C3 Glomerulopathy: Novel Treatment Paradigms

Abstract

C3 glomerulopathy (C3G) is diagnosed by kidney biopsy, with immunofluorescence showing isolated or dominant C3 staining, indicating hyperactivity of the alternative complement pathway as the key driver of glomerular injury. Therefore, the lesion is defined by its complement-mediated pathogenesis as much as its histological pattern. As a bevy of complement-targeting agents are moving through development and clinical trials, we review the evolution in treatment paradigms for C3G. Here we survey the limited efficacy of noncomplement targeting therapy before focusing on the work being done on targeting various components of the complement cascade in aiming to provide disease-specific therapy. C3 glomerulopathy (C3G) is diagnosed by kidney biopsy, with immunofluorescence showing isolated or dominant C3 staining, indicating hyperactivity of the alternative complement pathway as the key driver of glomerular injury. Therefore, the lesion is defined by its complement-mediated pathogenesis as much as its histological pattern. As a bevy of complement-targeting agents are moving through development and clinical trials, we review the evolution in treatment paradigms for C3G. Here we survey the limited efficacy of noncomplement targeting therapy before focusing on the work being done on targeting various components of the complement cascade in aiming to provide disease-specific therapy. C3G encompasses dense deposit disease and C3 glomerulonephritis, and is defined by its complement-mediated pathogenesis as much as its histological pattern. C3G results from a dysregulation in the alternative pathway (AP) of the complement system (Figure 1), which leads to the deposition of C3 fragments in the glomeruli, with trace or no presence of immunoglobulins.1Fakhouri F. Frémeaux-Bacchi V. Noël L.H. Cook H.T. Pickering M.C. C3 glomerulopathy: a new classification.Nat Rev Nephrol. 2010; 6: 494-499https://doi.org/10.1038/NRNEPH.2010.85Crossref PubMed Scopus (0) Google Scholar,2Pickering M.C. D’agati V.D. Nester C.M. et al.C3 glomerulopathy: consensus report.Kidney Int. 2013; 84: 1079-1089https://doi.org/10.1038/ki.2013.377Abstract Full Text Full Text PDF PubMed Scopus (448) Google Scholar Genetic or acquired abnormalities in 1 or more of the multiple components of the AP can lead to C3G.3Smith R.J.H. Appel G.B. Blom A.M. et al.C3 glomerulopathy-understanding a rare complement-driven renal disease.Nat Rev Nephrol. 2019; 15: 129-143https://doi.org/10.1038/s41581-018-0107-2Crossref PubMed Scopus (193) Google Scholar The clinical course includes proteinuria, hematuria, and progressive chronic kidney disease, with most patients reaching end-stage kidney disease within 2 decades of diagnosis.4Bomback A.S. Santoriello D. Avasare R.S. et al.C3 glomerulonephritis and dense deposit disease share a similar disease course in a large United States cohort of patients with C3 glomerulopathy.Kidney Int. 2018; 93: 977-985https://doi.org/10.1016/j.kint.2017.10.022Abstract Full Text Full Text PDF PubMed Scopus (100) Google Scholar, 5Servais A. Ne Noël L.-H. Roumenina L.T. et al.Acquired and genetic complement abnormalities play a critical role in dense deposit disease and other C3 glomerulopathies.Kidney Int. 2012; 82: 454-464https://doi.org/10.1038/ki.2012.63Abstract Full Text Full Text PDF PubMed Scopus (403) Google Scholar, 6Medjeral-Thomas N.R. O’Shaughnessy M.M. O’Regan J.A. et al.C3 glomerulopathy: clinicopathologic features and predictors of outcome.Clin J Am Soc Nephrol. 2014; 9: 46-53https://doi.org/10.2215/CJN.04700513Crossref PubMed Scopus (172) Google Scholar Current standard-of-care for C3G includes supportive measures for patients with mild disease and immunosuppression with mycophenolate mofetil (MMF) plus glucocorticoids for those with moderate to severe disease (>0.5–1 g/d of proteinuria, declining kidney function).7Rovin B.H. Adler S.G. Barratt J. et al.KDIGO 2021 clinical practice guideline for the management of glomerular diseases.Kidney Int. 2021; 100: S1-S276https://doi.org/10.1016/j.kint.2021.05.021Abstract Full Text Full Text PDF PubMed Scopus (750) Google Scholar,8Goodship T.H.J. Cook H.T. Fakhouri F. et al.Atypical hemolytic uremic syndrome and C3 glomerulopathy: conclusions from a “Kidney Disease: improving Global Outcomes” (KDIGO) Controversies Conference.Kidney Int. 2017; 91: 539-551https://doi.org/10.1016/j.kint.2016.10.005Abstract Full Text Full Text PDF PubMed Scopus (451) Google Scholar However, these nonspecific treatment approaches seem to have limited benefits among patients with C3G,5Servais A. Ne Noël L.