Peritoneal dialysis-related infections in elderly patients.

This review outlines the epidemiology, characteristics, risk factors, and prognosis of peritoneal dialysis (PD)-related peritonitis, PD catheter-related infections, and the effects of assisted PD in elderly patients from the Japanese perspective. Based on the literature, the incidence of peritonitis is likely to be higher in elderly patients than in younger patients. The most frequent causative bacteria in elderly patients are Gram-positive bacteria, as in adult PD patients, most commonly due to transcatheter infection. However, elderly patients may have difficulty recognizing cloudy drainage fluid due to decreased visual acuity. Hypokalemia, the use of gastric acid suppressants, prophylactic antibiotic use before endoscopy, biocompatible fluids and hypoalbuminemia considered modifiable risk factors for peritonitis. However, the mechanism by which treatment of hypokalemia prevents peritonitis is unknown. Currently, the relationship between gastric acid suppression therapy and peritonitis in elderly patients is debatable, with no evidence to strongly recommend uniform discontinuation of gastric acid suppression therapy. Exit-site infection (ESI) is a major risk factor for the development of peritonitis, and appropriate prevention and management of ESI may reduce infection-related hospitalizations in PD patients. Currently, no randomized, controlled trials have verified the effectiveness of antibiotic application for ESI in Japan, but results from other countries are awaited. In assisted PD, it is extremely important that family members, caregivers, and nurses who support the procedure receive sufficient education and training from medical professionals familiar with PD. Early detection and treatment of PD-related infections are required because the risk of death increases in elderly patients.

Clinical Impact of Malnutrition According to the Global Leadership Initiative on Malnutrition Criteria Combined With Kidney Dysfunction to Determine Mortality in Inpatients.

OBJECTIVE: The clinical impact of malnutrition based on the Global Leadership Initiative on Malnutrition (GLIM) criteria in patients with kidney dysfunction remains poorly understood. This study investigated the usefulness of GLIM criteria for malnutrition in predicting mortality in patients with kidney dysfunction and different clinical renal states, including no kidney disease (NKD), acute kidney injury (AKI), and chronic kidney disease (CKD). METHODS: This single-center retrospective cohort study included 6,712 patients aged ≥18 admitted between 2018 and 2019. The relationship between the estimated glomerular filtration rate (eGFR) groups, nutritional status based on the GLIM criteria, and the incidence of all-cause mortality was evaluated using a multivariate Cox proportional hazards model. Malnutrition was defined as at least one phenotype (weight loss, low body mass index, or reduced muscle mass) and one etiological criterion (reduced intake/assimilation or disease burden/inflammation). RESULTS: Multivariate Cox proportional hazards model showed that eGFR ≤29 (vs. eGFR: 60-89, adjusted hazard ratio [HR] = 1.84, 95% confidence interval [CI]: 1.52-2.22), 30-59 (vs. eGFR: 60-89, adjusted HR = 1.40, 95% CI: 1.20-1.64), and ≥90 (vs. eGFR: 60-89, adjusted HR = 1.40, 95% CI: 1.14-1.71), moderate and severe malnutrition (vs. without malnutrition, adjusted HR = 1.38 [1.18-1.62] and 2.18 [1.86-2.54], respectively) were independently associated with the incidence of death. The all-cause mortality rate was higher in patients with malnutrition or eGFR ≤29 (adjusted HR, 3.31; 95% CI: 2.51-4.35) than in patients without malnutrition or eGFR 60-89. Furthermore, moderate and severe malnutrition (vs. no malnutrition) was independently associated with death in patients with NKD, AKI, and CKD. CONCLUSION: Malnutrition based on the GLIM criteria was associated with increased all-cause mortality in inpatients, and malnutrition combined with kidney dysfunction was associated with a higher risk of mortality. Furthermore, patients with NKD, AKI, and CKD showed an association between malnutrition based on GLIM criteria and mortality.

Inhibition of Transglutaminase 2 Reduces Peritoneal Injury in a Chlorhexidine-Induced Peritoneal Fibrosis Model.

