Rituximab maintenance therapy for patients with antineutrophil cytoplasmic antibody-associated vasculitis in Japan.

OBJECTIVES: We examined the efficacy and safety of rituximab (RTX) maintenance therapy for patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) in Japan. METHODS: We conducted a retrospective study using a multi-center cohort database of vasculitis patients. All maintenance treatment courses were divided into three groups: a RTX group, a group treated with other immunosuppressant drugs (IS) and a group receiving glucocorticoid monotherapy (GC). The primary endpoint was the comparison of relapse-free survival after 1 year. We also analyzed the occurrence of severe adverse events (SAEs) to assess safety. RESULTS: We included 123 courses of 107 patients (RTX n = 14, IS n = 64, GC n = 45). Twelve of 14 in the RTX group patients were diagnosed with granulomatosis with polyangiitis (GPA). The relapse-free survival of RTX maintenance therapy was comparable to that in the other groups (p = .122). After 1 year of treatment, the RTX group was administered lower steroid doses and one-third of them could withdraw corticosteroid. The overall incidence of SAE was 0.54/patient-year in the RTX group, 0.39/patient-year in the IS group and 0.34/patient-year in the GC group. CONCLUSION: RTX maintenance therapy could be effective and safe in Japanese GPA patients.

High serum level of methylglyoxal-derived AGE, Nδ-(5-hydro-5-methyl-4-imidazolone-2-yl)-ornithine, independently relates to renal dysfunction.

BACKGROUND: The dicarbonyl methylglyoxal reacts primarily with arginine residues to form advanced glycation end products, including Nδ-(5-hydro-5-methyl-4 -imidazolone-2-yl)-ornithine (MG-H1), which are risk factors for not only diabetic complications but also lifestyle-related disease including renal dysfunction. However, the data on serum level and clinical significance of this substance in chronic kidney disease are limited. METHODS: Serum levels of MG-H1 and Nε-(carboxymethyl) lysine (CML) in 50 patients with renal dysfunction were measured by liquid chromatography/triple-quadruple mass spectrometry. RESULTS: The median serum MG-H1 levels in patients with estimated glomerular filtration rate (eGFR) of ≥30, 15-30, and <15 ml/min/1.73 m2 was 4.16, 12.58, and 14.66 mmol/mol Lys, respectively (p > 0.05). On the other hand, MG-H1 levels in patients with HbA1c of <6 and ≥6 % was 12.85 and 10.45 mmol/mol Lys, respectively, the difference between which is not significant. In logistic regression analysis, decreased renal function (eGFR <15 ml/min/1.73 m2) significantly associated with high serum levels of MG-H1 [odds ratio: 9.39 (95 % confidence interval 1.528-57.76), p = 0.015; Spearman rank correlation: MG-H1 vs. eGFR, r = -0.691, p < 0.01]. In contrast, the serum level of CML did not correlate with eGFR, but correlated with systolic blood pressure [odds ratio 16.17 (95 % confidence interval 1.973-132.5), p = 0.010; Spearman rank correlation coefficient: CML vs. eGFR, r = 0.454, p < 0.01]. CONCLUSION: These results showed that the serum concentration of MG-H1 was strongly related to renal function rather than to DM.

IL-1ß promotes tubulointerstitial injury in MPO-ANCA-associated glomerulonephritis
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BACKGROUND: It is widely accepted that tubulointerstitial injury (TII) is caused by glomerular injury (GI) in glomerular diseases. Glomerular endocapillary inflammation may result in crescent formation and exuded protein leakage, which may induce TII in antineutrophil cytoplasmic antibody-associated glomerulonephritis (ANCAGN). However, some reports have indicated a glomerulonephritis-independent mechanism of TII in ANCAGN. The aim of this study was to determine the principle cytokines correlated with TII severity and to elucidate a characteristic mechanism for TII in ANCAGN. METHODS: 28 myeloperoxidase-ANCA-positive ANCAGN patients were enrolled, and their kidney biopsy specimens were histologically evaluated with regard to GI and TII. The mRNA expression of various cytokines was examined in 28 specimens. RESULTS: Interleukin (IL)-1ß was significantly correlated with the severity of TII. The mRNA expression of Toll-like receptor 4 (TLR4) and Nod-like receptor family pyrin domain-containing-3 (NLRP3) also correlated with TII severity. Immunohistochemical analysis demonstrated that TLR4 protein was positively stained in the tubulointerstitial infiltrating cells. NRLP3 protein was detected in macrophages in the severe infiltrating area but was absent or only very faintly expressed in the glomeruli. These results indicated that NLRP3 inflammasome-dependent processing in macrophages releases the mature active form of IL-1ß, which may lead to the development and deterioration of TII. CONCLUSIONS: Sterile inflammation leads to the formation of ANCA-mediated neutrophil extracellular traps (NETs), which may stimulate macrophages and dendritic cells via TLR4 and induce NF-κB-dependent mRNA expression and translation of pro-IL-1ß. Simultaneously, damage-associated molecular pattern signals resulting from NETs promote NLRP3 inflammasome-dependent processing and release mature active IL-1ß. Sterile inflammation utilizing the NLRP3 inflammasome might be a characteristic reaction limited to the tubulointerstitium. Thus, neutralizing IL-1ß may be a promising strategy to suspend the progress of TII and improve the prognosis of chronic kidney disease resulting from ANCAGN.
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Recent advances in the treatment strategy for AAV improved outcomes with intensive GC tapering.

