aHUS “A Constellation of Symptoms”

Article No 380

24 September 2020

Today aHUS alliance Global Action  attended an online meeting via Zoom talk (as has become ubiquitous during COVID19 pandemic) for a talk  about  “differential TMA diagnosis – a renal pathologists approach” given by Dr Anthony Chang, who is a Professor of Pathology from Chicago but specialises in renal pathology.

Renal pathology is perhaps not as well known profession to aHUS patients; but its importance is in  focusing on the diagnosis and characterization of medical diseases (non-tumor) of the kidneys, whilst team working with nephrologists and transplant surgeons.  The renal pathologist may be the first to spot a TMA in a biopsy and will provide the comprehensive report to guide clinical management.

Dr Chang was open in his views about Complement,  admitting being a sceptic until with more understanding he said he was now “all in” on how Complement is a participant to some extent  in  all renal TMAs.

He remarked that it is only 70 years that antibiotics have been available, before then our ancestors relied entirely on the evolved  innate immune systems including Complement.He saw Complement as a “ingenious” and “ready to kill”  and something the body needed protection from too.

He described aHUS as the “great masquerader”, looking like something else and often the second and third diagnosis. Much as syphilis , lupus and HIV used to present diagnostic problems until they were defined. Diagnosing Complement aHUS is a struggle. Even TMA is often not on the radar.

There are clinical manifestations that can be seen , these can be Neurological, Renal, GI,  Cardiovascular and Pulmonary but some times what is expected to be among them  is not seen . He gave the example of classic aHUS evidence of schistocytes (red blood cell fragments) as sometimes not being visible as the spleen is good at clearing them out.

Dr Chang talked about the diagnostic differences of TTP, HUS and aHUS but even then complement may be driving the TMA. Adding in the difficulties of other TMAs associated with a whole host of conditions in which Complement plays a role.

He illustrated the difficulty by presenting a series of case studies of transplant, hypertensive and Lupus patients in whom  Family History , Medical History , Clinical Symptoms and Complement blood levels did not point immediately to them having  aHUS. Some losing renal function with a recurrence on transplant and even then aHUS was not thought of, as other causes e.g. calcineurin inhibitors become the new prime suspects . Treatment then continues as before, with the same results.

Dr Chang explained how he sees complement TMA featuring in the diseases of the African American population even in Sickle Cell disease. aHUS in this population is increasingly evident.

He also illustrated how in cases involving twins it is possible for one twin to have  C3GN and the other to onset with aHUS. In another case a C3 GN patient had a transplant which triggered aHUS.  Quite perplexing!

Not all aHUS genetic mutations have been catalogued yet, and more are still being found each year.

He went on to present a model of triggering factors and susceptibility conditions. Triggers ascend from ” weak to strong”  and susceptibilities ranged from least risky to those most risky like CFH mutations. A strong triggers can bring out aHUS in those least susceptible, but a weak trigger may be enough for a patient with high risk susceptibility. There are other permutations of triggers and susceptibilities in between.

Throughout his talk Dr Change referred to a “smouldering aHUS” where sub-clinical disease activity is taking place over time, often on and off. Gradually eroding the nephrons of the kidney until end stage renal failure can happen over decades or a few years. If renal injury is spotted how could that be attributed to an underlying TMA condition?

All of which describes the complexity of the challenge to  unmask the masquerader  from the “constellation of symptoms” in the aHUS diagnosis process.

Each aHUS patient has had their own diagnosis journey. Each experienced their own symptoms in an escalating severity until some one says “you’ve got aHUS

Collectively aHUS patients could map that “constellation” and join the dots  too. Adding a patient perspective from their experience  of what getting a differential diagnosis is like.

A thank you to Anthony for his talk and helping increasing awareness of the aHUS diagnosis challenge .

He finished  his talk by mentioning it was aHUS Awareness Day. Today he did his bit towards that.