Long-term peritoneal dialysis (PD) is often associated with peritoneal dysfunction leading to withdrawal from PD. The characteristic pathologic features of peritoneal dysfunction are widely attributed to peritoneal fibrosis and angiogenesis. The detailed mechanisms remain unclear, and treatment targets in clinical settings have yet to be identified. We investigated transglutaminase 2 (TG2) as a possible novel therapeutic target for peritoneal injury. TG2 and fibrosis, inflammation, and angiogenesis were investigated in a chlorhexidine gluconate (CG)-induced model of peritoneal inflammation and fibrosis, representing a noninfectious model of PD-related peritonitis. Transforming growth factor (TGF)-ß type I receptor (TGFßR-I) inhibitor and TG2-knockout mice were used for TGF-ß and TG2 inhibition studies, respectively. Double immunostaining was performed to identify cells expressing TG2 and endothelial-mesenchymal transition (EndMT). In the rat CG model of peritoneal fibrosis, in situ TG2 activity and protein expression increased during the development of peritoneal fibrosis, as well as increases in peritoneal thickness and numbers of blood vessels and macrophages. TGFßR-I inhibitor suppressed TG2 activity and protein expression, as well as peritoneal fibrosis and angiogenesis. TGF-ß1 expression, peritoneal fibrosis, and angiogenesis were suppressed in TG2-knockout mice. TG2 activity was detected by α-smooth muscle actin-positive myofibroblasts, CD31-positive endothelial cells, and ED-1-positive macrophages. CD31-positive endothelial cells in the CG model were α-smooth muscle actin-positive, vimentin-positive, and vascular endothelial-cadherin-negative, suggesting EndMT. In the CG model, EndMT was suppressed in TG2-knockout mice. TG2 was involved in the interactive regulation of TGF-ß. As inhibition of TG2 reduced peritoneal fibrosis, angiogenesis, and inflammation associated with TGF-ß and vascular endothelial growth factor-A suppression, TG2 may provide a new therapeutic target for ameliorating peritoneal injuries in PD.

Intimal growth on the luminal surface of arteriovenous grafts in rats.

BACKGROUND: Endothelial cells are known to grow on the luminal surface of arteriovenous grafts (AVGs) used in hemodialysis. Although endothelial cells are important for preventing infection, a detailed growth of endothelial cells in AVGs is unknown. This study sought to create a simpler animal model of AVGs and to investigate how endothelial cells form on the luminal surface. METHODS: Polyethylene grafts were placed between the cervical artery and vein of Wistar rats. The grafts were removed at 6 h, 24 h, 3 days, or 7 days after placement. The luminal surface was observed under optical and polarizing microscopy and stained with endothelial cell markers (LEL, CD31), the progenitor cell marker CD34, and the macrophage marker ED-1. RESULTS: Microscopy demonstrated many diffuse vascular endothelial cells on the luminal surface of AVGs after placement. While there was no difference in the number of LEL-positive cells between the arterial side (AS) and venous side (VS) at 6 h or 7 days, there were significantly more of these cells on the VS at both 24 h and 3 days (p < 0.05). Analysis at 24 h showed some CD31-positive cells and few CD34-positive cells. CONCLUSIONS: This was the first study to use a simple rat model of AVG placement. Endothelial cell formation was initially more active on the VS than on the AS, but these cells subsequently increased in number across the luminal surface. Future clinical studies might contribute clinically by confirming whether AS versus VS puncture results in different infection rates.

Pathophysiology of encapsulating peritoneal sclerosis: lessons from findings of the past three decades in Japan.

Encapsulating peritoneal sclerosis (EPS), a condition with a high mortality rate, is a serious complication of peritoneal dialysis (PD). In Japan, EPS became a central issue in the clinical setting during the mid-90s and the beginning of this century. However, following the introduction of biocompatible neutral PD solutions containing lower levels of glucose degradation products, the incidence and clinical severity of EPS has been greatly lessened. During the past three decades, the etiology of EPS has been elucidated by findings obtained by peritoneal biopsy, laparoscopy, and surgical intervention. Accumulating findings suggest the need for a paradigm change on the nature of EPS pathophysiology; notably, EPS appears not to reflect peritoneal sclerosis per se, but rather the formation of a neo-membrane as a biological reaction to peritoneal injury. This narrative review looks back on the history of EPS in Japan, and discusses EPS pathophysiology, the impact of neutral PD solution on peritoneal protection, and a future novel diagnostic approach, ultra-fine endoscope, for the identification of patients at high risk of EPS.

