Accumulation of amyloid fibrils from β2-microglobulin (β2M) was first recognized as a characteristic osteoarticular complication in long-term hemodialysis (HD) patients and called "HD-related amyloidosis" (HRA). However, this syndrome can also be observed in end-stage renal diseases (ESRD) patients undergoing peritoneal dialysis, and even in patients with chronic renal failure before the initiation of dialytic therapy, suggesting that HD is not a direct cause but that accumulation of β2M or some β2M-associated molecules in the body is a common pathogenesis. Currently the term "dialysis-related amyloidosis" (DRA) is widely used for β2M-amyloid (Aβ2M) amyloidosis associated with ESRD, although DRA patients consist mostly of those undergoing long-term HD. Factors other than β2M accumulation also play a role in the formation/local deposition of Aβ2M and disruption of tissue architecture. Conformational changes of β2M by misfolding/unfolding, and promoting/inhibitory effects induced by other coexisting molecules, advanced glycation and oxidation, and direct cell toxicity have also been documented. Two technological improvements of HD have been the keys to prevent the development and progression of DRA: the efficient removal of β2M by using high-flux membranes, high-volume convection and adsorptive column/membrane, as well as the use of biocompatible membranes and dialysates (eg, ultrapure and acetate-free dialysates) have minimized both inflammation and β2M production. Epidemiologically, a decrease in the incidence of DRA has recently been reported; however, longer survival of HD patients may contribute to the development of more DRA, though with a delayed onset. In this article, we describe the pathogenesis of DRA, the strategies developed for its prevention and minimization, and the favorable epidemiological data achieved by these efforts.

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Heart failure and chronic kidney disease are major causes of morbidity and mortality internationally. Although these dysfunctions are common and frequently coexist, the factors involved in their relationship in cardiorenal regulation are still largely unknown, mainly due to a lack of detailed molecular targets. Here, we found the increased plasma histamine in a preclinical mouse model of severe cardiac dysfunction, that had been cotreated with angiotensin II (Ang II), nephrectomy, and salt (ANS). The ANS mice exhibited impaired renal function accompanied with heart failure, and histamine depletion, by the genetic inactivation of histidine decarboxylase in mice, exacerbated the ANS-induced cardiac and renal abnormalities, including the reduction of left ventricular fractional shortening and renal glomerular and tubular injuries. Interestingly, while the pharmacological inhibition of the histamine receptor H3 facilitated heart failure and kidney injury in ANS mice, administration of the H3 agonist immethridine (Imm) was protective against cardiorenal damages. Transcriptome analysis of the kidney and biochemical examinations using blood samples illustrated that the increased inflammation in ANS mice was alleviated by Imm. Our results extend the pharmacological use of H3 agonists beyond the initial purposes of its drug development for neurogenerative diseases and have implications for therapeutic potential of H3 agonists that invoke the anti-inflammatory gene expression programming against cardiorenal damages.

BackgroundAnaemia is a common complication of patients with antineutrophil cytoplasmic antibody (ANCA)-associated renal vasculitis. Nevertheless, the cause and degree of such cases of anaemia have not been elucidated in detail. We aimed to investigate the prevalence, cause, pathogenesis of anaemia and the impact of anaemia on prognosis in patients with ANCA-associated renal vasculitis.MethodsWe identified 45 patients with ANCA-associated renal vasculitis that were clinically and/or histologically diagnosed and treated from 2003 to 2014 at University of Tsukuba Hospital. The relationships between anaemia and various clinicopathological findings were evaluated.ResultsAt the time of diagnosis of ANCA-associated renal vasculitis, all patients showed anaemia, with a mean haemoglobin level of 7.5 ± 1.3 g/dL. Renal anaemia was diagnosed in 92% of patients, anaemia of chronic disease (ACD) in 56%, and anaemia due to hemorrhage in 20%. Next, the patients were divided into two groups according to anaemia severity: minimum haemoglobin (min Hb) < 7.5 (n = 24) and min Hb ≥ 7.5 (n = 21). A comparison of baseline characteristics showed that serum albumin, maximum serum creatinine, minimum estimated glomerular filtration rate (eGFR), serum cystatin C, and the area of tubulointerstitial damage were significantly different between the haemoglobin groups (p <  0.05). No significant intergroup differences were observed in iron-related or inflammation-related data. With regard to the relationship between anaemia severity and prognosis, patients in the min Hb < 7.5 group tended to have a lower eGFR. Anaemia severity was associated with markedly lower survival (Log-rank test, p = 0.03).ConclusionsIn this cohort of patients with ANCA-associated renal vasculitis, all subjects exhibited anaemia. In regard to the cause and pathogenesis, the most prevalent form of anaemia was renal anaemia, not ACD, and a potential reason for the high prevalence of anaemia in our cohort may have been the interaction between renal anaemia and ACD. Moreover, anaemia severity was significantly associated with the degree of renal dysfunction and life prognosis.

