Analysis of the impact of obesity on the prognosis of IgA nephropathy according to renal function and sex.

BACKGROUND: Few studies have observed the direct effect of obesity on renal prognoses in immunoglobulin A nephropathy (IgAN) or separately evaluated its effects according to sex. We aimed to evaluate the direct and indirect effects of obesity on the renal outcomes of IgAN and observe these effects separately according to renal function and sex. METHODS: We extracted patients with body mass index (BMI) descriptions from a multicenter retrospective cohort analysis in Japan, and excluded those with < 30 days of follow-up, diabetes mellitus, and steroid treatment. Patients were divided into normal (n = 720; 18.5 ≤ BMI < 25) and obese (n = 212; BMI ≥ 25) groups, which were then compared. The endpoints were a 1.5-fold increase in serum creatinine levels and the initiation of renal replacement therapy. RESULTS: The obese group was older, included more males, and was more likely have hypertension, dyslipidemia, proteinuria, tubular atrophy, and lower renal function than the normal group. Patients with an eGFR < 60 mL/min/1.73 m2 had well-matched characteristics between the groups; however, hypertension, low high-density lipoprotein cholesterol, and hypertriglyceridemia were more common in the obese group. Obesity contributed to tubular atrophy, even when adjusted for renal function. In addition, it contributed to proteinuria only in females. However, obesity itself was not a significant prognostic factor. CONCLUSIONS: Although no independent effect on renal prognosis was observed during the study period, the obese group had more risk factors for IgAN progression and obesity contributed to tubular atrophy and female proteinuria. Our results suggest that separately analyzing the prognostic effect of obesity according to sex is important.

Effect of Low-Density Lipoprotein Apheresis on Quality of Life in Patients with Diabetes, Proteinuria, and Hypercholesterolemia.

INTRODUCTION: Treating diabetic nephropathy with low-density lipoprotein (LDL) apheresis reduces proteinuria and improves prognosis. However, its impact on patients' quality of life (QoL) is unclear. This study evaluated the effect of LDL apheresis on QoL in patients with diabetes, proteinuria, and hypercholesterolemia. METHODS: In this nationwide multicenter prospective study, we enrolled 40 patients with diabetes. Inclusion criteria were proteinuria (defined as an albumin/creatinine ratio ≥3 g/g), serum creatinine levels <2 mg/dL, and serum LDL ≥120 mg/dL despite drug treatment. LDL apheresis was performed 6-12 times within 12 weeks. The 36-item Short Form Health Survey (SF-36) was used to analyze QoL. RESULTS: The study enrolled 35 patients (27 men and 8 women; mean age 58.9 ± 11.9 years). A comparison of baseline SF-36 values with those at the end of the course of apheresis found an improvement in the mean physical component summary (37.9 ± 11.4 vs. 40.6 ± 10.5, p = 0.051) and a significant increase in the mean mental component summary (MCS) (49.4 ± 8.4 vs. 52.5 ± 10.9, p = 0.026). A multivariable linear regression analysis revealed a history of coronary heart disease negatively correlated with the MCS increase at the end of the course of apheresis (ß coefficient -6.935, 95% confidence interval, 13.313 to-0.556, p = 0.034). CONCLUSION: Our results suggest that LDL apheresis may improve the mental and physical QoL in patients with diabetes, proteinuria, and hypercholesterolemia.

Expert perspectives on pathological findings in vasculitis.

Pathological findings are important in the diagnosis of vasculitis. However, due to the rarity of the disease, standard textbooks usually devote only a few pages to this topic, and this makes it difficult for clinicians not specializing in vasculitis to fully understand the pathological findings in vasculitis. To address the paucity of information, we present representative pathological findings in vasculitis classified in the 2012 Revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides (CHCC2012). The CHCC2012 classifies 26 vasculitides into seven categories: (1) large-vessel vasculitis, (2) medium-vessel vasculitis, (3) small-vessel vasculitis, including antineutrophil cytoplasmic antibody-associated vasculitis and immune complex small-vessel vasculitis, (4) variable-vessel vasculitis, (5) single-organ vasculitis, (6) vasculitis associated with systemic disease, and (7) vasculitis associated with probable aetiology. Moreover, representative pathological findings of vasculitis-related diseases and non-inflammatory vasculopathy not mentioned in the CHCC2012 are also presented. This will be useful for clinicians to refer to typical pathological findings of vasculitis in daily practice.