Serum and plasma levels of Ba, but not those of soluble C5b-9, might be affected by renal function in chronic kidney disease patients.

BACKGROUND: During the last few decades, pathogenic mechanisms associated with uncontrolled activation of the complement (C) system and development of anti-C agents have been closely investigated in the field of nephrology. The usefulness of some C products such as C5a and sC5b-9 for diagnostic and prognostic purposes remains controversial. On the other hand, decreased renal function is being observed in many patients with or without nephritis as a background factor in progressively aging societies. We therefore investigated whether renal function influenced the evaluation of various complement components and activation products. METHODS: To investigate the influence of renal function on evaluations of C3, C4, CH50, Ba, C5a and sC5b-9, 40 patients were retrospectively chosen from among 844 patients without active glomerulonephritis from 2009 to 2016. We measured plasma and serum levels of C3, C4, CH50, Ba, C5a and sC5b-9 using enzyme-linked immunosorbent assays and compared the findings with inulin clearance (Cin) as a marker of preserved renal function. RESULTS: Both plasma and serum levels of Ba correlated significantly with Cin, but other values did not. Compared with patients with Cin ≥ 60 or ≥ 30 mL/min/1.73 m2, plasma and serum levels of Ba were increased in patients with Cin decreased to < 60 or < 30 mL/min/1.73 m2, but levels of C5a and sC5b-9 were not. CONCLUSION: The influence of renal function might need to be considered when evaluating Ba, but not C5a and sC5b-9, in plasma and serum samples from chronic kidney disease patients.

Tissue Sodium Accumulation Induces Organ Inflammation and Injury in Chronic Kidney Disease.

High salt intake is a primary cause of over-hydration in chronic kidney disease (CKD) patients. Inflammatory markers are predictors of CKD mortality; however, the pathogenesis of inflammation remains unclear. Sodium storage in tissues has recently emerged as an issue of concern. The binding of sodium to tissue glycosaminoglycans and its subsequent release regulates local tonicity. Many cell types express tonicity-responsive enhancer-binding protein (TonEBP), which is activated in a tonicity-dependent or tonicity-independent manner. Macrophage infiltration was observed in the heart, peritoneal wall, and para-aortic tissues in salt-loading subtotal nephrectomized mice, whereas macrophages were not prominent in tap water-loaded subtotal nephrectomized mice. TonEBP was increased in the heart and peritoneal wall, leading to the upregulation of inflammatory mediators associated with cardiac fibrosis and peritoneal membrane dysfunction, respectively. Reducing salt loading by a diuretic treatment or changing to tap water attenuated macrophage infiltration, TonEBP expression, and inflammatory marker expression. The role of TonEBP may be crucial during the cardiac fibrosis and peritoneal deterioration processes induced by sodium overload. Anti-interleukin-6 therapy improved cardiac inflammation and fibrosis and peritoneal membrane dysfunction. Further studies are necessary to establish a strategy to regulate organ dysfunction induced by TonEBP activation in CKD patients.

Peritoneal Expression of Membrane Complement Regulators Is Decreased in Peritoneal Dialysis Patients with Infected Peritonitis.

In peritoneal dialysis (PD) patients, fungi and Pseudomonas aeruginosa are considered important causative microorganisms for peritonitis with poor prognosis. Our objective was to explore expressions of membrane complement (C) regulators (CRegs) and tissue injuries in the peritoneum of patients with PD-related peritonitis, including fungal and Pseudomonas aeruginosa peritonitis. In peritoneal biopsy tissues obtained at PD catheter removal, we investigated the severity of peritonitis-associated peritoneal injuries and the expression of CRegs, CD46, CD55, and CD59 against peritoneal tissues without any episode of peritonitis. In addition, we evaluated peritoneal injuries among fungal and Pseudomonas aeruginosa-peritonitis (P1) and Gram-positive bacterial peritonitis (P2). We also observed deposition of C activation products such as activated C and C5b-9 and measured sC5b-9 in the PD fluid of patients. As a result, the severity of peritoneal injuries correlated inversely with the expression of peritoneal CRegs. Peritoneal CReg expression in peritonitis was significantly reduced compared to no peritonitis. Peritoneal injuries were more severe in P1 than in P2. CReg expression was further decreased and C5b-9 further increased in P1 than in P2. In conclusion, severe peritoneal injuries due to fungal and Pseudomonas aeruginosa-peritonitis decreased CReg expression and increased deposition of activated C3 and C5b-9 in the peritoneum, suggesting that peritonitis, particularly fungal and Pseudomonas aeruginosa-peritonitis, might induce susceptibility to further peritoneal injuries due to excessive C activation.

