Membranoproliferative glomerulonephritis: no longer the same disease and may need very different treatment

2021 ◽  
Author(s):  
Marina Noris ◽  
Erica Daina ◽  
Giuseppe Remuzzi
Keyword(s):  
Monoclonal Antibody ◽  
Membranoproliferative Glomerulonephritis ◽  
Accurate Diagnosis ◽  
C3 Glomerulopathy ◽  
Glomerular Injury ◽  
Small Series ◽  
Haematological Disorders ◽  
The Complement System ◽  
Terminal Complement ◽  
Different Levels

Abstract Membranoproliferative glomerulonephritis (MPGN) is a pattern of glomerular injury that may be primary or secondary to infections, autoimmune diseases and haematological disorders. Primary C3G and IC-MPGN are rare and the prognosis is unfavourable. Based on immunofluorescence findings, MPGN has been classified into complement-mediated C3 glomerulopathy (C3G), and immune complex-mediated MPGN (IC-MPGN). However, this classification leaves a number of issues unresolved. The finding of genetic and acquired complement abnormalities in both C3G and IC-MPGN indicates that they represent a heterogeneous spectrum rather than distinct diseases. An unsupervised hierarchical clustering in a cohort of patients with primary C3G and IC-MPGN identified 4 distinct pathogenetic patterns, characterised by specific histologic and clinical features and genetic and acquired complement abnormalities. These results provide the groundwork for a more accurate diagnosis and the development of targeted therapies. The drugs that are currently used, such as corticosteroids and immunosuppressants, are frequently ineffective in primary C3G and IC-MPGN. Eculizumab, an anti-C5 monoclonal antibody, has been used occasionally in single cases or small series. However, only a few patients have achieved remission. This heterogeneous response could be related to the extent of terminal complement activation, which may vary substantially from patient to patient. Several drugs that target the complement system at different levels are under investigation for C3G and IC-MPGN. However, clinical trials to test new therapeutics will be challenging and heavily influenced by the heterogeneity of these diseases. This creates the need to characterise each patient to match the specific complement abnormality with the type of intervention.

scholarly journals Different Aspects of Classical Pathway Overactivation in Patients With C3 Glomerulopathy and Immune Complex-Mediated Membranoproliferative Glomerulonephritis

2021 ◽  
Vol 12 ◽  
Author(s):  
Marloes A. H. M. Michels ◽  
Nicole C. A. J. van de Kar ◽  
Sanne A. W. van Kraaij ◽  
Sebastian A. Sarlea ◽  
Valentina Gracchi ◽  
...  
Keyword(s):  
Immune Complex ◽  
Membranoproliferative Glomerulonephritis ◽  
Alternative Pathway ◽  
Classical Pathway ◽  
Healthy Controls ◽  
C3 Glomerulopathy ◽  
Hemolytic Assay ◽  
The Stability ◽  
The Complement System

The rare and heterogeneous kidney disorder C3 glomerulopathy (C3G) is characterized by dysregulation of the alternative pathway (AP) of the complement system. C3G is often associated with autoantibodies stabilizing the AP C3 convertase named C3 nephritic factors (C3NeF). The role of classical pathway (CP) convertase stabilization in C3G and related diseases such as immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN) remains largely unknown. Here, we investigated the CP convertase activity in patients with C3G and IC-MPGN. Using a refined two-step hemolytic assay, we measured the stability of CP convertases directly in the serum of 52 patients and 17 healthy controls. In four patients, CP convertase activity was prolonged compared to healthy controls, i.e. the enzymatic complex was stabilized. In three patients (2 C3G, 1 IC-MPGN) the convertase stabilization was caused by immunoglobulins, indicating the presence of autoantibodies named C4 nephritic factors (C4NeFs). Importantly, the assay also enabled detection of non-immunoglobulin-mediated stabilization of the CP convertase in one patient with C3G. Prolonged CP convertase activity coincided with C3NeF activity in all patients and for up to 70 months of observation. Crucially, experiments with C3-depleted serum showed that C4NeFs stabilized the CP C3 convertase (C4bC2a), that does not contain C3NeF epitopes. All patients with prolonged CP convertase activity showed clear signs of complement activation, i.e. lowered C3 and C5 levels and elevated levels of C3d, C3bc, C3bBbP, and C5b-9. In conclusion, this work provides new insights into the diverse aspects and (non-)immunoglobulin nature of factors causing CP convertase overactivity in C3G/IC-MPGN.

