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A 73-year-old Japanese woman, with a history of Sweet syndrome diagnosed 3 years earlier and anti-myeloperoxidase (MPO) antibody anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis diagnosed 1 year earlier, presented with an episode of rapidly progressive glomerulonephritis (RPGN) with anti-glomerular basement membrane (GBM) disease. At the time of diagnosis of the ANCA-associated vasculitis 1 year earlier, serological testing yielded a negative result for anti-GBM antibody. However, at the present visit, serology for anti-MPO antibody was negative, while that for anti-GBM antibody was positive. This is the first report of anti-GBM disease developing sequentially after Sweet syndrome and ANCA-associated vasculitis. This case may provide clues to the potential immunological links among these three distinct conditions.

The association between the urinary sodium (Na)/potassium (K) ratio and hypertension is well recognized. We investigated whether the urinary Na/K ratio might be associated with hypertension in community-dwelling older adults and whether the association was influenced by habitual dietary patterns. We enrolled a total of 684 older adults (mean age, 76.8 years) and conducted health examinations at Kusatsu, Japan, in 2021. The urinary Na/K ratio was found to be independently associated with systolic blood pressure (SBP) (p 0.0001), years of education (p = 0.0027), number of cohabitants (p = 0.0175), estimated glomerular filtrate rate (eGFR) (p = 0.0244), and Geriatric Depression Scale short-version (GDS15) score (p = 0.0366). In addition, an unsupervised hierarchical clustering analysis revealed a spectrum of habitual dietary patterns for higher and lower values of the urinary Na/K ratio. The decision tree indicated that the urinary Na/K ratio was associated with the history of milk consumption. A positive history of daily milk consumption predicted a mean urinary Na/K ratio of 2.8, and a negative history of daily milk consumption predicted a mean urinary Na/K ratio of 3.3. Furthermore, the frequency of fruit and vegetable consumption also predicted the urinary Na/K ratio. The relationship between the urinary Na/K ratio and hypertension was influenced by the frequency of consumption of milk, fruits, and vegetables in the subjects. This finding might be due to the influence of education and/or depression. The results suggested the importance of nutritional education in the development of hypertension.

Diabetic kidney disease (DKD), a chronic kidney disease caused by diabetes and other comorbidities, is the leading cause of end-stage renal disease. The pathogenesis of DKD is diverse and influenced by various causes, some but not all of which cause proteinuria. Some factors such as hypertension can modify DKD. Therefore, the spectrum of DKD is difficult to elucidate and remains unsolved. This study aims to classify and characterize DKD.We examined autopsy specimens from type 2 diabetes mellitus (DM) (n = 44) and non-DM (n = 21) groups.The frequency of interstitial fibrosis and tubular atrophy was higher in patients with proteinuric DKD than in those with non-proteinuric DKD. The presence of polar vasculosis was associated with hypertension in DKD. In addition, an unsupervised hierarchical clustering analysis revealed the spectrum of renal histopathology findings for more-proteinuric and less-proteinuric DKD. With changes in the diagnostic criteria for hypertension and advances in antihypertensive drugs, the pathogenesis of DKD may be changing. Furthermore, a decision tree model suggested how diabetes, hypertension, and dyslipidemia interacted in predicting the characteristics of DKD.Polar vasculosis is a good indicator of the presence of DM and hypertension. Furthermore, the histopathological and clinical spectrum of DKD were related to the interaction of diabetes, hypertension, and dyslipidemia. These histopathological and clinical results may help to show the range of patient characteristics when conducting clinical trials and could help to determine whether chronic kidney disease is caused by DM or some other cause.

A slowly progressive middle-aged man initially diagnosed with thin basement membrane nephropathy based on extensive thinning of the glomerular basement membrane (GBM) was subsequently diagnosed with Alport syndrome (AS) by a serial renal biopsy eight years later. The ultrastructural analysis of the second biopsy indicated thickening and wrinkling with mild reticulation in the GBM, consistent with AS. However, a retrospective analysis of the first biopsy revealed mild attenuation of type IV collagen α5 chain staining, suggesting a potential diagnosis of AS, despite the lack of ultrastructural features of AS. We herein report the clinical usefulness of type IV collagen staining in the early diagnosis of AS.

Ascorbate functions as an electron donor and scavenges free radicals. Dehydroascorbic acid (DHA), the oxidized form of ascorbate, is generated as a result of these reactions. While low plasma ascorbate levels have been reported in hemodialysis patients worldwide, no studies have measured DHA because it is not generalized. In this study, we aimed to clarify whether plasma ascorbate levels are low in dialysis patients and whether plasma ascorbate levels fluctuate before and after dialysis. Moreover, we applied our previously established method to measure the plasma ascorbate and DHA levels in chronic kidney disease (CKD) stage G3–G5 non-hemodialysis-dependent patients, and pre- and post-dialysis plasma ascorbate and DHA levels in CKD stage G5D hemodialysis patients. The sample size was calculated using G-power software. The pre-dialysis plasma total ascorbate levels, including DHA, were significantly (56%) lower in hemodialysis patients than in non-hemodialysis-dependent CKD patients. After dialysis, there was a 40% reduction in the plasma total ascorbate levels. Hemodialysis increased the post-dialysis plasma proportions of DHA from 37% to 55%. The study results demonstrated lower plasma total ascorbate levels in hemodialysis patients compared with in non-hemodialysis-dependent CKD patients, these low levels in hemodialysis patients were further reduced by hemodialysis and increased DHA proportion.

The aim of this autopsy study was to clarify the differences of renal histopathology between non-chronic kidney disease (CKD) and CKD caused by hypertensive-nephrosclerosis in the elderly and during the aging process.We examined autopsy specimens from 105 elderly patients (53 male subjects; mean age, 86.2 years) including 44 patients with CKD as a result of nephrosclerosis. The analysis was divided into two groups depending on whether they had CKD.The incidences of arterial intimal thickening (AIT), obsolescent-type global glomerulosclerosis (OB), and interstitial fibrosis and tubular atrophy (IF/TA) were higher in the CKD group than in the non-CKD group (all p 0.01). These factors were all correlated with each other (AIT vs. OB, r = 0.43; AIT vs. IF/TA, r = 0.25; OB vs. IF/TA, r = 0.53). IF/TA had the strongest association with hypertension and decreased eGFR. In the non-CKD group, the frequency of OB was more than 20% in subjects aged 90 years or older. However, the individuals in the non-CKD group tended to have compensatory glomerular hypertrophy with increasing age and a retained eGFR, while the CKD group was unable to obtain compensatory hypertrophy and had a lower eGFR. We also found that AIT, OB and IF/TA occurred independently of systemic atherosclerosis.Non-CKD in the elderly refers to the so-called aging kidney. The progression from aging kidney to CKD caused by nephrosclerosis was influenced by increases in AIT, OB and IF/TA. IF/TA was thought to be the most important downstream factor in the progression of aging kidney to CKD.

