How does C3 glomerulopathy typically progress, and what is the long-term outlook for kidney function?

C3 glomerulopathy tends to worsen over time due to uncontrolled activation of the complement system, leading to progressive kidney damage. About half of affected individuals develop end-stage renal disease (ESRD) within 10 years after diagnosis.

What role does genetics play in C3 glomerulopathy, and is it always inherited?

C3 glomerulopathy is associated with changes in many genes that regulate the complement system, such as CFHR5, C3, and CFH. While specific mutations cause the condition in some cases, these account for only a small percentage, and in most cases, the cause remains unknown. Certain normal gene variants (polymorphisms) can also increase the likelihood of developing the condition.

C3 glomerulopathy

C3 glomerulopathy is a rare kidney disorder driven by uncontrolled activation of the complement system, leading to progressive kidney damage and often end‑stage renal disease within a decade.

Overview

C3 glomerulopathy is a group of related conditions that cause the kidneys to malfunction. The major features include high levels of protein in the urine (proteinuria), blood in the urine (hematuria), reduced urine output, low levels of protein in the blood, and swelling in many areas of the body. Affected individuals may have particularly low levels of a protein called complement component 3 (C3) in the blood. The kidney problems associated with C3 glomerulopathy tend to worsen over time, and about half of affected individuals develop end‑stage renal disease (ESRD) within 10 years after diagnosis.

Symptoms

Proteinuria (high protein in urine)
Hematuria (blood in urine)
Reduced urine output
Low blood protein levels
Swelling (edema) in various body areas

Causes & Risk Factors

C3 glomerulopathy is associated with changes in many genes that regulate the complement system, a group of proteins that destroy foreign invaders, trigger inflammation, and remove debris. The complement system must be carefully regulated to avoid damaging healthy cells.

Genetic Causes

A specific mutation in the CFHR5 gene has been found to cause C3 glomerulopathy in people from Cyprus. Mutations in the C3 and CFH genes, as well as other complement system–related genes, have been identified in other populations. These known mutations account for only a small percentage of all cases; in most cases the cause remains unknown.

Several normal variants (polymorphisms) in complement system–related genes are associated with an increased likelihood of developing C3 glomerulopathy. In some cases, a combination of specific variants in several genes—known as a C3 glomerulopathy at‑risk haplotype—raises risk, though many people with these changes never develop the condition.

Learn more about the genes associated with C3 glomerulopathy

C3
C8A
CFH
CFHR5
CFI

ADAM19
C3AR1
CD46
CFB
CFD
CFHR1
CFHR2
CFHR3
CR1

Autoantibodies

Specialized proteins called autoantibodies can also cause C3 glomerulopathy by altering the activity of proteins that regulate the complement system.

Associated Conditions

One form of C3 glomerulopathy, dense deposit disease, can be associated with conditions unrelated to kidney function. People with dense deposit disease may develop acquired partial lipodystrophy—a lack of fatty tissue under the skin in the upper body—and may also develop drusen, yellowish deposits in the retina that can cause vision problems later in life.

Frequency

C3 glomerulopathy is very rare, affecting 1 to 2 per million people worldwide, and is equally common in men and women.

Inheritance

Most cases are sporadic, occurring in individuals with no family history of the disorder. Only a few families have had more than one member with C3 glomerulopathy. Many affected people have close relatives with autoimmune diseases, though the connection is not fully understood.

Other Names for This Condition

C3 glomerulonephritis
C3G
DDD
DDD/MPGNII
Dense deposit disease
Membranoproliferative glomerulonephritis type II

Additional Information & Resources

Genetic Testing Information

Genetic Testing Registry: C3 Glomerulonephritis
Genetic Testing Registry: CFHR5 deficiency
Genetic Testing Registry: CFHR5‑Related Dense Deposit Disease / Membranoproliferative Glomerulonephritis Type II
Genetic Testing Registry: Factor H deficiency
Genetic Testing Registry: Mesangiocapillary glomerulonephritis, type II

Genetic and Rare Diseases Information Center

Dense deposit disease
Glomerulonephritis

Patient Support and Advocacy Resources

National Organization for Rare Disorders (NORD)

