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Key Clinical Message: Recently, hypoxia‐inducible factor prolyl hydroxylase (HIF‐PH) inhibitors have been used for renal anemia, but side effects have also been reported. We report on the association of central hypothyroidism and cholesterol with roxadustat. Based on this case and previous reports, we believe that patients receiving roxadustat should have their thyroid function and cholesterol levels checked regularly. [ABSTRACT FROM AUTHOR]

Key Clinical Message: CYP3A4 and CYP3A5 are the most abundant and important enzymes of the CYP3A subfamily, distributed in the liver, intestinal mucosa and kidney, and involved in tacrolimus metabolism. Here, we report a case of tacrolimus dosage refractoriness due to a genetic polymorphism of CYP3A5. [ABSTRACT FROM AUTHOR]

Key Clinical Message: Pleomorphic lung cancer is a very rare type of cancer and very few cases have been reported in the literature. We present a case of pleomorphic lung cancer in a patient with history of IgA nephropathy on hemodialysis. [ABSTRACT FROM AUTHOR]

Aims/Introduction: This multicenter cohort study retrospectively assessed the association between polar vasculosis and the progression of diabetic kidney disease (DKD) in type 2 diabetes. Materials and Methods: We enrolled 811 patients with type 2 diabetes, biopsy‐proven DKD, and proteinuria (≥0.15 g/g creatinine [g/day]). The association between polar vasculosis and other kidney lesions was explored. The outcome was DKD progression defined as a composite of renal replacement therapy initiation or 50% decline in estimated glomerular filtration rate (eGFR) from baseline. Results: Of the 811 cases, 677 (83.5%) had polar vasculosis. In multivariate logistic regression analysis, subendothelial widening of the glomerular basement membrane, glomerulomegaly, glomerular class in the Renal Pathology Society classification ≥IIb, vascular lesions, age, eGFR, and hemoglobin A1c were positively associated with polar vasculosis, whereas interstitial fibrosis and tubular atrophy (IFTA) was negatively associated with polar vasculosis. During a median follow‐up of 5.2 years, progression of DKD occurred in 322 of 677 (7.4 events/100 person‐years) and 79 of 134 (11.4 events/100 person‐years) cases with and without polar vasculosis, respectively. Kaplan–Meier analysis showed that polar vasculosis was associated with lower cumulative incidences of DKD progression. Multivariate Cox regression analyses showed that polar vasculosis was associated with a lower risk of DKD progression, regardless of eGFR or proteinuria subgroups. These associations between polar vasculosis and better kidney outcome were unchanged considering all‐cause mortality before DKD progression as a competing event. Conclusions: This study showed that polar vasculosis of DKD was associated with less advanced IFTA and a better kidney outcome in type 2 diabetes with proteinuria. [ABSTRACT FROM AUTHOR]

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This retrospective exploratory study aimed to identify early clinical indicators of kidney prognosis in primary nephrotic syndrome (NS). Univariate Cox proportional hazards regression analysis identified clinical parameters in the 2-month period after initiating immunosuppressive therapy (IST); it predicted 40% reduction in the estimated glomerular filtration rate (eGFR) in 36 patients with primary NS. Time-dependent receiver operating characteristic curve analysis was used to evaluate the performance of the predictors for the cumulative incidence of 40% reduction in the eGFR up to 8 years after initiating IST. The mean follow-up period was 71.9 months. The eGFR was reduced by 40% in four patients. Significant predictors for time to 40% reduction in the eGFR were as follows: an increase in the serum soluble urokinase plasminogen activator receptor (s-suPAR) 2 months after initiating IST (Δs-suPAR (2M); hazard ratio (HR) for every 500 pg/mL increase: 1.36, P = 0.006), s-suPAR at 2 months after initiating IST (s-suPAR (2M); HR for every 500 pg/mL increase: 1.13, P = 0.015), urinary protein-to-creatinine ratio (u-PCR) (u-PCR (2M); HR for every 1.0 g/gCr increase: 2.94, P = 0.003), and urinary liver-type fatty acid-binding protein (u-L-FABP) (u-L-FABP (2M); HR for every 1.0 μg/gCr increase: 1.14, P = 0.006). All four factors exhibited high predictive accuracy for cumulative incidence of 40% reduction in the eGFR up to 8 years after initiating IST, with areas under the receiver operating characteristic curve of 0.92 for Δs-suPAR (2M), 0.87 for s-suPAR (2M), 0.93 for u-PCR (2M), and 0.93 for u-L-FABP (2M). These findings suggest that Δs-suPAR (2M), s-suPAR (2M), u-PCR (2M), and u-L-FABP (2M) could be useful indicators of initial therapeutic response for predicting kidney prognosis in primary NS. [ABSTRACT FROM AUTHOR]

