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.

Impact of an angulated aorto-septal relationship on cardio-cerebrovascular outcomes in patients undergoing hemodialysis.

Aortic and valvular calcification are well-known risk factors for cardio-cerebrovascular events in patients undergoing hemodialysis. We investigated the clinical impact of an angulated aorto-septal angle as a result of aortic elongation due to aortic calcification on cardio-cerebrovascular outcomes in patients undergoing hemodialysis. We investigated 306 patients (mean age 65.4 years, 68% male) who underwent pre-scheduled routine echocardiography between April and September 2018. The angle between the anterior wall of the aorta and the ventricular septal surface (ASA) was quantified. We determined aortic and mitral valve calcification scores based on calcified cardiac changes; the aortic and mitral valve scores ranged between 0-9 and 0-6, respectively. The primary endpoint was a composite including cardio-cerebrovascular events and cardio-cerebrovascular death. The mean duration of dialysis among the patients in this analysis was 9.6 years. The primary endpoint was observed in 54 patients during the observational period (median 1095 days). Multivariable Cox proportional hazards analyses identified left ventricular ejection fraction (per 10% increase: hazard ratio [HR] 0.67; 95% confidential interval [CI] 0.53-0.84, P = 0.001), left ventricular mass index (per 10 g/m2 increase: HR 1.14; 95% CI 1.05-1.24, P = 0.001), ASA (per 10 degree increase: HR 0.69; 95% CI 0.54-0.88; P = 0.003), and aortic valve calcification score (HR 1.15; 95% CI 1.04-1.26, P = 0.005) as independent determinants of the primary endpoint. Kaplan-Meier analysis showed a higher incidence of the primary endpoint in patients with ASA <119.4 degrees than those with ASA ≥119.4 degrees (Log-rank P < 0.001). An angulated aorto-septal angle is an independent risk factor for cardio-cerebrovascular events and cardio-cerebrovascular death in patients undergoing hemodialysis.

Non-A Blood Type Is a Risk Factor for Poor Cardio-Cerebrovascular Outcomes in Patients Undergoing Dialysis.

The clinical impact of ABO blood type on cardio-cerebrovascular outcomes in patients undergoing dialysis has not been clarified. A total of 365 hemodialysis patients participated in the current study. The primary endpoint was defined as a composite including cardio-cerebrovascular events and cardio-cerebrovascular death. The primary endpoint was observed in 73 patients during a median follow-up period of 1182 days, including 16/149 (11%) with blood type A, 22/81 (27%) with blood type B, 26/99 (26%) with blood type O, and 9/36 (25%) with blood type AB. At baseline, no difference was found in the echocardiographic parameters. Multivariable Cox regression analyses revealed that blood type (type A vs. non-A type; hazard ratio (HR): 0.46, 95% confidence interval (95% CI): 0.26-0.81, p = 0.007), age (per 10-year increase; HR: 1.47, 95% CI: 1.18-1.84), antiplatelet or anticoagulation therapy (HR: 1.91, 95% CI: 1.07-3.41), LVEF (per 10% increase; HR: 0.78, 95% CI: 0.63-0.96), and LV mass index (per 10 g/m2 increase; HR: 1.07, 95% CI: 1.01-1.13) were the independent determinants of the primary endpoint. Kaplan-Meier curves also showed a higher incidence of the primary endpoint in the non-A type than type A (Log-rank p = 0.001). Dialysis patients with blood type A developed cardio-cerebrovascular events more frequently than non-A type patients.

Impact of left ventricular hypertrophy on clinical outcomes in patients with dialysis: a single-center study in Japan.

