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Background Prognosis of nephrotic syndrome has been evaluated based on pathological diagnosis, whereas its clinical course is monitored using objective items and the treatment strategy is largely the same. We examined whether the entire natural history of nephrotic syndrome could be evaluated using objective common clinical items. Methods Machine learning clustering was performed on 205 cases from the Japan Nephrotic Syndrome Cohort Study, whose clinical parameters, serum creatinine, serum albumin, dipstick hematuria, and proteinuria were traceable after kidney biopsy at 5 measured points up to 2 years. The clinical patterns of time-series data were learned using long short-term memory (LSTM)-encoder–decoder architecture, an unsupervised machine learning classifier. Clinical clusters were defined as Gaussian mixture distributions in a two-dimensional scatter plot based on the highest log-likelihood. Results Time-series data of nephrotic syndrome were classified into four clusters. Patients in the fourth cluster showed the increase in serum creatinine in the later part of the follow-up period. Patients in both the third and fourth clusters were initially high in both hematuria and proteinuria, whereas a lack of decline in the urinary protein level preceded the worsening of kidney function in fourth cluster. The original diseases of fourth cluster included all the disease studied in this cohort. Conclusions Four kinds of clinical courses were identified in nephrotic syndrome. This classified clinical course may help objectively grasp the actual condition or treatment resistance of individual patients with nephrotic syndrome.

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), presents with severe pneumonia and fatal systemic complications. Currently, SARS-CoV-2 vaccines are effective in reducing the risk of new onset and getting worse of the disease. However, autoimmune diseases such as antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis (AAV) have been reported to develop after COVID-19 vaccine administration. A 71-year-old woman presented with fever, malaise, urinary abnormalities, and renal dysfunction after receiving the COVID-19 vaccine (Pfizer-BioNTech). We clinically diagnosed AAV with her manifestations and serological test (myeloperoxidase-ANCA-positive). Her clinical findings were improved after immunosuppressive therapy. We examined her genetic susceptibility to AAV, and we found that her allele was HLA-DRB1*09:01, which is a risk allele of myeloperoxidase-AAV. Mechanistically, SARS-CoV-2 vaccines would activate immunity, including neutrophils, and trigger AAV onset in this patient with a genetic risk to develop AAV. The pathophysiology of this case would share with that of autoimmune/inflammatory syndrome induced by adjuvants in the absence of external adjuvants.

Since the beginning of 2020, tetracycline (TC), such as minocycline (MINO), has been used to inhibit coronavirus disease 2019 (COVID-19). Traditional Japanese Kampo medicine, such as Saiko-keishi-to (SKT), has recently received a lot of attention for its anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) effects. We describe a COVID-19 patient treated with MINO and SKT in anticipation of their anti-SARS-CoV-2 properties. A 90-year-old male patient with Alzheimer’s disease was referred to a medical clinic due to fever, appetite loss, and general malaise. Based on positive SARS-CoV-2 rapid antigen tests, he was diagnosed with COVID-19. He did not have COVID-19 pneumonia, but he had difficulty in eating on his own. As a result, he was referred to a hospital for admission. After admission, he was treated with molnupiravir to avoid aggravation. Seven days after his admission, he was discharged. After his discharge, he was referred to our hospital as an outpatient due to a prolonged mild fever and general malaise. As a precaution, a real-time reverse transcription-polymerase chain reaction (RT-PCR) test was performed, which yielded a positive result. Therefore, the aforementioned symptoms were thought to be caused by prolonged COVID-19. He was treated with MINO and SKT due to the anti-viral properties of these two drugs. The RT-PCR test became negative 7 days after receiving this treatment, and the fever and general malaise subsided.

