A virtual meeting was held between leading nephrologists and geneticists on the 1st April. The meeting was held to arrive at a consensus on diagnosis of aHUS. This was hosted by the Atypical HUS India Foundation and was supported by NephroPlus and AstraZeneca. Here is a video recording of the meeting:

Here is a summary of what was discussed:

Optimising Diagnosis of aHUS: Bridging Nephrology and Genetics

The multidisciplinary meeting brought together nephrologists and geneticists to address a critical challenge in modern nephrology—how to accurately and efficiently diagnose atypical hemolytic uremic syndrome (aHUS). The discussion emphasized the need for a pragmatic, collaborative, and resource-sensitive diagnostic pathway, particularly relevant to India and similar healthcare settings.

Evolving Understanding of aHUS

A central theme was the changing classification of HUS. Traditionally divided into “typical” (Shiga toxin-associated) and “atypical,” the field is now moving toward a more mechanistic classification:

Complement-mediated thrombotic microangiopathy (TMA) (formerly aHUS)
Non-complement-mediated TMA
Secondary TMAs (e.g., infections, pregnancy, malignancy)

This shift reflects growing evidence that complement dysregulation is the dominant driver in aHUS, with genetic or autoimmune mechanisms underlying most cases. Globally, about 50–60% of cases involve complement pathway abnormalities, particularly mutations in genes such as CFH, CFI, and CD46.

Interestingly, the Indian context differs: anti–factor H autoantibodies account for a disproportionately large share (up to ~50% in children), especially in the 5–15-year age group. This epidemiological distinction has major implications for diagnostic prioritization.

Clinical Presentation and Diagnostic Complexity

Clinically, aHUS presents as a thrombotic microangiopathy triad:

Microangiopathic hemolytic anemia
Thrombocytopenia
Acute kidney injury

However, this phenotype is shared across multiple conditions, making diagnosis inherently complex. The discussion emphasized that aHUS is largely a diagnosis of exclusion, requiring systematic elimination of other causes of TMA.

A Stepwise Diagnostic Approach

A consensus diagnostic algorithm was discussed, broadly aligned with international guidelines but adapted for local realities.

1. Exclude Common Mimics

The first step is to rule out conditions that can closely resemble aHUS:

Sepsis-associated TMA
Tropical infections (malaria, dengue, leptospirosis)
Disseminated intravascular coagulation

These are particularly relevant in India and must be excluded early to avoid misdiagnosis.

2. Evaluate for TTP

In adults especially, thrombotic thrombocytopenic purpura (TTP) must be considered:

Severe thrombocytopenia (<30,000)
Less prominent kidney injury
Multisystem involvement

Diagnosis depends on ADAMTS13 activity assays, which remain limited in availability and costly in India. Proper sample handling (plasma separation and freezing) is critical.

3. Assess for Shiga Toxin–Associated HUS

Although less common in India, Shiga toxin HUS (STEC-HUS) should be evaluated, especially in cases with:

Dysentery or diarrhea
Pediatric patients

Diagnostic challenges include:

Low yield of stool cultures
Need for PCR or antigen-based assays
Importance of early sample collection

The key reason for identifying STEC-HUS is that management is largely supportive, unlike aHUS, where aggressive therapy is required.

4. Screen for Metabolic Causes

An often overlooked but critical category is cobalamin (vitamin B12) metabolism disorders, accounting for 5–10% of cases.

Measured via plasma homocysteine
Requires early sample storage
Highly treatable with targeted therapy

Failure to diagnose these can lead to inappropriate treatment escalation.

5. Identify Secondary Causes

Secondary TMAs should be evaluated based on clinical context:

Autoimmune diseases (e.g., lupus)
Malignancy
Drug-induced TMA
Transplant-associated TMA
Malignant hypertension

These are more common in adults and often identifiable through routine investigations.

Confirming Complement-Mediated aHUS

Once other causes are excluded, attention turns to complement dysregulation, the hallmark of aHUS.

Key Investigations

Complement C3 levels
- Low in ~40–60% of cases
- Not universally reliable
Anti–factor H antibodies
- Particularly important in India
- High diagnostic yield (~55–57%)
- Requires robust ELISA methods
Genetic testing
- Whole exome sequencing (WES)
- MLPA for structural variants

A key insight was that not all patients require immediate genetic testing. In those with high anti-factor H antibody levels, genetic testing may not add value initially.

Challenges in Genetic Interpretation

Genetic testing introduces its own complexities:

Variants of uncertain significance (VUS)
Multiple mutations with unclear relevance
Difficulty distinguishing pathogenic vs incidental findings

Clinicians highlighted the need for close collaboration between nephrologists and geneticists to interpret results meaningfully, especially in decisions related to:

Long-term therapy
Transplant risk
Pregnancy counseling

Importance of Early Treatment

A critical consensus point was that treatment should not be delayed while awaiting genetic results.

Treatment Options

Plasma exchange (PLEX)
- Historically standard in India
- Removes autoantibodies and replaces complement factors
- Must be initiated within 24 hours
Complement inhibitors (e.g., eculizumab)
- Gold standard globally
- Dramatically improves outcomes
- Limited access in India

Early initiation of therapy—especially within 24 hours—was repeatedly emphasized as a determinant of outcomes.

Indian Context: Unique Realities

The discussion underscored several India-specific challenges:

High prevalence of anti-factor H antibody disease
Limited access to advanced diagnostics (ADAMTS13, genetic testing)
Cost constraints
Reliance on plasma exchange over complement inhibitors

Despite these constraints, Indian centers have developed effective adapted protocols, particularly combining plasma exchange with immunosuppression for antibody-mediated disease.

The Need for a Collaborative Model

Perhaps the most important takeaway was the need for integrated care pathways:

Nephrologists: clinical suspicion, acute management
Geneticists: variant interpretation, long-term risk stratification
Laboratories: standardized, reliable assays

The goal is a streamlined, pragmatic diagnostic algorithm that balances accuracy, speed, and feasibility.

Key Takeaways

aHUS is primarily a complement-mediated disease, but diagnosis requires systematic exclusion of multiple mimics.
Anti–factor H antibody disease is highly prevalent in India, making it a priority test in pediatric patients.
Early treatment (within 24 hours) is critical, and should not wait for genetic confirmation.
Close collaboration between nephrologists and geneticists is essential, especially for interpreting complex genetic findings and guiding long-term management.

Saturday, April 4, 2026

Optimising the diagnosis of aHUS: Meeting of Nephrologists and Geneticists