A case of non-traumatic rectus sheath hematoma in a post-kidney transplant patient undergoing catheter embolization during anticoagulation treatment for atrial fibrillation.

A 65-year-old man, a post living donor kidney transplant patient, was admitted to the intensive care unit (ICU) with a severe bacterial infection. He also tested positive for coronavirus disease and had a cough. On admission, heparin was administered for atrial fibrillation. On the third day of hospitalization, his general condition had recovered, and he was discharged from the ICU to the general ward. On the fourth day of hospitalization, he experienced abdominal pain, and a hard mass was palpated in the left lower abdomen. On the fifth day of hospitalization, contrast-enhanced computed tomography showed an extensive rectus sheath hematoma (RSH) extending from the left lower abdominal wall to the left side of the bladder, with extravasation from a small branch of the left inferior epigastric artery. Heparin was discontinued, and transcatheter arterial embolization was performed to control the bleeding. RSH is a rare disease, and cases of extensive hematoma in post-kidney transplant patients occur even less frequently. Patients taking anticoagulants and those with chronic kidney disease are at high risk for RSH, so physicians should be cognizant of this disease when these patients develop abdominal pain.

Detecting and exploring kidney-derived extracellular vesicles in plasma.

BACKGROUND: Extracellular vesicles (EVs) have received considerable attention as ideal biomarkers for kidney diseases. Most reports have focused on urinary EVs, that are mainly derived from the cells in the urinary tract. However, the detection and the application of kidney-derived EVs in plasma remains uncertain. METHODS: We examined the kidney-derived small EVs (sEVs) in plasma that were supposedly released from renal mesangial and glomerular endothelial cells, using clinical samples from healthy controls and patients with kidney transplants. Plasma from healthy controls underwent ultracentrifugation, followed by on-bead flow cytometry, targeting α8 integrin, an antigen-specific to mesangial cells. To confirm the presence of kidney-derived sEVs in peripheral blood, plasma from ABO-incompatible kidney transplant recipients was ultracentrifuged, followed by western blotting for donor blood type antigens. RESULTS: Immunohistochemistry and immunoelectron microscopy confirmed α8 integrin expression in kidney mesangial cells and their sEVs. The CD9-α8 integrin double-positive sEVs were successfully detected using on-bead flow cytometry. Western blot analysis further revealed transplanted kidney-derived sEVs containing blood type B antigens in non-blood type B recipients, who had received kidneys from blood type B donors. Notably, a patient experiencing graft kidney loss exhibited diminished signals of sEVs containing donor blood type antigens. CONCLUSION: Our findings demonstrate the potential usefulness of kidney-derived sEVs in plasma in future research for kidney diseases.

Changes in antibody titer after four and five doses of the SARS-CoV-2 vaccine in Japanese post-kidney transplant patients.

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.

A case of late-onset organizing pneumonia following COVID-19 infection in a post-kidney transplant patient.

A 50-year-old man who had undergone a living-donor kidney transplant 12 years prior for chronic renal failure due to autosomal dominant polycystic kidney disease contracted coronavirus disease 19 (COVID-19). He had a positive antigen test, mild symptoms, sore throat, and fever of 37.9 â„ƒ. The patient was treated with molnupiravir for 5 days, and the symptoms disappeared 5 days after onset. However, 10 days after onset, he developed a fever of approximately 37 â„ƒ and a non-productive cough; 27 days after onset, the patient was hospitalized for anorexia and a worsening respiratory condition. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antigen test results on admission were negative, and no antiviral medications were administered against SARS-CoV-2. Computed tomography revealed extensive ground-glass opacities in both lung fields. The patient was treated with steroid pulse therapy, ceftriaxone, atovaquone, azithromycin, and respiratory management using a high-flow nasal cannula. The combined therapies were successful, and the patient was managed with a nasal oxygen cannula after 3 days. Oxygen administration was discontinued after 6 days of hospitalization, and the patient was discharged after 14 days. Based on the laboratory findings, bacterial, interstitial, and Pneumocystis pneumonia were unlikely. The success of the steroid pulse therapy suggested that respiratory failure was caused by pneumonia due to the immune response after COVID-19 infection.

