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Most studies on vaccines of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have focused on antibody, but cellular immunities are also critical. We aimed to evaluate the immune reactions of hemodialysis (HD) patients after the administration of the booster dose from the perspective of both humoral and cellular immunities. Hemodialysis patients (HD group) and age- and sex-matched non-dialysis individuals (control group) receiving three doses of BNT162b2 vaccine were measured for anti-SARS-CoV-2 immunoglobulin (IgG) and T-SPOTⓇ.COVID test (T-SPOT) before, 3 weeks, and 3 months after the booster dose. The HD group had significantly higher SARS-CoV-2 IgG levels 3 weeks and 3 months after the booster dose than the control group, although both groups had no difference in SARS-CoV-2 IgG levels before the booster dose. Moreover, the HD group had significantly higher T-SPOT levels before and 3 weeks after the booster dose than the control group, but the difference was not significantly different 3 months after the booster dose. Furthermore, the incidence rates of local and systemic adverse reactions were significantly higher in the HD group than in the control group. HD patients obtained higher SARS-CoV-2 IgG levels and SARS-COV-2-specific T-cell responses after the booster dose than control.

Approximately 10 years have passed since the Peritoneal Dialysis Guidelines were formulated in 2009. Much evidence has been reported during the succeeding years, which were not taken into consideration in the previous guidelines, e.g., the next peritoneal dialysis PD trial of encapsulating peritoneal sclerosis (EPS) in Japan, the significance of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs), the effects of icodextrin solution, new developments in peritoneal pathology, and a new international recommendation on a proposal for exit-site management. It is essential to incorporate these new developments into the new clinical practice guidelines. Meanwhile, the process of creating such guidelines has changed dramatically worldwide and differs from the process of creating what were “clinical practice guides.” For this revision, we not only conducted systematic reviews using global standard methods but also decided to adopt a two-part structure to create a reference tool, which could be used widely by the society’s members attending a variety of patients. Through a working group consensus, it was decided that Part 1 would present conventional descriptions and Part 2 would pose clinical questions (CQs) in a systematic review format. Thus, Part 1 vastly covers PD that would satisfy the requirements of the members of the Japanese Society for Dialysis Therapy (JSDT). This article is the duplicated publication from the Japanese version of the guidelines and has been reproduced with permission from the JSDT.

A 65-year-old man with valvular disorder presented to his physician because of widespread purpura in both lower extremities. Blood tests showed elevated serum creatinine levels and proteinase 3-anti-neutrophil cytoplasmic antibody (ANCA) with hematuria, suggesting ANCA-related rapidly progressive glomerulonephritis (RPGN). Although multiple blood cultures were negative, transthoracic echocardiography revealed warts in the valves, and a renal biopsy also showed findings of glomerular infiltration by mononuclear leukocytes and C3 deposition in the glomeruli, suggesting infection-related glomerulonephritis. Later, Bartonella antibody turned positive. Antimicrobial treatment improved the purpura and renal function without any recurrence. ANCA-positive RPGN requires the exclusion of infective endocarditis, especially that induced by Bartonella spp.

This study compared the outcomes of dialysis patients who received SARS-CoV-2 vaccine with those who did not use data from the Japanese COVID-19 registry.A total of 1260 dialysis patients with confirmed positive SARS-CoV-2 infection was included in this study. Patients were divided into two groups: patients who experienced breakthrough infection and those who were unvaccinated. The need of oxygen supplementation and mortality risks were compared using multivariate logistic regression analysis.The mortality rate was 24.2% in unvaccinated patients and 8.6% in breakthrough patients. The odds ratio of need of oxygen supplementation in the breakthrough patients relative to unvaccinated patients was 0.197. The hazard ratio of mortality in the breakthrough patients relative to unvaccinated patients was 0.464.Our prospective observational study showed that SRAS-CoV-2 vaccination in hemodialysis patients is vital for reducing need of oxygen supplementation and mortality risk.

