Answer: B. Atypical hemolytic uremic syndrome
This patient presented with systemic lupus erythematosus (SLE), rapidly progressing glomerulonephritis caused by lupus nephritis, and TMA. TMA can be caused by HUS, thrombotic thrombocytopenic purpura (TTP), malignant hypertension, or medications. HUS is defined by the presence of renal failure, thrombocytopenia, and microangiopathic hemolytic anemia. Classically, HUS is associated with diarrhea resulting from Shiga toxin-producing Escherichia coli infection. However, 5% to 10% of HUS cases are classified as atypical HUS (aHUS) because the syndrome is not preceded by diarrheal illness. This is a relatively rare condition that results from unchecked activation of the alternative complement pathway.1 Patients with autoimmune diseases such as SLE may present with concurrent aHUS and TMA, such as in this case. The specific factors that trigger aHUS in a small subset of people with SLE but not in all of those with SLE remains unclear.
It is often difficult to differentiate aHUS from TTP as both present with hemolytic anemia, thrombocytopenia, and end organ damage. It is important to check ADAMTS13 activity to differentiate the 2 disease entities. ADAMTS13 activity is typically normal in aHUS and very low (<5%) in TTP. This is because TTP is a systemic disease with widespread von Willebrand factor-platelet thrombi formation in the arterioles and capillaries as a result of ADAMTS13 deficiency. Autoimmune inhibitors against ADAMTS13 can be found in most cases of TTP, whereas a small subset of patients have genetic mutations in ADAMTS13.2,3
In contrast to TTP, aHUS is not mediated by ADAMTS13 deficiency. As discussed earlier, it is caused by persistent, abnormal activation of the alternative complement pathway. Genetic mutations leading to either gain or loss of function of various complement factors such as complement factor H have been identified in association with aHUS.4
Additionally, autoantibodies against regulatory proteins involved in the alternative complement pathway have also been implicated in the development of aHUS. The end result of alternative complement activation is extensive formation of the membrane attack complex consisting of complement factor C5b-9 that leads to vascular endothelial damage and thrombosis.5,6
Eculizumab is a humanized monoclonal IgG antibody that binds to the complement protein C5, preventing its cleavage into C5a and C5b, thus forming the membrane attack complex. This therapy was initially approved to treat paroxysmal nocturnal hemoglobinuria. However, it has been shown to be effective in treating aHUS by targeting C5, the last step in activating the alternative complement pathway.7,8
- Waters AM, Licht C. aHUS caused by complement dysregulation: new therapies on the horizon. Pediatr Nephrol. 2011;26(1):41-57.
- Tsai H-M, Lian EC-Y. Antibodies to von Willebrand factor-cleaving protease in acute thrombotic thrombocytopenic purpura. N Engl J Med. 1998;339:1585-1594.
- Levy GG, Nichols WC, Lian EC, et al. Mutations in a member of the ADAMTS gene family cause thrombotic thrombocytopenic purpura. Nature. 2001;413:488-494.
- Fakhouri F, Zuber J, Frémeaux-Bacchi V, Loirat C. Haemolytic uraemic syndrome. Lancet. 2017;390(10095):681-696.
- Goodship TH, Cook HT, Fakhouri F, et al. Atypical hemolytic uremic syndrome and C3 glomerulopathy: conclusions from a “Kidney Disease: Improving Global Outcomes” (KDIGO) Controversies Conference. Kidney Int. 2017;91(3):539-551.
- Noris M, Remuzzi G. Atypical hemolytic-uremic syndrome. N Engl J Med. 2009;361(17):1676-1687.
- de Jorge EG, Macor P, Paixão-Cavalcante D, et al. The development of atypical hemolytic uremic syndrome depends on complement C5. J Am Soc Nephrol. 2011;22(1):137-145.
- Greenbaum LA, Fila M, Ardissino G, et al. Eculizumab is a safe and effective treatment in pediatric patients with atypical hemolytic uremic syndrome. Kidney Int. 2016;89(3):701-711.