Membranous nephropathy (MN) is a disease characterized by deposition of immune complexes on the glomerular basement membrane. More than 10 specific antigens for MN including M-type phospholipase A2 receptor (PLA2R), thrombospondin type-1 domain-containing 7A (THSD7A), exostosin 1/exostosin 2 (EXT1/EXT2) and neural epidermal growth factor-like 1 (NELL1) have so far been identified. Since the clinicopathologic characteristics of each type of MN in Japanese are not well understood, we first examined 107 cases of MN by immunohistochemistry for four antigens (PLA2R, THSD7A, EXT1, and NELL1) (MN-cohort). Of those 107 cases, 40% were PLA2R-positive, 13% were NELL1-positive, 11% were THSD7A-positive, 5% were EXT1-positive, 2% were PLA2R and NELL1-double-positive, and 29% were quadruple-negative. In one case of PLA2R and NELL1-double-positive, the first biopsy showed PLA2R-positive and the second biopsy showed PLA2R and NELL1-double-positive. Of the 16 cases of NELL1-positive, 12.5% had colon cancer, 18.8% had rheumatic diseases treated with bucillamine, and 63% had type 2 diabetes mellitus (T2DM). Next, 34 patients diagnosed with MN who had rheumatoid arthritis (RA) were examined (RA-MN cohort). Of those 34 patients, 79% were NELL1-positive, 6% were PLA2R-positive, and 15% were quadruple-negative. In the RA-MN cohort, 56% had a history of bucillamine use. In conclusion, NELL1-associated MN is a common MN in patients with RA using bucillamine and may also be associated with T2DM.

Factors affecting decline in renal function and cyst growth in patients with autosomal polycystic kidney disease (ADPKD) are not fully described, particularly in Japan. This was the first multi-facility, prospective, observational cohort study conducted in ADPKD patients at 14 centers in Japan. Patients in the J-PKD registry were assessed from December 2009 to June 2012 (follow-up until June 2017). Patients’ data including estimated glomerular filtration rate (eGFR) and total kidney volume (TKV) were assessed initially and a maximum of five times annually. Contributing factors to eGFR decline and TKV growth were identified using multiple linear regression analysis. Of the 340 patients in the J-PKD registry, data analysis was performed for 192 patients in whom serial changes for both eGFR and TKV were obtained. eGFR slope, eGFR change, and TKV change values were as follows: − 2.7 (− 4.2 to − 1.5) (ml/min/1.73 m2/year), − 5.0 (− 9.6 to − 2.3) (%/year), and 4.78 (0.86–8.22) (%/year), respectively. Lower high-density lipoprotein (HDL) cholesterol was an independent predictor of eGFR decline, using both eGFR slope and change (P = 0.04, P = 0.02, respectively), whereas lower hemoglobin and higher uric acid were significantly associated with greater eGFR change only (P = 0.02, P = 0.002, respectively). Younger age and higher fasting blood sugar were independent predictors of greater TKV change (P = 0.01, P = 0.02, respectively). This real-world study in Japan identified risk factors for renal function decline in ADPKD patients. These included lower HDL cholesterol, lower hemoglobin and higher uric acid for eGFR decline, and youth and higher blood sugar levels for TKV growth.

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is pathologically characterized by focal fibrinoid necrosis, in which ANCA-mediated neutrophil extracellular trap (NET) formation and subsequent endothelial cell necrosis occur. Cyclophilin D (CypD) plays an important role in mediation of cell necrosis and inflammation via the opening of mitochondrial permeability transition pores. This study was undertaken to examine the role of CypD in AAV pathogenesis.We assessed the role and mechanism of CypD in ANCA-stimulated neutrophils in vitro by immunostaining and electron microscopy observation. We performed a comprehensive RNA-sequencing analysis on ANCA-treated murine neutrophils. To investigate the role of CypD in vivo, we assessed disease features in CypD-knockout mice and wild-type mice using 2 different murine AAV models: anti-myeloperoxidase IgG transfer-induced AAV and spontaneous AAV.In vitro experiments showed that pharmacologic and genetic inhibition of CypD suppressed ANCA-induced NET formation via the suppression of reactive oxygen species and cytochrome c release from the mitochondria. RNA-sequencing analyses in ANCA-treated murine neutrophils revealed the involvement of inflammatory responses, with CypD deficiency reducing ANCA-induced alterations in gene expression. Furthermore, analyses of upstream regulators revealed the relevance of intracellular calcium (CypD activator) and cyclosporin (CypD inhibitor) in ANCA stimulation, indicating that the CypD-dependent opening of mitochondrial permeability transition pores is associated with ANCA-induced neutrophil activation and NETosis. In both AAV mouse models, the genetic deletion of CypD ameliorated crescentic glomerulonephritis via the inhibition of CypD-dependent neutrophil and endothelial necrosis.CypD targeting is a novel and specific therapeutic strategy for AAV via the resolution of necrotizing vasculitis.

