Monoclonal Gammopathy of Renal Significance Causes C3 Glomerulonephritis Via Monoclonal IgG Kappa Inhibition of Complement Factor H.
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ABSTRACT:
SUBMITTER: Johnson CK
PROVIDER: S-EPMC8418982 | biostudies-literature | 2021 Sep
REPOSITORIES: biostudies-literature
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Monoclonal Gammopathy of Renal Significance Causes C3 Glomerulonephritis Via Monoclonal IgG Kappa Inhibition of Complement Factor H.
Johnson Christopher K CK Zuniga Sandra Carias SC Dhawale Tejaswini T Zhang Yuzhou Y Smith Richard J H RJH Blosser Christopher D CD
Kidney international reports 20210627 9
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Project description:BackgroundC3 glomerulonephritis (GN) is a proliferative GN resulting from glomerular deposition of complement factors due to dysregulation of the alternative pathway of complement. Dysregulation of the alternative pathway of complement may occur as a result of mutations or functional inhibition of complement-regulating proteins. Functional inhibition of the complement-regulating proteins may result from a monoclonal gammopathy.Study designCase series.Setting & participants32 Mayo Clinic patients with C3 GN, 10 (31%) of whom had evidence of a monoclonal immunoglobulin in serum.OutcomesClinical features, hematologic and bone marrow biopsy findings, kidney biopsy findings, kidney measures, complement pathway abnormalities, treatment, and follow-up of patients with C3 GN that was associated with a monoclonal gammopathy.ResultsMean age of patients with C3 GN associated with monoclonal gammopathy was 54.5 years. Bone marrow biopsy done in 9 patients revealed monoclonal gammopathy of undetermined significance in 5 patients, small lymphocytic lymphoma/chronic lymphocytic leukemia in one patient, and no abnormal clones in the other 3 patients. Kidney biopsy showed membranoproliferative GN with bright capillary wall C3 staining in all 10 patients. Evaluation of the alternative pathway of complement showed abnormalities in 7 of 9 patients tested. No mutation in complement-regulating proteins was detected in any patient. As an index case, one patient with C3 GN and chronic lymphocytic leukemia was treated with rituximab, cyclophosphamide, vincristine, and prednisone, and one patient with C3 GN and monoclonal gammopathy of undetermined significance was treated with dexamethasone and bortezomib. Both patients showed significant decreases in hematuria and proteinuria and stabilization of kidney function.LimitationsStudies to show evidence of direct activation of the alternative pathway by monoclonal immunoglobulin were not done.ConclusionsThe study highlights the association of C3 GN and monoclonal gammopathy, in particular in the older population, and the importance of targeting the underlying hematologic malignancy as an approach to treating C3 GN.
| S-EPMC4435575 | biostudies-literature
Project description:BACKGROUND AND OBJECTIVES: Glomerular deposition of monoclonal Ig has been exceptionally described as the cause of membranoproliferative glomerulonephritis, through activation of the complement alternative pathway (CAP). DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We retrospectively studied six adults with monoclonal gammopathy and glomerulonephritis (GN) characterized by isolated C3 deposits. RESULTS: All patients presented with hematuria, associated with chronic renal failure and proteinuria in five patients, three of whom had nephrotic syndrome. Five patients had monoclonal gammopathy of undetermined significance and one had smoldering myeloma. The serum monoclonal IgG (κ four of six, λ two of six) was associated with light chain (LC) proteinuria in five patients. Four patients had low serum C3 and/or factor B levels. C4, factor H (CFH), and I protein levels were normal in five of five patients; none had detectable C3NeF. IgG anti-CFH activity was positive in one case. No mutations in CFH, CFI, and MCP genes were identified in four of four patients. Deposits were intramembranous, subepithelial, and mesangial by electron microscopy, and stained positive for C3 (six of six), properdin, and CFH (two of two) but negative for Ig LC and heavy chains, C4, and C1q (6/6) by immunofluorescence. Five patients progressed to end-stage renal disease over a median period of 47 months, despite chemotherapy in four patients. In one patient, monoclonal λLC deposits were observed on a follow-up kidney biopsy after 4 years. CONCLUSIONS: GN with isolated glomerular C3 deposits might represent an unusual complication of plasma cell dyscrasia, related to complement activation through an autoantibody activity of the monoclonal Ig against a CAP regulator protein.
