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Peritoneal dialysis (PD) is an important alternative treatment for end-stage renal disease. Continuous exposure to non-physiological fluids during PD is associated with pathological responses, such as sustained microinflammation, leading to tissue fibrosis and angiogenesis. However, the effect of PD fluid on submesothelial cells has not yet been investigated in detail.We investigated the association between macrophages and the expression of matrix metalloproteinase-12 (MMP-12), an elastin proteinase secreted by macrophages, in the peritoneal tissue of rats undergoing continuous PD.Morphological data revealed that the submesothelial layer of the peritoneum in PD model rats was markedly thickened, with fibrosis and angiogenesis. In the fibrillization area, elastin was disorganized and fragmented, and macrophages accumulated, which tended to have M2 characteristics. The expression of MMP-12 was enhanced by continuous exposure to PD fluid, suggesting that MMP-12 expression may be involved in PD fluid-induced peritoneal damage.The results of this study may lead to a better understanding of the mechanisms underlying fibrosis in PD.

Arginine vasopressin (AVP) is produced in the paraventricular (PVN) and supraoptic nuclei (SON). Peripheral AVP, which is secreted from the posterior pituitary, is produced in the magnocellular division of the PVN (mPVN) and SON. In addition, AVP is produced in the parvocellular division of the PVN (pPVN), where corticotrophin-releasing factor (CRF) is synthesized. These peptides synergistically modulate the hypothalamic-pituitary-adrenal (HPA) axis. Previous studies have revealed that the HPA axis was activated by hypovolemia. However, the detailed dynamics of AVP in the pPVN under hypovolemic state has not been elucidated. Here, we evaluated the effects of hypovolemia and hyperosmolality on the hypothalamus, using AVP-enhanced green fluorescent protein (eGFP) transgenic rats. Polyethylene glycol (PEG) or 3% hypertonic saline (HTN) was intraperitoneally administered to develop hypovolemia or hyperosmolality. AVP-eGFP intensity was robustly upregulated at 3 and 6 h after intraperitoneal administration of PEG or HTN in the mPVN. While in the pPVN, eGFP intensity was significantly increased at 6 h after intraperitoneal administration of PEG with significant induction of Fos-immunoreactive (-ir) neurons. Consistently, eGFP mRNA, AVP hnRNA, and CRF mRNA in the pPVN and plasma AVP and corticosterone were significantly increased at 6 h after intraperitoneal administration of PEG. The results suggest that AVP and CRF syntheses in the pPVN were activated by hypovolemia, resulting in the activation of the HPA axis.

Background Molecularly targeted therapies are emerging for treating lupus nephritis (LN). This study aimed to assess the immunohistochemical findings of the cytokines in renal tissue and their pathological and clinical relevance in LN. Methods Fifty patients with proliferative LN (ISN/RPS class III and IV), five with LN class II, IgA nephropathy, and five with idiopathic hematuria as controls were enrolled. Immunohistochemistry (IHC) for CD3, CD20, interferon-alpha (IFNα), interleukin (IL)-12/p40, and B-cell activating factor (BAFF) was performed. The IHC score was calculated by scoring the number of positive cells/area of the cortex. Proliferative LN cases were grouped by the dominant expression of IFN-α, IL-12/p40, and BAFF, and subsequently, clinicopathological features were compared. Results Clinical data of patients with proliferative LN included urine protein creatinine ratio, 2.2 g/gCre; anti-ds-DNA antibody, 200.9 IU/mL; CH50, 21.9 U/mL; Systemic Lupus Erythematosus Disease Activity Index, 19.8 points. Proliferative LN cases, including class III (n = 18) and IV (n = 32), were classified into three subgroups according to the IHC score based on the dominancy of IFN-α (n = 17), IL-12 (n = 16), and BAFF group (n = 17) proteins. Hypocomplementemia and glomerular endocapillary hypercellularity were significantly increased in the IFN-α group, whereas chronic lesions were significantly higher in the IL-12 group (p

Background Malnutrition is considered a risk factor for cardiovascular disease in patients with chronic kidney disease. However, no in vivo studies have reported on using optical coherence tomography to evaluate the effect of nutritional status on coronary atherosclerosis in hemodialysis patients. We aimed to conduct a detailed analysis of the effect of nutritional status on the coronary arteries in hemodialysis patients. Methods Among 64 hemodialysis patients who underwent percutaneous coronary interventions, 41 that underwent optical coherence tomography imaging were included in this study. And, among them, 24 patients that could also be evaluated using OCT also at the 6-month follow-up were included in this study. The patients were divided into two groups based on nutritional evaluation using the geriatric nutritional risk index. Culprit and non-culprit lesions were evaluated at baseline and after 6 months. Results In the culprit lesions at baseline, the length of the lipid plaque was significantly smaller in the malnutrition group. In contrast, the thickness and length of the calcified plaque and the angle of the calcified nodule were significantly larger (each p < 0.01). In the non-culprit lesions, the 6-month change in the angle of the calcified plaque was significantly greater in the malnutrition group (p = 0.02). The significant factors that affected the change in the angle of calcification were "malnutrition at geriatric nutritional risk index" [odds ratio, 8.17; 95% confidence interval, 1.79 to 37.33; p < 0.01] and "serum phosphorus level" (odds ratio, 3.73; 95% confidence interval, 1.42 to 9.81; p < 0.01). Conclusions Appropriate management of nutritional status is crucial for suppressing the progression of coronary artery disease in hemodialysis patients.

