ANCA-associated glomerulonephritis/systemic vasculitis in childhood: clinical features–outcome

Background

Antineutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis and systemic vasculitis (AAGNV) is uncommon in childhood.

Methods

This is a retrospective study of AAGNV cases diagnosed over a 13-year period in a tertiary pediatric nephrology department.

Results

Thirteen cases of AAGNV were identified: seven Wegener granulomatosis (WG) and six microscopic polyangiitis (MPA). Acute renal failure/nephrotic range proteinuria (NRP) was found in 77 % of the patients (4 with WG, all with MPA). Eleven (85 %) patients showed necrotizing glomerulonephritis (NGN), with ≥50 % crescents identified in nine patients (69 %) (4 with WG, 5 with MPA). Treatment with methylprednisolone, cyclophosphamide and plasma exchange resulted in extra-renal remission and antibody reduction in all patients and renal function improvement/stabilization in 77 % of the patients. Three patients, all without oliguria at presentation and few sclerotic lesions, had normal renal function at follow-up. Chronic kidney disease (CKD) stages 2 and 3–4 were observed in four (WG) and three (MPA) patients, respectively. Three patients (23 %) developed end stage renal disease: two were MPA patients with severe presentation (markedly impaired glomerular filtration rate, oliguria, NRP, crescentic NGN, glomerular sclerosis) and one was a WG patient with extensive interstitial fibrosis/tubular atrophy.

Conclusions

Severe renal involvement was more common in children with MPA than WG. Treatment with methylprednisolone, cyclophosphamide and plasma exchange induced extra-renal remission/serological response and renal function improvement/stabilization. Markedly decreased GFR, oliguria, NRP, and chronic glomerular lesions at presentation were predictors of poor outcome.     

ANCA in haemodialysis patients

The prevalence of positive ANCA as well as the prevalence ofPR-3 and MPO antibodies were examined in a cross-sectional sampleof 1277 haemodialysis patients from 16 German haemodialysiscentres. We found 32 patients positive for c-ANCA (median titre1:40; range 1:20–1:320) and 65 for p-ANCA (1:80; 1:20–1:1280).Twenty-two percent of the c-ANCA-positive and 31% of the p-ANCA-positivepatients had PR-3 and MPO antibodies by ELISA respectively.Clinical evidence of vasculitis was found in 11 of 32 c-ANCA-positiveand 19 of 65 p-ANCA-positive patients. Of the 11 c-ANCA-positive,four had a known diagnosis of Wegener's granulo-matosis (WG);WG was recognized after the test in a further five patientsand two had renal limited RPGN. Of the 19 p-ANCA-positive patients,three had a clinical diagnosis of microscopic polyarteritis(MP), MP was newly diagnosed in a further 12, WG in one andrenal limited RPGN in three. The patients had not received cyclophosphamide(the diagnosis had been non-specified ‘systemic disease’).Thus false-positive ANCA, as defined by absence of vasculitis,was found in 5% of dialysis patients versus 0% in patients withpreterminal renal failure {n=152) or blood donors (n=150). Patientswith vasculitis tended to have higher c-ANCA and p-ANCA titresrespectively, but there was a considerable overlap. Titres werenot higher in patients symptomatic at the time of examination(6 of 11 c-ANCA and 10 of 19 p-ANCA), but PR-3 and MPO ELISAwere positive in all but two. Thus c-ANCA were false positive(i.e. not associated with clinical vasculitis) in 66% and p-ANCAin 71%. In some patients ANCA was positive, but ELISA negative. We conclude that (i) in dialysis patients c-ANCA and p-ANCAare frequently present in the absence of vasculitis; (ii) specificitycan be improved, but sensitivity is lost, by using PR-3 andMPO ELISA respectively; (iii) serology permits the recognitionof WG or MP in cases where the diagnosis has been missed. Itis recommended that all patients with unknown primary renaldisease admitted to renal replacement therapy be examined usingboth ANCA-IF and PR-3/MPO ELISA.     

Renal histology in ANCA-associated vasculitis: differences between diagnostic and serologic subgroups.

