The efficacy and safety of ivabradine hydrochloride in hemodialysis patients with chronic heart failure.

INTRODUCTION: There is little evidence for ivabradine hydrochloride in patients undergoing hemodialysis. METHODS: In this open-label prospective interventional trial of hemodialysis patients with chronic heart failure, during 12 weeks of treatment, changes in Heart rate (HR), frequency of dialysis-related hypotension were examined, and we investigated health-related quality of life (HR-QOL) and adverse effects. RESULTS: 18 patients from 6 facilities were enrolled in the study. HR significantly decreased over time, from 87 ± 12.61/min at baseline to 75.85 ± 8.91/min (p = 0.0003), and systolic blood pressure also increased significantly (p < 0.0001). The frequency of dialysis-related hypotension was markedly reduced (p = 0.0001). The HR-QOL survey showed significant improvements in Social Functioning among others (p = 0.0178). No specific adverse events occurred. CONCLUSION: Ivabradine hydrochloride improved dialysis-related hypotension. Furthermore, the HR-QOL improvement effect were suggested. These results demonstrated the safety and effectiveness of ivabradine hydrochloride.

Intramuscular and abdominal fat measured by computed tomography and mortality of hemodialysis patients.

BACKGROUND: In hemodialysis patients, high body mass index is associated with low mortality while abdominal obesity relates to increased mortality. We aimed to investigate the association between muscle mass, intramuscular fat and abdominal fat measured by abdominal computed tomography (CT), and mortality in this patients population. METHODS: This two-center retrospective cohort study included hemodialysis patients who underwent abdominal CT between January 2013 and December 2018. Skeletal muscle mass index (SMI), muscle radiation attenuation (MRA) as an index of intramuscular fat, and visceral fat to subcutaneous fat ratio (VSR) were calculated using CT images at the third lumbar vertebral level. Multivariate Cox proportional hazards model was used to determine the independent predictors of all-cause, cardiovascular and non-cardiovascular mortalities. RESULTS: The study included 344 patients (median age 71.0 years; female 33.7%), among whom 145 died during a median follow-up of 4.9 years-46 and 99 from cardiovascular and non-cardiovascular causes, respectively. Lower MRA [hazard ratio (HR) 0.71, 95% confidence interval (CI) 0.58-0.87, P = .001] and higher VSR (HR 1.17, 95% CI 1.01-1.37, P = .04) were independently associated with higher all-cause mortality but not with lower SMI (HR 0.87, 95% CI 0.68-1.11, P = .26). Lower MRA (HR 0.51, 95% CI 0.35-0.73, P < .001) and higher VSR (HR 1.29, 95% CI 1.09-1.54, P = .003) were also associated with cardiovascular and non-cardiovascular mortality, respectively. CONCLUSIONS: Intramuscular fat and abdominal fat as measured using abdominal CT in hemodialysis patients are stronger independent predictors of mortality than muscle mass.

Association of Postexercise Vagal Dysfunction With Protein-Energy Wasting and Noncardiovascular Outcomes in Patients Receiving Hemodialysis: A Retrospective Cohort Study.

OBJECTIVE: Postexercise vagal dysfunction is linked to noncardiovascular mortality in hemodialysis patients, but the mechanism is unknown. This study aimed to determine the association of cardiovagal neuropathy with systemic inflammation, protein-energy wasting, and noncardiovascular hospitalization. METHODS: This 2-center retrospective cohort study analyzed data from 280 hemodialysis patients who underwent exercise test. Patients were assessed for heart rate (HR) recovery (bpm) for 1 minute after exercise, a marker of vagal function, and were divided into 3 categories (Low: ≤ 6, Mid: 7-11, High: ≥ 12 bpm). We followed 1-year changes in the systemic inflammation-based prognostic score (Glasgow Prognostic Score [GPS]), body weight, and creatinine generation rate (CGR), an indicator of muscle mass, as well as 2-year hospitalization. RESULTS: The HR recovery category was associated with serum C-reactive protein and albumin levels and GPS. After 1 year, the low HR recovery category was associated with worsening in GPS (low, 0 [0-0.5]; mid, 0 [0-1]; high, 0 [0-0]), weight (low, 100.0 [96.1-102.5]; mid, 101.3 [98.9-105.0]; high, 100.5 [98.2-102.9]%), and CGR (low, 97.0 [88.5-111.4]; mid, 110.2 [90.9-124.8]; high, 106.2 [95.5-115.5]%), and the correlations with GPS and CGR remained consistent after adjusting for confounders such as exercise capacity and hospitalization during the follow-up period. There were 117 patients hospitalized. Compared to the high HR recovery category, the mid (hazard ratio: 1.8, 95% confidence interval [CI]: 1.1-3.1, P = .02) and low (hazard ratio: 2.4, 95% CI: 1.5-4.0, P = .001) categories were independently associated with an increased risk of all-cause hospitalization. For noncardiovascular disease hospitalization, the low HR recovery category was independently associated with increased risk of hospitalization (hazard ratio: 2.1, 95% CI: 1.2-3.7, P = .007). CONCLUSIONS: Vagal neuropathy in this population can contribute to adverse outcomes associated with systemic inflammation and protein-energy wasting.