Tumour necrosis factor (TNF) inhibitors are used against a variety of connective tissue diseases, including rheumatoid arthritis. Contrarily, although rare, TNF inhibitors are known to induce autoimmune diseases, such as systemic lupus erythematosus and psoriasis as a paradoxical reaction. We experienced a case of rapidly progressive glomerulonephritis after introduction of certolizumab pegol. The patient was a 30-year-old woman who was previously diagnosed with rheumatoid arthritis in X-8. She received treatment with methotrexate (8 mg/week) and infliximab (3 mg/kg/8 weeks), following which she showed low disease activity and remission. In September X-1, methotrexate and infliximab were discontinued and certolizumab pegol was introduced because she desired to bear children. In March X, the patient experienced renal dysfunction, and urinary protein analysis revealed positivity for myeloperoxidase anti-neutrophil cytoplasmic autoantibody. Renal biopsy showed crescentic glomerulonephritis, and the patient was diagnosed with rapidly progressive glomerulonephritis due to TNF inhibitor-induced microscopic polyangiitis. As she desired to bear children, rituximab was introduced in addition to corticosteroids, which led to remission of the symptoms. TNF inhibitors should be discontinued in patients who develop rapidly progressive glomerulonephritis, and these patients should be treated with immunosuppressive drugs, such as massive corticosteroids and cyclophosphamide. In the present case, rituximab was useful for not only the treatment, but also for the preservation of fertility.

We examined whether the chemogenetic activation of endogenous arginine vasopressin (AVP) affects central nesfatin-1/NucB2 neurons, using a transgenic rat line that was previously generated. Saline (1 mL/kg) or clozapine-N-oxide (CNO, 1 mg/mL/kg), an agonist for hM3Dq, was subcutaneously administered in adult male AVP-hM3Dq-mCherry transgenic rats (300–370 g). Food and water intake were significantly suppressed after subcutaneous (s.c.) injection of CNO, with aberrant circadian rhythmicity. The percentages of Fos expression in nesfatin-1/NucB2-immunoreactive neurons were significantly increased in the hypothalamus and brainstem at 120 min after s.c. injection of CNO. Suppressed food intake that was induced by chemogenetic activation of endogenous AVP was ablated after intracerebroventricularly administered nesfatin-1/NucB2-neutralizing antibody in comparison with vehicle, without any alteration of water intake nor circadian rhythmicity. These results suggest that chemogenetic activation of endogenous AVP affects, at least in part, central nesfatin-1/NucB2 neurons and may exert anorexigenic effects in the transgenic rats.

Background In order to facilitate the safe and long-term delivery of peritoneal dialysis (PD), it is necessary to improve the biocompatibility of peritoneal dialysis fluids (PDFs). The novel bicarbonate/lactate-buffered neutral PDFs (B/L-PDFs) are expected to be improved biocompatible. This study evaluated the biocompatibility of B/L-PDFs by analysis on the profile of angiogenesis-related proteins in drained dialysate of patients undergoing PD. Methods Concentrations of 20 angiogenesis-related proteins in the dialysate were semi-quantitatively determined using a RayBio® Human Angiogenesis Antibody Array and were compared between B/L-PDFs and conventional lactate-buffered neutral PDFs (L-PDFs). Results The expression of growth-related oncogene (GRO α/β/γ), which belongs to the CXC chemokine family, decreased significantly after use of the B/L-PDFs compared to the L-PDFs (P = 0.03). The number of the proteins with lower level in the B/L-PDFs compared with L-PDFs was significantly negatively correlated with the PD duration (Spearman ρ = − 0.81, P = 0.004). Conclusion This study suggested that B/L-PDFs are more biocompatible than conventional PDFs.

We generated a transgenic rat line that expresses oxytocin (OXT)‐monomeric red fluorescent protein 1 (mRFP1) fusion gene to visualize the dynamics of OXT. In this transgenic rat line, hypothalamic OXT can be assessed under diverse physiological and pathophysiological conditions by semiquantitative fluorometry of mRFP1 fluorescence intensity as a surrogate marker for endogenous OXT. Using this transgenic rat line, we identified the changes in hypothalamic OXT synthesis under various physiological conditions. However, few reports have directly examined hypothalamic OXT synthesis under hyperosmolality or hypovolemia. In this study, hypothalamic OXT synthesis was investigated using the transgenic rat line after acute osmotic challenge and acute hypovolemia induced by intraperitoneal (i.p.) administration of 3% hypertonic saline (HTN) and polyethylene glycol (PEG), respectively. The mRFP1 fluorescence intensity in the paraventricular (PVN) and supraoptic nuclei (SON) was significantly increased after i.p. administration of HTN and PEG, along with robust Fos‐like immunoreactivity (co‐expression). Fos expression showed neuronal activation in the brain regions that are associated with the hypothalamus and/or are involved in maintaining water and electrolyte homeostasis in HTN‐ and PEG‐treated rats. OXT and mRFP1 gene expressions were dramatically increased after HTN and PEG administration. The plasma OXT level was extremely increased after HTN and PEG administration. Acute osmotic challenge and acute hypovolemia induced upregulation of hypothalamic OXT in the PVN and SON. These results suggest that not only endogenous arginine vasopressin (AVP) but also endogenous OXT has a key role in maintaining body fluid homeostasis to cope with hyperosmolality and hypovolemia., CVOs activation under hyperosmolality, and brainstem neurons and SFO activation under hypovolemia could upregulate OXT synthesis in the hypothalamus.

Intravascular ultrasound (IVUS)-derived minimum lumen cross-sectional area (MLA) is useful to predict myocardial ischemia using fractional flow reserve (FFR). Recent studies reported an increase in the intraluminal ultrasonic integrated backscatter (IB) value using IVUS across the coronary artery stenosis (CAS) was significantly correlated with FFR. However, these details have not been fully understood. We evaluated the utility of intraluminal IB analysis for predicting myocardial ischemia based on FFR measurements by comparing that with conventional IVUS-derived MLA. A total of 65 patients with 75 intermediate lesions underwent both FFR and IB-IVUS simultaneously were analyzed. We measured IVUS-derived MLA and intraluminal IB value at the coronary ostial site, 5 mm distal site to the CAS, and far distal site, which is the same as the position of the pressure wire sensor. The increase in IB values was calculated as the distal IB value - the ostial IB value (focal ∆IB) and the far distal IB value - the ostial IB value (total ∆IB). MLA did not show a significant correlation with FFR (p = 0.13); however, focal ∆IB and total ∆IB showed significant correlations with FFR (p = 0.008 and p