-H. Roumenina L.T. et al.Acquired and genetic complement abnormalities play a critical role in dense deposit disease and other C3 glomerulopathies.Kidney Int. 2012; 82: 454-464https://doi.org/10.1038/ki.2012.63Abstract Full Text Full Text PDF PubMed Scopus (403) Google Scholar,6Medjeral-Thomas N.R. O’Shaughnessy M.M. O’Regan J.A. et al.C3 glomerulopathy: clinicopathologic features and predictors of outcome.Clin J Am Soc Nephrol. 2014; 9: 46-53https://doi.org/10.2215/CJN.04700513Crossref PubMed Scopus (172) Google Scholar,9Caravaca-Fontán F. Díaz-Encarnación M.M. Lucientes L. et al.Mycophenolate mofetil in c3 glomerulopathy and pathogenic drivers of the disease.Clin J Am Soc Nephrol. 2020; 15: 1287-1298https://doi.org/10.2215/CJN.15241219Crossref PubMed Scopus (29) Google Scholar,10Caliskan Y. Torun E.S. Tiryaki T.O. et al.Immunosuppressive treatment in C3 glomerulopathy: is it really effective?.Am J Nephrol. 2017; 46: 96-107https://doi.org/10.1159/000479012Crossref PubMed Scopus (33) Google Scholar and complement blockade is expected to be the best strategy to explore in this population. To date, no complement inhibitor is approved for C3G, although eculizumab, a terminal complement blocker, is included in some clinical guidelines as a backup agent for patients with progressive disease who fail to respond to other therapies.7Rovin B.H. Adler S.G. Barratt J. et al.KDIGO 2021 clinical practice guideline for the management of glomerular diseases.Kidney Int. 2021; 100: S1-S276https://doi.org/10.1016/j.kint.2021.05.021Abstract Full Text Full Text PDF PubMed Scopus (750) Google Scholar,8Goodship T.H.J. Cook H.T. Fakhouri F. et al.Atypical hemolytic uremic syndrome and C3 glomerulopathy: conclusions from a “Kidney Disease: improving Global Outcomes” (KDIGO) Controversies Conference.Kidney Int. 2017; 91: 539-551https://doi.org/10.1016/j.kint.2016.10.005Abstract Full Text Full Text PDF PubMed Scopus (451) Google Scholar There are multiple reasons for the lack of an established optimal treatment for C3G. First, it is a rare entity, and often affecting pediatric population, making it difficult to carry out large randomized controlled trials; therefore, most evidence is based on retrospective analyses, case series, and observational studies. Second, the tests required to characterize genetic variants, complement functionality and complement-directed autoantibodies are costly and not generally available outside of the research setting. Lastly, comparing and interpreting these results is not straightforward because it also is a rather heterogenous disease in many aspects. In terms of disease drivers, abnormalities in complement genes are found in only 13% to 25% of patients, and the frequency of complement-targeting autoantibodies such as C3 nephritic factor (C3Nef) varies widely between populations, from 20% to 80%.4Bomback A.S. Santoriello D. Avasare R.S. et al.C3 glomerulonephritis and dense deposit disease share a similar disease course in a large United States cohort of patients with C3 glomerulopathy.Kidney Int. 2018; 93: 977-985https://doi.org/10.1016/j.kint.2017.10.022Abstract Full Text Full Text PDF PubMed Scopus (100) Google Scholar,5Servais A. Ne Noël L.-H. Roumenina L.T. et al.Acquired and genetic complement abnormalities play a critical role in dense deposit disease and other C3 glomerulopathies.Kidney Int. 2012; 82: 454-464https://doi.org/10.1038/ki.2012.63Abstract Full Text Full Text PDF PubMed Scopus (403) Google Scholar,11Iatropoulos P. Noris M. Mele C. et al.Complement gene variants determine the risk of immunoglobulin-associated MPGN and C3 glomerulopathy and predict long-term renal outcome.Mol Immunol. 