Background: Recent studies revealed that lysophospholipids (LPLs) and related molecules, such as autotaxin (ATX) and phosphatidylserine‐specific phospholipase A1 (PS‐PLA1), are candidates for novel biomarkers in melanoma, glaucoma and diabetic nephropathy. However, it is not clear whether serum levels of ATX/ PS‐PLA1 would be associated with pathological and clinical findings of lupus nephritis (LN). Methods: In this retrospective cohort study, serum samples were collected from 39 patients with LN and 37 patients with other glomerular diseases. The serum levels of ATX and PS‐PLA1 were evaluated for an association with renal pathology and clinical phenotypes of LN. Results: The serum levels of ATX and PS‐PLA1 were higher in the patients with LN as compared to those with other glomerular diseases. Among the classes of LN, the patients with class IV showed the trend of lower serum levels of ATX. Moreover, the patients with lower levels of ATX exhibited higher scores of activity index (AI) and chronicity index (CI). The level of ATX tended to be negatively correlated with AI and CI. These results might be explained by the effect of treatment, because the serum levels of ATX and PS‐PLA1 were inversely correlated with the daily amount of oral prednisolone. Moreover, they did not reflect the level of proteinuria or kidney survival in LN patients. Conclusion: Although the serum levels of ATX and PS‐PLA1 were affected by the treatment, these levels were higher in the patients with LN. The potential clinical benefits of these markers need to be clarified in further studies. [ABSTRACT FROM AUTHOR]

Aims/Introduction: The present retrospective study investigated the impact of renal arteriosclerosis (AS) and hypertension (HT) on long‐term renal and cardiovascular outcomes in Japanese type 2 diabetes patients with biopsy‐proven diabetic nephropathy. Materials and Methods: A total of 185 patients were enrolled. Patients were divided into four groups stratified by renal AS status and the presence of HT. The outcomes for this study were the first occurrence of renal events (a need for dialysis or a 30% decline in estimated glomerular filtration rate from baseline) and cardiovascular events (cardiovascular death, non‐fatal myocardial infarction, coronary intervention or non‐fatal stroke). Results: The proportion of renal AS scores ≥1 was 88.3% among patients with normal‐range blood pressure (BP) and 95.4% among patients with HT. During a mean follow‐up period of 7.6 years, 129 episodes of renal composite events and 55 episodes of cardiovascular events were observed. Compared with patients with no renal AS and normal‐range BP, a renal AS score ≥1 increased the risk of renal composite events with a multivariable‐adjusted hazard ratio of 3.21 (95% confidence interval [95% CI] 1.27–8.14) in patients with normal‐range BP and 4.99 (95% CI 1.98–12.54) in patients with HT, whereas renal AS score ≥1 increased the risk of cardiovascular events with a multivariable‐adjusted hazard ratio of 6.06 (95% CI 1.24–29.61) in patients with normal‐range BP and 10.02 (95% CI 1.92–52.39) in patients with HT. Conclusions: Renal AS was associated with increasing risks for renal composite events and cardiovascular events in both normal‐range BP and HT. The risks of renal composite events and cardiovascular events were the highest in both renal AS and HT. [ABSTRACT FROM AUTHOR]

Aim: High glucose (HG) induces endothelial injury in vasculature, leading to tissue injury in diabetic condition. Therefore, diabetes is one of the major cause of end‐stage kidney disease as well as cardiovascular diseases. Chronic inflammation is involved in the progression of HG‐induced cell injury. Recently, it has been reported that erythropoietin (EPO) protects the tissues from some kind of injury, such as hypoxia and mechanical stress. However, the contribution of EPO to HG‐induced tissue injury remains to be explored. Therefore, we hypothesized that EPO protects endothelial cells from HG‐induced injury via the regulation of inflammatory and anti‐inflammatory balance. Methods: We performed genome‐wide transcriptome profiling in human umbilical vein endothelial cells (HUVEC), which were stimulated by HG with/without EPO treatment and detected the expression of inflammation associated genes. Results: The expression pattern of mRNA expression in HG stimulated HUVEC with/without EPO were different in hieralchial clustering analysis. While inflammatory cytokines/chemokines mRNA expression were increased by the HG stimulation in HUVEC, Th2‐related cytokine receptors and intracellular signaling molecules showed the reduced mRNA expression levels. EPO treatment reduced inflammatory cytokines/chemokines mRNA expression and increased Th2‐related cytokine mRNA expression levels. Moreover, EPO stimulation increased mRNA expression of EPO receptor and β‐common receptor. Conclusion: EPO signaling protects HG‐induced cell injury by the regulation of immune balance. Summary at a Glance: The action of prolonged hyperglycaemia on the endothelium is important in the development of diabetic vascular complications, including diabetic kidney disease. While eythropoietin is critical to erythropoiesis, Yasuda et al show that it also possesses anti‐inflammatory effects on macrovascular endothelial cells stimulated by high glucose in vitro. [ABSTRACT FROM AUTHOR]

