Recent Trends in Home Hemodialysis Therapy in Japan.

BACKGROUND: Home hemodialysis (HHD) is rapidly becoming more widespread because HHD programs enable patients to receive a sufficient dialysis dose to improve their quality of life and survival rate without compromising their lifestyle. SUMMARY: Although HHD in Japan has a long history, the 529 dialysis patients being treated with HHD as of the end of 2014 account for only 0.17% of all dialysis patients. HHD is well indicated for patients who are younger, male, and nondiabetic. The major HHD dialysis programs were provided 4-6 times per week for 3-5 h per session, and 79.3% of HDD patients showed treatment adequacy with a hemodialysis product >72. Key Messages: To expand HHD in Japan, several challenges must be overcome. First, the government should clearly state that home medicine is the way forward and incentivize facilities to provide, and patients to receive, HHD. Second, we need to establish a typical business model for HHD to include the supply of medical devices, collection of disposals, and development of a special machine for HHD.

UVB Exposure Prevents Atherosclerosis by Regulating Immunoinflammatory Responses.

OBJECTIVE: UVB irradiation is an established treatment for immunoinflammatory cutaneous disorders and has been shown to suppress cutaneous and systemic inflammatory diseases through modulation of the adaptive immune response. However, it remains unknown whether UVB irradiation prevents an immunoinflammatory disease of arteries such as atherosclerosis. APPROACH AND RESULTS: Here, we show that UVB exposure inhibits the development and progression of atherosclerosis in atherosclerosis-prone mice by expanding and enhancing the functional capacity of CD4+ forkhead box P3+ regulatory T cells and regulating proatherogenic T-cell responses. Experimental studies in Langerhans cell-depleted mice revealed that epidermal Langerhans cells play a critical role in UVB-dependent induction of CD4+ forkhead box P3+ regulatory T cells, suppression of proatherogenic T-cell responses, and prevention of atherosclerotic plaque development. CONCLUSIONS: Our findings suggest the skin immune system as a novel therapeutic target for atherosclerosis and provide a novel strategy for the treatment and prevention of atherosclerosis.

The present status of and perspectives on home hemodialysis therapy in Japan.

Home hemodialysis (HHD) is one of the best choices for improving the quality of life and survival rate of dialysis patients because it can lead to longer and more frequent dialysis programs to aid in achieving adequate dialysis. There were 461 dialysis patients treated with HHD as of the end of 2013 in Japan, comprising only 0.1% of all dialysis patients in this country. Although this is a very small expansion rate, the number of HHD patients has been rapidly increasing in recent years. The Japanese Society for Home Hemodialysis was established in 1998 and formed the following 3 working groups to survey various problems underlying current HHD: Patient Registry, Supply and Waste, and Self-pay Burden. In order to achieve a successful HHD program in Japan, there are several issues to be resolved, including the development of standard recruitment and education programs, optimization of the composition of dialysis fluid, sufficient reimbursement for HHD, and the establishment of a business model for HHD similar to that for peritoneal dialysis.

Evaluation of a pseudo-one-compartment model for phosphorus kinetics by later-phase dialysate collection during blood purification.

PURPOSE: Phosphorus removal is a major issue to assess for physicians engaging in hemodialysis. A pseudo-one-compartment model was reported as a novel model for phosphorus kinetics. We aimed to evaluate the adequacy of this model from the standpoint of the total mass of removed phosphorus during prolonged treatment. METHODS: Dialysate was collected during 6-h hemodialysis and hemodiafiltration treatment in 5 patients. Later-phase (from 4 to 6 h) dialysate was collected separately. Mobilization clearance (K(m)) and dialyzer clearance (K) were calculated by simple arithmetic operations utilizing stable serum phosphorus concentrations in this later phase. Volume of the accessible compartment (V(0)) was estimated by a fitting method. Amounts of removed phosphorus were calculated with these parameters and compared with measured values. The best sampling time points during treatment were also assessed, when the parameters were determined by serial serum phosphorus concentrations alone. RESULTS: Pearson's correlation coefficient (R) between calculated and measured values of removed phosphorus was 0.991 and the concordance correlation coefficient (ρ) was 0.987. When K(m), K and V(0) were determined by serial serum concentrations alone, including those at 0, 1, 4, and 6 h, the calculated mass of removed phosphorus had high R (0.974-0.975) or ρ (0.966-0.972) with the measured values. CONCLUSIONS: We confirmed that a pseudo-one-compartment model is useful for the estimation of removed phosphorus mass during prolonged blood purification by collecting dialysate. When the parameters are determined by a fitting method using serial serum concentrations alone, sampling at 0, 1, 4, and 6 h seems to be adequate.