Background Despite recent advances in immunosuppressive therapy for patients with primary nephrotic syndrome, its effectiveness and safety have not been fully studied in recent nationwide real-world clinical data in Japan. Methods A 5-year cohort study, the Japan Nephrotic Syndrome Cohort Study, enrolled 374 patients with primary nephrotic syndrome in 55 hospitals in Japan, including 155, 148, 38, and 33 patients with minimal change disease (MCD), membranous nephropathy (MN), focal segmental glomerulosclerosis (FSGS), and other glomerulonephritides, respectively. The incidence rates of remission and relapse of proteinuria, 50% and 100% increases in serum creatinine, end-stage kidney disease (ESKD), all-cause mortality, and other major adverse outcomes were compared among glomerulonephritides using the Log-rank test. Incidence of hospitalization for infection, the most common cause of mortality, was compared using a multivariable-adjusted Cox proportional hazard model. Results Immunosuppressive therapy was administered in 339 (90.6%) patients. The cumulative probabilities of complete remission within 3 years of the baseline visit was ≥ 0.75 in patients with MCD, MN, and FSGS (0.95, 0.77, and 0.79, respectively). Diabetes was the most common adverse events associated with immunosuppressive therapy (incidence rate, 71.0 per 1000 person-years). All-cause mortality (15.6 per 1000 person-years), mainly infection-related mortality (47.8%), was more common than ESKD (8.9 per 1000 person-years), especially in patients with MCD and MN. MCD was significantly associated with hospitalization for infection than MN. Conclusions Patients with MCD and MN had a higher mortality, especially infection-related mortality, than ESKD. Nephrologists should pay more attention to infections in patients with primary nephrotic syndrome.

Although it is widely accepted that the autosomal dominant polycystic kidney disease (ADPKD) patients with large liver cysts have a significant decrement in quality of life (QOL), there is insufficient evidence that clearly demonstrates the relationship between the size of the liver cysts and QOL. Therefore, we started this prospective longitudinal study to investigate the impact of liver cysts on QOL.We grouped the 111 included ADPKD patients into 4 groups (control group A; 25%, group B; 25-49%, group C; 50-75%, group D; 75%) according to liver cysts-parenchyma ratio (CPR). QOL was measured by FANLTC + FACT-Hep scores. We compared QOL scores and several clinical parameters amongst these groups for 3 years.The number of patients in group A, B, C, and D was 31, 14, 14, and 23, respectively. Although there were no significant differences in AST (p = 0.107), ALT (p = 0.925), and serum albumin (p = 0.212) between the four groups, platelet count was significantly decreased along with the extension of cyst volume (p = 0.030). Overall, the mean FANLTC and FACT-Hep scores were 71.8 ± 12.5, and 32.4 ± 5.8, respectively. FANLTC (p = 0.017) and FACT-Hep scores (p = 0.003) were significantly decreased with increasing cyst volume. From the data collected at the time of registration, multivariate linear regression analysis demonstrated that the CPR had a significant influence on FANLTC and FACT-Hep scores.In this cross-sectional and prospective longitudinal study, we demonstrate the relationship between liver cyst volume and QOL in ADPKD patients. We hope to establish the long-term influence on QOL in this ongoing prospective longitudinal study.