OBJECTIVE: To evaluate trends in results of care and management for antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV). METHODS: We employed multicenter cohort data collected during 2011-2021, recruiting 43 patients with granulomatosis with polyangiitis (GPA) and 91 with microscopic polyangiitis (MPA). According to the median registration date of September 2015, patients have split into two groups: an early group and a late group (both of them, n = 67). To prevent bias, a propensity score according to numerous baseline characteristics variables was calculated; 50 matching members of each group were statistically extracted. Their treatments and clinical outcomes were examined at 6, 12, and 24 months after initial remission therapy. RESULTS: Statistics demonstrated that the baseline characteristics were similar. The late group used rituximab (RTX) more often for both remission induction and maintenance therapy, compared with the early group. The mean daily PSL doses of the late group were significantly lower than those of early group at each time point. The late group discontinued PSL 14.0% at 12 months and 23.3% at 24 months. Despite their intensive glucocorticoids (GC) tapering, the remission rates and the relapse rates were significantly fairer in the late group. The Vasculitis Damage Index (VDI) and VDI due to GC at each time point were lower in the late group, and those differences had become wider over time. CONCLUSION: Recent developments in AAV treatment have allowed efficient remission and prevention of relapses, which in turn enabled extensive GC tapering causing fewer sequelae.

Various roles of Th cytokine mRNA expression in different forms of glomerulonephritis.

BACKGROUND: Kidney disease is characterized by injurious immune responses to self or foreign antigens. The development and maintenance of immune responses generally involves activation of T lymphocytes. We evaluated mRNA expression patterns of T-cell cytokines to identify the principal Th-cell subset involved in the development of antineutrophil cytoplasmic antigen-associated pauci-immune crescentic glomerulonephritis (ANCAGN), membranoproliferative glomerulonephritis (MPGN), and membranous nephropathy (MN). METHODS: Kidney biopsy specimens from ANCAGN (17), MPGN (11), and MN (14) patients were evaluated for mRNA expression of various T-cell cytokines. RESULTS: Interferon-γ mRNA expression was detected in both ANCAGN and MPGN, but not in MN patients. Furthermore, mRNA expression of interleukin (IL)-12, a Th1-associated cytokine, was lower in MN patients than in ANCAGN and MPGN patients. In contrast, a significantly higher expression of IL-4 and IL-5 was observed in MN than in ANCAGN and MPGN patients. In the analyses of Th17-associated cytokine expression, a significantly higher expression of IL-6 and IL-17 was observed in ANCAGN than in MPGN and MN patients. No significant differences were observed in the expression of these cytokines between MPGN and MN patients. With regard to Treg-associated cytokines, a significantly higher IL-10 expression was observed in MN than in ANCAGN patients, and a significantly higher transforming growth factor-ß expression was observed in MN than in ANCAGN and MPGN patients. Similarly, Foxp3 expression was significantly higher in MN. CONCLUSION: Th1 and Th17 immune responses in ANCAGN, the Th1 response in MPGN, and Th2 and Treg responses in MN patients may be integral for the distinct histological features of these diseases.

Th2 and regulatory immune reactions contribute to IgG4 production and the initiation of Mikulicz disease.

