Hereditary angioedema with an acute attack resolved after bone marrow transplantation for acute myeloid leukemia: a case report.

BACKGROUND: Hereditary angioedema (HAE), which is caused by C1-inhibitor (C1-INH) deficiency or dysfunction, is a rare and potentially life-threatening disease. In patients with HAE, excess production of bradykinin causes acute unpredictable recurrent attacks of angioedema in localized regions, including the larynx and intestines. Given the fact that HAE is an autosomal dominant disease, C1-INH produced in patients with HAE is 50% of that produced in healthy individuals. However, most patients with HAE present plasma C1-INH function of < 25% owing to the chronic consumption of C1-INH by kallikrein-kinin, contact, complement, coagulation, and fibrinolysis cascades. Recently, several therapeutic options have been developed for acute attacks and prophylaxis in the treatment of HAE; however, currently, there is no curative therapy for HAE. CASE PRESENTATION: Here we report the case of a 48-year-old male patient who presented with a long-standing history of HAE and underwent bone marrow transplantation (BMT) for acute myeloid leukemia (AML) at the age of 39 years and has been in complete remission of AML and HAE thereafter. Notably, after BMT, his C1-INH function gradually increased as follows: < 25%, 29%, 37%, and 45.6%. Since his 20 s, he intermittently presented with an acute attack of HAE once every 3 months from the initial attack. Further, after undergoing BMT, the number of acute attacks decreased to twice within 4 years until the age of 45 years, and subsequently, the patient has been free of acute attacks. C1-INH is mainly synthesized by hepatocytes, but it is known to be partially produced and secreted from peripheral blood monocytes, macrophages, endothelial cells, and fibroblasts. We speculate that the C1-INH function may be increased by extrahepatic production of C1-INH, possibly synthesized by differentiated cells derived from hematopoietic and mesenchymal stem cells after BMT. CONCLUSIONS: This case report supports efforts to focus on extrahepatic production of C1-INH in the next strategy of new treatment development for HAE.

Post-Operative Kidney Function Using Deep Hypothermic Circulatory Arrest (DHCA) in Aortic Arch Operation.

Background: Although deep hypothermic circulatory arrest (DHCA) is a useful option to protect the central nervous system during aortic arch operations, the influence of simultaneous renal ischemia remains controversial. Patients and Methods: This is a retrospective observational study. Sixty-three patients who underwent thoracic aortic surgery with DHCA and 24 patients who underwent cardiac surgery without DHCA were included in this study. The mean age, preoperative serum creatinine (Cr) level, preoperative estimated glomerular filtration rate (eGFR), peak serum Cr level up to 48 hrs post-operative, elevation rate of Cr compared to the preoperative serum Cr, urine volume rate up to 48 hrs post-operative and AKI staging using the KDIGO criteria were estimated for each patient. Clinical parameters for 3 months after the operation and the 3-month post-operative mortality rate were assessed. Mean values indicating kidney function or distribution of the AKI stages were compared between patients with and without DHCA. Patients with DHCA were further divided according to the duration of ischemia to compare the values for the kidney function of each group, distribution of AKI stages and mortality. Results: The parameters indicating AKI of the patients with DHCA were significantly more severe than those without DHCA. Patients who had undergone an ischemic state for more than 40 min revealed significantly higher peak serum Cr, elevation rate of serum Cr, less urine volume up to 48 hrs post-operative compared with those without DHCA. Distribution of the AKI stages was related to the duration of ischemia. The 3-month post-operative mortality of the patients with DHCA was significantly higher than those without DHCA. Limitations: This study had limitations such as its retrospective design and small number patients, and the data will be required confirmation with other prospective studies. Conclusion: DHCA is closely related to AKI up to 48 hrs post-operative and death during the 3 months following surgery.

Evaluation of switching treatment from high dose of darbepoetin to lower dose of roxadustat in Japanese hemodialysis patients.

