C3 glomerulopathy

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Overview

Historical Perspective

Classification

Pathophysiology

Causes

Differentiating C3 glomerulopathy from other Diseases

Epidemiology and Demographics

Risk Factors

Screening

Natural History, Complications and Prognosis

Diagnosis

History and Symptoms

Physical Examination

Laboratory Findings

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MRI

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Medical Therapy

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Ali Poyan Mehr, M.D. [2];Associate Editor(s)-in-Chief: Vindhya BellamKonda, M.B.B.S [3]

Synonyms and keywords: glomerulonephritis; C3 glomerulonephritis; dense deposit disease

Overview

C3 glomerulopathy is a disorder of complement system, and can be due to inherited or acquired complement dysregulation and activation of the "alternative pathway". The category of C3 glomerulopathy contains a diverse group of disorders, including those leading to the inflammatory forms of C3 glomerulopathy, namely C3 glomerulonephritis (C3GN), as wells as those presenting as dense deposit disease (DDD). Both, C3GN and dense deposit disease are marked by C3 deposition along the capillary loop, the basement membrane, and the mesangium. It is a requirement for the diagnosis of C3 glomerulopathy, that the presence of C3 deposits comes without any concomitant immunoglobulin deposition.

The activation of the alternative pathway of the complement system can be either due to inherited, or acquired defects of the complement system. The inherited forms of complement dysregulation are due to numerous identified (and potentially yet to be identified) mutations of genes involved in complement pathway (see causes). The acquired forms of complement dysregulation are mostly due to autoimmunity against complement regulatory proteins.

Historical Perspective

Classification

  • Until recently, C3 glomerulopathy (C3 glomerulonephritis and DDD) were categorized under as a variant of MPGN, namely MPGN type 2. [5]
  • In 2007, Servais A. et al described C3GN as an entity by itself. C3 glomerulonephritis was described as glomerular disease with deposits made up of only C3 without the presence of any immunoglobulins, that may or may not have a membranoproliferative pattern [6].
  • Dense deposit disease refers to one subcategory of C3 glomerulopathy which is characterized by GBM deposits of C3 with characteristic appearance on electron micro graphs. Isolated C3 deposit in the glomerulus is the defining characteristics of C3 glomerulopathy. When deposit is linear, ribbon like and concentrated on the glomerular basement membrane, it is referred to as the Dense Deposit Disease (DDD). Currently, it is unknown whether the distinction between C3 glomerulonephritis and DDD has any therapeutic or prognostic relevance.
  • C3 Glomerulopathy may be classified into 2 main subtypes/groups:

Pathophysiology

  • The appropriate activation of complement system is under general circumstances triggered by infection. The inappropriate activation can be due to inherited or acquired disorders of complement pathway. Either a gain of function of complement “activators”, or a loss of function of complement “inhibitors” can lead to an activation of complement alternative pathway.
Activation of Classic Complement Pathway Activation of the Mannose-Binding-Lectin Pathway Activation of Alternative Complement Pathway
Acquired Acquired Acquired Inherited
Infection Apoptosis and necrosis Infection Infection Autoimmune disorder Paraneoplastic Genetic mutations

Causes

Several genetic or acquired causes have been described to date:

Like the majority of complement factors, CFH is a small glycoprotein which is produced in the liver, and circulates freely in the blood plasma . Several mutations in the CFH gene have been identified. While in type 1 mutations in this gene lead to a decrease in the level of functional CFH, the majority of mutations (type 2) do not affect the level of CFH, but rather decrease or diminish the function activity of this glycoprotein. Autoantibodies against CFH have been identified . [7]

MCP is a transmembrane protein, expressed by all nucleated cells and located at the cell surfaces. Together with Complement Factor I (CFI), MCP is required for the inactivation of C3b, which otherwise may initiate the formation of membrane attack complex. Mutations in the MCP gene can, similar to mutations in CFH lead to both, either a decrease in synthesis and expression of this protein, or a decreased activity.

Differentiating C3 Glomerulopathy from other Diseases

Mediacl condition Differentiating features
C3 glomerulopathy
  • Persistent glomerulonephritis over prolonged period
  • Decreased C3 levels persist
  • Immunofluorescence microscopy shows intense C3 staining without immunoglobulin staining.
Lupus nephritis
  • Anti C1q autoantibodies
  • Immune complex glomerulonephritis
  • Glomerular deposits of IgG, IgM, IgA, C3 and C1q
Poststreptococcal glomerulonephritis
  • Glomeruonephritis in most cases resolves after infection subsides
  • Decreased levels of C3 is transient
  • Immunoflouroescence microscopy shows immunoglobulin deposition in poststreptococcal infection
Staphylococcal associated glomerulonephritis
  • Glomerulonephritis resolves after infection subsides
  • Decreased C3 is transient
  • Immunofluorescence microscopy shows immunoglobulin deposition in staphylococcal associated glomerulonephritis.

Epidemiology and Demographics

Age

  • Patients of all age groups may develop C3 glomerulopathy but it commonly affects young adults and children (Dense deposit disease)

Gender

Race

Risk Factors

Natural History, Complications and Prognosis

Diagnosis

Diagnostic test of choice

Gold standard test of choice for C3 glomerulopathy is kidney biopsy.

Symptoms

Physical Examination

Appearance of the Patient

  • Patients with C3 glomerulopathy usually appear cachectic.