Minimal change disease (MCD) is characterized by a nephrotic syndrome usually steroid-sensitive and a high incidence of relapse of proteinuria. Previous cohort studies have reported conflicting results regarding the association between the time to remission and incidence of relapse.This multicenter prospective cohort study included 102 adult patients with steroid-sensitive MCD or focal segmental glomerulosclerosis from a 5-year cohort study of primary nephrotic syndrome, the Japan Nephrotic Syndrome Cohort Study, who achieved remission of proteinuria within 2 months of immunosuppressive therapy (IST). The association between the time to remission of proteinuria after immunosuppressive therapy and incidence of relapse was assessed using Cox proportional hazards models adjusted for clinically relevant factors.Remission was observed at 3-7, 8-14, 15-21, 22-28, and 30-56 days after initiation of immunosuppressive therapy in 17 (16.7%), 37 (36.3%), 21 (20.6%), 13 (12.7%), and 14 (13.7%) patients, respectively. During a median observation period of 2.3 years after the end of the 2nd month after initiation of immunosuppressive therapy, 46 (45.1%) patients relapsed. The time to remission was associated with the incidence of relapse in an inverse U-shaped pattern (multivariable-adjusted hazard ratios [95% confidence intervals] of the time to remission of 3-7, 8-14, 15-21, 22-28, 30-56 days: 1.00 [reference], 1.76 [0.56, 5.51], 6.06 [1.85, 19.80], 5.46 [1.44, 20.64], and 2.19 [0.52, 9.30], respectively).The time to remission was identified as a significant predictor of relapse in steroid-sensitive patients.

The aim of the present study was to clarify the prevalence of immunosuppressive drug use and outcomes in elderly and non-elderly patients with primary membranous nephropathy (MN) in nationwide real-world practice in Japan. Between 2009 and 2010, 374 patients with primary nephrotic syndrome were enrolled in the cohort study (The Japan Nephrotic Syndrome Cohort Study, JNSCS), including 126 adult patients with MN. Their clinical characteristics were compared with those of nephrotic patients with primary MN registered in a large nationwide registry (The Japan Renal Biopsy Registry, J-RBR). Outcomes and predictors in the elderly (≥ 65 years) and non-elderly groups were identified. Similar clinical characteristics were observed in JNSCS patients and J-RBR patients (n = 1808). At the early stage of 1 month, 84.1% of patients were treated with immunosuppressive therapies. No significant differences were observed in therapies between age groups. However, elderly patients achieved complete remission (CR) more frequently than non-elderly patients, particularly those treated with therapies that included corticosteroids. No significant differences were noted in serum creatinine (sCr) elevations at 50 or 100%, end-stage kidney disease, or all-cause mortality between age groups. Corticosteroids were identified as an independent predictor of CR (HR 2.749, 95%CI 1.593–4.745, p = 0.000) in the multivariate Cox’s model. sCr levels, hemoglobin levels, immunosuppressants, clinical remission, and relapse after CR were independent predictors of sCr × 1.5 or × 2.0. Early immunosuppressive therapy including corticosteroids for primary MN showed better remission rates in elderly patients in a nationwide cohort study.

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is characterized by necrotizing vasculitis with the presence of pathogenic ANCA. ANCA can potentially cause neutrophil activation and induce neutrophil extracellular traps (NETs), resulting in endothelial damage as well as activation of autoreactive B cells and alternative complement pathway. Recombinant thrombomodulin (rTM) protects the endothelium from vascular injury during disseminated intravascular coagulation, thus we hypothesized that rTM ameliorates necrotizing vasculitis in AAV. In this study, rTM was administered in an experimental AAV rat model. Treatment of experimental AAV rats with rTM improved pulmonary hemorrhage and glomerulonephritis, with a suppression of ANCA production and NETs formation. In addition, in vitro experiments showed that rTM bound to neutrophils via Mac-1 (macrophage-1 antigen) and inhibited ANCA-induced NETs formation accompanied by a suppression of histone citrullination, leading to a protection of the endothelium from NETs toxicity. Additionally, rTM affected lymphocytes leading to the inhibition of pro-inflammatory cytokine/chemokin in PBMC during the antibody production process, which might indirectly be involved in the reduction of pathogenic ANCA. Our data revealed that the rTM could ameliorate autoimmune vasculitis through a combination of different biological mechanisms.