Abstract: Mortality from infections has been reported to be higher in hemodialysis (HD) patients. Although dysfunction of neutrophils against bacterial infection was reported in HD patients, the precise mechanism remains to be clarified. We therefore examined the impacts of neutrophil inflammatory signaling on bactericidal activity in HD patients. Comprehensive analyses of intracellular signalings were performed in whole blood of HD patients and control using a microarray system. To confirm the contribution of the signaling to bactericidal activity in neutrophils, we examined the phosphorylation, bacterial killing function, reactive oxygen species (ROS) production, and myeloperoxidase (MPO) release in neutrophils against Staphylococcus aureus. RNA microarray analysis showed the suppression of p38 mitogen activated protein kinase (MAPK) signaling in HD patients. Neutrophils in HD patients showed the impairment of bactericidal activity against S. aureus compared to healthy subjects. Phosphorylation rate of p38MAPK of neutrophils in response to S. aureus was lower in HD patients than healthy subjects. The levels of ROS produced by neutrophils after co‐culture with S. aureus were lower in HD patients, on the other hand, there was no difference of MPO release between HD patients and healthy subjects. A selective pharmacological inhibitor of p38MAPK suppressed bacterial killing function as well as ROS production in neutrophils of healthy subjects. Impairment of p38MAPK signaling pathway might contribute to the suppression of neutrophil bactericidal activity in HD patients through less production of ROS. [ABSTRACT FROM AUTHOR]

Although rituximab (RTX) is a promising therapeutic agent for treating steroid‐resistant nephrotic syndrome (SRNS) resistant to various immunosuppressive agents, some patients have shown resistance to RTX. We report the case of a patient with RTX‐resistant nephrotic syndrome and SRNS who was successfully treated with leukocytapheresis (LCAP). After LCAP, there was a significant reduction in proteinuria and in the total number of lymphocytes, T cells, and HLA‐DR+‐activated T cells. Moreover, the patient became sensitive to steroids and RTX. LCAP reduced circulating immune cells including activated T cells and could be effective in treating rituximab‐resistant nephrotic syndrome and SRNS and in achieving remission of proteinuria. [ABSTRACT FROM AUTHOR]

Herein we describe a case of microangiopathic antiphospholipid syndrome ( MAPS) due to anti-phosphatidylserine/prothrombin complex ( aPS/ PT) IgM antibody successfully treated with rituximab. A significant correlation was observed between the clinical course and the aPS/ PT IgM antibody titer, which can rise earlier before the appearance of clinical symptoms. Rituximab can be safely and effectively used for MAPS. Although detection of only aPS/ PT IgM antibody is rare, aPS/ PT IgM antibody might be associated with the pathogenesis of MAPS and might be a useful marker of disease activity. [ABSTRACT FROM AUTHOR]

Mesenchymal stromal stem cells ( MSCs) are an attractive therapeutic model for regenerative medicine due to their pluripotency. MSCs are used as a treatment for several inflammatory diseases, including hepatitis. However, the detailed immunopathological impact of MSC treatment on liver disease, particularly for adipose tissue derived stromal stem cells ( ADSCs), has not been described. Here, we investigated the immuno-modulatory effect of ADSCs on hepatitis using an acute Con A C57 BL/6 murine hepatitis model. i.v. administration of ADSCs simultaneously or 3 h post injection prevented and treated Con A-induced hepatitis. Immunohistochemical analysis revealed higher numbers of CD11b+, Gr-1+, and F4/80+ cells in the liver of Con A-induced hepatitis mice was ameliorated after the administration of ADSCs. Hepatic expression of genes affected by ADSC administration indicated tissue regeneration-related biological processes, affecting myeloid-lineage immune-mediating Gr-1+ and CD11b+ cells. Pathway analysis of the genes expressed in ADSC-treated hepatic inflammatory cells revealed the possible involvement of T cells and macrophages. TNF-α and IFN-γ expression was downregulated in hepatic CD4+ T cells isolated from hepatitis livers co-cultured with ADSCs. Thus, the immunosuppressive effect of ADSCs in a C57 BL/6 murine Con A hepatitis model was dependent primarily on the suppression of myeloid-lineage cells and, in part, of CD4+ T cells. [ABSTRACT FROM AUTHOR]