Aim Neutrophil extracellular traps play key roles in the necrotizing vasculitis associated with anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV). However, the relationships between neutrophil extracellular traps formation and the distribution and phase of vasculitis are not well understood. In the present study, we clarified the clinicopathological characteristics of older AAV patients, as well as the expression of citrullinated histone H3 (citH3), a marker of neutrophil extracellular traps, in autopsied AAV patients. Methods We reviewed autopsy cases that were carried out at Tokyo Metropolitan Geriatric Hospital, Tokyo, Japan, from 2001 to 2018. The expression of citH3 was determined by immunostaining. Results AAV patients (six cases) were elderly (aged 73-94 years; three men and three women; myeloperoxidase anti-neutrophil cytoplasmic antibody-positive, five cases; proteinase-3 anti-neutrophil cytoplasmic antibody-positive, one case; disease duration was 1.5-5.5 months; and patients were treated with steroids. All patients had necrotizing vasculitis in the medium-to-small-sized vessels in various organs, and also severe vasculitis-associated lesions including brain hemorrhage, alveolar bleeding, interstitial pneumonia, crescentic nephritis, acute pancreatitis and gastrointestinal bleeding. Expression of citH3 was associated with the activity of inflammation. Conclusions We report severe clinicopathological characteristics of AAV in older patients. Expression of citH3 was a useful marker to evaluate vasculitis severity. Identification of these features might aid in the diagnosis of AAV. Geriatr Gerontol Int 2019; 19: 259-264.

Background: Low plasma ascorbate levels in hemodialysis patients have been reported worldwide; hence, many end-stage kidney disease patients are forced to restrict their diets, especially potassium-rich fruits and vegetables, to prevent hyperkalemia. In this study, we aimed to clarify whether plasma ascorbate levels are low in Japanese dialysis patients and whether plasma ascorbate levels fluctuate before and after dialysis. In addition, we aimed to clarify whether there are clinical test items that have a causal relationship with plasma ascorbate levels.Methods: Plasma ascorbate levels in 27 chronic kidney disease (CKD) stage G3–G5 patients (mean age 84 years) and pre- and post-dialysis plasma ascorbate levels in 19 CKD stage G5D hemodialysis patients (mean age 79 years) were determined using high-performance liquid chromatography and electrochemical detection.Results: Pre-dialysis plasma ascorbate levels in hemodialysis patients (12.0 ± 1.4 µM) were significantly lower (by 56%) than those in CKD stage G3–G5 patients (27.1 ± 2.7 µM). After dialysis, there was a 40% reduction in plasma ascorbate levels. Moreover, pre-dialysis ascorbate levels correlated significantly with plasma potassium levels.Conclusions: The study results indicate that Japanese hemodialysis patients have lower plasma ascorbate levels than CKD stage G3–G5 patients and that these low plasma ascorbate levels in hemodialysis patients were further reduced by hemodialysis. To avoid the development of scurvy in hemodialysis patients, it is necessary to take sufficient ascorbate from supplements or medicines.

Both the diagnosis of elderly-onset IgA vasculitis (IgAV) and its prognosis can be difficult because of its rarity and the likely presence of comorbidities. Furthermore, the treatment of elderly-onset IgAV remains controversial: the ideal dosages of corticosteroid and/or immunosuppressants have not been determined. In the elderly, corticosteroid adverse effects can lead to severe outcomes, and a consensus regarding its benefit and risk balance has not been reached. We report a case of IgAV in an 89-year-old patient who was admitted to our hospital to investigate a 30-day history of palpable purpura and pitting edema on her leg. A renal biopsy showed membranoproliferative glomerulonephritis with IgA deposits (The International Study of Kidney Disease in Children (ISKDC) grade VI), which is a predictor of a poor prognosis; these findings led to early intervention with low-dose corticosteroid (15 mg/day) and mizoribine. As a result, a complete remission without obvious adverse effects was obtained. Early intervention with low-dose corticosteroid and mizoribine based on renal histopathology results might be an effective treatment for elderly-onset ISKDC grade VI IgAV.

The objective of this study is to determine whether initial steroid therapy is actually effective for the treatment of iMN, and we examined a 40% reduction in estimated glomerular filtration rate (eGFR) and remission rates. This was a retrospective study between 1993 and 2013. First, we divided patients with iMN having a urinary protein level of ≥1 g/gCre into two groups: those who had received steroid therapy (Group S1; n = 52) within 6 months of diagnosis and those who had received supportive therapy (Group H1; n = 31). Second, we compared 20 cases using propensity score matching (Group S2, Group H2). Third, we compared patients with a urinary protein level of 1–3.5 g/gCre (Group S3, n = 18; Group H3, n = 19) and those with a urinary protein level ≥3.5 g/gCre (Group S4, n = 34; Group H4, n = 12). The primary endpoint was a 40% reduction in eGFR, and the secondary endpoint was the achievement of complete remission (CR). In Group S1 and Group H1, a 40% reduction in the eGFR was observed at the end of 5 years in 18 and 17% of the patients, respectively (P = 0.93); at the end of 10 years, these rates had increased to 43% and 50%, respectively (P = 0.88). The CR rates at the end of 5 years were 58% and 32%, respectively (P = 0.02), while the rates at 10 years were 65 and 39%, respectively (P = 0.02). No difference in renal outcomes was observed between Group S1 and Group H1. No significant differences were observed between Group S2 and Group H2, between Group S3 and Group H3, or between Group S4 and Group H4. Initial steroid therapy is not superior to supportive care within the first 6 months after diagnosis in terms of a 40% reduction in eGFR.

