Introduction:
C3 Glomerulopathy (C3G) is a rare kidney disease, with its main pathophysiology related to complement system dysregulation.
It is associated with poor outcome with current treatments, though new treatments have now available in the horizon.
Methods:
We reported a 50 years old male patient who is known to have well controlled diabetes mellitus , gouty arthritis and history of renal stone.
He presented with complains of abdominal pain generalized weakness and fatigue found to have very high blood pressure. further work showed high serum creatinine at 200 micromole/l, proteinuria reported 2 g/g creatinine as well as urine analysis showed significant RBC but no cast further work up showed low normal C3, normal C4, normal ANA, pANCA and cANCA hepatitis B and hepatitis C negative. Ultrasound KUB showed normal size kidney with mild increase echogenicity serum and urine protein electrophoresis both were within normal.
In view of high serum creatinine proteinuria and haematuria we did for him renal biopsy the first renal biopsy was not conclusive. the repeated renal biopsy showed :the light microscopy mesangial expansion , endocapillary proliferation ,segmental duplication of glomerular basement membrane. One cellular crescent. Tubular atrophy constituting 25% of cortical tissue core. The immunofluorescent : the glomeruli show capillary wall and mesangial immunoreactivity to IgG (2+), IgM (trace), C3 (3+), kappa light chain (2+).
Electron Microscopic study there are subendothelial electron dense deposits which are the main type of deposit in this specimen. There also few mesangial and subepithelial electron dense deposits.
The final diagnosis conclusion reported that : from the light, immunofluorescent and electron microscopic features are consistent with C3 dominant glomerulonephritis.
Of note infectious causes, autoimmune and monoclonal gammapathy renal disease all excluded.
Subsequently the patient initiated on supportive treatment in the form maximum tolerated dose of angiotensin receptor blockade also sGLT2i added .patient also received prednisolone and Mycophenolate Mofetile MMF.
Follow up revealed that creatinine fluctuated between 220 and peaked 300 micmol/l with average around 260 .his proteinuria peaked up to 3 g/g Cr then improved to 1. 5 g/g Cr urine still showing significant RBC . C3 level normal and trending up slightly.
so far the patient maintained on prednisolone and mycophenolate mofetile. and giving the fact that the patient is still have relatively significant proteinuria above one gram , high creatinine with active urine sediments the case was discussed in nephrology panel meeting and the main question whether we need to initiate him on the new emerging therapy for C3 GN the anti-complement namely iptacopan or pegcetacoplan.
Results:
With understanding the complement physiology, nowadays we become more familiar with complement-mediated diseases
C3 GN is a very rare disease with prevalence 1-3 cases per million . The clinical picture of C3GN is similar to other GN disease’s, with heamturia, proteinuria mostly non- nephrotic range , hypertension and renal dysfunction.
C3 complement levels are low in more than 50% and extra renal manifestations such as Retinal Drusen and Partial Lipodystrophy are rare .
Overall, the disease is associated with poor renal outcome if untreated with 50% of adult’s reaching ESRD within 10 years.
The main pathophysiology of C3 GN is related to dysregulation of complement alternative pathway. This occurs in majority of the patients due to the presence of acquired factors or autoantibodies that target the C3 or C5 convertases. In a minority of cases the driving factors for complement dysregulation are genetic mutations in complement regulating factors.
The two main subgroups of C3 glomerulopathy (C3G) are Dense Deposit Disease (DDD) and C3 glomerulonephritis (C3GN).
The main diagnostic approach is to do a renal biopsy where the light microscopy may show glomerular hypercellularity, mesangial proliferative and endocapillary proliferation with an overall a picture of MPGN pattern. However, immunofluorescence finding’s, in particular staining for C3 of at least two orders of magnitude greater intensity than for any other immune reactant is of diagnostic of C3 GN. Electron microscopy depositions help to distinguish the two major subtypes of C3 glomerulopathy (C3G): DDD and C3GN.
Further important diagnostic tests, as per expert opinion that suggest all patients needs to do comprehensive complement evaluation which includes assessment and screening for autoantibodies. of note the C3 nephritic factors and C5 nephritic factor are the autoantibodies most frequently identified .furthermore genetic testing should be considered, and should include screening of C3, CFB, CFH, CFHR5 and CFI,
In addition, all patients above age of 50 years should be screened for paraproteins, as monoclonal immunoglobulins can impair complement regulation (anti-FH and C3Nef factors) and may trigger C3 GN. Treatment of monoclonal gammopathy will stabilize kidney function in these patients.
There is high recurrence rate of C3G after renal transplantation of approximately 80 to 100 percent after renal transplantation, leading to allograft loss in approximately 50% of involved cases.
There is no optimal treatment for C3 Glomerulopathy.
ACEi/ARB and SGLT2i should be considered as antiproteinuric, renoprotective measures and for blood pressure control.
When come to immunosuppressive therapy the main role of immunosuppressive medication is cellular immune response inhibition and decrease autoantibody production.
The main immunosuppressive medications studied and still the first line used in C3 GN are mycophenolate mofetil MMF and steroids. However, it difficult to draw conclusions in regard to MMF and prednisolone in C3 GN as the data on outcomes are mixed in different studies. Furthermore, it is still unclear, which patients are most likely to respond to mycophenolate mofetil therapy, the optimal dosage and duration of therapy.
As complement dysregulation is the main cause of C3 GN, targeting with anti-complement agents is a potential treatment. Many cases series support the use of anti-C5, Eculizumab, as a therapeutic approach in a subset of patients.
Recently there has been an emergence of new anti-complement therapies. Clinical trials which showed promising results in treating C3 GN with Iptacopan and Pegcetacoplan.
Cases studies have shown positive response when theses medication used in C3 GN.
Conclusions:
C3G is very rare disease caused by complement dysregulation. It is diagnosed by renal histopathology and supplemented by complement panel study. Treatment is still not optimal with MMF and steroid widely used with poor clinical responses.
New anti-complement medications are in the near horizon, however more studies will be needed for treatment standardization .
I have no potential conflict of interest to disclose.
I did not use generative AI and AI-assisted technologies in the writing process.