Interleukin-6 blockade reduces salt-induced cardiac inflammation and fibrosis in subtotal nephrectomized mice.

Cardiovascular disease is the most common comorbidity in patients with chronic kidney disease (CKD), affecting both their prognosis and quality of life. Cardiac fibrosis is common in patients with CKD with left ventricular diastolic dysfunction, and it is associated with increased risk of heart failure and mortality. Recent evidence suggests that high salt intake activates immune responses associated with local accumulation of sodium. We reported that high salt intake promotes cardiac inflammation in subtotal nephrectomized (Nx) mice. We investigated the effects of administration of MR16-1, a rat anti-mouse monoclonal interleukin (IL)-6 receptor antibody, in Nx mice with salt loading (Nx-salt). Expression of monocyte chemoattractant protein-1, tumor necrosis factor-α, IL-1ß, and IL-6 mRNAs and macrophage infiltration was significantly reduced in the heart of Nx-salt mice treated with MR16-1 (Nx-salt-MR16-1) compared with Nx-salt mice treated with control rat rat IgG1 (Nx-salt-rat IgG1). Correspondingly, cardiac fibrosis was significantly attenuated in Nx-salt-MR16-1 mice compared with Nx-salt-rat IgG1 mice. Furthermore, in the heart of Nx-salt-MR16-1 mice, expression of mRNA for nicotinamide adenine dinucleotide phosphate oxidase-2, an oxidative stress marker, was significantly downregulated compared with Nx-salt-rat IgG1 mice. Increases in cardiac metabolites, including histidine and γ-butyrobetaine, were also reversed by IL-6 blockade treatment. In conclusion, IL-6 blockade exerts anti-inflammatory, antifibrotic, and partial antioxidative effects in the heart of Nx-salt mice.NEW & NOTEWORTHY In the present study, IL-6 blockade exerted anti-inflammatory, antifibrotic, and partial antioxidative effects on the hearts of mice with CKD on a high-salt diet. Therefore, IL-6 potentially mediates cardiac fibrosis induced by high salt intake in patients with CKD, a finding with therapeutic implications. Of note, the next therapeutic implication may simply be the reinforcement of low-salt diets or diuretics and further research on the anti-inflammatory effects of these measures rather than IL-6 blockade with high-salt diet.

TREC/KREC Newborn Screening followed by Next-Generation Sequencing for Severe Combined Immunodeficiency in Japan.

PURPOSE: The aim of this study is to evaluate the usefulness of T cell receptor excision circle (TREC) and/or kappa-deleting recombination excision circle (KREC) measurements integrated with diagnostic next-generation sequencing (NGS) analysis using a severe combined immunodeficiency (SCID) newborn screening (NBS) program. METHODS: TREC and/or KREC values were measured in 137,484 newborns between April 2017 and December 2021 using EnLite TREC (n = 80,791) or TREC/KREC kits (n = 56,693). For newborns with positive screening results, diagnostic NGS analysis was performed with a 349-gene panel to detect genetic mutations associated with primary immunodeficiencies (PIDs). RESULTS: A total of 145 newborns (0.11%) had abnormal TREC and/or KREC values, and a genetic diagnosis was established in 2 patients with SCID (1 in 68,742 newborns) (IL2RG-SCID and reticular dysgenesis) and 10 with non-SCID PIDs with T and/or B cell deficiencies (1 in 13,748 newborns) using NGS analysis. Furthermore, TREC values of 2849 newborns were measured and confirmed the significant correlation between the results of both TREC and TREC/KREC kits (P < 0.001) and naïve T cell counts. CONCLUSIONS: We performed the first large-scale TREC and TREC/KREC NBS programs in Japan. Our NBS programs followed by the diagnostic NGS analysis for newborns with abnormal TREC and/or KREC values are useful for the early identification and rapid molecular evaluation of not only SCID but also different non-SCID PIDs.