Background Cyclosporine A (CsA) is an essential immunosuppressant in organ transplantation. However, its chronic nephrotoxicity is an obstacle to long allograft survival that has not been overcome. Nuclear factor-κB (NF-κB) is activated in the renal tissue in CsA nephropathy. In this study, we aimed to investigate the effect of the specific NF-κB inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ), in a rat model of CsA nephrotoxicity. Methods We administered CsA (15 mg/kg) daily for 28 days to Sprague-Dawley rats that underwent 5/6 nephrectomy under a low-salt diet. We administered DHMEQ (8 mg/kg) simultaneously with CsA to the treatment group, daily for 28 days and evaluated its effect on CsA nephrotoxicity. Results DHMEQ significantly inhibited NF-κB activation and nuclear translocation due to CsA treatment. Elevated serum urea nitrogen and creatinine levels due to repeated CsA administration were significantly decreased by DHMEQ treatment (serum urea nitrogen in CsA + DHMEQ vs CsA vs control, 69 ± 6.4 vs 113.5 ± 8.8 vs 43.1 ± 1.1 mg/dL, respectively, p Conclusions These findings suggest that DHMEQ treatment in combination therapy with CsA-based immunosuppression is beneficial to prevent the development of CsA-induced nephrotoxicity.

Background and Objectives Topiroxostat, a selective xanthine oxidoreductase inhibitor, is used for the management of hyperuricemic patients with or without gout in Japan. Accumulating evidence has demonstrated the efficacy of topiroxostat for the treatment of hyperuricemia with or without gout. However, the safety and efficacy of topiroxostat in the clinical setting remain unclear, and there is little large-scale clinical evidence. We conducted a post-marketing observational study over 54 weeks. Patients and Methods Patients were centrally enrolled, and case report forms of 4491 patients were collected between April 2014 and March 2019 from 825 medical sites. Results Overall, 4329 patients were assessed for safety and 4253 patients for effectiveness. The overall incidence of adverse drug reactions was 6.95%, and the incidence rates of adverse drug reactions of gouty arthritis, hepatic dysfunction, and skin disorders, which are of special interest in this study, were 0.79%, 1.73%, and 0.95%, respectively. No case of serious gouty arthritis was observed. Serum urate levels decreased stably over time and showed a significant reduction rate at 54 weeks (21.19% ± 22.07%) and on the final visit (19.91% ± 23.35%) compared to the baseline. The rates for subjects who achieved serum uric acid levels ≤ 6.0 mg/dL at 18 and 54 weeks after administration were 43.80% and 48.28%, respectively. Conclusions This study suggests that there is no particular concern about adverse drug reactions or the efficacy of topiroxostat for hyperuricemic patients with or without gout in a post-marketing setting in Japan. Electronic supplementary material The online version of this article (10.1007/s40261-020-00941-3) contains supplementary material, which is available to authorized users.

Although combined therapy with peritoneal dialysis (PD) and hemodialysis (HD) is widespread in Japan, its clinical utility has been reported only in retrospective or before-and-after test lacking a control group.We conducted a prospective, multicenter, observational cohort study of 176 incident PD patients and compared patient survival and changes in clinical parameters between patients on different dialysis modalities.During a median follow-up of 41 months, 47 patients transferred to combined therapy and 35 patients transferred directly to HD. Patients transferred to combined therapy had a significantly better survival than those transferred directly to HD. However, we could not establish this difference in a multivariate analysis because only six patients died among these groups. The decreases in urea nitrogen and serum creatinine were more prominent among patients directly transferred to HD.This is the first report revealing clinical feasibility of transfer to combined therapy for PD patients.

