CFHR3 Mutation and Kidney Transplant Recurrence Prevention
Critical First Statement
For a kidney transplant candidate with a pathogenic CFHR3 mutation causing aHUS, prophylactic eculizumab is NOT universally required—instead, adopt a restrictive "treat-on-recurrence" strategy with intensive post-transplant monitoring, reserving eculizumab for documented thrombotic microangiopathy recurrence rather than routine prophylaxis. 1, 2
Genetic Testing and Donor Screening Algorithm
Pre-Transplant Genetic Evaluation
Confirm the recipient's CFHR3 mutation through comprehensive genetic testing including next-generation sequencing of complement genes (CFH, CFHR1-5, C3, CD46, CFI, THBD, DGKE, CFB) and multiplex ligation-dependent probe amplification specifically for CFHR genes 3
For living related donors, perform cascade genetic testing starting with the recipient's identified variant, then screening the donor candidate for the same pathogenic CFHR3 mutation 3
If the donor shares the pathogenic CFHR3 variant with the recipient, living donation should be discouraged due to dual risks: recurrence in the recipient and de novo aHUS in the donor 3
If the donor does not harbor the causative CFHR3 variant, living donation may proceed with appropriate monitoring protocols 3
Prophylactic Strategy: Restrictive Approach
Why NOT Routine Prophylaxis
Recent evidence from a 17-patient cohort with high-risk complement mutations (including CFH, C3, MCP) demonstrated successful living donor transplantation WITHOUT prophylactic eculizumab, with only 1 of 17 patients (5.9%) experiencing recurrence at 68 days post-transplant, which was successfully treated 1
The overall relapse rate after eculizumab discontinuation in complement-mediated TMA is 29.6%, meaning 70% of patients do NOT relapse, supporting selective rather than universal prophylaxis 4
Prophylactic eculizumab lacks definitive evidence for universal application, and restrictive protocols are increasingly recognized as feasible and cost-effective 2
Post-Transplant Monitoring Protocol
Intensive Surveillance Strategy
Monitor for TMA recurrence using combined clinical and laboratory parameters rather than relying on a single test, as no single marker is sufficiently sensitive 3
Weekly monitoring during the first 3 months should include:
After 3 months, continue monthly monitoring for the first year, then quarterly thereafter, as recurrence can occur late (one case at 68 days, another in the second year post-transplant) 6, 1
Critical pitfall: 13% of post-transplant TMA patients do not show significant platelet reduction and 38% lack significant anemia or thrombocytopenia, so do not exclude TMA diagnosis based solely on absence of these findings 3
Eculizumab Dosing IF Recurrence Occurs
Treatment Initiation
Administer eculizumab 900 mg IV weekly for 4 weeks, then 1200 mg at week 5, followed by 1200 mg every 2 weeks as the standard induction and maintenance regimen 7
Titrate dosing to achieve low functional complement C5 levels and low soluble membrane attack complex (sMAC) levels rather than using fixed dosing alone 7
Monitor complement hemolytic activity parameters (C3, C4, CH50, AP50) if extending the dosing interval beyond standard 2-week maintenance 3
Duration of Treatment
Continue eculizumab for a minimum of 3 months with stabilized/normalized renal function before considering discontinuation 3
Assess risk factors before discontinuation: presence of renal allograft (P=0.009), younger age (P=0.029), and specific gene variants (CFH, MCP/CD46, C3) are independently associated with relapse 4
CFHR3 variants specifically have lower relapse risk compared to CFH or canonical splice-site MCP/CD46 mutations, supporting potential discontinuation after stabilization 4
Meningococcal Prophylaxis (Mandatory with Eculizumab)
Vaccination Requirements
Vaccinate against meningococcus BEFORE initiating eculizumab whenever possible, as anti-C5 therapy dramatically increases invasive meningococcal disease risk 3
Administer quadrivalent meningococcal A, C, W, Y vaccine AND serogroup B meningococcal vaccine to all patients receiving eculizumab 3
If urgent eculizumab is required before vaccination can be completed, initiate antibiotic prophylaxis (typically penicillin or macrolide) until vaccination series is complete 3
Important caveat: immunosuppression may hamper vaccine response, so consider checking antibody titers post-vaccination 3
Alternatives If Eculizumab Unavailable
Second-Line Complement Inhibition
Ravulizumab (long-acting C5 inhibitor) is an alternative with similar efficacy but extended dosing intervals (every 8 weeks after loading) 3
Caplacizumab may be considered if ADAMTS13 activity is low with inhibitor present, though this is more relevant for TTP than complement-mediated aHUS 5
Non-Complement Therapies
Plasma exchange with fresh frozen plasma can be used as bridge therapy while awaiting complement inhibitor availability, though it is less effective than eculizumab for complement-mediated disease 5, 7
High-dose methylprednisolone (1 gram IV daily for 3 days) may be added as adjunctive therapy during acute TMA episodes 5
Immunosuppression Modifications
Optimized Maintenance Regimen
Target lower tacrolimus trough levels (specific protocol in successful cohort emphasized this strategy) to reduce endothelial toxicity risk 1
Maintain corticosteroids as baseline immunosuppression throughout the post-transplant period 5
Continue mycophenolate mofetil if tolerated, as antimetabolites are not implicated in aHUS pathogenesis 5
Aggressively treat hypertension as part of the protective protocol to minimize endothelial stress 1
Special Considerations for CFHR3 Variants
Risk Stratification
CFHR3 mutations are included in standard genetic testing panels via multiplex ligation-dependent probe amplification, confirming their recognized role in aHUS 3
Variants of uncertain significance (VUS) in CFHR3 carry increased relapse risk (P<0.001) compared to no variant, but likely pathogenic/pathogenic variants have even higher risk 4
CFHR3 variants generally have LOWER recurrence risk compared to CFH mutations (which have 80% recurrence risk and highest relapse rates after eculizumab discontinuation) 7, 4
Genetic Counseling
Provide genetic counseling performed by geneticists once diagnosis is confirmed, informing the patient about possible genetic transmission 3
Study household members to detect other possible cases at an early stage, as aHUS can cluster in families 3
Critical Pitfalls to Avoid
Do NOT transfuse platelets unless life-threatening bleeding occurs, as platelet transfusion may worsen thrombotic microangiopathy 5
Do NOT exclude TMA diagnosis based solely on absence of thrombocytopenia or anemia in the post-transplant setting, as 38% of cases lack these classic findings 3
Do NOT assume Chinese or Japanese descent patients will respond to C5 inhibitors—they may possess polymorphic C5 gene variants (c.2654 G→A, c.2653 C→T) causing resistance to anti-C5 monoclonal antibodies 3
Do NOT delay transfer to a rare disease reference center if aHUS is suspected, as diagnostic delay worsens outcomes 3
Do NOT discontinue eculizumab without thorough risk assessment, as 29.6% of patients relapse, with higher rates in those with renal allografts and specific gene variants 4
Long-Term Follow-Up
Monitor weekly hemoglobin and platelet counts until steroid taper is complete if eculizumab was used and then discontinued 5
Maintain long-term surveillance for chronic kidney disease in the allograft with regular creatinine and proteinuria monitoring 5
If relapse occurs after eculizumab discontinuation, retreatment with C5 inhibitor is recommended and typically effective 3