Membranoproliferative glomerulonephritis in a girl and her mother

A girl and her mother were diagnosed as having membranoproliferative glomerulonephritis (MPGN) type I. Microscopic hematuria and proteinuria presented at 9 years of age in the mother and at 14 years in the daughter. Both had persistent hypocomplementemia and were treated with steroids. When the mother was 40 years old, proteinuria was still continuing and creatinine clearance was 64.4 ml/min per 1.73 m². When the daughter was 15 years old, microscopic hematuria was still continuing. To our knowledge, familial cases of MPGN in two generations have not been reported in Japan.     

Immunotactoid glomerulopathy is a rare entity with monoclonal and polyclonal variants

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MPGN II – genetically determined by defective complement regulation?

MPGN II is a rare disease which is characterized by complement containing deposits within the GBM. The disease is characterized by functional impairment of the GBM causing progressive loss of renal function eventually resulting in end stage renal disease.It now becomes evident that in addition to C3NeF, which inhibits the inactivation of the alternative C3 convertase C3bBb, different genetically determined factors are also involved in the pathogenesis of MPGN II. These factors though different from C3NeF also result in defective complement regulation acting either through separate pathways or synergistically with C3NeF. Following the finding of MPGN II in Factor H deficient animals, patients with MPGN II were identified presenting with an activated complement system caused by Factor H deficiency. Factor H gene mutations result in a lack of plasma Factor H or in a functional defect of Factor H protein. Loss of Factor H function can also be caused by inactivating Factor H autoantibodies, C3 mutations preventing interaction between C3 and Factor H, or autoantibodies against C3. Identification of patients with MPGN II caused by defective complement control may allow treatment by replacement of the missing factor via plasma infusion, thus possibly preventing or at least delaying disease progress.     

Activated C3 (C3b) in the nephritic glomerulus

An autoradiographic technique was developed to assess in the nephritic glomerulus the relative amount of C3 which is in the activated form, C3b, compared with the inactivated form, iC3b. Frozen renal biopsy sections from children and young adults with glomerulonephritis were assessed for the C3b fraction of total C3, using a radiolabeled monoclonal anti-C3c. Grain counts with this antibody, before and after reacting the section with 0.0002% typsin, gave the relative amounts of total C3 and C3b, respectively. C3b was found in all diseases studied. To explain its presence, glomerular C3b acceptors which would restrict C3b inactivation were sought by immuno-fluorescence studies. C3b acceptor candidates were: igG in aggregated form, IgA as found in the IgA nephropathies and the C3/C5 convertase, C4b,2a,3b. In acute post-streptococcal glomerulonephritis and membranoproliferative glomerulonephritis type III, diseases in which these acceptors were lacking, it is postulated that the nephritis strain-associated protein and absence of membrane cofactor protein, respectively, may be responsible for C3b deposition. The phlogistic effect of C3b is mediated largely by one of its products, C5b-9. However, the C3b: total C3 ratio failed to correlate with indices of glomerular inflammation. probably in part because the ratio is not a measure of total glomerular C3b.     

C3 glomerulonephritis associated with monoclonal gammopathy: a retrospective case series study from a single institute in China

ObjectiveTo investigate the demographic and clinicopathological features and renal outcomes of Chinese patients with C3 glomerulonephritis in the setting of monoclonal gammopathy.MethodsPatients with renal biopsy-proven C3 glomerulonephritis and detectable serum and/or urine monoclonal immunoglobulin from 2006 to 2018 in Peking University First Hospital were included, their clinical data, renal pathology type, treatment, and prognosis were collected and analyzed.ResultsNineteen patients were enrolled, accounting for 24% of C3GN patients in the study period. The mean age of onset was 55 years old and the gender ratio was 4/15 (female/male). The mean eGFR at biopsy was 49.55 ± 29.81 ml/min/1.73m². The prominent clinical manifestations included nephrotic syndrome (58%), anemia (68%), microscopic hematuria and leukocyturia (58%), and hypocomplementemia (13, 68%). The IgG was the most common isotype of monoclonal Ig on immunofixation electrophoresis. Kidney biopsies revealed a relatively prominent MPGN pattern. Only two patients had direct evidence of monocle immunoglobulins acting as C3GN pathogenic factors. Two patients had concurrent TMA-like renal injuries. The median renal survival was 12 and 15 months, respectively in patients receiving conservative therapy and immunosuppressant therapy, without statistical significance. The efficacy of clone-targeted therapy needed further investigation. Plasma exchange therapy only improved one patient’s renal outcome.ConclusionsThis is the first case series report of C3GN combined with monoclonal Ig in northern China. The renal prognosis of these patients is poor, and immunosuppressant therapies show no advantage over supportive therapy in renal prognosis, while the benefit of clone-targeted chemotherapy is still requiring investigation.     