Mortality and hyperkalaemia-associated hospitalisation in patients with chronic kidney disease: comparison of sodium zirconium cyclosilicate and sodium/calcium polystyrene sulfonate.

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.

Establishment of an adverse effect prevention protocol on plasma exchange using fresh frozen plasma prior to ABO-incompatible living donor kidney transplantation at our hospital.

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.

Proliferative glomerulonephritis with monoclonal immunoglobulin deposits and atypical pathological findings treated with corticosteroid and rituximab.

A 16-year-old girl with fever that appeared after taking the second COVID-19 vaccine presented to the clinic with a serum creatinine of 0.89 mg/dL and C-reactive protein of 6.9 mg/dL. She had proteinuria and microscopic hematuria, with slowly worsening kidney function. Her kidney biopsy showed fibrocellular crescents in seven of nine glomeruli that were observed under light microscopy. Another glomerulus showed endocapillary hypercellularity and mesangial cell proliferation. Electron-dense deposits were significant in the mesangial area, with monoclonal IgG1-κ and C3 deposition by immunofluorescence. The patient was diagnosed with proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMID) and atypical pathological finding of diffuse crescent formation. The treatment regimen for PGNMID has not yet been established, and the appropriate duration of treatment is unknown. In our case, considering that rituximab acts by binding to CD20 on the surface of B cells through its crystallizable fragment, it was administered in addition to prednisolone, which successfully decreased the proteinuria over time.

Meflin is a marker of pancreatic stellate cells involved in fibrosis and epithelial regeneration in the pancreas.

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.

＜Editors' Choice＞ Mesenchymal stem/stromal cells generated from induced pluripotent stem cells are highly resistant to senescence.

The use of mesenchymal stem/stromal cells (MSCs) has attracted attention in the field of regenerative medicine based on their anti-inflammatory and tissue repair-promoting effects. Bone marrow is widely used as a source of MSCs; however, the performance of bone marrow (BM)-MSCs deteriorates as the cells age along with cell passaging. Recently, it has been reported that MSCs can be generated from induced pluripotent stem cells (iPSCs), which is expected to represent a new source of MSCs. However, few studies have investigated aging in iPSC-derived MSCs (iMSCs) and their functions. In this study, we investigated whether iMSCs overcome cellular senescence compared to that in BM-MSCs. Cellular senescence was quantitatively evaluated by staining iMSCs and BM-MSCs with fluorescein di-ß-D-galactopyranoside (FDG) and following flow cytometer analysis. The hepatocyte growth factor (HGF) concentration in the culture supernatant was also measured as a factor in the therapeutic efficacy of nephritis. The iMSCs did not reach their proliferation limit and their morphology did not change even after 10 passages. The FDG positivity of BM-MSCs increased with passaging, whereas that in iMSCs did not increase. The HGF concentration increased with passaging in iMSCs. In conclusion, our results suggest that iMSCs may be less susceptible to senescence than BM-MSCs and may be used in clinical applications.

Current status of low-density lipoprotein apheresis treatment for patients with peripheral artery disease and chronic kidney disease in Japanese clinical database.

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.

Prognosis and incidence of infections in chronic kidney disease patients with membranous nephropathy enrolled in a large Japanese clinical claims database.