BACKGROUND: Differences in renal histopathology between microscopic polyangiitis (MPA) and Wegener's granulomatosis (WG), and between anti-neutrophil cytoplasm autoantibody (ANCA) test results in patients with ANCA-associated vasculitis may provide insight into the differences in pathogenesis and raise the opportunity of classifying the vasculitides more accurately. The possible differences in histopathology are investigated in this study. METHODS: We report an analysis of 173 patients with renal disease in microscopic polyangiitis or Wegener's granulomatosis. A total of 173 renal biopsies, performed at diagnosis, were scored by two observers separately, using a previously standardized protocol. Consensus on each biopsy was achieved during a central review. RESULTS: Normal glomeruli were more common in WG than in MPA (P < 0.001). Glomerulosclerosis was more prominent in MPA than in WG (P=0.003). Interstitial fibrosis (P < 0.001), tubular atrophy (P < 0.001), and tubular casts (P=0.005) were more frequently present and more severe in MPA than in WG. Presence of glomerulosclerosis was more extensive in patients with myeloperoxidase (MPO)-ANCA than with proteinase 3 (PR3)-ANCA (P=0.022). Interstitial fibrosis (P=0.008), tubular necrosis (P=0.030), tubular atrophy (P=0.013), and intra-epithelial infiltrates (P=0.006) were more frequently present and more severe in MPO-ANCA than in PR3-ANCA. CONCLUSIONS: Glomerulonephritis in relation to MPA has more characteristics of chronic injury at the time of presentation than glomerulonephritis in relation to WG. This difference may be due to a delayed establishment of diagnosis in patients with MPA compared to patients with WG. Both active and chronic lesions are more abundantly present in MPO-ANCA-positive patients than in patients with PR3-ANCA-positivity, which suggests that the pathogenesis of renal disease in these ANCA subsets could be different. Our results also suggest that ANCA test results may be useful in classifying ANCA-associated vasculitides.     

ANCA相关性血管炎肾损害临床特征及早期诊治探讨

目的 分析抗中性粒细胞胞浆抗体(ANCA)相关性血管炎的临床表现和肾脏病理特征,探讨早期诊断和治疗对预后的影响.方法选取本院2000年1月至2009年8月明确诊断的ANCA相关性血管炎共21例,18例行肾活检.总结患者的临床病理资科.分析不同治疗时机对肾功能转归的影响.结果本组21例ANCA相关性血管炎平均年龄(52.5±11.5)岁,显微镜下多血管炎(MPA)16例,韦格纳肉芽肿(WG)3例,变应性肉芽肿性血管炎(CSS)2例.肾外表现主要为发烧17例(80.1%)、下呼吸道症状18例(85.7%)、肺影像学改变21例(100%)、贫血16例(76.2%)、眼耳鼻受累8例(38.1%);肾脏表现血尿21例(100%),蛋白尿19例(90.1%),血肌酐正常6例(28.5%),升高15例(71.4%),8例需透析替代.ANCA检测pANCA和MPO-ANCA阳性16例,cANCA和PR3-ANCA阳性3例.pANCA/MPO-ANCA和cANCA/PR3-ANCA均阳性1例,全阴性1例.肾活检可见节段性小血管壁纤维素样坏死,新月体多见.免疫荧光无或微量免疫复合物沉积.治疗采用糖皮质激素联合环磷酰胺,重症加用血浆置换.7例血肌酐异常但不需透析者5例治疗后血肌酐恢复正常;8例需透析者2例治疗后血肌酐恢复正常,2例脱离透析但血肌酐异常,4例未能脱离透析.结论ANCA相关性小血管炎临床表现多样,肺、肾是最常见的受累器官.ANCA检测和肾活检有助于早期诊断,尽早积极治疗有助于肾功能的恢复.     

