (95% CI) fractional iron absorption, corrected to a serum ferritin of 15 µg/L, was 26.6% (24.0, 29.5) in the CC variant and 18.5% (16.2, 21.1) in the TT variant (P=0.002). Overall, predictors of iron absorption were: serum ferritin (P<0.001); genetic variant (P=0.032); and hepcidin (P<0.001). In the models by variant, in the CC variant the model explained 67-71% of variability in absorption and serum ferritin was the only significant predictor (P<0.001); in the TT variant, the model explained only 35-43% of variability, and hemoglobin (P=0.032), soluble transferrin receptor (P=0.004) and hepcidin (P<0.001) were significant predictors. Women with the TMPRSS6 rs855791 (2321 C>T) polymorphism show altered iron homeostasis which affects oral iron absorption and may increase their risk for iron deficiency. The trial was registered at www.clinicaltrials.gov as NCT03317873, and funded by the Kaohsiung Chang-Gung Memorial Hospital, Kaohsiung, Taiwan, (grant CMRPG8F0721) and ETH Zurich, Switzerland.

The role of TRPM7 in vascular calcification: Comparison between phosphate and uremic toxin.

AIMS: Vascular calcification is a common complication in patients with chronic kidney disease and associated with increased morbidity and mortality. The role of TRPM7 in vascular smooth muscle cell (VSMC) transformation during vascular calcification is not clear. We aim to investigate the effects of phosphate and indoxyl sulphate on the expression of TRPM7 and calcification-related molecules in VSMC. MAIN METHODS: Human aortic smooth muscle cells (HASMC) were treated with phosphate (3.3 mM) or indoxyl sulphate (500 µM and 1000 µM). 2-APB, a channel blocker of TRPM7 was added simultaneously in blocking experiment. Cells were then examined grossly and alizarin red solution was employed for calcification assessment. Lastly, cells were harvested for gene expression and protein abundance analysis. KEY FINDINGS: Phosphate treatment induced significant increase in BMP2, RUNX2, BMP7, vitamin D receptor (VDR), calcium sensing receptor (CaSR) and TRPM7, but 1-alpha hydroxylase, klotho, DKK1 and sclerostin were not changed. The addition of 2-APB prevented increase of BMP2, RUNX2, BMP7, VDR, CaSR and TRPM7. Indoxyl sulphate treatment was associated with decrease in TRPM7 and DKK1, but increase in RUNX2, BMP2 and VDR were noted. There were no significant alterations in BMP7, CaSR, klotho,1-alpha hydroxylase and sclerostin. Co-treatment with 2-APB reversed the increase in VDR. SIGNIFICANCE: Both phosphate and indoxyl sulphate induced calcification in VSMC but it was more prominent in phosphate. TRPM7 was upregulated by phosphate but downregulated in indoxyl sulphate treatment. Vascular calcification was reduced by blocking TRPM7 with 2-APB and there was partial anti-calcification effect in indoxyl sulphate.

Comparison of uric acid reduction and renal outcomes of febuxostat vs allopurinol in patients with chronic kidney disease.

Whether the clinical trial treatment effect of urate-lowering therapy (ULT) in patient with chronic kidney disease (CKD) is generalizable to real-word settings is unclear. This study aimed to compare febuxostat with allopurinol for uric acid reduction and renal protection in patients with CKD. Adult CKD patients newly treated with ULT were identified using electronic health records from 2010 to 2015 from a large healthcare delivery system in Taiwan. Patients with renal replacement therapy or undergoing ULT for <3 months were excluded. Propensity score-matched cohort study design was conducted to compare outcomes between patients initiated with febuxostat or allopurinol therapy. Cox regression analyses were employed to compare the adjusted hazards ratio (aHR) of incident event of estimated glomerular filtration rate (eGFR) ≥ 30% decrease, and the difference in longitudinal changes in serum uric acid (SUA) and eGFR between groups was analyzed using linear mixed model. Overall, 1050 CKD patients who initiated febuxostat (n = 525) or allopurinol (n = 525) treatment were observed for 2.5 years. Compared with allopurinol, febuxostat use was associated with higher rate of patients maintaining SUA target <6 mg/dL in >80% of follow-up time with a reduction in mean SUA change. There were no significant differences in the mean eGFR changes over time between the febuxostat and allopurinol groups or in the risk of eGFR decline ≥30% of baseline. Febuxostat was associated with greater reduction in SUA level than allopurinol in patients with CKD. However, febuxostat and allopurinol showed no difference in renal function changes during study follow-up. These findings require further investigation with long-term follow up in CKD patients with hyperuricemia.

