Clinical Impact of Malnutrition According to the Global Leadership Initiative on Malnutrition Criteria Combined With Kidney Dysfunction to Determine Mortality in Inpatients.

OBJECTIVE: The clinical impact of malnutrition based on the Global Leadership Initiative on Malnutrition (GLIM) criteria in patients with kidney dysfunction remains poorly understood. This study investigated the usefulness of GLIM criteria for malnutrition in predicting mortality in patients with kidney dysfunction and different clinical renal states, including no kidney disease (NKD), acute kidney injury (AKI), and chronic kidney disease (CKD). METHODS: This single-center retrospective cohort study included 6,712 patients aged ≥18 admitted between 2018 and 2019. The relationship between the estimated glomerular filtration rate (eGFR) groups, nutritional status based on the GLIM criteria, and the incidence of all-cause mortality was evaluated using a multivariate Cox proportional hazards model. Malnutrition was defined as at least one phenotype (weight loss, low body mass index, or reduced muscle mass) and one etiological criterion (reduced intake/assimilation or disease burden/inflammation). RESULTS: Multivariate Cox proportional hazards model showed that eGFR ≤29 (vs. eGFR: 60-89, adjusted hazard ratio [HR] = 1.84, 95% confidence interval [CI]: 1.52-2.22), 30-59 (vs. eGFR: 60-89, adjusted HR = 1.40, 95% CI: 1.20-1.64), and ≥90 (vs. eGFR: 60-89, adjusted HR = 1.40, 95% CI: 1.14-1.71), moderate and severe malnutrition (vs. without malnutrition, adjusted HR = 1.38 [1.18-1.62] and 2.18 [1.86-2.54], respectively) were independently associated with the incidence of death. The all-cause mortality rate was higher in patients with malnutrition or eGFR ≤29 (adjusted HR, 3.31; 95% CI: 2.51-4.35) than in patients without malnutrition or eGFR 60-89. Furthermore, moderate and severe malnutrition (vs. no malnutrition) was independently associated with death in patients with NKD, AKI, and CKD. CONCLUSION: Malnutrition based on the GLIM criteria was associated with increased all-cause mortality in inpatients, and malnutrition combined with kidney dysfunction was associated with a higher risk of mortality. Furthermore, patients with NKD, AKI, and CKD showed an association between malnutrition based on GLIM criteria and mortality.

Role of endothelial hyaluronan in peritoneal membrane transport and disease conditions during peritoneal dialysis.

Peritoneal membrane dysfunction in peritoneal dialysis (PD) is primarily attributed to angiogenesis; however, the integrity of vascular endothelial cells can affect peritoneal permeability. Hyaluronan, a component of the endothelial glycocalyx, is reportedly involved in preventing proteinuria in the normal glomerulus. One hypothesis suggests that development of encapsulating peritoneal sclerosis (EPS) is triggered by protein leakage due to vascular endothelial injury. We therefore investigated the effect of hyaluronan in the glycocalyx on peritoneal permeability and disease conditions. After hyaluronidase-mediated degradation of hyaluronan on the endothelial cells of mice, macromolecules, including albumin and ß2 microglobulin, leaked into the dialysate. However, peritoneal transport of small solute molecules was not affected. Pathologically, hyaluronan expression was diminished; however, expression of vascular endothelial cadherin and heparan sulfate, a core protein of the glycocalyx, was preserved. Hyaluronan expression on endothelial cells was studied using 254 human peritoneal membrane samples. Hyaluronan expression decreased in patients undergoing long-term PD treatment and EPS patients treated with conventional solutions. Furthermore, the extent of hyaluronan loss correlated with the severity of vasculopathy. Hyaluronan on endothelial cells is involved in the peritoneal transport of macromolecules. Treatment strategies that preserve hyaluronan in the glycocalyx could prevent the leakage of macromolecules and subsequent related complications.

Association between reduced left ventricular ejection fraction and peritoneal dialysis related peritonitis: a single center retrospective cohort study in Japan.

