肾功能正常的抗肾小球基底膜病

一、病历摘要 患者,男性,23岁,因间断咯血4个月,血尿、蛋白尿1个月入院.患者4个月前无诱因间断出现痰中带血,未诊治.1个月前受凉后发热,T 38.2℃.     

Anti-glomerular basement membrane disease mediated by IgG and IgA: a case report

BackgroundAnti-glomerular basement membrane (anti-GBM) disease is a rare autoimmune condition responsible for rapidly progressive glomerulonephritis. This disease is usually mediated by IgG autoantibodies against the noncollagenous domain of the α3(IV) collagen chain. In rare cases, IgA or IgM anti-GBM antibodies are involved. This raises the question of whether there are different types of antibody-mediated anti-GBM disease at the same time.Case reportA 37-year-old woman with anti-GBM disease mediated by IgG and IgA. The patient developed rapidly progressive glomerulonephritis with nephrotic syndrome. Indirect immunofluorescence analysis indicated the presence of IgG and IgA antibodies reactive with a basement membrane component, identified by enzyme-linked immunoadsorbent assay and Western blotting as the α3(IV) collagen chain. After plasmapheresis and immunotherapy (steroids and cyclophosphamide), much improved the massive proteinuria and renal function. Follow up to date, she had normal renal function without proteinuria.ConclusionsThis is the first case report of anti-GBM disease mediated by IgG and IgA. If the clinical presentation and histopathological findings are suggestive of atypical anti-GBM disease, alternative laboratory tests such as Western blotting analysis can be used to confirm the diagnosis.     

Response of type I membranoproliferative glomerulonephritis to pulse methylprednisolone and alternate-day prednisone therapy

Sixteen children with biopsy-confirmed type I membranoproliferative glomerulonephritis (MPGN) were treated with six alternate-day intravenous pulses of methylprednisolone followed by single-dose alternate-day prednisone for 12–66 months (mean 37 months). The average length of follow-up was 52 months (range 12–127 months). Compared with pretreatment values, the frequency of hematuria (13/16 vs. 8/16,P<0.05) and the levels of serum albumin (2.66 ± 0.69 vs. 3.76 ± 0.39 g/dl,P < 0.001), creatinine clearance (97 ± 37 vs. 129 ± 26 ml/ min/1.73 m2,P<0.001), and proteinuria (5.2 ± 5.1 vs. 1.0 ± 0.8 g/day, P<0.001) were significantly improved after 3 months of therapy. Improvement has persisted through the end of the follow-up period. Repeat kidney biopsies showed a significant reduction in acute changes but an increase in chronic changes. Thirteen patients have been off therapy from 1 to 74 months (mean 20.8 months). Nine have a normal urinalysis, creatinine clearance, and protein excretion. The remainder have normal renal function but proteinuria ranging from 3.2 to 4.3 g/day. The data support the evidence of other investigators that corticosteroid therapy is beneficial in type I MPGN and suggest that initiation with pulse methylprednisolone may promote early stabilization of the disease.     

Membranous glomerulonephritis associated with anti-tubular and anti-alveolar basement membrane antibodies.

The renal biopsy of a 3-year old boy with complete Fanconi syndrome showed the association of a membranous glomerulonephritis with severe tubulointerstial changes. Immunofluorescence microscopy disclosed linear and granular deposits of Ig along tubular basement membranes. The presence of anti-tubular basement membrane antibodies in the patient's serum was demonstrated by indirect immunofluorescence and radioimmunoassay. The child also developed pulmonary involvement associated with episodes of acute anemia. Anti-alveolar basement membrane antibodies were detected by indirect immunofluorescence. The present case is the first reported example of auto-immune disease characterized by the presence of anti-tubular and alveolar basement membrane antibodies associated with an immune complex glomerulonephritis.     