Clinical features and outcomes of ANCA-associated renal vasculitis

To determine the patterns and outcomes of the pauci-immune vasculitis in the nephrology department at hospital La Conception in Marseille, we conducted a retrospective study including all patients with diagnosis of pauci-immune renal vasculitis between January 1, 2000 and December 31, 2007. Among 33 cases, 25 were diagnosed as Wegener granulomatosis (WG), seven as microscopic polyangitis (MPA) and one as Churg-Strauss syndrome (SCS). The median age of the patients was 57.7 years and the sex-ratio (M/F) was 1.6. The visceral manifestations included kidneys (100% of patients), lungs (75%), ENT (52% of WG), and nervous system (57% of MPA). The mean serum creatinine at admission was 3.3 mg/dL. Renal biopsies revealed a pauci-immune crescentic gromerulonephritis in 96% of the cases. Two patients with WG received plasmapheresis and seven patients required emergency hemodialysis. Induction therapy comprised cyclophosphamide IV and corticosteroids, while maintenance therapy included azathioprine for the majority of patients. Eighty four percent of the patients experienced complete remission after induction therapy. During maintenance therapy relapses were more frequent among patients with MPA (28%) compared to WG cases (12%). After 35 months of follow-up, eight patients ended on chronic hemodialysis, and five patients died. ANCA associated vasculitis are frequent in our patients. Long-term outcomes are relatively good despite a mortality rate of 15% and 25% of the patients entering dialysis after three years of follow-up.     

Serum levels of soluble interleukin-2 receptor in patients with ANCA-associated vasculitis

Serum soluble interleukin-2 receptor (sIL-2R) concentrations were determined using the ELISA method in 19 cases of ANCA-associated vasculitis. These patients were classified as 7 cases of Wegener's granulomatosis (WG) and 12 cases of microscopic polyangiitis (MPA). Elevated levels of sIL-2R were present in the sera of these patients. Levels of serum sIL-2R were not significantly different in patients with WG and MPA either in the active or inactive phase, so the results were expressed as a unified ANCA associated vasculitis group. Concentrations of serum sIL-2R were significantly higher in ANCA-associated vasculitis during the active phase than during the inactive phase (p<0.05), and serum sIL-2R levels were significantly increased in these patients, in the active or inactive stage, compared with a group of healthy subjects (p<0.05). In patients with vasculitis, serum sIL-2R levels correlated with serum levels of C-reactive protein (p<0.05). In the active phase, concentrations of serum sIL-2R correlated to creatinine concentrations. No correlation was found between sIL-2R and ANCA levels in any of the stages of the disease. These findings suggest cellular immune activation in ANCA associated vasculitis.     

Childhood microscopic polyangiitis associated with MPO-ANCA

We reviewed the clinical, histological and serological parameters of microscopic polyangiitis (MPA) associated with antineutrophil cytoplasmic antibodies (ANCA) specific to myeloperoxidase (MPO). Six girls and one boy aged 12.0±2.6 years (7–15 years) met the following inclusion criteria: (1) clinical manifestations of systemic small vessel involvement; (2) histological demonstration of pauci-immune necrotizing glomerulonephritis; and (3) serological findings of increased concentration of MPO-ANCA by ELISA test. The main clinical manifestations were: influenza-like symptoms (100%), hematuria/proteinuria (100%), purpura (100%), pulmonary-renal syndrome (57%), acute renal failure (ARF) (29%), ischemic cerebral insults (29%), and necrotizing vasculitis of the skin (29%). All patients underwent renal biopsy examined by immunohistochemistry with expression of alpha-smooth muscle actin (alpha SMA) in glomerular and interstitial spaces. Patients were followed from 6 months to 5.5 years (35.4± 23.2 months). None of the patients died. Two of seven children who had ARF progressed to end stage renal disease; one developed chronic renal failure, and four normalized renal function. ARF and central nervous system involvement at presentation were parameters of poor renal outcome. A high score of fibro-cellular glomerular crescents was associated with worse prognosis. Early treatment enables a favorable prognosis of MPO-ANCA-associated MPA in children.     

ANCA-associated vasculitis with renal involvement: an outcome analysis.

BACKGROUND: The anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides are a group of heterogeneous diseases. This study was undertaken to investigate the outcome of Wegener's granulomatosis (WG), microscopic polyangiitis (MPA) and renal-limited vasculitis (RLV). Furthermore, we analysed the differences in patients with proteinase 3-ANCA (PR3-ANCA) and those with myeloperoxidase-ANCA (MPO-ANCA), which have not been assessed in a homogeneously treated group of patients with renal involvement. METHODS: In this retrospective analysis, 80 patients with a new diagnosis of WG, MPA or RLV with biopsy-proven renal involvement were followed over a median of 46.7 months (range: 0.8-181.9 months). All patients had induction treatment with cyclophosphamide and oral corticosteroids. RESULTS: At the end of follow-up, 23% were dependent on dialysis. Renal survival was significantly worse in patients with WG compared with patients with MPA or RLV (P = 0.04). A higher rate of end-stage renal disease (ESRD) was noticed in PR3-ANCA- vs MPO-ANCA-positive patients. A total of 21 patients (26%) died. Predictors of patient mortality were development of ESRD, older age and the maximum creatinine in the first month. Mortality was found to be higher in patients with WG and was significantly higher in PR3-ANCA-positive cases (P = 0.02). The relative risk of death was 9.32 times higher in PR3-ANCA- vs MPO-ANCA-positive patients. CONCLUSIONS: Our data underscore the pathogenetic potential of ANCA by demonstrating a more aggressive disease state and a poorer outcome in patients with PR3-ANCA.     