An 84-year-old man with chronic renal failure, anemia, and diabetes was admitted for hemodialysis initiation. His vital signs were stable until the eighteenth hospital day, before acquiring an influenza A virus infection. Three days later, he died of septic shock with severe liver impairment. His leukocyte count, prothrombin time (PT-INR), and liver enzyme levels such as aspartate transaminase and alanine aminotransferase, were significantly increased. Hypercytokinemia was also observed. Autopsy revealed bilateral diffuse pneumonia with neutrophil infiltration. The liver showed extensive centrilobular hepatocyte necrosis. Immunohistochemistry for influenza A nucleoprotein revealed positivity in the ciliated columnar epithelium of the bronchi and negativity in the trachea, lungs, and liver. Hypoxic hepatitis is characterized by an abrupt and massive increase in aminotransferase levels (＞ 20 times upper normal limit) due to anoxic centrilobular hepatocyte necrosis. The occurrence of hypoxic hepatitis requires a pre-existing, chronic condition, such as anemia, causing reduced oxygen supply to the liver, followed by an acute decrease in hepatic oxygen supply, such as septic shock. Therefore, this report suggests that hypoxic hepatitis can be an important causative factor for acute liver failure associated with influenza virus infection.

Estimated glomerular filtration rate (eGFR) is routinely calculated based on the serum creatinine level. However, the validity of such calculation in the geriatric population has not been sufficiently assessed. To examine whether the discrepancies between the eGFR determined based on the serum creatinine (eGFRcr) and that based on the serum cystatin C (eGFRcys) may be influenced to a lesser degree, by factors such as aging and muscle mass. We measured the cystatin C and creatinine levels in 19,764 subjects (mean 77.0 years) and the eGFRcys and eGFRcr using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI), Japanese, and Berlin Invitation Study (BIS) equations were calculated. The mean measured eGFRcys and eGFRcr values by the CKD-EPI equation were 48.2 and 66.6 ml/min/1.73 m2 body surface area, respectively. The correlation between the eGFRcr (x) and eGFRcys (y) was y = 0.728x (r = 0.867; p

Antineutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis is commonly classified as pauci-immune glomerulonephritis; however, some cases have granular immunoglobulin deposition along the glomerular capillary. The pathogenesis of immune deposits is poorly studied.Of 66 patients diagnosed with ANCA-associated glomerulonephritis on renal biopsy, cases with immunoglobulin deposition along the glomerular capillary were identified and their clinicopathological characteristics were analyzed. We also performed myeloperoxidase (MPO) and double immunofluorescence (IF) stainings to determine the presence of immune complex antigens.Granular IgG deposition, IgG plus IgM deposition, and IgM deposition were observed in 15 (22.1%), 8 (11.2%), and 17 (25.0%) cases, respectively. In cases with granular IgG deposition, MPO-IgG double IF staining revealed co-localization of MPO and IgG. In cases with granular IgM deposition, MPO-IgM double IF staining did not co-localize. By electron microscopy, subepithelial deposition as well as intramembranous, subendothelial, and mesangial deposition was detected in the patients with IgG deposition. In addition, renal survival curves were not significantly different between the immunoglobulin deposition and non-deposition groups.Granular IgG and/or IgM deposition was observed in 60.6% of patients with ANCA-associated glomerulonephritis. In cases with IgG deposition, electron-dense deposits (EDDs) were observed at various sites in the glomerulus, and MPO and IgG immunocomplex deposition was frequently observed along the glomerular capillary. With IgM deposition, EDDs were not obvious in the glomerular basement membrane, and MPO and IgM immunocomplex was not detected. These data suggest differential mechanism between IgG deposition and IgM deposition.

Neutrophil extracellular traps play key roles in the necrotizing vasculitis associated with anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV). However, the relationships between neutrophil extracellular traps formation and the distribution and phase of vasculitis are not well understood. In the present study, we clarified the clinicopathological characteristics of older AAV patients, as well as the expression of citrullinated histone H3 (citH3), a marker of neutrophil extracellular traps, in autopsied AAV patients.We reviewed autopsy cases that were carried out at Tokyo Metropolitan Geriatric Hospital, Tokyo, Japan, from 2001 to 2018. The expression of citH3 was determined by immunostaining.AAV patients (six cases) were elderly (aged 73-94 years; three men and three women; myeloperoxidase anti-neutrophil cytoplasmic antibody-positive, five cases; proteinase-3 anti-neutrophil cytoplasmic antibody-positive, one case; disease duration was 1.5-5.5 months; and patients were treated with steroids. All patients had necrotizing vasculitis in the medium-to-small-sized vessels in various organs, and also severe vasculitis-associated lesions including brain hemorrhage, alveolar bleeding, interstitial pneumonia, crescentic nephritis, acute pancreatitis and gastrointestinal bleeding. Expression of citH3 was associated with the activity of inflammation.We report severe clinicopathological characteristics of AAV in older patients. Expression of citH3 was a useful marker to evaluate vasculitis severity. Identification of these features might aid in the diagnosis of AAV. Geriatr Gerontol Int 2019; 19: 259-264.

To provide evidence for the revision of clinical practice guideline (CPG) for the management of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) by the Japan Research Committee for Intractable Vasculitis.PubMed, CENTRAL, and the Japan Medical Abstracts Society were searched for articles published between January 1994 and January 2015 to conduct systematic review (SR), and the quality of evidence was assessed with GRADE approach.Nine randomized controlled trials (RCTs) and two non-RCTs were adopted for remission induction therapy, three RCTs and two non-RCTs for plasma exchange, and five RCTs and one non-RCT for remission maintenance therapy. A significant difference was found in efficacy and safety for the following comparisons. In the non-RCT adopted for remission induction therapy, glucocorticoid (GC) + cyclophosphamide (CY) was significantly superior to GC monotherapy regarding remission. GC + intravenous CY for remission induction therapy was superior to GC + oral CY regarding death at one year, serious adverse events, and serious infection. Concomitant use of plasma exchange for remission induction therapy of AAV with severe renal dysfunction reduced risk of end-stage renal disease versus non-users at month 3.This SR provided necessary evidence for developing CPG for the management of ANCA-associated vasculitis.