We present a single-center retrospective analysis of 228 Japanese patients with peritoneal dialysis, in which we examined whether reduced left ventricular ejection fraction (LVEF) is a risk factor for peritonitis development. Time-dependent multivariable-adjusted Cox proportional hazards models revealed that reduced LVEF (LVEF < 50% vs. preserved LVEF ≥ 50%, hazard ratio (HR) 2.10; 95% confidence interval (CI) 1.16-3.82) was associated with peritonitis. Qualitatively, similar associations with reduced LVEF (< 50%) were observed for enteric peritonitis (adjusted HR 7.68; 95% CI 2.51-23.5) but not for non-enteric peritonitis (adjusted HR 1.15; 95% CI 0.54-2.44). Reduced LVEF is associated with a significantly higher risk of subsequent peritonitis, particularly enteric peritonitis. These results indicate that patients with reduced LVEF may be at risk of enteric peritonitis from bowel sources caused by intestinal involvement due to cardiac dysfunction.

Lymphopenia is a risk factor for severe infections in older patients with microscopic polyangiitis: a retrospective cohort study in Japan.

Objective: Previous studies have identified the predictors of severe infections in ANCA-associated vasculitis. However, lymphopenia has not been fully evaluated as a predictor of subsequent severe infections in patients with microscopic polyangiitis (MPA). The aim of this study was to assess the association between lymphopenia and severe infections requiring hospitalization after receiving immunosuppressive therapy for MPA. Methods: This single-centre retrospective cohort study included 130 consecutive patients with newly diagnosed MPA from Aichi Medical University Hospital, Japan, who received immunosuppressive therapy between March 2004 and December 2020. The relationship between lymphopenia and subsequent severe infections was assessed using time-dependent multivariate Cox proportional hazard models adjusted for clinically relevant factors. Results: During the follow-up period (median: 38 months; interquartile range: 15-63 months), 56 severe infectious episodes occurred in 51 patients (39.2%). Time-dependent multivariate Cox proportional hazard analyses identified older age [adjusted hazard ratio (HR) = 1.74 per 10 years, 95% CI: 1.13, 2.67], methylprednisolone pulse therapy (adjusted HR = 2.04, 95% CI: 1.03, 4.02), moderate lymphopenia (vs normal, adjusted HR = 7.17, 95% CI: 3.10, 16.6) and severe lymphopenia (vs normal, adjusted HR = 36.1, 95% CI: 11.8, 110.9) as significant predictors of severe infection. Conclusion: Lymphopenia is a predictor of subsequent severe infections in patients with MPA who receive immunosuppressive therapy. These results suggest the importance of sustained infection surveillance, particularly in older patients who develop lymphopenia during strong immunosuppressive therapy.

Peritoneal Expression of Membrane Complement Regulators Is Decreased in Peritoneal Dialysis Patients with Infected Peritonitis.

In peritoneal dialysis (PD) patients, fungi and Pseudomonas aeruginosa are considered important causative microorganisms for peritonitis with poor prognosis. Our objective was to explore expressions of membrane complement (C) regulators (CRegs) and tissue injuries in the peritoneum of patients with PD-related peritonitis, including fungal and Pseudomonas aeruginosa peritonitis. In peritoneal biopsy tissues obtained at PD catheter removal, we investigated the severity of peritonitis-associated peritoneal injuries and the expression of CRegs, CD46, CD55, and CD59 against peritoneal tissues without any episode of peritonitis. In addition, we evaluated peritoneal injuries among fungal and Pseudomonas aeruginosa-peritonitis (P1) and Gram-positive bacterial peritonitis (P2). We also observed deposition of C activation products such as activated C and C5b-9 and measured sC5b-9 in the PD fluid of patients. As a result, the severity of peritoneal injuries correlated inversely with the expression of peritoneal CRegs. Peritoneal CReg expression in peritonitis was significantly reduced compared to no peritonitis. Peritoneal injuries were more severe in P1 than in P2. CReg expression was further decreased and C5b-9 further increased in P1 than in P2. In conclusion, severe peritoneal injuries due to fungal and Pseudomonas aeruginosa-peritonitis decreased CReg expression and increased deposition of activated C3 and C5b-9 in the peritoneum, suggesting that peritonitis, particularly fungal and Pseudomonas aeruginosa-peritonitis, might induce susceptibility to further peritoneal injuries due to excessive C activation.

Tissue Sodium Accumulation Induces Organ Inflammation and Injury in Chronic Kidney Disease.