Foxp3+ regulatory T cells play a protective role in angiotensin II-induced aortic aneurysm formation in mice.

Although regulatory T cells (Tregs) have been shown to play a protective role in abdominal aortic aneurysm (AAA) formation, it remains unclear whether expansion of endogenous Foxp3(+) Tregs prevents AAA. In the current study, we determined the effects of endogenous Foxp3(+) Treg expansion or depletion in an experimental model of AAA. We continuously infused 12-week-old apolipoprotein E-deficient mice fed a high-cholesterol diet with angiotensin II (n=60) or normal saline (n=12) by implanting osmotic mini-pumps and evaluated AAA formation at 16 weeks. The angiotensin II-infused mice received interleukin-2/anti-interleukin-2 monoclonal antibody complex (interleukin-2 complex; n=31) or PBS (n=29). Eighty-one percent of angiotensin II-infused mice developed AAA, with 42% mortality possibly because of aneurysm rupture. Interleukin-2 complex treatment systemically increased the number of Foxp3(+) Tregs and significantly decreased the incidence (52%) and mortality (17%) of AAA. Immunohistochemical analysis showed reduced accumulation of macrophages and increased numbers of Foxp3(+) Tregs in aneurysmal tissues, suggesting that expansion of Tregs may suppress local inflammation in the vessel wall and provide protection against AAA formation. Furthermore, genetic depletion of Foxp3(+) Tregs led to a significant increase in the mortality of AAA, suggesting the protective role of Foxp3(+) Tregs against AAA. Our findings suggest that Foxp3(+) Tregs may play a protective role in AAA formation and that promotion of an endogenous regulatory immune response may be a potentially valuable therapeutic approach for preventing AAA.

CD3 antibody and IL-2 complex combination therapy inhibits atherosclerosis by augmenting a regulatory immune response.

BACKGROUND: Accumulating evidence suggests that the balance between pathogenic effector T cells (Teffs) and regulatory T cells (Tregs) may be important for controlling atherosclerotic disease. We hypothesized that a combination therapy with anti-CD3 antibody (CD3-Ab) and IL-2/anti-IL-2 monoclonal antibody complex (IL-2 complex) aimed at increasing the ratio of Tregs to Teffs would effectively inhibit atherosclerosis in mice. METHODS AND RESULTS: We treated apolipoprotein E-deficient mice fed a high-cholesterol diet with vehicle, CD3-Ab, IL-2 complex, or their combination. Mice receiving the combination therapy had markedly reduced atherosclerotic lesions than mice treated with CD3-Ab or IL-2 complex alone. In addition, a striking increase in the Treg/Teff ratio of lymphoid organs and atherosclerotic lesions, along with plaque stabilization characterized by decreased macrophage content and increased collagen content was observed. The combination treatment also markedly reduced splenic Ly6C(high) inflammatory monocytes and might induce a favorable macrophage phenotype change in atherosclerotic lesions. CONCLUSIONS: Our results indicate that in addition to suppressing Teff responses, enhancing Treg-mediated immune responses is more efficacious in preventing atherosclerosis, suggesting a novel therapeutic approach for atherosclerosis.

Regression of atherosclerosis with anti-CD3 antibody via augmenting a regulatory T-cell response in mice.

AIMS: Although recent animal studies have investigated the cellular and molecular mechanisms underlying the process of atherosclerosis regression, it remains unknown whether adaptive immune responses including T cells are involved in this process. We investigated the role of T cells in atherosclerosis regression. METHODS AND RESULTS: LDL receptor-deficient mice were fed a high-cholesterol diet for 8 weeks to form atherosclerotic lesions and were then changed to a standard diet, and atherosclerosis was assessed 4 weeks later. Just before changing the diet, the mice received an iv injection of anti-CD3 antibody (CD3-Ab) or control immunoglobulin G for 5 consecutive days. CD3-Ab treatment regressed atherosclerosis and decreased the accumulation of macrophages and CD4(+) T cells in the plaques. CD3-Ab treatment also dramatically reduced CD4(+) T cells and increased the proportion of regulatory T cells (Tregs). Depletion of Tregs by anti-CD25 antibody injection abolished the regression of atherosclerosis seen in CD3-Ab-treated mice, indicating the essential role for Tregs in this process. CONCLUSION: CD3-Ab treatment induced rapid regression of established atherosclerosis via reducing CD4(+) T cells and increasing the proportion of Tregs. These findings suggest that therapeutic intervention for T-cell-mediated immune responses may represent a novel strategy to induce atherosclerosis regression in combination with lipid-lowering therapy.