OBJECTIVE: Mikulicz disease has been considered to be a subtype of Sjögren's syndrome (SS). However, recent studies have suggested that Mikulicz disease is an IgG4-related disease and is distinguishable from SS. In addition, it has been reported that both interleukin-4 (IL-4) and IL-10 induce IgG4 production and inhibit IgE. This study was undertaken to examine the expression of these cytokines in patients with Mikulicz disease and patients with SS. METHODS: Labial salivary gland (LSG) sections from 15 patients with Mikulicz disease and 18 patients with SS were examined for subsets of the infiltrating lymphocytes, expression patterns of messenger RNA (mRNA) for cytokines/chemokines, and relationships between the IgG4:IgG ratio and the expression of mRNA for IL-4 or IL-10. RESULTS: Immunohistochemical analysis showed lymphocyte infiltration of various subsets in the LSGs of SS patients, and the selective infiltration of IgG4-positive plasma cells and Treg cells in the LSGs of Mikulicz disease patients. The levels of mRNA for both Th1 and Th2 cytokines and chemokines in LSGs from patients with SS were significantly higher than in controls, while the expression of both Th2 and Treg cells was significantly higher in the patients with Mikulicz disease than in controls. Furthermore, the expression of IL-4 or IL-10 in the LSGs was correlated with the IgG4:IgG ratio. CONCLUSION: These results suggest that the pathogenesis of Mikulicz disease is different from that of SS. Mikulicz disease is a unique inflammatory disorder characterized by Th2 and regulatory immune reactions that might play key roles in IgG4 production.

Interleukin-21 contributes to germinal centre formation and immunoglobulin G4 production in IgG4-related dacryoadenitis and sialoadenitis, so-called Mikulicz's disease.

OBJECTIVES: Interleukin (IL)-21 is mainly produced by CD4 T helper (Th) cells including Th2, Th17 and follicular helper T (Tfh) cells. Recent studies have reported that IL-21 is involved in the formation of germinal centres (GCs) and class switching of IgG4. It has been suggested that IgG4-related dacryoadenitis and sialoadenitis (IgG4-DS), so-called Mikulicz's disease (MD), is distinct from Sjögren's syndrome (SS) and shows a high frequency of GC formation in salivary glands. In this study the expression of IL-21 in IgG4-DS and SS patients was examined. METHODS: Twelve patients with IgG4-DS, 15 with SS and 15 healthy subjects were screened for (1) ectopic GC formation in formalin-fixed labial salivary gland (LSG) biopsy samples; (2) expression of IL-21, Th2-, Th17- and Tfh-related molecules (cytokines, chemokine receptors and transcription factors) in LSGs; (3) relationship between IgG4/IgG ratio and mRNA expression of IL-21 in LSGs. RESULTS: mRNA expression of IL-21 and Bcl-6 in LSGs from patients with IgG4-DS was significantly higher than in patients with SS and controls. IL-21 and CXCR5 were detected by immunohistochemistry in or around GC in patients with SS and those with IgG4-DS. IL-21 was detected in infiltrating lymphocytes outside GC only in patients with IgG4-DS. Expression of IL-21 was consistent with that of Th2-related molecules while IL-17 was rarely seen in IgG4-DS. Furthermore, the expression of IL-21 in LSGs was correlated with the number of GC formations and the IgG4/IgG ratio in patients with IgG4-DS. CONCLUSIONS: These results suggest that overexpression of IL-21 by Th2 cells might play a key role in GC formation and IgG4 production in IgG4-DS.

Association of hypoalbuminemia with severe anemia in patients with diabetic nephrosclerosis.

BACKGROUND: Anemia in patients with early diabetes mellitus nephrosclerosis (DMN) is more severe than in patients with kidney disease of other origins, and the mechanism for this remains unclear. In this study, we carried out a retrospective study in order to identify the factors associated with anemia in patients with DMN. METHODS: To elucidate the factors that influence the severity of anemia in patients with DMN, we carried out a retrospective follow-up study of 124 biopsy-proven DMN cases [mean (SE) age, 55.3 (1.2) years; range, 18-78 years; male/female, 80/44]. First, a cluster analysis was performed using red blood cell counts and hemoglobin (Hb) and hematocrit levels. We then divided the clusters with regard to renal prognosis and survival and carried out simple and multifactorial analysis of clinical data, including the body mass index, age, systolic blood pressure (BP), diastolic BP, duration after the diagnosis of diabetes mellitus, serum albumin levels, blood urea nitrogen (BUN) concentrations, serum creatinine concentrations, the estimated glomerular filtration rate (eGFR) validated in the Japanese population, iron levels, total cholesterol levels, triglyceride levels, fasting blood sugar levels, HbA1c levels, urinary protein secretion, and pathohistological parameters. RESULTS: The factors that were significantly associated with the cluster group that showed severe anemia were sex (p = 0.0162), hypoalbuminemia (p < 0.0001), high BUN concentrations (p = 0.0020), low eGFR (p = 0.0104), and Kimmelstiel-Wilson nodules (p = 0.0022). In addition, hypoalbuminemia (p = 0.0277), high BUN concentrations (p = 0.0338), and a low eGFR (p = 0.0417) were significantly associated with this group in a multifactorial analysis. CONCLUSION: Our data strongly suggest that hypoalbuminemia is associated with severe anemia in DMN patients.

