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40 years!
Last updated:
1/19/23
Years published: 2005, 2010, 2013, 2015, 2018, 2023
NORD gratefully acknowledges Richard JH Smith, MD, Director of the Iowa Institute of Human Genetics and the Molecular Otolaryngology and Renal Research Laboratories at the University of Iowa, for assistance in the preparation of this report.
Over the past decade, important advances in our understanding of complement-mediated renal diseases have led to the adoption of new names or ‘disease categories’ to more precisely group diseases that appear to share a similar cause. Consider, for example, dense deposit disease (DDD), a very rare kidney disease characterized on a renal biopsy test called ‘immunofluorescence’ by an abundance of a protein called C3 in the renal glomeruli and named for the extremely dense ‘sausage-like’ deposits that are seen in the glomerular basement membrane (GBM) using electron microscopy. In 2013, after a consensus meeting, scientists recommended that DDD be sub-grouped under a new heading – C3 Glomerulopathy, abbreviated C3G. The adoption of this new term was driven by the recognition that there is another group of patients with glomerular disease whose kidney biopsy is reminiscent of DDD. On electron microscopy, the deposits in these patients are lighter in color and more widespread in location, but on immunofluorescence, as with DDD there is an abundance of C3 in the renal glomeruli. These patients are said to have C3 glomerulonephritis or C3GN. In recognition of shared similarities, both DDD and C3GN are now classified as sub-types of C3G. C3G, itself, falls under the category of C3 dominant glomerulopathy, which also includes monoclonal gammopathy of renal significance (MGRS) and post-infectious glomerulonephritis (PIGN), two diseases that can mimic C3G but are distinct in their causality, natural history and treatment.
What happens in C3G? The glomeruli are the filtering units of the kidney, where blood gets filtered under pressure through the GBM into another space, called Bowman’s space, as urine. About 1-2 million glomeruli in each kidney do the filtering, creating a filtrate of water, sodium, potassium, chloride, glucose and small proteins. In both DDD and C3GN, deposits of C3 and other proteins in the GBM disrupt kidney function. Progressive damage to the glomeruli occurs and after about 10 years, enough damage has occurred so that about half of all persons with C3G have kidney failure. When kidney failure occurs, dialysis must be started, or transplantation must be performed. The rate of progression to end-stage kidney failure and dialysis appears to be similar for both DDD and C3GN.
In addition to dense deposits in the kidney, persons with DDD can develop deposits in their eyes in an area called Bruch’s membrane. This occurs because the ‘choriocapillaris-Bruch’s membrane-retinal pigment epithelium’ interface in the eye is very similar to the capillary-GBM interface in the kidney. The eye deposits are called drusen. Whether they occur more or less frequently in patients with C3GN is not clear.
The signs and symptoms of DDD and C3GN are similar. They include blood in the urine, which is called hematuria; dark foamy urine, which signifies the presence of protein or ‘proteinuria’; cloudiness of the urine, reflecting the presence of white blood cells; swelling or ‘edema’, initially of the legs although any part of the body can be affected; high blood pressure; decreased urine output; and decreased alertness.
As mentioned earlier, when a kidney biopsy is done in a person with the above signs and symptoms if C3G (either DDD or C3GN) is suspected, the immunofluorescence analysis must show abundant C3 in the glomerular capillaries. This finding is a requirement and in its absence the diagnosis of C3G can be excluded. Sophisticated studies have been done to determine the precise composition of the electron-dense deposits in DDD and C3GN, and in addition to C3 and its breakdown fragments, glomeruli contain many other proteins that belong to a system called the complement system. Proteins from both the alternative pathway of complement and the terminal pathway of the complement are found. This finding agrees with our understanding of the pathophysiology of DDD and C3GN.
As might be expected, since complement proteins are typically in the blood stream, if they become trapped in the kidneys, blood stream levels will often be correspondingly reduced; and in fact, in persons with both DDD and C3GN several complement proteins in the blood stream circulate at lower-than-expected levels. The most notable is the decrease in C3, which tends to be reduced to a greater extent in persons with DDD as compared to C3GN. Studies are currently being done to measure the levels of many different complement proteins in persons with DDD and C3GN and to compare these levels to persons without any kidney disease to determine whether the ‘profile’ for DDD and C3GN is unique. This technique is called ‘complement biomarker profiling’. This type of information provides clinicians with insight into what is happening at the level of the complement system in their patients with DDD and C3GN and can help to drive treatment decisions.
The immediate cause of the symptoms of C3G is the change in the filtering mechanism of the kidney. The damaged glomeruli (the filters) permit protein and red and white blood cells to pass into the urine-containing space.
