An unusual case of IgA-mediated anti-glomerular basement membrane disease

Anti-glomerular basement membrane (GBM) disease is mediated by circulating autoantibodies, principally IgG, targeted at the type IV collagen of GBM. The IgA variant of anti-GBM disease has rarely been described. We report a 65-year-old man with uremia, undergoing hemodialysis, who 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. Circulating IgA anti-GBM antibody was found, as well as the presence of significant IgA deposition in a linear pattern along the GBM, suggesting an anti-GBM antibody-mediated disease. 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.     

原发性干燥综合征合并抗肾小球基底膜新月体肾炎一例

现报道1例原发性干燥综合征伴抗肾小球基底膜型新月体肾炎。患者,女,70岁,因眼干、口干、四肢肌痛1年,咳嗽发热2周,少尿伴血肌酐升高1周入院。患者1年前于当地医院查RF 397 U／ml,ANA 1:320,CRP 5 ,ESR 34 mm／h, at-SM(-),at-SSA(-),at-SSB(-),角膜荧光( ),腮腺造影及唇黏膜活检(唇腺病理:小唾液腺组织见灶性间质细胞淋巴浆细胞浸润,50个／HPF),支持干燥综合征诊断。 2周前元明显诱因出现发热38．9℃,畏寒,伴咳嗽、咳痰。     

Asymptomatic autoantibodies associate with future anti-glomerular basement membrane disease

The pathophysiology of anti-glomerular basement membrane (anti-GBM) disease before clinical presentation is unknown. The presence of anti-GBM, anti-proteinase 3 (PR3), and anti-myeloperoxidase (MPO) antibodies associate with the disease at the time of diagnosis, but little is known about the presence of these autoantibodies before diagnosis. We used serum samples from the Department of Defense Serum Repository to conduct a case-control study involving 30 patients diagnosed with anti-GBM disease and 30 healthy controls matched for the age, gender, race, and age of the serum samples. We analyzed a maximum of three samples from each subject: the most recent sample before diagnosis, the penultimate sample before diagnosis, and the oldest sample available; the average time between the most recent sample and diagnosis was 195 days (range, 4 to 1346 days). Elevated anti-GBM levels (≥3 U/ml) were present in four patients, all less than 1 year before diagnosis but in no controls. Detectable anti-GBM antibody levels (≥1 U/ml but <3 U/ml) in a single serum sample before diagnosis were more frequent in cases than controls (70% versus 17%, P < 0.001). Only study patients had detectable anti-GBM levels in multiple samples before diagnosis (50% versus 0%, P < 0.001). Almost all patients had detectable anti-PR3 and/or anti-MPO that preceded the onset of disease. Among patients with a clear antecedent antibody, anti-PR3 or anti-MPO always became detectable before the anti-GBM antibody. In summary, our data describe the subclinical formation of autoantibodies, which improves our understanding of the pathophysiology of anti-GBM disease.     

抗肾小球基膜病合并IgA肾病一例

我们收治最近1例抗肾小球基膜（抗-GBM）病合并IgA肾病，报道如下。     

A 25-year experience with pediatric anti-glomerular basement membrane disease

Anti-glomerular basement membrane (anti-GBM) disease, which is extremely uncommon in children, is characterized by rapidly progressive glomerulonephritis (RPGN) and autoantibodies against GBM collagen. Pulmonary hemorrhage is the third component in Goodpasture Syndrome. Cigarette smoking and exposure to hydrocarbons have been linked to anti-GBM disease in adults, but such an association has not been established in children. We reviewed renal biopsy and autopsy specimens over 25 years from a major tertiary care U.S. children's hospital, diagnosing anti-GBM by clinical RPGN, crescentic glomerulonephritis, and linear immunofluorescence (IF) immunoglobulin G staining in patients under 18 years of age. We identified four patients, with and without pulmonary manifestations. The sole autopsy case showed diagnostic IF despite undetectable serum anti-GBM antibodies and positive testing for serum anti-neutrophil cytoplasmic antibodies (ANCA). Three patients have survived 1–18 years following diagnosis, one of whom is recovering renal function. One adolescent had a history of smoking cigarettes and one had a probable hydrocarbon exposure. Anti-GBM disease is unusual in children, and the relationship to inhaled agents is incompletely understood. Serum anti-GBM antibodies are typically present, but cases with undetectable levels can occur. Some patients are anti-GBM and ANCA positive, with a small subset ANCA-positive, anti-GBM-negative. Ours is the first such described pediatric case.     