Focal segmental glomerulosclerosis and concurrent glomerular microangiopathy after long-term imatinib administration.

A 79-year-old Japanese man was admitted to our hospital because of proteinuria and kidney dysfunction. He was diagnosed with chronic myeloid leukemia 13 years before and was treated with imatinib. Deep molecular response was achieved but he developed 1+ proteinuria in the first year, which gradually worsened thereafter. Imatinib was discontinued 12 years later but proteinuria and kidney dysfunction were progressive. Percutaneous kidney biopsy revealed mild mesangial hyper-cellularity and matrix increase, swelling of endothelial cells, and partial double contours of glomerular tufts. Subendothelial edema in the interlobular artery was also noted. Immunofluorescence was not remarkable. Electron microscopy revealed endothelial injury with severe sub-endothelial edema. Since imatinib had already been discontinued, conservative therapy with maximal dose of azilsartan was administered. A second biopsy was performed 1 year later because of further deterioration of kidney function, which revealed markedly increased global glomerulosclerosis and severe interstitial fibrosis and tubular atrophy. Segmental glomerulosclerosis with podocyte hyperplasia was also observed. Electron microscopy revealed glomerulosclerotic changes and partially attenuated endothelial injury. Two and a half years later, proteinuria reduced, progression of kidney dysfunction slowed, and he was independent on dialysis therapy. Molecular response of chronic myeloid leukemia was also maintained. The clinical course suggested that endothelial and podocyte injuries were induced by imatinib, and that the nephrotoxic effects lasted for a few years after discontinuation.

Th subset balance in lupus nephritis.

Lupus nephritis, which has various histological patterns and variable clinical outcomes, is one of the most important complications of systemic lupus nephritis (SLE). This pathogenetic mechanism in each histologically different type of lupus nephritis (LN) remains unclear. Although SLE is suggested to be a Th2-driven disease, elevation of both Th1 and Th2 cytokines occurs in both humans and mice, suggesting that SLE is a complex disease driven by different lymphocyte subsets with high heterogeneity of clinical manifestations and organ involvement. Recent findings in LN elucidate an essential role for the Th1, IL-17 producing T cells and Th17 cells in the development of diffuse proliferative lupus nephritis (DPLN), and Th2 cytokine in that of membranous lupus nephritis (MLN). These data support the hypothesis that individual Th1/Th2 balance is one of the critical determinants for histopathology of LN.

Aggravation of diabetic nephropathy in OLETF rats by Thy-1.1 nephritis.

OBJECTIVE: To clarify whether the induction of Thy-1.1 nephritis aggravates diabetic nephropathy in the Otsuka Long-Evans Tokushima Fatty (OLETF) rat, which is a model of diabetes mellitus. METHOD: Forty-week-old OLETF rats were divided into 2 groups according to treatment: (1) 1 mg/kg body weight of OX7, an anti-Thy1.1 antibody (administered intravenously) (Group T, n = 14); (2) 0.9% saline (Group C, n = 14). The histological findings for the kidneys and the index of glomerulosclerosis (IGS) were determined 20 weeks after administration, and urine and serum chemistry were also assessed. The same procedure was performed as a control in 2 groups of Long-Evans Tokushima Otsuka (LETO) rats (i.e., nondiabetic OLETF rats). RESULTS: The urinary protein excretion values and the levels of serum albumin in the OX7-treated OLETF rats were significantly higher and lower than those in the untreated OLETF rats, respectively. Total cholesterol was significantly increased in the OX7-treated OLETF rats compared with the untreated OLETF rats. In the histological analysis, IGS was significantly higher in the OX7-treated OLETF rats than in the untreated OLETF rats. Neither deteriorations in the laboratory assessment values nor histological alterations were seen in the LETO rats. CONCLUSION: These findings indicate that an anti-Thy-1.1 antibody irreversibly aggravates diabetic nephropathy in the OLETF rat.

