Hypocomplementemic proliferative glomerulonephritis with C3 nephritic-factor-like activity in multiple myeloma

Advanced renal failure, nephrotic-range proteinuria due to proliferative glomerulonephritis and multiple myeloma with circulating IgG2 lambda and free lambda light-chain paraproteins occurred in a 31-year-old male. Commonly established causes of renal failure in multiple myeloma were excluded. Immunofluorescence revealed heavy granular glomerular deposition of C3. Serum C3 was decreased, and C3c was increased. C3 nephritic-factor (C3 NeF)-like activity was demonstrated in the serum. Plasmapheresis and chemotherapy resulted in a decrease in paraprotein concentration up to 90%, a decrease in C3 NeF-like activity to negligible, normal serum complement levels and a marked improvement in both renal function and proteinuria. With reference to the literature, the possibility of a syndrome of paraproteinemia, C3 NeF-like activity and glomerulonephritis is forwarded.     

Eculizumab and recurrent C3 glomerulonephritis

Background

Hyperactivity of the alternative complement pathway is the principle defect in C3 glomerulopathies (C3G). Eculizumab, a monoclonal antibody that binds C5 to prevent formation of the membrane attack complex, has been shown to be beneficial in some patients with this disease.

Methods

In this open-label, proof-of-concept efficacy-and-safety study, a patient with the initial diagnosis of dense deposit disease (DDD) and allograft recurrence of C3 glomerulonephritis (C3GN) was treated with eculizumab every other week for 1 year. The patient had pathological evidence of C3GN and proteinuria >1 g/day at enrollment. He underwent graft biopsy before enrollment and repeat biopsy at 6 and 12 months.

Results

Although no mutations were identified in complement genes, functional studies were positive for C3 nephritic factors and elevated levels of soluble membrane attack complex (sMAC). On therapy, sMAC levels normalized and although proteinuria initially decreased, it increased reaching pre-treatment levels at 12 months. Although serum creatinine remained stable, repeat allograft biopsies showed progression of disease.

Conclusions

Clinical and histopathologic data suggest a partial response to eculizumab in this patient. While eculizumab blocked activation of the terminal complement cascade, persistent dysregulation of the alternative pathway remained, indicating eculizumab alone cannot control disease in this patient. Additional research is required to identify effective anticomplement therapy for this group of C3G patients.     

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.     

Rapidly progressive,pauci-immune diffuse crescentic glomerulonephritis in an infant

A Japanese male infant presented with nephrotic syndrome at 41 days. His renal function progressively deteriorated, and he died at 4 months of the age. An open renal biopsy revealed diffuse crescentic glomerulonephritis (CrGN) without immune complex deposition, which is not characteristic of the congenital nephrotic syndrome (CNS). Examination for nephrin antigen using rabbit anti-nephrin extra- and intracellular site antibodies was positive. These clinical observations suggest that the patient had a unique histological variant of CNS. This is the first report of rapidly progressive, pauci-immune diffuse CrGN in infancy.     

C3 nephritic factor and mesangiocapillary glomerulonephritis

The association of a C3 splitting activity, known as C3 nephritic factor (C3NeF), with mesangiocapillary glomerulonephritis (MCGN), especially MCGN type II, has long been known. Several forms of C3NeF are now recognised, the main one being an IgG which acts as an autoantibody binding to factor H, a normally occurring component of the complement system. Complement is in a continuous state of activation with inbuilt checks and controls, and factor H plays a very important part in the controlling mechanisms by preventing the overwhelming activation of complement at the stage of C3 conversion. C3NeF binds to factor H, thus preventing its inhibitory action, and allowing complement activation to proceed with, in vivo, the well-known consequences in MCGN of very low serum levels of C3. The question naturally arose whether C3NeF causes MCGN. Complex relationships between MCGN, C3NeF and partial lipodystrophy, also characterised by C3NeF and hypocomplementaemia, but preceding the development of MCGN, suggest that hypocomplementaemia predisposes to MCGN. Another possibility is that C3NeF acts directly within glomeruli to cause local complement activation and ensuing damage. Neither possibility could be resolved, but some recent observations have restimulated interest in a possible causative role for C3NeF in MCGN. First, factor H deficiency, by mechanisms other than blocking by C3NeF, in animals and man is associated with MCGN. Second, adipocytes, now known themselves to produce complement system proteins, are lysed in vitro by C3NeF, thus suggesting a mechanism for partial lipodystrophy. By analogy, the C3NeF may produce glomerular damage, as glomerular cells produce complement components. Received July 18, 1996; accepted July 24, 1996     

Anaesthesia and breast-feeding--the effect on mother and infant.