High salt intake is a primary cause of over-hydration in chronic kidney disease (CKD) patients. Inflammatory markers are predictors of CKD mortality; however, the pathogenesis of inflammation remains unclear. Sodium storage in tissues has recently emerged as an issue of concern. The binding of sodium to tissue glycosaminoglycans and its subsequent release regulates local tonicity. Many cell types express tonicity-responsive enhancer-binding protein (TonEBP), which is activated in a tonicity-dependent or tonicity-independent manner. Macrophage infiltration was observed in the heart, peritoneal wall, and para-aortic tissues in salt-loading subtotal nephrectomized mice, whereas macrophages were not prominent in tap water-loaded subtotal nephrectomized mice. TonEBP was increased in the heart and peritoneal wall, leading to the upregulation of inflammatory mediators associated with cardiac fibrosis and peritoneal membrane dysfunction, respectively. Reducing salt loading by a diuretic treatment or changing to tap water attenuated macrophage infiltration, TonEBP expression, and inflammatory marker expression. The role of TonEBP may be crucial during the cardiac fibrosis and peritoneal deterioration processes induced by sodium overload. Anti-interleukin-6 therapy improved cardiac inflammation and fibrosis and peritoneal membrane dysfunction. Further studies are necessary to establish a strategy to regulate organ dysfunction induced by TonEBP activation in CKD patients.

Malnutrition according to the GLIM criteria with kidney dysfunction is associated with increased mortality in hospitalized patients with cardiovascular disease: A retrospective cohort study.

BACKGROUND & AIMS: Cardiovascular disease (CVD) is a significant cause of mortality and rising healthcare costs, involving numerous chronic and nutritional risk. Although several studies have reported that malnutrition based on the Global Leadership Initiative on Malnutrition (GLIM) criteria is associated with mortality in patients with CVD, they have not evaluated this association in terms of malnutrition severity (moderate or severe). Furthermore, the relationship between malnutrition combined with renal dysfunction, a risk factor for death in CVD patients, and mortality has not been previously evaluated. Thus, we aimed to assess the association between malnutrition severity and mortality, as well as malnutrition status stratified by kidney function and mortality, in patients hospitalized due to CVD events. METHODS: This single-centre, retrospective cohort study included 621 patients with CVD aged ≥18 years admitted to Aichi Medical University between 2019 and 2020. The relationship between nutritional status based on the GLIM criteria (without malnutrition, moderate malnutrition, or severe malnutrition) and the incidence of all-cause mortality was evaluated by multivariable Cox proportional hazards models. RESULTS: Patients with moderate and severe malnutrition were significantly more prone to mortality than those without malnutrition (adjusted hazard ratio [HR] of patients without, with moderate, and with severe malnutrition: 1.00 [reference], 1.94 [1.12-3.35], and 2.63 [1.53-4.50], respectively). Furthermore, we found the highest all-cause mortality rate in patients with malnutrition and a lower estimated glomerular filtration rate (eGFR <30 mL/min/1.73 m2) (adjusted HR, 10.1; confidence interval, 3.90-26.4) than in patients without malnutrition and normal eGFR (eGFR ≥60 mL/min/1.73 m2). CONCLUSIONS: The present study indicated that malnutrition according to the GLIM criteria was associated with increased all-cause mortality in patients with CVD, and malnutrition associated with kidney dysfunction was associated with a higher risk of mortality. These findings provide clinically relevant information to identify high mortality risk in patients with CVD and highlight the need for giving careful attention to malnutrition with kidney dysfunction among patients with CVD.

Inhibition of Transglutaminase 2 Reduces Peritoneal Injury in a Chlorhexidine-Induced Peritoneal Fibrosis Model.