Background This article is a duplicated publication from the Japanese version of “2019 JSDT Guidelines for Peritoneal Dialysis” with permission from the Japanese Society for Dialysis Therapy (JSDT). This clinical practice guideline (CPG) was developed primarily by the Working Group on Revision of Peritoneal Dialysis (PD) Guidelines of the Japanese Society for Dialysis Therapy. Recently, the definition and creation process for CPGs have become far more rigorous; traditional methods and formats no longer adhere to current standards. To improve the reliability of international transmission of our findings, CPGs are created in compliance with the methodologies developed by the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) working group. Part 2 of this PD guideline is the first CPG developed by our society that conforms to the GRADE approach. Methods Detailed processes were created in accordance with the Cochrane handbook and the GRADE approach developed by the GRADE working group. Results Clinical question (CQ)1: Is the use of renin-angiotensin system inhibitors (RAS inhibitors), such as angiotensin-converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB), effective in PD patients? Recommendation: We suggest the usage of RAS inhibitors (ACEI and ARB) in PD patients (GRADE 2C). CQ2: Icodextrin or glucose solution: which is more useful as a dialysate among patients with PD? Recommendation: We suggest using icodextrin when managing body fluids in PD patients (GRADE 2C). CQ3: Is it better to apply or not apply mupirocin/gentamicin ointment to the exit site? Recommendation: We suggest not applying mupirocin/gentamicin ointment to the exit sites of PD patients (GRADE 2C). CQ4: Which surgical approach is more desirable when a PD catheter is placed, open surgery or laparoscopic surgery? No recommendation. CQ5: Which administration route of antibiotics is better in PD patients with peritonitis, intravenous or intraperitoneal? Recommendation: We suggest intraperitoneal administration of antibiotics in PD patients with peritonitis (GRADE 2C). Note: The National Insurance does not currently cover intraperitoneal administration. CQ6: Is peritoneal dialysis or hemodialysis better as the first renal replacement therapy in diabetic patients? No recommendation. Conclusions In the future, we suggest that society members construct their own evidence to answer CQs not brought up in this guideline, and thereby show the achievements of Japan worldwide.

Hemofiltration removes water and small molecules from the blood via nanoporous filtering membranes. This paper discusses a pump-free hemofiltration device driven by the pressure difference between the artery and the vein. In the design of the filtering device, oncotic pressure needs to be taken into consideration. Transmembrane pressure (TMP) determines the amount and direction of hemofiltration, which is calculated by subtracting the oncotic pressure from the blood pressure. Blood pressure decreases as the channels progress from the inlet to the outlet, while oncotic pressure increases slightly since no protein is removed from the blood to the filtrate in hemofiltration. When TMP is negative, the filtrate returns to the blood, i.e., backfiltration takes place. A small region of the device with negative TMP would thus result in a small amount of or even zero filtrates. First, we investigated this phenomenon using in vitro experiments. We then designed a hemofiltration system taking backfiltration into consideration. We divided the device into two parts. In the first part, the device has channels for the blood and filtrate with a nanoporous membrane. In the second part, the device does not have channels for filtration. This design ensures TMP is always positive in the first part and prevents backfiltration. The concept was verified using in vitro experiments and ex vivo experiments in beagle dogs. Given the simplicity of the device without pumps or electrical components, the proposed pump-free hemofiltration device may prove useful for either implantable or wearable hemofiltration.

