Publications by authors named "Saori Nishio"

45 Publications

Comparison of administration of single- and triple-course steroid pulse therapy combined with tonsillectomy for immunoglobulin A nephropathy.

Medicine (Baltimore) 2021 Dec;100(50):e27778

Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan.

Abstract: Immunoglobulin A nephropathy (IgAN) is a form of chronic glomerulonephritis that can cause end-stage renal disease. Recently, tonsillectomy combined with corticosteroid pulse (TSP) has been shown to be effective for achieving clinical remission and favorable renal outcome in patients with IgAN. However, the standard regimen of corticosteroid use in TSP has not been established. Herein, we compared the effect of single- or triple-course steroid pulse therapy combined with tonsillectomy in patients with IgAN.This retrospective, observational cohort study included 122 patients with IgAN enrolled from January 2004 to December 2018 at 2 independent institutions. We divided the patients into 2 groups; single-course (TSP1: n = 70) and triple-course (TSP3: n = 52) of corticosteroid pulse therapy (1 course comprised 3 consecutive days' infusion of 0.5 g methylprednisolone) combined with tonsillectomy. The primary outcome for renal survival was defined as the first occurrence of ≧30% decrease in estimated glomerular filtration rate from baseline. Secondary outcomes included the incidence of clinical remission and recurrence of the disease.Regarding clinical parameters and findings at baseline, there were no significant differences between the 2 groups. The 8-years renal survival in the 2 groups was not significantly different according to Kaplan-Meier curves (TSP1; 82.5% vs TSP3; 69.2%, log-rank test P = .39). The cumulative incidence rates of remission of hematuria (94.4% vs 85.4%, P = .56) and clinical remission (85.0% vs 64.8%, P = .07) were comparable in both groups, while those of proteinuria showed higher rates in TSP1 than TSP3 (88.4% vs 65.4%, P = .02). The cumulative incidence of relapse of hematuria (5.6% vs 2.3%, P = .42) and proteinuria (7.1% vs 3.3%, P = .41) showed no significant differences in the 2 groups. Cox regression analyses showed that the number of courses of corticosteroid pulse therapy was not significantly associated with renal outcome (TSP1 vs TSP3; Hazard ratios 0.69, 95% confidence intervals 0.29-1.64, P = .39).The effect of single-course corticosteroid pulse therapy is not statistically, significantly different from triple-course in TSP protocol for improving renal outcome and preventing relapse in patients with IgAN. Single-course corticosteroid pulse therapy may become a treatment option for patients with IgAN.
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http://dx.doi.org/10.1097/MD.0000000000027778DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8677957PMC
December 2021

Factors predicting decline in renal function and kidney volume growth in autosomal dominant polycystic kidney disease: a prospective cohort study (Japanese Polycystic Kidney Disease registry: J-PKD).

Clin Exp Nephrol 2021 Sep 29;25(9):970-980. Epub 2021 Apr 29.

Department of Advanced Informatics for Genetic Disease, Juntendo University, Tokyo, Japan.

Background: Factors affecting decline in renal function and cyst growth in patients with autosomal polycystic kidney disease (ADPKD) are not fully described, particularly in Japan.

Methods: 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.

Results: 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 m/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).

Conclusions: 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.
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http://dx.doi.org/10.1007/s10157-021-02068-xDOI Listing
September 2021

Better remission rates in elderly Japanese patients with primary membranous nephropathy in nationwide real-world practice: The Japan Nephrotic Syndrome Cohort Study (JNSCS).

Clin Exp Nephrol 2020 Oct 19;24(10):893-909. Epub 2020 Jun 19.

Division of Nephrology, Department of Medicine, Kurume University School of Medicine, 67 Asahimachi, Kurume, Fukuoka, 830-0011, Japan.

Background: 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.

Patients And Methods: 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.

Results: 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.

Conclusion: Early immunosuppressive therapy including corticosteroids for primary MN showed better remission rates in elderly patients in a nationwide cohort study.
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http://dx.doi.org/10.1007/s10157-020-01913-9DOI Listing
October 2020

Increased urinary exosomal SYT17 levels in chronic active antibody-mediated rejection after kidney transplantation via the IL-6 amplifier.

Int Immunol 2020 09;32(10):653-662

Molecular Psychoimmunology, Institute for Genetic Medicine, Graduate School of Medicine, Hokkaido University, Sapporo, Japan.