A case of IgG4-related tubulointerstitial nephritis concurrent with Henoch-Schönlein purpura nephritis.

We describe a 72-year-old man, who had been suffered from Henoch-Schönlein purpura (HSP) several times, presented with hematoproteinuria with granular cast, and general lymphadenopathy. The immunological examination of the serum showed polyclonal hypergammagloburinemia with high value of IgG4. The renal biopsy revealed interstitial inflammatory cell infiltration, including infiltration of lymphocytes and plasma cells, and segmental glomerulonephritis. Direct immunofluorescence microscopy revealed apparent positive staining with anti-human IgA, and anti-human IgG in glomeruli, anti-human IgG4 antibody staining showed many positive plasma cells in the interstitium. The patient was diagnosed with HSP nephritis that was complicated by IgG4-related nephropathy. As a result of the treatment with 30mg prednisolone, the swelling of the LNs decreased, but the patient continued to have persistent hematoproteinuria.

Anemia in Diabetic Patients Reflects Severe Tubulointerstitial Injury and Aids in Clinically Predicting a Diagnosis of Diabetic Nephropathy.

Objective A kidney biopsy is generally performed in diabetic patients to discriminate between diabetic nephropathy (DN) and non-diabetic kidney disease (NDKD) and to provide more specific treatments. This study investigated the impact of anemia on the renal pathology and the clinical course in patients who underwent a kidney biopsy. Methods We reviewed 81 patients with type 2 diabetes who underwent a percutaneous kidney biopsy. Patients were classified into two groups: isolated DN (DN group, n=30) and NDKD alone or concurrent DN (NDKD group, n=51) groups. The laboratory and pathological findings and clinical courses were investigated. Results In the NDKD group, membranous nephropathy was the most common finding (23.5%), followed by IgA nephropathy (17.6%) and crescentic glomerulonephritis (13.7%). In the logistic regression analysis, the absence of severe hematuria and presence of anemia were significantly associated with a diagnosis of DN. Akaike's information criterion (AIC) and net reclassification improvement (NRI) analyses revealed improved predictive performance by adding anemia to the conventional factors (AIC 100.152 to 91.844; NRI 27.0%). The tissues of patients in the DN group demonstrated more severe interstitial fibrosis and tubular atrophy (IF/TA) than those in the NDKD group (p<0.05) regardless of the rate of global glomerulosclerosis, and IF/TA was related to the prevalence of anemia (odds ratio: 7.31, 95% confidence interval: 2.33-23.00, p<0.01) according to a multivariable regression analysis. Furthermore, the isolated DN group demonstrated a poorer prognosis than the NDKD group. Conclusion DN is associated with anemia because of severe IF/TA regardless of the renal function, and anemia helps clinician discriminate clinically between isolated DN and NDKD.

Concurrent minimal change disease and retroperitoneal liposarcoma successfully treated by tumor resection and steroid therapy.

A 54-year-old Japanese woman developed simultaneous abdominal distension and bilateral leg edema. Her medical history and results of periodic medical check-up were unremarkable. Blood tests revealed severe hypoproteinemia and acute kidney injury, and urinalysis revealed 4+ proteinuria and 2+ hematuria. Abdominal computed tomography revealed a large intra-abdominal mass with fat tissue density. She underwent emergency tumor excision, splenectomy, and distal pancreatectomy. However, hypoproteinemia and acute kidney injury worsened. Therefore, she was transferred to the nephrology division for confirmation of diagnosis and for treatment of acute kidney injury and nephrotic syndrome. We conducted percutaneous kidney biopsy and diagnosed minimal change disease (MCD). Intravenous prednisolone was started, and heavy proteinuria and systemic edema were gradually alleviated. She achieved complete remission 2 months later, and oral prednisolone was tapered. Histopathological diagnosis of abdominal tumor was dedifferentiated liposarcoma of retroperitoneal origin. Immunohistochemical staining revealed strong expression of vascular endothelial growth factor in the tumor cells in the dedifferentiated component. Currently, her clinical course is stable without recurrence of liposarcoma and nephrotic syndrome. MCD develops in patients with Hodgkin's lymphoma, solid organ cancers, hematological malignancies, and thymoma, whereas concurrent MCD and liposarcoma are rare. Remission of nephrotic syndrome and normalized kidney function induced by steroid therapy are important for better management of patients with malignancy.