Variation in Peritoneal Dialysis-Related Peritonitis Outcomes in the Peritoneal Dialysis Outcomes and Practice Patterns Study (PDOPPS).

RATIONALE & OBJECTIVE: Peritoneal dialysis (PD)-associated peritonitis is a significant PD-related complication. We describe the likelihood of cure after a peritonitis episode, exploring its association with various patient, peritonitis, and treatment characteristics. STUDY DESIGN: Observational prospective cohort study. SETTING & PARTICIPANTS: 1,631 peritonitis episodes (1,190 patients, 126 facilities) in Australia, New Zealand, Canada, Japan, Thailand, the United Kingdom, and the United States. EXPOSURE: Patient characteristics (demographics, patient history, laboratory values), peritonitis characteristics (organism category, concomitant exit-site infection), dialysis center characteristics (use of icodextrin and low glucose degradation product solutions, policies regarding antibiotic self-administration), and peritonitis treatment characteristics (antibiotic used). OUTCOME: Cure, defined as absence of death, transfer to hemodialysis (HD), PD catheter removal, relapse, or recurrent peritonitis within 50 days of a peritonitis episode. ANALYTICAL APPROACH: Mixed-effects logistic models. RESULTS: Overall, 65% of episodes resulted in a cure. Adjusted odds ratios (AOR) for cure were similar across countries (range, 54%-68%), by age, sex, dialysis vintage, and diabetes status. Compared with Gram-positive peritonitis, the odds of cure were lower for Gram-negative (AOR, 0.41 [95% CI, 0.30-0.57]), polymicrobial (AOR, 0.30 [95% CI, 0.20-0.47]), and fungal (AOR, 0.01 [95% CI, 0.00-0.07]) peritonitis. Odds of cure were higher with automated PD versus continuous ambulatory PD (AOR, 1.36 [95% CI, 1.02-1.82]), facility icodextrin use (AOR per 10% greater icodextrin use, 1.06 [95% CI, 1.01-1.12]), empirical aminoglycoside use (AOR, 3.95 [95% CI, 1.23-12.68]), and ciprofloxacin use versus ceftazidime use for Gram-negative peritonitis (AOR, 5.73 [95% CI, 1.07-30.61]). Prior peritonitis episodes (AOR, 0.85 [95% CI, 0.74-0.99]) and concomitant exit-site infection (AOR, 0.41 [95% CI, 0.26-0.64]) were associated with a lower odds of cure. LIMITATIONS: Sample selection may be biased and generalizability may be limited. Residual confounding and confounding by indication limit inferences. Use of facility-level treatment variables may not capture patient-level treatments. CONCLUSIONS: Outcomes after peritonitis vary by patient characteristics, peritonitis characteristics, and modifiable peritonitis treatment practices. Differences in the odds of cure across infecting organisms and antibiotic regimens suggest that organism-specific treatment considerations warrant further investigation.

International peritoneal dialysis training practices and the risk of peritonitis.

BACKGROUND: The effects of training practices on outcomes of patients receiving peritoneal dialysis (PD) are poorly understood and there is a lack of evidence informing best training practices. This prospective cohort study aims to describe and compare international PD training practices and their association with peritonitis. METHODS: Adult patients on PD <3 months participating in the Peritoneal Dialysis Outcomes and Practice Patterns Study (PDOPPS) were included. Training characteristics (including duration, location, nurse affiliation, modality, training of family members, use of individual/group training and use of written/oral competency assessments) were reported at patient and facility levels. The hazard ratio (HR) for time to first peritonitis was estimated using Cox models, adjusted for selected patient and facility case-mix variables. RESULTS: A total of 1376 PD patients from 120 facilities across seven countries were included. Training was most commonly performed at the facility (81%) by facility-affiliated nurses (87%) in a 1:1 setting (79%). In the UK, being trained by both facility and third-party nurses was associated with a reduced peritonitis risk [adjusted HR 0.31 (95% confidence interval 0.15-0.62) versus facility nurses only]. However, this training practice was utilized in only 5 of 14 UK facilities. No other training characteristics were convincingly associated with peritonitis risk. CONCLUSIONS: There was no evidence to support that peritonitis risk was associated with when, where, how or how long PD patients are trained.

