Summary for patients of recent meeting between nephrologists and geneticists on optimising aHUS Diagnosis

 

Understanding aHUS: Why Early and Accurate Diagnosis Matters

Atypical hemolytic uremic syndrome (aHUS) is a rare but serious condition that affects the blood and kidneys. Because its symptoms can look like several other illnesses, diagnosing it correctly—and quickly—is very important for saving kidney function and even lives.

This article summarizes key insights from experts in nephrology (kidney specialists) and genetics on how aHUS is diagnosed and managed.

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What is aHUS?

aHUS is a disease where small blood clots form in tiny blood vessels, especially in the kidneys. This leads to three main problems:

• Destruction of red blood cells (anemia)

• Low platelet counts (affecting clotting)

• Kidney injury

Most cases of aHUS are caused by problems in the body’s complement system, a part of the immune system that helps fight infections. When this system becomes overactive, it can damage the body’s own blood vessels.

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Why is Diagnosis Difficult?

The symptoms of aHUS are similar to many other conditions, such as:

• Severe infections (like sepsis or dengue)

• A related condition called TTP

• Diarrhea-related HUS (common in some countries)

• Autoimmune diseases

Because of this, doctors must first rule out these other conditions before confirming aHUS. 

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How Do Doctors Diagnose aHUS?

Doctors follow a step-by-step approach:

1. Rule out infections and common causes

   Tests are done for infections like malaria, dengue, or bacterial illnesses.

2. Check for related conditions

   Special tests may be needed to rule out TTP or rare metabolic disorders.

3. Look for complement system problems

   Blood tests help identify abnormalities in the immune system.

4. Test for antibodies and genes

   • In many Indian patients, the disease is caused by antibodies against a protein called factor H.

   • Genetic testing may also be done to identify inherited causes.

Importantly, doctors may start treatment before all test results are available, because delays can worsen outcomes. 

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Treatment Options

1. Plasma Exchange (Common in India)

This procedure removes harmful substances (like antibodies) from the blood and replaces them with healthy plasma. It is often started urgently.

2. Targeted Medicines

In many countries, drugs that block the complement system (such as eculizumab) are the standard treatment. These drugs can dramatically improve outcomes, but access may be limited in some regions.

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Why Early Treatment is Crucial

Experts strongly emphasize that treatment should begin within 24 hours of suspicion. Early treatment can:

• Prevent permanent kidney damage

• Reduce the need for dialysis

• Improve survival

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What Makes India Different?

In India, a large number of children with aHUS have a specific type caused by anti-factor H antibodies. This is important because:

• It is treatable with plasma exchange and medicines

• Outcomes can be good if treated early

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The Importance of Teamwork

Managing aHUS requires a team approach:

• Nephrologists diagnose and treat kidney problems

• Geneticists help interpret genetic tests

• Laboratories ensure accurate testing

Working together helps doctors choose the best treatment and prevent relapses.

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Key Takeaways

• aHUS is rare but serious—early diagnosis is critical.

• Symptoms can mimic other illnesses, so careful testing is needed.

• Treatment should start quickly, even before all results are confirmed.

• Many cases in India are treatable if identified early.

Optimising the diagnosis of aHUS: Meeting of Nephrologists and Geneticists

 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.

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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.

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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. 

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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. 

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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. 

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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. 

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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. 

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Confirming Complement-Mediated aHUS

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

Key Investigations

1. Complement C3 levels

   • Low in ~40–60% of cases

   • Not universally reliable

2. Anti–factor H antibodies

   • Particularly important in India

   • High diagnostic yield (~55–57%)

   • Requires robust ELISA methods

3. 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. 

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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

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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. 

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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.

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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.

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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.

Delays in processing funding applications by CoEs under NPRD

The Government of India has included atypical HUS in its National Policy for Rare Diseases (NPRD). Under this policy, several Centers of Excellence (CoEs) across the country were chosen to handle applications from doctors with patients suffering from these rare diseases for funding treatment to an extent of Rs. 50 lakhs.

Since Soliris became available in India, doctors have been applying for funds allocated for treating aHUS with this drug. Sadly, these applications are not being processed quickly. Atypical HUS is a very serious disease. Because of these delays, patients are either dying or developing kidney failure.

This is unfortunate because the government has provided funds for treating this disease and these funds are not being made available to deserving patients. Due to bureaucratic delays at the CoEs, patients are not getting the treatment they need. This is an appeal to all CoEs to process funding applications for atypical HUS quickly. Delays can endanger patients' lives and lead to death or kidney failure requiring dialysis.

