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Introduction: Immunosuppressed patients exhibit low antibody acquisition rates following severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) vaccination. Kidney transplant recipients previously exhibited low antibody acquisition rates after two vaccine doses, which increased after the third dose. We evaluated antibody titers of Japanese post‐kidney transplant patients after the fourth and fifth vaccinations. Methods: Antibody titers for SARS‐CoV‐2 spike protein were measured between 3 weeks and 3 months after the fourth or fifth vaccination. Results: Increased antibody acquisition rates were observed after the fourth (75.0% antibody‐positive) and fifth (81.5% antibody‐positive) vaccinations. The antibody‐acquired group after the fourth vaccination exhibited a higher body mass index and estimated glomerular filtration rate (eGFR) than the non‐acquired group. A higher eGFR was associated with antibody acquisition after the fifth vaccination. Conclusion: In Japanese post‐kidney transplant patients, the antibody acquisition rate increased with each vaccine additional dose. Additional vaccinations are recommended to protect against SARS‐CoV‐2 infection. [ABSTRACT FROM AUTHOR]

Millions of people worldwide with incurable end-stage lung disease die because of inadequate treatment options and limited availability of donor organs for lung transplantation.sup.1. Current bioengineering strategies to regenerate the lung have not been able to replicate its extraordinary cellular diversity and complex three-dimensional arrangement, which are indispensable for life-sustaining gas exchange.sup.2,3. Here we report the successful generation of functional lungs in mice through a conditional blastocyst complementation (CBC) approach that vacates a specific niche in chimeric hosts and allows for initiation of organogenesis by donor mouse pluripotent stem cells (PSCs). We show that wild-type donor PSCs rescued lung formation in genetically defective recipient mouse embryos unable to specify (due to Ctnnb1.sup.cnull mutation) or expand (due to Fgfr2.sup.cnull mutation) early respiratory endodermal progenitors. Rescued neonates survived into adulthood and had lungs functionally indistinguishable from those of wild-type littermates. Efficient chimera formation and lung complementation required newly developed culture conditions that maintained the developmental potential of the donor PSCs and were associated with global DNA hypomethylation and increased H4 histone acetylation. These results pave the way for the development of new strategies for generating lungs in large animals to enable modeling of human lung disease as well as cell-based therapeutic interventions.sup.4-6. Pluripotent stem cells can generate functional lungs when injected into blastocyst-stage mouse embryos, a step toward the goal of growing human lungs in large animals for disease modeling and therapeutic applications., Author(s): Munemasa Mori [sup.1] , Kazuhiro Furuhashi [sup.2] , Jennifer A. Danielsson [sup.3] , Yuichi Hirata [sup.2] , Miwako Kakiuchi [sup.2] , Chyuan-Sheng Lin [sup.4] , Mayu Ohta [sup.1] , [...]

Introduction: Simple plasma exchange (PE) with fresh‐frozen plasma replacement allows antibody removal for ABO‐incompatible living donor kidney transplantation, but is associated with a high incidence of allergic reactions. We developed, implemented, and evaluated a protocol for safe preoperative PE. Methods: The protocol comprised pretreatment (125 mg methylprednisolone infusion, 400 mg acetaminophen and 30 mg diphenhydramine orally) with a replacement fluid rate < 20 mL/min. Allergic reaction incidence was investigated in controls who underwent ABO‐incompatible living donor kidney transplantation between 2016 and March 2020 (group C) and patients who underwent the protocol and procedure between April 2020 and February 2023 (group N). Results: Ten (group C) and 19 (group N) patients performed 11 and 30 sessions of PE, respectively. Allergic reactions occurred in 81.8% and 36.7% (p = 0.014), respectively, with an odds ratio of the protocol was 0.056 (95% CI 0.0059–0.5380, P = 0.013). Conclusion: Our protocol resulted in a significantly lower incidence of allergic reactions. [ABSTRACT FROM AUTHOR]

Background Sodium zirconium cyclosilicate (SZC), a novel drug used for treating hyperkalaemia, is effective in reducing serum potassium levels. The effects of potassium adsorbents on the mortality and hyperkalaemia-associated hospitalisation rates remain unclear. We aimed to examine how mortality and hyperkalaemia-associated hospitalisation rates vary with usage of various potassium adsorbents. Methods This retrospective study used patients' data between April 2008 and August 2021 obtained from a large-scale Japanese medical claims database. Consecutive patients with chronic kidney disease (CKD) prescribed potassium adsorbents were enrolled and divided into three groups according to the adsorbent type [SZC, calcium polystyrene sulfonate (CPS), and sodium polystyrene sulfonate (SPS)] and were observed for 1 year. The primary outcome was a composite of mortality and hyperkalaemia-associated hospitalisation. Results In total, 234, 54 183, and 18 692 patients were prescribed SZC, CPS, and SPS, respectively. The SZC group showed a higher event-free survival rate than the other two groups. The hazard ratio for the primary outcome in the CPS and SPS groups was similar in the analyses of the subgroups of patients who did not receive renal replacement therapy and those who received haemodialysis. The SZC group had a higher renin-angiotensin-aldosterone system inhibitors (RAASi) continuation rate compared to CPS and SPS groups, the difference being especially significant for SPS. Conclusions This real-world study demonstrated the therapeutic effect of SZC in reducing mortality and hyperkalaemia-associated hospitalisations. The high RAASi continuation rate in the SZC group might be a contributing factor for improvement of the primary outcome. [ABSTRACT FROM AUTHOR]

