C3 Glomerulopathy (C3G) and Primary Immune Complex Membranoproliferative Glomerulonephritis (IC-MPGN)

C3G and primary IC-MPGN are rare kidney diseases. In both diseases, an important part of the immune system known as the complement cascade is overactive, which results in the excessive breakdown of a protein called C3.¹ These C3 breakdown products become trapped in the kidney, causing inflammation and damage to the organ.¹

Although C3G is a distinct disease from primary IC-MPGN, the underlying cause and progression of the two diseases are remarkably similar.^2,3 The signs and symptoms of C3G and primary IC-MPGN include blood in the urine (hematuria); dark foamy urine due to the presence of protein (proteinuria); edema (swelling), often in the legs, although any part of the body can be affected; high blood pressure; and decreased urine output.⁴C3G and primary IC-MPGN can lead to kidney failure within five to 10 years of diagnosis, requiring these patients to go on dialysis or get a kidney transplant.⁵

Pegcetacoplan in C3G and Primary IC-MPGN

Pegcetacoplan is a targeted C3 therapy under investigation for C3G and primary IC-MPGN. We believe pegcetacoplan may have the potential to target the underlying disease processes of C3G and primary IC-MPGN.

Common Questions about C3 Glomerulopathy (C3G) and Primary Immune Complex Membranoproliferative Glomerulonephritis (IC-MPGN)

What are C3G and primary IC-MPGN?

C3G and primary IC-MPGN are rare, progressive, and debilitating glomerular diseases that affect up to 18,000 children and adults in the United States and Europe.^6-9 These diseases cause damage to structures in the kidneys called glomeruli and lead to kidney damage and failure, requiring chronic dialysis and eventual transplantation.^6,7,10,11

What are the signs and symptoms of C3G and primary IC-MPGN?

Proteinuria^6,12,13
Hematuria^6,12,13
Fatigue¹⁴
Edema (swelling)¹⁴
Hypertension^6,7
Decreased glomerular filtration rate, a measure of kidney function^7,12,14
Low serum C3^7,15
Drusen^10,16

What causes C3G and primary IC-MPGN?

Overactivation of the complement system leads to excessive breakdown of C3, a central component of the complement system. Excessive deposition of C3 breakdown products (with or without the presence of immunoglobulins) in the glomeruli leads to kidney damage.^6,10,17,18

What is the complement system?

The complement system is an integral part of our immune defense system. In healthy people, complement orchestrates the destruction and clearance of pathogens or of the body’s own cells that need to be removed. It also has proinflammatory capabilities.¹⁸

Complement activation is regulated to avoid its overactivation and to protect the body against inappropriate immune attack. When regulation is compromised, hyperactivation of the complement cascade can lead to inflammation and inappropriate cell destruction.¹⁹

Three pathways converge with the cleavage of complement protein C3, which induces inflammation and labels cells for phagocytosis (destruction by special white blood cells). The complement cascade continues with the cleavage of complement protein C5, which triggers cell death via phagocytosis, inflammation, and ultimately activation of the membrane attack complex (MAC), which causes damage and cell death.¹⁸

Are C3G and primary IC-MPGN hereditary?

Both genetic and acquired factors can contribute to the complement overactivation that underlies C3G and primary IC-MPGN. Genetic abnormalities in complement genes have been found in ≈25% of patients with C3G and ≈16% of patients with primary IC-MPGN.^10,20

How are C3G and primary IC-MPGN diagnosed?

A kidney biopsy followed by histopathological analyses are required to diagnose C3G and primary IC-MPGN.^6,17

How can you differentiate C3G from primary IC-MPGN and other diseases with similar clinical presentation?

Light microscopy is used to assess general patterns of glomerular injury but is not sufficient to diagnose C3G or primary IC-MPGN.⁶Immunofluorescence microscopy is required to diagnose and distinguish between C3G and primary IC-MPGN. Both diseases show positive staining for the complement protein C3 while primary IC-MPGN will also display positive staining for immunoglobulins.^6,10,21Electron microscopy further distinguishes between 2 subtypes of C3G: C3 glomerulonephritis (C3GN) and dense deposit disease (DDD).^6,10

What is the typical patient journey for people diagnosed with C3G and primary IC-MPGN?