Long-term peritoneal dialysis (PD) is often associated with peritoneal dysfunction leading to withdrawal from PD. The characteristic pathologic features of peritoneal dysfunction are widely attributed to peritoneal fibrosis and angiogenesis. The detailed mechanisms remain unclear, and treatment targets in clinical settings have yet to be identified. We investigated transglutaminase 2 (TG2) as a possible novel therapeutic target for peritoneal injury. TG2 and fibrosis, inflammation, and angiogenesis were investigated in a chlorhexidine gluconate (CG)-induced model of peritoneal inflammation and fibrosis, representing a noninfectious model of PD-related peritonitis. Transforming growth factor (TGF)-ß type I receptor (TGFßR-I) inhibitor and TG2-knockout mice were used for TGF-ß and TG2 inhibition studies, respectively. Double immunostaining was performed to identify cells expressing TG2 and endothelial-mesenchymal transition (EndMT). In the rat CG model of peritoneal fibrosis, in situ TG2 activity and protein expression increased during the development of peritoneal fibrosis, as well as increases in peritoneal thickness and numbers of blood vessels and macrophages. TGFßR-I inhibitor suppressed TG2 activity and protein expression, as well as peritoneal fibrosis and angiogenesis. TGF-ß1 expression, peritoneal fibrosis, and angiogenesis were suppressed in TG2-knockout mice. TG2 activity was detected by α-smooth muscle actin-positive myofibroblasts, CD31-positive endothelial cells, and ED-1-positive macrophages. CD31-positive endothelial cells in the CG model were α-smooth muscle actin-positive, vimentin-positive, and vascular endothelial-cadherin-negative, suggesting EndMT. In the CG model, EndMT was suppressed in TG2-knockout mice. TG2 was involved in the interactive regulation of TGF-ß. As inhibition of TG2 reduced peritoneal fibrosis, angiogenesis, and inflammation associated with TGF-ß and vascular endothelial growth factor-A suppression, TG2 may provide a new therapeutic target for ameliorating peritoneal injuries in PD.

Population pharmacokinetics and limited sampling strategy for therapeutic drug monitoring of mycophenolate mofetil in Japanese patients with lupus nephritis.

BACKGROUND: Mycophenolate mofetil (MMF), a prodrug of the immunosuppressive agent mycophenolic acid (MPA), is difficult to administer because of the pharmacokinetic complexity of MPA. Although dosage adjustment according to the 12-h area under the concentration-time curve (AUC0-12) is thought to be desirable, multiple blood samplings for AUC calculation may pose a clinical challenge. A limited sampling strategy (LSS) would provide a solution; however, little is known about MPA pharmacokinetics in lupus nephritis patients, especially in those with Asian backgrounds, or few, if any, LSSs are reported for them. METHODS: Thirty-four adult Japanese patients receiving MMF for lupus nephritis were examined retrospectively. MPA pharmacokinetics were investigated, and a PPK model was developed using Phoenix® NLME™ software. Single and double blood sampling strategies from Bayesian estimation using the PPK model and from multiple linear regression were compared. Tolerability was also evaluated. RESULTS: In the pharmacokinetic analysis, renal function and serum albumin had significant effects on dose-normalized AUC0-12; and serum albumin, concomitant proton pump inhibitor (PPI) and iron/magnesium oxide did on dose-normalized maximum concentration. As a PPK model, a two-compartment model was developed with a transit absorption model and first-order elimination, in which creatinine clearance and serum albumin were covariates for MPA clearance. The double sampling strategy at 1 and 4 h by multiple linear regression showed the best agreement with the observed AUC0-12 (r2 = 0.885). Of the single sampling strategies, the one at 6 h by Bayesian estimation performed best (r2 = 0.769). The tolerability evaluation showed that correlations were suggested for gastrointestinal involvement. CONCLUSIONS: The present study developed the first PPK model of MPA for Japanese lupus nephritis patients. As for LSSs, a double sampling strategy at 1 and 4 h by multiple linear regression would work best; when only a single blood sampling is allowed, a strategy at 6 h by Bayesian estimation using the PPK model developed in this study would be best. The LSSs good enough for clinical use may facilitate safer, more effective, and individualized therapy.

A case of 2,8-DHA crystalline nephropathy caused by adenine phosphoribosyltransferase deficiency: diagnosis and treatment.

Adenine phosphoribosyltransferase (APRT) deficiency is a rare autosomal recessive disorder that leads to the accumulation of poorly soluble 2,8-dihydroxyadenine (DHA) in the kidneys, resulting in a variety of renal presentations including nephrolithiasis, acute kidney injury, and chronic kidney disease (CKD) caused by crystal nephropathy. Here, we report a case of a 43-year-old man with 2,8-DHA crystalline nephropathy caused by APRT deficiency strongly suspected by renal biopsy results and definitively diagnosed by a urine gas chromatography-mass spectrometry (GC/MS)-based plasma metabolomic assessment. This case represents the importance of awareness and recognition of the signs and symptoms of this rare condition and its progression to CKD, which can be prevented by the early administration of xanthine oxidoreductase inhibitors.