Segmental necrotizing glomerulonephritis: diagnostic, prognostic, and therapeutic significance

Renal biopsies from 50 patients with segmental necrotizing glomerulonephritis (SNGN) were divided into three groups on the basis of initial clinical information: (group A) Wegener's granulomatosis (WG)--14 patients; (group B) SNGN without renal vasculitis (RV)--21 patients; and (group C) SNGN with RV--15 patients. Renal biopsy findings did not distinguish the SNGN in WG from non-WG patients. However, focal endocapillary proliferation was more common in non-WG groups B (48%) and C (33%) than in WG (7%). In addition, GBM deposits of both IgG and C3 were present in 35% of biopsies in group B and 33% in group C in comparison to only 7% in WG. Glomerular fibrin deposition was common in all groups (54% group A, 70% group B, and 100% group C), suggesting that coagulation plays a role in the development of SNGN. Histologic parameters of severity and chronicity of the SNGN were inconsistent predictors of outcome, although an increased percentage of crescents in the non-WG groups correlated with a poorer prognosis. Chronic renal failure developed in 46% of group A patients, 65% group B, and 73% group C. After clinical follow-up, 15 patients had WG, 15 patients had documented or suspected systemic vasculitis (SV), and idiopathic SNGN was present in 20 patients. Sixty-six percent of patients with SV had RV, and 62% of biopsies with RV were from patients with SV. Chronic renal failure developed in 78% of patients with idiopathic SNGN and 57% patients with SV. These findings confirm that SNGN carries a poor prognosis, independent of its association with WG or SV. Fourteen of the 15 WG patients were treated with alkylating agents, and the development of chronic renal failure appeared to be related to delays in diagnosis and therapy. In the non-WG groups, presentation in acute renal failure with high serum creatinine and long duration of symptoms was predictive of development of chronic renal failure. Therapy in the non-WG patients consisted of alkylating agents (seven patients), steroids (20 patients), and dialysis only (seven patients). The seven non-WG patients treated with alkylating agents had clinical responses similar to WG patients, and cyclophosphamide therapy appeared to be most beneficial to patient outcome. Results of this retrospective study stress the importance of early diagnosis and, although based on small numbers of patients, suggest that aggressive chemotherapy should be recommended for SNGN, independent of its association with biopsy-proven WG or documented SV.     

Long-term outcome of patients with antineutrophil cytoplasmic autoantibody-associated vasculitis with renal involvement

BACKGROUND: Despite treatment, renal involvement in antineutrophil cytoplasmic autoantibody (ANCA)-positive vasculitis is still associated with significant long-term mortality and remains an important cause of end-stage renal failure. METHODS: We retrospectively analyzed a series of 61 consecutive patients with newly diagnosed ANCA-associated renal vasculitis (54.1% Wegener's granulomatosis, 23% renal-limited vasculitis, 16.4% microscopic polyangiitis, 4.9% Churg-Strauss syndrome) diagnosed between 1986 and 1997. RESULTS: The median creatinine level at diagnosis was 221.5 (63-762) micromol/l, i.e. 2.5 (0.7-8.6) mg/dl, 32.8% were dialysis-dependent. All patients were treated with cyclophosphamide. Remission was achieved in 87% of patients. Relapses occurred in 44.7%. The median renal disease-free interval was 62.5 (0-138) months. The estimated patient survival at 5 and 10 years was 78.3 and 62.2%, respectively. Mortality was associated with age (p = 0.04 when age limit 50 years) and advanced renal failure (p = 0.038 when compared dialysis-dependent and independent patients). Estimated renal survival time at 5 and 10 years was 69.2 and 55.8%, respectively. At the end of follow-up, 50.8% of patients were in complete remission, 31% had died. The median serum creatinine level was 137.5 (77-469) micromol/l, i.e. 1.56 (0.87-5.3) mg/dl, 24.6% of patients were on regular dialysis treatment. CONCLUSION: Patient survival, relapse rate and mortality were comparable to similar reports. In view of the severity of the renal disease and the length of follow-up, renal survival was very good. Despite effective treatment, the long-term outcome of patients with ANCA-associated renal vasculitis remains unsatisfactory.     