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.
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http://dx.doi.org/10.1093/intimm/dxaa032DOI Listing
September 2020

Incidence of remission and relapse of proteinuria, end-stage kidney disease, mortality, and major outcomes in primary nephrotic syndrome: the Japan Nephrotic Syndrome Cohort Study (JNSCS).

Clin Exp Nephrol 2020 Jun 7;24(6):526-540. Epub 2020 Mar 7.

Department of Nephrology, Nagasaki University Hospital, 1-7-1 Sakamoto, Nagasaki, Nagasaki, 852-8501, Japan.

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.
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http://dx.doi.org/10.1007/s10157-020-01864-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7248042PMC
June 2020

Recombinant thrombomodulin ameliorates autoimmune vasculitis via immune response regulation and tissue injury protection.

J Autoimmun 2020 03 26;108:102390. Epub 2019 Dec 26.

Faculty of Health Sciences, Hokkaido University, Sapporo, Japan.

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.
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http://dx.doi.org/10.1016/j.jaut.2019.102390DOI Listing
March 2020

The relationship between liver cyst volume and QOL in Japanese ADPKD patients.

Clin Exp Nephrol 2020 Apr 26;24(4):314-322. Epub 2019 Dec 26.

Department of Advanced Informatics for Genetic Disease, Juntendo University Graduate School of Medicine, Tokyo, Japan.

Background: 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.

Methods: 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.

Results: 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.

Conclusion: 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.
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http://dx.doi.org/10.1007/s10157-019-01830-6DOI Listing
April 2020

Monkeys mutant for PKD1 recapitulate human autosomal dominant polycystic kidney disease.

Nat Commun 2019 12 11;10(1):5517. Epub 2019 Dec 11.

Department of Stem Cells and Human Disease Models, Research Center for Animal Life Science, Shiga University of Medical Science, Shiga, 520-2192, Japan.

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.
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http://dx.doi.org/10.1038/s41467-019-13398-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6904451PMC
December 2019

The Pathogenicity of BPI-ANCA in a Patient With Systemic Vasculitis.

Front Immunol 2019 12;10:1334. Epub 2019 Jun 12.

Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan.

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. A 76-year-old Japanese man showed BPI-ANCA positive systemic vasculitis with a medical history of infection. BPI-ANCA IgGs were eluted from the patient serum using an immunoadsorbent column. 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. 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. BPI-ANCA could affect neutrophils leading to NET formation and may play a role in the development of systemic vasculitis as pathogenic autoantibody.
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http://dx.doi.org/10.3389/fimmu.2019.01334DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6583233PMC
October 2020

Impact of Weekly Teriparatide on the Bone and Mineral Metabolism in Hemodialysis Patients With Relatively Low Serum Parathyroid Hormone: A Pilot Study.

Ther Apher Dial 2020 Apr 21;24(2):146-153. Epub 2019 Jul 21.

Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan.

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.
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http://dx.doi.org/10.1111/1744-9987.12867DOI Listing
April 2020

A case report dysregulated neutrophil extracellular traps in a patient with propylthiouracil-induced anti-neutrophil cytoplasmic antibody-associated vasculitis.

Medicine (Baltimore) 2019 Apr;98(17):e15328

Department of Rheumatology, Nephrology and Endocrinology, Faculty of Medicine and Graduate School of Medicine.

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.
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http://dx.doi.org/10.1097/MD.0000000000015328DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6831184PMC
April 2019

The presence of anti-neutrophil extracellular trap antibody in patients with microscopic polyangiitis.

Rheumatology (Oxford) 2019 07;58(7):1293-1298

Department of Medical Laboratory Science, Faculty of Health Sciences, Hokkaido University, Sapporo, Japan.

Objective: Although ANCA is the major autoantibody in patients with ANCA-associated vasculitis, previous studies have suggested the presence of anti-neutrophil extracellular trap (NET) antibody in patients with microscopic polyangiitis (MPA), one type of ANCA-associated vasculitis. 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, MPO-ANCA, creatinine, CRP, 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 between ANETA and 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 in order to understand the pathophysiology of MPA.
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http://dx.doi.org/10.1093/rheumatology/kez089DOI Listing
July 2019

Initial experience with the use of tris-acryl gelatin microspheres for transcatheter arterial embolization for enlarged polycystic liver.