Chronic active antibody-mediated rejection (CAAMR) is a particular problem in kidney transplantation (KTx), and ~25% of grafts are lost by CAAMR. Further, the pathogenesis remains unclear, and there is no effective cure or marker. We previously found that a hyper NFκB-activating mechanism in non-immune cells, called the IL-6 amplifier, is induced by the co-activation of NFκB and STAT3, and that this activation can develop various chronic inflammatory diseases. Here, we show that synaptotagmin-17 (SYT17) is increased in an exosomal fraction of the urine from CAAMR patients, and that this increase is associated with activation of the IL-6 amplifier. Immunohistochemistry showed that SYT17 protein expression was increased in renal tubule cells of the CAAMR group. While SYT17 protein was not detectable in whole-urine samples by western blotting, urinary exosomal SYT17 levels were significantly elevated in the CAAMR group compared to three other histology groups (normal, interstitial fibrosis and tubular atrophy, and calcineurin inhibitors toxicity) after KTx. On the other hand, current clinical laboratory data could not differentiate the CAAMR group from these groups. These data suggest that urinary exosomal SYT17 is a potential diagnostic marker for CAAMR.

The lack of high-quality clinical evidences hindered broad consensus on optimal therapies for primary nephrotic syndromes. The aim of the present study was to compare prevalence of immunosuppressive drug use in patients with primary nephrotic syndrome across 6 regions in Japan. Between 2009 and 2010, 380 patients with primary nephrotic syndrome in 56 hospitals were enrolled in a prospective cohort study [Japan Nephrotic Syndrome Cohort Study (JNSCS)], including 141, 151, and 38 adult patients with minimal change disease (MCD), membranous nephropathy (MN), and focal segmental glomerulosclerosis (FSGS), respectively. Their clinical characteristics were compared with those of patients registered in a large nationwide registry of kidney biopsies [Japan Renal Biopsy Registry (J-RBR)]. The regional prevalence of use of each immunosuppressive drug was assessed among adult MCD, MN, and FSGS patients who underwent immunosuppressive therapy in the JNSCS (n = 139, 127, and 34, respectively). Predictors of its use were identified using multivariable-adjusted logistic regression models. The clinical characteristics of JNSCS patients were comparable to those of J-RBR patients, suggesting that the JNSCS included the representatives in the J-RBR. The secondary major immunosuppressive drugs were intravenous methylprednisolone [n = 33 (24.6%), 24 (19.7%), and 9 (28.1%) in MCD, MN, and FSGS, respectively] and cyclosporine [n = 25 (18.7%), 62 (50.8%), and 16 (50.0%), respectively]. The region was identified as a significant predictor of use of intravenous methylprednisolone in MCD and MN patients. Use of intravenous methylprednisolone for MCD and MN differed geographically in Japan. Its efficacy should be further evaluated in a well-designed trial.