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Project description:C3 glomerulopathy (C3G) results from acquired or genetic abnormalities in the complement alternative pathway (AP). C3G with monoclonal immunoglobulin (MIg-C3G) was recently included in the spectrum of "monoclonal gammopathy of renal significance." However, mechanisms of complement dysregulation in MIg-C3G are not described and the pathogenic effect of the monoclonal immunoglobulin is not understood. The purpose of this study was to investigate the mechanisms of complement dysregulation in a cohort of 41 patients with MIg-C3G. Low C3 level and elevated sC5b-9, both biomarkers of C3 and C5 convertase activation, were present in 44 and 78% of patients, respectively. Rare pathogenic variants were identified in 2/28 (7%) tested patients suggesting that the disease is acquired in a large majority of patients. Anti-complement auto-antibodies were found in 20/41 (49%) patients, including anti-FH (17%), anti-CR1 (27%), anti-FI (5%) auto-antibodies, and C3 Nephritic Factor (7%) and were polyclonal in 77% of patients. Using cofactor assay, the regulation of the AP was altered in presence of purified IgG from 3/9 and 4/7 patients with anti-FH or anti-CR1 antibodies respectively. By using fluid and solid phase AP activation, we showed that total purified IgG of 22/34 (65%) MIg-C3G patients were able to enhance C3 convertase activity. In five documented cases, we showed that the C3 convertase enhancement was mostly due to the monoclonal immunoglobulin, thus paving the way for a new mechanism of complement dysregulation in C3G. All together the results highlight the contribution of both polyclonal and monoclonal Ig in MIg-C3G. They provide direct insights to treatment approaches and opened up a potential way to a personalized therapeutic strategy based on chemotherapy adapted to the B cell clone or immunosuppressive therapy.
| S-EPMC6175995 | biostudies-literature
Project description:The clinical spectrum of diseases associated with monoclonal gammopathies is wide and they are most commonly the consequence of renal deposition of monoclonal immunoglobulin or its components. The differential diagnosis is difficult and renal biopsy is essential. To distinguish many of these pathologies is necessary to use techniques that are not always available, even in tertiary central hospitals. This review will discuss the clinical presentation, pathologic features, treatment, prognosis and common diagnostic difficulties of these entities.
| S-EPMC5339639 | biostudies-other
Project description:We report a case of monoclonal gammopathy of renal significance in a 63-year-old man who presented with nephrotic-range proteinuria and renal insufficiency. The kidney biopsy showed a membranoproliferative glomerulonephritis pattern with extensive crystalloid deposits in the glomerular capillary endothelial cells and very few in the tubular epithelial cells. The immunoperoxidase staining showed kappa light chain restriction. Subsequently, the bone marrow showed 6% plasma cells which confirmed the diagnosis of monoclonal gammopathy of renal significance. He responded well to bortezomib treatment with resolution of the nephrotic syndrome and normalization of renal function after 7 months.
| S-EPMC4377747 | biostudies-literature
Project description:Recent years have witnessed a rapid growth in our understanding of the pathogenic property of monoclonal proteins. It is evident that some of these small monoclonal proteins are capable of inducing end-organ damage as a result of their intrinsic physicochemical properties. Hence, an umbrella term, monoclonal gammopathy of clinical significance (MGCS), has been coined to include myriad conditions attributed to these pathogenic proteins. Because kidneys are the most commonly affected organ (but skin, peripheral nerves, and heart can also be involved), we discuss MGRS exclusively in this review. Mechanisms of renal damage may involve direct or indirect effects. Renal biopsy is mandatory and demonstration of monoclonal immunoglobulin in kidney, along with the corresponding immunoglobulin in serum or urine, is key to establish the diagnosis. Pitfalls exist at each diagnostic step, and a high degree of clinical suspicion is required to diagnose MGRS. Recognition of MGRS by hematologists and nephrologists is important, because timely clone-directed therapy improves renal outcomes. Autologous stem cell transplant may benefit selected patients.
