Background:Compared to the general population, individuals who are undergoing hemodialysis are at a higher risk of contracting severe infectious diseases, and their mortality rate from infectious diseases is also higher. We investigated the serum free interleukin-18 [free state of interleukin-18 (IL-18)] concentration as a prognostic factor for hemodialysis patients' infection risk. Methods:The Ibaraki Dialysis Initiation Cohort (iDIC) study is a multicenter prospective cohort investigation of patients undergoing a new initiation of dialysis in a local region of Japan. We performed a survival analysis of several events requiring hospitalization and compared the Kaplan-Meier curves of the "low" and "high" serum free IL-18 concentration groups. To adjust for confounding factors, we also performed a Cox proportional hazards analysis. Results:We analyzed the serum free IL-18 concentration of samples from 295 patients randomly selected from the blood sample bank of the iDIC study. The mean free IL-18 concentration was 8.7 ± 5.3 pmol/l. The cumulative incidence of infectious events was significantly higher in the low free IL-18 group (<6.0 pmol/l, log-rank test P < .01). The Cox proportional hazards analysis revealed that low serum free IL-18 (<6.0 pmol/l) was an independent factor associated with the development of infectious events. Total IL-18 and IL-18BP (binding protein) showed no association with infectious events. Conclusion:A low serum free IL-18 concentration in the dialysis initiation period is a potential marker for predicting the development of severe infection in these patients.

Objective We conducted a prospective, randomized controlled, open-label study to investigate the efficacy of a combination of cyclosporine and low-dose prednisolone in patients with idiopathic membranous nephropathy (IMN). Methods We recruited biopsy-proven IMN patients with nephrotic syndrome who had never been treated with immunosuppressants. The patients were randomized into 2 groups treated after randomization with cyclosporine (3 mg/kg/day) alone or with an oral low-dose corticosteroid (prednisolone 15 mg/day) for 24 months. Results We recruited 30 patients with IMN and nephrotic-range proteinuria, 28 of whom were included in this study. Fourteen patients were randomized for treatment with only cyclosporine (Group A), and 14 were randomized for treatment with cyclosporine plus low-dose corticosteroids (Group B). Cyclosporine monotherapy induced remission in 12 of the 14 patients in Group A, including partial remission in 7 patients (50.0%) and complete remission in 5 patients (36.7%). In Group B, 12 of 14 patients achieved proteinuria remission, including 11 (78.6%) with complete remission and 1 (7.1%) with partial remission. Although there was no marked difference in the overall remission rate, the complete remission rate was significantly higher in Group B than in Group A (p=0.02). Furthermore, there was a statistically significant difference between the groups in the time from the start of the study to complete remission (10.2±7.8 months in Group A; 9.5±6.1 months in Group B, p=0.03). Conclusion The combination of cyclosporine and low-dose corticosteroid treatment is an effective and important option in the management of patients with IMN with nephrotic-range proteinuria, either as an initial therapy or as a long-term treatment.

Patients with end-stage kidney disease (ESKD) are at high risk of cardiovascular disease including stroke, heart failure, and ischemic heart disease (IHD). To prevent the occurrence and progression of CVD, a reliable prognostic cardiac biomarker is essential. We investigated the prognostic value of NT-proBNP for each incident type of CVD. Male patients from the Ibaraki Dialysis Initiation Cohort (iDIC) study with preserved serum samples from dialysis initiation day (n = 212) were analyzed. Patients were classified into four groups according to quartiles of baseline NT-pro BNP levels. The relationship between NT-proBNP levels at the initiation of dialysis and the subsequent incidence of hospitalization events due to IHD, heart failure, and stroke was analyzed. The incidence rate for hospitalization due to IHD was significantly higher in the highest NT-proBNP category (Log rank p = 0.008); those of stroke and heart failure showed no significant differences among quartiles. Cox proportional hazards regression analysis revealed that serum NT-proBNT was the only prognostic factor for hospitalization for IHD after adjustment by major known IHD risk factors. (HR, 1.008; 95