Urinary Exosomal MicroRNA Signatures in Nephrotic, Biopsy-Proven Diabetic Nephropathy.

Diabetic kidney disease (DKD) is the leading cause of chronic kidney disease (CKD). Elucidating the mechanisms underlying proteinuria in DKD is crucial because it is a common problem in DKD-related mortality and morbidity. MicroRNAs (miRs) associated with DKD have been detected in experimental diabetes models and in patients with both diabetes and CKD. Here, we aimed to investigate pathologic miRs in diabetic nephropathy (DN) by prospectively following six nephrotic, biopsy-proven isolated DN patients (enrolled between August 2015 and July 2017) for one year. The urinary exosomes were isolated at the time of the biopsy and the contained miRs were analyzed by next-generation sequencing. The results were compared to the control group, composed of age-, gender-, and CKD stage-matched patients with proteinuric CKD who did not present diabetes. Among the 72 identified miRs, we investigated eight (miR-188-5p, miR-150-3p, miR-760, miR-3677-3p, miR-548ah-3p, miR-548p, miR-320e, and miR-23c) exhibiting the strongest upregulation (13-15 fold) and two (miR-133a-3p and miR-153-3p) with the strongest downregulation (7-9 fold). The functional analysis of these miRs showed that they were involved in known and novel pathways of DN, supporting their pathologic roles. The bioinformatics-based prediction of the target genes of these miRs will inspire future research on the mechanisms underlying DN pathogenesis.

Impaired production of immune mediators in dengue virus type 2-infected mononuclear cells of adults with end stage renal disease.

Chronic kidney disease is an epidemiologically identified risk factor for development of severe dengue in dengue-affected patients. However, available data on the immune pathogenesis in end stage renal disease (ESRD) patients affected by dengue is insufficient. We performed an in vitro study to evaluate the sequential immunological reactions and viral load in dengue virus type 2-infected mononuclear cells of patients with ESRD (n = 34) and in healthy controls (n = 30). The concentrations of interleukins (IL)-1 receptor antagonist (Ra), IL-2, IL-6, IL-8, IL-10, IL-12p40, granulocyte-macrophage colony-stimulating factor (GM-CSF), monocyte chemotactic protein-1 (MCP-1), macrophage inflammatory protein-1b (MIP-1b), vascular endothelial growth factor (VEGF), tumor necrosis factor (TNF)-α and viral load cycle threshold (Ct) were measured in the dengue virus type 2-infected mononuclear cells at 6 h, 24 h, 48 h, and 72 h post-infection. We found in the ESRD group significantly higher GM-CSF and IL-2 levels at 6 h post-infection. However, IL-8, IL-10, IL-12p40, TNF-α, MCP-1, and MIP-1b levels were found significantly lower than in the control group. At 24 h, 48 h, and 72 h post-infection, significantly lower levels of IL-1Ra, IL-6, IL-8, IL-10, IL-12p40, TNF-α, MCP-1, and MIP-1b were detected in ESRD group. Concentration of VEGF at 24 h and 48 h, and of GM-CSF at 48 h and 72 h were also found to be lower in ESRD group than in control group. Compared with controls, the viral load Ct values were significantly lower in ESRD group at 6 h and 24 h post-infection No significant difference in viral load Ct values between two groups was found at 48 h and 72 h post-infection. Our study discloses that the expression of immune mediators of dengue-infected mononuclear cells is impaired in ESRD patients.

Alterations of Renal Epithelial Glucose and Uric Acid Transporters in Fructose Induced Metabolic Syndrome.

