RARE DISEASE
Immunoglobulin-mediated membranoproliferative glomerulonephritis
Immunoglobulin-mediated membranoproliferative glomerulonephritis
Immunoglobulin-mediated membranoproliferative glomerulonephritis
Synonyms: Ig-mediated MPGN, Ig-mediated membranoproliferative glomerulonephritis, Immunoglobulin-mediated MPGN
Synonyms: Ig-mediated MPGN, Ig-mediated membranoproliferative glomerulonephritis, Immunoglobulin-mediated MPGN
Synonyms: Ig-mediated MPGN, Ig-mediated membranoproliferative glomerulonephritis, Immunoglobulin-mediated MPGN
Drug discovery
2
drugs
With orphan designations
Overview
Immunoglobulin-mediated membranoproliferative glomerulonephritis (Ig-MPGN) is a rare glomerular disease characterized by immune complex deposition in glomeruli, activating classical complement pathways. Histopathology reveals hypercellularity, glomerular basement membrane thickening, and immunoglobulin/complement deposits (C3, IgG) on immunofluorescence [1][2][6]. Clinical presentation ranges from asymptomatic proteinuria/hematuria to nephrotic syndrome (edema, hypoalbuminemia) and acute kidney injury [2][3]. Secondary causes include infections (hepatitis B/C), autoimmune diseases (lupus), and monoclonal gammopathies [1][6]. Diagnosis requires renal biopsy with specialist evaluation [3]. Treatment combines immunosuppression (corticosteroids, mycophenolate) and renin-angiotensin system (RAS) inhibitors, though prognosis remains guarded [8][12].
Categories: rare genetic diseases, rare renal diseases, rare transplant-related disorders
Research Papers
52 drug discovery papers about Immunoglobulin-mediated membranoproliferative glomerulonephritis, with 1 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
52 drug discovery papers about Immunoglobulin-mediated membranoproliferative glomerulonephritis, with 1 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2024-10-01 | Successful Management of Membranoproliferative Glomerulonephritis with Repository Corticotropin Injection
Introduction: Membranoproliferative glomerulonephritis (MPGN) is a pattern of glomerular injury subdivided by light microscopy into immune complex/monoclonal immunoglobulin-mediated, complement-mediated, and MPGN without immunoglobulin or complement deposition. Treating underlying causes is ideal, but idiopathic immune complex MPGN is often managed with immunosuppressive medications. Repository corticotropin injection shows promise in hard-to-treat cases, as illustrated in a successful treatment involving significant psychiatric side effects from steroids. Case Description: A 30-year-old female with MPGN diagnosed at age 16, presented to hospital with lower extremity edema and AKI. Before the presentation she was treated with prednisone 20 mg daily for many years and any attempt to taper prednisone resulted in MPGN flares. She was previously also trialed on mycophenolate with lower dose prednisone, but gastrointestinal side effects led to discontinuation of mycophenolate. She was then treated with repository corticotropin injection with prednisone 5 mg and was stable for two years until she had another flare with urine protein creatinine ratio (UPCR) rising to 3.2 g/g. Increasing prednisone to 50 mg/day temporarily improved UPCR, but severe depression with suicidal ideation prompted cessation of steroids. Subsequently, her renal function declined, with creatinine rising and UPCR reaching 4 g/g. After discontinuing all her medications for six months, severe deterioration ensued, with creatinine at 3.19 and UPCR at 12 g/g. She was admitted to hospital and renal biopsy was done which showed MPGN immune complex. Despite induction therapy with cyclophosphamide and rituximab her UPCR remained at 8.5 g/g after three months. Repository corticotropin injection was initiated at 80 mg biweekly, reducing UPCR to 4.35 g/g in a month and further to 0.75 g/g over three months. Discussion: Our case of difficult-to-treat idiopathic immune complex MPGN responded only to high steroid doses, which were discontinued due to steroid-induced suicidal ideation. Repository corticotropin injection, which stimulates endogenous steroid production, offered lower steroid exposure and fewer side effects. This may be a good option to avoid systemic side effects of steroids in other hard to treat cases.