The most abundant protein in the blood stream is albumin. As albumin passes into the urine and is lost from the blood stream, hypoalbuminemia or ‘low albumin in the blood stream’ develops. One consequence of hypoalbuminemia is that water leaks out of the circulation and accumulates in the surrounding tissues. This process leads to edema or swelling. Because of gravity and hydrostatic pressure (water pressure), the effects of fluid leakage are most apparent in the feet and ankles, which become swollen. As kidney function further deteriorates and urine output decreases, sodium and water are retained, and the swelling becomes magnified. High blood pressure also develops.
The specific cause of C3G is lack of regulation of the complement system. The causes of complement dysregulation can be divided into genetic and acquired factors. Amongst the former are changes in many of the complement genes, and amongst the latter are specific antibodies called C3 nephritic factors or C3Nefs that impair normal regulation of the complement system. It appears that patients with DDD are more likely to have C3Nefs, while patients with C3GN are more likely to have abnormalities in a group of proteins called the ‘complement factor H related’ proteins. Identifying drivers of complement dysregulation in C3G remains an active area of research because in about 30% of patients, a precise cause for complement dysregulation cannot be found.
C3G affects persons of all ages, although the mean age appears to be lower in DDD patients as compared to C3GN patients. The prevalence of C3G is estimated at 2-3 per 1,000,000 people. Persons over the age of 50 who present with a biopsy consistent with C3G should be evaluated for MGRS.
C3G can only be diagnosed by a kidney biopsy. The kidney deposits stain for the complement protein C3 and when examined under an electron microscope, dense deposits are present.
There is currently no specific therapy for C3G, however several non-specific treatments are appropriate. These treatments slow progression of chronic glomerular diseases through aggressive blood pressure control and reduction of proteinuria. Both angiotensin-converting enzyme (ACE) inhibitors and angiotensin II type-1 receptor blockers (ARBs) are first-line drugs to decrease spillage of protein into the urine and to improve kidney hemodynamics. These drugs may also limit the infiltration of white blood cells into the kidney. If hyperlipidemia (increased lipid in the blood stream) is present, lipid-lowering drugs can be used to reduce long-term atherosclerotic risks. These drugs may also delay progression of kidney disease.
Although widely used at one point, long steroid therapy should be avoided in C3G. It is, however, effective in a form of glomerulonephritis called juvenile acute non-proliferative glomerulonephritis (JANG), which can be confused with DDD. JANG can be distinguished from DDD because: 1) DDD is associated with low C3 levels; and 2) persons with DDD often have nephrotic syndrome (greater than 3.5 gm of protein in the urine over 24 hours; hypoalbuminemia; edema). In JANG, C3 levels remain at the lower limit of normal.
Some studies suggest that mycophenolate mofetil (MMF, +/- a short course of steroids) may be beneficial in patients with C3G by decreasing the rate of progression to end-stage kidney failure. MMF inhibits inosine monophosphate dehydrogenase, the enzyme that controls the rate of synthesis of guanine monophosphate.
One class of anti-complement drugs is widely available. Known as eculizumab or ravulizumab, these two drugs are humanized monoclonal antibodies against C5 that block activity of the terminal pathway of complement. Eculizumab requires dosing every two weeks while ravulizumab can be given every eight weeks. In studies that have looked at the effect of eculizumab in patients with C3G, it appears that eculizumab is effective in decreasing proteinuria and the rate of progression of kidney disease in some but not all patients. Identifying those patients who are likely to respond to eculizumab is difficult, but elevated levels of soluble C5b-9 may be indicative of a good response. Soluble C5b-9 is one of the biomarkers of complement activity that is regularly measured when complement biomarker profiling is done, as was mentioned earlier. However, because eculizumab blocks generation of a small cleavage product of C5 called C5a, eculizumab has a potent anti-inflammatory effect, which may contribute to some of its observed effect.
Persons with C3G who progress to end-stage kidney failure must receive dialysis – either peritoneal dialysis or hemodialysis – or a kidney transplantation. Transplantation is associated with a high rate of disease recurrence in the allograft and about half of transplants ultimately fail. There is some indication that pre-transplant complement biomarkers can predict which patients are more likely to develop clinically significant recurrence of C3G.
Many investigational anti-complement therapies are currently in clinical trials in Europe and North America. In the USA, all clinical trials receiving U.S. Government funding and some trials supported by private industry are posted on www.clinicaltrials.gov.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov
Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, contact:
https://www.centerwatch.com/
For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
Contact for additional information about this condition and clinical trials available at the University of Iowa, contact:
Richard JH Smith, MD
Director of the Molecular Otolaryngology and Renal Research Laboratories
University of Iowa
richard-smith@uiowa.edu
JOURNAL ARTICLES
Bomback AS, Kavanagh D, Vivarelli M, Meier M, Wang Y, Webb NJA, Trapani AJ, Smith RJH. Alternative complement pathway inhibition with iptacopan for the treatment of C3 glomerulopathy-study design of the APPEAR-C3G trial. Kidney Int Rep. 2022 Aug 2;7(10):2150-2159. doi: 10.1016/j.ekir.2022.07.004. PMID: 36217526; PMCID: PMC9546729.
