Immunoglobulin (Ig)M antibodies to proteinase 3 in granulomatosis with polyangiitis and microscopic polyangiitis

Anti‐neutrophil cytoplasmic antibodies (ANCA) appear to play an important role in the pathogenesis of ANCA‐associated vasculitis (AAV). However, ANCA alone are not sufficient to generate disease, and some evidence suggests that infectious triggers may serve as inciting events for AAV disease activity. Antibodies of the immunoglobulin (Ig)M isotype often serve as markers of recent infection, and IgM ANCA have been identified previously in patients with AAV, although the frequency and clinical relevance of IgM ANCA is not well established. We sought to characterize IgM ANCA more clearly by creating a novel enzyme‐linked immunosorbent assay (ELISA) for IgM antibodies to proteinase 3 [IgM proteinase 3 (PR3)–ANCA], which we applied to two large, clinically well‐characterized trial cohorts of patients with granulomatosis with polyangiitis and microscopic polyangiitis. In the first cohort, IgM PR3–ANCA occurred with a frequency of 15·0%, and were associated with a higher degree of disease severity and a trend towards a higher rate of alveolar haemorrhage (29·6 versus 15·7%, P = 0·10). Analysis of follow‐up samples in this cohort showed that the presence of IgM PR3–ANCA was transient, but could recur. In the second cohort, IgM PR3–ANCA occurred with a frequency of 41·1%, and were also associated with a higher degree of disease severity. A higher rate of alveolar haemorrhage was observed among those with IgM PR3–ANCA (45·3 versus 15·8%; P < 0·001). The association of transient IgM PR3–ANCA with an acute respiratory manifestation of AAV suggests a possible link between an infectious trigger and AAV disease activity.     

终末期肝病患者肝移植围手术期肾功能指标的变化

60 min及术后30 min两组患者尿β2-MG和NAG水平均高于术前(均P<0.05).重型肝炎组术前血TBIL高于肝癌肝硬化组(P<0.05).重型肝炎组术后24 h、术后1周血Scr、BUN和TBIL均明显高于肝癌肝硬化组(均P<0.05).结论 重型肝炎患者在肝移植围手术期肾功能损伤较肝癌肝硬化组严重,肝移植围手术期应注意保护重型肝炎患者的肾功能.     

终末期肝病患者肝移植围手术期肾功能指标的变化

60 min及术后30 min两组患者尿β2-MG和NAG水平均高于术前(均P<0.05).重型肝炎组术前血TBIL高于肝癌肝硬化组(P<0.05).重型肝炎组术后24 h、术后1周血Scr、BUN和TBIL均明显高于肝癌肝硬化组(均P<0.05).结论 重型肝炎患者在肝移植围手术期肾功能损伤较肝癌肝硬化组严重,肝移植围手术期应注意保护重型肝炎患者的肾功能.     

Different gender-associated genotype risks of Wegener's granulomatosis and microscopic polyangiitis

Wegener's granulomatosis (WG) and microscopic polyangiitis (MPA) are systemic small vessel vasculitides associated with ANCA (AAV). Predominant Th1 and Th2 cytokine patterns have been reported for WG and MPA, respectively. Consequently, genotypes suppressing Th1 responses or augmenting Th2 responses may be more frequent in MPA than in WG. Transforming growth beta1 (TGF-beta1) and interleukin-10 (IL-10) genes may modify the course of vasculitis. Therefore, we investigated associations between genotype frequencies of functional polymorphisms of these cytokine genes and clinical manifestations in AAV. One hundred sixty-one AAV patients and 153 healthy blood donors were genotyped for the biallelic polymorphism in codon 25 of the TGF-beta1 gene and the biallelic polymorphism at position -1082 of the IL-10 gene. No difference was found for TGF-beta1 codon 25 polymorphism between control and patient groups. In contrast, a significant shift toward the homozygous AA genotype of the IL-10 (-1082) polymorphism was found in WG (25%, p<0.005) and MPA patients (39%; p<0.00001) compared to controls (10.5%). Furthermore, in MPA the AA homozygous genotype was significantly more frequent in females (62.5%) compared to males (20%, p<0.05). A contribution of the TGF-beta1 codon 25 polymorphism to the susceptibility-defining genetic backgrounds of AAV appears unlikely. In contrast, our findings suggest a role of the enhanced IL-10 (-1082) PM in WG and MPA with a significant gender difference in MPA.     