2022-05-01 | Treatment with bortezomib for recurrent proliferative glomerulonephritis with monoclonal IgG deposits in kidney allograft. Case report and review of the literature
Abstract Proliferative glomerulonephritis with monoclonal immunoglobulin IgG deposits (PGNMID) is an already described form of renal involvement by monoclonal gammopathy. PGNMID is known to recur in kidney allografts. Bortezomib has shown clinical success in the treatment of multiple myeloma. However, its effect for recurrent PGNMID in kidney allografts has rarely been reported. We present the case of a 61-year-old woman who developed recurrent PGNMID 3 weeks after kidney transplantation. This patient was initially treated with steroid pulses (500 mg/day for 2 days) and two cycles of rituximab therapy (200 mg/body). However, disease progression was observed with mesangial matrix expansion and subendothelial deposits by light microscopy and stronger staining for IgG3 and kappa in the mesangial area by Immunofluorescence (IF) microscopy. Thus, we started treatment with bortezomib therapy (1.3 mg/m2, once weekly, on days 1, 8, 15, and 22 in a 5-week cycle, for a total of six cycles). Bortezomib therapy reduced massive proteinuria, although monoclonal immune deposits on IF and the serum creatinine level did not change during the treatment period. Seven months after completion of the first bortezomib course, we decided to prescribe a second course of bortezomib with the same regimen. Each course resulted in a > 50% reduction of proteinuria. Bortezomib may delay the progress of PGNMID in kidney allograft patients.
2019-06-01 | Recurrent membranoproliferative glomerulonephritis in a renal transplant secondary to monoclonal gammopathy of renal significance successfully treated with bortezomib
Internal Medicine JournalVolume 49, Issue 6 p. 801-802 Letters to the Editor Recurrent membranoproliferative glomerulonephritis in a renal transplant secondary to monoclonal gammopathy of renal significance successfully treated with bortezomib Ke Li Chow, Ke Li Chow orcid.org/0000-0002-4589-0735 Department of Nephrology, Monash Medical Centre, Melbourne, Victoria, AustraliaSearch for more papers by this authorJohn Kanellis, John Kanellis Department of Nephrology, Monash Medical Centre, Melbourne, Victoria, AustraliaSearch for more papers by this authorSukhpal Dayan, Sukhpal Dayan Department of Pathology, Monash Medical Centre, Melbourne, Victoria, AustraliaSearch for more papers by this authorJessica Ryan, Jessica Ryan Department of Nephrology, Monash Medical Centre, Melbourne, Victoria, Australia Department of Medicine, Monash University, Melbourne, Victoria, AustraliaSearch for more papers by this author Ke Li Chow, Ke Li Chow orcid.org/0000-0002-4589-0735 Department of Nephrology, Monash Medical Centre, Melbourne, Victoria, AustraliaSearch for more papers by this authorJohn Kanellis, John Kanellis Department of Nephrology, Monash Medical Centre, Melbourne, Victoria, AustraliaSearch for more papers by this authorSukhpal Dayan, Sukhpal Dayan Department of Pathology, Monash Medical Centre, Melbourne, Victoria, AustraliaSearch for more papers by this authorJessica Ryan, Jessica Ryan Department of Nephrology, Monash Medical Centre, Melbourne, Victoria, Australia Department of Medicine, Monash University, Melbourne, Victoria, AustraliaSearch for more papers by this author First published: 11 June 2019 https://doi.org/10.1111/imj.14313Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume49, Issue6June 2019Pages 801-802 RelatedInformation
2018-06-05 | Successful Renal Outcome in Membranoproliferative Glomerulonephritis Following Treatment of the Underlying Subtle Clone: A Case Report
Membranoproliferative glomerulonephritis (MPGN) secondary to a monoclonal gammopathy is a rare glomerular disease and is defined as a monoclonal gammopathy of renal significance. The disease is characterized by glomerular monotypic immunoglobulin deposits and specific changes on light microscopy and electron microscopy. Immunochemistry is required to establish monoclonality, and electron microscopy helps to characterize the deposits ultrastructurally. Investigation for the underlying monoclonal protein should be done. We report a case of MPGN secondary to monoclonal gammopathy of renal significance that responded to treatment of the underlying clone with chemotherapy, resulting in improvement in renal function. Patients with MPGN and immunoglobulin deposition should be evaluated for a monoclonal protein to guide the management strategy.