Overnight home hemodialysis: eight patients and six years of experience in Sakairumi clinics.

We started our home hemodialysis (HHD) program in July 2005 and have been promoting overnight HHD. As more than 6 years have passed since we started our HHD program, we review our HHD program and 8 overnight HHD patients (5 males and 3 females). Their underlying disease differs in each and none have diabetic nephropathy. Their average age was 49.2 ± 6.0 years (mean ± SD). Average duration of dialysis treatment, HHD, and overnight HHD was 9.4 ± 4.4, 3.5 ± 2.4, and 2.2 ± 1.7 years, respectively. Average treatment time per dialysis session was 6.9 ± 0.8 h/treatment, average treatment days weekly was 4.5 ± 0.8 days/week, and average treatment time weekly was 31.2 ± 7.0 h/week. Laboratory data were good and their blood pressure was well controlled without any antihypertensive drugs excluding a patient who was recently introduced to dialysis with some residual kidney function. Severe problems did not occur in these 6 years except for blood access infection twice, slipping out of a needle during dialysis with small blood loss once, and a drop in blood pressure at the end of dialysis once, which was recovered by her assistant's help. According to our HHD training program, the average training duration for HHD was 106 ± 42 days. The shortest was 60 days and longest 198 days. These differences among training durations might be because of the frequency of training and having a better hand of puncturing. We did not instruct any additional issues and points for overnight HHD, because performing overnight HHD is similar to standard HHD. Some patients moved to overnight HHD slowly starting with once weekly and the others started overnight HHD several days after they had started HHD.

Orally administered eicosapentaenoic acid induces rapid regression of atherosclerosis via modulating the phenotype of dendritic cells in LDL receptor-deficient mice.

OBJECTIVE: Eicosapentaenoic acid (EPA) has been shown to have beneficial effects on cardiovascular diseases, although the precise mechanism is unknown. We investigated the effect of EPA on the regression of atherosclerosis. METHODS AND RESULTS: LDL-receptor-deficient mice were fed a high-cholesterol diet for 8 weeks to build up aortic sinus atherosclerotic lesions and then were fed a normal diet with or without 5% EPA for 4 weeks. Atherosclerotic lesions were histologically assessed, and immunologic assays were performed. EPA treatment significantly regressed atherosclerosis (-22.7%, P<0.05) and decreased the content of macrophages, CD4(+) T cells, and dendritic cells (DCs) in atherosclerotic lesions, though only changing the chow never induced the regression. Flow cytometric analysis revealed that EPA increased immature DCs (CD11c(+) CD80(-) CD86(-)), increased the indoleamine 2,3-dioxygenase (IDO) in DCs, and decreased the number of CD4(+) T cells. In the presence of the IDO inhibitor, the beneficial effects of EPA on regression were inhibited, suggesting that the effect of EPA was mainly mediated through IDO. CONCLUSIONS: In addition to lowering plasma cholesterol, EPA regressed atherosclerosis probably due to modulation of DC phenotype and reduction in T cell numbers. The present findings might partly explain the beneficial effects of EPA in clinics and support clinical evidence.

Uremic toxins and oral adsorbents.

Uremic toxins are associated with various disorders in patients with end-stage renal disease and it is difficult to remove some of these toxins by dialysis. Since some uremic toxins are generated by bacterial metabolites in the colon, oral adsorbents that interfere with the absorption of uremic toxins or their precursors are believed to prevent their accumulation in the body. AST-120 adsorbs various uremic retention solutes in the gastrointestinal system and has potential for providing clinical benefit. Sevelamer hydrochloride binds some harmful compounds in addition to phosphate and seems to have pleiotropic effects that include lowering serum LDL cholesterol levels and reduction of inflammation. The effect of sevelamer hydrochloride on indoxyl sulfate and p-cresol has been shown in an in vitro study; however, in vivo studies in mice or humans did not demonstrate this effect on protein-binding uremic toxins. Oral adsorbents are thus one of the important modalities in the treatment of uremic syndrome.