Chauvet S, Hauer JJ, Petitprez F, Rabant M, Martins PV, Baudouin V, Delmas Y, Jourde-Chiche N, Cez A, Ribes D, Cloarec S, Servais A, Zaidan M, Daugas E, Delahousse M, Wynckel A, Ryckewaert A, Sellier-Leclerc AL, Boyer O, Thervet E, Karras A, Smith RJH, Frémeaux-Bacchi V. Results from a nationwide retrospective cohort measure the impact of C3 and soluble C5b-9 levels on kidney outcomes in C3 glomerulopathy. Kidney Int. 2022 Oct;102(4):904-916. doi: 10.1016/j.kint.2022.05.027. Epub 2022 Jun 22. PMID: 35752323.
Bomback AS, Appel GB, Gipson DS, Hladunewich MA, Lafayette R, Nester CM, Parikh SV, Smith RJH, Trachtman H, Heeger PS, Ram S, Rovin BH, Ali S, Arceneaux N, Ashoor I, Bailey-Wickins L, Barratt J, Beck L, Cattran DC, Cravedi P, Erkan E, Fervenza F, Frazer-Abel AA, Fremeaux-Bacchi V, Fuller L, Gbadegesin R, Hogan JJ, Kiryluk K, le Quintrec-Donnette M, Licht C, Mahan JD, Pickering MC, Quigg R, Rheault M, Ronco P, Sarwal MM, Sethna C, Spino C, Stegall M, Vivarelli M, Feldman DL, Thurman JM. Improving clinical trials for anticomplement therapies in complement-mediated glomerulopathies: report of a scientific workshop sponsored by the National Kidney Foundation. Am J Kidney Dis. 2021 Sep 24:S0272-6386(21)00884-2. doi: 10.1053/j.ajkd.2021.07.025. Epub ahead of print. PMID: 34571062.
Johnson CK, Zuniga SC, Dhawale T, Zhang Y, Smith RJH, Blosser CD. Monoclonal gammopathy of renal significance causes C3 glomerulonephritis via monoclonal IgG kappa inhibition of complement factor H. Kidney Int Rep. 2021 Jun 27;6(9):2505-2509. doi: 10.1016/j.ekir.2021.06.015. PMID: 34514215; PMCID: PMC8418982.
Zhang Y, Ghiringhelli Borsa N, Shao D, Dopler A, Jones MB, Meyer NC, Pitcher GR, Taylor AO, Nester CM, Schmidt CQ, Smith RJH. Factor H autoantibodies and complement-mediated diseases. Front Immunol. 2020 Dec 15;11:607211. doi: 10.3389/fimmu.2020.607211. PMID: 33384694; PMCID: PMC7770156.
Zhang Y, Keenan A, Dai DF, May KS, Anderson EE, Lindorfer MA, Henrich JB, Pitcher GR, Taylor RP, Smith RJ. C3(H2O) prevents rescue of complement-mediated C3 glomerulopathy in Cfh-/- Cfd-/- mice. JCI Insight. 2020 May 7;5(9):e135758. doi: 10.1172/jci.insight.135758. PMID: 32376801; PMCID:PMC7253029.
Schubart A, Anderson K, Mainolfi N, Sellner H, Ehara T, Adams CM, Mac Sweeney A, Liao SM, Crowley M, Littlewood-Evans A, Sarret S, Wieczorek G, Perrot L, Dubost V, Flandre T, Zhang Y, Smith RJH, Risitano AM, Karki RG, Zhang C, Valeur E, Sirockin F, Gerhartz B, Erbel P, Hughes N, Smith TM, Cumin F, Argikar UA, Haraldsson B, Mogi M, Sedrani R, Wiesmann C, Jaffee B, Maibaum J, Flohr S, Harrison R, Eder J. Small-molecule factor B inhibitor for the treatment of complement-mediated diseases. Proc Natl Acad Sci U S A. 2019 Apr 16;116(16):7926-7931. doi: 10.1073/pnas.1820892116. Epub 2019 Mar 29. PubMed PMID: 30926668; PubMed Central PMCID: PMC6475383
Smith RJH, Appel GB, Blom AM, Cook HT, D’Agati VD, Fakhouri F, Fremeaux-Bacchi V, Józsi M, Kavanagh D, Lambris JD, Noris M, Pickering MC, Remuzzi G, de Córdoba SR, Sethi S, Van der Vlag J, Zipfel PF, Nester CM. C3 glomerulopathy – understanding a rare complement-driven renal disease. Nat Rev Nephrol. 2019 Mar;15(3):129-143. doi: 10.1038/s41581-018-0107-2. Review. PubMed PMID: 30692664.