抗肾小球基底膜病临床病理及血浆置换疗效分析

目的 分析抗肾小球基底膜（GBM）病的临床病理特点和预后;评价双膜血浆置换（DFPP）清除抗GBM抗体的有效性和安全性。 方法 回顾分析北京协和医院1999年10月至2010年5月确诊为抗GBM病的35例住院患者的临床病理资料。患者根据临床表现分为3组：组Ⅰ：24例严重肺出血或急进型肾小球肾炎（RPGN）者,接受甲泼尼龙（7.5~15 mg·kg-1·d-1,3~5 d）冲击和（或）DFPP治疗,后续以泼尼松（1.0 mg·kg-1·d-1）和（或）环磷酰胺（CTX 0.1 g/d）;组Ⅱ：5例无严重肺出血或RPGN者予泼尼松和（或）CTX治疗;组Ⅲ：5例就诊时已为终末期肾病（ESRD）和1例肾功能正常者未给予免疫抑制治疗。观察患者临床病理特点,连续监测4例患者DFPP治疗前后抗GBM抗体滴度变化情况,计算抗体的清除率。分析影响预后的相关因素。 结果 35例患者平均年龄（41.06±16.55）岁,男女比例4∶3;16例（45.7%）患者表现为Goodpasture综合征;18例（51.4%）表现为抗GBM肾小球肾炎。24例接受肾穿刺活检患者中,13例（54.2%）表现为新月体肾小球肾炎;7例患者并发其他肾小球肾炎。组Ⅰ死亡7例,50%患者肾脏长期存活。与组Ⅱ相比,组Ⅰ患者入院时Scr水平、抗GBM抗体滴度、肾小球新月体比例均显著升高（P < 0.05）;老年患者、贫血、入院时Scr水平高（>300 μmol/L)及硬化肾小球比例更高;入院时少尿或无尿、需要血液透析治疗、肾脏预后差更普遍。18例患者的94次DFPP治疗中,无明显出血、低血压;4例连续动态监测抗GBM抗体滴度的患者中,4~6次DFPP后抗GBM抗体转阴,中位清除率为55%。 结论 根据不同临床表现选择个体化的治疗方案有助于改善预后,减少并发症。DFPP能安全有效地清除抗GBM抗体。     

Immunosuppressive therapy and plasmapheresis in rapidly progressive glomerulonephritis associated with bacterial endocarditis

A 25-year-old male presented with new cardiac murmurs and acute renal insufficiency. Blood cultures grew Streptococcus viridans and appropriate antibiotic therapy was initiated. A renal biopsy revealed diffuse proliferative glomerulonephritis with crescents involving more than 50% of the glomeruli. Treatment with antibiotics, plasmapheresis, and steroids resulted in renal recovery that paralleled reductions in circulating immune complexes. The rationale for this therapeutic approach is discussed, as well as a review of two similar case reports. These experiences suggest a possible role for plasmapheresis and immunosuppressive drugs in patients who develop rapidly progressive glomerulonephritis as a complication of bacterial endocarditis.     

Anti-glomerular basement membrane disease and dual positivity for antineutrophil cytoplasmic antibody in a patient with membranous nephropathy

We present the case of a 50-year-old man who underwent kidney biopsy for nephrotic syndrome. In addition to a membranous pattern, anti-glomerular basement membrane (anti-GBM) staining was noted before manifestations of anti-GBM disease. Hematuria and renal failure ensued 2 weeks later. In addition, he had simultaneous circulating levels of anti-GBM antibody and both perinuclear (P-) and cytoplasmic (C-) antineutrophil cytoplasmic antibody (ANCA).     