INTRODUCTION:Recent studies have identified increased blood calciprotein particle (CPP) levels as risk factors for vascular calcification and cardiovascular events in patients undergoing maintenance hemodialysis. Although positively correlated with serum phosphate levels, serum CPP levels vary considerably among patients with similar serum phosphate levels. We investigated the capacity of the ratio of serum CPP levels to serum phosphate levels (CPP/Pi ratio) to predict cardiovascular events in incident hemodialysis patients compared to the serum calcification propensity test (T50). METHODS AND RESULTS:The association between the CPP/Pi ratio and major adverse cardiac and cerebrovascular events (MACCE) was investigated in 174 incident hemodialysis patients. Multivariate analysis revealed that the CPP/Pi ratio was independently associated with MACCE [hazard ratio 1.60, 95% confidence interval (1.15-2.23), p = 0.006] but serum T50 levels were not. CONCLUSIONS:The CPP/Pi ratio is a useful, novel biomarker for predicting the risk of cardiovascular events in patients undergoing incident hemodialysis.

Visceral disseminated varicella zoster virus (VZV) infection is a severe complication, characterized by a notably high mortality rate. Herein, we present a case of a 36-year-old-man involving visceral disseminated VZV infection that emerged during remission induction therapy involving high-dose prednisolone (PSL), mycophenolate mofetil (MMF), and hydroxychloroquine for lupus nephritis. Two months after starting the immunosuppressive therapy, he experienced a rapid onset of severe upper abdominal pain. The following day, clinical manifestations and laboratory abnormalities rapidly deteriorated. Hyperferritinemia and hypertriglyceridemia, indicative of hemophagocytic lymphohistiocytosis (HLH), emerged, along with escalating liver and renal impairment and newly appeared disseminated intravascular coagulation, and multiple organ failure is suggested. The patient developed widespread blistering predominantly on the trunk and face, patient’s condition failed to ameliorate, ultimately culminating in his demise a few hours later. At autopsy, the cutaneous lesions with blisters revealed positive immunostaining with anti-VZV antibody, and similar findings were detected in multiple organs. HLH was confirmed in lymph nodes. It is crucial to emphasize the awareness of visceral disseminated VZV, particularly in cases patients are undergoing concurrent PSL therapy alongside MMF for SLE. The progression of this fatal condition usually begins with abdominal pain, followed by a skin rash a few days later. The present case is the first to show evidence of HLH occurring as a result of visceral disseminated VZV infection. This disease is extremely rare but extremely serious, therefore, VZV-DNA should be measured in cases where you suspect this disease for early diagnosis and treatment.

Miyazaki et al.1 recently suggested in Kidney International Reports that neural epidermal growth factor-like1 (NELL1) is a causative antigen in bucillamine-associated membranous nephropathy (MN), and they described 4 Japanese patients with NELL1-positve MN complicated by rheumatoid arthritis (RA). Among 221 patients with MN who underwent NELL1 staining, 10 (4.5%) were positive for NELL1. Among them, 6 patients (60%) had NELL1-positive MN with RA, including 4 with suspected bucillamine-induced MN.

Background Patients with end-stage kidney disease (ESKD) face higher risks of life-threatening events including cardiovascular disease. Various risk factors are identified as agents influencing the life prognosis of ESKD patients. Herein, we evaluated the risk factors related to the outcomes of Japanese patients with dialysis induction. We present the study protocol, the patients’ baseline characteristics, and their outcomes. Methods The Ibaraki Dialysis Initiation Cohort (iDIC) Study is a prospective multi-center cohort study in collaboration with 60 tertiary-care facilities in Ibaraki Prefecture, Japan. We collected baseline data from clinical records and analyzed blood and urine samples of these facilities’ patients with diabetic nephropathy, hypertensive nephrosclerosis, and chronic glomerulonephritis (CGN). The study’s primary outcome was the survival rate at 24 months after dialysis induction. We performed a Kaplan-Meier analysis for cumulative survival and a Cox proportional hazards analysis for all-cause mortality and hospitalization. Results We analyzed 636 patients’ cases (424 males, 212 females, age 67.4 ± 13.1 yrs. [mean ± SD]). We compared the patients’ baseline data with those of similar cohort studies. As the primary kidney disease, 327 cases (51.4%) were diagnosed as diabetic nephropathy, 101 (15.9%) as hypertensive nephrosclerosis, and 114 (17.9%) as CGN. The mean serum creatinine value was 9.1 ± 2.9 mg/dL. The mean estimated glomerular filtration rate was 5.6 ± 1.8 mL/min/1.73m 2 . The cumulative survival rates at 6 months and 24 months after dialysis induction were 95.2 and 87.7%, respectively. The cumulative survival rate was significantly lower with increasing age. A Cox proportional hazards regression analysis demonstrated that high age was significantly associated with all-cause mortality. Conclusions Regarding the clinical characteristics of these newly induced dialysis patients, the same trend as in other cohort studies was observed. Another study is underway to explore prognostic factors based on the iDIC Study’s findings.