2016; 71: 131-142https://doi.org/10.1016/J.MOLIMM.2016.01.010Crossref PubMed Scopus (0) Google Scholar Clinical presentation classically includes low C3 levels; however, this is not true for about 30% to 50% of patients.4Bomback A.S. Santoriello D. Avasare R.S. et al.C3 glomerulonephritis and dense deposit disease share a similar disease course in a large United States cohort of patients with C3 glomerulopathy.Kidney Int. 2018; 93: 977-985https://doi.org/10.1016/j.kint.2017.10.022Abstract Full Text Full Text PDF PubMed Scopus (100) Google Scholar,5Servais A. Ne Noël L.-H. Roumenina L.T. et al.Acquired and genetic complement abnormalities play a critical role in dense deposit disease and other C3 glomerulopathies.Kidney Int. 2012; 82: 454-464https://doi.org/10.1038/ki.2012.63Abstract Full Text Full Text PDF PubMed Scopus (403) Google Scholar,12Iatropoulos P. Daina E. Curreri M. et al.Cluster analysis identifies distinct pathogenetic patterns in c3 glomerulopathies/immune complex-mediated membranoproliferative GN.J Am Soc Nephrol. 2018; 29: 283-294https://doi.org/10.1681/ASN.2017030258Crossref PubMed Scopus (81) Google Scholar Histopathological definition has evolved, and earlier publications included patients with a membranoproliferative glomerulonephritis (MPGN); whereas now, other patterns of injury such as mesangial or endocapillary proliferative glomerulonephritis are recognized as C3G as well. Furthermore, many of the cited publications and ongoing clinical trials combine patients with C3G and immune complex-mediated MPGN (IC-MPGN) because the distinction between the 2 is questionable.13Fakhouri F. Le Quintrec M. Frémeaux-Bacchi V. Practical management of C3 glomerulopathy and Ig-mediated MPGN: facts and uncertainties.Kidney Int. 2020; 98: 1135-1148https://doi.org/10.1016/j.kint.2020.05.053Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar Although the difference is based on the hypothesis that results from complement pathway by many have a of the AP as by abnormalities in AP and in and A. Ne Noël L.-H. Roumenina L.T. et al.Acquired and genetic complement abnormalities play a critical role in dense deposit disease and other C3 glomerulopathies.Kidney Int. 2012; 82: 454-464https://doi.org/10.1038/ki.2012.63Abstract Full Text Full Text PDF PubMed Scopus (403) Google M. Daina E. no the disease and PubMed Scopus Google Scholar, M. F. clinical to with C3 Nephrol. PubMed Scopus (0) Google Scholar, A. et not a C3 glomerulopathy.Kidney 2019; Full Text Full Text PDF PubMed Google Scholar from a from to C3G in also the that these 2 be of the disease M. F. clinical to with C3 Nephrol. PubMed Scopus (0) Google J. A.S. et a definition of C3 glomerulopathy by Int. 2014; Full Text Full Text PDF PubMed Scopus Google Scholar these are multiple that have clinical trials for patients with C3G, of the complement system various In this we to the for of trials of complement in C3 in complement of of of in kidney of the of C3 to and of the of 2 not C3G, 2 C3 and of of of and of the of C3 and 2 and 2 of the of 2 2 because of efficacy of the of and and the of 1 of the of to its 2 and of C3 of of and and 2 of the of and and 2 C3G, C3 dense deposit immune complex-mediated membranoproliferative because of efficacy in a new C3G, C3 dense deposit immune complex-mediated membranoproliferative in AP C3 and is the of C3G making this the for the development of new R.J.H. Appel G.B. Blom A.M. et al.C3 glomerulopathy-understanding a rare complement-driven renal disease.Nat Rev Nephrol. 2019; 15: 129-143https://doi.org/10.1038/s41581-018-0107-2Crossref PubMed Scopus (193) Google Scholar this can also have a and an of the terminal can to an the of of alternative C3 can be found in a large of patients with C3G, among patients with dense deposit A. Ne Noël L.-H. Roumenina L.T. et al.Acquired and genetic complement abnormalities play a critical role in dense deposit disease and other C3 glomerulopathies.Kidney Int. 2012; 82: 454-464https://doi.org/10.1038/ki.2012.63Abstract Full Text Full Text PDF PubMed Scopus (403) Google Y. et of alternative pathway dysregulation in dense deposit disease.Clin J Am Soc Nephrol. 