The efficacy and safety of mizoribine for maintenance therapy in patients with myeloperoxidase anti-neutrophil cytoplasmic antibody (MPO-ANCA)-associated vasculitis: the usefulness of serum mizoribine monitoring.

BACKGROUND: The life prognosis of elderly patients with myeloperoxidase-anti-neutrophil cytoplasmic antibodies-associated vasculitis (MPO-AAV) has been improved by reducing the corticosteroid or cyclophosphamide dose to avoid opportunistic infection. However, many elderly MPO-AAV patients experience recurrence and renal death. An effective and safer maintenance treatment method is necessary to improve the renal prognosis of MPO-AAV. METHODS: Patients with MPO-AAV who reached complete or incomplete remission after induction therapy were prospectively and randomly divided into mizoribine (MZR; n = 25) and control (n = 28) groups. The primary endpoint was relapse of MPO-AAV. The patients' serum MZR concentration was measured before (C0) and 3 h after taking the MZR. The maximum drug concentration (Cmax) and the serum MZR concentration curves were determined using population pharmacokinetics parameters. We also assessed the relationship between the MZR concentrations and adverse events. The observation period was 12 months. RESULTS: Fifty-eight MPO-AAV patients from 16 hospitals in Japan were enrolled. Ten patients relapsed (MZR group, n = 6; control group, n = 4; a nonsignificant between-group difference). Changes in the serum MZR concentration could be estimated for 22 of the 25 MZR-treated patients: 2 of the 11 patients who reached a Cmax of 3 µg/mL relapsed, whereas 4 of the 11 patients who did not reach this Cmax relapsed. The treatment of one patient with C0 > 1 µg/mL was discontinued due to adverse events. No serious adverse events occurred. CONCLUSION: There was no significant difference in the recurrence rate of MPO-AAV between treatment with versus without MZR.

Effects of LDL apheresis on proteinuria in patients with diabetes mellitus, severe proteinuria, and dyslipidemia.

BACKGROUND: Patients with diabetes mellitus and severe proteinuria present with poor renal prognoses, despite improvements in diabetes and kidney disease therapies. In this study, we designed a low-density lipoprotein (LDL)-cholesterol apheresis treatment for patients with diabetic nephropathy (DN)/diabetic kidney disease and severe proteinuria. This was a multicenter prospective LICENSE study to confirm the impact of LDL apheresis on proteinuria that exhibited hyporesponsiveness to treatment. In addition, we sought to determine the efficacy and safety of LDL apheresis by comparing the outcomes to those of historical controls in patients with diabetes, refractory hypercholesterolemia, and severe proteinuria. METHODS: This was a prospective, multicenter study, including 40 patients with diabetes, severe proteinuria, and dyslipidemia. LDL apheresis was performed 6-12 times over a 12-week period. The primary endpoint was the proportion of patients with a decrease in proteinuria excretion of at least 30% in the 6 months after starting therapy. The secondary endpoints included serum creatinine levels and laboratory variables, which were evaluated 4, 6, 12, 18, and 24 months after therapy initiation. RESULTS: LDL apheresis was performed on 40 registered patients with diabetes. The proportion of cases in which proteinuria decreased by 30% or more after 6 months of LDL apheresis was 25%, which was similar to that of historical controls. The overall survival and end-stage kidney disease-free survival rates were significantly higher in the LICENSE group compared to those in historical controls. CONCLUSION: Our results suggest that LDL apheresis may be effective and safe for patients with diabetes, proteinuria, and dyslipidemia. TRIAL REGISTRATION: Trial registration number: jRCTs042180076.

Rationale of concomitant cyclophosphamide for remission-induction in patients with antineutrophil cytoplasmic antibody-associated vasculitis: A propensity score-matched analysis of two nationwide prospective cohort studies.