Mastellos DC, Reis ES, Ricklin D, Smith RJ, Lambris JD. Complement C3-targeted therapy: replacing long-held assertions with evidence-based discovery. Trends Immunol. 2017 Jun;38(6):383-394. doi: 10.1016/j.it.2017.03.003. Epub 2017 Apr 14. Review. PubMed PMID: 28416449; PubMed Central PMCID: PMC5447467.
Goodship TH, Cook HT, Fakhouri F, Fervenza FC, Frémeaux-Bacchi V, Kavanagh D, Nester CM, Noris M, Pickering MC, Rodríguez de Córdoba S, Roumenina LT, Sethi S, Smith RJ; Conference Participants. Atypical hemolytic uremic syndrome and C3 glomerulopathy: conclusions from a “kidney disease: improving global outcomes” (KDIGO) controversies conference. Kidney Int. 2016 Dec 15. pii: S0085-2538(16)30604-4. doi: 10.1016/j.kint.2016.10.005. [Epub ahead of print], 91(3):539-551, 2017.PubMed PMID: 27989322.
Nester CM, Smith RJH. Complement inhibition in C3 glomerulopathy. Semin Immunol. 2016 Jul 9 [Epub ahead of print] 28(3):241-9, 2016. doi: 10. 1016/j.smim.2016.06.002.
Rabasco C, Cavero T, Román E, Rojas-Rivera J, Olea T, Espinosa M, Cabello V, Fernández-Juarez G, González F, Ávila A, Baltar JM, Díaz M, Alegre R, Elías S, Antón M, Frutos MA, Pobes A, Blasco M, Martín F, Bernis C, Macías M, Barroso S, de Lorenzo A, Ariceta G, López-Mendoza M, Rivas B, López-Revuelta K, Campistol JM,
Mendizábal S, de Córdoba SR, Praga M. Effectiveness of mycophenolate mofetil in C3 glomerulonephritis. Kidney Int. 2015 Jul 29. doi: 10.1038/ki.2015.227.[Epub ahead of print].
Ruseva MM, Peng T, Lasaro MA, Bouchard K, Liu-Chen S, Sun F, Yu ZX, Marozsan A, Wang Y, Pickering MC. Efficacy of targeted complement inhibition in experimental C3 glomerulopathy. J Am Soc Nephrol. 2015 Jun 5. pii: ASN.2014121195. [Epub ahead of print].
Zhang Y, Shao D, Ricklin D, Hilkin BM, Nester CM, Lambris JD, Smith RJH. Compstatin analog Cp40 inhibits complement dysregulation in vitro in C3 glomerulopathy. Immunobiol 2015 May 5 [Epub ahead of print]; 220(8):993-8, 2015.
Zhang Y, Nester CM, Martin B, Skjoedt MO, Meyer NC, Shao D, Borsa N, Palarasah Y, Smith RJ. Defining the complement biomarker profile of C3 glomerulopathy. Clin J Am Soc Nephrol 2014 Oct 23 [Epub ahead of print]; 9 (11):1876-82, 2014.
Pickering MC, D’Agati VD, Nester CM, Smith RJ, Haas M, Appel GB, Alpers CE, Bajema IM, Bedrosian C, Braun M, Doyle M, Fakhouri F, Fervenza FC, Fogo AB, Frémeaux-Bacchi V, Gale DP, Goicoechea de Jorge E, Griffin G, Harris CL, Holers VM, Johnson S,Lavin PJ, Medjeral-Thomas N, Morgan BP, Nast CC, Noel L-H, Peters DK, Rodríguez de Córdoba S, Servais A, Sethi S, Song W-C, Tamburini P, Thurman JM, Zavros M, Cook TH. C3 glomerulopathy: consensus report. Kidney Inter 2013 Oct 30 [Epub ahead of print]; 84:1079-89, 2013.
Bomback AS, Smith RJH, Barile GR, Zhang Y, Heher EC, Herlitz L, Stokes MB, Markowitz GS, D’Agati VD, Canetta PA, Radhakrishnan J, Appel GB. Eculizumab for dense deposit disease and C3 glomerulonephritis. Clin J Am Soc Nephrol 2012 Mar 8 [Epub ahead of print]; 7(5):748-56, 2012.
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