What is the role of genetic testing in Complement (Complement system)-mediated kidney diseases?

From the Guidelines

Genetic testing is crucial in the evaluation of living kidney donor candidates for Complement-mediated kidney diseases, as it can identify genetic variants that may increase the risk of disease recurrence in the recipient or de novo disease in the donor. The role of genetic testing in these diseases, including atypical hemolytic uremic syndrome (aHUS), Focal and segmental glomerulosclerosis (FSGS), and Autosomal Dominant Tubulointerstitial Kidney Disease (ADTKD), is to confirm the diagnosis, guide treatment decisions, and provide prognostic information 1.

Key points to consider when evaluating the role of genetic testing in Complement-mediated kidney diseases include:

• Genetic testing can identify mutations in complement genes such as C3, CFH, CFI, CFB, THBD, MCP, or PLG, which are associated with aHUS 1.
• In FSGS, genetic testing can predict a substantially lower likelihood of disease recurrence in the recipient if a genetic cause is identified 1.
• In ADTKD, genetic testing offers confirmation of the diagnosis, and testing for a single base insertion in MUC1 may be necessary if initial testing is negative 1.
• When the related recipient candidate’s disease is unknown or not fully characterized, unbiased testing with a comprehensive gene panel or WES/WGS of the affected individual may be considered to identify the genetic cause of disease 1.

It is essential to interpret genetic test results in the context of clinical presentation and other diagnostic tests, as not all patients with these diseases will have an identifiable genetic mutation, and some individuals with mutations may never develop the disease 1. Genetic counseling is also recommended before and after testing to help patients understand the implications of the results. Ultimately, genetic testing can inform decisions about kidney transplantation and help minimize the risk of disease recurrence or de novo disease.

From the FDA Drug Label

In Study C08-003A/B, responses to SOLIRIS were similar in patients with and without identified mutations in genes encoding complement regulatory factor proteins. Fifty-three percent of pediatric patients had an identified complement regulatory factor mutation or auto-antibody. Fifty-one percent of patients had an identified complement regulatory factor mutation or auto-antibody.

The role of genetic testing in Complement-mediated kidney diseases is to identify mutations in genes encoding complement regulatory factor proteins. However, the presence or absence of these mutations does not appear to affect the response to treatment with eculizumab or ravulizumab.

• Key points:
  • Genetic testing can identify mutations in genes encoding complement regulatory factor proteins.
  • The presence or absence of these mutations does not affect the response to treatment.
  • Treatment with eculizumab or ravulizumab can be effective regardless of genetic mutation status. 2 3

From the Research

Role of Genetic Testing in Complement-Mediated Kidney Diseases

• Genetic testing plays a crucial role in identifying genetic mutations that contribute to the development of complement-mediated kidney diseases, such as atypical hemolytic uremic syndrome (aHUS) and C3 glomerulopathy (C3G) 4, 5, 6, 7.
• Genetic mutations in components of the alternative complement pathway, such as complement factor B, complement factor I, and membrane cofactor protein, can increase the risk of developing these diseases 5, 7.
• Genetic testing can help identify patients who are at risk of developing complement-mediated kidney diseases and guide treatment decisions, including the use of complement factor C5 inhibitors 4, 8.
• The presence of genetic variants can also influence the clinical presentation and outcome of these diseases, with some variants associated with a higher risk of graft loss after kidney transplantation 4, 5.

Importance of Genetic Screening

• Genetic screening is essential for patients with complement-mediated kidney diseases, as it can help identify underlying genetic mutations and guide treatment decisions 6, 7.
• Genetic screening can also help identify patients who are at risk of developing these diseases, allowing for early intervention and potentially improving outcomes 7.
• The identification of novel genetic variants can also provide new insights into the pathogenesis of these diseases and inform the development of new treatments 6.

Treatment Implications

• Genetic testing can inform treatment decisions, including the use of complement factor C5 inhibitors, which have been shown to improve outcomes in patients with complement-mediated kidney diseases 4, 8.
• The identification of genetic variants can also guide the use of other treatments, such as plasma exchange and immunosuppressive therapy 8.
• The development of new treatments, such as targeted complement inhibitor therapy, has improved outcomes for patients with complement-mediated kidney diseases 8.