拉米夫定联合甲泼尼龙片及来氟米特治疗乙型肝炎病毒相关性肾炎

目的 探讨拉米夫定联合甲泼尼龙片及来氟米特治疗乙型肝炎病毒相关性肾炎的疗效和安全性,以寻找HBV-GN有效的治疗方案指导以后的临床治疗.方法 选择20例HBV-GN患者,通过肾穿刺检查确定病理类型,观察在常规治疗的基础上加用拉米夫定联合甲泼尼龙片及来氟米特的近期疗效,疗程1年,观察治疗前后尿蛋白定量、血清白蛋白、肝肾功能、HBV标志物及HBV-DNA的变化情况及所有不良反应.结果 HBV-GN的病理分型:MsPGN6例(30％),IgAN6例(30％),MN5例(25％),MPGN3例(15％).以拉米夫定联合甲泼尼龙片及来氟米特治疗乙型肝炎病毒相关性肾炎总有效率80％ (16/20),显效率60％(12/20),未发现严重不良反应.结论 成人HBV-GN病理类型以IgAN、MsPGN为主,HBV-GN患者治疗前、后尿蛋白定量的多少并不取决于其病理类型及乙肝病毒活跃程度,拉米夫定联合甲泼尼龙片及来氟米特治疗HBV-GN的疗效与病理类型及乙肝病毒活跃程度无关;以拉米夫定联合糖皮质激素及来氟米特治疗HBV-GN疗效显著,安全、费用较低,值得临床推广应用.     

Successful treatment of HCV-related cryoglobulinemic glomerulonephritis with double-filtration plasmapheresis and interferon combination therapy

A 67-year-old, hepatitis C virus (HCV)-positive woman was admitted to our hospital because of proteinuria and leg edema. Laboratory examination showed decreased serum albumin and complement activity and positive cryoglobulin. The HCV RNA genotype was 1b with high viral load. Kidney biopsy showed membranoproliferative glomerulonephritis (MPGN) with capillary deposition of C3, IgM, and IgG, indicating HCV-associated glomerulonephritis. In addition to interferon (IFN) therapy, double-filtration plasmapheresis (DFPP) was performed to reduce HCV RNA blood levels in the early stage of IFN therapy. This treatment greatly reduced the viral load and induced clinical remission of MPGN, suggesting that DFPP plus IFN combination therapy may represent a potentially effective modality for refractory-type HCV-associated glomerulonephritis.     

Experimental autoimmune glomerulonephritis induced by homologous and isologous glomerular basement membrane in Brown-Norway rats

In order to study disease mechanisms and potential forms of therapy in glomerulonephritis, a model of experimental autoimmune glomerulonephritis (EAG) has been developed in the rat. We have examined the response of Brown-Norway (BN) rats to a single i.m. injection of collagenase-solubilised homologous (Sprague-Dawley, SD) or isologous (BN) glomerular basement membrane (GBM), with and without complete Freund's adjuvant (CFA). There was a dose-dependent circulating anti-GBM antibody response to all preparations of rat GBM. Animals given either antigen alone at a dose of 2 mg/kg developed circulating anti-GBM antibodies, which reached peak values by 6 weeks (63 +/- 5% following SD GBM; 53 +/- 8% following BN GBM), but did not develop glomerular deposits of IgG or nephritis. Animals given 2 mg/kg SD GBM in CFA developed greater concentrations of anti-GBM antibody by 6 weeks (122 +/- 20%) together with linear deposits of IgG on glomerular and tubular basement membranes (TBM), albuminuria (mean 7 mg/24 h), and variable focal segmental necrotising glomerulonephritis with mild interstitial nephritis. The same dose of BN GBM in CFA produced similar concentrations of circulating antibody (144 +/- 26%), with linear deposits of IgG on GBM but rarely TBM, little albuminuria, and variable mild focal glomerulonephritis. Other strains injected with SD GBM in CFA showed a variable circulating anti-GBM antibody response, which was similar to that of BN rats in PVG and DA rats but lower in LEW and WAG rats. Linear deposits of IgG on the GBM were detected in a proportion of PVG and DA rats, but not in LEW or WAG rats.(ABSTRACT TRUNCATED AT 250 WORDS)     