scholarly journals P0496THE IMPORTANCE OF COMPLEMENT LEVELS AND CLINICAL CHARACTERISTICS OF PRIMARY MEMBRANOPROLIFERATIVE GLOMERULONEPHRITIS IN TURKEY

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Erhan Tatar ◽  
Deren Oygar ◽  
Nurhan Seyahi ◽  
Necmi Eren ◽  
Yağmur Cantürk ◽  
...  
Keyword(s):  
Nephrotic Syndrome ◽  
Immune Complex ◽  
Membranoproliferative Glomerulonephritis ◽  
C3 Glomerulopathy ◽  
Complex Type ◽  
Glomerular Diseases ◽  
Nephritic Syndrome ◽  
Pathological Evaluation ◽  
Chronicity Index ◽  
The Complement System

Abstract Background and Aims Membranoproliferative glomerulonephritis (MPGN) may be caused by disturbances in the complement system. Hypocomplementemia is a characteristic of MPGN. Among these patients frequency of hypocomplementemia and their relation with clinical and histopathological findings are still not clearly known. The aim of this study is to evaluate the hypocomplementemia frequency among the primary MPGN patients in Turkey and its relation with histopathological subtypes, findings and demographic characteristics. Method The data was obtained from national multicentered (47 centers) records of primary glomerular diseases in Glomerulonephritis Study Group of the Turkish Society of Nephrology database from May 2009 to June 2019. Primary MPGN cases were evaluated and divided into 2 groups with and without hypocomplementemia. Results In total, 193 cases were included in the study. The indications for renal biopsy were isolated nephrotic syndrome (55.4%), nephritic syndrome (21.2%), nephrotic syndrome with a nephritic component (6.2%) and asymptomatic urinary findings (17.2%). 34.2% of the cases were reported as immune complex type, another 34.2% of the cases were reported as C3 glomerulopathy. 31.6% of patients were not specified. 82 (42.4%) of the cases presented hypocomplementemia. Hypocomplementemic patients were younger (34±14 vs 41±15, p=0.002) and most frequently female (56% vs 41%, p=0.03). At same time, serum albumin and hemoglobin levels were lower and anemic patient rates were higher (p<0.001). In this group, the nephrotic syndrome rates were higher (72% vs 54%, p=0,01). Hypocomplementemia rate in the C3 glomerulopathy was 52% (in DDD 40%, in C3GN 55% ) whereas in immune complex type 41% and in non specified type 34%. In the pathological evaluation; among the hypocomplementemic group the endocapillary proliferation and glomerular exudative differentiation rates presented significant increase. However the chronicity index were lower in the kidney biopsy (Table 1). Conclusion This multicenter study provided important data about the epidemiology of MPGN with importance of hypocomplementemia in Turkey. Hypocomplementemia is associated with both subtypes of MPGN patern, anemia and nephrotic syndrome. At the same time, hypocomplementemia is a valuable parameter for active MPGN pattern in the histopathological evaluation. This may be important in determining the treatment.

scholarly journals Membranoproliferative Glomerulonephritis Type 1 Secondary to an Infected Ventriculoperitoneal Shunt: a Case Report

2014 ◽  
Vol 12 (2) ◽  
pp. 119-121
Author(s):  
Christos Paliouras ◽  
Foteini Lamprianou ◽  
Georgios Ntetskas ◽  
Georgios Mattas ◽  
Nikolaos Karvouniaris ◽  
...  
Keyword(s):  
Ventriculoperitoneal Shunt ◽  
Membranoproliferative Glomerulonephritis ◽  
Classical Pathway ◽  
Glomerular Injury ◽  
Laboratory Findings ◽  
Immune Mediated ◽  
Histologic Pattern ◽  
Life Threatening ◽  
Subsequent Activation