Association of alcohol consumption with the incidence of proteinuria and chronic kidney disease: a retrospective cohort study in Japan.

BACKGROUND: The difference in the clinical impact of alcohol consumption on kidney function based on sex remains to be elucidated. This study aimed to assess the association between the dose of alcohol consumption and the incidence of proteinuria and chronic kidney disease stratified by sex. METHODS: This retrospective cohort study included 26,788 workers (19,702 men and 7086 women) with normal renal function (estimated glomerular filtration rate ≥ 60 mL/min/1.73 m2) at annual health examinations between January 2010 and March 2015 in Japan. The main exposure was alcohol consumption. The primary outcomes were the incidence of proteinuria (dipstick urinary protein ≥ 1) and incidence of low estimated glomerular filtration rate (eGFR; rate < 60 mL/min per 1.73 m2; decreased from the baseline eGFR by 25%). RESULTS: During a median observational period of 4 years (interquartile range: 2-6), 1993 (10.1%) men and 462 (6.5%) women developed proteinuria, whereas 667 (3.4%) men and 255 (3.6%) women developed low eGFR. After adjustment for clinically relevant factors using a Cox proportional hazards model, alcohol consumption of ≥ 46 g/day in females was significantly associated with the incidence of proteinuria (hazard ratio, 1.57; 95% confidence interval, 1.10-2.26) and low eGFR (hazard ratio, 1.62; 95% confidence interval, 1.04-2.53). However, no significant association between alcohol consumption and primary outcomes was observed in men. CONCLUSIONS: In conclusion, daily higher alcohol consumption was significantly associated with a higher incidence of proteinuria and low eGFR among women. Women might be prone to high alcohol consumption with kidney dysfunction.

Effects of cognitive impairment and assisted peritoneal dialysis on exit-site infection in older patients.

BACKGROUND: Elderly peritoneal dialysis (PD) patients required assistance for a variety of PD-related tasks. The usefulness of assisted PD in reducing the peritonitis risk has been reported; however, there is little evidence on the effectiveness of assisted PD in preventing exit-site infections in older patients. METHODS: This was a single-center, prospective cohort study. Thirty-three patients (mean age: 74.8 ± 5.9 years) on PD were evaluated for cognitive impairment (CI) using the Japanese version of the Montreal Cognitive Assessment. They were also evaluated to determine whether they performed the exit-site care procedure alone or with assistance. Patients were categorized into four groups based on the presence or absence of CI and the presence or absence of exit-site care assistance. They were followed up until the occurrence of peritonitis and exit-site infection at the end of the follow-up. RESULTS: Altogether, 8, 8, and 17 patients were assigned to the "without CI and without assistance", "without CI and with assistance", and "with CI and with assistance groups", respectively; no patients were assigned to the "with CI and without assistance group". Six and 16 patients experienced peritonitis and exit-site infection during follow-up, respectively. Kaplan-Meier analysis and log-rank tests revealed that the "without CI and without assistance group" was significantly associated with exit-site infection (log-rank < 0.05). CONCLUSION: Patients who did not receive assistance for exit-site care were at a higher risk of exit-site infections, even in the absence of CI. Caregiver assistance is important for preventing exit-site infections in older patients on PD.

Time to normalisation of CRP and incidence of relapse in microscopic polyangiitis: A medical records review study in Japan.

OBJECTIVES: Despite the identification of risk factors for relapses in anti-neutrophil cytoplasmic antibody-associated vasculitis, the relationship between changes in C-reactive protein levels after initial treatment and incidence of relapse remains unknown. This study aimed to assess the association between the time taken for normalisation of C-reactive protein levels and the incidence of relapse in Japanese adult patients with microscopic polyangiitis. METHODS: This study included 85 consecutive patients with newly diagnosed microscopic polyangiitis who achieved remission after six months of immunosuppressive treatment at the Aichi Medical University Hospital, between 2009 and 2017. The relationship between the time to normalisation of C-reactive protein after initial immunosuppressive treatment and relapse incidences was evaluated using multivariable Cox proportional hazard models. RESULTS: During the follow-up period, 13 (30.2%), 7 (41.2%), and 16 (64.0%) patients relapsed (P=0.025) within 1-14, 15-28, and ≥29 days of normalisation, respectively. Hazard ratios (95% confidence intervals) of the time to normalisation of C-reactive protein of 1-14, 15-28, and ≥29 days were 1.00 (reference), 2.42 (95%CI: 0.92-6.39), and 3.48 (95%CI: 1.56-7.76), respectively. CONCLUSIONS: A significant association between the time to normalisation of C-reactive protein and relapse incidence in Japanese patients with microscopic polyangiitis was observed.