Making available vials of Eculizumab to be used in emergencies

The National Programme for Rare Diseases in India has made drugs like Eculizumab available for patients with Atypical Hemolytic Uremic Syndrome. Centers of Excellence (CoEs) have been chosen to handle applications from doctors who need Eculizumab for their patients.

However, these centers are taking a long time to process applications and provide the drug to patients. Atypical HUS is a serious disease that can quickly lead to death or end-stage kidney disease, so delays are dangerous. 

To solve this problem, each center of excellence could keep a few vials of Eculizumab on hand for emergencies. When a patient shows signs of thrombotic microangiopathy, hemolytic anemia, and renal insufficiency - the triad classically associated with aHUS, they can be given the drug right away. This can help prevent kidney failure and stop the disease from getting worse.

For this plan to work, the government and CoEs need to cooperate and ensure that enough vials are available at each center. This way, patients can receive immediate treatment while waiting for further tests to confirm the diagnosis.

The Atypical HUS India Foundation urges the government and CoEs to work together to make this happen.

How you can get access to Soliris (Eculizumab) in India: Government Funding Route

The Government of India has a National Program for Rare Diseases (NPRD) that funds, up to a certain extent, treatment for rare diseases including aHUS. With Soliris (drug name: Eculizumab) now becoming available in India through the company directly, supply should be more reliable. Until now, the drug was available through importers who imported such drugs through unofficial, non-company based channels.

For those who can afford to pay for the drug out-of-pocket, please refer to this post for more details.

This post will outline the steps to take to apply for assistance in procuring the drug through the Government's NPRD.

• Identify the closest Centre of Excellence (CoE) to you. Here is a complete list of CoEs in India
• Visit the CoE campus and meet a senior doctor in the nephrologiy department. You may need to take an appointment by phone or in-person. At the time of enrolment, you will be given a Hospital ID. Keep this handy
• Carry the following with you when you meet the nephrologist:
• ID proof (Aadhaar / PAN / Voter ID) - original and 2 copies - if patient is a minor, also carry ID proof of parent / guardian
• 2 Passport size photographs
• Your medical file that has past prescriptions
• Any hospitalisation discharge summaries
• Current Prescription from the nephrologist treating you
• Recent lab reports - CBP, LDH, Kidney function tests, Urine Analysis etc.
• Genetic Test Reports, if available
• The nephrologist may require some other tests to be done or additional documents may need to be provided. Arrange these as requested by them
• Once all documents are provided, the nephrologist (or their assistant / adminstrator) will enter the details into the NPRD portal. this will include the number of vials, duration of treatment etc. An enrollment number will be generated and given to you. Keep this number safely
• There is a Rare Disease Committee that has been constituted at each CoE. This committee meets periodically and even on emergency basis to review all applications submitted and decides the merits of each application. The committee meets once every 1-3 months (depending on the hospital and the number of cases to review; they may also meet on emergency basis if needed). The committe decides to approve / reject / recomend to modify the application
• Once a decision has been reached, you will be notified of the decision
• Keep in touch with the nephrologist you met about this and any other queries you may have. Sometimes, the nephrologist might put you in touch with another coordinator who would be able to answer any queries you may have
• The committee may request additional documentation including some investigations. Make sure you get these in a timely manner
• Also, if you undergo any doctor consults / investigations after the initial form is submitted, make sure you give this to the doctor / assistant in the CoE to submit in the portal
• Note that approval by the committee might take up to a few months
• Once the application is approved, then the CoE will raise the funding requisition with the government for which you may be asked to sign some consent forms
• Once the funding request is approved, the CoE will procure the drug from the company through their pharmacy
• Once the drug reaches the pharmacy, speak to the nephrologist to discuss the next steps

Please be aware that this is a relatively new process for the CoEs. Even among the CoEs, there are some that are better equipped than others.  Remember, you need to advocate for yourself or your loved one. You will need to keep following up with the relevant stakeholders. Do not expect things to be handed to you on a platter. You will need to push people to help you. Do drop us a line with your experiences and we will do the best we can to help. All the best!

How you can get access to Soliris (Eculizumab) in India: Self Pay Route

Now that Soliris is available in India, it is important for patients and their families and doctors to know how to get access to the drug. It is obviously not something that you can walk into a pharmacy and buy.