BACKGROUND: The treatment of membranous nephropathy involves a combination of conservative approaches, steroids, and immunosuppressive agents. Infection is an adverse effect of these treatments and its incidence is a critical issue for patients with membranous nephropathy, as many of them are older adults. However, the incidence of infections remains unclear; hence, this study investigated this issue using data from a large Japanese clinical claims database. METHODS: From a database of patients with chronic kidney disease (n = 924,238), those diagnosed with membranous nephropathy from April 2008 to August 2021 with a history of one or more prescriptions and undergoing medical care were included. Patients who had undergone kidney replacement therapy were excluded. Patients were divided into three groups based on their prescriptions after diagnosis: prednisolone(PSL), who received steroids; PSL + IS, who were prescribed steroids and immunosuppressive agents; and C, who were treated without steroid or immunosuppressive agent use. The primary outcome was death or the initiation of kidney replacement therapy. The secondary outcome was death or hospitalization due to infection. Infectious diseases such as sepsis, pneumonia, urinary tract infections, cellulitis, cytomegalovirus infection, colitis, or hepatitis were defined as infections. Hazard ratios were expressed using group C as a reference. RESULTS: Of 1,642 patients, the incidence of the primary outcome occurred in 62/460 individuals in the PSL group, 81/635 individuals in the PSL + IS group, and 47/547 individuals in the C group. The Kaplan-Meier survival curve showed no significant differences (P = 0.088). The incidence of secondary outcomes occurred in 80/460 individuals, 102/635 individuals, and 37/547 individuals in the PSL, PSL + IS, and C groups, respectively. The incidence of secondary outcomes was significantly higher in the PSL group (hazard ratio [HR] 2.43 [95% confidence interval [CI] 1.64-3.62, P < 0.01]) and PSL + IS group (HR 2.23 [95% CI 1.51-3.30, P < 0.01]). CONCLUSIONS: The outcome of membranous nephropathy was not completely satisfactory. Patients who use steroids and immunosuppressive agents have a high incidence of infection and may require close monitoring during the course of treatment.High-efficacy treatment with a low incidence of infections is desirable. The significance of this study lies in the fact that the impressions of membranous nephropathy, which have been recognized as tacit knowledge, were quantified using a clinical database.

Assessment of Antibody-Titer Changes after Second and Third Severe Acute Respiratory Syndrome Coronavirus 2 mRNA Vaccination in Japanese Post-Kidney-Transplant Patients.

Post-renal-transplant patients have a relatively low antibody-acquisition rate following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccination. In this study, antibody titers were measured 5−6 months and 3 weeks to 3 months after the second and third SARS-CoV-2 mRNA vaccinations, respectively. Post-renal-transplant patients visiting our hospital who had received three SARS-CoV-2 mRNA vaccine doses were included in the study. SARS-CoV-2 immunoglobulin G antibody titers were measured three times: between 3 weeks and 3 months after the second vaccination, 5−6 months after the second vaccination, and between 3 weeks and 3 months after the third vaccination. A total of 62 (40 men and 22 women) were included, 44 of whom (71.0%) were antibody positive after their third vaccination. On comparing the antibody-acquired and antibody-non-acquired groups, body mass index (BMI, odds ratio [OR]: 1.44, 95% confidence interval [CI]: 1.07−1.93, p < 0.05) and the estimated glomerular filtration rate (eGFR, OR: 1.14, 95% CI: 1.06−1.24, p < 0.01) were associated with antibody acquisition. Therefore, in Japanese post-kidney-transplant patients, increases in the antibody-acquisition rate and absolute antibody titer after the third vaccination were observed, with BMI and eGFR associated with the antibody-acquisition rate.

Long non-coding RNA lnc-CHAF1B-3 promotes renal interstitial fibrosis by regulating EMT-related genes in renal proximal tubular cells.

Renal interstitial fibrosis (RIF) is a common pathological manifestation of chronic kidney diseases. Epithelial-mesenchymal transition (EMT) of tubular epithelial cells is considered a major cause of RIF. Although long non-coding RNAs (lncRNAs) are reportedly involved in various pathophysiological processes, the roles and underlying molecular mechanisms of lncRNAs in the progression of RIF are poorly understood. In this study, we investigated the function of lncRNAs in RIF. Microarray assays showed that expression of the lncRNA lnc-CHAF1B-3 (also called claudin 14 antisense RNA 1) was significantly upregulated in human renal proximal tubular cells by both transforming growth factor-ß1 (TGF-ß1) and hypoxic stimulation, accompanied with increased expression of EMT-related genes. Knockdown of lnc-CHAF1B-3 significantly suppressed TGF-ß1-induced upregulated expression of collagen type I alpha 1, cadherin-2, plasminogen activator inhibitor-1, snail family transcriptional repressor I (SNAI1) and SNAI2. Quantitative reverse transcriptase PCR analyses of paraffin-embedded kidney biopsy samples from IgA nephropathy patients revealed lnc-CHAF1B-3 expression was correlated positively with urinary protein levels and correlated negatively with estimated glomerular filtration rate. In situ hybridization demonstrated that lnc-CHAF1B-3 is expressed only in proximal tubules. These findings suggest lnc-CHAF1B-3 affects the progression of RIF by regulating EMT-related signaling. Thus, lnc-CHAF1B-3 is a potential target in the treatment of RIF.