PURPOSE: Left ventricular hypertrophy (LVH) is a well-known risk factor for poor clinical outcomes in patients undergoing dialysis. However, little evidence supports the above notion in Japan, and the influence of subtypes of LVH on prognosis. METHODS: We investigated 367 patients undergoing dialysis who underwent routine echocardiographic examinations between April and September 2018. LVH was defined as any LV mass ≥ 115 g/m2 in men and ≥ 95 g/m2 in women obtained by echocardiography. The primary endpoint was a composite outcome including all-cause death, admission due to heart failure, and ischemic heart event or stroke. LVH was divided into subtype-groups according to eccentric hypertrophy or concentric hypertrophy, and with and without hypertension. RESULTS: LVH was observed in 171 (47%) patients. The primary endpoint was observed in 58 patients (16%) during the median follow-up period of 500 days. Multivariable Cox regression analyses identified four independent risk factors for the primary endpoint: age, pulse rate, serum albumin level, and LV mass index (per 10-g/m2 increase; hazard ratio: 1.12, 95% confidence interval: 1.06-1.18, P < 0.001). Kaplan-Meier analyses demonstrated that patients with LVH had a worse prognosis than those without LVH in terms of the primary endpoint (log-rank P < 0.001). The incidence of the primary outcome was not significantly different between patients with eccentric or concentric hypertrophy, and between LVH patients with and without hypertension. CONCLUSION: Japanese patients with LVH undergoing dialysis had a worse prognosis than those without LVH in terms of the composite clinical endpoint.

Long-term peritoneal dialysate exposure modulates expression of membrane complement regulators in human peritoneal mesothelial cells.

The membrane complement regulators (CRegs) CD46, CD55, and CD59 are highly expressed on human peritoneal mesothelial cells. However, how mesothelial CRegs change according to the peritoneal dialysis (PD) history of patients has remained unclear. We therefore examined longitudinal changes in CRegs in primary cultured mesothelial cells from PD patients (human peritoneal mesothelial cells; HPMCs) and examined which components of PD fluid (PDF) affect CRegs in vitro. We measured levels of soluble C5b-9 in overnight-dwelling PDF in PD patients and also evaluated changes in CRegs expression on HPMCs collected from PDF using flow cytometry and polymerase chain reaction at a 1-year interval of PD therapy. We also evaluated changes in CReg expressions with stimulation by each component of PDF (glucose, lactic acid and pH) using the Met5A human mesothelial cell line. Levels of sC5b-9 in PDF decreased significantly during 1 year, while expressions of CD46 and CD59 proteins and mRNAs increased significantly in HPMCs during 1 year. Analyzing Met-5A cells, we observed that expressions of the three CRegs were increased by glucose and lactic acid in a concentration-dependent manner, but conversely that expressions of CRegs were decreased by lower pH stimulation. History of PD might influence expression of CRegs by HPMCs through properties of PDF such as glucose, lactic acid, and pH. These results suggest that mesothelial cells may alter expression of CRegs for the purpose of protecting the peritoneum and the presence of PDF might affect peritoneal homeostasis associated with the complement system.

Recurrent infectious subcapsular renal hematoma accompanied by microaneurysm.

An 80-year-old woman was admitted to the hospital complaining of loss of appetite. 10 days earlier, her oral intake gradually decreased with no other specific symptoms, such as abdominal pain, nausea, vomiting, headache, or low back pain. Abdominal computed tomography (CT) scan revealed a left subcapsular renal hematoma. We suspected infective subcapsular renal hematoma, so percutaneous needle aspiration and drainage were performed. Intravenous sulbactam-ampicillin was started immediately. On day 9 after admission, repeat CT scan revealed the subcapsular hematoma had reduced in size. The drain was removed, and intravenous antibiotics were discontinued. Follow-up CT scan on day 21 revealed increased subcapsular renal hematoma size. The patient also had high fever. Suspecting recurrence of infective subcapsular renal hematoma, we repeated the drainage of the hematoma and restarted intravenous antibiotics. Renal arteriography showed a renal artery microaneurysm and her condition improved with renal artery embolization. Renal arteriography was useful for detecting renal artery microaneurysm in infective subcapsular renal hematoma that did not resolve after antibiotic treatment and drainage.

Thrombotic microangiopathy on kidney biopsy in a patient with TAFRO syndrome.