In this paper, we summarise the physiology of lactation and discuss the pathophysiology brought about by fasting, stress and anaesthetic drugs. Drug secretion into breast milk and subsequent absorption by the infant is considered. Maternal hydration must be well maintained with intravenous fluids, allowing an added 500 to 1000 ml for daily fluid loss in lactation. Maternal premedication, general anaesthesia and routine postoperative analgesics are also discussed as to the effects on the breast-fed infant. Drug side-effects may be avoided by timing breast feeding just before the next due dose. Sedatives with long half-lives should not be used. Endocrine and metabolic responses to anaesthesia and surgery are less with regional anaesthesia than with general, hence regional anaesthesia is preferred where it is a reasonable alternative technique.     

Crescentic and necrotizing glomerulonephritis with C3 deposition

Case 1: A 38-year-old female with a history of tonsillitis and sinusitis was admitted to our hospital because of lung edema. On admission, her serum creatinine increased to 5.57 mg/dL. Hypocomplementemia was not found. ASO and MPO-ANCA were 24 U/mL and 12 EU, respectively. She underwent emergency hemodialysis. Renal biopsy showed global sclerosis and fibrocellular crescentic formation, and marked angionecrosis was noted by light microscopy. Granular deposition of C3, IgG and IgM was seen along the capillary walls on immunofluorescence study. Glomerular intramembranous deposits were scattered on electron microscopy. She was treated with intravenous methylprednisolone pulse therapy, and following oral prednisolone administration was decreased gradually. No therapeutic effects were observed, and intermittent hemodialysis was continued and became maintenance hemodialysis therapy. Case 2: A 28-year-old female suffering from both pharyngitis and acute renal failure with systemic edema was admitted to our hospital. On admission, her serum creatinine and ASO were 4.31 mg/dL and 239 U/mL, respectively. MPO-ANCA was negative and CH50 was normal. Hemodialysis was initiated on the 6th hospital day. In renal biopsy, most glomeruli showed cellular crescentic formation, and marked angionecrosis was noted by light microscopy. Global sclerosis was not found in this case. Granular deposition of C3 resembling a starry sky pattern was seen along the capillary walls on immunofluorescence study. Electron microscopy revealed scattered glomerular subepithelial deposits. She was treated with intravenous methylprednisolone pulse therapy and then oral prednisolone administration. Because of the gradual improvement in renal function, hemodialysis was terminated after 53 sessions, however, the patient's chronic renal failure has persisted to date. In these two cases, the pathological findings supported the diagnosis of severe acute post-infectious glomerulonephritis with the characteristic crescentic and necrotizing glomerulonephritis with C3 deposition.     

Extrahepatic biliary atresia and caudal regression syndrome in an infant of a diabetic mother

Although most cases of extrahepatic biliary atresia are thought to result from perinatal obliterating inflammation, some are associated with a faulty morphogenesis. The authors report on a baby girl of a mother with ill-managed insulin-dependent diabetes mellitus. The baby presented with sacro-coccygeal agenesis, clubfoot, and ano-urinary incontinence. In addition, there was polysplenia, no inferior vena cava, and the portal vein was grossly distorted. Progressive conjugated hyperbilirubinemia prompted liver biopsy at 4 weeks of age, showing intracanalicular cholestasis without fibrosis. The diagnosis of extrahepatic biliary atresia was confirmed during laparotomy performed for hepatoportojejunostomy. Some cases of extrahepatic biliary atresia might be part of a spectrum of malformations associated with maternal diabetes mellitus.     