Background Immune dysfunction in hemodialysis patients is partially due to NK cell impairment. Ligands for NK activating receptors such as NKG2D expressed on cancer cells are involved in NK cell dysfunction and can lead to cancer development. Methods A cohort with 370 patients who started hemodialysis (HD) was investigated. Serum levels of soluble NKG2D ligands were measured. Cancer history was defined as any cancer diagnosis at induction and hospitalization and death due to cancer during 2-year follow-up. Results Sixty-two patients with and 308 patients without a cancer history showed mostly comparable biochemical parameters and uremic status at HD induction. Soluble MICB, ULBP-1, and ULBP-2 were detected in sera from most patients starting HD rather than MICA, the most representative NKG2D ligand. Measured NKG2D ligands, except for ULBP-1, were strongly correlated with each other. Correlations between NKG2D ligands and renal function were significant but modest in patients starting HD. Cancer history did not have any impact on levels of soluble NKG2D ligands. Discussion Even though this investigation lacked a control cohort and serial measurement of parameters, expression patterns of NKG2D ligands were comprehensively described, and the significance of cancer in patients starting HD was elucidated for the first time. Elevated levels of soluble NKG2D ligands occurred potentially due to complex mechanisms of oxidative stress, with insufficient metabolism and excretion in a uremic milieu, but they might mask the significance of elevations in serum levels of soluble NKG2DLs in patients with a cancer history.

60歳台，男性．めまい・倦怠感でA病院を受診し，急性腎不全で入院となった．入院時より心エコーで肺高血圧と右心系の拡大を認め，翌日に突然の血圧低下と意識障害，アシドーシスの急激な進行を認めた．数時間後に心停止し，緊急でV-A ECMO（veno-arterial extracorporeal membrane oxygenation）を導入した．その後も血圧低値が遷延したが，ビタミンB1の補充を行ったところ，血行動態は安定し，衝心脚気と診断した．原因不明の急性右心不全・肺高血圧の症例ではその可能性も念頭に置く必要がある．