Background The effects of pharmacological blood-pressure-lowering on cardiovascular outcomes in individuals aged 70 years and older, particularly when blood pressure is not substantially increased, is uncertain. We compared the effects of blood-pressure-lowering treatment on the risk of major cardiovascular events in groups of patients stratified by age and blood pressure at baseline. Methods We did a meta-analysis using individual participant-level data from randomised controlled trials of pharmacological blood-pressure-lowering versus placebo or other classes of blood-pressure-lowering medications, or between more versus less intensive treatment strategies, which had at least 1000 persons-years of follow-up in each treatment group. Participants with previous history of heart failure were excluded. Data were obtained from the Blood Pressure Lowering Treatment Triallists' Collaboration. We pooled the data and categorised participants into baseline age groups (Findings We included data from 358 707 participants from 51 randomised clinical trials. The age of participants at randomisation ranged from 21 years to 105 years (median 65 years [IQR 59–75]), with 42 960 (12·0%) participants younger than 55 years, 128 437 (35·8%) aged 55–64 years, 128 506 (35·8%) 65–74 years, 54 016 (15·1%) 75–84 years, and 4788 (1·3%) 85 years and older. The hazard ratios for the risk of major cardiovascular events per 5 mm Hg reduction in systolic blood pressure for each age group were 0·82 (95% CI 0·76–0·88) in individuals younger than 55 years, 0·91 (0·88–0·95) in those aged 55–64 years, 0·91 (0·88–0·95) in those aged 65–74 years, 0·91 (0·87–0·96) in those aged 75–84 years, and 0·99 (0·87–1·12) in those aged 85 years and older (adjusted pinteraction=0·050). Similar patterns of proportional risk reductions were observed for a 3 mm Hg reduction in diastolic blood pressure. Absolute risk reductions for major cardiovascular events varied by age and were larger in older groups (adjusted pinteraction=0·024). We did not find evidence for any clinically meaningful heterogeneity of relative treatment effects across different baseline blood pressure categories in any age group. Interpretation Pharmacological blood pressure reduction is effective into old age, with no evidence that relative risk reductions for prevention of major cardiovascular events vary by systolic or diastolic blood pressure levels at randomisation, down to less than 120/70 mm Hg. Pharmacological blood pressure reduction should, therefore, be considered an important treatment option regardless of age, with the removal of age-related blood-pressure thresholds from international guidelines. Funding British Heart Foundation, National Institute of Health Research Oxford Biomedical Research Centre, Oxford Martin School.

Although Na+ homeostasis in vivo is essential for mammals, it is known that excessive salt (NaCl) intake has played a major role in the development of hypertension. In vivo, there is a hormonal system, the renin-angiotensin-aldosterone system (RAAS), that specializes in regulating Na+ retention, especially the amount of Na+ in plasma. Na+ homeostasis in vivo has been achieved mainly by the RAAS, through regulation of vascular tonus (blood pressure) and Na+ handling in the kidney (Na+ diuresis). Recent studies have revealed a third mechanism of Na+ homeostasis in vivo: regulation of interstitial Na+ levels in tissues, such as subcutaneous tissues, by tissue macrophage immunity. In the pathogenesis of salt-sensitive hypertension, Recent research have been revealed that three molecular axes (Ang II - Rho/NOX-eNOS system, Aldosterone-rac1 -ENaC system, and tissue Na+ − TonEBP in macrophage -VEGF-c) are significantly involved in maintaining Na+ homeostasis in salt induced hypertension. Furthermore, the mechanism by which salt causes hypertension via the immune system (intestinal, local mucosal, and tissue immunity) has also been reported. In this article, we would like to propose that three molecular dysfunctions are involved in the development of salt-sensitive hypertension through three immunological mechanisms in the maintenance of Na+ homeostasis. Next, I would like to explain the importance of gut-RAAS and abnormality of intestinal microflora (dysbiosis) in salt-sensitive hypertension. It has been known that the metabolites (e.g., short-chain fatty acid neural amino) produced by microflora are deeply involved in central (CNS) and sympathetic nervous system (SNS) activity. In addition, we would like to explain of the importance of brain-RAAS and cerebral inflammation in salt-sensitive hypertension. Moreover, recent research have revealed that the detection-mechanism in the brain for Na+ concentration([Na+]) in vivo and in the tongue for [Na+] in diet. These finding suggests that excessive salt intake may cause brain dysfunction, most delicate organ, before the onset of salt sensitive hypertension, and may also destroy brain structure after the onset of salt sensitive hypertension. Thus, we would like to insist that excessive salt intake might not only induce hypertension, but also be toxic especially for brain. Finally, we would like to explain that The DASH diet (Dietary Approaches to Stop Hypertension) is one of the universal diets for adult human, not only by reducing salt, but also by reducing metabolic stress and improving of dysbiosis.