Roxadustat is one of the oral hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) that stimulates erythropoiesis and regulates the genes related to iron metabolism. The treatment of HIF-PHIs is useful compared with that of erythropoietin stimulating agent (ESA) using various instruments and procedures. Few clinical researchers have examined the efficacy and safety of switching treatment from Darbepoetin to Roxadustat in Japanese hemodialysis (HD) patients. However, HIF-PHIs have severe adverse drug reactions, such as thrombotic events. In the present study, we evaluated the lower dose of roxadustat in HD patients receiving high dose of ESA therapy. Eighteen anemic HD patients receiving an ESA, that is,, darbepoetin over 40 µg per week, were enrolled in this study. The treatment of these patients was changed to 20 mg of roxadustat three times weekly for 6 months, after which doses were adjusted to achieve a hemoglobin (Hb) target of 10.0-12.0 g/dL. An increase of 58.1 ± 32.5 mg roxadustat three times weekly increased Hb. It also achieved and then maintained levels within the target range at month 6. Ferritin levels of more than 100 ng/mL or TSAT levels of more than 20% were maintained during the 6-month treatment periods with oral or intravenous iron supplementation. It seems unnecessary to increase the initial dose of roxadustat for patients using high doses of ESA. It is suggested that a reconsideration of the starting dose of roxadustat in Japanese HD patients is needed. (Ikegami General Hospital, Medical Corporation SHOWAKAI、Approval number: 2020-4).

Immunotactoid Glomerulopathy with Nontuberculous Mycobacterial Infection: A Novel Association.

A 70-year-old woman underwent a renal biopsy due to nephrotic syndrome. She had suffered from nontuberculous mycobacterial infection (NTM) for 14 years. The patient was diagnosed as having membranoproliferative glomerulonephritis (MPGN) type 3 and immunoglobulin (Ig)-associated MPGN based upon LM/erythromycin and IF findings, respectively. In high-magnification imaging, electron-dense deposits showed immunotactoid glomerulopathy (ITG). There was no evidence of hematological cancer, and the patient improved after receiving treatments for NTM. To the best of our knowledge, this patient is the first to show an association between ITG and NTM. Although ITG is generally considered as related to lymphoproliferative disease, it is suggested that ITG is driven by bacterial infection and is a potential outcome of Ig-associated MPGN.

Utility of remission criteria for the renal prognosis of IgA nephropathy.

BACKGROUND: Novel criteria for the remission of Immunoglobulin A nephropathy (IgAN) based on an opinion survey of Japanese nephrologists and literature review were proposed in 2013. This single-center, longitudinal retrospective cohort study was conducted to validate this criteria. METHODS: Present study included the IgAN patients diagnosed between 2001 and 2005 in the Juntendo University Hospital. Remission of hematuria was defined as three consecutive dipstick test results of ( -) to ( ±) or a red blood cell count < 5 in urinary sediment per high-power field during at least 6 months. Remission of proteinuria was defined as three consecutive dipstick results of ( -) to ( ±) during at least 6 months. We categorized four groups according to the remission status which was assessed 2 years after the renal biopsy. The primary outcome was a 50% increase in the serum creatinine over the baseline. We evaluated the slope of eGFR decline (mL/min/1.73 m2/year) and a decrease in the eGFR of 30% from baseline eGFR as the secondary outcome, respectively. RESULTS: A total of 74 patients (male: 47.3%, median age: 30 years) were included and were followed for a median of 86.5 months. During the period, forty-one patients achieved neither remission of proteinuria nor hematuria (NR). Twelve patients met the primary study outcome. A survival analysis revealed that the NR had the worst prognosis and the steepest slope of eGFR decline. CONCLUSION: Although further validation in a large cohort is necessary, these novel remission criteria for IgAN patients appear to predict the renal prognosis.

Multicenter laparoscopic evaluation of the peritoneum in peritoneal dialysis patients.

Laparoscopic findings have been used to confirm peritoneal degenerations in peritoneal dialysis (PD) therapy. This study evaluated morphological changes in the peritoneum and their clinical relevance in patients undergoing PD. Laparoscopic findings at the rectovesical peritoneum were evaluated and scored using an imaging system at the time of PD catheter removal in this multicenter study. Angiogenesis evaluated by the vascular score (VS), color changes score (CCS), plaque score (PS), PD duration, history of peritonitis, dialysate/plasma creatinine (D/P Cr) levels, and age at PD termination were statistically analyzed. The VS of patients with PD duration more than 96 months was significantly decreased compared with that of the other patients and was negatively correlated with D/P Cr levels at PD termination. The CCS for patients with PD duration more than 96 months were significantly higher than those for the other patients and positively correlated with D/P Cr levels at PD termination. The PS of patients with recurring peritonitis were significantly higher than those of the other patients. Diminished vascularity and increased color changes in the peritoneum may be predictive of D/P Cr levels with peritoneal degradation. Laparoscopic evaluation of the abdominal cavity can provide detailed information about peritoneal injury.