Abstract Background and Aims In general population, there are weekly and seasonal variabilities of blood pressure (BP) which are supposed to be the risk of cardiovascular disease. Home BP is well correlated to the cardiovascular risk compared to clinic BP. We already reported home and clinic BP of hemodialysis (HD) patients fluctuate seasonally partly due to temperature. The aim of this study is to determine in large number of HD patients whether the seasonal BP variability correlates to the volume status and temperature. Method One hundred sixty nine dialysis patients (93 male, 76 female) in ten Saiseikai hospitals in various districts in Japan were recruited. All patients were asked to measure BP at least four times a day in a sitting position, twice consecutively in the morning after urination before breakfast and medication and twice consecutively in the evening just before going to bed. The mean of twice measurements was defined as the data of measurement time. Data from Oct. 2015 to Oct. 2017 were analyzed. If the dialysis were performed 3 times a week (Mon, Wed, Fri), Monday was defined as 1st day. If the dialysis were performed on Tue. Thurs. and Sat., Tuesday was defined as 1st day. Seasonal variabilities in morning home BP and night home BP were evaluated. Seasonal changes in clinic BP just before and after HD were also evaluated in 61 patients. Results Weekly home BP variability in the morning, 1st day 153±16 / 78±13 mmHg, 2nd day 144±28 / 76±12, 3rd day 150±14 / 77±13, 4th day 142±26 / 75±13, 5th day 149±14 / 77±12, 6th day 144±24 / 76±13, 7th day 149±16 / 78±13. Systolic home BPs in 1st, 3rd and 5th days were significantly elevated compared with 2nd, 4th and 6th days. Morning home BP significantly elevated gradually from 6th, 7th and to 1st day. Lowest SBP in the morning was 4th day but not 6th day which was the same as the previous result (CJASN 3: 416-422, 2008). Seasonal variability of morning home BP in 1st day was evident with the rise in autumn and winter (spring 153±19 / 78±12, summer 146±17 / 77±12, autumn 158±16* / 80±12, winter 156±19* / 80±13, * p<0.05 vs summer) (figure). There was almost same seasonal morning home BP variability in 4th day which had the lowest value of morning home BP in a week. Seasonal changes of night home BP in 5th day were not significant through four seasons, which night was supposed to be the driest volume status in a week. Seasonal changes in clinic BP just before and after HD, in 1st day before HD: spring 147±19 / 74±13 mmHg, summer 144±20 / 71±11, autumn 150±19 / 74±13, winter 147±21 / 74±12. Systolic BP in autumn was significantly elevated compared to summer. In the other clinic BPs before and after HD in 3rd and 5th days, there were no significant seasonal changes observed. Seasonal changes of highest temperature were significant (spring 19.9±3.1*°C, summer 30.9±2.6, autumn 23.3±2.7*, winter 8.5±2.8*, *p<0.05 vs summer). Morning BP of 1st day in a randomly selected patient was correlated with highest temperature (r=-0.397 p<0.0001). Discussion There is seasonal home BP variability probably due to temperature change because BP was correlated well with temperature. Seasonal morning BP variability was evident in the 1st day of the HD week, but this seasonal home BP variability was disappeared measuring BP in the night without volume overload. We assumed that vasoconstriction due to change in temperature was enhanced by volume overload and sympathetic activation in the morning. Conclusion In the large number of HD patients in multicenter of various districts in Japan, seasonal BP variabilities were affected by the volume status and temperature.

A 69(cid:514)year(cid:514)old male had a history of a thoracic dissecting aortic aneurysm, which was conservatively monitored. He was started on dialysis due to nephrosclerosis in year X(cid:514)2. However, it was difficult to create an arteriove-nous fistula because of his bleeding tendency. Resurgery and hematoma removal were

Thrombotic thrombocytopenic purpura (TTP) is a rare but life-threatening disease. Although plasma exchange (PE) therapy and corticosteroids are standard remission induction and maintenance therapies, some patients are easily refractory and frequently relapse under treatment with this therapy, and require additional treatment. However, there are limited data about additional treatment interventions. We report a case of 56-year-old man who was hospitalized for fever, general fatigue and hemoglobinuria. Owing to the symptoms and the laboratory findings of hemolysis, he was diagnosed with TTP. He was treated with PE therapy and corticosteroids, and the TTP went into remission. However, his TTP relapsed and remission induction was attempted again. As a remission maintenance treatment, we used combination therapy with the purine-synthesis inhibitor mizoribine (MZR) and corticosteroids. The administration of MZR maintained disease activity with no adverse event for long periods and allowed us to gradually reduce the corticosteroids dose. Hence, we propose that MZR is an effective treatment for TTP maintenance.

A 77-year-old woman was diagnosed nephrotic syndrome with Waldenström’s macroglobulinemia (WM). Renal biopsy revealed MPGN-like lesions with extensive glomerular capillary thrombi which were positive for anti-IgM and anti-lambda-light chain immunofluorescence. The electron microscopy showed characteristic thrombi intra glomerular capillary walls which were occupied with a lot of vacuoles. These structures were similar with them of lipoprotein glomerulopathy. The patient was started to treat with R-CHOP, and then nephrotic syndrome and her renal insufficiency were completely recovered. There were no previous reports of nephrotic syndrome and acute renal failure caused by oil-rich intracapillary thrombi in WM in the literature.