Minimal change nephrotic syndrome (MCNS) usually responds to steroids but frequently relapses, requiring additional treatment with immunosuppressive agents. Rituximab is a chimeric murine/human monoclonal immunoglobulin G1 antibody that targets CD20, a B-cell differentiation marker. B-cell recovery begins at approximately 6 months following the completion of treatment. Rituximab has a beneficial effect, with the sustained remission or reduction of proteinuria in patients with steroid-dependent MCNS. Relapses are thought to be associated with an increase in CD19 cells. The mean serum half-life of rituximab was reported to be 10-15 days in patients with steroid-dependent MCNS. Only infusion reactions, such as rash and chills, occurred after single-dose rituximab infusion and can be managed by pre-medication or infusion rate adjustments. Even though severe adverse effects of rituximab are not expected, we must be aware of potentially life-threatening adverse effects. Controlled randomized trials that include adult patients with steroid-dependent MCNS are required to prove the efficacy and safety of rituximab and to evaluate the cost-effectiveness of rituximab treatment. In this review, we highlight recent studies and discuss the effects of these studies on the management of patients with MCNS in adults.

Atypical hemolytic uremic syndrome (aHUS) in allograft kidney transplantation is caused by various factors including rejection, infection, and immunosuppressive drugs. We present a case of a 32 year old woman with aHUS four years after an ABO-incompatible kidney transplantation from a living relative. The primary cause of end-stage renal disease was unknown; however, IgA nephropathy (IgAN) was suspected from her clinical course. She underwent pre-emptive kidney transplantation from her 60 year old mother. The allograft preserved good renal function [serum creatinine (sCr) level 110-130 μmol/L] until a sudden attack of abdominal pain four years after transplant, with acute renal failure (sCr level, 385.3 μmol/L), decreasing platelet count, and hemolytic anemia with schizocytes. On allograft biopsy, there was thrombotic microangiopathy in the glomeruli, with a cellular crescent formation and mesangial IgA and C3 deposition. Microvascular inflammation, such as glomerulitis, peritubular capillaritis, and arteriole endarteritis were also detected. A disintegrin-like and metalloproteinase with thrombospondin type 1 motifs 13 (ADAMTS13) did not decrease and Shiga toxin was not detected. Donor-specific antibodies or autoantibodies, including anti-neutrophil cytoplasmic antibody and anti-glomerular basement membrane (anti-GBM) antibody, were negative. The patient was diagnosed with aHUS and received three sessions of plasmapheresis and methylprednisolone pulse therapy, followed by oral methylprednisolone (0.25-0.5 mg/kg) instead of tacrolimus. She temporarily required hemodialysis (sCr level, 658.3 μmol/L). Thereafter, her sCr level improved to 284.5 μmol/L without dialysis therapy. This case is clinically considered as aHUS after kidney transplantation, associated with various factors, including rejection, glomerulonephritis, and toxicity from drugs such as tacrolimus.

Endothelial dysfunction is often found in both hyperuricemia and hemodialysis patients. Recent studies have shown that treating hyperuricemia with allopurinol improves endothelial dysfunction. This study is performed to assess the effect of febuxostat on endothelial dysfunction in hemodialysis patients with hyperuricemia. We randomly assigned 53 hemodialysis patients with hyperuricemia to a febuxostat (10 mg daily) group and a control group and measured flow-mediated dilation, serum uric acid (UA) levels, systolic and diastolic blood pressure, malondialdehyde-modified low-density lipoprotein (MDA-LDL), and highly sensitive C-reactive protein (hsCRP) at baseline and at the end of a 4-week study period. Flow-mediated dilation increased from 5.3% ± 2.4% to 8.9% ± 3.6% in the febuxostat group but did not change significantly in the control group. Treatment with febuxostat resulted in a significant decrease in serum UA level and a significant decrease in MDA-LDL compared with baseline, but no significant difference was observed in hsCRP level or blood pressure. No significant differences were observed in the control group. Febuxostat improved endothelial dysfunction and reduced serum UA levels and oxidative stress in hemodialysis patients with hyperuricemia.

Caveolae on human renal glomerular endothelial cells (HRGECs) are increased in glomerular disease and correlate with the degree of albuminuria. To assess the mechanism by which caveolae contribute to albuminuria, we investigated whether albumin enters into HRGECs through caveolae. HRGECs were incubated with Alexa Fluor 488 labeled BSA or transferrin, followed by immunofluorescence localization with antibody to caveolin-1 (Cav-1), the main structural protein of caveolae, or clathrin, the major structural protein of clathrin coated pits, to assess whether BSA colocalized with Cav-1. HRGECs were also incubated with albumin and caveolae disrupting agents, including methyl beta cyclodextrin (MBCD) and nystatin, to determine whether disrupting caveolae interfered with albumin endocytosis into HRGECs. HRGECs were also incubated with albumin after transfection with Cav-1 small interfering RNAs (siRNAs). Labeled BSA colocalized with Cav-1, but not with clathrin. In contrast, labeled transferrin colocalized with clathrin, but not with Cav-1. Incubation of HRGECs with MBCD or nystatin, or transfection with Cav-1 siRNA, significantly reduced the intracellular amounts of albumin and Cav-1, relative to normal HRGECs, as shown by western blotting and immunofluorescence. These findings indicate that albumin enters HRGECs through the caveolae, suggesting that caveolae play an important role in the pathogenesis of albuminuria by providing a pathway through which albumin can enter glomerular endothelial cells.

OBJECTIVE Immunoglobulin A nephropathy (IgAN) exhibits a peak onset that coincides with the reproductive age. Therefore, many young women with IgAN may become pregnant. However, the outcome of pregnancy in women with renal diseases remains controversial, and the characteristics and outcome of pregnancy in IgAN patients must be further evaluated. METHODS A prospective follow-up study of 64 pregnant women with IgAN was performed by analyzing the laboratory data and prognosis. To clarify the influence of renal insufficiency, we compared these patients according to the chronic kidney disease (CKD) stage with special attention to CKD stage 3 [N=16 in total, N=9 for estimated glomerular filtration rate (eGFR) ≥45 mL/min, N=7 for

Hyperuricemia is a frequent complication of chronic kidney disease (CKD). Febuxostat is a novel xanthine oxidase inhibitor that is metabolized by many metabolic pathways in the kidney and the liver. We performed a 1-year cohort study of 73 hyperuricemic patients who had an estimated glomerular filtration rate (eGFR) below 45 ml/min and were being treated with urate-lowering therapy. In 51 patients, treatment was changed from allopurinol to febuxostat, and the other 22 patients were continued on allopurinol. The serum levels of uric acid (UA) level, creatinine, and other biochemical parameters were measured at baseline and after 3, 6, 9, and 12 months of treatment. The serum UA levels significantly decreased from 6.1 ± 1.0 to 5.7 ± 1.2 mg/dl in the febuxostat group and significantly increased from 6.2 ± 1.1 to 6.6 ± 1.1 mg/dl in the allopurinol group. The eGFR decreased 27.3 to 25.7 ml/min in the febuxostat group and from 26.1 to 19.9 ml/min in the allopurinol group. The switch from allopurinol to febuxostat was significantly associated with the changes in eGFR according to a multiple regression analysis (β = −0.22145, P < 0.05). Febuxostat reduced the serum UA levels and slowed the progression of renal disease in our CKD cohort in comparison with allopurinol.

