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May 10, 2019

Disease Week: C3 Glomerulonephritis

C3 glomerulonephritis is a recently described entity which is due to dysregulation in the alternative complement pathway. Patients typically present with hematuria and/or proteinuria in the face of persistently low serum levels of C3. The annual incidence of biopsy-proven disease is 1 to 2 per million with both sexes affected equally. The median age of diagnosis is 21 years of age, but there is a second spike after the age of 50 due to paraprotein-associated disease. The most common glomerular disease pattern is a membranoproliferative pattern. The hallmark of the disease is dominant C3 staining on immunofluorescence which is defined as two orders of magnitude greater than any other immune reactant. It is prudent to rule out “masked deposits” using immunofluorescence staining on paraffin-embedded tissue and to rule out an infection clinically. By electron microscopy, there are electron dense deposits corresponding to the immunofluorescence staining of C3 (there is no transformation of the GBMs as seen in dense deposit disease). Autoantibodies to C3 nephritic factor are present in approximately 50% of cases of C3 glomerulonephritis. Quiescent abnormalities within the alternative complement pathway are reported in 33% of patients. Optimal treatment for C3 glomerulonephritis has not been established, but some patients respond to mycophenolate and/or eculizumab. 67% of patients who receive a renal transplant have a recurrence of their original disease.

C3 glomerulonephritis has been a success story in precision medicine where the bedside truly has met the laboratory. From the nephrologists who refer patients for specialized complement testing to the basic science laboratory and pharmaceutical industry, there has been shared interest in targeting different steps in the complement pathway. Basic science has found new mutations and drivers of complement, the clinical lab has tested for these mutations, and the pharmaceutical industry has worked on new, targeted therapies. The drug eculizumab (human monoclonal antibody against the complement protein 5) has been given to patients “off label” for C3 glomerulonephritis. Specialty laboratories (University of Iowa, National Jewish Health Colorado, and Cincinnati Children’s Hospital) offer a full complement workup including identification of auto-antibodies, alternative pathway functional assays, and genetic testing of individual complement proteins. Hopefully, over the next few years, there will continue to be a sustained effort to further understand the regulation of the complement cascade.

Athanasiou Y, Voskarides K etc Familial C3 Glomerulopathy associated with CFHR5 mutations: clinical characteristics of 91 patients in 16 pedigrees. Clin J Am Soc Nephol 2011 Jun; 6(6):1436-46
Smith RJH, Appel GB, etc C3 Glomulopathy – understanding a rare complement-driven renal disease. Nat Rev Nephrol 2019 Mar; 15(3): 129-143