Type 17 T-helper (Th17) cells have been suggested to be involved in the pathogenesis of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). Th17 cell proliferation is promoted by tumor necrosis factor (TNF)-like ligand 1A (TL1A), which binds to death receptor 3 (DR3) expressed on Th17 cells. Decoy receptor 3 (DcR3) is known to block the TL1A-DR3 pathway by binding TL1A. To evaluate the Th17-TL1A systems as disease activity markers in AAV, we investigated the serum levels of TL1A and DcR3 in AAV patients. Serum IL-17, IL-23, TL1A, and DcR3 were measured by ELISA in 24 AAV patients with microscopic polyangiitis before the initial treatment, 24 AAV patients during remission, and 20 control subjects. There were no significant differences in serum IL-17, IL-23, and TL1A levels among the active-vasculitis patients, inactive-vasculitis patients, and controls. The mean serum DcR3 level was significantly higher in the active-vasculitis patients than in the inactive-vasculitis patients and controls (P < 0.0001, respectively). There were significant positive correlations between the serum DcR3 levels and Birmingham Vasculitis Activity Score (BVAS), myeloperoxidase (MPO)-ANCA titers, white blood cell counts, serum creatinine levels, and serum C-reactive protein levels. In a multiple regression analysis, there was a significant positive correlation between the serum DcR3 level and BVAS (β = 0.650, P = 0.0462). The mean BVAS level was significantly higher in the active-vasculitis patients with high serum DcR3 levels than in those with the low serum DcR3 levels (P = 0.0202). The serum level of DcR3 may be a useful marker for disease activity in AAV.

BACKGROUND:The incidence of post-infectious glomerulonephritis (PIGN) in developed countries has decreased over the last 50 years. Here we identified the trends of the incidence of PIGN in Japan during the past four decades. METHODS:We explored the frequency, clinicopathological findings, and prognosis of PIGN based on 6,369 cases from the Renal Biopsy Database of our institute in the Kanto region of Japan, diagnosed histologically from 1976 to 2009. RESULTS:The numbers of PIGN cases were 131 (2.1%) in total, and 2.4%, 1.1%, 2.6% and 2.1% identified in the 1970s, 1980s, 1990s, and 2000s, respectively. Acute glomerulonephritis (AGN), including post-streptococcal glomerulonephritis (PSGN), accounted for almost all of the PIGN cases in the 1970s, but decreased to approx. 40%-50% since the 1990s. In the 1990s, Staphylococcus aureus infection-related nephritis (SARN) showed a rapid increase in rate, reaching 30%. The incidence of hepatitis C virus infection-associated GN (HCVGN) has increased since the 1990s. The average age at onset rose from 33 to 51 years over the study period. These transitions can be summarized as increases in SARN and HCVGN and decreases in PSGN and other types of AGN, since SARN and HCVGN have older onsets compared to PSGN and other AGN types. The clinicopathological features were marked for each PIGN. Regarding the prognosis, the renal death rates of both the SARN and HCVGN groups were significantly higher than those of other PIGN. CONCLUSION:Based on our analysis of the Renal Biopsy Database, the incidence of PIGN in Japan reached its peak in the 1990s. The temporal changes in the incidence of PIGN reflected the trends in infectious diseases of each decade and the continual aging of the population, with a related higher susceptibility to infections.