BACKGROUND Antineutrophil cytoplasmic autoantibody (ANCA) directed against myeloperoxidase (MPO), a diagnostic criterion in MPO-ANCA-associated vasculitis (MPO-AAV), does not always correlate with disease activity. Here, we detected autoantibodies against moesin, which was located on the surface of stimulated endothelial cells, in the serum of patients. METHODS The anti-moesin autoantibody titer was evaluated by ELISA. Seventeen kinds of cytokines/chemokines were measured by a Bio-Plex system. RESULTS Serum creatinine in the anti-moesin autoantibody-positive group was higher than that in the negative group. Additionally, interferon (IFN)-γ, macrophage chemotactic peptide-1 (MCP-1), interleukin (IL)-2, IL-7, IL-12p70, IL-13, granulocyte/macrophage colony-stimulating factor (GM-CSF) and granulocyte colony-stimulating factor were significantly higher in the positive group. Furthermore, IL-7 and IL-12p70 levels correlated with the anti-moesin autoantibody titer. Based on these findings and the binding of anti-moesin IgG to neutrophils and monocytes, we detected the secretion of cytokines/chemokines such as IFN-γ, MCP-1 and GM-CSF from these cells. CONCLUSIONS The anti-moesin autoantibody existed in the serum of patients with MPO-AAV and was associated with the production of inflammatory cytokines/chemokines targeting neutrophils with a cytoplasmic profile, which suggests that the anti-moesin autoantibody has the possibility to be a novel autoantibody developing vasculitis via neutrophil and endothelial cell activation.

OBJECTIVE The beneficial effects of renin-angiotensin-aldosterone system inhibitors (RASI) and the omega-3 polyunsaturated fatty acid eicosapentaenoic acid (EPA) on IgA nephropathy (IgAN) have been reported. However, it is unknown whether these agents have any synergistic interactions. METHODS We divided 38 IgAN patients into two groups: an EPA group (n=18) treated with RASI plus EPA and a DILAZEP group (n=20) treated with RASI plus dilazep dihydrochloride. We analyzed the clinical and histological background of each patient, any relevant clinical findings obtained one year after treatment and any factors significantly related to decreases in proteinuria. RESULTS The clinical findings were largely similar between the groups, except for body mass index (24.9±4.5 in the EPA group vs. 21.4±2.1 in the DILAZEP group, p=0.0041) and total cholesterol (median: 206.0 vs. 177.5 mg/dL, p=0.0493). The histological findings, evaluated according to the Oxford classification, were also similar between the groups. At one year after treatment, the EPA group demonstrated a significantly decreased mean blood pressure (from 94.7±9.0 to 86.4±7.2 mmHg, p=0.0007) and a significantly decreased median level of proteinuria (from 0.80 to 0.41 g/g creatinine, p

The prognostic value of renal biopsy in anti-neutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis is widely recognized; however, there is no consensus regarding its pathological classification. Berden et al. proposed a new classification of glomerulonephritis in ANCA-associated vasculitis (AAV) categorized into focal, crescentic, mixed, and sclerotic classes and showed its prognostic value in 100 international multicenter cohorts for 1- and 5-year renal outcomes. In order to evaluate whether this new classification has predictive value and reproducibility in Japanese AAV cases, 87 cohorts with only microscopic polyangiitis in 3 limited centers in Japan were analyzed. In addition, those from Japan, Europe (Berden's cohorts) and China were compared in a recent report.

Background. Steroid-dependent minimal-change nephrotic syndrome (MCNS) requires administration of prolonged courses of prednisolone (PSL); therefore, a paradigm shift from such toxic ‘non-specific’ therapies to selective immunomodulating regimens is necessary for these cases. Methods. To assess the therapeutic effects of rituximab (an anti-CD20 antibody) in adult patients with steroiddependent MCNS, we performed a prospective trial of the effects of a single dose of rituximab administered twice at an interval of 6 months in 25 MCNS patients. We evaluated the biochemical parameters and compared the clinical findings between the 12-month period before and 12-month period after the first rituximab infusion. Results. A significant reduction in the number of relapses and the total dose and the maintenance dose of PSL administered was observed during the 12-month period after the first rituximab infusion when compared with the findings during the 12month period before the first rituximab infusion [25 (100%) versus 4 (16%), P < 0.001; 8.2 versus 3.3 g, P < 0.001; 26.4 mg/ day at baseline versus 1.1 mg/day at 12-month, P < 0.0001]. Complete remission was achieved/maintained in all patients undergoing B-cell depletion. Four of 17 patients with B-cell repletion developed relapse. Conclusions. Our results revealed that rituximab therapy was associated with a reduction in the number of relapses and in the total dose of PSL needed. Therefore, rituximab appears to be a useful therapeutic agent for adult patients with steroid-dependent MCNS. These results suggest that this treatment is rational and should be considered as an important option in the management of adult patients with steroid-dependent MCNS.

