Recurrent allograft C3 glomerulonephritis and unsuccessful eculizumab treatment.

There is a great lack of efficient treatments for membranoproliferative glomerulonephritis (MPGN) and recently emerged complement therapies have been proposed to be useful. We report a patient with a complement-mediated MPGN having recurrencies in kidney allografts and an unsuccessful treatment with complement inhibitor, eculizumab (anti-C5 monoclonal antibody). Nephritic factor (C3Nef), an autoantibody against C3bBb, in the patient serum activated C3 but not C5 showing that major damage was mediated by C3 activation with clearly less involvement of C5 explaining unresponsiveness to eculizumab. Analyzing C3Nef-mediated C3 and C5 activation separately could help in choosing the right patients for eculizumab therapy.

C4 Nephritic Factors in C3 Glomerulopathy: A Case Series.

BACKGROUND: C3 glomerulopathy (C3G) defines a group of rare complement-mediated kidney diseases with a shared underlying pathophysiology: dysregulation of complement in the fluid phase and glomerular microenvironment. Dysregulation can be driven by autoantibodies to C3 and C5 convertases. STUDY DESIGN: Case series. SETTING & PARTICIPANTS: 168 patients with C3G (dense deposit disease, 68; C3 glumerulonephritis, 100) selected from our C3G biobank. OUTCOMES: Patient-purified immunoglobulin Gs were tested for C4 nephritic factors (C4NeFs). These autoantibodies recognize C4b2a, the C3 convertase of the classical pathway of complement. MEASUREMENTS: C4NeFs were detected using a modified hemolytic assay. RESULTS: C4NeFs were identified in 5 patients, 4 of whom had C3 glomerulonephritis. C4NeFs were associated with dysregulation of C3 and C5 convertases, and they appear to stabilize these convertases in a dose-dependent manner. C4NeFs also appear to protect C4b2a from decay mediated by soluble CR1 and C4 binding protein. The stabilizing activity of the autoantibodies was further demonstrated by using heat treatment to inactivate complement. C4NeFs were not detected in 150 patients with another complement-mediated kidney disease, atypical hemolytic uremic syndrome. They were also absent in 300 apparently healthy controls. LIMITATIONS: In addition to C4NeFs, 2 patients had positive findings for other autoantibodies: one patient also had autoantibodies to factor H; the other patient also had autoantibodies to C3bBb (C3NeFs). CONCLUSIONS: The finding of C4NeFs in a small percentage of patients with C3G highlights the challenge in identifying autoantibodies that drive complement dysregulation and underscores the complexity of the autoantibody repertoire that can be identified in these patients.

Dense deposit disease in a child with febrile sore throat.

Dense deposit disease or membranoproliferative glomerulonephritis type II is a rare glomerulopathy characterized on renal biopsy by deposition of abnormal electron-dense material in the glomerular basement membrane. The pathophysiologic basis is uncontrolled systemic activation of the alternate pathway of the complement cascade. C3 nephritic factor, an autoantibody directed against the C3 convertase of the alternate pathway, plays a key role. In some patients, complement gene mutations have been identified. We report the case of a child who had persistent microscopic hematuria, proteinuria, and hypocomplementemia C3 for over 2 months. Renal biopsy confirmed the diagnosis of dense deposit disease.

Rituximab fails where eculizumab restores renal function in C3nef-related DDD.