The aim of this study was to clarify the consequences of Mx1, one of the IFN-inducible proteins, in the peripheral blood as well as in renal tissues in patients with systemic lupus erythematosus (SLE).Mx1 protein concentrations in (PBMCs) from 18 SLE patients mostly in their stable disease status, 11 IgA nephropathy (IgAN) patients, 5 ANCA-associated vasculitis (AAV) patients and 16 healthy controls were measured using enzyme-linked immunosorbent assay (ELISA). Mx1 expression in renal specimens from 18 patients with lupus nephritis (LN), 18 with IgAN and 10 with AAV were evaluated using immunohistochemistry.Mx1 protein concentrations in lysates of PBMCs were significantly higher in SLE patients compared with those in other three groups. Mx1-positive area in renal tissues was significantly dominant in both glomeruli and renal tubules of LN compared with other renal diseases. Renal Mx1 protein levels were lower in LN after immunosuppressive treatment, compared with those from immunosuppressant-naïve patients.Mx1 levels were upregulated in lupus peripheral blood even when their disease activities were stable. On the other hand, Mx1 was highly expressed in kidneys from patients with LN before treatment, which was decreased after immunosuppressive treatment. These results suggest that Mx1 is a potential marker for the diagnosis of SLE in the peripheral blood and also for the activity of lupus nephritis in the kidney.

Objective: ANCA associated vasculitis (AAV) is characterized by systemic necrotizing vasculitis with the presence of ANCA. Although BPI-ANCA is one of the atypical ANCAs and is occasionally seen in patients with vasculitis, the pathogenicity of BPI-ANCA remains unclear. This study was performed to examine the pathogenic role of BPI-ANCA against neutrophils. Methods: A 76-year-old Japanese man showed BPI-ANCA positive systemic vasculitis with a medical history of Pseudomonas aeruginosa infection. BPI-ANCA IgGs were eluted from the patient serum using an immunoadsorbent column. In vitro experiment, healthy donor neutrophils were treated with BPI-AAV IgGs, MPO-AAV IgGs, healthy control IgGs under TNFα stimulation. After 3 h incubation, neutrophil extracellular trap (NET) was assessed by immunofluorescent imaging. To determine the pathogenicity of BPI-ANCA, TNFα-primed neutrophils were incubated with monoclonal BPI-ANCA in the presence or absence of recombinant BPI. Results: BPI-AAV IgGs-treated neutrophils showed NET formation with histone citrullination. Interestingly, the monoclonal BPI-ANCA did not induce NET, but the immune complexes (ICs) of recombinant BPI and BPI-ANCA induced TNFα-dependent NET formation with hypercitrullination. Furthermore, TNFα increased the expression of BPIs in neutrophils and the BPIs were translocated to cell surface. Conclusion: BPI-ANCA could affect neutrophils leading to NET formation and may play a role in the development of systemic vasculitis as pathogenic autoantibody.

Adynamic bone disease in HD patients is characterized by skeletal resistance to parathyroid hormone (PTH) or suppression of PTH release, leading to a downregulated bone turnover and bone fracture. Hence, we examined the efficacy of weekly teriparatide for HD patients with low PTH indicating adynamic bone disease without a history of parathyroidectomy. Fifteen HD patients with low PTH were recruited in this prospective observational study. Of them, 10 received teriparatide for 12 months and five nontreated patients were enrolled as control. Primary outcomes were defined as the changes in bone mineral density and bone turnover markers. Bone mineral density at the lumbar spine increased by 3.7% and 2.5% at 6 and 12 months, respectively, and bone formation markers increased, while bone resorption markers did not change in the teriparatide group. At 12 months after teriparatide administration, endogenous PTH was secreted followed by the recovery of low bone turnover. 40% of patients in the teriparatide group dropped out due to adverse events and the most common adverse event was transient hypotension. This study suggests that weekly teriparatide for HD patients with low PTH in the absence of parathyroidectomy accelerates bone formation and bone turnover, leading to increased trabecular bone mass and secretion of endogenous PTH.