The drug can be accessed on one of two ways:

1. Paying yourself for it
2. Getting it through the Government's National Program for Rare Diseases (NPRD)

You can get more information of the contours of the NPRD and how it works here.

The Atypical HUS India Foundation has consulted the manufacturers of the drug and understood the steps to be taken by patients or their families to get access to the drug.

Cost of the drug for self-paying patients

The drug comes in vials of 300 mg each. Each vial costs about Rs. 95,000-100,000. Adults require about 3-4 vials each time, typically twice a month at steady state. There is a higher dosage required in the first few weeks. The dosage for children is typically lower. Please consult your doctor to determine the right dosage and frequency.

Steps to follow to get access to the drug

• The first step is to speak to your doctor to prescribe the drug on a prescription note along with the history and the tests conducted to make the decision to prescribe. Your doctor will need to ascertain your clinical condition to confirm if the drug is likely to help you. A lot will depend on your current clinical condition including (and not limited to) the following:
• Are you recently diagnosed and you still retain significant kidney function?
• Have you progressed to kidney failure requiring dialysis?
• Are you a candidate for a kidney transplant?
• Do you have willing related donor?
• Are you on the cadaver transplant list?
• Once the prescription is ready, your doctor will need to contact AstraZeneca. The Atypical HUS India Foundation can also help make this connection. Email us at ahusindia@gmail.com.
• The company's medical team will then speak with the doctor directly to understand the clinical background and requirements.
• The AstraZeneca commercial team will then liaise with the doctor / hospital pharmacy and arrange the drug through the appropriate authorized distributor.
• Escalation for urgent support: If you face challenges in accessing the drug, or if the physician is temporarily unavailable, you can write to med.info3@astrazeneca.com with a cc to ahusindia@gmail.com and oshin.santoshi@astrazeneca.com.

We will soon publish steps to access the drug through the second pathway - through the government's NPRD.

Eculizumab Launched in India

In a long-awaited welcome development, Eculizumab has been formally launched in India. In a press release issued recently, AstraZeneca, the company that acquired Alexion Pharmaceuticals, the manufacturer of the drug (brand name: Soliris) said, "Until now, limited awareness, diagnosis, and access to targeted therapies have contributed to prolonged hospitalisations and increased complications for those affected. The availability of Eculizumab marks a breakthrough in the standard of care."

For aHUS patients in India, this is a tremendous breakthrough in their collective journey. Until now, the drug was either not available or available only by importing it specifically for their use - a very arduous and complicated process.

Hopefully now, that would be a thing of the past. While there is still some lack of clarity on how the drug can be accessed and the cost at which it is available (which the aHUS India Foundation is working closely with the company on getting more information about), at least the delays in importing the drug would not be there.

The aHUS India Foundation strongly urges patients to speak to their doctors on their treatment plans and how they would change with the availability of the drug.

The Foundation also urges doctors with aHUS patients to be aware that the drug is now available and to please reach out to the company or us (ahusindia@gmail.com) and get access to the drug for your patients.

We, at the aHUS India Foundation are grateful to the company and the regulatory authorities for their efforts in making the drug available in India.

Soliris gets approval for sale in India

Soliris (brand name for the drug Eculizumab from Alexion Pharmaceuticals, now acquired by Astra Zeneca) was finally approved by the Indian drug control body, Central Drugs Standard Control Organization (CDSCO) yesterday.

The drug was advised for approval by the Experts Committee in May last year. The approval finally came yesterday. This is very welcome news for patients afflicted by life-changing diseases such as Atypical Hemolytic Uremic Syndrome (aHUS).

This clears the way for Astra Zeneca to start marketing and selling the drug in the country.

What remains to be seen though - and this is critical for a country like India - is what the drug will be priced at by the company. This is what will dictate if anything at all changes for aHUS patients. If the drug is priced even close to what it is priced at in developed countries, this approval does not mean anything at all. At least for most aHUS patients.

A lot of the discussion around this drug often centres around patients who need it short term. While there are patients who need it short term - some cancer patients, patients with certain conditions and even some aHUS patients with a certain set of mutations - the vast majority of aHUS patients are affected by mutations like those in the Complement Factor H (CFH). These patients would need the drug long term, potentially life long.

The Indian Government's Rare Disease Program provides a grant of Rupees Fifty Lakh (5 million) to rare disease patients which, at the current rates in developed countries, will barely fund the drug for a few months. What happens after that?