The Association of Airway Comorbidities With the Clinical Phenotypes and Outcomes of Patients With Antineutrophil Cytoplasmic Autoantibody-associated Vasculitis.

OBJECTIVE: We investigated the association of airway comorbidities with the clinical phenotypes and outcomes of myeloperoxidase (MPO)-antineutrophil cytoplasmic antibodies (ANCA)-positive ANCA-associated vasculitis (AAV). METHODS: An AAV patient multicenter cohort trial was established in 13 hospitals in western Japan between 2012 and 2018. We examined 143 of the new-onset MPO-ANCA-positive AAV patients. Their clinical characteristics and comorbidities at disease onset were compared based on clinical phenotypes. Multivariate analysis was performed to identify factors predictive of remission and death. RESULTS: Twenty-seven cases with granulomatosis with polyangiitis (GPA), 10 with eosinophilic GPA (EGPA), 81 with microscopic polyangiitis (MPA), and 25 with unclassified AAV were identified. The average age of MPO-ANCA-positive patients was 71.4 years. Comorbidity (87.4%) and airway comorbidity (70.6%) were frequently observed in these patients. Examination of the clinical phenotypes revealed that the cases of GPA were frequently accompanied by infectious airway comorbidity (upper airway disease, bronchiectasis, pulmonary infections), and most of the cases of MPA and unclassified AAV were accompanied by fibrotic interstitial lung disease (fILD) or emphysema. Among MPO-ANCA-positive patients, infectious airway comorbidity was predictive of both remission (HR 1.58, P = 0.03) and mortality (HR 2.64, P = 0.04), and fILD was predictive of mortality (HR 7.55, P = 0.008). The combination of infectious airway comorbidities and fILD caused the worst survival outcomes in patients. CONCLUSION: MPO-ANCA-positive AAV was frequently accompanied by airway comorbidities. In addition to fILD, infectious airway comorbidities were closely associated with those clinical phenotypes and outcomes.

Improvement of dyslipidemia in OLETF rats by the prostaglandin I(2) analog beraprost sodium.

The Otsuka Long-Evans Tokushima Fatty (OLETF) rat was established as an animal model of human type 2 diabetes. Improvement of dyslipidemia by BPS has been confirmed in OLETF rats. The aim of this report is to clarify the mechanisms associated with improvement of dyslipidemia by BPS in OLETF rats. We divided male OLETF rats into three groups; 400microg/kg BPS treated (Group H), 200microg/kg BPS treated (Group L), and untreated control (Group C). After sacrifice, using the quantitative real-time PCR, we assayed the transcription levels of the HMG-CoA reductase (Hmgcr) for cholesterol biosynthesis, monoacylglycerol O-acyltransferase 1 (Mogat1) as TG synthetase, hepatic triglyceride lipase (Lipc) and lipoprotein lipase (Lpl) as triglycerides (TG) reductase in the liver. The mRNA expression of transketolase (Tkt) for pentose phosphate pathway (PPP) enzyme was also evaluated in the liver and kidney. Hmgcr and Mogat1 RNA expression levels were reduced in the livers and those of Tkt were increased in the kidney of BPS treated rats compared with those in untreated rats. The protein expressions of transketolase (Tkt) of BPS treated rats were similarly increased both in the kidney and liver. These results suggest that dyslipidemia was not improved by the acceleration of TG metabolism but by the suppression of activated cholesterol and TG biosyntheses in OLETF rats treated with BPS. High activity of Tkt induced by BPS may be involved in the suppression of such synthetic mechanisms.

[Case of suspicious lansoprazole-associated collagenous colitis in ANCA-associated nephritis].