C1 inhibitor mitigates peritoneal injury in zymosan-induced peritonitis.

Peritonitis, due to a fungal or bacterial infection, leads to injury of the peritoneal lining and thereby forms a hazard for the long-term success of peritoneal dialysis (PD) and remains a lethal complication in patients with PD. This study investigated whether C1 inhibitor (C1-INH) could protect against the progression of peritoneal injuries with five daily administrations of zymosan after mechanical scraping of the rat peritoneum to mimic fungal peritonitis. Severe peritoneal injuries were seen in this model, accompanied by fibrinogen/fibrin exudation and peritoneal deposition of complement activation products such as activated C3 and C5b-9. However, intraperitoneal injection of C1-INH decreased peritoneal depositions of activated C3 and C5b-9, ameliorated peritoneal thickening, reduced the influx of inflammatory cells, and prevented the production of peritoneal fibrous layers with both one and two doses of C1-INH each day. Our results suggest that C1-INH might be useful to protect against peritoneal injuries after causes of peritonitis such as fungal infection. This clinically available agent may thus help extend the duration of PD.NEW & NOTEWORTHY Peritoneal injuries associated with peritonitis comprise an important issue to prevent long-term peritoneal dialysis (PD) therapy. Here, we showed that C1 inhibitor (C1-INH), as an anticomplement agent, protected against peritoneal injuries in a peritonitis animal model related to fungal infection. Therefore, C1-INH might be useful to protect against peritoneal injuries after peritonitis due to fungal infection. This clinically available agent may thus help extend the duration of PD.

Phospholipase A2 from bee venom increases poly(I:C)-induced activation in human keratinocytes.

Bee venom (BV) induces skin inflammation, characterized by erythema, blisters, edemas, pain and itching. Although BV has been found to have an inhibitory effect on toll-like receptors (TLRs), we here show that BV enhances keratinocyte responses to polyinosinic-polycytidylic acid [poly(I:C)], a ligand for TLR3. Our results revealed that the enhanced TLR activity was primarily induced by secretory phospholipase A2 (sPLA2), a component of BV (BV-sPLA2). PLA2 mediates the hydrolysis of membrane phospholipids into lysophospholipids and free fatty acids. We demonstrated that BV-sPLA2 increased the intracellular uptake of poly(I:C), phosphorylation of the nuclear factor-kappa B (NF-κB) and mitogen-activated protein kinases (MAPKs), and poly(I:C)-mediated interleukin 8 production in human keratinocytes. We further showed that the enzymatic activity of BV-sPLA2 was essential for the increased uptake of poly(I:C). These findings suggest that BV-sPLA2 may induce a modification of the cell membrane structure, leading to enhanced poly(I:C) uptake in keratinocytes. BV-sPLA2 might be able to promote wound healing by enhancing TLR3 responses.

Vasculopathy plays an important role during the development and relapse of encapsulating peritoneal sclerosis with conventional peritoneal dialysis solutions.

BACKGROUND: Encapsulating peritoneal sclerosis (EPS) is an uncommon but life-threatening complication of peritoneal dialysis (PD) therapy. The causative factors of EPS remain unclear. Pathological studies of the peritoneum affected by EPS and relationships with clinical factors including PD solutions remain lacking. The objective of this study was to examine peritoneal samples from EPS patients and to identify the associations of peritoneal pathology with different clinical factors. METHODS: Peritoneal specimens were obtained at the time of surgical enterolysis in Tsuchiya General Hospital from 1993 to 2016. A total of 223 PD patients were enrolled and analyzed. Tissues were fixed with formalin and processed with hematoxylin and eosin and Masson's trichrome staining, as well as immunohistochemical staining for CD31 and CD68. RESULTS: Evaluations could be made in 174 patients who received surgical enterolysis. Conventional or pH-neutral low-glucose degradation product PD solutions were utilized during PD treatment. The conventional PD solution group showed less angiogenesis (P = 0.013) but more severe vasculopathy, in the form of a lower ratio of luminal diameter to vessel diameter (L/V ratio) (P < 0.001) in association with longer PD treatment. Multivariate Cox proportional hazard models revealed that L/V ratio (per 0.1 increase, hazard ratio = 0.88, 95% confidence interval 0.77-0.99, P = 0.047) was significantly associated with a lower incidence of EPS relapse. In contrast, most of the cases in the pH-neutral solution group showed milder vasculopathy. CONCLUSIONS: The pathology of EPS differed between conventional and pH-neutral solution groups. Vasculopathy was related to the development and relapse of EPS in the conventional solution group.