So, while aHUS patients in India do have a reason to cheer news of this approval, we cannot start celebrating yet. News on pricing of this drug is the next most critical aspect that we now await.

Soliris recommended for approval for aHUS in India

In some very welcome news for Indian aHUS patients who are not generally used to any such news, the Experts Committee under India's drug regulator, the Central Drug Standard Control Organisation (CDSCO) has recommended to grant approval to Astra Zeneca (the company that owns Alexion Pharmaceuticals) to import and market the drug Soliris (Eculizumab) in India.

Some important takeaways:

1. This approval is subject to Astra Zeneca India conducting Phase IV clinical trials to establish safety and effectiveness in the Indian population. There is no clarity yet on how this will be done and how long it will take.

2. Only "Centres of Excellence" will be authorised to prescribe this drug. This is likely to include reputed institutes such as AIIMS, PGI, Chandigarh etc.

3. There is still no clarity on when the drug will actually become available in India.

4. Most importantly, there is no information on how Astra Zeneca will price the drug. In many developed countries where the drug is available, it is one of the most expensive drugs in the world with the cost of one vial running into several lakhs of rupees and a dose being needed at least every two to four weeks.

aHUS patients and their families should be aware that the Indian government recently expanded their Rare Disease Program to increase the grant provided under this scheme from Rs. 20 lakhs to Rs. 50 lakhs. While this may still not be enough beyond a few months, at least it is a start. aHUS is also included in the list of diseases that are covered by this program. Please see this and this for more information.

After all these years of despondence, there is finally some hope for us. Clearly, we are not out of the woods yet. But there is hope that a path will emerge soon.

Crovalimab trial in India in children and adults

Just a few weeks back, we posted this article where we alerted Indian aHUS patients to a trial on Iptacopan, an oral aHUS drug. And now there is another trial for aHUS patients for the drug Crovalimab from Roche.

Crovalimab is a complement inhibitor which can be administered to patients recently diagnosed with aHUS. The Phase III trial is for both adults and children who have not yet progressed to kidney failure (are dialysis dependent). 

Here are the details of the two trials of this new drug:

Adults and Adolescents:

Information about the trial

Participating sites & Investigators (Currently Active for Enrolment)

1. All India Institute of Medical Sciences, Delhi,  Principal Investigator: Dr Aditi Sinha

2. Medanta, The Medicity, Gurugram | Principal Investigator: Dr Sidharth Sethi

3. Sawai Man Singh (SMS) Hospital, Jaipur, Principal Investigator: Dr Dhananjai Agrawal

Children:

Information about the trial

Participating sites & Investigators (Currently Active for Enrolment)

1. All India Institute of Medical Sciences, Delhi,  Principal Investigator: Dr Aditi Sinha

2. Medanta, The Medicity, Gurugram | Principal Investigator: Dr Sidharth Sethi

This is an earnest request to all nephrologists and other doctors who come across aHUS patients in India. Please take this opportunity to enrol your patients into these trials. Until now, aHUS patients had nowhere to turn to. We no at least have trials happening in the country which should hopefully, pave the way for general availability in due course.

An aHUS Drug may finally come to India!

The Atypical HUS India Foundation recently learnt of a clinical trial involving a complement inhibitor being conducted by Novartis. Iptacopan is an oral drug being manufactured by Novartis. They have also started a clinical trial for adult aHUS patients (read more here: NCT04889430) for which recruitment is ongoing.

This article titled aHUS Trial Watch 15 highlights key information for the currently enrolling Novartis APPELHUS study. With a twice daily oral delivery, and seemingly a small molecule drug rather than a biopharmaceutical, Iptacopan holds potential to become an aHUS therapeutic drug candidate which may finally address the dual issues of cost and access.

The Atypical HUS India Foundation is in touch with Novartis and they are looking for clinicians in India who might be interested in participating in this trial.

If you are a clinician interested in participating in this trial, please let us know by emailing us at ahusindia@gmail.com and we will forward your email to the right person in Novartis and hopefully connect the dots. 

Also, please let us know of any other doctors who might be interested in this adult trial and we will reach out to them as well. Thanks!

If you are an adult aHUS patient, please share this website link with your doctor and encourage them to participate in this trial.

India has never seen a trial for a complement inhibitor. So, this is a fantastic opportunity for clinicians, patients and the aHUS community in general.

Once the trial completes, hopefully, if the results are as expected, Indians may soon have access to a complement inhibitor at last!