Previous optical coherence tomography (OCT) study reported that irregular protrusion (IP) post drug-eluting stent (DES) implantation was an independent predictor of clinical outcome; however, the relationship between IP and the presence of subsequent in-stent neoatherosclerosis remains unclear. This study aimed to assess the relationship between IP and in-stent neoatheroscrerosis formation using OCT. We evaluated 83 patients (101 lesions) who underwent second-generation DES implantation and 8-month follow-up (8M-FU) using OCT. Lesions were divided into two groups in presence of IP (IP: n = 43, non-IP: n = 58). At prepercutaneous coronary intervention (pre-PCI), lipid-rich plaque, lesions with positive remodeling, and in-stent thrombus formation were more frequent in IP than in non-IP. On multivariate analysis, the thrombus at pre-PCI and the lesions with positive remodeling were independent predictors of IP. At 8M-FU, heterogeneous neointima, microvessel, lipid-laden neointima, and thin-cap fibro-atheroma like neointima were more frequent in IP than in non-IP (respectively, P < 0.05). On multivariate analysis, IP was associated with heterogeneous neointima. Binary restenosis was more frequent and late lumen loss tended to be larger in IP than in non-IP (19% versus 5%, P = 0.04; 1.25 ± 1.24 mm versus 0.91 ± 0.63 mm, P = 0.09); however, the target lesion revascularization rate was similar in both groups at 8M-FU. In conclusion, our study suggested that poststent IP was associated with subsequent neoatherosclerosis formation at 8M-FU after the second-generation DES implantation.

We investigated the effects of bicarbonate/lactate-buffered peritoneal dialysis fluid (B/L-PDF) and lactate-buffered PDF (L-PDF) on cell viability and apoptosis, focusing on monocarboxylate transporters (MCTs). MCT-1 transports lactate into cells. Cell viability and apoptosis of human peritoneal mesothelial cells (HPMCs) were examined by water-soluble tetrazolium salt-1 and TUNEL assays, respectively. The relative number of viable HPMCs was significantly decreased by L-PDF at 48 h (8.8 ± 0.4%) compared with cells cultured in M199, but not by B/L-PDF (66.7 ± 1.1%). Apoptosis was markedly induced by L-PDF at 48 h (69.3 ± 16.2%), but not by B/L-PDF (2.6 ± 0.3%). Knockdown of MCT-1 by small interfering RNA (siRNA) attenuated the L-PDF-induced reduction of viable cells and increased apoptosis compared with control siRNA, but MCT-4 knockdown had no effect. B/L-PDF had lesser effects on cell viability and apoptosis of HPMCs compared with L-PDF. These results suggest that B/L-PDF biocompatibility occurs by avoiding the induction of apoptosis in HPMCs.

Recent studies reported that cardiac troponin elevation after percutaneous coronary intervention is related to adverse cardiac events. Intravascular ultrasound (IVUS) and optical coherence tomography (OCT) are often used to assess lesion characteristics in the coronary arteries. However, little is known about the trend of cardiac troponin elevation after diagnostic invasive intracoronary examination and the prognostic influence. We assessed the relationship between myocardial injury manifested by the high-sensitivity cardiac troponin T (hs-cTnT) level after invasive intracoronary examination and future adverse cardiac outcomes. We evaluated 115 patients with stable coronary artery disease who underwent IVUS or OCT for detailed coronary assessment during coronary angiography (CAG). Baseline and post-procedural (within 24 hours after examination) hs-cTnT were measured. In consequence, post-procedural hs-cTnT level and percentage increase were higher in patients with IVUS or OCT during CAG than in those without. Periprocedural myocardial injury (PMI, defined as post-procedural hs-cTnT with upper reference limit greater than five-fold) occurred in 10 (8.6%) patients. There were no significant differences in baseline characteristics between patients with and without PMI, except for left-ventricular diastolic dimension. Only two major adverse cardiac events (MACE, defined as cardiovascular death, nonfatal myocardial infarction, and target lesion revascularization) occurred in non-PMI during a mean observation period of 32 ± 18 months. On Kaplan-Meier analysis, MACE-free survival rate was similar between PMI and non-PMI. In conclusion, a few imperceptible PMI derived by hs-cTnT assay occurred after diagnostic invasive intracoronary examination. However, it was not associated with subsequent poor cardiac outcome.

Dual-antiplatelet therapy (DAPT) after second-generation drug-eluting stent (2nd-DES) implantation reduces the risk of stent thrombosis and subsequent ischemic events, with an increase in bleeding risk. Although chronic kidney disease patients have both high ischemic and bleeding events, little is known about both risks during DAPT in hemodialysis (HD) patients.From July 2009 to March 2017, we retrospectively analyzed bleeding events and major adverse cardiac and cerebrovascular events (MACCE) in 644 consecutive patients who underwent successful percutaneous coronary intervention (PCI) with 2nd-DES implantation in our institution. We divided the patients into 2 groups [102 HD and 518 non-HD patients] after excluding 24 patients. The primary endpoint was bleeding events of Bleeding Academic Research Consortium (BARC) type 2, 3, or 5. The secondary endpoint was MACCE. We also investigated potential bleeding risk factors in those patients.At a median follow-up of 49 months, bleeding events occurred in 76 (12.3%) patients. Critical bleeding events of BARC type 3 or 5 occurred more frequently in HD (HD vs. non-HD: 16.7% vs. 7.1%; p=0.004). Most events tended to occur within 6 months post PCI. Multivariate analysis demonstrated that HD [hazard ratio (HR) 2.50, 95% confidence interval (CI) 1.03-3.16; p=0.04], body mass index (BMI) (HR 0.91, 95%CI 0.87-0.99, p=0.02), and serum albumin (HR 0.35, 95%CI 0.34-0.96, p=0.03) were independent predictors of bleeding events. MACCE also occurred more frequently in HD (HD vs. non-HD: 53.9% vs. 29.3%; p0.001). Multivariate analysis demonstrated that pre-dialysis systolic blood pressure (HR 1.03, 95%CI 1.00-1.06, p=0.02) and high-sensitive C-reactive protein level (HR 1.76, 95%CI 1.06-2.72, p=0.03) were independent predictors of bleeding events in HD.HD displayed more adverse bleeding and ischemic events compared with non-HD. Therefore, practitioners should reconsider the current regimen of DAPT in this patient cohort to prevent critical bleeding complications and spates of ischemic events.