Galactose-deficient IgA1 Is Involved in IgA Deposition in Renal Grafts Biopsied One Hour after Kidney Transplantation.

Objective Asymptomatic renal immunoglobulin A (IgA) deposition occurs in healthy subjects, but its etiologic role in disease is unclear. Galactose-deficient IgA1 (Gd-IgA1) is involved in the pathogenesis of IgA nephropathy. We investigated Gd-IgA1 deposition in transplanted kidneys that were considered healthy showing subclinical latent IgA deposition one hour after transplantation. Methods A total of 723 transplanted kidney specimens biopsied 1 h after kidney transplantation from 2009 to 2016 at Nagoya Red Cross Hospital were examined. A total of 81 cases of IgA deposition were extracted, and 41 were ultimately studied. Double immunofluorescence staining for Gd-IgA1 and IgA was conducted to investigate the role of Gd-IgA1 in subclinical IgA deposition. Results Light microscopy findings for the 41 cases indicated only minor glomerular abnormalities. Immunofluorescence analyses revealed that all cases were positive for IgA. C3, IgG, and IgM positivity rates were 78.0%, 7.3%, and 60.9%, respectively. All 41 cases were positive for Gd-IgA1, which merged with IgA deposition in immunofluorescence double staining. IgA disappeared in 26 of 40 cases (65.0%) 1 year after kidney transplantation. In contrast, IgA redeposition was observed in three cases. Conclusion Gd-IgA1 was demonstrated in all transplanted kidneys, with latent IgA deposition noted in otherwise healthy kidneys. Deposition of Gd-IgA1 might indicate the initial stage of IgA nephropathy; however, additional factors, such as IgG deposition, are required for the ultimate development of IgA nephropathy.

Mepolizumab administration for eosinophilic granulomatosis with polyangiitis in an elderly patient with an abrupt onset of limb ischaemia and peripheral neuropathy: A case-based literature review.

Eosinophilic granulomatosis with polyangiitis (EGPA) is a type of anti-neutrophil cytoplasmic antibody-associated vasculitis characterised by small- to medium-sized vessel vasculitis and is typically associated with eosinophilic granulomatous inflammation. EGPA can affect any organ system, most commonly the lungs, skin, and the nervous system. However, limb ulcers are rare complications and have only been described in few case reports. Furthermore, no documented cases of EGPA have been treated with mepolizumab. Herein, we report a case of an 86-year-old Japanese woman with anti-neutrophil cytoplasmic antibody-negative EGPA, who had an abrupt onset of upper limb ulcers and bilateral foot drop due to multiple mononeuropathy. Clinicopathological sural nerve biopsy showed eosinophil-associated vascular damage. The patient was administered steroids, intravenous immunoglobulin, vasodilators, and mepolizumab; this resulted in clinical improvement of her finger ulcers and peripheral neuropathy without any adverse effects. In cases of an abrupt onset of limb ischaemia and peripheral neuropathy, physicians should consider the possibility of EGPA as a differential diagnosis. Furthermore, the early administration of mepolizumab might yield better outcomes in terms of improving limb ischaemia and peripheral neuropathy.

Time to normalisation of CRP and incidence of relapse in microscopic polyangiitis: A medical records review study in Japan.

OBJECTIVES: Despite the identification of risk factors for relapses in anti-neutrophil cytoplasmic antibody-associated vasculitis, the relationship between changes in C-reactive protein levels after initial treatment and incidence of relapse remains unknown. This study aimed to assess the association between the time taken for normalisation of C-reactive protein levels and the incidence of relapse in Japanese adult patients with microscopic polyangiitis. METHODS: This study included 85 consecutive patients with newly diagnosed microscopic polyangiitis who achieved remission after six months of immunosuppressive treatment at the Aichi Medical University Hospital, between 2009 and 2017. The relationship between the time to normalisation of C-reactive protein after initial immunosuppressive treatment and relapse incidences was evaluated using multivariable Cox proportional hazard models. RESULTS: During the follow-up period, 13 (30.2%), 7 (41.2%), and 16 (64.0%) patients relapsed (P=0.025) within 1-14, 15-28, and ≥29 days of normalisation, respectively. Hazard ratios (95% confidence intervals) of the time to normalisation of C-reactive protein of 1-14, 15-28, and ≥29 days were 1.00 (reference), 2.42 (95%CI: 0.92-6.39), and 3.48 (95%CI: 1.56-7.76), respectively. CONCLUSIONS: A significant association between the time to normalisation of C-reactive protein and relapse incidence in Japanese patients with microscopic polyangiitis was observed.