Clinical Trials

ClinicalTrials.gov

Catalog of Genes and Diseases from OMIM

C3 GLOMERULOPATHY 3; C3G3
COMPLEMENT FACTOR H DEFICIENCY; CFHD

Scientific Articles on PubMed

Abrera‑Abeleda MA, Nishimura C, Frees K, Jones M, Maga T, Katz LM, Zhang Y, Smith RJ. Allelic variants of complement genes associated with dense deposit disease. J Am Soc Nephrol. 2011 Aug;22(8):1551-9. doi: 10.1681/ASN.2010080795.
Barbour TD, Ruseva MM, Pickering MC. Update on C3 glomerulopathy. Nephrol Dial Transplant. 2016 May;31(5):717-25. doi: 10.1093/ndt/gfu317.
Bu F, Borsa NG, Jones MB, Takanami E, Nishimura C, Hauer JJ, Azaiez H, Black‑Ziegelbein EA, Meyer NC, Kolbe DL, Li Y, Frees K, Schnieders MJ, Thomas C, Nester C, Smith RJ. High‑Throughput Genetic Testing for Thrombotic Microangiopathies and C3 Glomerulopathies. J Am Soc Nephrol. 2016 Apr;27(4):1245-53. doi: 10.1681/ASN.2015040385.
Fakhouri F, Fremeaux‑Bacchi V, Noel LH, Cook HT, Pickering MC. C3 glomerulopathy: a new classification. Nat Rev Nephrol. 2010 Aug;6(8):494-9. doi: 10.1038/nrneph.2010.85.
Martin B, Smith RJH. C3 Glomerulopathy. 2007 Jul 20 [updated 2018 Apr 5]. In: Adam MP, Bick S, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews(R) [Internet]. Seattle (WA): University of Washington, Seattle; 1993‑2026. Available from http://www.ncbi.nlm.nih.gov/books/NBK1425/
Medjeral‑Thomas NR, O'Shaughnessy MM, O'Regan JA, Traynor C, Flanagan M, Wong L, Teoh CW, Awan A, Waldron M, Cairns T, O'Kelly P, Dorman AM, Pickering MC, Conlon PJ, Cook HT. C3 glomerulopathy: clinicopathologic features and predictors of outcome. Clin J Am Soc Nephrol. 2014 Jan;9(1):46-53. doi: 10.2215/CJN.04700513.
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, Fremeaux‑Bacchi V, Gale DP, Goicoechea de Jorge E, Griffin G, Harris CL, Holers VM, Johnson S, Lavin PJ, Medjeral‑Thomas N, Paul Morgan B, Nast CC, Noel LH, Peters DK, Rodriguez de Cordoba S, Servais A, Sethi S, Song WC, Tamburini P, Thurman JM, Zavros M, Cook HT. C3 glomerulopathy: consensus report. Kidney Int. 2013 Dec;84(6):1079-89. doi: 10.1038/ki.2013.377.
Servais A, Noel LH, Roumenina LT, Le Quintrec M, Ngo S, Dragon‑Durey MA, Macher MA, Zuber J, Karras A, Provot F, Moulin B, Grunfeld JP, Niaudet P, Lesavre P, Fremeaux‑Bacchi V. Acquired and genetic complement abnormalities play a critical role in dense deposit disease and other C3 glomerulopathies. Kidney Int. 2012 Aug;82(4):454-64. doi: 10.1038/ki.2012.63.
Xiao X, Pickering MC, Smith RJ. C3 glomerulopathy: the genetic and clinical findings in dense deposit disease and C3 glomerulonephritis. Semin Thromb Hemost. 2014 Jun;40(4):465-71. doi: 10.1055/s-0034-1376334.
Zipfel PF, Skerka C, Chen Q, Wiech T, Goodship T, Johnson S, Fremeaux‑Bacchi V, Nester C, de Cordoba SR, Noris M, Pickering M, Smith R. The role of complement in C3 glomerulopathy. Mol Immunol. 2015 Sep;67(1):21-30. doi: 10.1016/j.molimm.2015.03.012.

Medical Encyclopedia

Genetics
Glomerulonephritis

Understanding Genetics

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