Comparison of intradialytic continuous and interval training on hemodynamics and dialysis adequacy: A crossover randomized controlled trial.

AIM: Circulating blood volume (BV) during exercise changes depending on the intensity and duration, and post-exercise hypotension is observed after continuous exercise. We investigated the safety and efficacy of both interval and continuous IDE at anaerobic threshold (AT) levels with respect to hemodynamic stability and dialysis efficiency. METHODS: In this crossover randomized controlled trial, 16 patients on haemodialysis were subjected to three trial arms, including non-IDE, interval-IDE, and continuous-IDE arms. Systolic blood pressure (SBP), BV, and ultraviolet absorbance - an indicator of dialysis efficiency - were continuously measured, and each change was compared between the three arms by two-way analysis of variance. RESULTS: Continuous IDE decreased SBP from post-exercise to the end of dialysis compared with baseline (pre 142.8 ± 19.0 vs. post 127.5 ± 24.5 mmHg, p = .02), whereas interval IDE maintained better SBP levels post-exercise (pre 139.9 ± 17.1 vs. post 140.1 ± 15.8 mmHg, p = 1.0) than continuous IDE (non-IDE 133.2 ± 19.9 vs. interval 140.1 ± 15.8 vs. continuous 127.5 ± 24.5 mmHg, p = .04). Moreover, interval IDE caused less tiredness and few symptoms (p < .05), despite reaching higher intensity than continuous IDE (p = .001). The BV of each IDE arm decreased during exercise and recovered post-exercise to the same level as non-IDE. Ultraviolet absorbance was not different between each arm (p = .16). CONCLUSION: AT-level interval IDE maintains better hemodynamic stability from post-exercise to the end of dialysis and may represent a novel approach that can be effectively performed with fewer symptoms.

Relationships between frailty and exercise capacity in patients undergoing hemodialysis: A cross-sectional study.

AIM: Hemodialysis (HD) patients have a high prevalence of frailty. The association between frailty and exercise capacity in HD patients has not been established. This study aimed to clarify the relationships between frailty and exercise capacity in HD patients. METHODS: This two-center cross-sectional study included HD patients who performed cardiopulmonary exercise testing. Participants were divided by frailty phenotype into robust, pre-frail, and frail using the revised Japanese version of the Cardiovascular Health Study criteria. Peak oxygen uptake (peakVO2 ) measured by cardiopulmonary exercise testing was compared with each frailty phenotype. The association between peakVO2 and frailty phenotype was analyzed using multivariate linear regression analysis adjusted for age, sex, body mass index diabetes mellitus, cardiovascular disease, cancer, history of fracture, hemoglobin, left ventricle ejection fraction, and percentage of heart rate reserve. RESULTS: The study included 136 patients (median age, 71.0 years; female, 23.5%), with 15.4%, 44.9%, and 39.7% with frailty phenotypes robust, pre-frail, and frail, respectively. PeakVO2 decreased with deterioration of the frailty phenotype (robust, median 15.1 [13.7-18.3] mL/min/kg; pre-frail, median 12.2 [10.5-14.4] mL/min/kg; frail, median 10.6 [9.2-12.5] mL/min/kg, P < 0.05). PeakVO2 decline was significantly associated with frail (B = -2.19, P = 0.004). Modeling individual frailty components showed a significant association between peakVO2 , usual gait speed (B = 2.38, P = 0.04), and low physical activity (B = -1.44, P = 0.004). CONCLUSION: Frailty in HD patients was associated with a decline in exercise capacity. HD patients with frailty need to improve exercise capacity, gait speed, and physical activity. Geriatr Gerontol Int 2023; 23: 795-802.