Clin Exp Nephrol 2019 Jun 15;23(6):825-833. Epub 2019 Feb 15.

Department of Radiology, St. Marianna University School of Medicine, Kawasaki, Japan.

Purpose: 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).

Materials And Methods: 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.

Results: 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.

Conclusion: TAE with microspheres can be a safe and effective treatment for symptomatic enlarged PCLD.
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http://dx.doi.org/10.1007/s10157-019-01714-9DOI Listing
June 2019

Regional variations in immunosuppressive therapy in patients with primary nephrotic syndrome: the Japan nephrotic syndrome cohort study.

Clin Exp Nephrol 2018 Dec 20;22(6):1266-1280. Epub 2018 Apr 20.

Division of Nephrology, Department of Medicine, Kurume University School of Medicine, 67 Asahimachi, Kurume, Fukuoka, 830-0011, Japan.

Background: 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.

Methods: 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.

Results: 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.

Conclusion: Use of intravenous methylprednisolone for MCD and MN differed geographically in Japan. Its efficacy should be further evaluated in a well-designed trial.
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http://dx.doi.org/10.1007/s10157-018-1579-xDOI Listing
December 2018

Interferon-inducible Mx1 protein is highly expressed in renal tissues from treatment-naïve lupus nephritis, but not in those under immunosuppressive treatment.

Mod Rheumatol 2018 Jul 30;28(4):661-669. Epub 2017 Nov 30.

a Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine , Hokkaido University , Sapporo , Japan.

Objectives: 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).

Patients And Methods: 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.

Results: 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.

Conclusion: 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.
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http://dx.doi.org/10.1080/14397595.2017.1404711DOI Listing
July 2018

Branched-chain amino acids enhance cyst development in autosomal dominant polycystic kidney disease.

Kidney Int 2017 08 22;92(2):377-387. Epub 2017 Mar 22.

Division of Rheumatology, Endocrinology and Nephrology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.

Autosomal dominant polycystic kidney disease (ADPKD) is characterized by the progressive development of kidney and liver cysts. The mammalian target of rapamycin (mTOR) cascade is one of the important pathways regulating cyst growth in ADPKD. Branched-chain amino acids (BCAAs), including leucine, play a crucial role to activate mTOR pathway. Therefore, we administered BCAA dissolved in the drinking water to Pkd1:Mx1-Cre (cystic) mice from four to 22 weeks of age after polyinosinic-polycytidylic acid-induced conditional Pkd1 knockout at two weeks of age. The BCAA group showed significantly greater kidney/body weight ratio and higher cystic index in both the kidney and liver compared to the placebo-treated mice. We found that the L-type amino acid transporter 1 that facilitates BCAA entry into cells is strongly expressed in cells lining the cysts. We also found increased cyst-lining cell proliferation and upregulation of mTOR and mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) pathways in the BCAA group. In vitro, we cultured renal epithelial cell lines from Pkd1 null mice with or without leucine. Leucine was found to stimulate cell proliferation, as well as activate mTOR and MAPK/ERK pathways in these cells. Thus, BCAA accelerated disease progression by mTOR and MAPK/ERK pathways. Hence, BCAA may be harmful to patients with ADPKD.
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http://dx.doi.org/10.1016/j.kint.2017.01.021DOI Listing
August 2017

Peptidylarginine Deiminase Inhibitor Suppresses Neutrophil Extracellular Trap Formation and MPO-ANCA Production.

Front Immunol 2016 8;7:227. Epub 2016 Jun 8.

Faculty of Health Sciences, Hokkaido University , Sapporo , Japan.

