From the Guidelines
Genetic testing is crucial in Complement-mediated kidney diseases, including atypical hemolytic uremic syndrome (aHUS), to guide diagnosis, treatment, and family screening, as it helps identify genetic variants that can cause dysregulation of the complement system, leading to kidney damage. The testing approach typically involves next-generation sequencing panels that examine multiple complement genes simultaneously, which is more efficient than sequential single-gene testing 1.
Key Considerations
- Genetic testing should focus on genes encoding complement regulatory proteins (CFH, CFI, MCP/CD46), complement components (C3, CFB), and related proteins (THBD, DGKE) 1.
- Patients with aHUS should receive complement inhibition therapy with eculizumab or ravulizumab while genetic testing is pending, as early treatment improves outcomes 1.
- Genetic findings help determine treatment duration, transplant eligibility, and identify at-risk family members 1.
- Identification of a causative variant in a patient with FSGS has several clinical benefits, including sparing individuals from potentially toxic therapies, predicting disease recurrence after kidney transplantation, and identifying other family members who may be at risk 1.
Testing Approach
- For related living donor (LD) candidates whose recipients have aHUS-related end-stage kidney disease (ESKD), genetic testing is typically advised, starting with the affected transplant candidate, and if a causal or contributing variant is identified, then the donor undergoes cascade testing 1.
- If the donor shares the genetic variant for aHUS with the recipient, then living donation should be discouraged 1.
- For patients with focal and segmental glomerulosclerosis (FSGS), sequential genetic testing of the affected individual followed by the LD candidate should be considered if a genetic cause for FSGS is a possibility 1.
Clinical Utility
- Genetic testing can help identify patients with genetic causes of FSGS, who are less likely to respond to immunosuppression and have a lower risk of disease recurrence after kidney transplantation 1.
- Results of genetic testing may impact enrollment in clinical trials as novel molecular therapies are currently being tested 1.
Recommendation
Genetic testing should be performed in all patients with suspected Complement-mediated kidney diseases, including aHUS and FSGS, to guide diagnosis, treatment, and family screening, and to identify genetic variants that can cause dysregulation of the complement system, leading to kidney damage 1.
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.
- Eculizumab and ravulizumab are effective in treating Complement-mediated kidney diseases, regardless of genetic mutations. 2 3
From the Research
Role of Genetic Testing in Complement-Mediated Kidney Diseases
- Genetic testing plays a crucial role in diagnosing and understanding the pathogenesis of complement-mediated kidney diseases, such as atypical hemolytic uremic syndrome (aHUS) and C3 glomerulopathy 4, 5, 6.
- Genetic variations in complement and complement control proteins have been associated with renal disease, including polymorphisms at the complement factor H-related gene locus and rare mutations in genes such as complement factor I and membrane cofactor protein 5, 7.
- Genetic testing can help identify patients with inherited kidney complement diseases, which can inform treatment decisions and improve patient outcomes 6.
- The genetic background of a patient can influence the phenotype of complement-mediated kidney diseases, with certain genetic combinations increasing the risk of developing specific diseases such as aHUS or C3 glomerulopathy 5.
Diagnostic Approaches
- Diagnosing complement-mediated kidney diseases requires detailed investigations, including genetic analyses and the measurement of specific complement factors 4.
- Urinary complement biomarkers may provide a non-invasive and easily accessible way to assess disease activity and predict treatment response in immune-mediated kidney diseases 8.
- Comprehensive complement analyses, including biomarker profiling, pathway activity, and autoantibody testing, can help diagnose and understand the pathogenesis of complement-mediated kidney diseases 5.
Therapeutic Implications
- Genetic testing can inform treatment decisions for patients with complement-mediated kidney diseases, with certain genetic mutations responding better to specific therapies 6.
- New therapeutic approaches targeting the complement system are being developed, which may offer promising treatment options for patients with complement-mediated kidney diseases 4, 7.
- The use of anti-C5 antibody therapy and other complement inhibitors may be effective in treating certain complement-mediated kidney diseases, such as aHUS and C3 glomerulopathy 7.