Progressive Renal Dysfunction due to IgG4-Related Kidney Disease Refractory to Steroid Therapy: A Case Report.

Recently, as the number of case reports of IgG4-related kidney disease (IgG4-RKD) has increased, the histopathological features and clinical approach have been clarified. IgG4-RKD generally has a benign prognosis due to the efficacy of steroid therapy and rarely requires dialysis. Herein, we report a case of IgG4-RKD that presented with a subacute onset, advanced to end-stage kidney disease, and finally required maintenance hemodialysis despite steroid therapy. A 75-year-old man was admitted to our hospital for further evaluation of subacute renal failure. Diffuse enlargement of the kidney on computed tomography and increased urinary N-acetyl-ß-D-glucosaminidase and α1-microglobulin levels led us to suspect IgG4-RKD. Upon admission, the laboratory serological findings were as follows: creatinine 3.3 mg/dL, urea nitrogen 46.9 mg/dL, and IgG4 235 mg/dL. Urinalysis showed slight proteinuria without hematuria. Percutaneous renal needle biopsy showed diffuse infiltration of abundant lymphocytes and IgG4-positive plasma cells and storiform fibrosis, which is specific to IgG4-RKD, in the interstitium on light microscopy. Slight linear deposition of C3 was also observed in the tubules on immunofluorescence microscopy, with no electron-dense deposits. He was definitively diagnosed as having IgG4-RKD and started on prednisolone 0.6 mg/kg/day. However, the renal insufficiency continued to progress and hemodialysis was necessary. As the prednisolone was tapered, renal function did not improve and maintenance hemodialysis was started. In conclusion, this case indicates that the prognosis of IgG4-RKD is not necessarily benign and that further studies involving more patients are needed.

MPGN Type 3 Associated with Pemphigus Herpetiformis Mimicking PGNMID and Dermatitis Herpetiformis.

A 45-year-old man suffering from dermal blistering disease with proteinuria and hematuria underwent renal biopsy. The renal biopsy specimen suggested proliferative glomerulonephritis with monoclonal IgG deposits under routine light, immunofluorescence and electron microscopy. The staining for IgG subclasses (IgG1 and IgG2) and κ/λ light chain indicated secondary immune complex type MPGN type 3. The patient had been diagnosed as having dermatitis herpetiformis (DH), a phenotype of gluten hypersensitivity prior to the appearance of the renal abnormality. Although common autoantibodies might be related to the pathogenesis of disorders in the skin and kidney, DH is mainly driven by IgA autoantibody, while MPGN is induced by IgG immune complexes. IgA was not observed in the glomeruli by immunofluorescence. Neither the examination for DH specific autoantibodies nor HLA-DQB1 genotype supported the diagnosis of DH. Reassessment of the skin biopsy record revealed that the blister was localized in the epidermis, suggesting pemphigus herpetiformis by IgG class anti-epidermal autoantibody, which also affected the renal disorder.

A grading system that predicts the risk of dialysis induction in IgA nephropathy patients based on the combination of the clinical and histological severity.

Histological classification is essential in the clinical management of immunoglobulin A nephropathy (IgAN). However, there are limitations in predicting the prognosis of IgAN based on histological information alone, which suggests the need for better prognostic models. Therefore, we defined a prognostic model by combining the grade of clinical severity with the histological grading system by the following processes. We included 270 patients and explored the clinical variables associated with progression to end-stage renal disease (ESRD). Then, we created a predictive clinical grading system and defined the risk grades for dialysis induction by a combination of the clinical grade (CG) and the histological grade (HG). A logistic regression analysis revealed that the 24-h urinary protein excretion (UPE) and the estimated glomerular filtration rate (eGFR) were significant independent variables. We selected UPE of 0.5 g/day and eGFR of 60 ml/min/1.73 m2 as the threshold values for the classification of CG. The risk of progression to ESRD of patients with CG II and III was significantly higher than that of patients with CG I. The patients were then re-classified into nine compartments based on the combination of CG and HG. Furthermore, the nine compartments were grouped into four risk groups. The risk of ESRD in the moderate, high, and super-high-risk groups was significantly higher than that in the low-risk group. Herein, we are giving a detailed description of our grading system for IgA nephropathy that predicted the risk of dialysis based on the combination of CG and HG.