Influence of COVID-19 on the 10-year carbon footprint of the Nagoya University Hospital and medical research centre.

BACKGROUND: Amidst the climate crisis, a key goal of the medical sector is to reduce its large carbon footprint. Although the Coronavirus disease 2019 (COVID-19) pandemic greatly impacted the medical sector, its influence on carbon footprints remains unknown. Therefore, the aim of this study was to evaluate changes in the carbon footprint of a university hospital with a medical research centre over the past 10 years. METHODS: Data on electricity, gas, and water usage, pharmaceutical and medical supply costs, and waste amounts were recorded for Nagoya University Hospital from April 2010 to March 2021. The relevant emission factors were obtained from the Japanese government and the overall monthly carbon footprint was reported according to the Greenhouse Gas Protocol. The effect of the COVID-19 pandemic on the carbon footprint was then compared for three types of emission sources. Moreover, a regression model was used to plot quadratic functions as approximate functions using monthly carbon emissions and monthly average external temperatures. Finally, the monthly carbon footprint was calculated per hospital admission. RESULTS: The overall carbon footprint of the hospital was 73,546 tCO2e in 2020, revealing an increase of 26.60% over the last 10 years. Carbon emissions from electricity consumption represented 26% of total emissions. The individual carbon footprints of pharmaceuticals, medical supplies, waste, and water usage also increased from 2010 to 2020. The overall monthly carbon footprint was positively correlated with the average monthly temperature (R2 = 0.7566, p < 0.001). Compared with 2019, the overall carbon footprint decreased by 2.19% in 2020. Moreover, the monthly carbon footprint per hospital admission increased significantly between 2018 (0.24 tCO2e/admission) and 2020 (0.26 tCO2e/admission) (p = 0.002). CONCLUSION: The overall carbon footprint of the hospital generally increased over the last decade. During the COVID-19 epidemic in 2020, the carbon footprint decreased slightly, likely because of the reduced number of patients. However, the carbon footprint per admission increased, which was attributed to more complicated patient backgrounds because of the ageing population. Therefore, evaluation of carbon emissions in the medical sector is urgently required in order to act on the climate crisis as soon as possible.

Systematic characterization of seed overlap microRNA cotargeting associated with lupus pathogenesis.

BACKGROUND: Combinatorial gene regulation by multiple microRNAs (miRNAs) is widespread and closely spaced target sites often act cooperatively to achieve stronger repression ("neighborhood" miRNA cotargeting). While miRNA cotarget sites are suggested to be more conserved and implicated in developmental control, the pathological significance of miRNA cotargeting remains elusive. RESULTS: Here, we report the pathogenic impacts of combinatorial miRNA regulation on inflammation in systemic lupus erythematosus (SLE). In the SLE mouse model, we identified the downregulation of two miRNAs, miR-128 and miR-148a, by TLR7 stimulation in plasmacytoid dendritic cells. Functional analyses using human cell lines demonstrated that miR-128 and miR-148a additively target KLF4 via extensively overlapping target sites ("seed overlap" miRNA cotargeting) and suppress the inflammatory responses. At the transcriptome level, "seed overlap" miRNA cotargeting increases susceptibility to downregulation by two miRNAs, consistent with additive but not cooperative recruitment of two miRNAs. Systematic characterization further revealed that extensive "seed overlap" is a prevalent feature among broadly conserved miRNAs. Highly conserved target sites of broadly conserved miRNAs are largely divided into two classes-those conserved among eutherian mammals and from human to Coelacanth, and the latter, including KLF4-cotargeting sites, has a stronger association with both "seed overlap" and "neighborhood" miRNA cotargeting. Furthermore, a deeply conserved miRNA target class has a higher probability of haplo-insufficient genes. CONCLUSIONS: Our study collectively suggests the complexity of distinct modes of miRNA cotargeting and the importance of their perturbations in human diseases.