Anti-glomerular basement membrane antibody disease: a case report and a review of Japanese patients with and without alveolar hemorrhage

A 73-year-old man was admitted to our hospital because he had developed loss of appetite, abnormal behaviors, and consciousness disturbances that had begun in late February 1998. On admission, a renal biopsy was performed because of progressive deterioration of renal function, as evidenced by a serum urea nitrogen (UN) level of 109 mg/dl and a serum creatinine level of 16.3 mg/dl. Light microscopic examination showed severe cellular crescent formation with fibrin deposition in glomeruli and markedly degenerated Bowman's capsule. Immunofluorescence examination revealed linear deposits of IgG along glomerular basement membranes (GBM), and granular deposits of C3 on the GBM, as well as deposits of fibrinogen in Bowman's capsule. The patient was diagnosed as having anti-GBM antibody disease, based on negative results for myeloperoxidase (MPO)/proteinase-3 (PR-3)-anti-neutrophil cytoplasmic antibody (ANCA), high serum anti-GBM antibody titers, and the absence of pulmonary hemorrhage. He was treated with both combination therapy (cyclophosphamide and prednisolone) and plasmapheresis. In spite of the disappearance of anti-GBM antibody, his renal function did not improve, and he has been treated with regular hemodialysis since March 1998. We reviewed 49 cases of anti-GBM antibody disease in patients with alveolar hemorrhage (group A; Goodpasture's syndrome) and 39 cases in patients without it (group B) reported in Japan from 1975 to 1999, examining the differences between these groups, and we clarified the characteristics of these rare diseases in Japan. There was no difference in age, sex, and ANCA positivity between the two groups. The mortality rate was higher in group A (56.2%) than in group B (18.4%). About half of the patients underwent plasmapheresis, but it did not reduce the mortality rate or improve the renal prognosis. Received: November 20, 2000 / Accepted: November 19, 2001     

Multimodal therapy with combined plasmapheresis, photoapheresis, and intravenous immunoglobulin for acute antibody-mediated renal transplant rejection: a 2-year follow-up

Background

Recently, the role of antibodies has been documented in the development of acute rejection episodes. Antibody-mediated acute rejection (AMAR) may develop at any time after transplantation, with an incidence of almost 7%. Several therapeutic approaches have been proposed in the past decades. However, no data exist regarding combined plasma treatment (PT) and extracorporeal photopheresis (ECP). The aim of this study was to report an initial single-center experience of combined PT and ECP with high-dose intravenous immunoglobulin (IVIg) for the treatment of AMAR.

Methods

Three patients were treated with this approach.

Results

In 2 cases, we observed immediate restoration of graft function, and in 1 case, in which we interrupted the protocol owing to lack of patient consent, the graft was lost. No organ infections were reported during the therapy period. The rationale for use of ECP is related to the presence of mixed antibody and cell-mediated mechanisms in acute rejection episodes. ECP inhibits specific pathogenic T cells.

Conclusion

Our approach seemed to give good results in terms of graft survival and safety.     

Effect of methylprednisolone pulse therapy in patients with lupus nephritis assessed by WHO morphologic classification

To determine indications for treatment with high-dose intravenous methylprednisolone pulse therapy in lupus nephritis, we retrospectively assessed the response to pulse therapy over oral prednisolone administration in 120 biopsy proven lupus nephritis patients according to WHO morphologic classification. In the pulse group, 1 g of methylprednisolone was administered on three consecutive days and oral steroid therapy (40-30 mg) was started. In many occasions in treating class III and IV-b, repeated pulse therapy was performed. In control oral prednisolone group, middle-dose steroid therapy (50-30 mg) was started. In patients with minor glomerular abnormalities and mesangial lupus nephritis, rapid improvement of serological activities was observed in pulse group assessed by serum complement level, anti-DNA antibodies, and anti-nuclear antibodies. In patients with focal lupus nephritis, rapid rise in serum complement level and fall in proteinuria was observed in the pulse group. In patients with diffuse proliferative lupus nephritis with active necrotizing lesions, faster rise in serum complement level and proteinuria were observed in the pulse group. In patients with membranous lupus nephritis there was no significant difference between two groups. In comparison with the effect of pulse therapy among each morphologic class, the rise of serum complement level was slowest in class IV-b. Both group of IV-b and V manifested nephrotic syndrome and by pulse therapy the decrease in urinary protein was faster and more significant in class IV-b compared with class V. No significant adverse effect of methylprednisolone was observed during about 150 times of pulse therapy. Bacterial, viral infections such as herpes zoster and fungal infections were observed in pulse group as often as control group.     