Safety and utility of the alpha-replacer for treatment of intraluminal obstruction of peritoneal catheters by fibrin clots.

BACKGROUND: The Moncrief-Popovich technique of peritoneal catheter implantation has beneficial effects for peritoneal dialysis (PD) initiation. However, it might increase the risk of peritoneal catheter obstruction by fibrin clots, because the catheter is buried under the skin for several weeks to months. Effects of treatment of intraluminal occlusion of PD catheters with tissue plasminogen activator, recommended by the International Society for Peritoneal Dialysis guidelines/recommendations are reportedly limited. We investigated the effectiveness of the 'alpha-replacer' (JMS, Tokyo, Japan) for PD catheter obstruction. METHODS: We retrospectively analyzed a total of 193 patients in whom PD was initiated. PD catheters were embedded using the Moncrief-Popovich technique in 130 of these patients. We assessed the occurrence rates of peritoneal catheter obstruction and the utility of the alpha-replacer for treating intraluminal catheter occlusion by fibrin clots. RESULTS: Catheter obstruction occurred in eight cases with embedded catheters, one due to omental wrapping and the others due to fibrin clots, in which median catheter burial durations were 477 (interquartile range [IQR], 226-510) days. All catheter obstructions due to fibrin clots were successfully treated with the alpha-replacer, leading to improved catheter drainage. The median amount of contrast agent used in catheterography was 10 (IQR 9-10) mL, which did not adversely affect residual renal function. There were no complications. No recurrence occurred during the observation period (median 111, IQR 55.5-141 months). CONCLUSION: Our results suggest that treatment with the alpha-replacer is a safe and effective treatment option for intraluminal obstruction of PD catheters by fibrin clots.

Low-GDP, pH-neutral solutions preserve peritoneal endothelial glycocalyx during long-term peritoneal dialysis.

BACKGROUND: During peritoneal dialysis (PD), solute transport and ultrafiltration are mainly achieved by the peritoneal blood vasculature. Glycocalyx lies on the surface of endothelial cells and plays a role in vascular permeability. Low-glucose degradation product (GDP), pH-neutral PD solutions reportedly offer higher biocompatibility and lead to less peritoneal injury. However, the effects on the vasculature have not been clarified. METHODS: Peritoneal tissues from 11 patients treated with conventional acidic solutions (acidic group) and 11 patients treated with low-GDP, pH-neutral solutions (neutral group) were examined. Control tissues were acquired from 5 healthy donors of kidney transplants (control group). CD31 and ratio of luminal diameter to vessel diameter (L/V ratio) were evaluated to identify endothelial cells and vasculopathy, respectively. Immunostaining for heparan sulfate (HS) domains and Ulex europaeus agglutinin-1 (UEA-1) binding was performed to assess sulfated glycosaminoglycans and the fucose-containing sugar chain of glycocalyx. RESULTS: Compared with the acidic group, the neutral group showed higher CD31 positivity. L/V ratio was significantly higher in the neutral group, suggesting less progression of vasculopathy. Both HS expression and UEA-1 binding were higher in the neutral group, whereas HS expression was markedly more preserved than UEA-1 binding in the acidic group. In vessels with low L/V ratio, which were found only in the acidic group, HS expression and UEA-1 binding were diminished, suggesting a loss of glycocalyx. CONCLUSION: Peritoneal endothelial glycocalyx was more preserved in patients treated with low-GDP, pH-neutral solution. The use of low-GDP, pH-neutral solutions could help to protect peritoneal vascular structures and functions.