In January 2003, a 70-year-old female consulted a doctor for a fever of unknown origin. She had microscopic hematuria, proteinuria, BUN 41 mg/dL, Cr 2.1 mg/dL and MPO-ANCA 44 U/mL, and was suspected of having ANCA-associated nephritis. A renal biopsy was not conducted because the patient had just one kidney. She was treated with prednisolone (PSL ; 40 mg/day). Subsequently, because of Cr level improvement, the amount of PSL was decreased. In October 2006, the patient again had microscopic hematuria, proteinuria and a slightly elevated Cr level. Lowering of BP and dehydration caused by a common cold were considered to be the cause of her renal dysfunction. She was admitted to Fukuoka University Hospital for 2 weeks, where she received diet therapy and a changed medication schedule in which furosemide was stopped and the dose of enalapril was decreased from 5 mg/day to 2.5 mg/day. Because the MPO-ANCA level was < 10 EU, the amount of PSL was not changed. After 11 months, treatment with lansoprazole at 30 mg/day was started. At the end of the same month, however, she exhibited gait disturbance due to swelling, redness and tenderness in the bilateral pedal joints. After one month of receiving lansoprazole, she experienced a high fever and an elevated Cr level. Accordingly she was again admitted to the hospital, where she was diagnosed with venous thrombosis in the lower limbs, and warfarization was begun. Her condition improved, gradually, and she was discharged from the hospital. After the discharge, she began to exhibit watery diarrhea three to four times per day. Therefore, treatment with warfarin potassium was stopped 50 days after it was begun. In spite of the cessation of warfarization, the diarrhea continued. She underwent bacterial culturing and lower endoscopic examinations (no biopsy was done), which showed erosion of the colon, but the cause of the diarrhea was not found. After 181 days of treatment with lansoprazole, administration of this drug was stopped. The symptoms disappeared within 5 days. There have been few reports of collagenous colitis with chronic diarrhea, but a good prognosis has been described in these cases. Clinicians should consider drug treatment as a possible cause of collagenous colitis in the case of patients with chronic diarrhea of unknown origin during the administration of medication.

Secondary renal amyloidosis associated with asbestos-related pleuropulmonary diseases.

Here, we present a 67-year-old Japanese man who developed insidious-onset nephrotic syndrome. He had a history of occupational asbestos exposure for about 8 years during his 30s, and was found to have pleural effusion 3 years before his present illness. At that time, repeated cytology testing of his pleural effusion found no malignant cells, and pleural biopsy found fibrous pleuritis without evidence of malignant mesothelioma. Percutaneous kidney biopsy found massive deposits of AA-type amyloid in the glomeruli, small arteries, and medulla. Computed tomography showed a calcified mass in the right lower lung that was positive for 67Ga uptake, but transbronchial lung biopsy and bronchoalveolar lavage found no evidence of malignancy. He was diagnosed with rounded atelectasis and diffuse pleural thickening. As these benign asbestos-related diseases have no standard treatment, we administered low-dose angiotensin II receptor blocker to preserve kidney function. Unfortunately, his nephrotic syndrome persists, with progressive chronic kidney failure. Kidney involvement in patients with asbestos-related disease is rare. To our knowledge, this is the first case to present with secondary amyloidosis. Kidney biopsy should be considered for patients with existing asbestos-related pleuropulmonary diseases who have urinary abnormalities or renal dysfunction, to clarify the incidence and pathophysiology of renal manifestations.

Amelioration of diabetic nephropathy in OLETF rats by prostaglandin I(2) analog, beraprost sodium.

BACKGROUND: Strict control of blood glucose and blood pressure levels sometimes fails to delay the development of diabetic nephropathy, and an effective therapy is not yet available. The present study aimed to examine whether the prostaglandin I(2) analog beraprost sodium (BPS) ameliorates diabetic nephropathy in Otsuka Long-Evans Tokushima Fatty (OLETF) rat. METHOD: Fifty-week-old OLETF rats were divided into three groups according to treatment; 400 microg/kg body weight (BW) BPS, 200 microg/kg BW BPS, and 0.9% saline administration. Kidney histology, index of glomerulosclerosis, and glomerular volume were determined, and urine and serum chemistry were assessed. RESULTS: The values for urine protein excretion and serum blood urea nitrogen in BPS-treated rats were significantly lower than those in untreated rats. In rats treated with 400 microg/kg BW BPS, neither sclerotic changes nor inflammatory cell infiltration were observed. Index of glomerulosclerosis and glomerular volume were also significantly reduced compared with untreated rats. Intriguingly, BPS reduced the level of serum triglyceride. In the glomerulus of treated rats, advanced glycation end product formation and macrophage influx were suppressed in a dose-dependent manner. CONCLUSION: These findings indicate that BPS has a therapeutic effect on diabetic nephropathy in the OLETF rat, which suggests a potential application of this drug in the treatment of human diabetic nephropathy.