| S-EPMC6693003 | biostudies-literature
Project description:Renal disease associated with paraproteinemias is classically predicated upon pathologic paraprotein deposition in the kidney. However, growing evidence suggests that paraproteins may be able to systemically activate complement or neutrophils to drive renal damage. This may provide an alternative pathologic mechanism for renal injury in rare cases.We report a case of a patient with crescentic pauci-immune glomerulonephritis presenting with rapidly progressive renal failure, polyarthropathy, and a purpuric rash in association with a monoclonal immunoglobulin G ?-light-chain producing multiple myeloma. Serum anti-neutrophil cytoplasmic antibodies were not detected. Kidney biopsy, including with Pronase digestion, did not reveal pathologic paraprotein deposition. Two previously published similar case reports are also discussed.We propose a novel pathologic mechanism involving monoclonal proteins as a trigger for pauci-immune glomerulonephritis, potentially via complement dysregulation and/or neutrophil activation. This requires further epidemiologic and mechanistic study.
| S-EPMC5642763 | biostudies-other
Project description:Monoclonal gammopathy of undetermined significance (MGUS) is a benign but precancerous condition that can progress to multiple myeloma. Patients with MGUS are typically monitored closely for signs of disease progression, but in some cases, they may also develop renal insufficiency, a condition known as monoclonal gammopathy of renal significance (MGRS). In MGRS, M-protein secreted by a nonmalignant or premalignant cell clone triggers renal damage by definition. Herein, we report a case of a 66-year-old Asian male with MGUS complicated by renal insufficiency. A kidney biopsy showed no evidence of renal injury mediated by M-protein; instead, the direct infiltration of clonal cells into renal tissues was observed. Although five similar cases have been previously reported, our case is unique in that the involvement of clonal cells was directly confirmed by fluorescence in situ hybridization. Our findings suggest the need to consider a novel disease concept, as this phenomenon appears to be reproduced.
| S-EPMC10435693 | biostudies-literature
Project description: Not available
| S-EPMC6732723 | biostudies-literature
Project description:PurposeDiagnostic criteria for monoclonal gammopathy of undetermined significance (MGUS) do not currently include ocular phenotypic changes. Here, we offer a new diagnostic approach that is useful in patients with posteriorly located corneal depositions and present evidence to support the theory that the aqueous humor is a source for monoclonal proteins accumulated in the cornea.ObservationsA 77-year-old woman presented to the clinic with a gradual decrease in visual acuity over 6 months. Slit lamp examination revealed bilateral central guttae consistent with Fuchs corneal dystrophy, peripheral circular band-like corneal opacities in the deep stroma, and bilateral nuclear sclerotic and cortical cataracts. Anterior segment optical coherence tomography confirmed corneal opacities in the posterior stroma and Descemet membrane. Immunological studies revealed increased serum IgG levels of 3220 mg/dL and serum electrophoresis showed an abnormal monoclonal band of 2.4 g/dL identified as IgG lambda by immunofixation electrophoresis. The patient was referred to the hematology clinic where she underwent further systemic workup and was diagnosed with MGUS. Immunofixation electrophoresis of aqueous sampling, which was performed at the time of cataract surgery, confirmed the presence of the IgG lambda gammopathy in the anterior chamber.Conclusions and importanceMonoclonal gammopathy, although rare, should be included in the differential diagnosis of corneal opacities, as the ocular finding can be the initial manifestation of a systemic disease that can potentially be life-threatening. When corneal biopsy is not feasible due to the location of corneal pathology, aqueous sampling may be an alternative approach towards a clinical diagnosis. We propose a new terminology, "monoclonal gammopathy of ocular significance," for patients diagnosed with MGUS, however, their only significant clinical finding is ocular manifestation.
| S-EPMC6535680 | biostudies-literature