Neurofilament heavy polypeptide protects against reduction in synaptopodin expression and prevents podocyte detachment.

Podocytes are highly specialized cells that line the glomerulus of the kidney and play a role in filtration. Podocyte injury plays a critical role in the development of many kidney diseases, but the underlying mechanisms remain unclear. In this study, we identified that neurofilament heavy polypeptide (NEFH), an intermediate filament component, protects podocyte from injury. We observed that NEFH was upregulated after ADRIAMYCIN(ADR)-induced podocyte injury in both mice and cultured murine podocytes. Immunofluorescence and co-immunoprecipitation analyses revealed that NEFH was colocalized with synaptopodin, a podocyte-specific marker. High NEFH expression in podocytes prevented the Adriamycin-induced reduction in synaptopodin expression. The siRNA-mediated knockdown of NEFH in podocytes reduced the number of vinculin-containing focal contacts, thereby reducing adhesion to the extracellular matrix and increasing podocyte detachment. In addition, NEFH expression was significantly increased in renal biopsy specimens from patients with focal segmental glomerulosclerosis and membranous nephropathy, but in those with minimal change disease. These findings indicate that NEFH is expressed in podocytes during the disease course and that it prevents the reduction in synaptopodin expression and detachment of podocytes.

Rac1 in podocytes promotes glomerular repair and limits the formation of sclerosis.

Rac1, a Rho family member, is ubiquitously expressed and participates in various biological processes. Rac1 expression is induced early in podocyte injury, but its role in repair is unclear. To investigate the role of Rac1 expression in podocytes under pathological conditions, we used podocyte-specific Rac1 conditional knock-out (cKO) mice administered adriamycin (ADR), which causes nephrosis and glomerulosclerosis. Larger areas of detached podocytes, more adhesion of the GBM to Bowman's capsule, and a higher ratio of sclerotic glomeruli were observed in Rac1 cKO mice than in control mice, whereas no differences were observed in glomerular podocyte numbers in both groups after ADR treatment. The mammalian target of rapamycin (mTOR) pathway, which regulates the cell size, was more strongly suppressed in the podocytes of Rac1 cKO mice than in those of control mice under pathological conditions. In accordance with this result, the volumes of podocytes in Rac1 cKO mice were significantly reduced compared with those of control mice. Experiments using in vitro ADR-administered Rac1 knockdown podocytes also supported that a reduction in Rac1 suppressed mTOR activity in injured podocytes. Taken together, these data indicate that Rac1-associated mTOR activation in podocytes plays an important role in preventing the kidneys from developing glomerulosclerosis.

Scavenging of reactive oxygen species by astaxanthin inhibits epithelial-mesenchymal transition in high glucose-stimulated mesothelial cells.

BACKGROUND: High glucose concentrations influence the functional and structural development of the peritoneal membrane. We previously reported that the oral administration of astaxanthin (AST) suppressed peritoneal fibrosis (PF) as well as inhibited oxidative stress, inflammation, and epithelial-mesenchymal transition (EMT) of peritoneal mesothelial cells (PMCs) in a chlorhexidine-induced PF rat model. This suggests that oxidative stress induction of EMT is a key event during peritoneal damage. The present study evaluated the therapeutic effect of AST in suppressing EMT, in response to glucose-induced oxidative stress. METHODS: Temperature-sensitive mesothelial cells (TSMCs) were cultured in the presence or absence of AST and then treated with 140 mM glucose for 3 or 12 hours. Expression levels of TNF-α, TGF-ß, and VEGF were determined at the mRNA and protein levels, and nuclear factor kappa B (NF-κB) activity was evaluated. We measured NO2-/NO3- concentrations in cellular supernatants and determined 8-hydroxy-2'-deoxyguanosine (8-OHdG) levels in mitochondrial and nuclear DNA. The expressions of E-cadherin and alpha-smooth muscle actin (α-SMA) were evaluated by double immunofluorescence and protein levels. RESULTS: High glucose concentrations induced overproduction of reactive oxidative species (ROS), increasing 8-OHdG mitochondrial DNA and cytokine levels. The NF-κB pathway was activated in response to high glucose concentrations, whereas de novo α-SMA expression was observed with decreased E-cadherin expression. AST treatment attenuated ROS production, inflammatory cytokine production, NF-κB activation, and EMT. CONCLUSION: The findings of the present study indicate that AST may have an anti-EMT effect due to anti-oxidative and anti-inflammatory activities by scavenging glucose-induced ROS from mitochondria in PMCs. AST may be an efficacious treatment for PF.