Circulating soluble adhesion molecules in ANCA-associated vasculitis.

BACKGROUND: To evaluate whether changes in concentrations of soluble (s) E-selectin, sP-selectin, sL-selectin, intercellular adhesion molecule 1 (sICAM-1), and vascular cell adhesion molecule 1 (sVCAM-1) reflect disease activity in patients with ANCA-associated vasculitis and whether serum levels of these adhesion molecules are related to the degree of renal failure in patients with chronic renal failure (CRF). SUBJECTS AND METHODS: A sandwich ELISA was used to measure these soluble adhesion molecules in (i) sera from 20 patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (10 patients with Wegener's granulomatosis (WG) and 10 patients with microscopic polyangiitis (MPA)), obtained at the time of diagnosis and during the remission period; (ii) sera from 40 patients with CRF not undergoing haemodialysis. RESULTS: At the time of diagnosis, serum levels of sE-selectin, sICAM-1 and sVCAM-1 (88+/-42 ng/ml, 437+/-184 ng/ml, 1720+/-1174 ng/ml respectively) were significantly higher in patients with ANCA-associated vasculitis than in healthy controls (P<0.0001, P=0.002 and P=0.001 respectively). Serum sP-selectin values did not differ from those obtained in normal donors. In contrast, sL-selectin levels (940+/-349 ng/ml) were significantly lower in patients than those recorded in healthy controls (P<0.0001). A significant decrease in concentrations of sE-selectin, sP-selectin, sICAM-1, and sVCAM-1 was observed between active and remission phases (P<0.0001, P=0.002, P=0.001 and P=0.001 respectively). No significant differences were observed in sL-selectin levels between active and remission phases. sL-selectin concentrations (802+/-306 ng/ml) during the remission phase remained lower than those observed in healthy controls (P<0.0001). No correlation was observed between serum creatinine and sE-selectin, sP-selectin, sICAM-1 and sVCAM-1 in patients of the CRF group. A slight negative correlation was established between creatinine and sL-selectin concentration. CONCLUSIONS: Increased serum levels of sE-selectin, sICAM-1, and sVCAM-1 and decreased levels of sL-selectin in active ANCA-associated vasculitis, and the normalization of sE-selectin, sICAM-1, and sVCAM-1 during the remission phase suggest that the concentration of soluble levels of these adhesion molecules reflects disease activity. The decrease in sP-selectin levels between active and inactive phases also suggest that this receptor may reflect clinical activity. The lack of correlation between serum levels of sE-selectin, sP-selectin, sICAM-1, and sVCAM-1 and the degree of renal failure in patients with CRF suggests that the mechanism of clearance of these molecules is not renal.     

Retrospective study of 97 ANCA-positive patients: epidemiologic and clinical spectrum

We analysed the clinical profile of antineutrophil cytoplasmic antibodies (ANCA) positive patients in a retrospective study including all cases of ANCA positivity (determined by ELISA) from the Nephrology Clinic, Parhon University Hospital Iasi during the interval 1998-2003. There were 97 ANCA positive patients (mean age 43.7 ?18-75? years, female/male ratio 1.55), of whom almost two thirds had c-ANCA, almost one third p-ANCA, while 9 patients had both types of antibodies. The incidence was 22.5/pmp for the North-Eastern province of Romania. Just 19.3% from the suspected cases with ANCA-associated disease were positive for these antibodies. 47.7% had systemic vasculitis (10 with microscopic polyangiitis--MA, 6 with Wegener's granulomatosis--WG, 1 with Churg-Strauss angiitis, 29 with non-specific vasculitis--NSV). Twenty-seven (27.8%) had connective tissue disease--CTD (systemic lupus erythematosus, rheumatoid arthritis, polymyositis, systemic sclerosis, mixed connective tissue disease, and sarcoidosis), while in 5 cases ANCA were associated with other diseases. Nine cases presented with rapid progressive glomerulonephritis (RPGN) without signs of systemic involvement, and other ten with advanced chronic renal failure (CRF). The most frequent clinical manifestations involved the kidney (71%), the skin, the muscles and joints, and the cardiovascular system. CONCLUSIONS: ANCA positivity is associated with a wide spectrum of diseases, mostly with CTD and NSV. c-ANCA was predominantly seen in WG and advanced CRF, while p-ANCA was associated with MA. In nonspecific vasculitis and connective tissue diseases, both patterns were present. We recommend ANCA determination as a screening method in all cases with renal dysfunction and nephritic syndrome and/or with signs of systemic vasculitis and/or collagenosis.     