An equation to predict peak heart rate for prescribing exercise intensity in middle-aged to older patients requiring hemodialysis.

PURPOSE: Exercise prescription based on a population-specific physiological response can help ensure safe and effective physical interventions. However, as a facile approach for exercise prescription in hemodialysis population that is based on their exercise capacity has not yet been established, the aim of our study was to develop a unique prediction formula for peak heart rate (HR) that can be used in this population. METHODS: This cross-sectional study measured physical function and HR at peak exercise and anaerobic threshold (AT) during cardiopulmonary exercise tests in 126 individuals. Participants were randomly assigned to the development group (n = 78), whose data were used to calculate the prediction equation, or the validation group (n = 48). RESULTS: The HR reserve in this population was significantly lower (0.44 ± 0.20%) and there was a large discrepancy between conventional age-predicted maximal HR and measured peak-HR values (R = 0.36). The average of the ratio between HR at AT point and peak HR was 85% (95% CI, 83.5%-86.4%). The peak-HR prediction equation was based on resting HR, presence of diabetes, physical dysfunction (gait speed < 1.0 m/s), and hypoalbuminemia (< 3.5 g/dL). It showed high prediction accuracy (R2 [95%CI] = 0.71 [0.70-0.71]) with similar correlation coefficients between the development and validation groups (R = 0.82). CONCLUSION: Aerobic exercise based on estimated peak HR < 85% obtained from the equation in this study may enable safe and effective physical intervention in this population.

Association of cardiac autonomic neuropathy assessed by heart rate response during exercise with intradialytic hypotension and mortality in hemodialysis patients.

The heart rate (HR) reflects the dynamic behavior of the autonomic nervous system, and HR profiles during the exercise test provide prognostic information. However, there are no reports of these factors in hemodialysis patients. Data from 256 patients (mean 68.8 years old) who underwent an exercise test were statistically analyzed. Patients were evaluated for the percent HR reserve from HR at peak exercise, HR recovery for one minute after peak exercise, and exercise capacity, as well as intradialytic hypotension (IDH). The prevalence of chronotropic incompetence (96.1%), defined as under 80% HR reserve, and abnormal HR recovery (60.5%), defined as under 12 beats, were very common. Eighty-four deaths occurred during the follow-up period (median, 3.8 years). A slow HR recovery under 7 beats was associated with IDH after adjustment (odds ratio 2.7, 95% confidence interval 1.1-6.4). HR recovery under 12 beats (hazard ratio over study period 5.1, 95% confidence interval 2.5-10.5), HR reserve under 26.2% (3.4, 1.7-6.8), and IDH (1.7, 1.1-2.8) were associated with all-cause mortality after adjustment. Considering the confounding of all three variables, only HR recovery under 12 beats remained associated with the all-cause and cause-specific mortality ("cardiovascular" and "non-cardiovascular"). This association was consistent even in subgroup analyses based on the presence of diabetes and cardiovascular disease. Thus, HR profiles during the exercise can reflect potential health conditions related to cardiac autonomic neuropathy in hemodialysis patients that affect IDH and their survival.

Effect of blood volume change related to intensity of intradialytic aerobic exercise on hemodialysis adequacy: a pilot study.

PURPOSE: Intradialytic exercise may improve dialysis efficiency; however, the association between changes in blood volume (BV) related to exercise intensity and solute removal kinetics remains unknown. We herein investigated the relationship between changes in BV with exercise and removal of solute molecules during hemodialysis. METHODS: Each of the 21 hemodialysis patients underwent cardiopulmonary exercise test to measure anaerobic threshold (AT). According to the exercise intensity, patients were classified into two groups, the low group (n = 12), whose intensity was below the AT, and the high group (n = 9), whose intensity was at the AT level. Each patient completed two trial arms of resting and discontinuous exercise dialysis sessions in a randomized manner. RESULTS: The change in BV with the exercise dialysis session in the high group decreased during exercise (p = 0.028) and remained decreased after exercise (p = 0.016), compared with the low group. In the low group, compared with routine sessions, the removal of potassium (p = 0.030), phosphate (p = 0.024), and urea nitrogen (p = 0.065) increased during exercise, but the total removal of these solutes did not change. In the high group, the removal of phosphate (p < 0.001) and urea nitrogen (p = 0.018) after exercise and even total phosphate (p = 0.027) decreased. CONCLUSION: These findings suggest that the removal of small solute molecules is improved during exercise in intradialytic low-intensity exercise with no change in BV, and decreased after exercise in high-intensity exercise with a decrease in BV. CLINICAL TRIALS REGISTRY: Trial retrospectively registered at the UMIN Clinical Trials Registry: study number UMIN000038629 (Registration date: September 7, 2019).