Furosemide, which is used worldwide as a diuretic agent, inhibits sodium reabsorption in the Henle's loop, resulting in diuresis and natriuresis. Arginine vasopressin (AVP) is synthesized in the supraoptic nucleus (SON), paraventricular nucleus (PVN), and suprachiasmatic nucleus (SCN) of the hypothalamus. The synthesis AVP in the magnocellular neurons of SON and PVN physiologically regulated by plasma osmolality and blood volume and contributed water homeostasis by increasing water reabsorption in the collecting duct. Central AVP dynamics after peripheral administration of furosemide remain unclear. Here, we studied the effects of intraperitoneal (i.p.) administration of furosemide (20 mg/kg) on hypothalamic AVP by using transgenic rats expressing AVP-enhanced green fluorescent protein (eGFP) under the AVP promoter. The i.p. administration of furosemide did not affect plasma osmolality in the present study; however, eGFP in the SON and magnocellular divisions of the PVN (mPVN) were significantly increased after furosemide administration compared to the control. Immunohistochemical analysis revealed Fos-like immunoreactivity (IR) in eGFP-positive neurons in the SON and mPVN 90 min after i.p. administration of furosemide, and AVP heteronuclear (hn) RNA and eGFP mRNA levels were significantly increased. These furosemide-induced changes were not observed in the suprachiasmatic AVP neurons. Furthermore, furosemide induced a remarkable increase in Fos-IR in the organum vasculosum laminae terminals (OVLT), median preoptic nucleus (MnPO), subfornical organ (SFO), locus coeruleus (LC), nucleus of the solitary tract (NTS), and rostral ventrolateral medulla (RVLM) after i.p. administration of furosemide. In conclusion, we were able to visualize and quantitatively evaluate AVP-eGFP synthesis and neuronal activations after peripheral administration of furosemide, using the AVP-eGFP transgenic rats. The results of this study may provide new insights into the elucidation of physiological mechanisms underlying body fluid homeostasis induced by furosemide. This article is protected by copyright. All rights reserved.

Previous optical coherence tomography (OCT) study reported that irregular protrusion (IP) post drug-eluting stent (DES) implantation was an independent predictor of clinical outcome; however, the relationship between IP and the presence of subsequent in-stent neoatherosclerosis remains unclear. This study aimed to assess the relationship between IP and in-stent neoatheroscrerosis formation using OCT. We evaluated 83 patients (101 lesions) who underwent second-generation DES implantation and 8-month follow-up (8M-FU) using OCT. Lesions were divided into two groups in presence of IP (IP: n = 43, non-IP: n = 58). At prepercutaneous coronary intervention (pre-PCI), lipid-rich plaque, lesions with positive remodeling, and in-stent thrombus formation were more frequent in IP than in non-IP. On multivariate analysis, the thrombus at pre-PCI and the lesions with positive remodeling were independent predictors of IP. At 8M-FU, heterogeneous neointima, microvessel, lipid-laden neointima, and thin-cap fibro-atheroma like neointima were more frequent in IP than in non-IP (respectively, P0.05). On multivariate analysis, IP was associated with heterogeneous neointima. Binary restenosis was more frequent and late lumen loss tended to be larger in IP than in non-IP (19% versus 5%, P = 0.04; 1.25 ± 1.24 mm versus 0.91 ± 0.63 mm, P = 0.09); however, the target lesion revascularization rate was similar in both groups at 8M-FU. In conclusion, our study suggested that poststent IP was associated with subsequent neoatherosclerosis formation at 8M-FU after the second-generation DES implantation.

In addition to corticosteroids and inhibition of the renin–angiotensin–aldosterone system, tonsillectomy with steroid pulse therapy (TSP) may have a beneficial impact on the clinical course of IgA nephropathy (IgAN). However, there is still much uncertainty regarding the indications for therapy, treatment protocol, and therapeutic options for IgAN. In this multicenter retrospective cohort study, we enrolled 284 patients with biopsy-proven IgAN who received TSP or corticosteroid therapy or conservative therapy. The effects of TSP on clinical remission (CR) were evaluated after a median follow-up period of 4.1 years in relation to histological classifications. Among the 284 participants, 161 patients received TSP. During the observation time, 141 patients (49.6 %) achieved CR, with a median time to remission of 397 days. In multivariate Cox regression analyses, TSP had an impact on achieving CR in only the group with histological grade 3 defined as glomerulosclerosis, crescent formation or adhesion to Bowman’s capsule in 10–30 % of all biopsied glomeruli, or mild cellular infiltration in the interstitium (hazard ratio (HR) 4.29, 95 % confidence interval (95 %CI) 1.88–11.19, P

The Muller maneuver (MM) has been incorporated as one of the physiologic, low-intensity stresses tests. Increasing negative intrathoracic pressure during MM causes an increase in left ventricular (LV) transmural pressure (TMP) [(1)][1], which theoretically acts as an elevated LV afterload. This

Anorexia is one of the most widespread eating disorders that appears to contribute to malnutrition in patients with advanced kidney dysfunction. The changes of neuropeptides controlling feeding behaviors synthesized in the hypothalamus under several physiological condition could induce anorexia. While several mechanisms underlying uremic anorexia have been proposed, the changes of hypothalamic neuropeptides controlling feeding behaviors of uremic patients are poorly understood. The gene expressions of hypothalamic neuropeptides controlling feeding behaviors were evaluated after bilateral nephrectomy, which is a model of acute kidney dysfunction, by in situ hybridization histochemistry. Food consumption decreased markedly in bilateral nephrectomized rats. The mRNA levels of corticotrophin-releasing hormone, proopiomelanocortin, cocaine- and amphetamine-regulated transcript, which suppress feeding behavior, were significantly higher in bilateral nephrectomized rats than in sham-operated rats. On the other hand, the mRNA levels of Agouti-related peptide, neuropeptide Y, melanin-concentrating hormone, and orexin, which promote feeding behavior, were significantly lower in bilateral nephrectomized rats than in sham-operated rats. In addition, the plasma level of leptin, which has an anorexic effect, increased after bilateral nephrectomy. The results suggest that hypothalamic neuropeptides controlling feeding behaviors may be involved in the development of anorexia in bilateral nephrectomized rats. This report is the first step to elucidating the physiological mechanisms of anorexia in patients with kidney dysfunction.