Mesenchymal stem cells exert renoprotection via extracellular vesicle-mediated modulation of M2 macrophages and spleen-kidney network.

Adipose-derived mesenchymal stem cells (ASCs) have shown therapeutic potentials against refractory diseases. However, the detailed therapeutic mechanisms remain unclear. Here, we report the therapeutic actions of human ASCs in nephritis, focusing on cellular dynamics and multi-organ networks. Intravenously-administered ASCs accumulated in spleen but not kidneys. Nevertheless, ASCs increased M2 macrophages and Tregs in kidneys and drove strong renoprotection. Splenectomy abolished these therapeutic effects. ASC-derived extracellular vesicles (EVs) were transferred to M2 macrophages, which entered the bloodstream from spleen. EVs induced the transcriptomic signatures of hyperpolarization and PGE2 stimulation in M2 macrophages and ameliorated glomerulonephritis. ASCs, ASC-derived EVs, and EV-transferred M2 macrophages enhanced Treg induction. These findings suggest that EV transfer from spleen-accumulated ASCs to M2 macrophages and subsequent modulation of renal immune-environment underlie the renoprotective effects of ASCs. Our results provide insights into the therapeutic actions of ASCs, focusing on EV-mediated modulation of macrophages and the spleen-kidney immune network.

Protocol for a Phase 1, Open-Label, Multiple-Center, Dose-Escalation Study to Evaluate the Safety and Tolerability of ADR-001 in the Treatment of Immunoglobulin A Nephropathy.

Introduction: Immunoglobulin A (IgA) nephropathy is a disease that presents with urinary symptoms such as glomerular hematuria and urinary protein positivity, with predominant deposition of IgA in the mesangial region of the glomerulus. Corticosteroids are mainly used for treatment; however, infection is a serious adverse event, and evidence regarding therapeutic efficacy is insufficient, thus new treatments are strongly desired. Mesenchymal stem cells (MSCs) contribute to the amelioration of inflammation and recovery of organ function in inflammatory environments by converting the character of leukocytes from inflammatory to anti-inflammatory and inducing the proliferation and differentiation of organ component cells, respectively. These properties of MSCs have led to their clinical application in various inflammatory diseases, but this study is the first clinical trial of MSCs for refractory glomerulonephritis in the world. This study is registered and assigned the number, jRCT2043200002 and NCT04342325. Methods: This will be a phase 1, open-label, multiple-center, dose-escalation study of adult patients with refractory IgA nephropathy resistant to or difficult to treat with existing therapies. ADR-001 will be administered intravenously to from three to six patients at a dose of 1 × 108 cells once in the first cohort and to six patients twice at 2-week intervals in the second cohort, and observation will continue until 52 weeks. The primary endpoint will be the evaluation of adverse events up to 6 weeks after the start of ADR-001 administration. Secondary endpoints will be the respective percentages of patients with adverse events, clinical remission, partial remission, remission of urine protein, remission of hematuria, time to remission, changes in urine protein, hematuria, and estimated glomerular filtration rate. Results: Following the administration of ADR-001 to patients with IgA nephropathy, the respective percentages of patients with adverse events, asymptomatic pulmonary emboli, clinical remission, partial remission, urine protein remission, hematuria remission, their time to remission, changes in urine protein, hematuria, and glomerular filtration rate will be determined. Conclusion: This study will evaluate the safety and tolerability of ADR-001 and confirm its therapeutic efficacy in adult patients with refractory IgA nephropathy.

Mortality and Cardiovascular Events in Patients With Chronic Kidney Disease and Sleep Apnea Syndrome.