Interleukin-6 blockade reduces salt-induced cardiac inflammation and fibrosis in subtotal nephrectomized mice.

Cardiovascular disease is the most common comorbidity in patients with chronic kidney disease (CKD), affecting both their prognosis and quality of life. Cardiac fibrosis is common in patients with CKD with left ventricular diastolic dysfunction, and it is associated with increased risk of heart failure and mortality. Recent evidence suggests that high salt intake activates immune responses associated with local accumulation of sodium. We reported that high salt intake promotes cardiac inflammation in subtotal nephrectomized (Nx) mice. We investigated the effects of administration of MR16-1, a rat anti-mouse monoclonal interleukin (IL)-6 receptor antibody, in Nx mice with salt loading (Nx-salt). Expression of monocyte chemoattractant protein-1, tumor necrosis factor-α, IL-1ß, and IL-6 mRNAs and macrophage infiltration was significantly reduced in the heart of Nx-salt mice treated with MR16-1 (Nx-salt-MR16-1) compared with Nx-salt mice treated with control rat rat IgG1 (Nx-salt-rat IgG1). Correspondingly, cardiac fibrosis was significantly attenuated in Nx-salt-MR16-1 mice compared with Nx-salt-rat IgG1 mice. Furthermore, in the heart of Nx-salt-MR16-1 mice, expression of mRNA for nicotinamide adenine dinucleotide phosphate oxidase-2, an oxidative stress marker, was significantly downregulated compared with Nx-salt-rat IgG1 mice. Increases in cardiac metabolites, including histidine and γ-butyrobetaine, were also reversed by IL-6 blockade treatment. In conclusion, IL-6 blockade exerts anti-inflammatory, antifibrotic, and partial antioxidative effects in the heart of Nx-salt mice.NEW & NOTEWORTHY In the present study, IL-6 blockade exerted anti-inflammatory, antifibrotic, and partial antioxidative effects on the hearts of mice with CKD on a high-salt diet. Therefore, IL-6 potentially mediates cardiac fibrosis induced by high salt intake in patients with CKD, a finding with therapeutic implications. Of note, the next therapeutic implication may simply be the reinforcement of low-salt diets or diuretics and further research on the anti-inflammatory effects of these measures rather than IL-6 blockade with high-salt diet.

Association between renal-limited vasculitis and relapse of antineutrophil cytoplasmic antibody-associated vasculitis: A single-center retrospective cohort study in Japan.

BACKGROUND: Several previous studies have evaluated the predictors of relapse in antineutrophil cytoplasmic antibody-associated vasculitis. Nonetheless, the association between renal-limited vasculitis and relapse has not been evaluated. OBJECTIVE: To assess the association between renal-limited vasculitis and the incidence of relapse in Japan among patients with microscopic polyangiitis/renal-limited vasculitis. METHODS: This retrospective cohort study included consecutive patients in remission at 6 months, with renal-limited vasculitis (n = 24, renal-limited vasculitis group) and microscopic polyangiitis with renal and extra-renal involvement (n = 56, non-renal-limited vasculitis group) between 2004 and 2020. RESULTS: During the median follow-up period of 35 (range, 15‒57) months, 28 (35.0%) patients had a relapse. Multivariable Cox proportional hazards models revealed that the lower estimated glomerular filtration rate (per -10 mL/min/1.73 m2; adjusted hazard ratio = 0.87, 95% confidence interval: 0.76-0.99; P =  0.043), renal-limited vasculitis (adjusted hazard ratio =  0.23, 95% confidence interval: 0.08-0.68; P =  0.008), and glucocorticoid combined with intravenous cyclophosphamide or rituximab (adjusted HR = 0.32, 95% CI: 0.11-0.96; P = 0.042) were associated with a decreased risk of relapse. Glucocorticoid dose during the observation period was lower in the renal-limited vasculitis group than in the non-renal-limited vasculitis group. CONCLUSIONS: Renal-limited vasculitis was associated with a lower risk of relapse than non-renal-limited vasculitis. Our data may contribute to the development of optimal management for renal-limited vasculitis, which may assist in minimizing the adverse effects of immunosuppressive therapy.