Pulmonary renal syndrome associated with Wegener’s granulomatosis: a case report and review of literature

Pulmonary renal syndromes are rare but serious complications of systemic vasculitis. The majority of these cases are related to ANCA-associated vasculitis. These syndromes represent a combination of diffuse alveolar hemorrhage and rapidly progressive glomerulonephritis. Here we report a case of 21-year-old female with a clinical picture of community-acquired pneumonia that rapidly evolved to pulmonary hemorrhage and acute renal failure. Combined pulse steroid treatment, immunosuppressive treatment, and plasmapheresis were instituted and resulted in the improvement of the patient. The diagnosis of Wegener’s granulomatosis was established based on the clinical and serological findings (positive cANCA). Here we review the relevant literature on pulmonary renal syndromes associated with Wegener’s granulomatosis and discuss their diverse clinicopathologic features.     

Clinical course and symptomatic prediagnostic period of patients with wegener's granulomatosis and microscopic polyangiitis

The clinical course of 15 patients with Wegener's granulomatosis (WG) and eight patients with microscopic polyangiitis (MPA) from one nephrological clinical center is presented for the period from 1984 to 1993, when testing for antineutrophil cytoplasmic antibodies (ANCA) was gradually introduced into routine clinical practice. We found a high degree of prolonged time periods with symptoms attributable to WG or MPA until the specific diagnosis was made. Nine patients with WG and one patient with MPA had symptomatic prediagnostic periods of more than three years, which extended in one case up to twenty years. In these prediagnostic periods, often even severe flares of vasculitic activity resulted in spontaneous remission without immunosuppressive therapy. One patient on chronic dialysis for four months because of rapidly progressive glomerulonephritis, experienced sufficient spontaneous regain of residual renal function to stay off dialysis for 6 years. Despite a high amount of spontaneous recovery, recurrent flares of disease eventually led to death in those cases without sufficient immunosuppressive therapy. Contrary to long courses of disease, one patient with WG had a fulminate exacerbation of disease with lethal hemoptysis after a prediagnostic period of only three months. Renal disease, respiratory and other symptoms did not occur sequentially, but each could precede the other. We conclude in agreement with published former experience, that WG and MPA show a highly variable spontaneous disease course, that requires extended observational periods for evaluating maintenance therapies.     

Clinicopathologic features of antineutrophil cytoplasm autoantibody (ANCA)-associated acute renal failure in Chinese patients

Summary: The clinical course and renal pathologic features of anti-neutrophil cytoplasm auto-antibody (ANCA)-associated renal disease were studied among Chinese patients from a single centre. Eight ANCA positive patients with acute renal impairment were studied, four of whom required dialysis shortly after presentation. Their mean age at presentation was 61.6 ± 4.2 years. Renal histology, obtained in seven patients, showed paucummune crescentic glomerulonephritis in five patients, interstitial nephritis in two patients, and small vessel vasculitis in one patient. Pulmonary baemorrhage was the other common disease manifestation, present in four of the eight patients, necessitating ventilatory support in three patients. Neurologic, cutaneous, and gastrointestinal involvement were also observed. Seven of the eight patients tested positive for pANCA and anti-myeloperoxidase, while cANCA was detected in one patient of the eight patients, six (75%) responded to therapy, consisting of prednisolone and cyclophosphamide in five patients, and antibacterial therapy alone in one patient, who had interstitial nephritis but no evidence of vasculitis. Two patients died from sepsis and severe debilitation one month after presentation. of the other six patients, five had significant improvement of renal function, while one became dialysis-dependent. the levels of ANCA and C-reactive protein remained normal, and disease reactivation was not observed during follow-up for 32.4 ± 6.1 months. Patient and renal survival rates at one year were 75% and 62.5%, respectively. It was concluded that the clinical and pathologic features of ANCA-associated renal disease in Chinese patients are, in general, similar to those described in Caucasians. Nevertheless, cANCA-positivity is distinctly uncommon. the demonstration of interstitial nephritis in two of the eight patients underlines the importance of renal biopsy for correct histologic diagnosis. Early institution of aggressive immunosuppression and supportive therapies are essential for the achievement of favourable outcome in patients with vasculitis.     