Re-expression of Sall1 in podocytes protects against adriamycin-induced nephrosis.

The highly conserved spalt (sal) gene family members encode proteins characterized by multiple double zinc finger motifs of the C2H2 type. Humans and mice each have four known Sal-like genes (SALL1-4 in humans and Sall1-4 in mice). Sall1 is known to have a crucial role in kidney development. To explore the significance of Sall1 in differentiated podocytes, we investigated podocyte-specific Sall1-deficient mice (Sall1 KOp°d°/p°d°) using a podocin-Cre/loxP system and siRNA Sall1 knockdown (Sall1 KD) podocytes. Under physiological conditions, Sall1 KOp°d°/p°d° mice exhibited no proteinuria during their lifetime, but foot-process effacement was detected in some of the podocytes. To elucidate the role of Sall1 in injured podocytes, we used an adriamycin (ADR)-induced model of nephrosis and glomerulosclerosis. Surprisingly, the expression of Sall1 was elevated in control mice on day 14 after ADR injection. On day 28 after ADR injection, Sall1 KOp°d°/p°d° mice exhibited significantly higher levels of proteinuria and higher numbers of sclerotic glomeruli. Differentiated Sall1 KD podocytes showed a loss of synaptopodin, suppressed stress fiber formation, and, ultimately, impaired directed cell migration. In addition, the loss of Sall1 increased the number of apoptotic podocytes following ADR treatment. These results indicated that Sall1 has a protective role in podocytes; thus, we investigated the endoplasmic reticulum stress marker GRP78. GRP78 expression was higher in ADR-treated Sall1 KOp°d°/p°d° mice than in control mice. Sall1 appeared to influence the expression of GRP78 in injured podocytes. These results suggest that Sall1 is associated with actin reorganization, endoplasmic reticulum stress, and apoptosis in injured podocytes. These protective aspects of Sall1 re-expression in injured podocytes may have the potential to reduce apoptosis and possibly glomerulosclerosis.

Diminished capacity of opsonization and immune complex solubilization, and detection of anti-C1q antibodies in sera from patients with hereditary angioedema.

BACKGROUND: Hereditary angioedema (HAE) is an autosomal dominant disease caused by deficiency of C1 esterase inhibitor. Symptoms of HAE include edema, which can potentially cause suffocation. Some patients with HAE exhibit immunological abnormalities, which could prevent an accurate diagnosis. Low levels of complement components are characteristic of HAE and in other settings are thought to reduce elimination of apoptotic cells and immune complex (IC). Thus, we aimed to experimentally clarify the mechanism of immunological abnormalities using sera from HAE patients. METHODS: Serum samples from 18 patients with HAE were collected when free from angioedema attack and compared with normal human pooled sera (NHPS) from 20 healthy volunteers. Opsonization was measured as the rate of phagocytosis of apoptotic Jurkat cells by macrophages differentiated from THP-1 cells incubated with serum. IC solubilization in serum was analyzed by quantifying peroxidase released from a synthetic IC composed of peroxidase and anti-peroxidase antibodies. Anti-C1q antibody levels were detected using an enzyme-linked immunosorbent assay. RESULTS: Serological immunological abnormalities were detected in 12 patients. Opsonization in serum samples from each patient with HAE was lower than that in NHPS (∼20% versus 70%, respectively). The rate of IC solubilization was lower in serum from HAE patients than NHPS. Some patients had high serum anti-C1q antibody levels with increased serum IC levels. CONCLUSIONS: Sera from patients with HAE exhibit anti-C1q antibodies, with a lower capacity for opsonization and IC solubilization. This may be associated with immunological abnormalities and should be investigated further to facilitate accurate diagnosis of HAE.

Effect of tonsillectomy with steroid pulse therapy on circulating tumor necrosis factor receptors 1 and 2 in IgA nephropathy.