Differences in clinical findings,pathology, and outcomes between C3 glomerulonephritis and membranoproliferative glomerulonephritis

Background

To clarify the clinical manifestations of pediatric complement component C3 glomerulonephritis (C3GN), we retrospectively evaluated differences in the clinicopathological findings and prognosis between C3GN and immune-complex-mediated membranoproliferative glomerulonephritis (IC-MPGN).

Methods

Thirty-seven patients diagnosed with “idiopathic MPGN” were enrolled in this retrospective study. The patients were divided into two groups, with Group 1 consisting of 19 patients diagnosed with IC-MPGN and Group 2 consisting of 18 patients diagnosed with C3GN. The clinical findings and the prognosis were investigated for both groups.

Results

Thirteen patients in Group 2 were identified by mandatory annual school screening for urinary abnormalities. The incidence of macro-hematuria and the frequency of low serum C4 values were lower in Group 2 patients than in Group 1 patients. At the time of the second renal biopsy, urinary protein excretion, incidence of hematuria, frequency of low serum C3 values, and scores for mesangial proliferation, glomerular sclerosis, and interstitial fibrosis were higher in Group 2 patients than in Group 1 patients. At the most recent follow-up examination, the number of patients categorized as non-responding or with end-stage renal disease was higher in Group 2 patients than in Group 1 patients.

Conclusions

Our results suggest that the treatment response and prognosis of patients with C3GN are worse than those of patients with IC-mediated MPGN. Therefore, in the clinical context regarding treatment options and prognosis, it may be useful to classify idiopathic MPGN as C3GN or IC-MPGN. In addition, long-term follow-up of C3GN is necessary.

     

C3 metabolism in acute glomerulonephritis: implications for sites of complement activation

Immunochemical and metabolic studies of complement were performed in 11 patients with acute poststreptococcal glomerulonephritis (AGN) to determine the mechanism(s) of hypocomplementemia. Four patients with profound reduction in serum C3 showed metabolic changes comparable to those seen in hypocomplementemic mesangiocapillary GN (MCGN), that is, nonlinear plasma disappearance of 125I.C3 and a gross (that is, 30-fold) reduction in C3 synthesis (0.01 to 0.02 mg/kg/hr); fractional catabolic rate (FCR) and extravascular/intravascular distribution (EV/IV) ratio were also increased (3.02 to 6.99%/hr; 1.14 to 2.96, respectively). The remaining seven patients had less (or no) reduction in C3 and showed normal or elevated values for all three metabolic parameters; six had linear plasma disappearance curves. Metabolic data in five simultaneously studied control subjects were FCR: 1.56 to 2.12%/hr; EV/IV ratio: 0.12 to 0.41 and synthesis rate: 0.30 to 0.52 mg/kg/hr. C3 nephritic factor (NeF) could not be detected in any sera and a significant reduction in serum C5 accompanied the changes in C3 (r = 0.89; P less than 0.001). Previous studies of C3 NeF-associated MCGN show that the fluid phase alternative pathway convertase seen in this condition has little or no C5 cleaving ability. We propose, therefore, that complement activation in AGN occurs via a surface-bound convertase which is capable of cleaving both C3 and C5. The glomerular capillary could provide such a site for activation.     

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。     

Hypocomplementemic type II membranoproliferative glomerulonephritis in a male patient with familial lecithin-cholesterol acyltransferase deficiency due to two different allelic mutations.

Patients with familial lecithin-cholesterol acyltransferase (LCAT) deficiency very often show progressive glomerulosclerosis with evolution to end-stage disease. High levels of an abnormal lipoprotein (lipoprotein X) cause glomerular capillary endothelial damage. The ultrastructural study of renal biopsy specimens shows characteristic glomerular deposits of membrane-like, cross-striated structures and vacuole structures. The gene encoding for LCAT has been mapped to chromosome 16q22.1, and several mutations of this gene cause LCAT deficiency which is inherited as an autosomal recessive trait and which is characterized by corneal opacities, normochromic normocytic anemia, and renal dysfunction. Herein we report clinical features and renal histological findings concerning a 24-year-old male patient with classical familial LCAT deficiency due to two different allelic mutations: a nonsense mutation inherited from the father and a missense mutation inherited from the mother. Moreover, the patient showed glomerular histological lesions and an immunofluorescent glomerular pattern typical of hypocomplementemic membranoproliferative type II glomerulonephritis (dense-deposit disease). The nature of electron-dense material that characterizes dense-deposit disease is still unknown, but there are suggestions that some chemical modifications might occur in the renal basement membranes. Therefore, this clinical case might induce to consider possible relations between disorders of the lipoprotein metabolism and renal dense-deposit disease.     