Advances in the genetics of anti-glomerular basement membrane disease

Anti-glomerular basement membrane (GBM) disease is a rare but lethal autoimmune disorder. Over the past few years, the nature of the autoantigen and its epitopes has been defined, as well as the possible pathogenic role played by environmental factors, and by cellular and humoral immunity. However, the majority of data on anti-GBM disease comes from studies conducted on animal models, since human studies are relatively scarce. Genetic studies have highlighted strong positive associations of anti-GBM disease with the HLA-DRB1*1501 allele. In addition, the disease has been associated with genes of the FCGR and KLK families. Important as they are, these findings have to be considered preliminary, if not contentious. Here, we provide an overview of recent discoveries in the genetics of anti-GBM disease that may help elucidate the disease pathogenesis while improving therapeutic approaches. We also discuss the limitations of such discoveries. Finally, we suggest that extensive collaboration between investigators and novel integrative approaches are essential to the progress of our understanding of the anti-GBM disease. We attempted to summarize the current knowledge on the pathogenesis of anti-GBM disease by providing different but complementary perspectives from previous reviews.     

Late presentation of Alport posttransplantation anti-glomerular basement membrane disease

We describe a female patient with Alport disease who developed antiglomerular basement membrane nephritis late after kidney transplantation during the treatment of an acute bacterial pyelonephritis and discuss the potential role of the infection as a trigger for the development of this nephritis.     

An unusual case of nephrotic syndrome and glucosuria

We report a case of a 57-year-old man with hypertension and smoking history who presented with decreased glomerular filtration rate, nephrotic-range proteinuria, and persistent glucosuria. He underwent a kidney biopsy that showed nodular glomerulosclerosis. We discuss the clinicopathologic entities of idiopathic nodular glomerulosclerosis and primary renal glucosuria.     

Superimposed glomerular immune complexes in anti-glomerular basement membrane disease

The association of anti-glomerular basement membrane (GBM) antibody-mediated glomerulonephritis and glomerular immune complexes is common and probably arises from a number of mechanisms. In the series, glomerular immune complexes were identified in 6 of 17 patients who initially presented with anti-GBM disease. In four cases, glomerular immune complexes were noted in renal biopsies obtained at clinical presentation; in the other two, they were first demonstrated seven and 28 months after presentation, when circulating anti-GBM antibody levels were undetectable. Circulating immune complexes were detected in only two of six patients, either 28 months before or 17 months after the demonstration of the glomerular membranous lesion. The association of glomerular immune complexes and anti-GBM disease may be coincidental with immunologically-unrelated immune complexes localizing in the GBM for physico-chemical reasons; or the presence of glomerular-bound anti-GBM antibodies may predispose to the deposition of molecules with particular affinity for these antibodies. One patient with glomerular immune complexes used heroin, which may be associated with immune complex formation and the development of glomerulonephritis; and one patient was subsequently thought to have systemic lupus erythematosus (SLE). An antecedent infection was found in two of the four patients who had glomerular complexes at presentation, but in only three of 13 with uncomplicated anti-GBM disease. Three of 6 patients with superimposed glomerular complexes had a history of exposure to organic solvents before the onset of disease, while none in the group with anti-GBM disease alone had.     

Rituximab for the treatment of refractory anti-glomerular basement membrane disease

BackgroundAnti-glomerular basement membrane (anti-GBM) disease is a rare but severe autoantibody-mediated immune disorder. The typical clinical presentation includes rapidly progressive glomerulonephritis and often concurrent pulmonary hemorrhage. The present study is aimed to investigate the therapeutic effects of rituximab either used alone or with other immunosuppressants.MethodsEight patients diagnosed with anti-GBM disease and treated with rituximab from 2014 to 2020 were retrospectively reviewed.ResultsEight patients included 5 males and 3 females with a median age of 58.5 years. They all presented severe kidney injuries and 1 patient had lung hemorrhage. At diagnosis, the median of serum creatinine was 246 µmol/L (ranging from 91 to 850 µmol/L), with 3 patients requiring dialysis. All of them received corticosteroids and plasmapheresis. Rituximab was given as either standard four weekly doses or one pulse ranging from 100 to 600 mg. After a median follow-up of 34.5 months, kidney function was partially recovered or stabilized in 5/8 (62.5%) patients, free of dialysis. Anti-GBM antibodies remained undetected in all patients during follow-up. No severe adverse effect associated with rituximab was observed.ConclusionRituximab may be an alternative therapy in the treatment of patient with severe or refractory anti-GBM disease.     