OBJECTIVES: We evaluated the effectiveness of cyclophosphamide for patients with microscopic polyangiitis and granulomatosis with polyangiitis. METHODS: Patients treated with cyclophosphamide and glucocorticoid (cyclophosphamide group) or glucocorticoid alone (non-cyclophosphamide group) for remission-induction were enrolled from two Japanese nationwide prospective inception cohort studies. The effectiveness and safety outcomes were compared before and after propensity score (PS)- matching. RESULTS: Proportion of patients achieving Birmingham Vasculitis Activity Score (BVAS)-remission and BVAS-remission plus a daily prednisolone dosage of ≤10 mg (GC-remission) by Month 6 were not significantly different between cyclophosphamide and non-cyclophosphamide groups before (n = 144 and 155) and after (n = 94 for each group) PS-matching. In myeloperoxidase-antineutrophil cytoplasmic antibody (MPO-ANCA)-positive PS-matched patients, GC-remission by Month 6 was superior in CYC group (n = 82) than in non-CYC group (n = 91) (49 vs. 31%, p = .020). Overall, end-stage renal disease-free and relapse-free survival rates, Vasculitis Damage Index score, and proportions of serious infection were comparable between the two groups both in the unmatched and PS-matched patients. Prednisolone doses at any point after treatment initiation in the PS-matched patients were lower in the cyclophosphamide group than in a non-cyclophosphamide group. CONCLUSIONS: Concomitant cyclophosphamide use may improve GC-remission by Month 6 in MPO-ANCA-positive patients and could exert glucocorticoid sparing effect.

Apolipoprotein E-related glomerular disorders.

Of the glomerular disorders that occur due to apolipoprotein E (apoE) mutations, apoE2 homozygote glomerulopathy and lipoprotein glomerulopathy (LPG) have been characterized. ApoE2 homozygote glomerulopathy has been found in individuals expressing homozygous apoE2/2. This was characterized histologically by glomerulosclerosis with marked infiltration of foam cells derived from macrophages, and occasionally with non-lamellated lipoprotein thrombi. Recently, several cases of apoE Toyonaka (Ser197Cys) combined with homozygous apoE2/2 have been reported, in which non-immune membranous nephropathy-like features were observed in glomeruli. Interestingly, in these cases, apoE accumulation was identified by tandem mass spectrometry. Therefore, it is speculated that these findings may arise from apoE molecules without lipids, which result from hinge damage by apoE Toyonaka and may cross the glomerular basement membrane as small molecules. LPG is primarily associated with heterozygous apoE mutations surrounding the low-density lipoprotein-receptor binding site, and it is histologically characterized by lamellated lipoprotein thrombi that lack foam cells. Recent studies have suggested that LPG can be induced by thermodynamic destabilization, hydrophobic surface exposure, and the aggregation of apoE resulting from the incompatibility of apoE mutated residues within helical regions. Additionally, apoE5 may play a supporting role in the development of LPG and in lipid-induced kidney diseases via hyperlipoproteinemia. Thus, it is interesting that many apoE mutations contribute to characteristic glomerular disorders through various mechanisms. In particular, macrophages may uptake lipoproteins into the cytoplasm and contribute to the development of apoE2 homozygote glomerulopathy as foam cells, and their dysfunction may contribute to the accumulation of lipoproteins in the glomerulus, causing lipoprotein thrombi in LPG.

Impaired HVJ-stimulated Interferon producing capacity in MPO-ANCA-associated vasculitis with rapidly progressive glomerulonephritis lead to susceptibility to infection.

ANCA-associated RPGN leads to renal failure through systemic vasculitis and diffuse crescentic glomerulonephritis. MPO-ANCA-RPGN patients are highly susceptible to infections. Our aim in this study was to uncover reasons why these patients were susceptible to infections. We analyzed various aspects of type I interferon system including HVJ-stimulated IFN-α producing capacity and plasmacytoid dendritic cell (pDC) number in whole blood in MPO-ANCA-RPGN patients. Compared with healthy subjects, MPO-ANCA-RPGN patients showed impaired HVJ-stimulated IFN-α producing capacity and lower pDC number with or without glucocorticoid treatment. Immuno-histological staining of MPO-ANCA-RPGN kidney samples revealed a few but apparent pDC in T cell infiltrating regions even in patients with low pDC number in their peripheral blood. Patients' low HVJ-stimulated IFN-α producing capacity and pDC numbers persisted even after patients underwent several years of treatment. Former infection was determined using patients' serum BPI, Lamp-2 and Calprotectin, since they are reflective of a history of infection. These markers were higher in MPO-ANCA-RPGN patients than in healthy subjects. These results indicate that impaired HVJ-stimulated IFN-α production as well as dysfunction of the IFN system might have resulted from a previous bout of infection and can be partially implicated in patients' long-term susceptibility and vulnerability to infection.