Vital Signs

  • new onset hypertension

Skin

HEENT

Neck

Lungs

  • Rales may be heard

Heart

Abdomen

  • Edema

Laboratory Findings

  • The following blood tests need to be done in the evaluation of C3 glomerulopathy.
  • CBC
  • Blood glucose levels and Hemoglobin A1C
  • BUN and Creatinine levels
  • Blood levels of Complement C3, C3 Nef, Serum factor H, CFHR ( Complement factor H-related protein)
  • 24-hr urine protein analysis

Imaging Findings

  • There are no imaging findings specific to C3 glomerulopathy

Other Diagnostic Studies

  • C3 glomerulopathy may also be diagnosed using light microscopy, immunofluorescence microscopy and electron microscopy
  • Findings on electron microscopy include mesangial proliferative glomerulonephritis, membranoproliferative glomerulonephritis and crescentic glomerulonephritis[11]
  • Immunofluorescence microscopy: C3 deposits along the Bowman's capsule, glomerular and tubular basement membranes
  • Electron microscopy findings in Dense Deposit Disease: Electron dense material in the glomerular basement membrane, lamina densa widening. Electron dense material is absent in C3 glomerulopathy. Subepithelial "humps" are found in both C3GN and Dense deposit disease. <ref name="pmid13867660">BERGER J, GALLE P (1962). "[Unusual change of the basal membranes of the kidney]". J Urol Nephrol (Paris) (in French). 68: 116–22. PMID 13867660.</ref

Treatment

Medical Therapy

  • Treatment is based on type of C3 glomerulopathy, severity and available treatment modalities.
  • Adequate control of proteinuria and hypertension is important. T.
  • Patients with DDD or C3GN may be treated with lipid lowering medications to prevent cardiovascular events.
  • All patients should be closely monitored with scheduled checkups and diagnostic laboratory workups.
  • Genetic screening is also advised for family members of patients that have genetic mutations.
  • Patients’ support groups can be found with groups like NEPHCURE Kidney International and other foundation that provide support for kidney patients and their families.


Prevention

  • There are no primary preventive measures available for C3 glomerulopathy .
  • Effective measures for the primary prevention of [disease name] include [measure1], [measure2], and [measure3].
  • Once diagnosed and successfully treated, patients with [disease name] are followed-up every [duration]. Follow-up testing includes [test 1], [test 2], and [test 3].

References

  1. SELIGMANN M, HANAU C (1958). "[Immuno-electrophoretic study of the blood of disseminated lupus erythematosus patients]". Rev Hematol (in French). 13 (2): 239–48. PMID 13568372.
  2. WEST CD, NORTHWAY JD, DAVIS NC (August 1964). "SERUM LEVELS OF BETA-1C GLOBULIN, A COMPLEMENT COMPONENT, IN THE NEPHRITIDES, LIPOID NEPHROSIS, AND OTHER CONDITIONS". J. Clin. Invest. 43: 1507–17. doi:10.1172/JCI105027. PMC 441951. PMID 14201535.
  3. BERGER J, GALLE P (1962). "[Unusual change of the basal membranes of the kidney]". J Urol Nephrol (Paris). 68: 116–22. PMID 13867660.
  4. Fakhouri F, Frémeaux-Bacchi V, Noël LH, Cook HT, Pickering MC (August 2010). "C3 glomerulopathy: a new classification". Nat Rev Nephrol. 6 (8): 494–9. doi:10.1038/nrneph.2010.85. PMID 20606628.
  5. Appel GB, Cook HT, Hageman G, Jennette JC, Kashgarian M, Kirschfink M, Lambris JD, Lanning L, Lutz HU, Meri S, Rose NR, Salant DJ, Sethi S, Smith RJ, Smoyer W, Tully HF, Tully SP, Walker P, Welsh M, Würzner R, Zipfel PF (May 2005). "Membranoproliferative glomerulonephritis type II (dense deposit disease): an update". J. Am. Soc. Nephrol. 16 (5): 1392–403. doi:10.1681/ASN.2005010078. PMID 15800116.
  6. Servais A, Frémeaux-Bacchi V, Lequintrec M, Salomon R, Blouin J, Knebelmann B; et al. (2007). "Primary glomerulonephritis with isolated C3 deposits: a new entity which shares common genetic risk factors with haemolytic uraemic syndrome". J Med Genet. 44 (3): 193–9. doi:10.1136/jmg.2006.045328. PMC 2598029. PMID 17018561.
  7. Noris M, Donadelli R, Remuzzi G (June 2018). "Autoimmune abnormalities of the alternative complement pathway in membranoproliferative glomerulonephritis and C3 glomerulopathy". Pediatr. Nephrol. doi:10.1007/s00467-018-3989-0. PMID 29948306.
  8. Togarsimalemath SK, Sethi SK, Duggal R, Le Quintrec M, Jha P, Daniel R, Gonnet F, Bansal S, Roumenina LT, Fremeaux-Bacchi V, Kher V, Dragon-Durey MA (October 2017). "A novel CFHR1-CFHR5 hybrid leads to a familial dominant C3 glomerulopathy". Kidney Int. 92 (4): 876–887. doi:10.1016/j.kint.2017.04.025. PMID 28729035.
  9. Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean L, Stephens K, Amemiya A, Martín B, Smith R. PMID 20301598. Vancouver style error: initials (help); Missing or empty |title= (help)
  10. Ito N, Ohashi R, Nagata M (August 2017). "C3 glomerulopathy and current dilemmas". Clin. Exp. Nephrol. 21 (4): 541–551. doi:10.1007/s10157-016-1358-5. PMC 5721121. PMID 27878657.
  11. Thomas S, Ranganathan D, Francis L, Madhan K, John GT (November 2014). "Current concepts in C3 glomerulopathy". Indian J Nephrol. 24 (6): 339–48. doi:10.4103/0971-4065.134089. PMC 4244712. PMID 25484526.