2012; PubMed Scopus Google Y. et al.C3 complement glomerular and Int. 2012; 82: Full Text Full Text PDF PubMed Scopus Google Scholar variants in complement genes have in to 20% to 25% of although more for have of case to variants the of such as variants in the genes for C3 factor factor factor or and in F. Lucientes L. M. on C3 glomerulopathy: a complement-mediated 2020; PubMed Scopus (29) Google R.J.H. C3 glomerulopathy: an complement-mediated renal J PubMed Scopus Google Scholar C3 a of C3 in the are low in 50% to of patients with A.S. Santoriello D. Avasare R.S. et al.C3 glomerulonephritis and dense deposit disease share a similar disease course in a large United States cohort of patients with C3 glomerulopathy.Kidney Int. 2018; 93: 977-985https://doi.org/10.1016/j.kint.2017.10.022Abstract Full Text Full Text PDF PubMed Scopus (100) Google Scholar,5Servais A. Ne Noël L.-H. Roumenina L.T. et al.Acquired and genetic complement abnormalities play a critical role in dense deposit disease and other C3 glomerulopathies.Kidney Int. 2012; 82: 454-464https://doi.org/10.1038/ki.2012.63Abstract Full Text Full Text PDF PubMed Scopus (403) Google A. A.S. C3 glomerulopathy: 2018; 93: Full Text Full Text PDF PubMed Scopus Google Scholar with C3 in which can in the from C3 such as of factor and C3 be of to AP C3 of the AP the of the and which the risk of by that has with L. risk for disease among patients of 2017; PubMed Google Scholar C3 the of and to a in immune and whereas a more targeting factor or factor not and terminal complement the and M. A. et al.Complement the of C3 or reasons for ongoing terminal pathway 2021; PubMed Scopus (0) Google Scholar However, genetic of factor C. J. M. in complement factor J 2013; PubMed Scopus (0) Google Scholar and factor et with complement factor PubMed Scopus (0) Google Scholar have with by measures such as and and be to patients the critical role of this of the AP in the disease, many new targeting the components are being (Figure is a a of that to to C3 C3 from A. of complement by a isolated from a Immunol. PubMed Google A. D. a inhibitor of to complement Immunol. PubMed Scopus Google Scholar 2 clinical patients with C3G, the with and C3G. of the patients in the C3G cohort L. et and efficacy of in a 2 of patients with C3 glomerulopathy and other complement-mediated glomerular diseases.Kidney Full Text Full Text PDF PubMed Scopus Google Scholar patients for with the to treatment in an the treatment on system also and the from a of to in the and kidney a glomerular of the from to with a in C3 to and a of it severe or C3G, which is expected in patients with C3G who kidney be in the a 2 to the and efficacy of in patients with C3G or The of the is a randomized controlled with and the other no The is the of with in on renal the which patients be The a is aiming to with or C3G or be for and for or a for by an of therapy for for proteinuria, renal and in the of the C3G A.S. Santoriello D. Avasare R.S. et al.C3 glomerulonephritis and dense deposit disease share a similar disease course in a large United States cohort of patients with C3 glomerulopathy.Kidney Int. 2018; 93: 977-985https://doi.org/10.1016/j.kint.2017.10.022Abstract Full Text Full Text PDF PubMed Scopus (100) Google Scholar as as The have an the to the long-term and efficacy in this population. is a that the of factor is a key in the its is the with of the AP C3 and AP is expected to have a on in an and of the A. et factor inhibitor for the treatment of complement-mediated A. 2019; PubMed Scopus (0) Google Scholar The results of a in patients with or C3G E. 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PubMed Scopus Google Scholar of for and of the AP not although evidence of AP in limited and clinical in have to the of development of in C3G, whereas research for other complement-mediated such as are is complement factor inhibitor in Although it is not being among patients with C3G, is a 2 clinical for patients with and is the targeting the and it by its similar to agent be in a to the and in patients with C3G in and of 2 trials for in and complement-mediated have also is an agent to of C3 and is being in a 1 among by with C3G and to with the of the and or The the the results of an analysis of the of the on showing an in C3 levels; a in a of AP hemolytic with a results from ongoing of for treatment of complement Scholar The is and moving to on with C3G and pathway to play a role in C3G rather the nephritic in C3G are found in with and are more among patients with C3 glomerulonephritis those with dense deposit Le Quintrec M. et nephritic the of C3 glomerulopathies.Kidney Int. 2017; Full Text Full Text PDF PubMed Scopus Google Scholar patients with C3 glomerulonephritis terminal those with dense deposit disease for the such as low and Y. Nester C.M. et the complement of C3 J Am Soc Nephrol. 