Fig 3 from Wilson et al, © National Kidney Foundation.

Atypical hemolytic uremic syndrome (aHUS) is characterized by excessive microvascular complement activation. Many mutations have now been described that lead to aHUS and its associated entity, C3 glomerulopathy. In a recent AJKD article, Wilson et al describe a case of aHUS in a patient with a homozygous CFH mutation (c.2880delT [p.Phe960fs]) secondary to uniparental isodisomy. Dr. Timothy Goodship (TG), the corresponding author, discusses this topic with Dr Sethi (eAJKD), eAJKD Advisory Board member.

eAJKD: What is your clinical approach to a patient with aHUS? Is genetic testing indicated in all patients?

TG: Certain serologic complement factors are important to test. The results of the factor H autoantibodies along with levels of C3, C4, factor H, and factor I are available within a few days. Although these results may provide a clue as to whether there is an underlying genetic abnormality, a screening for mutations in genes encoding factor H, factor I, CD46, C3, and factor B is essential. We also routinely look for evidence of deletions, duplications, and hybrid genes. In addition, we also look for mutation in the genes encoding thrombomodulin and DGK epsilon in selected patients.

eAJKD: Do you have an algorithmic approach to the diagnosis of aHUS?

TG: If a patient presents with features compatible with a diagnosis of aHUS, we request an “aHUS checklist” be completed. This form asks for features within the clinical history (including initiating triggers, extra-renal manifestations, family history, and current treatment), results of investigations that confirm a TMA with acute kidney injury (platelet count, blood film, LDH, haptoglobins, prothrombin time, creatinine, and kidney biopsy), and results of investigations that exclude other causes of TMA and AKI such as TTP (ADAMTS13 activity), STEC HUS (stool culture and IgM E.coli endotoxin antibodies), APL antibody syndrome (APL antibody), SLE (dsDNA), HIV, scleroderma (ANA, anticentromere antibodies and anti-acl-70 antibodies), and cobalamin C disease (plasma homocysteine levels and plasma/urine methylmalonic acid levels). We do not request that the results of all these investigations, apart from the ADAMTS13 activity, be available. A group of us then independently look at this information and decide whether this aHUS and whether treatment with eculizumab should be started. If eculizumab is to be started, we request the patient be immediately vaccinated with a tetravalent meningococcal vaccine and started on long-term prophylactic antibiotics. We have just received approval to give prophylactic eculizumab to aHUS patients on dialysis to enable them to undergo transplantation.

eAJKD: Do you analyze FHL-1 protein in all patients, or is it dependent on some clinical or biochemical clues?

TG: We routinely use MLPA to determine the copy number of the gene encoding complement factor H related protein 1 and to look for any potential hybrid genes that might involve CFHR1. We do not routinely perform a Western blot or sequencing of CFHR1.

eAJKD: Do you analyze the Shiga toxin assay or antibodies to Shiga toxin in all patients before calling them aHUS?

TG: We ask that all patients have a stool sample sent for culture and a blood sample screened for IgM E.coli endotoxin antibodies.

eAJKD: Are there expected serum complement abnormalities in various CD46 haplotypes?

TG: There are no detectable abnormalities in the serum complement levels or CD46 expression in the various CD46 haplotypes.

eAJKD: Should we screen all aHUS, MPGN, and C3 glomerulonephritis for CD46 haplotypes?

TG: No, I don’t think this would change the current management of such patients.

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