BACKGROUND Segmental and global mitral valve prolapse (MVP) comprise 2 representative phenotypes in this syndrome. While mitral regurgitation (MR) severity is a major factor causing left atrial (LA) remodeling in MVP, prominent mitral valve (MV) annulus dilatation in global MVP may specifically cause inferiorly predominant LA remodeling. We compared MV annulus and LA geometry in patients with segmental and global MVP.Methods and Results:LA volume as well as inferior, middle, and superior LA cross-sectional areas (CSA) were measured on 3-D echocardiography in 20 controls, in 40 patients with segmental MVP, and in 18 with global MVP. On multivariate analysis, MR severity was primarily associated with LA dilatation in segmental MVP (P

BACKGROUND Whether pacing from the right ventricular (RV) septum improves prognosis is unclear. Furthermore, the clinical characteristics of patients who develop atrial fibrillation (AF) and cardiovascular events during long-term RV septal pacing have not been described.Methods and Results:We retrospectively evaluated the incidence of AF and cardiovascular events, including cardiac death, heart failure requiring hospitalization, or stroke, for a median of 4.0 years in 123 recipients of dual-chamber pacemakers implanted for atrioventricular block with preserved left ventricular function, who were free from AF before device implantation. AF developed in 30 patients (24%), and multivariable analysis suggested that the cumulative percentage of RV pacing was the only independent predictor of newly developed AF (hazard ratio: 1.19 for each 10% increment; 95% confidence interval: 1.04-1.41; P=0.01). Furthermore, older age, newly developed AF and a paced QRS duration ≥155 ms at pacemaker implantation were significant predictors of cardiovascular events. CONCLUSIONS RV septum pacing may induce AF in up to one-quarter of patients paced for atrioventricular block, according to the frequency of pacing. More importantly, in such patients, AF induced by RV pacing and a paced QRS duration ≥155 ms at pacemaker implantation are significantly associated with poor prognosis. Therefore, we recommend pacing from sites producing a paced QRS duration

Continuous exposure to peritoneal dialysis fluids (PDFs) is associated with pathological responses such as persistent micro-inflammation, which leads to ultrafiltration failure. Pentraxin-3 (PTX3), a multifunctional soluble pattern recognition receptor, is produced at sites of inflammation by a wide range of cell types. This study investigates the in vivo expression of PTX3 in the peritoneal membrane of a rat continuous peritoneal dialysis (PD) model, as well as the effect of high glucose on the in vitro expression of PTX3.The expression of PTX3 was analyzed using RT-PCR, real-time PCR, immunohistochemistry and western blotting in a PD rat model receiving saline or conventional PDF containing 3.86% glucose for 8 weeks. The effects of high glucose on the expression of PTX3 were examined in cultured rat peritoneal mesothelial cells (RPMCs), mouse macrophage-like cells, and mouse fibroblasts.In a rat model of PD, eight-week instillation of the conventional PDF produced increased submesothelial thickening, followed by substantially enhanced PTX3 protein levels in the submesothelial layer of peritoneal membrane. PTX3 was detected in peritoneal mesothelial cells, macrophages and fibroblasts in the thickened submesothelial area. Glucose was found to induce PTX3 protein expression in RPMCs as well as macrophage-like cells and fibroblasts.Continuous exposure to conventional PDF induces PTX3 expression in the peritoneal membrane of rats. High glucose may be involved in the mechanism of PDF-induced local micro-inflammation in the peritoneum.

We investigated the effects of bicarbonate/lactate-buffered peritoneal dialysis fluid (B/L-PDF) and lactate-buffered PDF (L-PDF) on cell viability and apoptosis, focusing on monocarboxylate transporters (MCTs). MCT-1 transports lactate into cells. Cell viability and apoptosis of human peritoneal mesothelial cells (HPMCs) were examined by water-soluble tetrazolium salt-1 and TUNEL assays, respectively. The relative number of viable HPMCs was significantly decreased by L-PDF at 48 h (8.8 ± 0.4%) compared with cells cultured in M199, but not by B/L-PDF (66.7 ± 1.1%). Apoptosis was markedly induced by L-PDF at 48 h (69.3 ± 16.2%), but not by B/L-PDF (2.6 ± 0.3%). Knockdown of MCT-1 by small interfering RNA (siRNA) attenuated the L-PDF-induced reduction of viable cells and increased apoptosis compared with control siRNA, but MCT-4 knockdown had no effect. B/L-PDF had lesser effects on cell viability and apoptosis of HPMCs compared with L-PDF. These results suggest that B/L-PDF biocompatibility occurs by avoiding the induction of apoptosis in HPMCs.