Background The effects of pharmacological blood pressure lowering at normal or high-normal blood pressure ranges in people with or without pre-existing cardiovascular disease remains uncertain. We analysed individual participant data from randomised trials to investigate the effects of blood pressure lowering treatment on the risk of major cardiovascular events by baseline levels of systolic blood pressure. Methods We did a meta-analysis of individual participant-level data from 48 randomised trials of pharmacological blood pressure lowering medications versus placebo or other classes of blood pressure-lowering medications, or between more versus less intensive treatment regimens, which had at least 1000 persons-years of follow-up in each group. Trials exclusively done with participants with heart failure or short-term interventions in participants with acute myocardial infarction or other acute settings were excluded. Data from 51 studies published between 1972 and 2013 were obtained by the Blood Pressure Lowering Treatment Trialists' Collaboration (Oxford University, Oxford, UK). We pooled the data to investigate the stratified effects of blood pressure-lowering treatment in participants with and without prevalent cardiovascular disease (ie, any reports of stroke, myocardial infarction, or ischaemic heart disease before randomisation), overall and across seven systolic blood pressure categories (ranging from

Previous studies showed that microRNA-29b (miR-29b) inhibits renal fibrosis. Therefore, miR-29b replacement therapy represents a promising approach for treating renal fibrosis. However, an efficient method of kidney-targeted miRNA delivery has yet to be established. Recombinant adeno-associated virus (rAAV) vectors have great potential for clinical application. For kidney-targeted gene delivery, the most suitable AAV serotype has yet to be established. Here, we identified the most suitable AAV serotype for kidney-targeted gene delivery and determined that AAV-mediated miR-29b delivery can suppress renal fibrosis in vivo. To determine which AAV serotype is suitable for kidney cells, GFP-positive cells were identified by flow cytometry after the infection of rAAV serotype 1–9 vectors containing the EGFP gene. Next, we injected rAAV vectors into the renal pelvis to determine transduction efficiency in vivo. GFP expression was measured seven days after injecting rAAV serotype 1–9 vectors carrying the EGFP gene. Finally, we investigated whether rAAV6-mediated miR-29b delivery can suppress renal fibrosis in UUO mouse model. We found that rAAV6 vector is the most suitable for targeting kidney cells regardless of animal species in vitro and rAAV6 is the most suitable vector for kidney-targeted in vivo gene delivery in mice. Intra-renal pelvic injection of rAAV vectors can transduce genes into kidney TECs. Furthermore, rAAV6-mediated miR-29b delivery attenuated renal fibrosis in UUO model by suppressing Snail1 expression. Our study has revealed that rAAV6 is the most suitable serotype for kidney-targeted gene delivery and rAAV6-mediated miR-29b delivery into kidney TECs can suppress established renal fibrosis.

Patients receiving dialysis therapy often have frailty, protein energy wasting, and sarcopenia. However, medical staff in Japan, except for registered dietitians, do not receive training in nutritional management at school or on the job. Moreover, registered dietitians work separately from patients and medical staff even inside a hospital, and there are many medical institutions that do not have registered dietitians. In such institutions, medical staff are required to manage patients’ nutritional disorders without assistance from a specialist. Recent studies have shown that salt intake should not be restricted under conditions of low nutrition in frail subjects or those undergoing dialysis, and protein consumption should be targeted at 0.9 to 1.2 g/kg/day. The Japanese Society of Dialysis Therapy suggests that the Nutritional Risk Index-Japanese Hemodialysis (NRI-JH) is a useful tool to screen for older patients with malnutrition.

Background. Combined therapy with peritoneal dialysis (PD) and hemodialysis (HD) represents a treatment option for PD patients who cannot maintain adequacy of dialysis. Although several reports have indicated the clinical utility of combined therapy, most such studies have been small-scale, single-centered, retrospective and before-and-after test investigations lacking a control group. Methods. We conducted a prospective, multicenter, observational cohort study of 176 incident PD patients and compared patient survival and time-course changes in clinical parameters between patients switched from PD alone to combined therapy and patients switched directly to HD. Results. During a median follow-up of 41 months, 47 patients transferred to combined therapy and 35 patients transferred directly to HD. Among patients transferred to combined therapy, 66% transferred because of inadequate dialysis, and/or fluid overload, compared to only 29% among patients directly transferred to HD. Five patients died after transfer to HD alone, whereas 1 patient died after transfer to combined therapy. Although mortality was greater among patients transferred to HD directly than among patients transferred to combined therapy, this difference disappeared after matching for fluid overload and/or inadequate dialysis.Conclusion. This is the first report comparing clinical outcomes for patients on PD alone transferred to combined therapy with those for patients directly transferred to HD. Although comparison of patient survival was difficult because of the small number of deaths, PD patients suffering from inadequate dialysis and/or volume overload could clearly continue PD therapy safely by switching to combined therapy. Further study with a larger number of outcomes is needed.

