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C3G Highlights

Available data on C3G support the following:

C3G is a rare complement-mediated renal disease.  DDD and C3GN are subtypes of C3G. Within 10 years of diagnosis, ESRD develops in about 50% of patients. 

The diagnosis of C3G requires renal biopsy. Both DDD and C3GN show C3 dominance by immunofluorescence microscopy.  Electron microscopy is required to differentiate DDD and C3GN. Features of partial lipodystrophy can accompany DDD and ocular drusen can occur with both DDD and C3GN. Drusen may lead to decreased visual acuity in approximately 10% of affected patients. 

The pathophysiologic basis for C3G is uncontrolled systemic activation of the alternative pathway of the complement cascade.  Triggers that result in alternative pathway dysfunction include genetic mutations in complement genes and auto-antibodies.  

C3Nefs are NOT identical. The triggers that lead to the development of autoantibodies like C3Nefs are not known.  There are multiple assays to test for C3Nefs. Different assays have different sensitivities. 

Most treatments are ineffective at curing C3G. Symptomatic treatment for proteinuria with ACEs and ARBs is recommended. About 30% of C3GN patients will respond to MMF.

C3G and Eculizumab. About 30% of patients with C3G may respond to Eculizumab. Response can be predicted by assaying levels of soluble C5b-9 in the serum. This test should be ordered if you are considering Eculizumab. 

C3G Clinical Trials

The University of Iowa’s Glomerular Disease Clinic and the Molecular Otolaryngology and Renal Research Laboratories pride themselves on being strong advocates for assisting patients and families both with understand their disease and gaining access to new anticomplement therapeutics as they become available.  A great way for both patients and physicians to find out what might be available via a clinical trial is to go to clinicaltrials.gov and type in C3 Glomerulopathy in the “condition or disease” box. 

You will then be provided with a listing of the active trials – by agent, entry criteria and the location for any trials for C3 Glomerulopathy. 

We know that locating a convenient site may be difficult.  The MORL feels so strongly about being a portal to access for patients that we have made it our mission to bring as many trials as we can to our site.  [We choose those sponsors who are willing support patient travel.]  We are currently participating in the following trials:

We are available to consult with local providers on patient suitability for the various clinical trials.  We are also happy to walk local providers through the clinical trial process in case they may be interested in bringing a trial into their setting.

Finally, we recognized that not all patients will meet inclusion/exclusion criteria.  For those patients we have developed a managed access program.  We hope that the combined programs provide the ultimate level of access to you and your patient population.

For more information contact Monica Hall, the Rare Renal Disease Coordinator at monica-hall@uiowa.edu.

C3G Natural History Study

Researchers at the Molecular Otolaryngology & Renal Research Laboratories (MORL) spend a lot of time studying the natural history of C3G, however there is still more to learn. What we know currently is that C3G often leads to chronic kidney disease and up to 50% of patients will suffer end stage renal disease within 10 years of diagnosis. Recurrence of C3 deposition in a transplant kidney happens in up to 90% of patients. 50% of transplant patients will develop important clinical recurrence and lose their kidney within 5 years.
There are currently no targeted (complement specific) treatments for C3G. Treatment is supportive initially, with escalation in approach based primarily on urine protein and changes in creatinine.

The C3G Natural History Study goals are to:

• Create a C3G database for patient-related information.
• Collect data on each person (such as medical history, family history, etc).
• Get blood and urine samples from people with C3G for biomarker and genetic testing.
• Collect, interpret, and store kidney biopsy slides.
• Evaluate all complement pathway biomarkers and genetic data.
• Use the newest statistical methods and machine learning to compare patient clinical information with
• biomarker and genetic data and the kidney biopsy.
• Share discoveries with other doctors and scientists through:
  • Scientific journals
  • Seminar presentations
  • Conferences (local, national, international)
• Be available to treating physicians to assist in the care of their patients.
• Link people to clinical trials.
• Offer people access to new medicines and innovative treatments by acting as a hub site for complement drug trials.

For more information about the C3G Natural History Study please contact Rare Renal Disease Coordinator, Monica Hall at monica-hall@uiowa.edu.

For relevant articles on C3G please see:

Vivarelli M, van de Kar N, Labbadia R, Diomedi-Camassei F, Thurman JM. A clinical approach to children with C3 glomerulopathy. Pediatr Nephrol. 2022 Mar;37(3):521-535. doi: 10.1007/s00467-021-05088-7. Epub 2021 May 18. PMID: 34002292.
Vivarelli et al Ped Nephrology 2021

Kidney Disease: Improving Global Outcomes (KDIGO) Glomerular Diseases Work Group. KDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases. Kidney Int. 2021 Oct;100(4S):S1-S276. doi: 10.1016/j.kint.2021.05.021. PMID: 34556256.
KDIGO - Guideline for the Managment of Glomerular Diseases

Smith RJH, Appel GB, Blom AM, Cook HT, D'Agati VD, Fakhouri F, Fremeaux-Bacchi V, Józsi M, Kavanagh D, Lambris JD, Noris M, Pickering MC, Remuzzi G, de Córdoba SR, Sethi S, Van der Vlag J, Zipfel PF, Nester CM. C3 glomerulopathy - understanding a rare complement-driven renal disease. Nat Rev Nephrol. 2019 Mar;15(3):129-143. doi: 10.1038/s41581-018-0107-2. PMID: 30692664; PMCID: PMC6876298.
Smith et al Nat Rev Nephrol 2019