Aims Exposure to glucose and its metabolites in peritoneal dialysis fluid (PDF) results in structural alterations of the peritoneal membrane. Icodextrin-containing PDF eliminates glucose and reduces deterioration of peritoneal membrane function, but direct effects of icodextrin molecules on peritoneal mesothelial cells have yet to be elucidated. We compared the impacts of icodextrin itself with those of glucose under PDF-free conditions on wound healing processes of injured mesothelial cell monolayers, focusing on integrin-mediated cell adhesion mechanisms. Main methods Regeneration processes of the peritoneal mesothelial cell monolayer were investigated employing an in vitro wound healing assay of cultured rat peritoneal mesothelial cells treated with icodextrin powder- or glucose-dissolved culture medium without PDF, as well as icodextrin- or glucose-containing PDF. The effects of icodextrin on integrin-mediated cell adhesions were examined by immunocytochemistry and Western blotting against focal adhesion kinase (FAK). Key findings Cell migration over fibronectin was inhibited in conventional glucose-containing PDF, while icodextrin-containing PDF exerted no significant inhibitory effects. Culture medium containing 1.5% glucose without PDF also inhibited wound healing of mesothelial cells, while 7.5% icodextrin-dissolved culture medium without PDF had no inhibitory effects. Glucose suppressed cell motility by inhibiting tyrosine phosphorylation of FAK, formation of focal adhesions, and cell spreading, while icodextrin had no effects on any of these mesothelial cell functions. Significance Our results demonstrate icodextrin to have no adverse effects on wound healing processes of peritoneal mesothelial cells. Preservation of integrin-mediated cell adhesion might be one of the molecular mechanisms accounting for the superior biocompatibility of icodextrin-containing PDF.

Background While chronic kidney disease (CKD) is associated with dysmetabolism including a marked insulin resistance, the postprandial response has not comprehensively been studied in CKD patients. Methods We conducted an intervention study comparing fasting and postprandial circulating biomarkers of glucose and lipid homeostasis, incretins, anabolic hormones, inflammation and oxidative stress in nine prevalent non-diabetic hemodialysis (HD) patients and 10 matched controls assessed after a standardized meal consisting of 75 g of milk fat, 80 g of carbohydrates and 6 g of proteins/m(2) of body surface area. Results Glucose and triglyceride increased in a similar manner following the meal, while insulin, C-peptide and glucose-dependent insulinotropic polypeptide increased more in HD patients. HDL and LDL cholesterol decreased slightly with no significant difference between the groups. The elevated baseline growth hormone (GH) in patients dropped, resulting in comparable levels in both groups 240 min after the meal; however, there was no change in insulin-like growth factor 1 (IGF-1) levels. No marked changes of interleukin 6 and tumor necrosis factor-α were observed in either group. An elevation in the DNA oxidative product 8-hydroxydeoxyguanosine was observed in HD patients. Conclusions The postprandial state in CKD is characterized by impaired insulin sensitivity with increased incretin levels, along with GH/IGF-1 axis uncoupling and an elevation in an oxidative stress marker.

Background. Circulating fibroblast growth factor-23 (FGF23) promotes renal phosphate excretion and is markedly increased in patients with chronic kidney disease. High serum FGF23 is associated with cardiovascular risk factors and was recently identified as a predictor of total mortality in haemodialysis patients. Herein, our aim was to evaluate the relation between FGF23 and mortality, including the impact of gender and cardiovascular disease (CVD), in a Swedish cohort of 'incident' dialysis patients. Methods. Two hundred and twenty-nine incident dialysis patients (149 males; mean age 55 years) were included. Serum intact FGF23, calcium, phosphate, S-albumin, parathyroid hormone, high-sensitivity C-reactive protein and interleukin-6 were measured at baseline. Cardiovascular disease was defined as clinical symptoms and/or a history of CVD. Results. During a median follow-up time of 23 months, 66 patients (29%) died. FGF23 levels positively correlated to calcium (r = 0.27, P < 0.0001), phosphate (r = 0.40, P < 0.0001), calcium x phosphate product (r = 0.52, P < 0.0001) and creatinine (r = 0.18, P = 0.007). In Cox proportional hazard models, FGF23 was not associated with increased mortality risk, neither in crude nor in multivariate adjusted models. However, in a subgroup analysis of men with prevalent CVD, FGF23 level above median was associated with higher mortality risk in crude models [hazard ratio 2.19, 95% confidence interval 1.04-4.60, P = 0.04]. Conclusions. In primary analysis, serum FGF23 was not associated with increased mortality risk in this cohort of 'incident' dialysis patients. Our data support that the impact of FGF23 on mortality may be modified by gender and CVD and, as previously shown, is blunted in the setting of pronounced hyperphosphatemia.

BACKGROUND: Bioincompatible peritoneal dialysis fluids (PDFs) cause pathological changes in the peritoneal membrane, related to membrane dysfunction and progressive peritoneal fibrosis. We investigated the effects of Pro-His-Ser-Arg-Asn (PHSRN) peptide, one of the fibronectin cell-binding domains that activates integrins and reinforces wound healing, on peritoneal remodelling in a rat peritoneal injury model undergoing peritoneal dialysis. METHODS: The peritoneal mesothelial monolayer was removed by a stripping procedure in rats receiving conventional high glucose-containing PDF supplemented with or without PHSRN or control His-Ser-Pro-Asn-Hrg (HSPNR) peptides. Effects of PHSRN on cell motility and signalling molecules were examined in cultured rat peritoneal mesothelial cells (RPMCs) and normal rat kidney fibroblasts (NRKs). RESULTS: The cytokeratin- and HBME-1-positive mesothelial cell monolayer was selectively removed by the procedure. By day 6, HBME-1-positive cells had regenerated to 53.3 +/- 6.5% of the peritoneal surface in the control group. Regeneration of the mesothelial layer was delayed in the PDF group (35.2 +/- 10.2%, P < 0.05), but PHSRN reversed the effects of PDF (51.7 +/- 9.6%, P < 0.05). PDF treatment increased thickening of granulomatous submesothelial tissue and numbers of ED1-, CD31- and alpha-smooth muscle actin-positive cells, but PHSRN ameliorated these effects. HSPNR had no effects on mesothelial regeneration or peritoneal wound healing. PHSRN, but not HSPNR, recovered glucose-induced inhibition of cell motility and phosphorylation of focal adhesion kinase and its downstream p130(Cas) in RPMCs and NRKs. CONCLUSIONS: These results suggest that PHSRN has beneficial effects on peritoneal regeneration by reducing the inhibitory effects of conventional PDF on integrin-mediated wound healing.