Membranoproliferative glomerulonephritis with C3NeF and genetic complement dysregulation

The development of membranoproliferative glomerulonephritis (MPGN) is associated with uncontrolled activation of the complement alternative pathway. This dysregulation is related either to C3 nephritic factor (C3NeF), an auto-antibody directed against the alternative C3 convertase, or to homozygous loss-of-function mutation of the complement regulatory protein factor H. Heterozygous mutations in the genes coding for factor H, or for the other alternative pathway inhibitory proteins factor I and membrane cofactor protein, have recently been identified in a small number of patients with MPGN with exclusive C3 deposits. We report three hypocomplementemic children with dense deposit disease (n = 1) or immune-complex-mediated MPGN type I (n = 2), associated with both C3NeF activity and heterozygous mutation of factor H or factor I. These observations highlight the possible combination of genetic and acquired defect in complement control in various subtypes of MPGN, a finding that may influence the treatment strategy in some patients.     

C3 Glomerulopathy and post-infectious glomerulonephritis define a disease spectrum

Background

Post-infectious glomerulonephritis (PIGN) usually follows a benign course, but few children have an atypical, severe presentation, and these exceptional cases have been linked to the dysregulation of the complement alternative pathway (CAP). There is a considerable overlap in the histopathological features of PIGN and C3 glomerulopathy (C3G), which is also associated with CAP dysregulation but has a poorer outcome. We hypothesized that PIGN and C3G define a disease spectrum, and that in the past there may be some children with C3G who were misclassified with PIGN before C3G was described as a separate disease entity.

Methods

Children with PIGN (n?=?33) diagnosed between 1985 and 2010 who underwent a renal biopsy due to their unusual course were reviewed and of them, 8 were reclassified into C3G based on the current classification criteria. Outcome was based on the degree of proteinuria, C3 level, and renal function at follow-up.

Results

Sixteen (72.7%) children with typical PIGN recovered completely as compared to only 2 (25%) with C3G. Of note, children with “typical” PIGN had a more severe disease course at onset; however, the outcome at last follow up was favorable.

Conclusions

Our results support the hypothesis that PIGN and C3G form a disease spectrum and have different long-term clinical implications and management strategies.

     

Membranoproliferative glomerulonephritis and C3 glomerulopathy: resolving the confusion

Membranoproliferative glomerulonephritis (MPGN) denotes a general pattern of glomerular injury that is easily recognized by light microscopy. With additional studies, MPGN subgrouping is possible. For example, electron microscopy resolves differences in electron-dense deposition that are classically referred to as MPGN type I (MPGN I), MPGN II, and MPGN III, while immunofluorescence typically detects immunoglobulins in MPGN I and MPGN III but not in MPGN II. All three MPGN types stain positive for complement component 3 (C3). Subgrouping has led to unnecessary confusion, primarily because immunoglobulin-negative MPGN I and MPGN III are more common than once recognized. Together with MPGN II, which is now called dense deposit disease, immunoglobulin-negative, C3-positive glomerular diseases fall under the umbrella of C3 glomerulopathies (C3G). The evaluation of immunoglobulin-positive MPGN should focus on identifying the underlying trigger driving the chronic antigenemia or circulating immune complexes in order to begin disease-specific treatment. The evaluation of C3G, in contrast, should focus on the complement cascade, as dysregulation of the alternative pathway and terminal complement cascade underlies pathogenesis. Although there are no disease-specific treatments currently available for C3G, a better understanding of their pathogenesis would set the stage for the possible use of anti-complement drugs.