Oral administration of an active form of vitamin D3 (calcitriol) decreases atherosclerosis in mice by inducing regulatory T cells and immature dendritic cells with tolerogenic functions.

OBJECTIVE: To determine whether the administration of an active form of vitamin D(3) (calcitriol) could prevent atherosclerosis through anti-inflammatory actions. METHODS AND RESULTS: Recent clinical studies have shown that lack of vitamin D(3) is a risk factor for cardiovascular events. Oral calcitriol administration decreased atherosclerotic lesions, macrophage accumulation, and CD4(+) T-cell infiltration at the aortic sinus, when compared with the corresponding observations in control mice. We observed a significant increase in Foxp3(+) regulatory T cells and a decrease in CD80(+)CD86(+) dendritic cells (DCs) in the mesenteric lymph nodes, spleen, and atherosclerotic lesions in oral calcitriol-treated mice in association with increased interleukin 10 and decreased interleukin 12 mRNA expression. CD11c(+) DCs from the calcitriol group showed reduced proliferative activity of T lymphocytes, suggesting the suppression of DC maturation. Neutralization of CD25 in vivo revealed that calcitriol inhibited atherosclerosis mainly in a regulatory T cell-dependent manner but also partly because of a decrease in DC maturation. CONCLUSIONS: Oral calcitriol treatment could prevent the development of atherosclerosis by changing the function or differentiation of DCs and regulatory T cells. These findings suggest that intestinal and systemic immune modulation by calcitriol may be a potentially valuable therapeutic approach against atherosclerosis.

Depressed expression of Klotho and FGF receptor 1 in hyperplastic parathyroid glands from uremic patients.

Fibroblast growth factor 23 (FGF23) exerts its effect by binding to its cognate FGF receptor 1 (FGFR1) in the presence of its co-receptor Klotho. Parathyroid glands express both FGFR1 and Klotho, and FGF23 decreases parathyroid hormone gene expression and hormone secretion directly. In uremic patients with secondary hyperparathyroidism (SHPT), however, parathyroid hormone secretion remains elevated despite extremely high FGF23 levels. To determine the mechanism of this resistance, we measured the expression of Klotho, FGFR1, and the proliferative marker Ki67 in 7 normal and 80 hyperplastic parathyroid glands from uremic patients by immunohistochemistry. All uremic patients had severe SHPT along with markedly high FGF23 levels. Quantitative real-time reverse transcription PCR showed that the mRNA levels for Klotho and FGFR1correlated significantly with their semi-quantitative immunohistochemical intensity. Compared with normal tissue, the immunohistochemical expression of Klotho and FGFR1 decreased, but Ki67 expression increased significantly in hyperplastic parathyroid glands, particularly in glands with nodular hyperplasia. These results suggest that the depressed expression of the Klotho-FGFR1 complex in hyperplastic glands underlies the pathogenesis of SHPT and its resistance to extremely high FGF23 levels in uremic patients.

Torsades de Pointes with QT prolongation related to donepezil use.

An 83-year-old female, who had a history of anterior myocardial infarction, was treated for Alzheimer's disease with donepezil. She suffered from repeated diarrhea and vomiting, and experienced syncope. She was admitted to our hospital and was diagnosed with acute colitis and syncope. On admission, her heart rate was 54 beats/min with regular rhythm. Laboratory data showed a low plasma potassium level. Electrocardiogram (ECG) showed poor R progression, ST elevation, negative T in precordial leads, and marked QT prolongation. Transthoracic echocardiogram showed the enlargement of the left atrium and aneurysmal area at the apex. Torsades de Pointes (TdP) with syncope and convulsion were confirmed on ECG monitoring twice after admission. We treated her with potassium chloride and started magnesium sulfate and lidocaine, and then added isoprenaline injection. After these treatments, her heart rate increased and we did not detect TdP again. With the aging population in Japan, prescriptions for donepezil are increasing. We have to be vigilant for syncope in patients taking donepezil, which is possibly related to QT prolongation and TdP.