BACKGROUND/AIMS: Hyperglycemia and hyperuricemia are two major disorders of Metabolic syndrome. Kidney plays a crucial role in maintaining the homeostasis of uric acid and glucose. The aim of the study was to examine the changes of renal glucose and uric acid transporters in animals with metabolic syndrome. METHODS: Sprague-Dawley rats were fed with high fructose diet (60%) for 3 months (FR-3) and 5 months (FR-5). At the end study, serum and urine biochemical data were compared. Gene expression and protein abundance of renal GLUT1, GLUT2, GLUT9, SGLT1, SGLT2, UAT and URAT1 was investigated by using RT-PCR and immunohistochemical staining. RESULTS: Metabolic syndrome was induced by high-fructose diet. Systolic blood pressure and proteinuria was significantly increased in FR-5 animals. In kidney tissue, gene expression of GLUT2 and SGLT2 increased significantly in a time dependent manner. GLUT9, SGLT1 and UAT were also significantly upregulated in FR-5. Immunohistochemical study showed a significant increase of SGLT1 in both FR-3 (413.5 ± 88.3% of control, p< 0.001) and FR-5 (677.6 ± 26.5% of control, p< 0.001). Also, SGLT2 protein was increased in both FR-3 (643.1 ± 41.3% of control, p< 0.001) and FR-5 (563.3 ± 21.7% of control, p< 0.001). Fructose rich food also induced increase of UAT by nearly 5-fold in both FR-3 and FR-5 (both p< 0.05) and more than 3-fold of GLUT-9 in FR-3 and FR-5 (both p< 0.05). CONCLUSION: Long term high fructose diet induced metabolic syndrome with increased blood pressure and proteinuria in rats. Metabolic syndrome was associated with dual increase in renal glucose and uric acid transporters, including SGLT1, SGLT2, GLUT2, GLUT9 and UAT.

The Number of Comorbidities Predicts Renal Outcomes in Patients with Stage 3⁻5 Chronic Kidney Disease.

BACKGROUND: Chronic kidney disease (CKD) is a global health threat affecting approximately 10% of the adult population worldwide. Multimorbidity is common in CKD, but its impacts on disease outcomes are seldom investigated. METHODS: This prospective cohort analysis followed patients, who were part of a multidisciplinary CKD care program, for 10 years. We aimed to determine the impact of multimorbidity on renal outcomes. RESULTS: Overall, 1463 patients with stage 3⁻5 CKD were enrolled and stratified by the number of comorbidities. Mean follow-up time was 6.39 ± 1.19 years. We found that stage 3⁻5 CKD patients with at least three comorbidities at enrollment initiated dialysis earlier (hazard ratio (HR): 2.971) than patients without comorbidities. Risk factors for multimorbidity included old age, smoking, and proteinuria. CONCLUSIONS: By analyzing the number of comorbidities, a simple and readily applicable method, we demonstrated an association between multimorbidity and poor renal outcomes in stage 3⁻5 CKD patients. In addition to current guideline-based approaches, our results suggest an urgent need for tailored CKD care strategies for high-risk groups.

Relationship between body mass index and renal function deterioration among the Taiwanese chronic kidney disease population.

This study investigated the characteristics of patients with different chronic kidney disease (CKD) stages according to various body mass index (BMI) categories and determined the influence of BMI in renal function deterioration. We conducted a multicenter, longitudinal cohort study based on the Epidemiology and Risk Factors Surveillance of CKD project (2008-2013) and National Health Insurance Research Database (2001-2013). A total of 7357 patients with CKD aged 20-85 years from 14 hospitals were included in the study. A higher male sex, diabetes mellitus (DM) and hypertension were noted among overweight and obese CKD patients, while more cancer prevalence was noted among underweight CKD patients. Charlson comorbidity index was significantly higher and correlated with BMI among late CKD patients. Patients with BMI < 18.5 kg/m2 exhibited non-significantly higher events of eGFR decline events in both early and late CKD stages than other BMI groups. BMI alone is not a determinant of CKD progression among our Taiwanese CKD patients. Obesity should be re-defined and body weight manipulation should be individualized in CKD patients.

Maternal melatonin or agomelatine therapy prevents programmed hypertension in male offspring of mother exposed to continuous light.

Hypertension can originate from early-life insults, whereas maternal melatonin therapy can be protective in a variety of models of programmed hypertension. We hypothesize that melatonin or melatonin receptor agonist agomelatine can prevent programmed hypertension in adult offspring induced by maternal exposure to continuous light. Female Sprague-Dawley pregnant rats randomly divided into four groups: controls, rats exposed to continuous light, exposed to continuous light plus treated with agomelatine (50 mg/day i.p.), and exposed to continuous light plus treated with 0.01% melatonin in drinking water throughout pregnancy and lactation period. Male offspring (n = 10/group) from three litters were examined at 12 weeks of age. Maternal continuous light exposure-induced hypertension in male offspring, which was prevented by melatonin or agomelatine therapy. Continuous light exposure did not affect melatonin pathway in adult offspring kidney. Genes that belong to the renin-angiotensin system (RAS), sodium transporters, AMP-activated protein kinase pathway, and circadian rhythm were potentially involved in the maternal exposure to continuous light-induced programmed hypertension. Maternal agomelatine therapy decreased Ace expression but increased Agtr2 and Mas1. Maternal melatonin therapy prevented the increases of Slc9a3, Slc12a3, and Atp1a1 expression induced by maternal continuous light exposure. In conclusion, maternal melatonin or agomelatine therapy prevents programmed hypertension induced by maternal exposure to continuous light. Agomelatine and melatonin reprogram the RAS and sodium transporters differentially, to prevent negative programming of continuous light. Our data highlight candidate genes and pathways in renal programming as targets for therapeutic approaches to prevent programmed hypertension caused by early-life disturbance of the circadian rhythm.