BACKGROUND: High circulating levels of soluble tumor necrosis factor receptors (TNFRs: TNFR1, TNFR2) predict renal function decline in a variety of kidney diseases. Tonsillectomy with steroid pulse (TSP) therapy has been reported as a remission induction therapy in IgA nephropathy (IgAN), mainly in Japan. However, little is known about whether TNFR levels change after TSP therapy in patients with IgAN. METHODS: Two hundred twenty-three patients with IgAN were stratified according to the estimated glomerular filtration rate (eGFR): Group I (eGFR ≥ 60 mL/min/1.73 m2, n = 172) and Group II (eGFR < 60 mL/min/1.73 m2, n = 51). We measured serum TNFR levels with immunoassay in all patients at the time of renal biopsy, and also in patients whose samples just before the first (after tonsillectomy) (n = 34) and/or the third steroid pulse therapy (n = 77) were available. RESULTS: The TNFR levels were significantly higher in Group II than in Group I. A significant negative correlation was observed between TNFR levels and eGFR at baseline (TNFRs: r > -0.50). In multivariate logistic regression analysis, both TNFRs were associated with renal function decline, independent of age and uric acid levels. Proteinuria and hematuria remarkably improved after TSP therapy, as expected. In comparison with baseline TNFR levels, the levels of TNFR2, but not TNFR1, decreased significantly just before the third steroid pulse therapy, although both levels did not change after tonsillectomy. CONCLUSIONS: The TNFR2 level did not change after tonsillectomy alone but decreased significantly after steroid pulse therapy in patients with IgAN.

Sorting Nexin 9 facilitates podocin endocytosis in the injured podocyte.

The irreversibility of glomerulosclerotic changes depends on the degree of podocyte injury. We have previously demonstrated the endocytic translocation of podocin to the subcellular area in severely injured podocytes and found that this process is the primary disease trigger. Here we identified the protein sorting nexin 9 (SNX9) as a novel facilitator of podocin endocytosis in a yeast two-hybrid analysis. SNX9 is involved in clathrin-mediated endocytosis, actin rearrangement and vesicle transport regulation. Our results revealed and confirmed that SNX9 interacts with podocin exclusively through the Bin-Amphiphysin-Rvs (BAR) domain of SNX9. Immunofluorescence staining revealed the expression of SNX9 in response to podocyte adriamycin-induced injury both in vitro and in vivo. Finally, an analysis of human glomerular disease biopsy samples demonstrated strong SNX9 expression and co-localization with podocin in samples representative of severe podocyte injury, such as IgA nephropathy with poor prognosis, membranous nephropathy and focal segmental glomerulosclerosis. In conclusion, we identified SNX9 as a facilitator of podocin endocytosis in severe podocyte injury and demonstrated the expression of SNX9 in the podocytes of both nephropathy model mice and human patients with irreversible glomerular disease.

Circulating TNF Receptors 1 and 2 Predict Mortality in Patients with End-stage Renal Disease Undergoing Dialysis.

Relatively high circulating levels of soluble tumor necrosis factor (TNF) receptors (TNFRs: TNFR1, TNFR2) have been associated with not only progression to end-stage renal disease but also mortality in patients with diabetes. It remains unknown whether elevated TNFR levels in haemodialysis patients are associated with mortality. We studied 319 patients receiving maintenance haemodialysis who were followed for a median of 53 months. Circulating markers of TNF pathway (TNFα and TNFRs) were measured with immunoassay. Strong positive correlations between TNFR1 and TNFR2 were observed (r = 0.81, P < 0.0001). During follow-up, 88 (27.6%) patients died of any cause (40 [45.5%] died of cardiovascular disease). In the Cox multivariate model, either TNFR but not TNFα remained a significant independent predictor of all-cause mortality (TNFR1: hazard ratio [HR] 2.34, 95% confidence interval [CI], 1.50-3.64; TNFR2: HR 2.13, 95% CI 1.38-3.29) after adjustment for age, prior cardiovascular disease, predialysis systolic blood pressure, and large systolic blood pressure decline during dialysis session. For cardiovascular mortality, significance was only observed in TNFR1 (TNFR1: HR 2.15, 95% CI 1.13-4.10). Elevated TNFRs levels were associated with the risk of cardiovascular and/or all-cause mortality independent of all relevant covariates in patients undergoing haemodialysis.

High doses of antipsychotic polypharmacy are related to an increase in serum levels of pentosidine in patients with schizophrenia.