Association between social frailty as well as early physical dysfunction and exercise intolerance among older patients receiving hemodialysis.

BACKGROUND: Recently, social frailty has been increasingly recognized as a factor associated with adverse health outcomes, including physical disability and mortality. However, there are no studies about the importance of this factor among hemodialysis patients. Therefore, we investigated the relationship between social frailty and early physical dysfunction in this group of patients. METHODS: This was a two-center cross-sectional study. Older patients receiving hemodialysis were prospectively enrolled. Moreover, participants were evaluated for social frailty based on the definition of previous study and for physical function, peak oxygen uptake (peak VO2 ), ventilatory equivalent for carbon dioxide (VE/VCO2 ) slope and heart rate reserve. Then, they were divided into two groups based on the presence of physical frailty. RESULTS: Data collected from 158 individuals were statistically analyzed. The prevalence rate of social frailty was 59.5%. In the non-physical frailty group, social frailty was found to be independently associated with reduced gait speed (P = 0.007), leg strength (P = 0.040) and peak VO2 (P = 0.023), but not with hand grip strength (P = 0.36). In the physical frailty group, there was no association between social frailty and physical function. Moreover, in patients without physical and social frailty, physical function was maintained at above accepted threshold levels, whereas peak VO2 (14.1 ± 3.3 mL/kg/min), VE/VCO2 slope (32.3 ± 5.5) and heart rate reserve (50.8% ± 21.7%) were substantially impaired. CONCLUSIONS: Patients receiving hemodialysis can present with social frailty and exercise intolerance with cardiac dysfunction in the early phase, which may contribute to subsequent dysfunction. Geriatr Gerontol Int 2021; 21: 664-669.

Polythiol-containing, recombinant mannosylated-albumin is a superior CD68+/CD206+ Kupffer cell-targeted nanoantioxidant for treatment of two acute hepatitis models.

Since reactive oxygen species (ROS) derived from Kupffer cells (KC), especially CD68(+) KC, play a key role in the induction of hepatic oxidative stress and injuries, we developed a polythiolated- and mannosylated human serum albumin (SH-Man-HSA), which functions as a novel nanoantioxidant for delivering thiol to CD68(+) KC. In vitro electron paramagnetic resonance coupled with pharmacokinetics and immunohistochemical studies showed that SH-Man-HSA possessed powerful radical-scavenging activity and rapidly and selectively delivered thiols to the liver via mannose receptor (CD206) on CD68(+) cells. SH-Man-HSA significantly improved the survival rate of concanavalin-A (Con-A)-treated mice. Moreover, SH-Man-HSA exhibited excellent hepatoprotective functions, not by decreasing tumor necrosis factor or interferon-γ production that is closely associated with Con-A-induced hepatitis, but by suppressing ROS production. Interestingly, the protective effect of SH-Man-HSA was superior to N-acetyl cysteine (NAC). This could be attributed to the difference in the inhibition of hepatic oxidative stress between the two antioxidants depending on their potential for thiol delivery to the liver. Similar results were also observed for acetaminophen (APAP)-induced hepatopathy models. Flow cytometric data further confirmed that an increase in F4/80(+)/ROS(+) cells was dramatically decreased by SH-Man-HSA. The administration of SH-Man-HSA at 4 hours following a Con-A or APAP injection also exhibited a profound hepatoprotective action against these hepatitis models, whereas this was not observed for NAC. It can be concluded therefore that SH-Man-HSA has great potential for use in a rescue therapy for hepatopathy as a nanoantioxidant because of its ability to efficiently and rapidly deliver thiols to CD68(+)/CD206(+) KC.

Lack of Th17 cell generation in patients with severe burn injuries.

