Shedding light on a rare renal disease - C3 Glomerulopathy
Main Author: Hudaa Mehkri
Abu Dhabi, United Arab Emirates
Sheick Khalifa Medical City
Background(s): The C3 glomerulopathies refer to a set of uncommon kidney disorders marked by irregular complement activity. This leads to significant deposition of complement C3 in kidney biopsy samples. The primary subgroups within C3 glomerulopathy, namely dense deposit disease (DDD) and C3 glomerulonephritis (C3GN), exhibit similar clinical and pathological traits, indicating a potential continuum of the disease.
We are reporting a case of biopsy proven C3GN presented to our institution. Our objective is to enhance awareness of this rare condition and shedding light on some complex pathophysiologic and genetic aspects of the disease and importance of genetic testing in such cases.
Method(s): 21 year old female, was admitted in childhood at age of 12 years at our hospital with history of presumed post streptococcal glomerulonephritis in 2012, at that time she had proteinuria which was treated with ACEI. Was followed up by pediatric nephrology
Result(s): In 2013, a consensus among experts led to the adoption of the term “C3 glomerulopathy” to describe a set of rare kidney diseases resulting from dysregulation in the complement cascade. This disease is exceedingly uncommon, and estimates from small cohort studies, though not highly reliable, suggest its prevalence is around 1-3 cases per 1,000,000 in the USA. European studies propose estimates of approximately 0.2-1.0 cases per 1,000,000. These figures are likely an underestimation, with the actual prevalence expected to be higher. The prevalence of this condition in the UAE and the Middle East remains unreported.
Over all it is caused by dysregulation of the alternative pathway in the circulation as opposed to on the cell surface. It has a complex pathophysiology which includes genetic factors and acquired factors. Comprehensive genetic studies have shown that ~25% of patients with C3 glomerulopathy carry rare or unique variants in complement-related genes. Most often these variants are found in the two convertase genes ; C3 and CFB , complexes of these two proteins form C3bBb (C3 convertase) and C3bBbC3b (C5 convertase), variants are also found in the complement regulator genes CFH and CFI; or in enhancer of complement activation like CFHR5. It is also not unusual for patients with C3 glomerulopathy to carry multiple variants in complement-related genes.
Such genetic complexity might partially explain why families in which the affected individual has a first-degree or second-degree relative with the same diagnosis are very rare. Specific haplotypes can contribute to the variable penetrance of C3 glomerulopathy by increasing or decreasing the likelihood of disease, possibly by affecting circulating levels of specific complement proteins. Among patients who are identified as having familial C3 glomerulopathy, the renal phenotype is more commonly C3GN than DDD. The most frequent genetic finding in these patients is rearrangement of the CFH locus. The most commonly reported genomic rearrangement in the CFH region is a CFHR5 gene variant, endemic in Cyprus.
Acquired factors involves presence of autoantibodies to a variety of complement proteins and complexes e.g C3 nephritic factors, C4 nephritic factors, Factor H autoantibodies..etc.
The most common autoantibodies is C3 nephritic factors which target C3bBb.
C3 glomerulopathy can manifest in various ways, ranging from asymptomatic hematuria and proteinuria to an acute onset characterized by typical glomerulonephritis symptoms. Although most patients exhibit low serum C3 levels, diagnosing C3 glomerulopathy is reliant on histopathology. Distinguishing between the two main subtypes, DDD and C3GN, necessitates electron microscopy.
Although definitive treatment for C3 glomerulopathy remains undefined, emerging data indicate the potential benefits of plasma therapy and anti-complement treatment, including the use of eculizumab. Ongoing research is introducing new anti-complement therapies e.g Avacopan (antiC5Ar1) . Recognizing and diagnosing this condition is of utmost importance, as it significantly contributes to kidney damage and is frequently overlooked due to its rarity.
Conclusion(s): We are presenting a patient with C3 glomerulopathies which is often not diagnosed promptly, potentially resulting in adverse health outcomes. It is a disease to look for whenever there is kidney disease with unknown etiology.
It’s important to consider genetic testing and should include screening of C3, CFB, CFH, CFHR5 and CFI, as well as testing for variations and rearrangements of the CFH–CFHR gene cluster. All patients with C3 glomerulopathy should also undergo screening for autoantibodies mainly C3 nephritic factors and C5 nephritic factors which are the most frequently identified autoantibodies. More data is needed on the topic given the rarity of its occurrence and more cases should be published to emphasize the significance of early diagnosis and management.