Rationale: Neutrophil extracellular traps (NETs) are immune defence systems that release extracellular chromatin and myeloid granules including myeloperoxidase (MPO) to kill pathogens. An experimental animal study recently demonstrated that disordered NETs induced by propylthiouracil (PTU) could contribute to the production of MPO anti-neutrophil cytoplasmic antibody (ANCA) and the development of ANCA-associated vasculitis (AAV). However, the role of dysregulated NETs in the pathogenesis of human AAV remains unclear. Patient concerns: We report a 19-year-old woman with Graves’ disease on PTU presented fever, polyarthralgia, and lung hemorrhage with high titer of MPO-ANCA. This patient had a variety of atypical ANCAs and disordered NETs in vitro. Diagnoses: A diagnosis of PTU-induced AAV (PTU-AAV). Interventions: The PTU was discontinued and she was treated with immunosuppressants and plasmapheresis for reducing pathogenic autoantibodies. Outcomes: Clinical manifestations including fever, polyarthralgia, and lung hemorrhage were on remission with a decrease of dysregulated NETs. Lessons: The clinical course of this PTU-AAV case indicated that dysregulated NETs would play a role in the development of ANCA and the pathogenesis of AAV.

Objective Although anti-neutrophil cytoplasmic antibody (ANCA) is the major autoantibody in patients with ANCA-associated vasculitis (AAV), previous studies have suggested the presence of anti-neutrophil extracellular trap (NET) antibody in patients with microscopic polyangiitis (MPA), one type of AAV. In this study, we aimed to determine the prevalence and pathogenic role of anti-NET antibody (ANETA) in MPA. Methods We examined the presence or absence of ANETA in sera obtained from 19 MPA patients by indirect immunofluorescence. We compared the clinical parameters, including age, sex, myeloperoxidase (MPO)-ANCA, creatinine, C-reactive protein, MPO-DNA complexes, and vasculitis activity, in ANETA-positive and ANETA-negative MPA patients. We investigated the serum NET induction and degradation abilities of ANETA-positive and ANETA-negative MPA patients with reference to healthy controls (n=8). Furthermore, we assessed the relationship of ANETA with the effect of IgG depletion on the serum NET degradation ability. Results ANETA was present in 10 of the 19 MPA patients. There was no significant difference in the clinical parameters in ANCA-positive and ANCA-negative MPA patients. Although the NET induction ability was higher and the NET degradation ability was lower in MPA sera than those in healthy controls, these abilities were not different between ANETA-positive and ANETA-negative MPA sera. Interestingly, the NET degradation ability in some sera with ANETA was markedly increased by IgG depletion. Conclusion Some MPA patients produce ANETA and some ANETA possess an inhibitory function against the serum NET degradation ability. Although further studies are needed, ANETA is worthy of attention for understanding the pathophysiology of MPA.

ADPKD is the most common hereditary cystic kidney disease. ADPKD is characterized by the progressive development of fluid-filled cysts derived from renal tubular epithelial cells and the development of disorders in several organs. Bilateral renal cysts enlarge progressively, gradually compromising renal function, and finally, end-stage renal disease (ESRD) requiring renal replacement therapy occurs in approximately 50 % of patients by the age of 60 years. The pattern of transmission in ADPKD is autosomal dominant inheritance. A male or female with a mutant allele develops the disease. In case that both parents are unaffected, disease in the offspring results from new mutation. ADPKD is caused by a germ line mutation in PKD1 (16p13.3)(85 % of cases) or PKD2 (4q21)(15 % of cases).

Neutrophil extracellular traps (NETs) are net-like chromatin fibers decorated with antimicrobial proteins, which are released from dying neutrophils. The death of neutrophils with NET formation is called NETosis. Although NETs play important roles in the innate immunity, especially in the elimination of microbes, the extracellular release of DNA and intra-cytoplasmic/nuclear proteins can, on the other hand, result in diverse adversities to the hosts. Therefore, NETosis is adequately regulated in vivo. Currently, two mechanisms, namely DNase I-dependent digestion and phagocytosis by macrophages, have been shown as such regulatory mechanisms. In this study, we focused on the interaction of macrophages and neutrophils that underwent NETosis. Results demonstrated that macrophages displayed a phenotype dependent response after degradation of NETs. Several hours after the interaction, M2 macrophages induced a pro-inflammatory response, while M1 macrophages underwent cell death with nuclear decondensation. This nuclear decondensation of M1 macrophages occurred in a peptidylarginine deiminase 4-dependent manner and resulted in a local release of extracellular DNA. Thereafter, M1 macrophages degraded DNA derived from themselves in a caspase-activated DNase-dependent manner resulting in the clearance of extracellular DNA within 24 h. This transient increase and subsequent clearance mechanism of extracellular DNA seems very reasonable in terms of the double-edged sword-like property of NETs. The collective findings demonstrate a novel phenotype- and time-dependent regulation of NETosis by macrophages. (C) 2015 The Authors. Published by Elsevier Ltd.