Pancreatic stellate cells (PSCs) are stromal cells in the pancreas that play an important role in pancreatic pathology. In chronic pancreatitis (CP) and pancreatic ductal adenocarcinoma (PDAC), PSCs are known to get activated to form myofibroblasts or cancer‐associated fibroblasts (CAFs) that promote stromal fibroinflammatory reactions. However, previous studies on PSCs were mainly based on the findings obtained using ex vivo expanded PSCs, with few studies that addressed the significance of in situ tissue‐resident PSCs using animal models. Their contributions to fibrotic reactions in CP and PDAC are also lesser‐known. These limitations in our understanding of PSC biology have been attributed to the lack of specific molecular markers of PSCs. Herein, we established Meflin (Islr), a glycosylphosphatidylinositol‐anchored membrane protein, as a PSC‐specific marker in both mouse and human by using human pancreatic tissue samples and Meflin reporter mice. Meflin‐positive (Meflin+) cells contain lipid droplets and express the conventional PSC marker Desmin in normal mouse pancreas, with some cells also positive for Gli1, the marker of pancreatic tissue‐resident fibroblasts. Three‐dimensional analysis of the cleared pancreas of Meflin reporter mice showed that Meflin+ PSCs have long and thin cytoplasmic protrusions, and are localised on the abluminal side of vessels in the normal pancreas. Lineage tracing experiments revealed that Meflin+ PSCs constitute one of the origins of fibroblasts and CAFs in CP and PDAC, respectively. In these diseases, Meflin+ PSC‐derived fibroblasts showed a distinctive morphology and distribution from Meflin+ PSCs in the normal pancreas. Furthermore, we showed that the genetic depletion of Meflin+ PSCs accelerated fibrosis and attenuated epithelial regeneration and stromal R‐spondin 3 expression, thereby implying that Meflin+ PSCs and their lineage cells may support tissue recovery and Wnt/R‐spondin signalling after pancreatic injury and PDAC development. Together, these data indicate that Meflin may be a marker specific to tissue‐resident PSCs and useful for studying their biology in both health and disease. © 2023 The Pathological Society of Great Britain and Ireland. [ABSTRACT FROM AUTHOR]

Introduction: Patients with peripheral arterial disease (PAD) have a poorer prognosis than those without PAD. PAD complications worsen the prognosis of patients with chronic kidney disease (CKD), especially those on maintenance dialysis. Although low‐density lipoprotein apheresis (LDL‐A) is expected to be effective in treating severe PAD, there are no large‐scale reports on the prognosis of patients undergoing LDL‐A. Methods: We obtained a clinical database from April 2008 to August 2021 and selected 924 238 patients with CKD. We selected patients with disease codes of lower limb arteriosclerosis obliterans, arteriosclerosis obliterans, and critical limb ischemia or foot ulcer. Patients who were prescribed antithrombotic medications were included. Patients who used steroids were excluded. Among these patients, those undergoing blood purification considered LDL‐A were selected, and their current status was investigated. Results: We included 147 patients (113 males and 34 females). The mean patient age was 70 ± 10 years. Diabetes mellitus was present in 86%, ischemic heart disease in 34%, and stroke in 48%. Maintenance dialysis patients accounted for 86% of the patients. Statins were administered to 40% of the patients, and bypass surgery was performed in 2.7%. The median observation period was 812 days, and the mortality rate was 41%. Conclusion: LDL‐A was performed in a small population of patients with CKD with the most severe form of PAD. The prognosis for these patients is extremely poor. Therefore, strategies to improve prognosis are important. [ABSTRACT FROM AUTHOR]

The kidney glomerular capillaries are frequent sites of immune complex deposition and subsequent neutrophil accumulation in post-infectious and rapidly progressive glomerulonephritis. However, the mechanisms of neutrophil recruitment remain enigmatic, and there is no targeted therapeutic to avert this proximal event in glomerular inflammation. The uniquely human activating Fc receptor Fc[gamma]RIlA promotes glomerular neutrophil accumulation and damage in anti-glomerular basement membrane-induced (anti-GBM-induced) glomerulonephritis when expressed on murine neutrophils. Here, we found that neutrophils are directly captured by immobilized IgG antibodies under physiological flow conditions in vitro through Fc[gamma]RIIA dependent, Abl/Src tyrosine kinase-mediated F-actin polymerization. Biophysical measurements showed that the lifetime of Fc[gamma]RIIA-IgG bonds increased under mechanical force in an F-actin-dependent manner, which could enable the capture of neutrophils under physiological flow. Kidney intravital microscopy revealed that circulating neutrophils, which were similar in diameter to glomerular capillaries, abruptly arrested following anti-GBM antibody deposition via neutrophil Fc[gamma]RIIA and Abl/Src kinases. Accordingly, inhibition of Abl/Src with bosutinib reduced Fc[gamma]RIIA-mediated glomerular neutrophil accumulation and renal injury in experimental, crescentic anti-GBM nephritis. These data identify a pathway of neutrophil recruitment within glomerular capillaries following IgG deposition that may be targeted by bosutinib to avert glomerular injury., Introduction Infiltration of myeloid-derived cells in the glomerulus of the kidney is a key pathogenic event in autoantibody-mediated glomerulonephritis (GN), a leading cause of end-stage renal disease (1-4). Glomerular neutrophil [...]