2012-07-20 | Factor H and Properdin Recognize Different Epitopes on Renal Tubular Epithelial Heparan Sulfate
During proteinuria, renal tubular epithelial cells become exposed to ultrafiltrate-derived serum proteins, including complement factors. Recently, we showed that properdin binds to tubular heparan sulfates (HS). We now document that factor H also binds to tubular HS, although to a different epitope than properdin. Factor H was present on the urinary side of renal tubular cells in proteinuric, but not in normal renal tissues and colocalized with properdin in proteinuric kidneys. Factor H dose-dependently bound to proximal tubular epithelial cells (PTEC) in vitro. Preincubation of factor H with exogenous heparin and pretreatment of PTECs with heparitinase abolished the binding to PTECs. Surface plasmon resonance experiments showed high affinity of factor H for heparin and HS (KD values of 32 and 93 nm, respectively). Using a library of HS-like polysaccharides, we showed that chain length and high sulfation density are the most important determinants for glycosaminoglycan-factor H interaction and clearly differ from properdin-heparinoid interaction. Coincubation of properdin and factor H did not hamper HS/heparin binding of one another, indicating recognition of different nonoverlapping epitopes on HS/heparin by factor H and properdin. Finally we showed that certain low anticoagulant heparinoids can inhibit properdin binding to tubular HS, with a minor effect on factor H binding to tubular HS. As a result, these heparinoids can control the alternative complement pathway. In conclusion, factor H and properdin interact with different HS epitopes of PTECs. These interactions can be manipulated with some low anticoagulant heparinoids, which can be important for preventing complement-derived tubular injury in proteinuric renal diseases.
antibodies
2020-03-01 | Rituximab use in adult glomerulopathies and its rationale
Abstract Glomerulopathies are one of the leading causes of end-stage renal disease. In the last years, clinical research has made significant contributions to the understanding of such conditions. Recently, rituximab (RTX) has appeared as a reasonably safe treatment. The Kidney Disease: Improving Global Outcomes guidelines (KDIGO) recommended RTX only as initial treatment in antineutrophil cytoplasm antibody associated vasculitis (AAV) and in non-responders patients with lupus nephritis (LN), but these guidelines have not been updated since 2012. Nowadays, RTX seems to be at least as effective as other immunosuppressive regimens in idiopathic membranous nephropathy (IMN). In minimal-change disease, (MCD) this drug might allow a long-lasting remission period in steroid-dependent or frequently relapsing patients. Preliminary results support the use of RTX in patients with pure membranous LN and immunoglobulin-mediated membranoproliferative glomerulonephritis (MPGN), but not in patients with class III/IV LN or complement-mediated MPGN. No conclusion can be drawn in idiopathic focal segmental glomerulosclerosis (FSGS) and anti-glomerular basement membrane antibody glomerulonephritis (anti-GBM GN) because studies are small, heterogeneous, and scarce. Lastly, immunosuppression including RTX is not particularly useful in IgA nephropathy. This review presents the general background, outcomes, and safety for RTX treatment in different glomerulopathies. In this regard, we describe randomized controlled trials (RCTs) performed in adults, whenever possible. A literature search was performed using clinicaltrials.gov and PubMed.
2019-02-14 | Complete biopsy-proven resolution of deposits in recurrent proliferative glomerulonephritis with monoclonal IgG deposits (PGNMIGD) following rituximab treatment in renal allograft
Proliferative glomerulonephritis with monoclonal IgG deposits (PGNMIGD) is a disease entity classified under the group of "Monoclonal gammopathy-related kidney diseases", and can recur after transplant. Clinical remission of proteinuria in patients with PGNMIGD has been previously shown following anti-B cell and/or anti-plasma cell therapies. Our case is the first to show complete histologic resolution of the glomerular monoclonal IgG kappa deposits in a case of recurrent PGNMIGD in renal allograft after rituximab and steroid treatment. This is a novel finding and it shows that the deposits are amenable to therapy. This case also highlights the importance of IgG subclass staining in the recognition of the monoclonal nature of the deposits. It is particularly important in PGNMIGD because only 20 to 30% of patients with this disease are reported to have detectable monoclonal gammopathy, and the deposits do not have any organized substructure on electron microscopic examination. Morphologically, they resemble polyclonal immune-type deposits seen in other immune complex glomerulonephritides such as lupus nephritis, infection-associated glomerulonephritis, and membranoproliferative glomerulonephritis (MPGN type I). The patient is a 44 year old Caucasian male who received a living unrelated donor kidney transplant for end-stage renal disease diagnosed 7 years before transplant. The reported native kidney biopsy diagnosis was membranoproliferative glomerulonephritis (MPGN) with IgG, C3 and kappa restricted deposits. Fourteen months post-transplant, he presented with abrupt worsening of graft function, proteinuria and serum IgG kappa monoclonal spike. Allograft biopsy was consistent with recurrent PGNMIGD, considering the native kidney diagnosis and interval post-transplant. He underwent plasmapheresis, IV pooled immune globulin, steroid pulse and taper, and anti-CD-20 Rituximab therapy. Patient had gradual decline in proteinuria and complete resolution of the immune deposits on repeat biopsy 3 months later. Unfortunately he subsequently developed chronic antibody-mediated rejection and transplant glomerulopathy and graft failure 34 months post-transplant. In a transplant setting, repeat allograft biopsies are frequently performed for graft dysfunction. This provides a good opportunity to study the evolution of the immune deposits following treatment. Our case shows complete histologic resolution of the deposits in allograft PGNMIGD.