Autosomal dominant polycystic kidney disease (ADPKD) caused by PKD1 mutations is one of the most common hereditary disorders. However, the key pathological processes underlying cyst development and exacerbation in pre-symptomatic stages remain unknown, because rodent models do not recapitulate critical disease phenotypes, including disease onset in heterozygotes. Here, using CRISPR/Cas9, we generate ADPKD models with PKD1 mutations in cynomolgus monkeys. As in humans and mice, near-complete PKD1 depletion induces severe cyst formation mainly in collecting ducts. Importantly, unlike in mice, PKD1 heterozygote monkeys exhibit cyst formation perinatally in distal tubules, possibly reflecting the initial pathology in humans. Many monkeys in these models survive after cyst formation, and cysts progress with age. Furthermore, we succeed in generating selective heterozygous mutations using allele-specific targeting. We propose that our models elucidate the onset and progression of ADPKD, which will serve as a critical basis for establishing new therapeutic strategies, including drug treatments., ゲノム編集技術を用いてカニクイザルモデルにおいて常染色体優性多発性嚢胞腎(ADPKD)の病態再現に成功 --小動物では病態再現できない難病の研究に新たな道--. 京都大学プレスリリース. 2019-12-13.

To assess the safety and effectiveness of transcatheter arterial embolization (TAE) with tris-acryl gelatin microspheres for patients with symptomatic enlarged polycystic liver disease (PCLD). This prospective study was approved by our hospital’s institutional review board and planned for patients with symptoms related to enlarged PCLD, such as distended abdomen, gastrointestinal obstruction and abdominal pain. Hemi-hepatic embolization with tris-acryl gelatin microspheres was performed in the hepatic artery supplying the hepatic lobe that showed the predominant presence of cysts. Each patient underwent an assessment of liver function, a questionnaire survey about symptoms, measurement of the estimated volume of the whole liver before and after TAE, and an assessment of complications associated with TAE. Five patients (four females, one male; mean age 52.6 ± 9.1 years) were treated. All five patients successfully completed TAE. The left lobe was treated in three patients and the right in two. After TAE, post-embolization syndrome and transient elevation of white blood cells, aspartate aminotransferase, and alanine aminotransferase occurred in all patients, but none developed hepatic insufficiency or severe complications. The mean whole liver volume was 7406 ± 2323 mL before TAE, and 6995 ± 2139 mL (95.1 ± 5.2% of the pre-therapeutic value) at 3 months and 6855 ± 2246 mL (93.3 ± 9.7%) at 12 months after TAE. Three of the five patients reported an improvement of clinical symptoms within 12 months after TAE. TAE with microspheres can be a safe and effective treatment for symptomatic enlarged PCLD.

The various forms of hereditary systemic amyloidosis without peripheral neuropathy have often been referred to as “Ostertag-type amyloidosis” [1,2]. The majority of cases have been so far reported ...

We herein report a case of spontaneous pregnancy and preterm delivery in a 29-year-old patient with myeloperoxidase-antineutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis. Her basal serum creatinine level before pregnancy was 1.4 mg/dL and her urinary protein level was approximately 2 g/day. The proteinuria and hematuria increased during pregnancy, and the patient was admitted to our hospital and treated with prednisolone (PSL). At 27 weeks of gestation, she delivered a live infant weighing 848 g via cesarean section. No relapse of ANCA-associated glomerulonephritis occurred. © 2013 The Japanese Society of Internal Medicine.