We report a patient treated with rituximab for interstitial pneumonia (IP) associated with microscopic polyangiitis (MPA) and who was undergoing hemodialysis. A 59-year-old woman who had been treated with tacrolimus for 1 year for rheumatic arthritis was referred to the Department of Nephrology for fatigue, fever, weight loss, and rapidly developing renal dysfunction. On the first admission, severe renal dysfunction, proteinuria, hematuria, and an elevated titer of MPO-ANCA were observed, and the woman was diagnosed with rapidly progressive glomerulonephritis because of MPA. At that point, IP was found to be present but not active. Although steroid semipulse therapy following an initial prednisolone (PSL) administration of 40 mg/day, IVCY, and plasma exchange were administered, renal dysfunction did not recover, and the patient required maintenance hemodialysis. Upon discharge, a high titer of MPO-ANCA was continuously observed. Nine months after the initiation of hemodialysis, respiratory discomfort and desaturation developed. Interstitial shadow and ground glass opacity were seen on a CT scan, and the patient was diagnosed with exacerbation of interstitial pneumonia caused by MPA recurrence. At the second admission, acute findings identified by imaging techniques had improved. However, the high titer of MPO-ANCA continued in spite of the steroid semi-pulse therapy following PSL administration, and rituximab corresponding to 200 mg/weekly for 1 month was also administered. The dose of rituximab was decreased subsequently because the patient was judged to be compromised by the hemodialysis. At the same time, internal administration of sulfamethoxazole/trimethoprim was initiated. After the rituximab treatment, MPO-ANCA antibodies gradually decreased, and the respiratory condition improved. Five months after the rituximab treatment, respiratory dysfunction recurred. Based on the CT findings and a high level of β-D-glycan, the patient was diagnosed with ARDS due to pneumocystis pneumonia. In this case, rituximab was effective for IP due to MPA, but pneumocystis pneumonia could not be prevented in spite of prophylactic antibiotics. This case suggests that deliberative dose adjustments, careful patient observation, and prophylactic measures for infection are critical in rituximab treatment.

Familial renal hypouricemia is a hereditary disease characterized by extraordinary high renal uric acid (UA) clearance and is associated with acute renal failure (ARF). A 17-year-old Japanese male developed ARF after anerobic exercise. Renal function improved completely after approximately 2 weeks of hydration treatment. After remission, hypouricemia became evident (1.0 mg/dL) from the initial level of UA (4.8 mg/dL) and fractional excretion of uric acid (FEUA) was >50%. His parents showed normal levels of UA and FEUA. Polymerase chain reaction of a urate anion exchanger known to regulate UA level [SLC22A12 gene: UA transporter 1 (URAT1)] demonstrated compound heterozygous mutations (Q297X and R90H). Thus, we describe a Japanese male with hypouricemia complicated by anerobic exercise-induced ARF, with definite demonstration of a genetic abnormality in the responsible gene, URAT1.

The validity of the Birmingham Vasculitis Activity Score (BVAS) as an index of disease activity and a predictor of the prognosis and outcome in patients with MPA has not yet been established in Japan. We conducted a retrospective study of the data of 73 patients with MPA who were followed up for at least 2 years. We divided the patients into two groups according to the BVAS, namely, the high-BVAS group (≥16) and the low-BVAS group (

Blockade of the renin–angiotensin–aldosterone system is a therapeutic mainstay in patients with chronic kidney disease (CKD). However, the renoprotective effect of the novel direct renin inhibitor aliskiren is unknown. We performed a prospective study in 10 CKD patients. All 10 patients with persistent proteinuria (urinary protein-to-creatinin ratio 0.3–3.5 g/g), despite good blood pressure control (

Background: A paradigm shift from such toxic ‘nonspecific’ therapies to selective immunomodulating regimens is necessary for glomerular diseases. Rituximab, which acts by inhibiting CD20-mediated B cell proliferation and differentiation, could be effective in the treatment of nephrotic syndrome as shown in recent reports. Design: To assess the effects of rituximab in patients with primary glomerular diseases, including minimal-change disease, immunoglobulin A (IgA) nephropathy, focal segmental glomerulonephritis, membranous nephropathy and membranoproliferative glomerulonephritis, we performed a prospective trial of the effects of single-dose rituximab therapy in 24 patients. We prospectively evaluated the serum and urinary biochemical parameters before and after 6 months of therapy. Results: In all of the patients studied, depletion of CD19 and CD20 cells was noted, with significant reduction in the degree of proteinuria from 3.7 ± 3.4 g/day at baseline to 1.3 ± 2.0 g/day at 6 months after the drug administration (p = 0.002). However, no significant changes of the serum creatinine, urinary RBC sediment, serum CD4/8 or serum IL-4 levels were observed at 6 months after the drug administration. In subjects with IgA nephropathy, while depletion of CD19 and CD20 cells was noted, no significant change in the severity of proteinuria was observed at 6 months after the drug administration as compared with the level at the baseline. Conclusion: For the treatment of primary glomerular diseases, the use of a single dose of rituximab is demonstrated with no serious adverse events. Further study of the mechanism of action of rituximab in successfully treated patients could encourage new perspectives in the treatment of primary glomerular diseases.

The pharmacokinetics of orally administered tacrolimus were examined in six female lupus nephritis patients (mean age 43 years, range 24-55 years). Tacrolimus (3 mg) was administered after supper, and blood tacrolimus concentrations were measured just prior to dosing and 1, 2, 4, 6, 8, 12 and 24 h after administration. The maximum blood concentration (C(max)) was observed 4-8 h (mean: 6.7 h) after administration. The mean C(max) and area under the tacrolimus concentrationti-me curve (AUC(0-24 h)) were 12.7 ng/ml and 163.1 ng x h/ml, respectively. Although there was a weak correlation between AUC(0-24 h) values and tacrolimus concentrations 2, 4, and 6 h after administration, concentrations at 12 h and 24 h were highly correlated with AUC(0-24 h) values, suggesting that the trough concentration (C(24 h)) and C(12 h) are valid markers for therapeutic tacrolimus monitoring. Enzyme-linked immunoabsorbent assay (ELISA) and microparticle enzyme immunoassay (MEIA) measurements of blood tacrolimus concentrations were similar. We recommend that monitoring should be carried out by C(12 h) in lupus nephritis outpatients.

Background: Immunoglobulin A nephropathy (IgAN) has a peak onset that coincides with the reproductive age. Therefore, many young women who are affected become pregnant. The effects and outcome of pregnancy in women with renal diseases remain controversial, and the characteristics and outcome of pregnancy in IgAN patients must be further evaluated. Methods: A prospective follow-up study of 29 pregnant women with IgAN was performed by analyzing laboratory data, histology and prognosis. To clarify the influence of renal insufficiency, we compared these patients according to the chronic kidney disease (CKD) stage. Results: We found that pregnancy and delivery did not produce any significant changes of the renal function in any of the patients at 3 years after delivery, although the proteinuria was elevated at 30 weeks of pregnancy and at 3 months after delivery. Finally, the data of pregnant women with IgAN were compared with those of 45 nonpregnant women who had similar clinical and demographic characteristics. Conclusion: The pregnant patients with IgAN did not exhibit any significant reduction of renal function at 3 years after delivery as compared with the baseline, which is similar to the findings in nonpregnant patients. Furthermore, pregnancy with stage 2 or 3 CKD was not a risk factor for renal dysfunction or delivery.