Histopathological classification of anti-neutrophil cytoplasmic antibody-associated glomerulonephritis in a nationwide Japanese prospective 2-year follow-up cohort study.

BACKGROUND: The prognostic value of the EUVAS-proposed histopathological classification of anti-neutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis has been evaluated throughout the world. Here, we performed a Japanese nationwide biopsy survey to assess the association between this histopathological classification and renal prognosis after 2-year follow-up in ANCA-associated glomerulonephritis. METHODS: We collected 67 renal biopsy materials of the 321 entries in the RemIT-JAV-RPGN cohort study, and assessed their histologies. Based on the EUVAS-proposed histopathological classification and some histological parameters, we statistically evaluated renal survival and the comparison of renal function for 2 years. RESULTS: Based on the histopathological classification, the largest number of biopsy samples belonged to the Focal class, followed by the Mixed, Crescentic, and Sclerotic classes (n = 30, 19, 10, 8, respectively). Although the number of events might be too low (four patients with renal death) to make this conclusion, the Focal and Mixed classes had higher renal-survival rates compared to the others in the renal-survival curve. Comparing renal function among all classes, the estimated glomerular filtration rate (eGFR) throughout 2-year follow-up period was significantly higher in the Focal class compared to the other 3 classes. The eGFR-values in the Crescentic, Mixed, and Sclerotic classes increased with time. Based on both combined results, the Focal class could be the best prognosis. CONCLUSION: This histopathological classification was valuable for both the stratification of renal function and the estimation of partial renal survival during 2-year follow-up in ANCA-associated glomerulonephritis.

Crescentic poststreptococcal acute glomerulonephritis accompanied by small vessel vasculitis: case report of an elderly male.

BACKGROUND: Poststreptococcal acute glomerulonephritis (PSAGN) in the elderly tends to have a severe clinical course and often presents with crescentic necrotizing glomerulonephritis in the renal biopsy. However, vasculitis lesions are unusual. CASE PRESENTATION: We present a 71-year-old man who was admitted to our hospital for a recurrent gout attack with a rapid decline of renal function. Low C3 levels and a high anti-streptolysin O titer were observed, while myeloperoxidase- and proteinase 3- antineutrophil cytoplasmic antibody (ANCA) were negative. In addition to cellular crescent and necrosis lesions, diffuse peritubular capillaritis and venulitis as well as small arteriole vasculitis in the glomerular hilus were also apparent. Although granular C3c deposits in the capillary wall and hump lesions were not found, immunofluorescent staining for nephritis-associated plasmin receptor (NAPlr) and in situ zymography for plasmin activity were both positive. We thus diagnosed PSAGN accompanied by small vessel vasculitis. Steroid therapy gradually improved the patient's renal function, and hemodialysis was discontinued after 1 month. CONCLUSIONS: In our case, streptococcus infection might have concurrently provoked vasculitis, and NAPlr staining was useful for confirming diagnosis.

The features in IgA-dominant infection-related glomerulonephritis distinct from IgA nephropathy: a single-center study.

