A recent multidisciplinary webinar jointly organized by NephroPlus, the Atypical HUS India Foundation and the Kidney Warriors Foundation, with support from AstraZeneca, brought together leading experts in complement-mediated diseases to examine current challenges, evolving strategies, and systemic gaps in the management of atypical hemolytic uremic syndrome (aHUS). Participants included clinicians with extensive experience in adult and pediatric thrombotic microangiopathies (TMAs) such as Dr. Vivekanand Jha, Dr. Arvind Bagga, Dr. Nicole Isbel, Dr. Aditi Sinha, Dr. Manisha Sahay, Dr. Raja Ramchandran, Dr. Sreebhushan Raju, Dr. Sayali Thakare, Dr. Sandhya Suresh and Dr. Arun. The session aimed to distill global experience, regional realities, and clinical insights into a cohesive framework for improving diagnosis and care of complement-mediated TMA in India.
Diagnostic Complexity in Complement-Mediated TMA
One of the recurrent themes was the inherent diagnostic complexity of aHUS and its frequent misclassification in early stages. The syndrome often presents with the familiar triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury—features that overlap significantly with sepsis, malignant hypertension, shiga-toxin–associated HUS, pregnancy-related disorders, and thrombotic thrombocytopenic purpura (TTP). This overlap leads to delayed recognition in peripheral centers, where supportive care is often initiated without a dedicated evaluation for complement-mediated disease.
Experts emphasized that certain patterns should heighten suspicion for complement-mediated TMA: disproportionately severe AKI relative to systemic illness, persistent thrombocytopenia despite clinical improvement elsewhere, markedly elevated LDH, and schistocytosis. Early ADAMTS13 testing was highlighted as a critical step in distinguishing complement-mediated processes from TTP, and several speakers underscored the importance of not allowing the absence of immediate ADAMTS13 results to delay the initiation of diagnostic pathways or consideration of complement blockade.
Importance of Early Complement Blockade
Timely initiation of C5 inhibition remains the single most important modifiable determinant of renal recovery in aHUS. International registries and national cohorts demonstrate that earlier initiation leads to a higher likelihood of renal salvage, fewer long-term dialysis requirements, and lower relapse risk. Plasma exchange, once a mainstay of therapy, is now recognized as potentially counterproductive once complement blockade is initiated, given its impact on drug clearance.
Neurological involvement, while variably reported in literature, was discussed as a marker of severe endothelial injury. In such situations, early and aggressive complement inhibition may help halt progression. Similarly, postpartum TMAs that fail to improve after several days of supportive care may represent complement-driven endothelial injury rather than classical preeclampsia or HELLP syndrome, warranting reconsideration of therapeutic priorities.
Complement Testing and Genetic Evaluation
The webinar highlighted the dual importance and limitation of genetic testing in aHUS. While genetic variants in complement regulators and effectors—such as CFH, CFI, MCP, C3, and CFHR rearrangements—provide valuable prognostic information, their absence does not exclude complement dysregulation. This is especially true in settings where environmental or physiologic triggers such as pregnancy or infections may unmask latent pathway vulnerabilities.
Experts noted the challenges faced in India: variability in assay quality, limited availability of specialized laboratories, long turnaround times for genetic panels, and frequent preanalytical errors in complement sampling. Proper sample handling—rapid processing, cold-chain integrity, and avoidance of complement activation ex vivo—was emphasised repeatedly. Several speakers highlighted that complement levels may appear normal even in active disease due to dynamic consumption, reinforcing the primacy of clinical judgement.
Management of Anti–Factor H Antibody–Associated aHUS
A detailed pediatric case underscored the complexity of managing anti–factor H antibody–mediated aHUS, a phenotype more prevalent in South Asian populations. These patients often present with severe renal injury, very high antibody titers, and substantial complement activation. Effective management requires an integrated approach: plasmapheresis to remove circulating antibodies, immunosuppression (often multi-agent) to suppress antibody production, and complement inhibition to arrest endothelial injury.
Relapses, often triggered by infections, highlight the need for vigilant long-term monitoring. Decisions regarding B-cell–targeted therapies such as rituximab, or newer agents, depend on persistence or rebound of antibody titers. Persistent proteinuria despite hematologic remission remains an important marker of chronic complement-mediated damage, warranting longitudinal nephrology follow-up.
Pregnancy-Associated TMA: Recognizing the Complement Continuum
Pregnancy-associated TMA surfaced as an especially challenging scenario. The clinical overlap with preeclampsia, eclampsia, and HELLP syndrome complicates early diagnosis. However, recurrent episodes across pregnancies, early-onset severe hypertension, precipitous renal injury, or poor fetal outcomes may point towards underlying complement dysregulation. Several experts noted that pregnancy can serve as a physiologic stressor that unmask latent complement pathway abnormalities.
The group discussed the role of prophylactic measures such as aspirin and hydroxychloroquine, which may reduce endothelial activation but do not directly modulate complement activity. In cases where complement-mediated TMA is strongly suspected, early complement inhibition may interrupt the cascade of endothelial injury and improve both maternal and renal outcomes.
Long-Term Management, Relapse Monitoring, and Withdrawal Strategies
The webinar also explored long-term management strategies, including when and how to consider withdrawal of complement blockade. Decisions must incorporate genetic background, disease severity, organ involvement, presence of anti–factor H antibodies, and patient-specific risk factors. Close monitoring after withdrawal—through regular labs, blood pressure tracking, and symptom surveillance—is critical, particularly in patients with complement gene variants or history of relapse.
Relapse risk is highest in the first year after withdrawal and in individuals with pathogenic complement variants. Several experts advocated for structured relapse action plans that empower patients and clinicians to recognize early warning signs and reinitiate therapy promptly.
Building a Better aHUS Care Ecosystem in India
The session concluded with a forward-looking examination of systemic barriers in India. Key needs include: expanding access to complement assays and genetic testing; improving diagnostic capacity in regional hospitals; establishing national registries to track epidemiology, mutations, and outcomes; and developing designated Centers of Excellence with multidisciplinary TMA teams. Strengthening referral pathways and ensuring equitable access to complement inhibition remain high priorities for improving outcomes nationwide.
Key Takeaways
• Complement-mediated TMA is frequently misdiagnosed; early clinical suspicion is essential.
• Early C5 inhibition significantly improves renal recovery and reduces long-term morbidity.
• Genetic testing informs prognosis but must not delay therapy.
• Anti–factor H antibody–mediated aHUS requires integrated immunosuppression, plasmapheresis, and complement blockade.
• Pregnancy-associated TMA often reflects unmasked complement dysregulation.
• India needs improved diagnostic infrastructure, national referral pathways, and Centers of Excellence.
• Long-term follow-up and structured relapse plans are essential due to ongoing risk.
