Co-occurrence of aHUS, TMA, and Alport Syndrome Suggest Shared Mechanism, Case Report Says

Abnormal activation of the immune system’s complement pathway — a common response to fight germs — may represent a mechanism shared among three distinct kidney conditions, a case report suggests.

The rare case report of a patient who showed signs of thrombotic microangiopathy (TMA), Alport syndrome, and atypical hemolytic uremic syndrome (aHUS) was published in the journal BMC Nephrology.

Led by researchers from Stanford University, the study was titled “A rare case of Alport syndrome, atypical hemolytic uremic syndrome and Pauci-immune crescentic glomerulonephritis.”

The patient, a 26-year-old woman, went to the hospital because of progressive shortness of breath.

She had a medical history of asthma diagnosed at age 3, hearing loss at age 23, and hypertension diagnosed at age 24. Ten months before, a urine analysis detected increased levels of protein and blood, but this finding was not further investigated at that time.

After admission, a new urine analysis detected high levels of white and red blood cells, and about five times the normal levels of protein. Blood analysis also showed reduced platelet counts and hemoglobin levels, while white blood cells, blood urea nitrogen and creatinine levels were increased.

Analysis of relevant autoimmune-related antibodies and possible infections were all within normal ranges.

These findings were consistent with kidney impairment or injury, with active inflammation. She started hemodialysis and a kidney biopsy was performed.

A tissue sample showed signs of cell damage with accumulation of scarred tissue and atrophy of important filtration structures. The blood vessels within the kidney did not show signs of inflammation, yet there was indication of possible swollen blood vessels. Alteration of the basement membrane of the filtration unit was detected, which would be consistent with a diagnosis of Alport syndrome.

A second biopsy revealed that the scarred tissue covered more than 80% of the renal cortex (outer portion of the kidney). The woman also had some signs of cell proliferation in the filtration units (glomerular crescents).

She was found to have abnormal type IV collagen levels, with an absent alpha-3 chain and reduced alpha-5 chain, confirming the diagnosis of Alport syndrome. Additional analysis of the blood vessels showed she also had TMA, characterized by defects in the blood vessel wall lining and accumulation of immune complement proteins.

The clinical team also performed a genetic analysis, which showed that she carried at least three variants of alternative complement pathway genes previously linked to aHUS, which is an autoimmune complement-mediated rare disease.

Supported by the results and the patient’s symptoms, she was diagnosed with TMA, Alport syndrome, and aHUS with glomerular crescents.

“We hypothesize that this genetic predisposition in this unfortunate patient led to precipitation of aHUS and potentially pauci-immune crescentic glomerulonephritis (PCGN) in the context of an unidentified environmental trigger,” researchers stated.

She started treatment with corticosteroids (oral prednisolone). She also started plasma exchange to remove potentially harmful antibodies or other proteins, but this was soon discontinued.

After the results of kidney biopsies were made available, she started treatment with Citoxan (cyclophosphamide) and Soliris (eculizumab, marketed by Alexion).

Despite continued treatment, her kidney function remained poor, requiring maintenance hemodialysis.

Previous studies have shown that TMA, aHUS, and PCGN are associated with deregulation of the immune system’s complement pathway. Given so, the team stated that this case further demonstrates that deregulation of the “complement pathway may represent a common [disease-causing] link between these three distinct entities” and Alport syndrome.