2018-01-17 | Membranoproliferative glomerulonephritis and C3 glomerulopathy in children: change in treatment modality? A report of a case series
Membranoproliferative glomerulonephritis (MPGN) with immune complexes and C3 glomerulopathy (C3G) in children are rare and have a variable outcome, with some patients progressing to end-stage renal disease (ESRD). Mutations in genes encoding regulatory proteins of the alternative complement pathway and of complement C3 (C3) have been identified as concausative factors.Three children with MPGN type I, four with C3G, i.e. three with C3 glomerulonephritis (C3GN) and one with dense deposit disease (DDD), were followed. Clinical, autoimmune data, histological characteristics, estimated glomerular filtration rate (eGFR), proteinuria, serum C3, genetic and biochemical analysis were assessed.The median age at onset was 7.3 years and the median eGFR was 72 mL/min/1.73 m2. Six children had marked proteinuria. All were treated with renin-angiotensin-aldosterone system (RAAS) blockers. Three were given one or more immunosuppressive drugs and two eculizumab. At the last median follow-up of 9 years after diagnosis, three children had normal eGFR and no or mild proteinuria on RAAS blockers only. Among four patients without remission of proteinuria, genetic analysis revealed mutations in complement regulator proteins of the alternative pathway. None of the three patients with immunosuppressive treatment achieved partial or complete remission of proteinuria and two progressed to ESRD and renal transplantation. Two patients treated with eculizumab revealed relevant decreases in proteinuria.In children with MPGN type I and C3G, the outcomes of renal function and response to treatment modality show great variability independent from histological diagnosis at disease onset. In case of severe clinical presentation at disease onset, early genetic and biochemical analysis of the alternative pathway dysregulation is recommended. Treatment with eculizumab appears to be an option to slow disease progression in single cases.
2016-12-15 | Complement related kidney diseases: Recurrence after transplantation
The recurrence of renal disease after renal transplantation is becoming one of the main causes of graft loss after kidney transplantation. This principally concerns some of the original diseases as the atypical hemolytic uremic syndrome (HUS), the membranoproliferative glomerulonephritis (MPGN), in particular the MPGN now called C3 glomerulopathy. Both this groups of renal diseases are characterized by congenital (genetic) or acquired (auto-antibodies) modifications of the alternative pathway of complement. These abnormalities often remain after transplantation because they are constitutional and poorly influenced by the immunosuppression. This fact justifies the high recurrence rate of these diseases. Early diagnosis of recurrence is essential for an optimal therapeutically approach, whenever possible. Patients affected by end stage renal disease due to C3 glomerulopathies or to atypical HUS, may be transplanted with extreme caution. Living donor donation from relatives is not recommended because members of the same family may be affected by the same gene mutation. Different therapeutically approaches have been attempted either for recurrence prevention and treatment. The most promising approach is represented by complement inhibitors. Eculizumab, a monoclonal antibody against C5 convertase is the most promising drug, even if to date is not known how long the therapy should be continued and which are the best dosing. These facts face the high costs of the treatment. Eculizumab resistant patients have been described. They could benefit by a C3 convertase inhibitor, but this class of drugs is by now the object of randomized controlled trials.
2016-08-01 | Rituximab use in adult primary glomerulopathy: where is the evidence?