Background Minimal-change nephrotic syndrome (MCNS) is treated by the administration of prednisolone (PSL) at high doses. Steroid-induced osteoporosis is a serious adverse effect of this drug. Methods Patients with MCNS were randomly assigned to two groups, the risedronate (2.5 mg/day) + alfacalcidol (0.25 μg/day) group (n=20) and the alfacalcidol (0.25 μg/day)-alone group (n=20). All the patients had received PSL and the clinical characteristics were compared between the two groups at baseline and at 12 months. Results A significant decrease of the mean bone mineral density (BMD) of the lumbar spine from 0.710±0.162 (g/cm2) to 0.588±0.125 was observed in the alfacalcidol-alone group (p=0.02), while no such decrease of the bone mineral density was found in the risedronate + alfacalcidol group (0.663±0.169 at baseline and 0.626±0.129 at 12 months). No significant differences in the results of other biochemical tests performed at the baseline and at 12 months were observed between the two groups. The likelihood of development of steroid-induced osteoporosis was influenced by the cumulative dose of PSL, the mean BMD at the baseline, occurrence of disease relapse, and risedronate therapy. Conclusion Risedronate appears to be effective in preventing steroid-induced osteoporosis. It is necessary to use bisphosphonates to maintain the BMD in patients with MCNS receiving prolonged steroid therapy.

A 48-year-old woman who had bilateral swelling in the eyelids and submandibular region was admitted. Clinical findings suggested that her renal function had deteriorated. Laboratory data showed renal insufficiency (2.52 mg/dl), hypergammaglobulinemia (IgG 3,729 mg/dl, IgA 124 mg/dl, IgM 73 mg/dl). Gallium-67 scintigram indicated abnormal uptake in bilateral lacrimal glands, submandibular glands, and kidneys. A diagnosis of Mikulicz's disease and interstitial nephritis was made, since biopsy specimens of her lacrimal gland and minor salivary gland showed diffuse infiltration of lymphocytes. In addition, renal biopsy specimens showed diffuse severe interstitial infiltration of IgG4-positive mononuclear cells. Symptoms and laboratory data normalized in response to methylprednisolone semi-pulse therapy and prednisolone 50 mg/day. Mikulicz's disease was recently reported to be IgG4 associated disease. In our case, Mikulicz's disease complicated with diffuse severe interstitial nephritis was successfully treated by corticosteroid. The present case supports the hypothesis that IgG4-related autoimmune disease could be causes of Mikulicz's disease and interstitial nephritis.

Two cases of anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitis (ANCA-V) occurred in the transplanted kidney were reported. Case 1 was a 57 yr-old female whose original disease was MPO-ANCA-V. A relapse of necrotizing crescentic glomerulonephritis occurred one year after transplantation with positive serum reaction for MPO-ANCA. In spite of several immunosuppressive treatments, the disease progressed and she returned to hemodialysis treatment three yr and seven months after transplantation. Case 2 was a 34 yr-old female whose original disease was IgA nephropathy. She had a stable clinical condition during 13 yr after transplantation; however, de novo onset of necrotizing crescentic glomerulonephritis occurred at 14 yr 10 months after transplantation with positive serum reaction for MPO-ANCA. She returned to hemodialysis treatment five yr after the onset of ANCA-V. Urinary abnormities such as microhematuria and proteinuria were useful diagnostic findings but the titers of serum MPO-ANCA were relatively low in both patients. Concerning the treatment, steroid pulse therapy was effective in some extents but the disease progressed to graft failure in both cases. ANCA-V is a severe glomerulonephritis which can occur in kidney allograft in the manner of relapse and de novo. Detection of urinary abnormalities and positive serum ANCA combined with histological confirmation of necrotizing crescentic glomerulonephritis and/or vasculitis is required for early diagnosis and effective treatment of ANCA-V in renal transplant patients.

Minimal change nephrotic syndrome (MCNS) usually is considered to have a good renal prognosis, but the frequency of relapses is a therapeutic challenge to physicians. The treatment of patients with multiple relapses remains a matter of controversy, because few controlled studies are available. We report the case of a 25-year-old man who experienced relapses of MCNS. Single-dose rituximab therapy (total dose 500 mg) was given during the fourth relapse. Complete remission occurred 10 days later, when no CD19/20-positive B cells were detected in the blood. This the first report of efficacy of single-dose rituximab therapy to treat multi-relapsing MCNS in an adult patient.

We present the case of a 55-year-old man with ruptured arterial aneurysm accompanied by microscopic polyangiitis in the kidney. He was admitted to our hospital because of general fatigue, fever and serious numbness of his extremities. Microscopic polyangiitis (MPA) was diagnosed on the basis of cardinal symptoms, including rapidly progressive glomerular nephritis, peripheral nerve disorder and the lung abnormality, as well as positive MPO-ANCA findings. Hemodialysis had to be started on admission because of renal failure. Renal biopsy demonstrated necrotizing glomeruli, crescent formation with interstitial infiltrates. There were no immune deposits on immunofluorescence study or electron micrographs. The pathological diagnosis was necrotizing glomerulonephritis involving small and medium-sized arteries. He was treated with intravenous semi-pulse methylprednisolone therapy because of the intensely pathological renal activation and the abnormal shadow on chest X-ray. The inflammatory reaction subsequently improved, MPO-ANCA decreased and the lung lesions diminished. He complained of sharp pain of sudden onset on his left side. His hemoglobin dropped from 9.8 g/dl to 6.0 g/dl developed in the subsequent hours, but there were no sign of hemorrhage. Abdominal CT scan showed a large left-sided perinephric, intracapsular hematoma. Selective arterial angiography showed multiple aneurysms in renal and hepatic arteries. No active bleeding was present and he recovered with transfusion, supportive therapy and monitoring alone. Multiple aneurysms detected by angiography in the renal and hepatic arteries showed improvement. He is currently stable on regular hemodialysis treatment with a low dose of oral prednisolone.