BACKGROUND: Carbonyl stress in patients with schizophrenia has been reported to be reflected by an increase in peripheral pentosidine levels. This cohort study tested whether the accumulation of pentosidine was related to the disease severity or the treatment (routine administration of high antipsychotic doses). METHODS: We followed up our original investigation using a new group of 137 patients with acute schizophrenia and 45 healthy subjects, and then pooled the two cohorts to conduct the following analysis on a total of 274 patients. The associations of serum pentosidine and pyridoxal levels with duration of education, estimated duration of medication, the severity of symptoms, and daily doses of antipsychotics, antiparkinsonian drugs, and anxiolytics were evaluated by multiple linear regression analysis. RESULTS: The combined cohort of 274 patients exhibited abnormally high serum levels of pentosidine, were associated with a higher daily dose of antipsychotic drugs and a longer estimated duration of medication without statistical significance of diagnosis. This was also observed in the patients treated with antipsychotic polypharmacy, but the serum pentosidine levels of patients treated with first- or second-generation antipsychotic monotherapy showed no relationship with these two variables. CONCLUSION: High levels of serum pentosidine were associated with high daily doses of antipsychotic drugs and a longer estimated duration of medication in patients treated with antipsychotic polypharmacy.

High serum soluble tumor necrosis factor receptor 1 predicts poor treatment response in acute-stage schizophrenia.

Inflammation may be involved in the pathophysiology of schizophrenia. However, few cross-sectional or longitudinal studies have examined changes in biomarker expression to evaluate diagnostic and prognostic efficacy in acute-stage schizophrenia. We compared serum inflammatory biomarker concentrations in 87 patients with acute-stage schizophrenia on admission to 105 age-, sex-, and body mass index (BMI)-matched healthy controls. The measured biomarkers were soluble tumor necrosis factor receptor 1 (sTNFR1) and adiponectin, which are associated with inflammatory responses, and pigment epithelium-derived factor (PEDF), which has anti-inflammatory properties. We then investigated biomarker concentrations and associations with clinical factors in 213 patients (including 42 medication-free patients) and 110 unmatched healthy controls to model conditions typical of clinical practice. Clinical symptoms were assessed using the Brief Psychiatric Rating Scale and Global Assessment of Function. In 121 patients, biomarker levels and clinical status were evaluated at both admission and discharge. Serum sTNFR1 was significantly higher in patients with acute-stage schizophrenia compared to matched controls while no significant group differences were observed for the other markers. Serum sTNFR1 was also significantly higher in the 213 patients compared to unmatched controls. The 42 unmedicated patients had significantly lower PEDF levels compared to controls. Between admission and discharge, sTNFR1 levels decreased significantly; however, biomarker changes did not correlate with clinical symptoms. The discriminant accuracy of sTNFR1 was 93.2% between controls and patients, showing no symptom improvement during care. Inflammation and a low-level anti-inflammatory state may be involved in both schizophrenia pathogenesis and acute-stage onset. High serum sTNFR1 in the acute stage could be a useful prognostic biomarker for treatment response in clinical practice.

Toll-Like Receptor 9 Stimulation Induces Aberrant Expression of a Proliferation-Inducing Ligand by Tonsillar Germinal Center B Cells in IgA Nephropathy.

The TNF family member a proliferation-inducing ligand (APRIL; also known as TNFSF13), produced by myeloid cells, participates in the generation and survival of antibody-producing plasma cells. We studied the potential role of APRIL in the pathogenesis of IgA nephropathy (IgAN). We found that a significant proportion of germinal centers (GCs) in tonsils of patients with IgAN contained cells aberrantly producing APRIL, contributing to an overall upregulation of tonsillar APRIL expression compared with that in tonsils of control patients with tonsillitis. In IgAN GC, antigen-experienced IgD-CD38+/-CD19+ B cells expressing a switched IgG/IgA B cell receptor produced APRIL. Notably, these GC B cells expressed mRNA encoding the common cleavable APRIL-α but also, the less frequent APRIL-δ/ζ mRNA, which encodes a protein that lacks a furin cleavage site and is, thus, the uncleavable membrane-bound form. Significant correlation between TLR9 and APRIL expression levels existed in tonsils from patients with IgAN. In vitro, repeated TLR9 stimulation induced APRIL expression in tonsillar B cells from control patients with tonsillitis. Clinically, aberrant APRIL expression in tonsillar GC correlated with greater proteinuria, and patients with IgAN and aberrant APRIL overexpression in tonsillar GC responded well to tonsillectomy, with parallel decreases in serum levels of galactose-deficient IgA1. Taken together, our data indicate that antibody disorders in IgAN associate with TLR9-induced aberrant expression of APRIL in tonsillar GC B cells.