Rituximab is a chimeric anti-CD20 antibody that results in depletion of B-cell lymphocytes. It is currently used in the treatment of a variety of autoimmune diseases, in addition to CD20-positive lymphomas. The use of rituximab in the treatment of the adult primary glomerular diseases has emerged recently, although not yet established as first-line therapy in international guidelines. In patients with steroid-dependent minimal change disease or frequently relapsing disease, and in patients with idiopathic membranous nephropathy (IMN), several retrospective and prospective studies support the use of rituximab to induce remission, whereas in idiopathic focal and segmental glomerulosclerosis (FSGS), the use of rituximab has resulted in variable results. Evidence is still lacking for the use of rituximab in patients with immunoglobulin A nephropathy (IgAN) and idiopathic membranoproliferative glomerulonephritis (MPGN), as only few reports used rituximab in these two entities. Randomized controlled trials (RCTs) are warranted and clearly needed to establish the definitive role of rituximab in the management of steroid-dependent and frequently relapsing minimal change disease, IMN, both as first-line and second-line treatment, and in MPGN. We await the results of an ongoing RCT of rituximab use in IgAN. Although current evidence for the use of rituximab in patients with idiopathic FSGS is poor, more RCTs are needed to clarify its role, if any, in the management of steroid-resistant or steroid-dependent FSGS.
small molecules
2024-10-01 | Successful Management of Membranoproliferative Glomerulonephritis with Repository Corticotropin Injection
Introduction: Membranoproliferative glomerulonephritis (MPGN) is a pattern of glomerular injury subdivided by light microscopy into immune complex/monoclonal immunoglobulin-mediated, complement-mediated, and MPGN without immunoglobulin or complement deposition. Treating underlying causes is ideal, but idiopathic immune complex MPGN is often managed with immunosuppressive medications. Repository corticotropin injection shows promise in hard-to-treat cases, as illustrated in a successful treatment involving significant psychiatric side effects from steroids. Case Description: A 30-year-old female with MPGN diagnosed at age 16, presented to hospital with lower extremity edema and AKI. Before the presentation she was treated with prednisone 20 mg daily for many years and any attempt to taper prednisone resulted in MPGN flares. She was previously also trialed on mycophenolate with lower dose prednisone, but gastrointestinal side effects led to discontinuation of mycophenolate. She was then treated with repository corticotropin injection with prednisone 5 mg and was stable for two years until she had another flare with urine protein creatinine ratio (UPCR) rising to 3.2 g/g. Increasing prednisone to 50 mg/day temporarily improved UPCR, but severe depression with suicidal ideation prompted cessation of steroids. Subsequently, her renal function declined, with creatinine rising and UPCR reaching 4 g/g. After discontinuing all her medications for six months, severe deterioration ensued, with creatinine at 3.19 and UPCR at 12 g/g. She was admitted to hospital and renal biopsy was done which showed MPGN immune complex. Despite induction therapy with cyclophosphamide and rituximab her UPCR remained at 8.5 g/g after three months. Repository corticotropin injection was initiated at 80 mg biweekly, reducing UPCR to 4.35 g/g in a month and further to 0.75 g/g over three months. Discussion: Our case of difficult-to-treat idiopathic immune complex MPGN responded only to high steroid doses, which were discontinued due to steroid-induced suicidal ideation. Repository corticotropin injection, which stimulates endogenous steroid production, offered lower steroid exposure and fewer side effects. This may be a good option to avoid systemic side effects of steroids in other hard to treat cases.
2022-05-01 | Treatment with bortezomib for recurrent proliferative glomerulonephritis with monoclonal IgG deposits in kidney allograft. Case report and review of the literature
Abstract Proliferative glomerulonephritis with monoclonal immunoglobulin IgG deposits (PGNMID) is an already described form of renal involvement by monoclonal gammopathy. PGNMID is known to recur in kidney allografts. Bortezomib has shown clinical success in the treatment of multiple myeloma. However, its effect for recurrent PGNMID in kidney allografts has rarely been reported. We present the case of a 61-year-old woman who developed recurrent PGNMID 3 weeks after kidney transplantation. This patient was initially treated with steroid pulses (500 mg/day for 2 days) and two cycles of rituximab therapy (200 mg/body). However, disease progression was observed with mesangial matrix expansion and subendothelial deposits by light microscopy and stronger staining for IgG3 and kappa in the mesangial area by Immunofluorescence (IF) microscopy. Thus, we started treatment with bortezomib therapy (1.3 mg/m2, once weekly, on days 1, 8, 15, and 22 in a 5-week cycle, for a total of six cycles). Bortezomib therapy reduced massive proteinuria, although monoclonal immune deposits on IF and the serum creatinine level did not change during the treatment period. Seven months after completion of the first bortezomib course, we decided to prescribe a second course of bortezomib with the same regimen. Each course resulted in a > 50% reduction of proteinuria. Bortezomib may delay the progress of PGNMID in kidney allograft patients.