TAFRO syndrome represents a characteristic constellation of symptoms comprising Thrombocytopenia, Anasarca, myeloFibrosis, Renal dysfunction, and Organomegaly, and is considered to be a clinicopathologic variant of idiopathic multicentric Castleman disease. A 51-year-old woman was admitted to the hospital complaining of abdominal distension. Findings on physical examination were indicative of anasarca. Computed tomography revealed mild splenomegaly, pericardial effusion, pleural effusion, ascites, and paraaortic lymphadenopathy. Blood tests showed thrombocytopenia, and urinalysis demonstrated hematuria, proteinuria, and worsening renal function. Kidney biopsy was performed and revealed thrombotic microangiopathy-like lesions with global sclerosis of 1 of the 16 glomeruli on light microscopy. The remaining glomeruli had a distinct lobular pattern, with mesangiolysis, double contours of the glomerular basement membranes, and marked endothelial swelling. Immunofluorescence studies for IgG, IgM, IgA, C1q, C3, C4, κ-light chains, and λ-light chains were indeterminate. Electron microscopy showed marked endothelial swelling. We made a diagnosis of TAFRO syndrome and started steroid treatment, following which her symptoms gradually improved. There are few reports describing renal pathology in a patient with TAFRO syndrome.

The Type of Vascular Access and the Incidence of Mortality in Japanese Dialysis Patients.

Objective The National Kidney Foundation (NKF) Kidney Disease Outcome Quality Initiative (KDOQI) guidelines have recommended the use of arteriovenous fistula (AVF) at the initiation of dialysis. However, there are significant differences in the dialysis environments of Japan and the United States, and there are few people who receive hemodialysis via a central venous catheter (CVC) in Japan. The aim of the present study was to examine the association between the type of vascular access at the initiation of dialysis and the incidence of mortality in Japan. Methods This study was a prospective, multicenter, cohort study. The data was collected by the Aichi Cohort study of Prognosis in Patients newly initiated into dialysis (AICOPP) in which 18 Japanese tertiary care centers participated. The present study enrolled 1,524 patients who were newly introduced to dialysis (the patients started maintenance dialysis between October 2011 and September 2013). After excluding 183 patients with missing data, 1,341 patients were enrolled. The Cox proportional hazards model was used to evaluate mortality based on the type of vascular access. The types of vascular access were divided into four categories: AVF, arteriovenous graft (AVG), CVC changed to AVF during the course (CAVF), CVC changed to AVG during the course (CAVG). Results A multivariate analysis revealed that AVG, CAVF and CAVG were associated with a higher risk of mortality in comparison to AVF [hazard ratio (HR), 1.60; p=0.048; HR, 2.26; p=0.003; and HR, 2.45; p=0.001, respectively]. Conclusion The research proved that the survival rate among patients in whom hemodialysis was initiated with AVF was significantly higher than that in patients in whom hemodialysis was initiated with AVG or CVC.

Asymptomatic colitis induced by low-dose methotrexate.

A woman aged 77 years with a history of rheumatoid arthritis (RA) presented with inflammatory colitis confined to her rectum, which was incidentally found by a screening colonoscopy. Histopathological examination of colonic biopsies showed non-specific inflammatory infiltrates of lymphocytes, the cause of which was unknown. She had been diagnosed with RA 5 years before, and she was receiving methotrexate 6 mg weekly, to which tocilizumab had been added 4 years earlier, which achieved stable control of her disease. She had no gastrointestinal symptoms or other health problems. Tocilizumab-induced colitis was considered likely, and the drug was discontinued. Metronidazole was also prescribed because of possible Clostridium difficile-associated colitis. 3 months later, a repeat colonoscopy showed no improvement of the colitis. The methotrexate was also discontinued, and folinic acid was prescribed daily for 2 weeks, leading to complete resolution of the colitis observed at repeat colonoscopy.

A Fatal Case of Metformin-associated Lactic Acidosis.

A 72-year-old woman with a history of type 2 diabetes mellitus was brought to the ER with metformin-associated lactic acidosis. She received continuous hemofiltration and hemodialysis, but the laboratory analyses showed no improvement. She died 11 hours after admission. Metformin is minimally bound to proteins and is readily dialyzable, but a prolonged period of dialysis is required, because metformin has a very large distribution volume and is distributed to multiple compartments. The peak blood metformin level was 432 mg/L in this case, which is one of the highest metformin concentrations ever reported, and eight hours of hemodialysis were not sufficient to reduce the serum level.