Myeloperoxidase-antineutrophil cytoplasmic antibody (MPO-ANCA)-associated vasculitis is a systemic small-vessel vasculitis, wherein, MPO-ANCA plays a critical role in the pathogenesis. Neutrophil extracellular traps (NETs) released from activated neutrophils are composed of extracellular web-like DNA and antimicrobial proteins, including MPO. Diverse stimuli, such as phorbol myristate acetate (PMA) and ligands of toll-like receptors (TLR), induce NETs. Although TLR-mediated NET formation can occur with preservation of living neutrophilic functions (called vital NETosis), PMA-stimulated neutrophils undergo cell death with NET formation (called suicidal NETosis). In the process of suicidal NETosis, histones are citrullinated by peptidylarginine deiminase 4 (PAD4). Since this step is necessary for decondensation of DNA, PAD4 plays a pivotal role in suicidal NETosis. Although NETs are essential for elimination of microorganisms, excessive formation of NETs has been suggested to be implicated in MPO-ANCA production. This study aimed to determine if pan-PAD inhibitors could suppress MPO-ANCA production in vivo. At first, NETs were induced in peripheral blood neutrophils derived from healthy donors (1 × 10(6)/ml) by stimulation with 20 nM PMA with or without 20 μM propylthiouracil (PTU), an anti-thyroid drug. We then determined that the in vitro NET formation was inhibited completely by 200 μM Cl-amidine, a pan-PAD inhibitor. Next, we established mouse models with MPO-ANCA production. BALB/c mice were given intraperitoneal (i.p.) injection of PMA (50 ng at days 0 and 7) and oral PTU (2.5 mg/day) for 2 weeks. These mice were divided into two groups; the first group was given daily i.p. injection of PBS (200 μl/day) (n = 13) and the other group with daily i.p. injection of Cl-amidine (0.3 mg/200 μl PBS/day) (n = 7). Two weeks later, citrullination as an indicator of NET formation in the peritoneum and serum MPO-ANCA titer was compared between the two groups. Results demonstrated that citrullination in the peritoneum was significantly reduced in the Cl-amidine-treated mice compared with the vehicle-injected control mice (38% reduction). Additionally, the serum MPO-ANCA titer of the Cl-amidine-treated mice (32.3 ± 31.0 ng/ml) was significantly lower than that in the vehicle-injected mice (132.1 ± 41.6 ng/ml). The collective findings indicate that excessive formation of NETs may be implicated in MPO-ANCA production in vivo.
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http://dx.doi.org/10.3389/fimmu.2016.00227DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4896908PMC
July 2016

[Polycystic kidney disease].

Authors:
Saori Nishio

Nihon Jinzo Gakkai Shi 2015 ;57(8):1354-8

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May 2016

The responses of macrophages in interaction with neutrophils that undergo NETosis.

J Autoimmun 2016 Feb 4;67:19-28. Epub 2015 Sep 4.

Faculty of Health Sciences, Hokkaido University, Sapporo 0600812, Japan. Electronic address:

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.
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http://dx.doi.org/10.1016/j.jaut.2015.08.018DOI Listing
February 2016

The first pure form of Ostertag-type amyloidosis in Japan: a sporadic case of hereditary fibrinogen Aα-chain amyloidosis associated with a novel frameshift variant.

Amyloid 2015 27;22(2):142-4. Epub 2015 May 27.

Department of Biological Sciences for Intractable Neurological Disorders, Institute for Biomedical Sciences, Shinshu University , Matsumoto , Japan .

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http://dx.doi.org/10.3109/13506129.2015.1037389DOI Listing
April 2016

Transcatheter Arterial Embolization with Ethanol Injection in Symptomatic Patients with Enlarged Polycystic Kidneys.

Radiology 2015 Oct 29;277(1):277-85. Epub 2015 Apr 29.

From the Department of Diagnostic and Interventional Radiology (Y.S., D.A., T.S., K.K.), Department of Medicine II (S.N.), Department of Urology (K.M.), and Translational Research and Clinical Trial Center (K.O.), Hokkaido University Hospital, N-14, W-5, Kita-ku, Sapporo, Hokkaido 060-0848, Japan; Department of Diagnostic Radiology, Sapporo City General Hospital, Sapporo, Japan (Y.H.); Department of Radiology, Steel Memorial Muroran Hospital, Murofan, Japan (N.Y.); Department of Medicine IV, Tokyo Women's Medical University, Tokyo, Japan (T.M.); and Department of Radiation Medicine, Hokkaido University Graduate School of Medicine, Sapporo, Japan (H.S.).

Purpose: To evaluate the safety and effectiveness of transcatheter arterial embolization (TAE) with ethanol in symptomatic patients with enlarged polycystic kidney disease.

Materials And Methods: This prospective study was institutional review board approved and was planned for patients with symptoms related to enlarged polycystic kidney disease, such as a markedly distended abdomen, gastroesophageal reflux, and abdominal pain. At the time of TAE, all patients were undergoing dialysis therapy for chronic renal failure, and their urinary volume had decreased to less than 500 mL per day. Bilateral renal TAE with absolute ethanol was performed, and changes in kidney volume, clinical symptoms, laboratory data, and complications were evaluated after TAE. The differences in patients' kidney volumes, clinical symptoms, abdominal circumference, and dry weights before and after TAE were analyzed with a mixed effect model.