2019-06-01 | Recurrent membranoproliferative glomerulonephritis in a renal transplant secondary to monoclonal gammopathy of renal significance successfully treated with bortezomib
Internal Medicine JournalVolume 49, Issue 6 p. 801-802 Letters to the Editor Recurrent membranoproliferative glomerulonephritis in a renal transplant secondary to monoclonal gammopathy of renal significance successfully treated with bortezomib Ke Li Chow, Ke Li Chow orcid.org/0000-0002-4589-0735 Department of Nephrology, Monash Medical Centre, Melbourne, Victoria, AustraliaSearch for more papers by this authorJohn Kanellis, John Kanellis Department of Nephrology, Monash Medical Centre, Melbourne, Victoria, AustraliaSearch for more papers by this authorSukhpal Dayan, Sukhpal Dayan Department of Pathology, Monash Medical Centre, Melbourne, Victoria, AustraliaSearch for more papers by this authorJessica Ryan, Jessica Ryan Department of Nephrology, Monash Medical Centre, Melbourne, Victoria, Australia Department of Medicine, Monash University, Melbourne, Victoria, AustraliaSearch for more papers by this author Ke Li Chow, Ke Li Chow orcid.org/0000-0002-4589-0735 Department of Nephrology, Monash Medical Centre, Melbourne, Victoria, AustraliaSearch for more papers by this authorJohn Kanellis, John Kanellis Department of Nephrology, Monash Medical Centre, Melbourne, Victoria, AustraliaSearch for more papers by this authorSukhpal Dayan, Sukhpal Dayan Department of Pathology, Monash Medical Centre, Melbourne, Victoria, AustraliaSearch for more papers by this authorJessica Ryan, Jessica Ryan Department of Nephrology, Monash Medical Centre, Melbourne, Victoria, Australia Department of Medicine, Monash University, Melbourne, Victoria, AustraliaSearch for more papers by this author First published: 11 June 2019 https://doi.org/10.1111/imj.14313Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume49, Issue6June 2019Pages 801-802 RelatedInformation
2018-06-05 | Successful Renal Outcome in Membranoproliferative Glomerulonephritis Following Treatment of the Underlying Subtle Clone: A Case Report
Membranoproliferative glomerulonephritis (MPGN) secondary to a monoclonal gammopathy is a rare glomerular disease and is defined as a monoclonal gammopathy of renal significance. The disease is characterized by glomerular monotypic immunoglobulin deposits and specific changes on light microscopy and electron microscopy. Immunochemistry is required to establish monoclonality, and electron microscopy helps to characterize the deposits ultrastructurally. Investigation for the underlying monoclonal protein should be done. We report a case of MPGN secondary to monoclonal gammopathy of renal significance that responded to treatment of the underlying clone with chemotherapy, resulting in improvement in renal function. Patients with MPGN and immunoglobulin deposition should be evaluated for a monoclonal protein to guide the management strategy.
2012-07-20 | Factor H and Properdin Recognize Different Epitopes on Renal Tubular Epithelial Heparan Sulfate
During proteinuria, renal tubular epithelial cells become exposed to ultrafiltrate-derived serum proteins, including complement factors. Recently, we showed that properdin binds to tubular heparan sulfates (HS). We now document that factor H also binds to tubular HS, although to a different epitope than properdin. Factor H was present on the urinary side of renal tubular cells in proteinuric, but not in normal renal tissues and colocalized with properdin in proteinuric kidneys. Factor H dose-dependently bound to proximal tubular epithelial cells (PTEC) in vitro. Preincubation of factor H with exogenous heparin and pretreatment of PTECs with heparitinase abolished the binding to PTECs. Surface plasmon resonance experiments showed high affinity of factor H for heparin and HS (KD values of 32 and 93 nm, respectively). Using a library of HS-like polysaccharides, we showed that chain length and high sulfation density are the most important determinants for glycosaminoglycan-factor H interaction and clearly differ from properdin-heparinoid interaction. Coincubation of properdin and factor H did not hamper HS/heparin binding of one another, indicating recognition of different nonoverlapping epitopes on HS/heparin by factor H and properdin. Finally we showed that certain low anticoagulant heparinoids can inhibit properdin binding to tubular HS, with a minor effect on factor H binding to tubular HS. As a result, these heparinoids can control the alternative complement pathway. In conclusion, factor H and properdin interact with different HS epitopes of PTECs. These interactions can be manipulated with some low anticoagulant heparinoids, which can be important for preventing complement-derived tubular injury in proteinuric renal diseases.