Aims Insulin-like growth factor (IGF)-1 is a major mitogenic growth factor for mesangial cells (MCs). Statins slow the progression of chronic kidney disease by affecting inflammatory cell signaling pathways, in addition to improving lipid profile, however, no studies have investigated the effects of fluvastatin on mitogen-activated protein (MAP) kinase activity or MC proliferation in kidney cells. We investigated the effects of fluvastatin on IGF-1-induced activation of intracellular signal pathways and MC proliferation, and examined the inhibitory mechanisms of fluvastatin. Main methods Western blotting and cell proliferation assay were used. Key findings IGF-1 induced phosphorylation of extracellular-related kinase (ERK)1/2, MAP or ERK kinase (MEK)1/2, and Akt, expression of cyclin D1, and MC proliferation in cultured human MCs. Fluvastatin or PD98059, an MEK1 inhibitor, completely abolished IGF-1-induced MEK1/2 and ERK1/2 phosphorylation and MC proliferation, whereas inhibition of Akt had no effect on MC proliferation. Mevalonic acid prevented fluvastatin inhibition of IGF-1-induced MEK1/2 and ERK1/2 phosphorylation, cyclin D1 expression, and MC proliferation. Significance Fluvastatin inhibits IGF-1-induced activation of the MAP kinase pathway and MC proliferation by mevalonic acid depletion, and might have renoprotective effects by inhibiting IGF-1-mediated MC proliferation.

Uromodulin-associated kidney disease (UAKD) is an autosomal dominant disease caused by a mutation in the uromodulin (UMOD) gene, leading to end-stage renal disease. We herein report the case of a family with UAKD caused by a novel mutation (C135G) in the UMOD gene. A 31-year-old woman had a low estimated glomerular filtration rate (59.7 mL/min per 1.73 m(2)). Her father, grandfather and paternal aunt had received maintenance hemodialysis therapy since their 40's. This case underscores the importance of performing genetic testing in young patients even in cases involving only moderate abnormalities in the kidney function.

Mizoribine (MZR) has shown to be effective against antineutrophil cytoplasmic antibody (ANCA)-related vasculitis; however, no reports have described the successful treatment of steroid-resistant ANCA-related vasculitis with MZR in patients with renal insufficiency requiring hemodialysis. We herein report the case of a 39-year-old man undergoing hemodialysis in whom MZR successfully lowered the myeloperoxidase (MPO)-ANCA titer accompanied by remission of interstitial pneumonia, together with the pharmacokinetics of MZR. The patient developed severe renal insufficiency and interstitial pneumonia, and was started on hemodialysis. Although prednisolone was administered followed by azathioprine, the MPO-ANCA level and interstitial pneumonia showed insufficient improvement. Azathioprine was replaced by MZR and the administered dose of MZR was determined by measuring serum concentrations of MZR at the start of the dialysis session; this was because we confirmed that MZR could only be removed via dialysis, and that the serum concentration of MZR was maintained until the next dialysis session. The maintenance dose was finally set at MZR 75 mg after each dialysis. Subsequently, the ANCA titer decreased and interstitial pneumonia resolved without any MZR-related side effects. This case demonstrates that MZR is safe and effective, even in patients with steroid-resistant ANCA-related vasculitis undergoing hemodialysis, and can be monitored by measuring serum concentrations of MZR.

The steady state and quasi-steady processes of infinite- and finite-width sheet z-pinches are studied. The relations corresponding to the Bennett relation and Pease-Braginskii current of cylindrical fiber z-pinches depend on a geometrical factor in the sheet z-pinches. The finite-width sheet z-pinch is approximated by a segment of infinite-width sheet z-pinch, if it is wide enough, and corresponds to a number of (width/thickness) times fiber z-pinch plasmas of the diameter that equals the sheet thickness. If the sheet current equals this number times the fiber current, the plasma created in the sheet z-pinches is as dense as in the fiber z-pinches. The total energy of plasma and magnetic field per unit mass is approximately equal in both pinches. Quasi-static transient processes are different in several aspects from the fiber z-pinch. No radiation collapse occurs in the sheet z-pinch. The stability is improved in the sheet z-pinches. The fusion criterions and the experimental arrangements to produce the s...

The pressure equilibrium and steady state of z-pinches trapping a small amount of axial magnetic flux are studied. The Bennett relation and the Pease–Braginskii-current are modified, taking into account the superposed axial field. The line energy density decreases in the modified Bennett relation, but the decrease is only of the order e2, where e = (the axial field strength at the axis)/(the azimuthal field strength at the plasma periphery) ≪ 1. On the other hand, the current in the steady state can increase without being limited by the Pease–Braginskii-current. Hence, the radiation collapse is prevented. The decrease of line energy density in the modified Bennett relation is almost canceled in the steady state.

Summary Background and objectives Pentraxin-3 (PTX3) belongs to the same pentraxin superfamily of acute-phase reactants as C-reactive protein (CRP). Abdominal fat accumulation in ESRD is considered a chronic inflammatory state, but the relationship of PTX3 to this phenomenon is unknown. This study assesses plausible associations between PTX3 and surrogates of fat mass deposits in dialysis patients. Design, setting, participants, & measurements Circulating levels of PTX3, CRP, and IL-6 were cross-sectionally analyzed in relation to anthropometric and nutritional surrogate markers of fat tissue in two cohorts comprising 156 prevalent hemodialysis (HD) and 216 incident dialysis patients. Results In both cohorts, PTX3 was negatively associated with body mass index (BMI) and fat body mass index (FBMI) derived from anthropometrics and leptin, whereas there was a positive association with adiponectin. In prevalent HD patients, those with larger waist circumference (above gender-specific median values) had lower PTX3, higher CRP, and higher IL-6 levels. This was also true in multivariate analyses. In both cohorts, multivariate regression analyses showed that PTX3 was negatively and CRP (or IL-6) was positively associated with FBMI. Conclusions Although CRP and IL-6 were directly associated with body fat, PTX3 levels showed negative correlations with surrogates of adipose tissue in two independent cohorts of ESRD patients. Understanding the underlying reasons behind these opposite associations may have clinical relevance given the survival advantage described for obese patients on dialysis.