While the clinical presentation and disease progression of C3G and primary IC-MPGN can vary widely, up to 50% of patients progress to end-stage renal disease (ESRD) in 5-10 years and may require dialysis and/or transplantation.^6,7,11 Because transplantation does not target the underlying complement overactivation that causes C3G and primary IC-MPGN, it is not curative; up to 89% of patients experience disease recurrence post transplant.^7,11,22-26

Are any therapies under investigation for C3G and primary IC-MPGN?

Multiple therapies targeting various components of the complement system (eg, proximal, central, terminal) are currently under investigation.^8,27,28

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References

Genetics Home Reference. Available at: https://ghr.nlm.nih.gov/condition/c3-glomerulopathy. Accessed November 27, 2019.
Noris M, Donadelli R, Remuzzi G. Autoimmune abnormalities of the alternative complement pathway in membranoproliferative glomerulonephritis and C3 glomerulopathy. Pediatr Nephrol. 2019 Aug;34(8):1311-1323.
Cook HT. Evolving complexity of complement-related diseases: C3 glomerulopathy and atypical haemolytic uremic syndrome. Curr Opin Nephrol Hypertens. 2018 May;27(3):165-170.
Complement 3 Glomerulopathy (C3G). National Kidney Foundation Website. https://www.kidney.org/atoz/content/complement-3-glomerulopathy-c3g. Accessed November 21, 2019.
C3 glomerulopathy. National Institute of Health, Genetics Home Reference. https://ghr.nlm.nih.gov/condition/c3-glomerulopathy#resources. Accessed November 21, 2019.
Smith RJH, et al. Nat Rev Nephrol. 2019;15(3):129-143.
Servais A, et al. Kidney Int. 2012;82(4):454-464.
Noris M, et al. Nephrol Dial Transplant. 2024;39(2):202-214.
Data on file, 2019.
Caravaca-Fontán F, et al. Nephron. 2020;144(6):272-280.
Zand L, et al. J Am Soc Nephrol. 2014;25(5):1110-1117.
Schena FP, et al. Int J Mol Sci. 2020;21(2):525.
Noris M, et al. Nephrol Dial Transplant. 2023;38(2):283-290.
National Kidney Foundation. Accessed May 10, 2024. https://www.kidney.org/sites/default/files/C3G_EL-PFDD_VoP-Report_3-29-18.pdf
Zhang Y, et al. Clin J Am Soc Nephrol. 2014;9(11):1876-1882.
Bradley DT, et al. Eye (Lond). 2011 Jun;25(6):683-693.
Sethi S, et al. N Engl J Med. 2012;366(12):1119-1131.
Dixon BP, et al. Kidney Int Rep. 2023;8(11):2284-2293.
Janeway CA Jr, et al, eds. The complement system and innate immunity. In: Immunobiology: The Immune System in Health and Disease. 5th ed. Garland Science; 2001. Accessed Oct 7, 2024. https://www.ncbi.nlm.nih.gov/books/NBK27100/.
Iatropoulos P, et al. J Am Soc Nephrol. 2018;29(1):283-294.
Hou J, et al. Kidney Int. 2014;85(2):450-456.
Caravaca-Fontán F, et al. Nephrol Dial Transplant. 2023;38(1):222-235.
Medjeral-Thomas NR, et al. Clin J Am Soc Nephrol. 2014;9(1):46-53.
Regunathan-Shenk R, et al. Am J Kidney Dis. 2019;73(3):316-323.
Frangou E, et al. Nephrol Dial Transplant. 2019;34(10):1780-1788.
Tarragón B, et al. Clin J Am Soc Nephrol. 2024;19(8):1005-1015.
Nester C, et al. Clin J Am Soc Nephrol. 2024;19(9):1201-1208.
Tarragón Estebanez B, et al. Kidney Int Rep. 2024;9(3):569-579.

C3 Glomerulopathy (C3G) and Primary Immune Complex Membranoproliferative Glomerulonephritis (IC-MPGN)

Common Questions about C3 Glomerulopathy (C3G) and Primary Immune Complex Membranoproliferative Glomerulonephritis (IC-MPGN)

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