AbstractVentricular shunting is the usual method for treatment of congenital or acquired hydrocephalus. Immune-mediated glomerulonephritis (shunt nephritis) is a rare but life-threatening complication of this neurosurgical technique. Intraglomerular deposition of circulating immune complexes and the subsequent activation of the classical pathway of serum complement’s cascade result in glomerular inflammation. Membranoproliferative gomerulonephritis is the most common histologic pattern observed in renal biopsy. The diagnosis needs high suspicion and is based on clinical and laboratory findings. Deterioration of renal function in association with signs of infection and low levels of serum complement’s proteins C3 and C4 make the diagnosis possible. The prognosis is variable and depends on the time of diagnosis after the onset of glomerular injury. The optimal treatment includes timely removal of the infected shunt in combination with aggressive antibiotic therapy. In this paper we present the case of a membranoproliferative glomerulonephritis type 1 in a patient with a ventriculoperitoneal shunt. Although this type of shunting is considered safer than the ventriculoatrial one, the risk of complications such as an immune-mediated glomerulonephritis still exists.

Morphofunctional Effects of C5 Convertase Blockade in Immune Complex-Mediated Membranoproliferative Glomerulonephritis: Report of Two Cases with Evidence of Terminal Complement Activation

Nephron ◽  
2020 ◽  
Vol 144 (4) ◽  
pp. 195-203
Author(s):  
Camillo Carrara ◽  
Manuel Alfredo Podestà ◽  
Mauro Abbate ◽  
Paola Rizzo ◽  
Rossella Piras ◽  
...  
Keyword(s):  
Immune Complex ◽  
Complement Activation ◽  
Membranoproliferative Glomerulonephritis ◽  
Terminal Complement

Eculizumab in the treatment of neuromyelitis optica spectrum disorder

Immunotherapy ◽  
2020 ◽  
Vol 12 (14) ◽  
pp. 1053-1066
Author(s):  
Katrin Giglhuber ◽  
Achim Berthele
Keyword(s):  
Neuromyelitis Optica ◽  
Controlled Trial ◽  
Water Channel ◽  
Spectrum Disorder ◽  
Phase Iii ◽  
Neuromyelitis Optica Spectrum Disorder ◽  
Humanized Monoclonal Antibody ◽  
The Complement System ◽  
Terminal Complement ◽  
Aqp4 Antibody

Neuromyelitis optica spectrum disorder (NMOSD) is a rare autoimmune disease of the CNS which is distinct from multiple sclerosis and typically presents with a relapsing course of optic neuritis, myelitis and midline brain inflammatory lesions. In at least two-thirds of cases, antibodies against the water channel AQP4 can be found, which lead to an antibody-mediated activation of the complement system with consecutive damage to neuronal structures. Eculizumab, a humanized monoclonal antibody against the terminal complement component 5, was shown to significantly reduce the risk of NMOSD relapse in a Phase III placebo-controlled trial. Based on this, eculizumab (Soliris®) was the first drug to be formally approved for the treatment of anti-AQP4-antibody positive NMOSD in 2019.

Therapy and outcomes of C3 glomerulopathy and immune-complex membranoproliferative glomerulonephritis

2020 ◽  
Author(s):  
Priyanka Khandelwal ◽  
Swati Bhardwaj ◽  
Geetika Singh ◽  
Aditi Sinha ◽  
Pankaj Hari ◽  
...  
Keyword(s):  
Immune Complex ◽  
Membranoproliferative Glomerulonephritis ◽  
C3 Glomerulopathy

scholarly journals Membranoproliferative glomerulonephritis and C3 glomerulopathy: resolving the confusion

2012 ◽  
Vol 81 (5) ◽  
pp. 434-441 ◽  
Author(s):  
Sanjeev Sethi ◽  
Carla M. Nester ◽  
Richard J.H. Smith
Keyword(s):  
Membranoproliferative Glomerulonephritis ◽  
C3 Glomerulopathy
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