C3-glomerulopathy N05.2

C3 glomerulopathy is a new group of kidney diseases in which deposits of complement factor C3 are typically found in the glomeruli, (in the mesangium and at the glomerular basement membrane) without significant involvement of immunoglobulins or components of the classical pathway of complement activation (Cook HT 2017). Thus, this is not a classical immunocomplex disease.

Note: C3-glomerulopathies are often detected under the diagnosis "Membranoproliferative Glomerulonephritis (MPGN)".

According to histological and electron microscopic criteria 2 subtypes are distinguished

• "Dense Deposit Disease (DDD)
• and
• C3 glomerulonephritis (C3GN): C3 glomerulopathy without the characteristics of dense deposit disease

The exact etiopathogenesis is unknown. A differently triggered dysregulation of the alternative activation pathway of the complement cascade is assumed (Riedl M et al. 2017). The consequence is C3b amplification in the circulation and/or along the glomerular basement membrane (Barbour TD et al. 2016).

In familial C3-glomerulopathy a mutation in the CFHR gene is found as the genetic basis. This genetic defect leads to a deficiency of functional complement factor H(CFH). CFH is able to antagonize dysregulatory C3 activation (Barbour TD et al. 2016).

Further causes for a dysregulatory complement cascade are the occurrence of autoantibodies against C3 convertase (C3 nephritic factor) and its loss of activity (Riedl M et al. 2017). In some cases antibodies (C4 nephritic factors) against C4b2a were detectable (Zhang Y et al. 2017). In some cases, infections (postinfectious GN) were identified as potential triggers of C3 glomerulopathy (Pirozzi N et al. 2018).

About 1% of all kidney biopsies can be assigned to this diagnosis (Cook HT 2017).

Nephrotic syndrome (30%), microhaematuria (87%), hypertension (30%), hypocomplementary anaemia (44.6%), monoclonal gammopathy (28.9%), often progressive renal failure (Ravindran A et al. 2018)

Histologically there are mesangial proliferative, membranoproliferative, and endocapillary proliferative changes of the glomerula.

In DIF (direct immunofluorescence) deposits of complement factor C3c can be detected in the absence of immunoglobulins (Ito N et al. 2017). The depositions are probably caused by a differently triggered dysregulation of the alternative activation pathway of the complement cascade.

Electron microscopically, in some cases, electron-tight deposits are found on the basement membranes of the glomerula (dense deposits).

Hypocomplementaemia in 80% of patients with DDD and up to 50% in patients with C3GN

Renal biopsies are required to allow histological, immunohistological and electron microscopic classification. The detection of C3 deposits in the glomeruli without significant involvement of immunoglobulins leads to the classification of renal disease as C3 glomerulopathy (Pickering MC et al. 2013).

Serological detection of C3Nef (nephritic factor) in almost all patients with DDD and in <50% of patients with C3GN. Detection of anti-CFH antibodies in patients with low C3 levels and absence of C3Nef.

Proteinuria indicates glomerular damage of the kidneys.

Therapies with cyclophosphamide, rituximab, mycophenolate mofetil mostly in combination with corticosteroids showed different response rates (Ravindran A et al. 2018).

Plasmapheresis: therapeutic effects were different.

Alternative eculizumab: Eculizumab (an antibody directed against C3) is able to improve the symptoms (such as proteinuria and increase in renal values) in individual cases. Larger randomized case studies are missing so far (Le Quintrec M et al.2018).

Alternative kidney transplantation: This can improve renal insufficiency. Nevertheless, there is a risk of recurrence of C3 glomerulopathy (Wong L et al. 2016).

Alternative multimodal therapy approaches: In patients with autoantibodies against C3 convertase (C3Nef), satisfactory therapeutic effects could be achieved by multimodal therapy with plasma infusions, corticosteroids and mycophenolate mofetil (Avasare RS et al. 2018).

Experimental: Combined liver-kidney transplantation. The evaluation of therapeutic approaches with combined liver-kidney transplantation in patients with C3-glomerulopathy and factor H deficiency is still open.

C3-glomerulopathy is progressive and leads to renal insufficiency and dialysis in the late stages.

The common occurrence of C3 nephropathy with cystic fibrosis has been described Santoro D et al (2018).

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