New-onset eosinophilic granulomatosis with polyangiitis in 2 patients during treatment with IL-5 pathway inhibitors

Immunologic Research -     

Immunological monitoring in patients with end-stage renal disease

Parameters of cell-mediated immune function were determined in 76 patients with end-stage renal disease. Lymphocyte subpopulations (OKT3, OKT4, OKT8, OKIal, OKM1, OKT9, OKT10), natural killer (NK)-cell activity (percentage⁵¹Cr release from K562 targets), and delayed cutaneous hypersensitivity were measured and correlated with other variables. The results indicate that (1) uremic patients have a significant diminution in the OKT4-lymphocyte subpopulation and OKT4/OKT8 (helper/suppressor) ratio compared to normal controls; (2 blood transfusions do not induce significant alterations in the helper/suppressor-cell ratio; (3) uremic patients have a significant increase in OKM1 cells compared to normal controls; (4) the majority of uremic patients in this series developed delayed cutaneous hypersensitivity responses to recall antigens and could be de novo sensitized to 2,4-dinitrochlorobenzene (DNCB); (5) skin-test reactivity could not be correlated with total circulating T cells or levels of any lymphocyte subpopulations; and (6) NK-cell activity in uremic patients is not significantly different from that in normal controls. These results highlight the varying levels and function of different lymphocyte subsets in patients with end-stage renal disease when they are treated with chronic maintenance hemodialysis.     

Model for end-stage liver disease predicts right ventricular failure in patients with left ventricular assist devices

High rates of right ventricular failure continue to affect postoperative outcomes in patients implanted with left ventricular assist devices (LVADs). Development of right ventricular failure and implantation with right ventricular assist devices is known to be associated with significantly increased mortality. The model for end-stage liver disease (MELD) score is an effective means of evaluating liver dysfunction. We investigated the prognostic utility of postoperative MELD on post-LVAD implantation outcomes. MELD scores, demographic data, and outcomes including length of stay, survival, and postoperative right ventricular failure were collected for 256 patients implanted with continuous flow LVADs. Regression and Kaplan–Meier analyses were used to investigate the relationship between MELD and all outcomes. Increased MELD score was found to be an independent predictor of both right heart failure and necessity for RVAD implantation (OR 1.097, CI 1.040–1.158, p = 0.001; OR 1.121, CI 1.015, p = 0.024, respectively). Patients with RV failure and who underwent RVAD implantation had reduced postoperative survival compared to patients with RV dysfunction (no RV failure = 651.4 ± 609.8 days, RV failure = 392.6 ± 444.8 days, RVAD = 89.3 ± 72.8 days; p < 0.001). In conclusion, MELD can be used to reliably predict postoperative right heart failure and the necessity for RVAD implantation. Those patients with RV failure and RVADs experience significantly increased postoperative mortality compared to those without RV dysfunction.     

Circulating mitochondrial DNA in serum of patients with granulomatosis with polyangiitis

Neutrophil is a key cell in pathophysiology of granulomatosis with polyangiitis. Recently, neutrophil extracellular traps were described in this disease. Mitochondrial DNA is also released during traps formation. We measured circulating cell‐free mitochondrial and genomic DNA in serum of patients with granulomatosis with polyangiitis. Subjects with the disease (14 active and 11 in remission stage) and 10 healthy controls were enrolled. Quantitative real‐time polymerase chain reaction (PCR) was used to measure 79 base pairs (bp) and 230 bp mtDNA fragments. Alu repeats were quantified to evaluate abundance of nuclear DNA in serum at the presence of plasmid control. Both fragments of mtDNA (79 bp and 230 bp) and genomic DNA were elevated significantly in granulomatosis with polyangiitis compared to controls. Only the shorter 79bp mtDNA correlated with active stage of granulomatosis with polyangiitis and clinical symptoms. A mechanism of extracellular release of mitochondrial DNA accompanies the active stage of the disease. Circulating mtDNA is extremely high in untreated patients. This suggests that biomarker properties of mtDNA are useful for monitoring of treatment.     

Depressive symptomatology and treatment in patients with end-stage renal disease

A sample of 60 patients selected at random from an adult population of 419 patients with end-stage renal disease was assessed for major depression. Diagnoses were based on a structured interview using DSM-III criteria. Eighteen patients (30%) met criteria for a major depression on a lifetime basis. In addition, depressive symptoms and treatment for each depressed patient are reported.     