Background: The incidence of sleep apnea syndrome (SAS) is reported to be markedly high in patients with chronic kidney disease (CKD). Therefore, it is extremely important to know whether SAS affects prognosis in patients with CKD. Further, it is imperative to understand the prognostic impact of home continuous positive airway pressure (CPAP) therapy, which is one of the most common treatments for SAS. Materials and Methods: We used a clinical database to identify patients with CKD using diagnosis codes. We included patients with CKD aged 20 years or more, not on renal replacement therapy, with a known change in renal function for at least 1 year. The propensity score was used to compare event rates for patients with SAS and those without SAS. In addition, the prognostic impact of CPAP therapy was investigated. The primary outcome is a composite of death, initiation of renal replacement therapy, hospitalization for heart failure, ischemic heart disease, and cerebrovascular disease. Results: From the database, 31,294 patients with CKD without SAS and 1,026 with SAS were found to be eligible. Of these, 419 (41%) patients with SAS and 10,713 (34%) patients without SAS (P < 0.01) reached the primary outcome. After adjustment with the propensity score, the SAS group was found to have a similarly poor prognosis (P < 0.01): the hazard ratio for the primary outcome was 1.26 (95% CI, 1.08-1.45, P < 0.01) in the group with SAS compared with the group without SAS. Conversely, in patients with SAS and using CPAP, the hazard ratio was lower and did not differ significantly (HR 0.96, 95% CI: 0.76-1.22, P = 0.76). Conclusion: In patients with CKD and SAS, the risk of death and cardiovascular disease is high. In addition, patients treated with CPAP may have improved life expectancy.

Monocytes transition to macrophages within the inflamed vasculature via monocyte CCR2 and endothelial TNFR2.

Monocytes undergo phenotypic and functional changes in response to inflammatory cues, but the molecular signals that drive different monocyte states remain largely undefined. We show that monocytes acquire macrophage markers upon glomerulonephritis and may be derived from CCR2+CX3CR1+ double-positive monocytes, which are preferentially recruited, dwell within glomerular capillaries, and acquire proinflammatory characteristics in the nephritic kidney. Mechanistically, the transition to immature macrophages begins within the vasculature and relies on CCR2 in circulating cells and TNFR2 in parenchymal cells, findings that are recapitulated in vitro with monocytes cocultured with TNF-TNFR2-activated endothelial cells generating CCR2 ligands. Single-cell RNA sequencing of cocultures defines a CCR2-dependent monocyte differentiation path associated with the acquisition of immune effector functions and generation of CCR2 ligands. Immature macrophages are detected in the urine of lupus nephritis patients, and their frequency correlates with clinical disease. In conclusion, CCR2-dependent functional specialization of monocytes into macrophages begins within the TNF-TNFR2-activated vasculature and may establish a CCR2-based autocrine, feed-forward loop that amplifies renal inflammation.

Antibody response to double SARS-CoV-2 mRNA vaccination in Japanese kidney transplant recipients.

Immunocompromised patients, especially those who undergo kidney transplantation, have lower antibody levels following SARS-CoV-2 mRNA vaccination. The situation of transplant treatment, such as transplant source and immunosuppressive drugs, is different in Japan than that in other countries. Therefore, it is necessary to clarify whether antibody acquisition rates differ between Japan and other countries. This retrospective study included patients with post-kidney transplant who were attending at the Nagoya University Hospital. The anti-SARS-CoV-2 IgG antibody titers were measured between 3 weeks and 3 months after vaccination. Seventy-three patients (45 men and 28 women) were included. Of these, 23 (31.5%) showed antibody presence, and the rates of antibody acquisition were very low than those in the control group (100.0% vs. 31.5%, P < 0.05). Antibody acquisition rates were associated with body mass index (odds ratio [OR]: 1.21, 95% confidence interval [CI]: 1.04-1.39, P < 0.05) and the duration between transplantation and vaccination (OR: 1.01, 95% CI: 1.00-1.02, P < 0.05). The immunosuppressive drugs used were: prednisolone in all cases, tacrolimus in 89.0%, cyclosporine in 9.6%, and mofetil mycophenolate in 97.3%. None of the patients were excluded from receiving two doses of the vaccine due to adverse effects. The study indicated that vaccination-induced antibody acquisition rates against SARS-CoV-2 were extremely low in Japanese patients who underwent post-kidney transplantation. Thus, despite two doses of vaccination, it is necessary to closely monitor infection control in such patients.