BACKGROUND: Dense deposit disease (DDD), a C3 glomerulopathy (C3G), is a rare disease with unfavorable progression towards end-stage kidney disease. The pathogenesis of DDD is due to cytotoxic effects related to acquired or genetic dysregulation of the complement alternative pathway, which is at times accompanied by the production of C3 nephritic factor (C3NeF), an auto-antibody directed against the alternative C3 convertase. Available treatments include plasma exchange, CD20-targeted antibodies, and a terminal complement blockade via the anti-C5 monoclonal antibody eculizumab. CASE-DIAGNOSIS/TREATMENT: We report here the case of an 8-year-old child with C3NeF and refractory DDD who presented with a nephritic syndrome. She tested positive for C3NeF activity; C3 was undetectable. Genetic analyses of the alternative complement pathway were normal. Methylprednisolone pulses and mycophenolate mofetil treatment resulted in complete recovery of renal function and a reduction in proteinuria. Corticosteroids were tapered and then withdrawn. Four months after corticosteroid discontinuation, hematuria and proteinuria recurred, and a renal biopsy confirmed an active DDD with a majority of extracapillary crescents. Despite an increase in immunosuppressive drugs, including methylprednisolone pulses and rituximab therapy, the patient suffered acute renal failure within 3 weeks, requiring dialysis. Eculizumab treatment resulted in a quick and impressive response. Hematuria very quickly resolved, kidney function improved, and no further dialysis was required. The patient received bimonthly eculizumab injections of 600 mg, allowing for normalization of renal function and reduction of proteinuria to <0.5 g per day. Since then, she continues to receive eculizumab. CONCLUSION: Complement regulation pathway-targeted therapy may be a specific and useful treatment for rapidly progressing DDD prior to the development of glomerulosclerosis. Our data provide evidence supporting the pivotal role of complement alternative pathway abnormalities in C3G with DDD.

Proliferative glomerulonephritis secondary to dysfunction of the alternative pathway of complement.

BACKGROUND AND OBJECTIVES: dense deposit disease (DDD) is the prototypical membranoproliferative glomerulonephritis (MPGN), in which fluid-phase dysregulation of the alternative pathway (AP) of complement results in the accumulation of complement debris in the glomeruli, often producing an MPGN pattern of injury in the absence of immune complexes. A recently described entity referred to as GN with C3 deposition (GN-C3) bears many similarities to DDD. The purpose of this study was to evaluate AP function in cases of GN-C3. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Five recent cases of MPGN with extensive C3 deposition were studied. Renal biopsy in one case exhibited the classic findings of DDD. Three cases showed GN-C3 in the absence of significant Ig deposition; however, the classic hallmark of DDD-dense deposits along the glomerular basement membranes and mesangium-was absent. The remaining case exhibited features of both DDD and GN-C3. RESULTS: Evidence of AP activation was demonstrable in all cases and included increased levels of soluble membrane attack complex (all cases), positive AP functional assays (four cases), and a positive hemolytic assay (one case). Autoantibodies were found to C3 convertase (two cases) and to factor H (one case). Factor H mutation screening identified the H402 allele (all cases) and a c.C2867T p.T956M missence mutation (one case). Laser microdissection and mass spectrometry of glomeruli of GN-C3 (two cases) showed a proteomic profile very similar to DDD. CONCLUSIONS: These studies implicate AP dysregulation in a spectrum of rare renal diseases that includes GN-C3 and DDD.

Composition of nephritic factor-generated glomerular deposits in membranoproliferative glomerulonephritis type 2.

Two observations suggest that nephritic factors (NFs) may be nephritogenic. First, glomerulonephritis is present in unusual frequency in three conditions in which the function of factor H is blocked, a dysfunction also produced by NFS: Second, in membranoproliferative glomerulonephritis (MPGN) type 2, subepithelial deposits on the paramesangial portion of the glomerular basement membrane are found only in renal biopsy specimens obtained during hypocomplementemia when NF is presumably present. In the present study, the composition of these deposits with respect to C3 derivatives was assessed by immunohistological evaluation using anti-C3c and anti-C3d. The assessment used routinely obtained photomicrographs, as well as immunohistologic examination of freshly cut tissue using the double-antibody method. Deposits in patients with typical hypocomplementemic MPGN type 2 reacted only with anti-C3c, whereas those in two patients with rapidly progressive MPGN type 2, six patients with poststreptococcal acute glomerulonephritis, and five patients with juvenile acute nonproliferative glomerulitis reacted with anti-C3d, as well as anti-C3c. Because all products derived from the breakdown of C3 except C3c react with anti-C3d, the deposits in typical MPGN type 2 must be composed only of C3c. With complete breakdown of bound C3b, C3c is released into the fluid phase. Therefore, the C3c in the deposits cannot be a product of a glomerular complement reaction, but instead must be formed in the circulation by the reaction of NF with native C3. Supporting C3c as the only constituent of these deposits is the observation that they are devoid of properdin and C5 is present in only small amounts.