Inflammation is a major driving force of the uremic phenotype. This review provides an update on inflammatory biomarkers in chronic kidney disease and possible therapeutic approaches targeting the uremic inflammatory milieu.Single and longitudinal changes of C-reactive protein provide important outcome prediction. The uremic phenotype, which includes persistent inflammation, oxidative stress and protein energy wasting, has recently been shown to overshadow the traditional risk profile. As several small randomized controlled trials have shown that various nutritional, nonspecific immunomodulatory and targeted anticytokine interventions may have anti-inflammatory potential, future randomized control trials are needed to explore whether interventions specifically targeting inflammation will improve the dismal prognosis in end-stage renal disease.Because circulating inflammatory markers predict outcomes in patients with end-stage renal disease, inflammation may be a logical future therapeutic target for nutritional and pharmacological interventions.

Summary Background and objectives Follistatin mediates muscle growth and bone mineralization. At present, it is unknown whether circulating follistatin levels are altered in chronic kidney disease (CKD) or links to CKD risk factors and outcomes. Design, setting, participants, & measurements Plasma follistatin levels were cross-sectionally analyzed in relation to protein-energy wasting (PEW), handgrip strength (HGS), bone mineral density (BMD), and inflammatory markers in 280 CKD stage 5 patients, 32 CKD stage 4 patients, 16 CKD stage 3 patients, and 32 control subjects. In CKD stage 5 patients survival was prospectively investigated during a follow-up period of up to 5 years. Results The plasma follistatin concentration was not higher in CKD stage 5 patients than in other CKD stages or controls. In CKD stage 5 patients, circulating follistatin positively correlated with age, high-sensitivity C-reactive protein (hsCRP), and IL-6; negatively correlated with HGS, serum creatinine, and BMD; and was increased in patients with PEW. In a multivariate logistic regression model, lower HGS, lower BMD, and higher hsCRP independently correlated with higher follistatin levels. In a Cox regression model, follistatin levels were not associated with all-cause mortality. Conclusions Circulating follistatin levels were neither elevated nor predicted outcome in patients with CKD. However, increased follistatin levels occurred together with increased inflammation, reduced muscle strength, and low BMD, suggesting an involvement of a mechanism including follistatin in the uremic wasting process.

Background and objectives: The soluble receptor of advanced glycation end products (sRAGE) may exert anti-inflammatory protective roles on the vasculature. In contrast, the RAGE ligand S100A12 (also known as EN-RAGE) contributes to inflammation and the development of atherosclerosis in animal models. Whether alterations at this level contribute to the increased mortality observed in patients on dialysis is currently unknown. Design, setting, participants, & measurements: Prospective study including 184 prevalent hemodialysis patients and 50 healthy controls matched for age and gender. Plasma concentrations of S100A12 and sRAGE were studied in relation to risk profile and mortality after a median follow-up period of 41 months. Results: S100A12 and sRAGE levels were significantly elevated in hemodialysis patients compared with healthy controls. S100A12 had a strong positive correlation with C-reactive protein and IL-6, whereas sRAGE negatively associated with C-reactive protein. S100A12, but not sRAGE, was independently and positively associated with clinical cardiovascular disease (CVD). During follow-up, 85 (33 cardiovascular-related) deaths occurred. Whereas sRAGE did not predict mortality, S100A12 was associated with both all-cause (per log10 ng/ml hazard ratio [HR] 1.93, 95% confidence interval [CI] 1.18 to 3.15) and CVD-related (HR 3.23, 95% CI 1.48 to 7.01) mortality, even after adjustment for age, sex, vintage, and comorbidities. Further adjustment for inflammation made the predictive value of S100A12 disappear for all-cause mortality, but still persisted in CVD-related mortality. Conclusions: Circulating S100A12 and sRAGE are both elevated in hemodialysis patients. However, only S100A12 associates with mortality, partly explained by its links with inflammation.

Strongyloidiasis, a chronic infection caused by the intestinal parasite Strongyloides stercoralis, is prevalent in the Nansei Islands of Japan. Here, we report our findings on a case of strongyloidiasis complicated with steroid-resistant minimal change nephrotic syndrome in a 69-year-old male resident of Fukuoka Prefecture who had lived in Yakushima, one of the Nansei Islands, until age 15. In October 2006, he developed proteinuria and edema, and was diagnosed with minimal change nephrotic syndrome on the basis of the renal biopsy findings. Following treatment with prednisolone, the level of proteinuria decreased to 0.29 g/day by day 35. However, 5 days later (day 40), the patient developed persistent watery diarrhea and vomiting, leading to dehydration and malnutrition. Pneumonia and bacterial meningitis subsequently developed (day 146); filarial (infectious-type) and rhabditiform (noninfectious-type) S. stercoralis larvae were detected for the first time in the patient’s sputum, gastric juice, feces, and urine. Although treatment with ivermectin was started immediately and the parasitosis responded to the treatment, the patient died of sepsis. Consequently, although strongyloidiasis is a rare infection except in endemic regions, it is essential to consider the possibility of this disease and begin treatment early for patients who have lived in endemic areas and who complain of unexplained diarrhea during steroid-induced or other immunosuppression.

Fusion criteria for dense cylindrical and sheet z-pinches [1] are investigated and compared with each other. It is difficult to achieve the inertia fusion limit of cylindrical z-pinches. The fusion criterion is considerably relaxed in the dense sheet z-pinches. Hence, one dimensional liner compression by means of two plane conductors is more effective than the two dimensional compression by imploding cylindrical liner.

The axial magnetic field is applied to an annular gas-puff z-pinch for the control of radial dynamics and x-ray emission from the pinched plasma. K-shell and L-shell radiations of Ar ions are detected separately, and only the K-shell radiation is suppressed significantly by the axial field. The radial motion of the plasma is analyzed assuming a simple circuit model. The characteristic radius of the plasma increased with increasing the axial field.