2014; 9: PubMed Scopus Google Scholar The of this in C3G has also to disease deposition of in kidney has with renal of N.R. O’Shaughnessy M.M. O’Regan J.A. et al.C3 glomerulopathy: clinicopathologic features and predictors of outcome.Clin J Am Soc Nephrol. 2014; 9: 46-53https://doi.org/10.2215/CJN.04700513Crossref PubMed Scopus (172) Google Scholar In with the of a severe whereas the of out a role not of the of the by M.C. J. et of and glomerulonephritis in factor A. PubMed Scopus (0) Google Scholar Therefore, patients with evidence of terminal pathway be for As results in a risk of by to the of L. risk for disease among patients of 2017; PubMed Google Scholar targeting and with a on the for complement-targeting the and only complement inhibitor available for glomerular for many is a that an of in the to the AP the of and and the of the as a therapy for a therapy for many other as the role of complement in is available to C3G on an in complement-mediated hemolytic uremic the of in C3G to be The clinical of in patients with C3G, a included with C3G who of for 1 renal or in 2 renal of as a of A.S. et for dense deposit disease and C3 J Am Soc Nephrol. 2012; PubMed Scopus Google Scholar In 2 patients with MPGN or C3 glomerulonephritis for by a of the terminal pathway by of in However, only patients and the other The presence of as a for P. Daina E. A. et blockade in membranoproliferative a clinical J 2019; Full Text Full Text PDF PubMed Scopus Google Scholar retrospective have also to the of to among patients with C3G. case of patients with C3G, of or that a of of no in patients, and with the the patients with a kidney a more progressive course and more on kidney The that the have a of glomerular rather the of complement Quintrec M. A. et of clinical to in patients with C3 J 2018; Full Text Full Text PDF PubMed Scopus Google Scholar In a of included patients with C3G for a of the of of an in a renal and the other F. L. et as a treatment for C3 glomerulopathy: a retrospective Nephrol. PubMed Google Scholar an is a that the of to its is a of the of through with as a and of in and has a on and M. The disease, and PubMed Google Scholar not it has on the to a showing results as an therapy to standard-of-care therapy in patients with is being in other glomerular of P. for the treatment of J 2021; PubMed Scopus (0) Google Scholar The a has with C3G to a for which the for in the results in A. P. of a on glomerulopathy of disease Full Text Full Text PDF Google Scholar and in and a of disease in the patients the However, the of in disease no between and in disease also in patients that from to A. P. of a on glomerulopathy of disease Full Text Full Text PDF Google Scholar is the and only therapy with a the C3 and to be in is an that with consensus of which AP C3 2 is aiming to with C3G or to the and or of the optimal in 1 of the in 2 this agent or a The is in and in as as or and The pathway is such as or in the of pathogenic or immune a with 1 and which and to the pathway C3 (Figure The pathway has as a in glomerular such as and however, the in C3G pathogenesis has not In a of patients with C3G, a nephritic an to to and can be M. P. M. an of and clinical Immunol. 2019; PubMed Scopus Google Scholar 1 and have to in the although a of 1 or not complement in an of M.M. M. Pickering M.C. C3 dysregulation to factor is and in Immunol. 