Association of alcohol consumption with the incidence of proteinuria and chronic kidney disease: a retrospective cohort study in Japan.

BACKGROUND: The difference in the clinical impact of alcohol consumption on kidney function based on sex remains to be elucidated. This study aimed to assess the association between the dose of alcohol consumption and the incidence of proteinuria and chronic kidney disease stratified by sex. METHODS: This retrospective cohort study included 26,788 workers (19,702 men and 7086 women) with normal renal function (estimated glomerular filtration rate ≥ 60 mL/min/1.73 m2) at annual health examinations between January 2010 and March 2015 in Japan. The main exposure was alcohol consumption. The primary outcomes were the incidence of proteinuria (dipstick urinary protein ≥ 1) and incidence of low estimated glomerular filtration rate (eGFR; rate < 60 mL/min per 1.73 m2; decreased from the baseline eGFR by 25%). RESULTS: During a median observational period of 4 years (interquartile range: 2-6), 1993 (10.1%) men and 462 (6.5%) women developed proteinuria, whereas 667 (3.4%) men and 255 (3.6%) women developed low eGFR. After adjustment for clinically relevant factors using a Cox proportional hazards model, alcohol consumption of ≥ 46 g/day in females was significantly associated with the incidence of proteinuria (hazard ratio, 1.57; 95% confidence interval, 1.10-2.26) and low eGFR (hazard ratio, 1.62; 95% confidence interval, 1.04-2.53). However, no significant association between alcohol consumption and primary outcomes was observed in men. CONCLUSIONS: In conclusion, daily higher alcohol consumption was significantly associated with a higher incidence of proteinuria and low eGFR among women. Women might be prone to high alcohol consumption with kidney dysfunction.

Anti-neutrophil cytoplasmic antibody-associated vasculitis complicated by thrombotic microangiopathy with posterior reversible encephalopathy syndrome successfully treated with eculizumab: A case report.

Thrombotic microangiopathy is characterised by endothelial cell injury, intravascular platelet-fibrin thrombi, and vascular damage, leading to acute kidney injury, thrombocytopenia, and microangiopathic haemolytic anaemia. Among the autoimmune diseases related to thrombotic microangiopathy, anti-neutrophil cytoplasmic antibody-associated vasculitis-related thrombotic microangiopathy cases have been rarely reported; therefore, the optimal treatment for associated vasculitis-related thrombotic microangiopathy remains unknown. An 84-year-old woman without significant medical history presented with a 1-month history of general fatigue, fever, and deteriorating bilateral leg numbness and was admitted to our hospital. She had elevated myeloperoxidase anti-neutrophil cytoplasmic antibody levels, polyneuropathy, and rapid progressive glomerulonephritis because of pauci-immune crescentic glomerulonephritis, as revealed by a kidney biopsy. Accordingly, we diagnosed her with microscopic polyangiitis. After administering methylprednisolone pulse therapy, rituximab, and intravenous immunoglobulin, the patient's mental state deteriorated, presenting signs of thrombotic microangiopathy with posterior reversible encephalopathy syndrome. Intermittent haemodialysis and plasma exchange were initiated; however, her condition did not improve, and eculizumab administration was initiated thereafter. The patient's symptoms showed a remarkable response to eculizumab; thrombotic microangiopathy findings, kidney function, and neurological symptoms improved after only two doses of eculizumab, and she achieved sustained remission. The extremely effective course of eculizumab treatment indicated that overt complement activation affected the development of thrombotic microangiopathy. Anti-neutrophil cytoplasmic antibody-associated vasculitis-related thrombotic microangiopathy may be mediated by complement activation, and prompt induction of eculizumab therapy may be a superior strategy to prevent organ damage. Further studies should elucidate the role of complement activation in associated vasculitis-related thrombotic microangiopathy and the efficacy of eculizumab treatment.

Long-term good outcome of the fibrocavitary form of pulmonary Mycobacterium avium complex disease with concomitant abatacept monotherapy in a patient with rheumatoid arthritis.