Association of IgM with IgG ANCA in patients presenting with pulmonary hemorrhage.

ANCA are markers for systemic vasculitis such as Wegener's granulomatosis (WG) and microscopic polyarteritis (MPA) and are usually of the IgG isotype. However, IgM ANCA may rarely occur in isolation, and in these circumstances, we have found that they are associated clinically with a syndrome of pulmonary hemorrhage and systemic vasculitis. How frequently IgM ANCA may occur in conjunction with IgG has not previously been investigated. We report here a study of 24 consecutive patients with IgG ANCA-positive systemic vasculitis (14 WG, 10 MPA) in whom we determined whether IgM ANCA occurred in association with IgG ANCA, and if so, whether this had clinical importance. Eight patients were found to have IgM ANCA as well as IgG ANCA, and of these, seven presented with severe pulmonary hemorrhage. None of the IgM ANCA-negative patients presented with pulmonary hemorrhage. Although the occurrence of pulmonary hemorrhage in ANCA positive vasculitis was closely correlated with the presence of IgM ANCA, the antigen specificity of these IgM autoantibodies was variable, since both myeloperoxidase (4 patients), PR3 (3 patients), and an unknown ANCA antigen (1 patient) were found to be targets. We conclude that knowledge of ANCA isotype may have important clinical and therapeutic implications for the management of patients with systemic vasculitis.     

ANCA titres, even of IgG subclasses, and soluble CD14 fail to predict relapses in patients with ANCA-associated vasculitis.

BACKGROUND: Antineutrophil cytoplasmic autoantibodies (ANCA) are presumed to reflect disease-activity and to be useful for guidance of immunosuppressive therapy of ANCA-associated systemic vasculitis (AASV), but with respect to conventional ANCA assays this is controversial. ANCA titres, measured in the IgG3 subclass and modern capture ELISAs, have been said to be superior predictors of relapses of AASV. METHODS: In this retrospective study serial measurements of ANCA parameters and soluble CD14 (sCD14) were performed in 169 consecutive sera over a median of 21 months in 18 patients with AASV and related to disease activity, assessed by Birmingham Vasculitis Activity Score (BVAS) for new or deteriorated (BVAS1), and for chronic disease activity (BVAS2). Fourteen patients had Wegener's granulomatosis (WG) and were C-ANCA positive with Pr 3-antibodies and four patients had microscopic polyangiitis (MPA) with P-ANCA and MPO-antibodies. In WG patients ANCA by IIF, Pr 3-ELISA for IgG, IgG1, IgG3, IgG4 and sCD14 were measured, as well as capture ELISA for Pr 3, and in MPA patients ANCA by IIF, MPO-ELISA for IgG and IgG1, IgG3, IgG4, and sCD14 respectively. In eight patients, data collection started at diagnosis, in 10 patients at remission. RESULTS: The parameters predicted neither the nine major relapses (increase of immunosuppression necessary), nor the 26 minor relapses (increase of BVAS1>2) with sufficient sensitivity (>80%) or specificity (> 90%90%), and they also failed to predict relapses within the following 2 months. ANCA-IgG3 and capture ELISA for Pr 3 were not advantageous for prediction of relapses (sensitivity 0.45 and 0.19 respectively), and sCD14 remained elevated in all samples irrespective of disease activity. CONCLUSIONS: There is no rationale for serial measurements of ANCA in AASV. For changes of therapy, the ANCA parameters should only be used in conjunction with clinical information.     