Results: Fifteen patients (seven men and eight women; mean age, 57.7 years ± 5.3 [standard deviation]) were treated. Among the 15 patients, the follow-up period was 24 months in 13 patients, 6 months in one patient, and 3 months in one patient. The mean kidney volume was 3380 mL before renal TAE, and at 3, 12, and 24 months after TAE, it significantly decreased to 60.9%, 39.8%, and 32.1% of the pretherapeutic value, respectively (P < .001). All patients reported improved clinical symptoms within 3 months after TAE (P < .001). Abdominal circumferences were significantly decreased after TAE (P < .001). The dry weights also continued to significantly decreased until 6 months after TAE (P < .001), at which point they began to slightly increase until 24 months after TAE. Abdominal pain, nausea, and inflammatory response developed in all patients after TAE, but these symptoms improved with conservative treatment. Abscess formation was found in one kidney, and drainage catheter placement was performed. No major complications related to TAE occurred in the remaining patients.

Conclusion: Renal contraction therapy by TAE with ethanol injection appears to be a safe and effective treatment in patients with symptomatic enlarged polycystic kidney disease.
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http://dx.doi.org/10.1148/radiol.2015141637DOI Listing
October 2015

Outcomes of primary nephrotic syndrome in elderly Japanese: retrospective analysis of the Japan Renal Biopsy Registry (J-RBR).

Clin Exp Nephrol 2015 Jun 18;19(3):496-505. Epub 2014 Sep 18.

Department of Nephrology, Nagoya University Graduate School of Medicine, Nagoya, Japan.

Background And Objectives: There are very little data available regarding nephrotic syndrome (NS) in elderly (aged ≥65 years) Japanese. The aim of this study was to examine the causes and outcomes of NS in elderly patients who underwent renal biopsies between 2007 and 2010.

Design, Setting, Participants, And Measurements: From July 2007 to June 2010, all of the elderly (aged ≥65 years) Japanese primary NS patients who underwent native renal biopsies and were registered in the Japan renal biopsy registry (J-RBR; 438 patients including 226 males and 212 females) were identified. From this cohort, 61 patients [28 males and 33 females including 29, 19, 6, 4, and 3 patients with membranous nephropathy (MN), minimal change nephrotic syndrome (MCNS), focal segmental glomerulosclerosis (FSGS), membranoproliferative glomerulonephritis (MPGN), and other conditions, respectively] were registered from the representative multi-centers over all districts of Japan, and analyzed retrospectively. The treatment outcome was assessed using proteinuria-based criteria; i.e., complete remission (CR) was defined as urinary protein level of <0.3 g/day or g/g Cr, and incomplete remission type I (ICR-I) was defined as urinary protein level of <1.0-0.3 g/day or g/g Cr, and renal dysfunction was defined as a serum creatinine (Cr) level of 1.5 times the baseline level.

Results: In this elderly primary NS cohort, MN was the most common histological type of NS (54.8 %), followed by MCNS (19.4 %), FSGS (17.4 %), and MPGN (8.4 %). Of the patients with MN, MCNS, or FSGS, immunosuppressive therapy involving oral prednisolone was performed in 25 MN patients (86.2 %), 18 MCNS patients (94.7 %), and all 6 FSGS patients (100 %). CR was achieved in all 19 (100 %) MCNS patients. In addition, CR and ICR-I were achieved in 16 (55.2 %) and 18 (62.1 %) MN patients and 4 (66.7 %) and 5 (83.3 %) FSGS patients, respectively. There were significant differences in the median time to CR among the MCNS, FSGS, and MN patients (median: 26 vs. 271 vs. 461 days, respectively, p < 0.001), and between the elderly (65-74 years, n = 7) and very elderly (aged ≥75 years, n = 12) MCNS patients (7 vs. 22 days, p = 0.037). Relapse occurred in two (6.9 %) of the MN and nine (47.4 %) of the MCNS patients. Renal dysfunction was observed in five (7.2 %) of the MN patients. Serious complications developed in eight (14.8 %) patients, i.e., two (3.7 %) patients died, four (7.4 %, including three MCNS patients) were hospitalized due to infectious disease, and two (3.7 %) developed malignancies. The initiation of diabetic therapy was necessary in 14 of the 61 patients (23.0 %) with much higher initial steroid dosage.