Immunodeficient patients with severe burn injuries are extremely susceptible to infection with Candida albicans. In addition to Th1 cells, IL-17-producing CD4(+) T cells (Th17 cells) have recently been described as an important effector cell in host anti-Candida resistance. In this study, therefore, we tried to induce Th17 cells in cultures of severely burned patient PBMC by stimulation with the C. albicans Ag (CAg). In the results, the biomarkers for Th17 cells (IL-17 production and intracellular expression of IL-17 and retinoic acid receptor-related orphan receptor γt) were not displayed by burn patient PBMC stimulated with CAg, whereas these biomarkers of Th17 cells were detected in cultures of healthy donor PBMC stimulated with CAg. Burn patient sera were shown to be inhibitory on CAg-stimulated Th17 cell generation in healthy donor PBMC cultures; however, Th17 cells were induced by CAg in healthy donor PBMC cultures supplemented with burn patient sera that were previously treated with anti-IL-10 mAb. Also, the biomarkers of Th17 cells were not induced by CAg in healthy donor PBMC cultures supplemented with rIL-10. IL-10 was detected in serum specimens derived from severely burned patients. These results indicate that Th17 cells are not generated in burn patient PBMC cultures supplemented with CAg. IL-10, produced in response to burn injuries, is shown to be inhibitory on Th17 cell generation. The high susceptibility of severely burned patients to C. albicans infection might be influenced if burn-associated IL-10 production is intervened.

Enhancement of neutrophil function by interleukin-18 therapy protects burn-injured mice from methicillin-resistant Staphylococcus aureus.

Methicillin-resistant Staphylococcus aureus (MRSA) infection is a grave concern in burn-injured patients. We investigated the efficacy of interleukin-18 (IL-18) treatment in postburn MRSA infection. Alternate-day injections of IL-18 into burn-injured C57BL/6 mice significantly increased their survival after MRSA infection and after methicillin-sensitive S. aureus infection. Although IL-18 treatment of burn-injured mice augmented natural IgM production before MRSA infection and gamma interferon (IFN-γ) production after MRSA infection, neither IgM nor IFN-γ significantly contributed to the improvement in mouse survival. IL-18 treatment increased/restored the serum tumor necrosis factor (TNF), IL-17, IL-23, granulocyte colony-stimulating factor (G-CSF), and macrophage inflammatory protein (MIP-2) levels, as well as the neutrophil count, after MRSA infection of burn-injured mice; it also improved impaired neutrophil functions, phagocytic activity, production of reactive oxygen species, and MRSA-killing activity. However, IL-18 treatment was ineffective against MRSA infection in both burn- and sham-injured neutropenic mice. Enhancement of neutrophil functions by IL-18 was also observed in vitro. Furthermore, when neutrophils from IL-18-treated burn-injured mice were adoptively transferred into nontreated burn-injured mice 2 days after MRSA challenge, survival of the recipient mice increased. NOD-SCID mice that have functionally intact neutrophils and macrophages (but not T, B, or NK cells) were substantially resistant to MRSA infection. IL-18 treatment increased the survival of NOD-SCID mice after burn injury and MRSA infection. An adoptive transfer of neutrophils using NOD-SCID mice also showed a beneficial effect of IL-18-activated neutrophils, similar to that seen in C57BL/6 mice. Thus, although neutrophil functions were impaired in burn-injured mice, IL-18 therapy markedly activated neutrophil functions, thereby increasing survival from postburn MRSA infection.

Cardiac dysfunction induced by experimental myocardial infarction impairs the host defense response to bacterial infection in mice because of reduced phagocytosis of Kupffer cells.