BACKGROUND: IgA-dominant infection-related glomerulonephritis (IgA-IRGN) is a unique form of IRGN, which needs to be distinguished from IgA nephropathy (IgAN). METHODS: Thirteen patients with IgA-IRGN (IgA-IRGN group) and 122 with IgAN (IgAN group) were selected from 1788 patients who underwent kidney biopsy between 2000 and 2015 in Kitano Hospital. Data selected included clinical and serological parameters; light and electron microscope findings; immunofluorescence findings; and prognostic parameters like renal and overall survival and creatinine increase by > 50%. In addition, a 26-patient IgAN cohort (matching-IgAN), matching with IgA-IRGN group with respect to age, sex, estimated glomerular filtration rate (eGFR), and proteinuria was segregated for comparison. RESULTS: Compared to IgAN group, IgA-IRGN group were older, had lower hemoglobin, higher CRP, lower eGFR, heavier proteinuria, lower serum albumin, and higher serum IgG and IgA levels (p < 0.05). Endocapillary hypercellularity, deposition of immune complexes along the glomerular capillary wall, and subendothelial and subepithelial electron dense deposits were more frequently observed (p < 0.05); and they were more susceptible to renal dysfunction and poorer prognosis. After propensity score-matching, serum albumin was significantly lower in the IgA-IRGN group. Significantly subendothelial and subepithelial deposits were frequently observed in this group. Matching-IgAN group showed relatively advanced sclerotic lesions with more global sclerosis and fibrous crescent. CONCLUSION: Local inflammation involved glomerular capillary wall in IgA-IRGN, in contrast to relatively chronic and sclerotic renal lesion in IgAN, might result in poorer prognosis in former, even under indistinguishable condition of deteriorated renal function and proteinuria.

Rationale and study design of a clinical trial to assess the effects of LDL apheresis on proteinuria in diabetic patients with severe proteinuria and dyslipidemia.

BACKGROUND: Diabetic nephropathy is a leading cause of end-stage kidney disease in the world. Although various types of treatment for diabetes, hypertension and dyslipidemia have improved prognosis and quality of life in patients with diabetic nephropathy, there still exist some diabetic patients with severe proteinuria showing poor prognosis. This clinical trial, LICENSE, aims to confirm the impact of LDL apheresis on proteinuria exhibiting hyporesponsiveness to treatment. METHODS: This ongoing trial is a multicenter, prospective study of diabetic patients with severe proteinuria. The objective is to examine the impact of LDL apheresis on proteinuria in patients with diabetic nephropathy. The other subject is to investigate safety of LDL apheresis in these patients. RESULTS: The subjects consist of diabetic patients with serum creatinine (Cr) levels below 2 mg/dL who present severe proteinuria above 3 g/g Cr or 3 g/day and LDL cholesterol above 120 mg/dL. The target number of registered patients will be 35 patients. Urinary protein excretion and renal function will be observed for 24 weeks after the treatment of LDL apheresis. CONCLUSION: This study will determine the effectiveness and safety of LDL apheresis for diabetic nephropathy patients with severe proteinuria and dyslipidemia.

A clinical evaluation of renal amyloidosis in the Japan renal biopsy registry: a cross-sectional study.

BACKGROUND AND AIM: The available clinical data are limited in a rare glomerular disease, renal amyloidosis. We aimed to clarify the clinical features of renal amyloidosis from database of the Japan Renal Biopsy Registry (J-RBR). METHODS: We performed a cross-sectional study with database of the J-RBR of the Japanese Society of Nephrology. We identified 281 cases of renal amyloidosis from 20,997 cases enrolled into the J-RBR from 2007 to 2014. Systolic blood pressure (SBP) and diastolic blood pressure (DBP) were compared among the levels of ages, amount of urine protein excretion (AUPE) or CKD G stages. RESULTS: The prevalence of renal amyloidosis was 1.3 % (281/20,997). DBP significantly decreased in higher age quartiles (P = 0.034). SBP and DBP did not increase in the progression of AUPE levels and CKD G stages. In multiple regression analysis, eGFR was a significant independent factor for SBP in all cases and a subgroup without hypertensive agents. There was a reverse significant relationship between SBP and eGFR. CONCLUSION: Blood pressure did not significantly increase in elderly and much proteinuric condition in renal amyloidosis. The progression of CKD and decrease of eGFR did not produce the higher SBP. The mechanism underlying these results remains unclear; however, they are unique features of renal amyloidosis. The couple of hypotensive and hypertensive conditions might produce no relationship between blood pressure and CKD stages.

Exploring the origin and limitations of kidney regeneration.