A 53-year-old woman diagnosed with rheumatoid arthritis (RA) demonstrated thick-walled large cavities with consolidation in the left upper lobe on chest computed tomography (CT). Mycobacterium avium was isolated from sputum cultures, and she was diagnosed as having the fibrocavitary (FC) form of pulmonary Mycobacterium avium complex (MAC) disease. Clarithromycin-containing, multidrug, anti-MAC chemotherapy was started immediately. After 7 months, the cavitary lesions improved, and sputum cultures showed negative conversion. Thereafter, abatacept monotherapy was started due to high RA disease activity. Clinical remission of RA has been sustained and cavitary lesions disappeared by concomitant abatacept and anti-MAC therapy for more than 5 years. Immediate initiation of anti-MAC therapy and prior confirmed efficacy are needed for the treatment of the FC form. Abatacept and anti-MAC therapy could be continued, leading to the withdrawal of prednisolone, along with careful observation by strict chest CT evaluation and repeated sputum cultures. Biologics are generally contraindicated for pulmonary MAC disease, particularly the FC form. When there is a pre-existing lung lesion apparently of FC type, abatacept cannot be started without prior anti-MAC chemotherapy. This case suggests that abatacept may be carefully used to avoid progressive joint destruction after FC lesions of pulmonary MAC disease are resolved.

Case report: Thrombotic microangiopathy concomitant with macrophage activation syndrome in systemic lupus erythematosus refractory to conventional treatment successfully treated with eculizumab.

Thrombotic microangiopathy (TMA) is a rare but life-threatening complication of systemic lupus erythematosus (SLE). Macrophage activation syndrome (MAS) is also a rare, life-threatening hyperinflammatory condition that is comorbid with SLE. However, the association between TMA and MAS in patients with SLE has rarely been assessed, and the difficulty of diagnosing these conditions remains prevalent. The efficacy of eculizumab has been reported for SLE patients whose conditions are complicated with TMA. However, no study has investigated the therapeutic efficacy of eculizumab for TMA concomitant with SLE-associated MAS. Herein, we report the first case of TMA concomitant with SLE-associated MAS that was initially refractory to conventional immunosuppressive therapy but showed remarkable recovery after eculizumab treatment. Furthermore, we evaluated serum syndecan-1 and hyaluronan levels, which are biomarkers of endothelial damage. We found that these levels decreased after the administration of eculizumab, suggesting that TMA was the main pathology of the patient. This case illustrates that it is important to appropriately assess the possibility of TMA during the course of SLE-associated MAS and consider the use of eculizumab as necessary.

Roles of glomerular endothelial hyaluronan in the development of proteinuria.

Vascular endothelial cells are covered with glycocalyx comprising heparan sulfate, hyaluronan, chondroitin sulfate, and associated proteins. Glomerular endothelial glycocalyx is involved in protecting against induction of proteinuria and structural damage, but the specific components in glycocalyx that represent therapeutic targets remain unclear. Anti-vascular endothelial growth factor (VEGF) therapy is associated with an increased risk of glomerular endothelial injury. This study investigated whether hyaluronan could provide a therapeutic target to protect against proteinuria. We conducted ex vivo and in vivo experiments to explore the effects of degrading glomerular hyaluronan by administering hyaluronidase and of supplementation with hyaluronan. We investigated hyaluronan expression using biotin-labeled hyaluronan-binding protein (HABP) in human kidney specimens or serum hyaluronan in endothelial injuries under inhibition of VEGF signaling. We directly demonstrated hyaluronan in glomerular endothelial layers using HABP staining. Ex vivo and in vivo experiments showed the development of proteinuria after digestion of hyaluronan in glomerular capillaries. Supplementation with hyaluronan after hyaluronidase treatment suppressed proteinuria. Mice in the in vivo study developed albuminuria after intraperitoneal injection of hyaluronidase with decreased glomerular hyaluronan and increased serum hyaluronan. In human kidneys with endothelial cell dysfunction and proteinuria due to inhibition of VEGF, glomerular expression of hyaluronan was reduced even in normal-appearing glomeruli. Serum hyaluronan levels were elevated in patients with pre-eclampsia with VEGF signaling inhibition. Our data suggest that hyaluronan itself plays crucial roles in preventing proteinuria and preserving the integrity of endothelial cells. Hyaluronan could provide a therapeutic target for preventing glomerular endothelial glycocalyx damage, including VEGF signaling inhibition.