antibodies
2020-03-01 | Rituximab use in adult glomerulopathies and its rationale
Abstract Glomerulopathies are one of the leading causes of end-stage renal disease. In the last years, clinical research has made significant contributions to the understanding of such conditions. Recently, rituximab (RTX) has appeared as a reasonably safe treatment. The Kidney Disease: Improving Global Outcomes guidelines (KDIGO) recommended RTX only as initial treatment in antineutrophil cytoplasm antibody associated vasculitis (AAV) and in non-responders patients with lupus nephritis (LN), but these guidelines have not been updated since 2012. Nowadays, RTX seems to be at least as effective as other immunosuppressive regimens in idiopathic membranous nephropathy (IMN). In minimal-change disease, (MCD) this drug might allow a long-lasting remission period in steroid-dependent or frequently relapsing patients. Preliminary results support the use of RTX in patients with pure membranous LN and immunoglobulin-mediated membranoproliferative glomerulonephritis (MPGN), but not in patients with class III/IV LN or complement-mediated MPGN. No conclusion can be drawn in idiopathic focal segmental glomerulosclerosis (FSGS) and anti-glomerular basement membrane antibody glomerulonephritis (anti-GBM GN) because studies are small, heterogeneous, and scarce. Lastly, immunosuppression including RTX is not particularly useful in IgA nephropathy. This review presents the general background, outcomes, and safety for RTX treatment in different glomerulopathies. In this regard, we describe randomized controlled trials (RCTs) performed in adults, whenever possible. A literature search was performed using clinicaltrials.gov and PubMed.
2019-02-14 | Complete biopsy-proven resolution of deposits in recurrent proliferative glomerulonephritis with monoclonal IgG deposits (PGNMIGD) following rituximab treatment in renal allograft
Proliferative glomerulonephritis with monoclonal IgG deposits (PGNMIGD) is a disease entity classified under the group of "Monoclonal gammopathy-related kidney diseases", and can recur after transplant. Clinical remission of proteinuria in patients with PGNMIGD has been previously shown following anti-B cell and/or anti-plasma cell therapies. Our case is the first to show complete histologic resolution of the glomerular monoclonal IgG kappa deposits in a case of recurrent PGNMIGD in renal allograft after rituximab and steroid treatment. This is a novel finding and it shows that the deposits are amenable to therapy. This case also highlights the importance of IgG subclass staining in the recognition of the monoclonal nature of the deposits. It is particularly important in PGNMIGD because only 20 to 30% of patients with this disease are reported to have detectable monoclonal gammopathy, and the deposits do not have any organized substructure on electron microscopic examination. Morphologically, they resemble polyclonal immune-type deposits seen in other immune complex glomerulonephritides such as lupus nephritis, infection-associated glomerulonephritis, and membranoproliferative glomerulonephritis (MPGN type I). The patient is a 44 year old Caucasian male who received a living unrelated donor kidney transplant for end-stage renal disease diagnosed 7 years before transplant. The reported native kidney biopsy diagnosis was membranoproliferative glomerulonephritis (MPGN) with IgG, C3 and kappa restricted deposits. Fourteen months post-transplant, he presented with abrupt worsening of graft function, proteinuria and serum IgG kappa monoclonal spike. Allograft biopsy was consistent with recurrent PGNMIGD, considering the native kidney diagnosis and interval post-transplant. He underwent plasmapheresis, IV pooled immune globulin, steroid pulse and taper, and anti-CD-20 Rituximab therapy. Patient had gradual decline in proteinuria and complete resolution of the immune deposits on repeat biopsy 3 months later. Unfortunately he subsequently developed chronic antibody-mediated rejection and transplant glomerulopathy and graft failure 34 months post-transplant. In a transplant setting, repeat allograft biopsies are frequently performed for graft dysfunction. This provides a good opportunity to study the evolution of the immune deposits following treatment. Our case shows complete histologic resolution of the deposits in allograft PGNMIGD.