Sepsis is characterized by a systemic inflammatory response to a microbial pathogen. In sepsis, capillary permeability is a tightly regulated feature of microcirculation in all organ beds and is fundamentally altered. We investigated the vascular endothelial growth factor (VEGF) level as a vascular permeability factor and the soluble fms-like tyrosine kinase-1 (Flt-1) level as an antagonist of the VEGF receptors. Serum VEGF and soluble Flt-1 levels in 21 patients with septic shock, who were treated with direct hemoperfusion with a polymyxin B-immobilized fiber column (DHP-PMX), were measured by enzyme-linked immunoassay. The VEGF and the soluble Flt-1 levels were more elevated in patients with septic shock than in controls. Between 14 survivors and 7 non-survivors, there was no significant difference in VEGF level before the DHP-PMX therapy, but the soluble Flt-1 level of survivors was significantly lower than that of non-survivors. Although there was no significant difference between starting and ending VEGF levels in survivors, in non-survivors the VEGF level at the end of DHP-PMX therapy was significantly lower than that at the start. In survivors, the soluble Flt-1 level at the end of DHP-PMX therapy was significantly lower than that at the start. On the other hand, in non-survivors, there was no significant difference between the ending and starting soluble Flt-1 levels. The soluble Flt-1 level may be a suitable marker of disease severity and mortality.

Most of the diseases for which apheresis therapy is indicated are intractable and rare, and each patient has a different background and treatment course prior to apheresis therapy initiation. Therefore, it is difficult to conduct largescale randomized controlled trials to secure high-quality evidence. Under such circumstances, the American Society for Apheresis (ASFA) issued its guidelines in 2007, which were repeatedly revised until the latest edition in 2019. The ASFA guidelines are comprehensive. However, in the United States, a centrifugal separation method is mainly used for apheresis, whereas the mainstream procedure in Japan is the membrane separation method. The target diseases and their backgrounds are different from those in Japan. Due to these differences, the direct adoption of the ASFA guidelines in Japanese practice creates various problems. One of the features of apheresis in Japan is the development of treatment methods using hollow-fiber devices such as double filtration plasmapheresis (DFPP) and selective plasma exchange and adsorptiontype devices such as polymyxin B-immobilized endotoxin adsorption columns. Specialists in emergency medicine, hematology, collagen diseases/rheumatology, respiratory medicine, cardiovascular medicine, gastroenterology, neurology, nephrology, and dermatology who are familiar with apheresis therapy gathered for this guideline, which covers 86 diseases. In addition, since apheresis therapy involves not only physicians but also clinical engineers, nurses, dieticians, and many other medical professionals, this guideline was prepared in the form of a worksheet so that it can be easily understood at the bedside. Moreover, to the clinical purposes, this guideline is designed to summarize apheresis therapy in Japan and to disseminate and further develop Japanese apheresis technology to the world. As diagnostic and therapeutic techniques are constantly advancing, the guidelines need to be revised every few years. In order to ensure the high quality of apheresis therapy in Japan, both the Japanese Society for Apheresis Registry and the guidelines will be inseparable.

Cryofiltration (CF) is a technique in which separated plasma is chilled before being subjected to a plasma fractionator (PF), leading to cryoglobulin precipitation or cryogel formation. In CF using the Evaflux-5A as the PF, there is no consensus on the necessity of albumin supplementation, and when or how often the PF column should be washed. We analyzed the sieving effects of various solutes (albumin, IgG, IgM, LDL, HCV-RNA, and cryoglobulin) depending on transmembrane pressure (TMPPF ) during CF using the Evaflux-5A in a patient with hepatitis C virus-associated cryoglobulinemic glomerulonephritis. Five CF treatments were initially performed and a sixth one later, at disease recurrence. Quantitative detection of cryoglobulin and a marked rise in TMPPF to 400 mm Hg were observed only at the first and sixth treatment, and albumin losses during these treatments were very high, at 16.8 g, and 14.6 g, respectively, while those of others (from the second to fifth) were 6.7 g, 6.4 g, 5.9 g, and 7.0 g, respectively. The sieving coefficients (SCs) of both albumin and IgG were stable (0.8-1.0) at TMPPF < 200 mm Hg, but significantly decreased at TMPPF  ≥ 200 mm Hg (P < 0.01). The SC of IgM tended to decrease at TMPPF  ≥ 200 mm Hg, but not significantly, while that of LDL was zero regardless of the TMPPF . Albumin loss per treatment likely depends on degree of TMPPF rise, which is mainly affected by the patient's cryoglobulinemic status. In CF using Evaflux-5A, washing the PF column to keep TMPPF < 200 mm Hg during treatment may be a recommended for selective removal and albumin salvage.

Abstract.A Pulse Coupled Neural Network (PCNN) is a kind of numerical model of cat visual cortex and it can explain synchronous dynamics of neurons' activity in the visual cortex. On the other hand, as an engineering application, it is shown that the PCNN can applied to the image processing, e.g. segmentation, edge enhancement, and so on. The PCNN model consists of neurons and two kind of inputs, namely feeding inputs and linking inputs with leaky integrators. These inputs lead to discrete time evolution of its internal state and neurons generate spike output according to the internal state. The linking and feeding inputs are received from the neurons' receptive field which is defined by excitatory synaptic weights. In this study, we propose a PCNN with inhibitory connections and describe an application to a color image segmentation. In proposed model, inhibitory connections are defined by negative synaptic weights among specific neurons which detect RGB component of particular pixel of the image. Simulation results show successful results for the color image segmentation.