Review article: Pathogenic role of complement activation in anti-neutrophil cytoplasmic auto-antibody-associated vasculitis

Small-vessel vasculitides associated with anti-neutrophil cytoplasmic auto-antibodies (ANCA) are severe systemic diseases that may affect any organ. Increasing evidence from clinical, animal and in vitro studies indicates that ANCA are causally involved in disease pathogenesis mainly through activation of neutrophils resulting in endothelial cell injury. Recent studies suggest a previously unsuspected but crucial role for alternative pathway complement activation in ANCA disease pathogenesis. In this brief review, we will discuss the evidence for complement system activation in ANCA-associated vasculitides and propose a working model that links ANCA, neutrophils and complement activation in causing an inflammatory amplification loop that may explain the severe leukocytoclastic inflammation that is typical for ANCA-associated vasculitis.     

The co-existence of membranoproliferat?ve glomerulonephritis type?1 and coeliac disease: a case report

Coeliac disease is an autoimmune enteropathy characterised by chronic inflammation of the small intestinal mucosa and the presence of typical autoantibodies. Coeliac disease may be a risk factor for renal disease. Immunoglobulin A (IgA) nephropathy is reported in the majority of these cases. Only one adult patient had been reported with membranoproliferative glomerulonephritis (MPGN) and coeliac disease. Here, we report a case in a 12-year-old girl with coeliac disease who presented with severe anaemia and later developed nephrotic syndrome. Renal biopsy of the patient was consistent with MPGN type 1, which has not been previously reported in children with coeliac disease. A gluten-free diet was started. After 6 months of this diet, her nephrotic syndrome resolved completely. This case is presented to draw attention to the rare association of coeliac disease and MPGN type 1.     

C3肾小球肾炎的诊断和中西医结合治疗

C3肾小球肾炎(C3GN)是指免疫荧光仅见C3沉积而免疫球蛋白和C1q阴性,电镜下见内皮下和(或)系膜区电子致密物沉积的一种肾小球病。随着病理学、免疫学的逐步发展,我们对C3GN的认识不断提高。目前临床医生主要通过临床表现、实验室检查(补体成分异常)及病理三方面来对C3GN进行诊断。C3GN作为一种最近提出的疾病,现有资料有限,在诊断上需要慎重鉴别。C3GN尚无特效的治疗方法,作用于C5的人造单克隆抗体依库丽单抗、补体调节剂CR1以及以雷公藤甲苷为代表的中西医结合对症治疗有望获得良好的疗效。本病预后呈多样性,在对症支持的基础上,中西医结合治疗通过免疫抑制等机制有望控制疾病的进展,而更加有效的药物亟待研发。     

Nephritic factor and recurrence in the renal transplant of membranoproliferative glomerulonephritis type II

Animal models suggest a role for nephritic factor in the pathogenesis of glomerular disease, but evidence for a role in human disease is lacking. To assess its role, we applied a recently developed method that allows measurement of low levels of nephritic factor activity to stored serum specimens from three patients who had membranoproliferative glomerulonephritis (MPGN) type II. All three had had renal transplants, and one lost two of three transplants from recurrent disease. Evidence for a role for nephritic factor in human disease was a positive correlation between the level of nephritic factor activity and both the severity of recurrence and an increase in serum creatinine concentration. However, the hypocomplementemia was never severe; C3 levels of 49-76 mg/dl and nephritic factor levels of 89 U/ml were associated with severe recurrences. We have previously seen severe disease with mild hypocomplementemia. In contrast, patients with partial lipodystrophy often have severe hypocomplementemia and, presumably, high levels of nephritic factor yet have a mild glomerulonephritis. Disease severity and nephritic factor levels thus appear to be inversely related. The disease is progressive when only moderate amounts of nephritic factor have been circulating and C3 only mildly depressed.     

Familial occurrence of primary glomerulonephritis: evidence for a role of genetic factors.

Chronic glomerulonephritis was diagnosed in 23 patients born in a small valley in Northern Italy and in five additional patients with one parent or a more remote ancestor born in the same area, all belonging to three potentially related families. Eighteen patients had biopsy-proven glomerulonephritis: 11 IgA nephropathy, 3 IgM nephropathy, 2 membranoproliferative type I, and 2 mesangial proliferative glomerulonephritis with isolated C3 deposits. Ten had clinical glomerulonephritis. A community screening programme discovered six additional related patients. Two underwent renal biopsy (1 IgA nephropathy; 1 focal glomerulosclerosis); four were diagnosed as having clinical glomerulonephritis. Genealogical investigation identified five deceased family members with diagnoses of chronic nephritis recorded on their death certificates. No environmental nephrotoxic factors were identified. Restriction fragment length polymorphism (RFLP) analysis of HLA-DR beta, HLA-DQ alpha and beta genes, and complement typing for C4A, C4B, and Bf polymorphisms were carried out for 29 patients, 168 healthy relatives, and 24 local controls. The frequency of HLA-Dw8.1 specificity, related to DR beta 8, DQ beta 3b, and DQ alpha 1a RFLPs, was significantly increased more in the affected and unaffected pedigree members than in Italian controls.