Randomized trial of plasma exchange or high-dosage methylprednisolone as adjunctive therapy for severe renal vasculitis

Systemic vasculitis associated with autoantibodies to neutrophil cytoplasmic antigens (ANCA) is the most frequent cause of rapidly progressive glomerulonephritis. Renal failure at presentation carries an increased risk for ESRD and death despite immunosuppressive therapy. This study investigated whether the addition of plasma exchange was more effective than intravenous methylprednisolone in the achievement of renal recovery in those who presented with a serum creatinine >500 micromol/L (5.8 mg/dl). A total of 137 patients with a new diagnosis of ANCA-associated systemic vasculitis confirmed by renal biopsy and serum creatinine >500 micromol/L (5.8 mg/dl) were randomly assigned to receive seven plasma exchanges (n = 70) or 3000 mg of intravenous methylprednisolone (n = 67). Both groups received oral cyclophosphamide and oral prednisolone. The primary end point was dialysis independence at 3 mo. Secondary end points included renal and patient survival at 1 yr and severe adverse event rates. At 3 mo, 33 (49%) of 67 after intravenous methylprednisolone compared with 48 (69%) or 70 after plasma exchange were alive and independent of dialysis (95% confidence interval for the difference 18 to 35%; P = 0.02). As compared with intravenous methylprednisolone, plasma exchange was associated with a reduction in risk for progression to ESRD of 24% (95% confidence interval 6.1 to 41%), from 43 to 19%, at 12 mo. Patient survival and severe adverse event rates at 1 yr were 51 (76%) of 67 and 32 of 67 (48%) in the intravenous methylprednisolone group and 51 (73%) of 70 and 35 of (50%) 70 in the plasma exchange group, respectively. Plasma exchange increased the rate of renal recovery in ANCA-associated systemic vasculitis that presented with renal failure when compared with intravenous methylprednisolone. Patient survival and severe adverse event rates were similar in both groups.     

Hémorragie sous-arachnoïdienne anévrismale et maladie de Wegener : une association peu commune

Background

Wegener granulomatosis (WG) is an uncommon systemic necrotizing vasculitis that demonstrates renal and respiratory tropism. While the pathogenesis of WG remains controversial, autoimmune and inflammatory mechanisms are likely to be involved. The nervous system could be affected in up to 54% of cases. Although central nervous system involvement has been reported in 7-11% of cases, aneurysmal subarachnoid hemorrhage (SAH) occurrence is exceptional.

Methods

We describe the third reported case of WG-related aneurysmal SAH and then discuss the diagnosis and pathogenesis of WG along with the physiopathology of intracranial aneurysm in light of recent data reported in the literature.

Results

A 63-year-old woman with WG was referred to our neurosurgical department for aneurysmal SAH. The vasculitis diagnosis had been established 4 years earlier when she presented with chronic sinusitis, recurrent cystitis, and renal failure. The cerebral angiography revealed an anterior communicating artery dysplastic aneurysm. The neurosurgical management of the aneurysm was scheduled but delayed because the patient was experiencing a vasculitis flare-up. Immunosuppressive therapy and intravenous corticotherapy were given, with the patient's improvement, allowing neurosurgical clipping of the aneurysm.

Conclusions

Wegener granulomatosis-related aneurysmal SAH is an exceptional condition in neurovascular pathology. As inflammatory mechanisms are involved in the pathogenesis of aneurysm, the vasculitis flare-up could account for this SAH. The management of WG could benefit from anti-inflammatory therapy, as could the vasculitis-related SAH. SAH occurrence in patients with systemic vasculitis could indicate a vasculitis flare-up.     

Renal Transplantation in the ANCA-Associated Vasculitides

Despite advances in the diagnosis and treatment of the antineutrophil cytoplasmic autoantibodies (ANCA)-associated vasculitides, renal morbidity is common. End-stage renal disease occurs in up to 20% of patients with these diagnoses, which include Wegener's granulomatosis and microscopic polyangiitis. As the mortality of patients with ANCA-associated vasculitis continues to improve, our ability to address the consequences of renal failure in this patient population becomes paramount. Renal transplantation is an important therapeutic option for these patients. Graft and patient survival rates among patients with ANCA-associated vasculitis are comparable to those observed in nondiabetic patients. This review summarizes our current knowledge of indications and contraindications for renal transplantation in these patients, the recurrence of vasculitis after transplantation and the impact of posttransplant immunosuppression on the clinical course of these patients.