OBJECTIVE: This study was undertaken to investigate the effects of cardiac dysfunction induced by experimental myocardial infarction on the host defense response to bacterial infection and the role of Kupffer cells in mediating this response. METHODS: Myocardial infarction was induced in C57BL/6 mice by ligation of the left anterior descending coronary artery. Mice were challenged with Escherichia coli intravenously 1, 5, and 14 days after myocardial infarction or sham operation. Thereafter, the cytokine production and the function of their Kupffer cells were assessed. RESULTS: Mice with myocardial infarction showed remarkable cardiac dysfunction and had a significantly lower survival than sham mice after bacterial challenge at 5 days after surgery; bacterial challenge at 1 or 14 days after surgery resulted in no difference in survival between myocardial infarction and sham mice. The phagocytic activity of Kupffer cells, assessed by fluorescein isothiocyanate microspheres, remarkably decreased in mice with myocardial infarction 5 days after surgery. Serum peaks of tumor necrosis factor and interferon-gamma after bacterial challenge were also suppressed in mice with myocardial infarction at 5 days. Production of these cytokines and immunoglobulin-M from liver mononuclear cells was also impaired in mice with myocardial infarction. Enhancement of the phagocytic activity of Kupffer cells by C-reactive protein significantly improved survival after infection in mice with myocardial infarction, although neither interleukin-18 nor immunoglobulin-M treatment improved survival. CONCLUSIONS: Cardiac dysfunction induced by myocardial infarction renders mice susceptible to bacterial infection and increases mortality because of a reduced ability of Kupffer cells to clear infectious bacteria. C-reactive protein-enhanced phagocytic activity of Kupffer cells may improve the poor prognosis after bacterial infection in mice with myocardial infarction.

Novel mechanism of C-reactive protein for enhancing mouse liver innate immunity.

UNLABELLED: Although C-reactive protein (CRP) is a representative acute-phase protein produced by hepatocytes, the role of CRP in liver innate immunity remains unclear. Using C57BL/6 mice, the present study investigated how CRP affects the functions of liver macrophages, Kupffer cells, and natural killer / natural killer T (NK/NKT) cells under various conditions, including Escherichia coli infection, septic shock, and multiorgan dysfunction induced by interleukin (IL)-12/lipopolysaccharide (LPS) (generalized Shwartzman reaction [GSR]), and LPS-induced lethal hepatitis in Propionibacterium acnes-primed mice. When mice were challenged with a lethal dose of E. coli, synthetic CRP peptide decreased the mortality without decreasing serum tumor necrosis factor (TNF), presumably by enhancing the phagocytic activity of Kupffer cells. Synthetic CRP greatly decreased the production of TNF and reactive oxygen species from Kupffer cells and thereby rescued mice after lethal LPS challenge. CRP also decreased the mortality from GSR and lethal hepatitis by inhibiting TNF production from Kupffer cells, especially phagocytosing Kupffer cells. However, interferon-gamma production from NK/NKT cells was generally not so affected. CRP reportedly binds to FcgammaRI and FcgammaRII, and the injection of anti-FcgammaRII/III Ab into mice abrogated TNF production from, but increased the phagocytic activity of, Kupffer cells. Furthermore, CRP pretreatment restored the decreased phagocytic activity of Kupffer cells in burn-injured mice and decreased TNF production by Kupffer cells and thereby inhibited mortality after sublethal E. coli infection. If CRP was injected into mice at 1 hour after lethal E. coli challenge, it slightly but significantly increased the survival rate. CONCLUSION: CRP thus enhances the phagocytosis of Kupffer cells but decreases their TNF production in a complex manner in which the pathway by way of FcgammaRII may be involved.

Functional alterations of liver innate immunity of mice with aging in response to CpG-oligodeoxynucleotide.

UNLABELLED: Immune functions of liver natural killer T (NKT) cells induced by the synthetic ligand alpha-galactosylceramide enhanced age-dependently; hepatic injury and multiorgan dysfunction syndrome (MODS) induced by ligand-activated NKT cells were also enhanced. This study investigated how aging affects liver innate immunity after common bacteria DNA stimulation. Young (6 weeks) and old (50-60 weeks) C57BL/6 mice were injected with CpG oligodeoxynucleotides (CpG-ODN), and the functions of liver leukocytes were assessed. A CpG-ODN injection into the old mice remarkably increased tumor necrosis factor (TNF) production in Kupffer cells, and MODS and lethal shock were induced, both of which are rarely seen in young mice. Old Kupffer cells showed increased Toll-like receptor-9 expression, and CpG-ODN challenge augmented TNF receptor and Fas-L expression in liver NKT cells. Experiments using mice depleted of natural killer (NK) cells by anti-asialoGM1 antibody (Ab), perforin knockout mice, and mice pretreated with neutralizing interferon (IFN)-gamma Ab demonstrated the important role of liver NK cells in antitumor immunity. The production capacities of old mice for IFN-gamma, IFN-alpha, and perforin were much lower than those of young mice, and the CpG-induced antitumor cytotoxicity of liver NK cells lessened. Lethal shock and MODS greatly decreased in old mice depleted/deficient in TNF, FasL, or NKT cells. However, depletion of NK cells also decreased serum TNF levels and FasL expression of NKT cells, which resulted in improved hepatic injury and survival, suggesting that NK cells are indirectly involved in MODS/lethal shock induced by NKT cells. Neutralization of TNF did not reduce the CpG-induced antitumor effect in the liver. CONCLUSION: Hepatic injury and MODS mediated by NKT cells via the TNF and FasL-mediated pathway after CpG injection increased, but the antitumor activity of liver NK cells decreased with aging.