Synergic Impact of Vascular Calcification and Low Autonomic Tone in Mortality of Hemodialysis Patients.

BACKGROUND: Both cardiovascular calcification and autonomic dysfunction are frequently encountered in hemodialysis patients. We aimed to investigate the relationship between cardiovascular calcification and heart rate variability (HRV) and their influence on long-term outcome. METHODS: Seventy-eight hemodialysis patients underwent echocardiogram and radiography of the pelvis and hands to identify valvular and vascular calcification. HRV was evaluated using a commercial machine. RESULTS: Based on the average, the patients were divided into higher and lower subgroups of high frequency (HF) and low frequency (LF) respectively. Patients with higher LF were younger and were found to have a lower proportion of diabetes. Their hemoglobin, albumin, and bone morphogenic protein (BMP)-7 levels were significantly higher and both high-sensitive C-reactive protein (hs-CRP) and osteoprotegerin levels were lower (all p < 0.05). In patients of the higher HF group, the proportion of diabetes was lower but they were found to have higher levels of BMP-7 and lower levels of hs-CRP, interleukin-6 (all p < 0.05). Significantly higher LF and HF were noted in patients without vascular calcification, but only hand artery (HA) calcification was negatively correlated with both LF and HF in multivariate analysis. Low LF and high hs-CRP were the independent predictors of mortality. Coexistence of low LF band and HA calcification was associated with the worse outcome. CONCLUSIONS: Abnormal autonomic nervous function was closely related to inflammation and mortality in hemodialysis patients. Calcification of HA was associated with autonomic dysfunction and patients with lower autonomic tone and HA calcification had the highest mortality rate in this population.

Febuxostat-induced agranulocytosis in an end-stage renal disease patient: A case report.

INTRODUCTION: Febuxostat, a nonpurine xanthine oxidase inhibitor, is approved as the first-line urate-lowering therapy in gout patients with normal renal function or mild to moderate renal impairment. The most common adverse effects of febuxostat are liver function test abnormalities, diarrhea, and skin rash. However, there is insufficient data in patients with severe renal impairment and end-stage renal disease (ESRD). We report the first case, to our knowledge, in which agranulocytosis developed after febuxostat treatment in an ESRD patient. CLINICAL PRESENTATION: A 67-year-old woman with gout and ESRD received febuxostat 40 mg a day for 2.5 months. She subsequently complicated with febrile neutropenia and the absolute neutrophil count was only 14/µL. After broad-spectrum antibiotics treatment and no more exposure to febuxostat for 17 days, her infection and neutrophil count recovered. Bone marrow study during neutropenic period showed myeloid hypoplasia without evidence of hematologic neoplasms. CONCLUSION: As febuxostat use may become more common in the population of advanced renal failure, clinicians should be aware of this rare but potentially life-threatening adverse effect. Based on our experience, close monitoring hemogram and immediate discontinuation of this medication may prevent serious consequences.

Higher blood MLL1 mRNA and BDNF promoter IV on histone H3K4me3 levels in patients with schizophrenia.

We investigated the blood levels of mixed-lineage leukemia 1 (MLL1) mRNA and BDNF (brain derived neurotrophic factor) exon IV promoter on histone Histone 3 lysine 4 trimethylation (H3K4me3) in peripheral blood of patients with schizophrenia and controls. Over one year, 36 patients with schizophrenia and 32 controls were recruited. Psychiatric diagnoses were made based on DSM-IV criteria. Higher blood MLL1 mRNA and BDNF exon IV promoter on H3K4me3 levels were noted in patients with schizophrenia than in controls. The results showed that blood MLL1 mRNA and BDNF exon IV on H3K4me3 levels might be involved in the psychopathology of schizophrenia.