Although minimal-change nephrotic syndrome (MCNS) is highly steroid-responsive, the frequency of relapses in some patients is high, necessitating the administration of repeated courses of prednisolone in high doses. It is, therefore, necessary to identify factors that can predict this increased risk of relapse in some patients in order to establish useful treatment methods to reduce the risk.To clarify the factors that might increase the risk of relapses, the data of 82 Japanese adult patients with MCNS receiving treatment at our department were analyzed retrospectively. Of the total, 55 patients (67.1%) experienced relapse after showing an initial response. We divided the patients into two groups; namely, the nonrelapse group (n = 27) and the relapse group (n = 55), and compared the clinico-pathophysiological characteristics between the two groups.Significantly increased serum immunoglobulin E (IgE) levels (P = 0.0002) and increased frequency of steroid side effects were observed in the relapse group as compared to the nonrelapse group.To develop effective therapeutic modalities, it is important to have a thorough understanding of the clinico-pathophysiological characteristics of MCNS patients showing relapse.

Endothelial dysfunction is often found in both hyperuricemia and hemodialysis patients. Recent studies have shown that treating hyperuricemia with allopurinol improves endothelial dysfunction. This study is performed to assess the effect of febuxostat on endothelial dysfunction in hemodialysis patients with hyperuricemia. We randomly assigned 53 hemodialysis patients with hyperuricemia to a febuxostat (10 mg daily) group and a control group and measured flow-mediated dilation, serum uric acid (UA) levels, systolic and diastolic blood pressure, malondialdehyde-modified low-density lipoprotein (MDA-LDL), and highly sensitive C-reactive protein (hsCRP) at baseline and at the end of a 4-week study period. Flow-mediated dilation increased from 5.3% ± 2.4% to 8.9% ± 3.6% in the febuxostat group but did not change significantly in the control group. Treatment with febuxostat resulted in a significant decrease in serum UA level and a significant decrease in MDA-LDL compared with baseline, but no significant difference was observed in hsCRP level or blood pressure. No significant differences were observed in the control group. Febuxostat improved endothelial dysfunction and reduced serum UA levels and oxidative stress in hemodialysis patients with hyperuricemia.

Atypical hemolytic uremic syndrome (aHUS) in allograft kidney transplantation is caused by various factors including rejection, infection, and immunosuppressive drugs. We present a case of a 32 year old woman with aHUS four years after an ABO-incompatible kidney transplantation from a living relative. The primary cause of end-stage renal disease was unknown; however, IgA nephropathy (IgAN) was suspected from her clinical course. She underwent pre-emptive kidney transplantation from her 60 year old mother. The allograft preserved good renal function [serum creatinine (sCr) level 110-130 μmol/L] until a sudden attack of abdominal pain four years after transplant, with acute renal failure (sCr level, 385.3 μmol/L), decreasing platelet count, and hemolytic anemia with schizocytes. On allograft biopsy, there was thrombotic microangiopathy in the glomeruli, with a cellular crescent formation and mesangial IgA and C3 deposition. Microvascular inflammation, such as glomerulitis, peritubular capillaritis, and arteriole endarteritis were also detected. A disintegrin-like and metalloproteinase with thrombospondin type 1 motifs 13 (ADAMTS13) did not decrease and Shiga toxin was not detected. Donor-specific antibodies or autoantibodies, including anti-neutrophil cytoplasmic antibody and anti-glomerular basement membrane (anti-GBM) antibody, were negative. The patient was diagnosed with aHUS and received three sessions of plasmapheresis and methylprednisolone pulse therapy, followed by oral methylprednisolone (0.25-0.5 mg/kg) instead of tacrolimus. She temporarily required hemodialysis (sCr level, 658.3 μmol/L). Thereafter, her sCr level improved to 284.5 μmol/L without dialysis therapy. This case is clinically considered as aHUS after kidney transplantation, associated with various factors, including rejection, glomerulonephritis, and toxicity from drugs such as tacrolimus.

A 48-year-old male was admitted to our hospital with nephrotic syndrome. Light-microscopic examination of a renal biopsy specimen showed almost normal glomerular appearance, however, immunofluorescence examination revealed linear and granular IgG deposits on the glomerular basement membrane (GBM), accompanied by slight IgG deposition in the tubular basement membrane (TBM). Further investigation of the IgG subclass and light chain staining revealed that the glomerular deposits were composed of IgG1 and IgG4, with both κ and λ light chains, while the tubular deposits were composed of only IgG4 and κ light chains. The electron-microscopic findings of small granular deposits in the GBM and TBM closely resembled those of light and heavy chain deposition disease (LHCDD). Immunoelectron microscopy confirmed the presence of κ and λ chains in the GBM and TBM, however, only significant κ chain deposition was found in the TBM. There was no evidence of monoclonal gammopathy. Clinically, the patient subsequently developed neutropenia and thrombocytopenia associated with the presence of anti-neutrophil antibody and anti-GPIIb/IIIa antibody-producing B cells in the blood. Oral steroid administration was initiated, which led to amelioration of the neutropenia, thrombocytopenia and proteinuria. This may be a very rare case of combined IgG4κ and IgG1λ deposition disease accompanied by autoimmune neutropenia (AIN) and immune thrombocytopenia (ITP) suggestive of biclonal immunoglobulin deposition disease (BIDD). Investigation of the IgG subclass and of the light chains was useful for recognizing the clonality of the immunoglobulin deposits in the kidney.

We established a novel model mouse for myeloperoxidase anti-neutrophil cytoplasmic antibody (MPO-ANCA)-associated glomerulonephritis with crescentic formation, which was induced by administering bovine serum albumin (BSA). Neutrophil infiltration into the renal glomeruli began at 8 weeks and crescent formation was observed from 10 weeks after the first BSA injection. Platelet and neutrophil counts significantly increased, and proteinuria was observed from 5 weeks. MPO-ANCA increased slightly at 4 and markedly at 9 weeks, and the TNF-alpha level increased at 11 weeks. Glomerular neutrophil infiltration was correlated with MPO-ANCA levels. In addition, proteinuria also significantly correlated with MPO-ANCA levels. Finally, renal crescent formation was associated with an increase of MPO-ANCA levels and neutrophil infiltration into glomeruli. The glomerular immune deposition of IgG and C3 was observed. These findings indicate that BSA induces neutrophil activation of peripheral blood followed by the elevation of MPO-ANCA, resulting in the development of crescentic glomerulonephritis in mice.