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。     

High prevalence of antithyroid antibodies in anti-glomerular basement membrane antibody-mediated disease

Anti-glomerular basement membrane antibody (anti-GBM Ab)-mediated disease and autoimmune thyroiditis are characterized by the presence of organ-specific antibodies. The diagnosis of autoimmune thyroiditis is usually based on the presence of serum antithyroid antibodies. Few studies have addressed the relationship between anti GBM-Ab mediated disease and autoimmune thyroid pathology. Given that this disorder is often asymptomatic, associations of the two pathologies may be under-diagnosed. This study investigated the prevalence of serum antithyroid antibodies (antithyroglobulin (anti-TG) and anti-thyroid peroxidase (anti-TPO)) in patients with anti-GBM Ab-mediated disease. Antithyroid antibodies presence was investigated in sera from 35 patients in whom anti-GBM Ab-mediated disease had been diagnosed. Anti-glomerular basement membrane antibodies and anti-thyroid antibodies (anti-TG and anti-TPO) were assayed using an enzyme-linked immunosorbent assay. Forty-five percent of patients with anti-GBM Ab-mediated disease (16/35) had positive antithyroid antibody titers. Eighteen percent (3/16) suffered from subclinical hypothyroidism. In conclusion, the high prevalence of antithyroid antibodies in these patients suggests a possible pathogenic link between autoimmune thyroiditis and anti GBM Ab-mediated disease.     

Concurrent anti-glomerular basement membrane disease and membranous glomerulonephritis: a case report and literature review

BACKGROUND: Anti-glomerular basement membrane disease (anti-GBM) is a relatively rare entity characterized by antibodies to collagen type IV of glomerular and alveolar basement membranes. The sequential or simultaneous presentation of anti-glomerular basement membrane disease with membranous glomerulonephritis has been infrequently described. CASE: We present the case of a 49-year-old man who had fatigue, flank pain, hematuria and renal failure. Serology was positive for anti-GBM antibodies; crescentic glomerulonephritis was seen on renal biopsy. Immunofluorescence and electron microscopy demonstrated evidence of both anti-GBM glomerulonephritis and membranous deposits. DISCUSSION: Simultaneous anti-GBM disease and membranous glomerulonephritis is the most common temporal presentation of this rare entity. However, cases of membranous glomerulonephritis preceding or following recovery from anti-GBM disease have been described. Study of such cases provides insight into pathophysiologic mechanisms, including the possibility of increased antigen synthesis, exposure of cryptic epitopes, and/or capping and shedding of antigen-antibody complexes, in analogy to Heymann nephritis.     

Histopathological atlas of renal diseases: anti-glomerular basement membrane antibody disease

The main diagnostic feature of anti-glomerular basement membrane (anti-GBM) antibody disease is represented by the immunofluorescence pattern of intense and diffuse linear IgG deposition along the glomerular basement membrane. By light microscopy several histological patterns can be observed.     

应用抗肾小球基底膜抗体的中和性单克隆抗体治疗抗肾小球基底膜肾炎大鼠的实验研究

目的 应用抗肾小球基底膜（GBM）抗体的中和性单克隆抗体注射抗GBM肾炎大鼠,观察各种生化指标及肾脏病理学的变化。 方法 将Wistar大鼠随机分为5组,每组9只：(1)肾炎模型组：经尾静脉注入人抗GBM抗体;(2)正常对照Ⅰ组:经尾静脉注入非抗体性的健康人lgG;(3)对照Ⅱ组：经尾静脉注入抗GBM抗体的中和性单克隆抗体;(4)干预Ⅰ组：经尾静脉注入人抗GBM抗体,第7天后再经尾静脉注入抗GBM抗体的中和性单克隆抗体(1.5 ml/100 g);(5)干预Ⅱ组：经尾静脉注入人抗GBM抗体,第14天后再经尾静脉注入抗GBM抗体的中和性单克隆抗体。分别在实验后第7、14、21天观察大鼠24 h尿蛋白量、BUN、Scr和肾组织病理学的变化。 结果 第21天干预Ⅰ组尿蛋白量为（16.62±5.53） g/d、BUN为（11.53±2.26） mmol/L、Scr为（102.46±16.86） μmol/L,均显著低于肾炎模型组（P < 0.05）;干预Ⅱ组较肾炎模型组也有所降低,但差异无统计学意义（P > 0.05）。干预Ⅰ组和干预Ⅱ组肾脏细胞增生、新月体的形成及免疫复合物的沉积均少于肾炎模型组,但干预I组更为明显。对照Ⅰ组和对照Ⅱ组之间无明显变化。 结论 早期应用抗GBM抗体的中和性单克隆抗体能够有效改善抗GBM肾炎大鼠的肾脏病变。     

Good outcome in anti-glomerular basement membrane nephritis

We report a 6-year-old boy with anti-glomerular basement membrane nephritis (Goodpasture's syndrome). Intensive treatment with plasmaphaeresis and immunosuppression resulted in clearance of antibody and good recovery of renal function.