Objectives: The contribution of infections to the mortality of patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is important, and early and careful infection control is necessary. We investigated the usefulness of the serum-soluble haemoglobin scavenger receptor CD163 for detecting the presence of infectious complications regardless of disease activity. Method: Soluble CD163 in serum obtained from 45 Japanese patients with myeloperoxidase (MPO)-AAV was measured by an enzyme-linked immunosorbent assay (ELISA). We evaluated 36 samples from active-vasculitis patients, 36 samples from inactive-vasculitis patients without infection, and 19 samples from inactive-vasculitis patients with infectious complications. Serum-soluble CD163 was also measured in 15 infectious patients without vasculitis and in 30 normal controls. Results: The mean serum-soluble CD163 level was higher in the patients with infectious complications than in the active-vasculitis patients, inactive-vasculitis patients, and normal controls. There were significant positive correlations between serum-soluble CD163 levels and white blood cell (WBC) count, serum C-reactive protein (CRP) levels, and serum albumin levels, but only serum CRP levels were correlated with serum-soluble CD163 levels in a multiple regression analysis. On the receiver-operating characteristic (ROC) curve, serum-soluble CD163 levels had 80.6% sensitivity and 86.7% specificity for differentiating patients with infection from those without infection. Among the active-vasculitis patients, the mean serum-soluble CD163 level of the patients with alveolar haemorrhage was significantly lower than that of the patients with interstitial lung diseases and that of the patients without pulmonary lesions. Conclusions: The serum-soluble CD163 level may be a useful marker for the detection of infectious complications in MPO-AAV patients.

Acute kidney injury (AKI) occurs in approximately 50% of patients in septic shock, and mortality from septic AKI is extremely high. Angiopoietin levels may play a role in the pathogenesis of vascular permeability. It was reported that direct hemoperfusion with a polymyxin B-immobilized fiber column (DHP-PMX) therapy ameliorates the angiopoietin balance in patients with sepsis. Although dysregulated angiopoietin balance in sepsis has been demonstrated, mechanisms underlying the development of AKI in sepsis have not been identified. We investigated angiopoietin levels in septic patients with/without AKI treated with DHP-PMX therapy. We used an enzyme-linked immunoassay to measure serum angiopoietin-1 and -2 levels in 38 septic shock patients treated with DHP-PMX. The renal function of all patients was normal for less than 3months. Twenty-seven of the patients were diagnosed with AKI. The angiopoietin-1 level of the AKI group was significantly lower than that of the non-AKI group at the initiation of DHP-PMX therapy, but there was no significant difference between the two groups at the end of DHP-PMX therapy. In the AKI group with recovery, the mean angiopoietin-1 level at the end of DHP-PMX therapy was significantly elevated compared to the level before DHP-PMX therapy, and the mean angiopoietin-2 level at the end of DHP-PMX therapy was significantly decreased compared to the level before DHP-PMX therapy. These results suggest that angiopoietins may play a role in the pathogenesis of AKI and that DHP-PMX therapy may ameliorate the angiopoietin balance in AKI patients with sepsis.

Purpose: The CD40/CD40 ligand (CD40L) system is associated with pathogenic processes of inflammatory diseases, and elevated levels of soluble CD40L have been observed in sera from patients with autoimmune diseases. To determine the diagnostic value of serum-soluble CD40L in Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), we investigated patients with MPO-AAV at various stages of the disease. Methods: Twenty-eight samples were from patients with active MPO-AAV: 28 samples from inactive-vasculitis patients without infection and 16 samples from inactive-vasculitis patients with infectious complications. Serum soluble CD40L was measured by an enzyme-linked immunosorbent assay. Serum-soluble CD40L was also measured in 15 patients with infectious diseases and in 28 control subjects. Results: The serum-soluble CD40L level was higher in the patients with inactive vasculitis with infectious complications than in those with inactive vasculitis without infection and the normal control, but there was no significant difference in CD40L levels between the patients with active vasculitis and those with inactive vasculitis with infectious complications. There were significant correlations between the serum levels of soluble CD40L and the serum creatinine and CRP levels. The serum soluble CD40L/creatinine ratio was higher in the inactive vasculitis with infectious complications group than in the active vasculitis group, inactive vasculitis without infection group and the normal control. Comparative receiver-operating-characteristic curves showed that this ratio had 92.8% sensitivity and 96.8% specificity for differentiating patients with infection from those without infection. Conclusion: Serum-soluble CD40L was not associated with disease activity, but it may be a useful marker for the detection of infectious complications in MPO-AAV.