Conclusion: Renal biopsy is a valuable diagnostic tool for elderly Japanese NS patients. In this study, most of elderly primary NS patients respond to immunosuppressive therapy with favorable clinical outcomes. On the other hand, infectious disease is a harmful complication among elderly NS patients, especially those with MCNS. In future, modified clinical guidelines for elderly NS patients should be developed.
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http://dx.doi.org/10.1007/s10157-014-1022-xDOI Listing
June 2015

Diffuse renal (18)F-FDG uptake of a patient with fever of unknown origin revealed sarcoidosis.

Clin Nucl Med 2014 Jul;39(7):648-9

From the Departments of *Nuclear Medicine, and †Internal Medicine II, Hokkaido University Graduate School of Medicine; and ‡Department of Pathology, KKR Sapporo Medical Center, Sapporo, Hokkaido, Japan.

We report about the usefulness of F-FDG PET for the detection and therapy response evaluation of renal sarcoidosis. A 55-year-old woman presented with a condition diagnosed with pulmonary and ocular sarcoidosis 2 years before having anemia and acute deterioration of renal function. FDG PET revealed diffuse increased FDG uptake in both kidneys and the spleen. Histopathologic examination of a renal biopsy sample revealed granulomatous interstitial nephritis with sarcoidosis. After methylprednisolone treatment, the abnormal FDG uptake resolved completely with improvement of symptoms. FDG PET is a useful tool to detect active sarcoidosis regions and to monitor treatment efficacy.
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http://dx.doi.org/10.1097/RLU.0000000000000488DOI Listing
July 2014

[NETs in pathogenesis of vasculitis].

Nihon Jinzo Gakkai Shi 2014 ;56(2):117-23

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May 2014

Enhanced formation and disordered regulation of NETs in myeloperoxidase-ANCA-associated microscopic polyangiitis.

J Am Soc Nephrol 2014 May 2;25(5):990-7. Epub 2014 Jan 2.

Faculty of Health Sciences, Hokkaido University, Sapporo, Japan

Microscopic polyangiitis (MPA) is an ANCA-associated vasculitis that affects small vessels, especially renal glomeruli. We recently demonstrated that the abnormal formation and impaired degradation of neutrophil extracellular traps (NETs) may be crucially involved in the generation of myeloperoxidase (MPO)-ANCA and subsequent development of MPA. This study assessed the formation and regulation of NETs in patients with MPO-ANCA-associated MPA. Peripheral blood samples were obtained from 38 patients with MPO-ANCA-associated MPA, 23 patients with systemic lupus erythematosus (SLE), and 8 healthy controls. IgG eluted from MPO-ANCA-associated MPA sera demonstrated the highest ability to induce NETs, and this ability correlated with disease activity and paralleled ANCA affinity for MPO. Moreover, addition of recombinant human MPO to these IgG samples reduced NET induction. Additionally, MPO-ANCA-associated MPA sera exhibited lower rates of NET degradation that recovered partially upon depletion of IgG. The activity of DNase I, an important regulator of NETs, was also lower in MPO-ANCA-associated MPA and SLE sera. IgG depletion from MPO-ANCA-associated MPA sera partially restored the rate of NET degradation, and addition of DNase I synergistically enhanced this restoration. Addition of anti-MPO antibodies did not inhibit DNase I activity, and some MPO-ANCA-associated MPA sera contained anti-NET antibodies at levels not correlated with MPO-ANCA titers, suggesting the involvement of unidentified autoantibodies as well. The collective evidence suggests a vicious cycle involving MPO-ANCA and the regulation of NETs could be critically involved in the pathogenesis of MPO-ANCA-associated MPA.
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http://dx.doi.org/10.1681/ASN.2013060606DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4005303PMC
May 2014

Successful delivery in a patient with antineutrophil cytoplasmic antibody-associated glomerulonephritis.

Intern Med 2013 15;52(14):1605-9. Epub 2013 Jul 15.

Division of Nephrology, Kanazawa University Hospital, Japan.

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.
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http://dx.doi.org/10.2169/internalmedicine.52.0243DOI Listing
March 2014
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