Nucleotide sequence of a human autoantibody to the alternative pathway C3/C5 convertase (C3NeF).

The production of autoantibodies to the alternative pathway C3/C5 convertase or C3 Nephritic Factor (C3NeF) is one characteristic of membranoproliferative glomerulonephritis. The complete nucleotide sequences of the heavy and light chain variable regions of an IgG C3NeF produced by an EBV transformed B cell line derived from a patient with membranoproliferative glomerulonephritis were determined. The VH and VL gene segments used by this C3NeF are extensively mutated suggesting that antigenic selection and affinity maturation may occur during the generation of these autoantibodies.

[Chronic urticaria and acquired complement deficiency due to a nephritic factor (C3NeF)]. / Urticaire chronique et hypocomplémentémie acquise due á un facteur néphrétique (C3NeF).

Several studies have suggested that complement activation processes are frequently involved in the pathogenesis of urticaria. We report clinical evolution and studies of complement-mediated functions in a 47-year-old previously described patient presenting with chronic urticaria, in whom we found persistent low complement hemolytic activity (65-75% of normal values), depressed levels of third complement component (C3, between 55% and 65%) and of factor B (between 60% and 75%), together with C1, C4, C2, C5, C5b neoantigen and fluid phase terminal complement (SC5b-9) complex within the normal range, pointing to activation of the alternative pathway. A circulating low affinity C3 nephritic factor (C3NeF), known to enhance cleavage of human serum C3, was detected. The urticarial lesions, which were initially pruritic and persisted for less than 24 hours, became subsequently fixed and burning, and were accompanied by fever and arthralgia. Skin biopsy specimens showed moderate leukocytoclastic vasculitis. Response to varied treatment regimens, including antihistamines and colchicine, was poor. Therapy with oral corticosteroids produced some improvement. The association of chronic urticaria with C3NeF without clinical and biological signs of membranoproliferative glomerulonephritis and partial lipodystrophy has not to our knowledge been reported before. This observation raises the question of a possible role of C3NeF in the pathogenesis of urticaria.

Familial incidence of C3 nephritic factor, partial lipodystrophy and membranoproliferative glomerulonephritis.

C3 nephritic factor is an IgG autoantibody that causes complement activation by stabilizing the alternative pathway C3 convertase. It is associated with partial lipodystrophy and membrano-proliferative glomerulonephritis. The occurrence of C3 nephritic factor, partial lipodystrophy and membranoproliferative glomerulonephritis, whether singly or in any combination, is usually sporadic. We describe the coexistence of all three of these conditions in members spanning two generations of a single family. This suggests that the pathogenesis of these conditions may be linked and that genetically determined factors may, in some circumstances, contribute to disease susceptibility.

The complement system in pediatric renal disease.

A brief review of the classical and the alternative pathways of complement activation is presented. Clinically, according to the complement system, we can divide the children with glomerulonephritis into two groups, normocomplementemic and hypocomplementemic. In addition, inherited complement deficiencies can be identified associated with renal diseases. We discuss the three possible sources of complement in urine, although more control studies are necessary in patients with different causes of proteinuria in order to define the clinical significance of complementuria. The immunohistological results of glomerular nephritic biopsy material by the fluorescence antibody technique is analyzed with respect to clinical diagnosis and evaluation of the treatment. The nature of C3NeF as an antibody to factor B-C3 complex is demonstrated by different groups and in different diseases. Finally, the presence of a receptor for complement in the glomerulus, is explained in human disease by the deposition of immune complexes into the renal glomeruli.