IgA variant of anti-glomerular basement membrane glomerulonephritis associated with pulmonary hemorrhage and microangiopathic hemolytic anemia

A 70-year-old man with uremia was referred because of hemoptysis. A chest X-ray showed diffuse infiltration in the right lung field. Laboratory data were remarkable for renal failure, anemia, and thrombocytopenia. Furthermore, laboratory evidence of microangiopathic hemolytic anemia was present. A kidney biopsy revealed diffuse crescentic glomerulonephritis with linear staining of IgA along the glomerular basement membrane (GBM). No thrombotic microangiopathy was noted on renal biopsy. Circulating IgG anti-GBM antibody was not detected, and IgA anti-GBM antibody was not tested. The patient was treated with plasmapheresis and pulse steroid therapy, which resulted in an immediate improvement in the pulmonary hemorrhage and hematological abnormalities. However, the patient did not regain renal function and remained on hemodialysis.     

Glomerular basement membrane splitting and microaneurysm formation associated with nitrosourea therapy

A patient who developed renal insufficiency following nitrosourea therapy is reported. Light, immunohistochemical, and electron microscopic studies of the renal biopsy disclosed an unusual glomerular basement membrane injury. Light microscopy showed extensive basement membrane splitting and capillary aneurysm formation. Electron microscopic examination revealed an extensive subendothelial accumulation of electron-lucent granular material. The glomerular basement membrane was separated from the mesangium and showed splitting of the lamina densa. Immunofluorescent and immunoperoxidase staining of the glomeruli was negative for immunoglobulin, complement, and fibrinogen. This form of nitrosourea-associated glomerular injury has not been described previously.     

Rituximab treatment combined with methylprednisolone pulse therapy and immunosuppressants for childhood steroid-resistant nephrotic syndrome

Background

Calcineurin inhibitors (CIs) with/without intravenous methylprednisolone pulse therapy (MPT) constitute the standard treatment for childhood-onset, steroid-resistant nephrotic syndrome (SRNS). However, some patients fail to achieve remission. We treated SRNS patients resistant to CIs and MPT with additional rituximab combined with MPT and immunosuppressive agents.

Methods

Ten patients (aged 2–14 years) with CI- and MPT-resistant SRNS were enrolled. Patients were administered rituximab (1–4 doses; 375 mg/m²) followed by MPT (30 mg/kg/day of methylprednisolone for 3 consecutive days) once every 2–4 weeks until complete remission (CR). We analyzed clinical outcome and safety.

Results

Six patients received a single dose of rituximab, 2 received two doses, and 2 received four doses. Seven patients achieved CR, 1 achieved partial remission, and 2 showed no response. Although 2 patients with no response progressed to end-stage renal failure, 7 patients with CR preserved normal renal function without proteinuria at the last observation. There were two serious adverse events.

Conclusions

Additional rituximab combined with conventional MPT and immunosuppressive agents is a promising option for overcoming refractory SRNS. Aggressive B cell suppression by rituximab may ameliorate resistance to conventional treatments and a cocktail of other immunosuppressive agents, such as CIs, MMF, mizoribine, may be beneficial. However, as intense immunosuppression may cause serious adverse events, further evaluation is necessary.