The prevalence, clinical associations and pathogenic role of newly identified autoantibodies to the erythropoietin receptor ( EPOR) in patients with anaemia were investigated. Sera from 203 patients with immune-related or chronic kidney diseases were screened for anti- EPOR antibodies by enzyme-linked immunosorbent assay, and antibody specificity was evaluated by immunoprecipitating EPOR from AS- E2 cells using purified immunoglobulin ( Ig) fractions. In addition, the pathogenic role of anti- EPOR antibodies was determined by examining their inhibitory effects on AS- E2 cell proliferation. Clinical findings were compared between patients with and without anti- EPOR antibodies, in all patients and those with systemic lupus erythematosus ( SLE). Serum anti- EPOR antibodies were detected in 52 patients. Purified Ig G or Ig M fractions from anti- EPOR antibody-positive sera immunoprecipitated EPOR and inhibited the EPO-dependent proliferation of AS- E2 cells in a dose-dependent manner. Anti- EPOR antibodies were associated with low haemoglobin concentrations and reticulocytopenia in all patients enrolled and those with SLE. Further, there was a negative correlation between the levels of anti- EPOR antibodies and the number of bone marrow erythroblasts in patients who underwent bone marrow examinations. These findings suggest that EPOR autoantibodies are present in a subset of patients with anaemia and that impaired erythropoiesis can be mediated by anti- EPOR antibodies, which functionally neutralize EPO activity. [ABSTRACT FROM AUTHOR]

Lupus nephritis (LN) is a major clinical manifestation of systemic lupus erythematosus (SLE). Although numerous abnormalities of immune system have been proposed, cytokine overexpression plays an essential role in the pathogenesis of LN. In the initial phase of the disease, the immune deposits and/or autoantibodies induce cytokine production in renal resident cells, leading to further inflammatory cytokine/chemokine expression and leukocyte infiltration and activation. Then, infiltrate leukocytes, such as macrophages (Mφ) and dendritic cells (DCs), secrete a variety of cytokines and activate naïve T cells, leading the cytokine profile towards T helper (Th)1, Th2, and/or Th17. Recent studies revealed these inflammatory processes in experimental animal models as well as human LN. The cytokine targeted intervention may have the therapeutic potentials for LN. This paper focuses on the expression of cytokine and its functional role in the pathogenesis of LN. [ABSTRACT FROM AUTHOR]

This article overviews the immunomodulation effects and clinical evidence of apheresis in renal diseases. in particular primary and secondary glomerulonephritis. A considerable permeability factor(s) derived from circulating T cells is speculated to have a crucial role in the proteinuria of nephrotic syndrome (NS). Plasma exchange (PE), immunoadsorption using Protein A sepharose cartridges, low-density lipoprotein apheresis and lymphocyte apheresis (LCAP) were tried to remove such factors or pathogenic T cells. Other glomerular diseases induced by specific antibodies such as antiglomerular basement membrane antibodies, antineutrophil cytoplasmic antibodies and immune-complexes such as lupus nephritis were also treated with PE, double filtration plasma apheresis, IAPP and LCAP. Many reports suggested that apheresis might have beneficial immunomodulation effects for the treatment of glomerular diseases: however, the recommendations based on evidence from small cohorts remain at low-level in most. [ABSTRACT FROM AUTHOR]

A considerable permeability factor (or factors) derived from circulating T cells has a crucial role in proteinuria of nephrotic syndrome (NS). We attempted to remove pathogenic T cells through lymphocytapheresis (LCAP) in 6 patients with primary NS, 2 patients with minimal change nephrotic syndrome (MCNS), 2 patients with focal segmental glomerulosclerosis (FSGS), 1 patient with membranous nephropathy (MN), and 1 patient with MN and FSGS using Cellsorba (Asahi Medical Co., Osaka, Japan). LCAP was performed 2 times in 2 consecutive weeks and was followed with corticosteroid therapy with or without cyclosporine A in 5 patients. Two patients with MCNS, 1 with FSGS, and 1 with MN and FSGS showed a dramatic decrease of proteinuria (-30% and -94%) in their urine protein/creatinine ratio. Three out of 4 patients had a complete or partial remission (proteinuria <1g/day) within 8 weeks following immunosuppressive therapy. During the LCAP, T cells, especially activated T cells, decreased significantly in the response group. The other 2 patients, 1 with FSGS and 1 with MN, however, had no response to LCAP and following immunosuppressive therapy or low-density lipoprotein apheresis and suffered from end-stage renal failure or death by pneumonia. These results suggested that LCAP might have a beneficial effect on the treatment of NS, especially MCNS and in some patients with FSGS, despite varying responses to LCAP and concomitant immunosuppressive therapy. [ABSTRACT FROM AUTHOR]