Hypertension is the most common complication of kidney disease, diabetes, and other cardiovascular diseases. In addition, it is a critical factor in the progression of these diseases, and hence, blood pressure management is highly recommended worldwide, in accordance with the major guidelines. However, there are two blind spots in the management system: one concerns patients with cancer, and the other concerns patients receiving renal replacement therapy. End-stage renal failure is the final stage of hypertension, and nephrologists usually treat hypertension in both nondialysis patients and dialysis patients. Nephrologists first attempt to manage the blood pressure of dialysis patients using the same method employed for nondialysis patients, i.e., by deciding on a target blood pressure at the clinic. However, this is exceedingly difficult because dialysis patients have lost their most important body-fluid autoregulatory mechanism and have varying body weights during the dialysis session. Moreover, numerous lines of evidence and clinicians' observations have suggested that hypotension during a dialysis session leads to an unfavorable prognosis. However, when the target blood pressure is increased to avoid hypotension during a dialysis session, the risk of atherosclerosis and bleeding complications will be increased. Many nephrologists may feel unsure of choosing a target blood pressure using traditional methods. Recently, home blood pressure and average blood pressure have become new indices of blood pressure management. We believe that further advancements of this old and important theme will be possible with new technologies and big-data analytical methods.

In Japan, the first case of COVID‐19 in dialysis patients was reported on March 1, 2020. A total of 31 cases were reported by April 10, and it increased to 95 by May 15. Thereafter, with the rapid increase in the number of COVID‐19 cases in the general population since late March, there was a not surprising increase in the number of COVID‐19 cases in dialysis patients. The mortality rate is 16.2% (16/99 cases) in dialysis patients, which is higher than 5.3% (874/16532 cases) in the general population. This higher mortality rate in dialysis patients with COVID‐19 might be related to their age; the majority of COVID‐19 cases are aged between 70 and 90 years in dialysis patients, compared with between 20 and 60 years in the general population. As COVID‐19 presents with severe symptoms and is associated with a high mortality rate in dialysis patients, dialysis patients who have contracted SARS‐CoV‐2 infection confirmed by polymerase chain reaction (PCR) testing are required to be hospitalized under Japanese government policy. In cases of COVID‐19 hospitalizations, it is essential to prevent nosocomial infection. Therefore, patients must be sufficiently instructed in infection prevention and robust measures to prevent contraction and spread of the infection must be taken at dialysis facilities. This article is protected by copyright. All rights reserved.

Recently, dialysis patients are often suffering from frailty, protein energy wasting, and sarcopenia. Nutritional intervention is one of the important treatments to these statuses. Japanese Society of Dialysis Therapy published the standard nutrition intake in dialysis patients, which basically indicated the minimum nutritional requirements to avoid the dialysis complication, such as calcification, atherosclerosis, hypotension during dialysis therapy. But, theoretically maximum nutritional intake is much larger than the standard intake. Indeed, 60 kg dialysis patients could take 12.6 g/day at maximum, according to the relationship between body weight increase between dialysis sessions and mortality. Moreover, recent improvement of phosphate binders and dialysis therapy itself enlarged the allowance of nutritional intake. Under these circumstances, more aggressive nutritional intervention had become available for dialysis patients. Nutritional intervention could improve not only protein energy wasting, but also sarcopenia, or frailty itself, because these three concepts measured the same condition that aged patients are fragile from another aspect. Dual intervention (nutritional intervention and exercise intervention) had reported to improve not only nutritional or physical factors, but also quality of life, which indicating that dual intervention could ameliorate frailty itself. Multiple interventions to Frailty including aggressive nutritional intervention are expected to improve the mortality of dialysis patients.