2018-01-17 | Membranoproliferative glomerulonephritis and C3 glomerulopathy in children: change in treatment modality? A report of a case series
Membranoproliferative glomerulonephritis (MPGN) with immune complexes and C3 glomerulopathy (C3G) in children are rare and have a variable outcome, with some patients progressing to end-stage renal disease (ESRD). Mutations in genes encoding regulatory proteins of the alternative complement pathway and of complement C3 (C3) have been identified as concausative factors.Three children with MPGN type I, four with C3G, i.e. three with C3 glomerulonephritis (C3GN) and one with dense deposit disease (DDD), were followed. Clinical, autoimmune data, histological characteristics, estimated glomerular filtration rate (eGFR), proteinuria, serum C3, genetic and biochemical analysis were assessed.The median age at onset was 7.3 years and the median eGFR was 72 mL/min/1.73 m2. Six children had marked proteinuria. All were treated with renin-angiotensin-aldosterone system (RAAS) blockers. Three were given one or more immunosuppressive drugs and two eculizumab. At the last median follow-up of 9 years after diagnosis, three children had normal eGFR and no or mild proteinuria on RAAS blockers only. Among four patients without remission of proteinuria, genetic analysis revealed mutations in complement regulator proteins of the alternative pathway. None of the three patients with immunosuppressive treatment achieved partial or complete remission of proteinuria and two progressed to ESRD and renal transplantation. Two patients treated with eculizumab revealed relevant decreases in proteinuria.In children with MPGN type I and C3G, the outcomes of renal function and response to treatment modality show great variability independent from histological diagnosis at disease onset. In case of severe clinical presentation at disease onset, early genetic and biochemical analysis of the alternative pathway dysregulation is recommended. Treatment with eculizumab appears to be an option to slow disease progression in single cases.
2016-12-15 | Complement related kidney diseases: Recurrence after transplantation
The recurrence of renal disease after renal transplantation is becoming one of the main causes of graft loss after kidney transplantation. This principally concerns some of the original diseases as the atypical hemolytic uremic syndrome (HUS), the membranoproliferative glomerulonephritis (MPGN), in particular the MPGN now called C3 glomerulopathy. Both this groups of renal diseases are characterized by congenital (genetic) or acquired (auto-antibodies) modifications of the alternative pathway of complement. These abnormalities often remain after transplantation because they are constitutional and poorly influenced by the immunosuppression. This fact justifies the high recurrence rate of these diseases. Early diagnosis of recurrence is essential for an optimal therapeutically approach, whenever possible. Patients affected by end stage renal disease due to C3 glomerulopathies or to atypical HUS, may be transplanted with extreme caution. Living donor donation from relatives is not recommended because members of the same family may be affected by the same gene mutation. Different therapeutically approaches have been attempted either for recurrence prevention and treatment. The most promising approach is represented by complement inhibitors. Eculizumab, a monoclonal antibody against C5 convertase is the most promising drug, even if to date is not known how long the therapy should be continued and which are the best dosing. These facts face the high costs of the treatment. Eculizumab resistant patients have been described. They could benefit by a C3 convertase inhibitor, but this class of drugs is by now the object of randomized controlled trials.
2016-08-01 | Rituximab use in adult primary glomerulopathy: where is the evidence?
Rituximab is a chimeric anti-CD20 antibody that results in depletion of B-cell lymphocytes. It is currently used in the treatment of a variety of autoimmune diseases, in addition to CD20-positive lymphomas. The use of rituximab in the treatment of the adult primary glomerular diseases has emerged recently, although not yet established as first-line therapy in international guidelines. In patients with steroid-dependent minimal change disease or frequently relapsing disease, and in patients with idiopathic membranous nephropathy (IMN), several retrospective and prospective studies support the use of rituximab to induce remission, whereas in idiopathic focal and segmental glomerulosclerosis (FSGS), the use of rituximab has resulted in variable results. Evidence is still lacking for the use of rituximab in patients with immunoglobulin A nephropathy (IgAN) and idiopathic membranoproliferative glomerulonephritis (MPGN), as only few reports used rituximab in these two entities. Randomized controlled trials (RCTs) are warranted and clearly needed to establish the definitive role of rituximab in the management of steroid-dependent and frequently relapsing minimal change disease, IMN, both as first-line and second-line treatment, and in MPGN. We await the results of an ongoing RCT of rituximab use in IgAN. Although current evidence for the use of rituximab in patients with idiopathic FSGS is poor, more RCTs are needed to clarify its role, if any, in the management of steroid-resistant or steroid-dependent FSGS.
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Drug Discovery Landscape
2 orphan drug designations for Immunoglobulin-mediated membranoproliferative glomerulonephritis, including 1 approved therapy.
2 orphan drug designations for Immunoglobulin-mediated membranoproliferative glomerulonephritis, including 1 approved therapy.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
a chemically synthesized double-stranded oligonucleotide directed against C3 messenger RNA | RNAs | FDA | 2026-02-23 | — | Sanegene Bio USA Inc. |
pegcetacoplan [Empaveli] | antibodies | FDA | 2022-06-07 | 2025-07-28 | Apellis Pharmaceuticals, Inc. |
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