Epidemiological findings indicate that acute kidney injury (AKI) increases the risk for chronic kidney disease (CKD), although the molecular mechanism remains unclear. Genetic fate mapping demonstrated that nephrons, functional units in the kidney, are repaired by surviving nephrons after AKI. However, the cell population that repairs damaged nephrons and their repair capacity limitations remain controversial. To answer these questions, we generated a new transgenic mouse strain in which mature proximal tubules, the segment predominantly damaged during AKI, could be genetically labelled at desired time points. Using this strain, massive proliferation of mature proximal tubules is observed during repair, with no dilution of the genetic label after the repair process, demonstrating that proximal tubules are repaired mainly by their own proliferation. Furthermore, acute tubular injury caused significant shortening of proximal tubules associated with interstitial fibrosis, suggesting that proximal tubules have a limited capacity to repair. Understanding the mechanism of this limitation might clarify the mechanism of the AKI-to-CKD continuum.

Pulmonary involvements of anti-neutrophil cytoplasmic autoantibody-associated renal vasculitis in Japan.

BACKGROUND: Pulmonary involvement is one of the hallmark lesions of anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV) as well as rapidly progressive glomerulonephritis (RPGN). However, the pulmonary involvement of AAV patients seems to differ between Europe and Japan, as does the ANCA serotype. METHODS: This retrospective and prospective multicenter cohort study collected the clinical data of the features and outcomes of 1772 RPGN patients treated from 1989 to 2007 in Japan. Based on this nationwide RPGN survey, we analyzed the cases of 1147 AAV patients. RESULTS: We found that 52.3% of the AAV patients had pulmonary involvements: 15.4% of the AAV patients had alveolar hemorrhage (AH), 26.2% had interstitial lung disease (ILD), 2.8% had bronchial asthma, 2.4% had pulmonary granuloma and 12.8% had a chest X-ray abnormality without AH, ILD or pulmonary granuloma. Patient survival was significantly different among the following six groups: the 5-year survival rate was 41.5% in the patients with AH, 50.2% in those with ILD, 67.9% in those with bronchial asthma, 62.5% in those with pulmonary granuloma, 55.8% in those with chest X-ray abnormality and 73.3% in those without pulmonary involvement. AH was one of the predictors of 1- and 5-year mortality for patient survival in AAV, and ILD was added as one of the predictors of 5-year mortality. CONCLUSION: In these AAV patients, not only AH but also ILD was frequently observed. AH was associated with the prognosis, but ILD was associated with the long-term prognosis of AAV.

Immediate therapeutic efficacy of low-density lipoprotein apheresis for drug-resistant nephrotic syndrome: evidence from the short-term results from the POLARIS Study.

BACKGROUND: Hyperlipidemia is not merely a complication but a major exacerbating factor in longstanding nephrotic syndrome (NS). Low-density lipoprotein apheresis (LDL-A) has been reported to ameliorate dyslipidemia and induce rapid remission of NS. Several clinical studies have suggested the therapeutic efficacy of LDL-A, but the level of clinical evidence is insufficient. Therefore, a multicenter prospective study, POLARIS (Prospective Observational Survey on the Long-Term Effects of LDL Apheresis on Drug-Resistant Nephrotic Syndrome), was initiated in Japan. METHOD: Patients with drug-resistant NS were prospectively recruited into the study and treated with LDL-A in facilities that were registered in advance. In the POLARIS study design, the clinical data are to be followed up for 2 years. In the current study, we aimed at evaluating the short-term efficacy based on the treatment outcome of LDL-A immediately after completion of treatment. RESULTS: Along with rapid improvement of hyperlipidemia, LDL-A significantly improved proteinuria and hypoproteinemia after treatment. More than half of the patients showed remission of NS based on the urinary protein level at the completion of LDL-A. The duration of NS before the start of treatment was significantly shorter in patients who responded to LDL-A. CONCLUSIONS: An analysis of patients registered in the POLARIS study indicated that LDL-A has short-term efficacy for drug-resistant NS. Rapid relief of dyslipidemia by LDL-A may provide early remission in about half of the NS patients who are resistant to conventional medication. Completion of the POLARIS study may reveal additional long-term effects of LDL-A in these patients.

Gender- and disease-specific urinary thioredoxin in chronic kidney disease patients with or without type 2 diabetic nephropathy.