2014; PubMed Scopus (0) Google Scholar The only therapy being for pathway in complement-mediated is a that 2 to with and C3G or and the measures included as as in proteinuria, and complement results in patients with although is no available on the C3G B.H. J.A. J. Barratt J. and efficacy of a inhibitor for the treatment of 2020; Full Text Full Text PDF PubMed Scopus Google Scholar of C3G it is not that 2 complement in C3G. agents have in trials with in and in results in complement AP and glomerular deposit agents have the complement AP the of targeting C3 for in an C3G of with of for of of AP and of glomerular C. M. D. et targeting complement C3 in a of C3 Immunol. PubMed Google Scholar complement of the to the AP C3 and on with variants in the and this agent the and of factor and as as proteinuria, hematuria, glomerular C3 and glomerular and glomerulonephritis M. et of C3 glomerulopathy by complement of the Am Soc Nephrol. 2018; 29: PubMed Scopus Google Scholar of has the of in with or of of The not benefits in those with a of who a severe C3G with C3 and glomerular C3 However, among with a of the C3G the it C3 and glomerular C3 C. M. D. et factor to C3 glomerulopathy: evidence from a of complement Immunol. PubMed Scopus Google Scholar the role of have with for a the of glomerular deposit more and are such as a of from complement 2 and complement a with of as as and consensus agents have in and in of C3 as as in glomerular and M.M. et of complement in C3 Am Soc Nephrol. 2016; PubMed Scopus Google Scholar, F. A. et is a complement inhibitor with Am Soc Nephrol. 2018; 29: PubMed Scopus Google Scholar, Y. et complement factor for treatment of C3 Am Soc Nephrol. 2018; 29: PubMed Scopus Google Scholar the we have in of C3G as as in the and development of complement however, some clinical trials have a key role to in those A.S. Appel G.B. et clinical trials for in complement-mediated of a by the J Full Text Full Text PDF PubMed Scopus Google Scholar which patients most from these is of with a a for of kidney to and kidney in proteinuria, presence of or and features in kidney biopsy, such as or and A.S. Santoriello D. Avasare R.S. et al.C3 glomerulonephritis and dense deposit disease share a similar disease course in a large United States cohort of patients with C3 glomerulopathy.Kidney Int. 2018; 93: 977-985https://doi.org/10.1016/j.kint.2017.10.022Abstract Full Text Full Text PDF PubMed Scopus (100) Google Scholar,5Servais A. Ne Noël L.-H. Roumenina L.T. et al.Acquired and genetic complement abnormalities play a critical role in dense deposit disease and other C3 glomerulopathies.Kidney Int. 2012; 82: 454-464https://doi.org/10.1038/ki.2012.63Abstract Full Text Full Text PDF PubMed Scopus (403) Google Scholar,11Iatropoulos P. Noris M. Mele C. et al.Complement gene variants determine the risk of immunoglobulin-associated MPGN and C3 glomerulopathy and predict long-term renal outcome.Mol Immunol. 2016; 71: 131-142https://doi.org/10.1016/J.MOLIMM.2016.01.010Crossref PubMed Scopus (0) Google N.R. et of with in C3 glomerulopathy and immunoglobulin-associated membranoproliferative J Am Soc Nephrol. PubMed Scopus Google Scholar, F. F. M. of a to the of C3 2021; PubMed Google Scholar, F. Díaz-Encarnación M. V. et in and kidney in C3 PubMed Google Scholar and be of clinical to to these and a between and the most therapy for also a the of agents the driver of the disease in case through genetic and complement be key to abnormalities in components of the AP be are and be included in clinical trials to predictors of to treatment and of treatment In with this some have a to immunosuppression with and among patients with with those with genetic F. Díaz-Encarnación M.M. Lucientes L. et al.Mycophenolate mofetil in c3 glomerulopathy and pathogenic drivers of the disease.Clin J Am Soc Nephrol. 2020; 15: 1287-1298https://doi.org/10.2215/CJN.15241219Crossref PubMed Scopus (29) Google A. A.S. C3 glomerulopathy: 2018; 93: Full Text Full Text PDF PubMed Scopus Google Scholar complement be an or a for immunosuppression is also for is as with an expected of therapy in most to disease in to is showing results in the treatment of C3G as as other complement-mediated strategy has the to provide patients with therapy and the from nonspecific agents such as some and to be before we can these agents in patients with C3G, among and long-term

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