Survival with dialysis and transplantation in patients with end-stage renal disease

We examined the survival experience of 1038 white patients with end-stage renal disease to compare transplantation with maintenance dialysis. A mathematical model was used that permitted adjustment for the confounding effects of age and morbidity at the start of treatment as well as for the year in which treatment began. For patients with all kinds of renal disease, survival was related to age and morbidity but not to the year of starting treatment. Transplantation with a graft from a living related donor was associated with significantly better survival than either transplantation with a cadaveric graft (relative risk, 0.54) or dialysis (relative risk, 0.55). No significant difference in survival was found between treatment by dialysis and by cadaveric transplantation (relative risk, 1.01). In view of this experience, the decision about whether a patient on dialysis should receive a cadaveric transplant should be based on evaluation of the differences in complications associated with the two treatments and the potential effects of these on the patient's general life style, opportunity for rehabilitation, and family and social responsibilities. Whether the use of cyclosporine will change this assessment in the future remains to be seen.     

Coagulation abnormalities in patients with end-stage renal disease treated with hemodialysis

Plasma levels of various blood coagulation factors, antithrombin III and plasminogen were measured in 18 patients with end-stage renal disease treated by longterm hemodialysis. The results were compared with those obtained in a group of normal volunteers. Factors XII, IX and II activities were significantly reduced; factors VIII, VII and X levels were increased; and factors XI and V activities and high molecular weight kininogen concentration were comparable to the control group. Antithrombin III activity and concentration were significantly reduced. The mean plasma fibrinogen concentration was normal although levels above and below normal limits were noted in a few patients. Similarly the mean platelet count was normal, although mild thrombocytopenia occurred in several patients and thrombocytosis in one. In conclusion, the present study confirms published results about factor VIII and AT-III, and provides new information on changes of other coagulation factors in uremia treated by long-term hemodialysis.     

Important predictor of mortality in patients with end-stage liver disease

Prognosis is an essential part of the baseline assessment of any disease. For predicting prognosis of end-stage liver disease, many prognostic models were proposed. Child-Pugh score has been the reference for assessing the prognosis of cirrhosis for about three decades in end-stage liver disease. Despite of several limitations, recent large systematic review showed that Child-Pugh score was still robust predictors and it''s components (bilirubin, albumin and prothrombin time) were followed by Child-Pugh score. Recently, Model for end-stage liver disease (MELD) score emerged as a "modern" alternative to Child-Pugh score. The MELD score has been an important role to accurately predict the severity of liver disease and effectively assess the risk of mortality. Due to several weakness of MELD score, new modified MELD scores (MELD-Na, Delta MELD) have been developed and validated. This review summarizes the current knowledge about the prognostic factors in end-stage liver disease, focusing on the role of Child-Pugh and MELD score.     

Appraisal of lung cancer survival in patients with end-stage renal disease

IntroductionThe survival outcome of lung cancer patients with end-stage renal disease has been poorly studied in the literature. In this study, we evaluated the effect of end-stage renal disease on lung cancer survival.Material and methodsA retrospective, multicenter, matched-cohort study of lung cancer patients with end-stage renal disease under renal replacement therapy (WITH-ESRD) and without end-stage renal disease (WITHOUT-ESRD) was performed. One WITH-ESRD patient was matched to four WITHOUT-ESRD patients.ResultsBaseline clinical characteristics did not differ statistically significantly after matching between the WITH-ESRD and WITHOUT-ESRD groups. WITH-ESRD included 133 patients and WITHOUT-ESRD included 532 patients. Kaplan-Meier survival analysis demonstrated no significant difference in median overall survival between WITH-ESRD patients and WITHOUT-ESRD patients (7.36 months versus 12.25 months, respectively, p = 0.133). Lung cancer WITH-ESRD patients receiving medical treatment had a median overall survival of 5.98 months (95% CI: 4.34–11.76) compared to 14.13 months (95% CI: 11.30–16.43) for WITHOUT-ESRD patients, p = 0.019. Although patients receiving surgical treatment compared to those receiving medical treatment had an improvement of survival by 46% (HR = 0.54, 95% CI: 0.19–1.53, p = 0.243), the difference did not reach statistical significance. Cox regression analysis revealed that male gender and stage IIIA-IV were independent factors associated with poor outcome for WITH-ESRD patients.ConclusionsIn our limited experience, the survival for lung cancer with ESRD is not inferior to lung cancer patients without ESRD. The reasons for poor survival for the WITH-ESRD medical treatment group and late diagnosis despite frequent medical visits merit further investigation.