AIM: The role of urinary (U-) thioredoxin (Trx), a class of small redox proteins, in physiological and pathological conditions, in addition to its gender specificity, has been insufficiently determined in chronic kidney disease (CKD) patients, especially in diabetes mellitus (DM) nephropathy. METHODS: U-Trx was measured cross-sectionally in 110 CKD outpatients with estimated glomerular filtration rate (eGFR) of >15 mL/min per 1.73 m(2) , namely, in 57 type 2 DM patients (male: n = 41, female: n = 16) and 53 non-DM patients (M: n = 33, F: n = 20), as well as 30 healthy controls (M: n = 11, F: n = 19). Comparisons were made among controls, DM and non-DM, and between M and F, with clinical parameters compared in each group. In addition, a comparison between average U-Trx level and the changes of renal function during a one-year period was performed. RESULTS: U-Trx was significantly higher in females than in males in controls (P < 0.05) and in non-DM patients (P < 0.05). Multiple regression analysis revealed that urinary protein (UP)/creatinine (Cr) ratio, female sex and HbA1c were independent factors affecting U-Trx among all subjects (adjusted R(2) = 0.468). In DM patients, U-Trx was negatively correlated with eGFR, especially in males, and positively correlated with UP/Cr and NAG in both sexes (all P < 0.01), as well as with systolic blood pressure in all (P < 0.05). Average U-Trx was positively correlated with the rate of annual eGFR decline of male (P < 0.01) but not female DM patients. CONCLUSION: U-Trx might have a gender-specific physiological and pathological role and be a potent marker of renal damage in DM nephropathy.

Long-term safety and efficacy of rituximab in 7 Japanese patients with ANCA-associated vasculitis.

OBJECTIVES: The safety and efficacy of rituximab were examined in a multicenter open-label pilot study in patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) in Japan. METHODS: Patients with refractory AAV were administered a rituximab infusion at a weekly dose of 375 mg/m(2) for 4 weeks. All patients also received oral daily prednisolone. The primary outcome was complete remission, which was defined as a Birmingham Vasculitis Activity Score (BVAS) of 0 or 1. RESULTS: The mean age of the 7 patients was 57 (range, 34-71) years. The mean follow-up period after rituximab treatment was 62.9 (range, 4.8-81) months. The mean BVAS at entry was 16.7 (range, 2-34). Complete remission occurred in all cases, except in 1 case in which the patient died, with a significant decline in BVAS from baseline at 12 months after initiation of rituximab. Rituximab reduced granulomatous orbital involvement in a patient with granulomatosis with polyangiitis. Relapse occurred in five patients. Adverse events included de novo hepatitis B in one patient, cancer (hepatocellular carcinoma and prostate cancer) in two patients, and transient visual disturbance, atypical mycobacterial infection, urinary tract infection, sepsis, and cytomegalovirus infection. Two patients died due to recurrent infections and airway obstruction, caused by an AAV lesion. CONCLUSIONS: Rituximab had a beneficial effect on refractory AAV in Japanese patients, but several adverse effects occurred during rituximab treatment.

Renal redox dysregulation in AKI: application for oxidative stress marker of AKI.

Oxidative stress is a major determinant of acute kidney injury (AKI); however, the effects of an AKI on renal redox system are unclear, and few existing AKI markers are suitable for evaluating oxidative stress. We measured urinary levels of the redox-regulatory protein thioredoxin 1 (TRX1) in patients with various kinds of kidney disease and in mice with renal ischemia-reperfusion injury. Urinary TRX1 levels were markedly higher in patients with AKI than in those with chronic kidney disease or in healthy subjects. In a receiver operating characteristic curve analysis to differentiate between AKI and other renal diseases, the area under the curve for urinary TRX1 was 0.94 (95% confidence interval, 0.90-0.98), and the sensitivity and specificity were 0.88 and 0.88, respectively, at the optimal cutoff value of 43.0 µg/g creatinine. Immunostaining revealed TRX1 to be diffusely distributed in the tubules of normal kidneys, but to be shifted to the brush borders or urinary lumen in injured tubules in both mice and humans with AKI. Urinary TRX1 in AKI was predominantly in the oxidized form. In cultured human proximal tubular epithelial cells, hydrogen peroxide specifically and dose dependently increased TRX1 levels in the culture supernatant, while reducing intracellular levels. These findings suggest that urinary TRX1 is an oxidative stress-specific biomarker useful for distinguishing AKI from chronic kidney disease and healthy kidneys.