IL-15-induced CD8+CD122+ T cells increase antibacterial and anti-tumor immune responses: implications for immune function in aged mice.

We previously proposed that mouse CD8(+)CD122(+) T cells and human CD57(+) T cells, which increase with age and exhibit potent IFN-gamma production, represent a double-edged sword as they play critical roles in host defense and the lethal IL-12/LPS-induced generalized Shwartzman reaction (GSR). However, our proposal was based solely on comparisons of young and old mice. In this study, we attempted to increase CD8(+)CD122(+) T cells in young mice with exogenous IL-15 and confirm their countervailing functions in young mice. After young mice (6 weeks) were injected with IL-15, they showed significant increases in CD8(+)CD122(+) T cells in the liver and spleen. Liver CD8(+)CD122(+) T cells from IL-15-pretreated mice had a potent capacity to produce IFN-gamma after IL-12 injection or Escherichia coli infection. IL-15-pretreated mice showed increased survival to E. coli infections and enhanced anti-tumor activities against liver metastatic EL4 cells, as well as an exacerbation of the GSR. Correspondingly, liver CD8(+)CD122(+) T cells produced more perforin than CD8(+)CD122(-) T cells in EL4-inoculated mice. Unexpectedly, comparable IL-15 treatment did not induce further increases in CD8(+)CD122(+) T cells in aged mice and did not enhance their defenses against bacterial infection or tumor growth. Interestingly, however, nontreated, aged mice (50 weeks) showed twofold higher IL-15 levels (but not TNF or IFN-gamma) in liver homogenates compared with young mice. Our results further support that CD8(+)CD122(+) T cells, which are increased physiologically or therapeutically by IL-15, are involved in antibacterial immunity, anti-tumor immunity, and the GSR.

Unique angiopathy after herpes virus infection.

OBJECTIVE: We describe 3 Japanese patients with peculiar renal and/or coronary arterial stenosis and/or multiple aneurysms after herpes virus infection, following ischemic symptoms. We investigated for viral antigens and viral DNA in situ, and for shared abnormalities of cellular immunity. METHODS: Panarteriography was performed diagnostically, and patients were grouped as follows: 3 patients with peculiar renal and/or coronary artery narrowing and/or multiple aneurysms; another 3 patients with renal fibromuscular dysplasia; and other young adults with effort angina, with no history of herpes virus infection, as controls. Detection of viral antigens and viral DNA in situ was done by polymerase chain reaction method and immunohistochemical staining. Cellular immunity was examined at the time of ischemic symptoms. RESULTS: Viral antigens and DNA were scarcely detected, except in herpes zoster skin lesion with leukocytoclastic vasculitis. However, shared abnormalities of cellular immunity, such as a decreased CD4+ T cell number and reduced natural killer cell activity, were more prominent in the 3 patients with unique vasculopathy after herpes virus infection. CONCLUSION: Unique vasculopathy following herpes virus infection might be a more severe and extensive disease. We speculate that sustained viral infection, repetitive activation of virus related antigens, and suppressed immune state might contribute to formation of peculiar vascular alterations.

Antineutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis with intrarenal aneurysms and renal arteriovenous fistulaes.

A 78-year-old Japanese man was admitted with a complaint of slight fever and weight loss. At admission, he tested positive for myeloperoxidase (MPO)-ANCA and had renal failure. An abdominal angiography revealed atrophy of the right kidney, two or more arteriovenous fistulae (AVF) in the right renal interlobular arteries, and multiple aneurysms in both kidneys. A renal biopsy specimen showed diffuse crescentic glomerulonephritis accompanied by tubulo-interstitial changes. This case suggests the possibility of some relationship between ANCA-associated vasculitides and the formation of aneurysms and AVFs.