Usefulness of transesophageal echocardiographic observation during chemotherapy for cardiac metastasis of non-Hodgkin lymphoma complicated with left ventricular diastolic collapse.

A 53-year-old man, who had been treated for penile origin diffuse large B cell type non-Hodgkin lymphoma (NHL), suffered from right femoral pain and dyspnea. Positron emission tomography (PET) revealed abnormal accumulation in his right femur and cardiac segments. Transthoracic echocardiography revealed massive localized pericardial effusion with the collapse of both ventricles and the mass-like echo in the left atrium. We performed emergent pericardiocentesis and diagnosed this case as a recurrence of NHL with cardiac metastasis. With the use of transesophageal echocardiography (TEE), we confirmed the mass-like echo around the inter-atrial septum, which directly invaded to the aortic ring and the right atrial wall. In order to evaluate the effect of chemotherapy, we performed TEE and observed the precise changes of intra-cardiac tumor size. With the use of TEE monitoring, we could select the appropriate chemotherapeutic regimen, and the tumor became smaller and finally diminished. The femoral accumulation detected by PET also disappeared. We experienced a case of cardiac metastasis of NHL complicated with left ventricular diastolic collapse due to the massive localized pericardial effusion. TEE is a useful tool to evaluate precisely the efficacy of chemotherapy for intra-cardiac tumors.

Mitral regurgitation resulting from the consecutive multiple perforations by infective endocarditis mimicking the isolated anterior mitral cleft.

A 60-year-old man, suffering from sustained cough and dyspnea on effort, was diagnosed as congestive heart failure. He did not yield the history of having fever or other inflammatory events. His physical examination disclosed a pan-systolic murmur at the apex. Transthoracic color Doppler echocardiography showed moderate to severe mitral regurgitation originated from the linear tear of the anterior mitral leaflet. The tear reached to the mid-portion of the leaflet just within the postero-medial commissure and the regurgitant flow convergence was not hemispheric, but box-like shaped, suggesting that the linear tear was the isolated mitral cleft. Transesophageal echocardiography showed the almost same findings and we found no other anomalies. Surgical treatment was selected to repair the mitral regurgitation. Under operation, we found three consecutive perforations located linearly in the anterior mitral leaflet. The mitral valve replaced with the prosthetic one. The pathological examination of the resected valve showed mucinous degeneration of the chordae tendineae and fibrinoid change without inflammatory cellular infiltration. These findings were compatible with the healed infective endocarditis. Here we experienced a curious case of mitral regurgitation, caused by consecutive three mitral perforations mimicking the isolated anterior mitral cleft.

Effects of systemic and central nervous system localized inflammation on the contributions of metabolic precursors to the L-kynurenine and quinolinic acid pools in brain.

L-Kynurenine and quinolinic acid are neuroactive L-tryptophan-kynurenine pathway metabolites of potential importance in pathogenesis and treatment of neurologic disease. To identify precursors of these metabolites in brain, [(2)H(3) ]-L-kynurenine was infused subcutaneously by osmotic pump into three groups of gerbils: controls, CNS-localized immune-activated, and systemically immune-activated. The specific activity of L-kynurenine and quinolinate in blood, brain and systemic tissues at equilibrium was then quantified by mass spectrometry and the results applied to a model of metabolism to differentiate the relative contributions of various metabolic precursors. In control gerbils, 22% of L-kynurenine in brain was derived via local synthesis from L-tryptophan/formylkynurenine versus 78% from L-kynurenine from blood. Quinolinate in brain was derived from several sources, including: local tissue L-tryptophan/formylkynurenine (10%), blood L-kynurenine (35%), blood 3-hydroxykynurenine/3-hydroxyanthranilate (7%), and blood quinolinate (48%). After systemic immune-activation, however, L-kynurenine in brain was derived exclusively from blood, whereas quinolinate in brain was derived from three sources: blood L-kynurenine (52%), blood 3-hydroxykynurenine or 3-hydroxyanthranilate (8%), and blood quinolinate (40%). During CNS-localized immune activation, > 98% of both L-kynurenine and quinolinate were derived via local synthesis in brain. Thus, immune activation and its site determine the sources from which L-kynurenine and quinolinate are synthesized in brain. Successful therapeutic modulation of their concentrations must take into account the metabolic and compartment sources.