Correct Answer A:Yes, it is appropriate to guide the post-transplant management and to exclude the disease in the donor.
Thrombotic microangiopathy (TMA) defines a histopathological lesion of vessel wall thickening (mainly arterioles or capillaries), intraluminal platelet thrombosis and obstruction of the vessel lumen. Consumption of platelets and erythrocytes occurs in the microvasculature of kidney, brain and other organs, which causes laboratory features of thrombocytopenia and microangiopathic hemolytic anemia. Depending on whether brain or renal lesions prevail, two clinical entities have been described: the thrombotic thrombocytopenic purpura and the hemolytic uremic syndrome
(HUS) (Noris American Journal of Transplantation 2010; 10: 1517–1523)
Typical HUS is caused by strains of E. coli (STEC) that produce Shiga-like toxins (Stx) and cause a hemorrhagic colitis. There are atypical forms, which are unrelated to STEC and account for less than 10% of cases (aHUS). These forms can occur sporadically or within families. The clinical outcome of aHUS is unfavorable (Noris American Journal of Transplantation 2010; 10: 1517–1523)
However, diarrhea may be an initial trigger of the disease in 39% of children (Clin J Am Soc Nephrol 8: 554–562, 2013). Thus, diarrhea at onset does not exclude an atypical HUS
Various hereditary or acquired deficiencies in the complement alternative pathway proteins have been identified, including inactivating mutations in the genes coding for regulatory proteins
of the alternative pathway C3 convertase (C3bBb), factor H (CFH), factor I (CFI), membrane cofactor protein (MCP), or thrombomodulin (THBD), anti-CFH antibodies associated with homozygous CFHR1-CFHR3 deletion and gain-of-function mutations in the genes coding for two components of the C3bBb convertase, factor B (CFB) and C3 (Clin J Am Soc Nephrol 8: 554–562, 2013.)
Risk of recurrence is significantly correlated with the type of mutation. The risk is highest (approximately 80 %) in patients with CFH, C3 or CFB mutations, and approximately
50 % in patients with CFI mutation, compared to approximately 20 % in patients with no identified complement mutation. The risk of post-transplant recurrence in patients with MCP mutation has been shown to be low. No post-transplant recurrence has been observed to date in patients with DGKE mutation. The recurrence risk is low in anti-CFH antibody-associated HUS if the antibody titer is low (<500–1,000 AU/ml) at the time of transplantation, while substantial if elevated. THBD mutation may be followed by post-transplant recurrence (Pediatr Nephrol (2016) 31:15–39)
In aHUS patients with high risk of recurrence, treatment with anti-C5 therapy proved to be highly effective for preventing and treating posttransplant aHUS recurrence (American Journal of Transplantation 2012; 12: 3337–3354) and Eculizumab alone, without plasma therapy (plasma infusion and/or plasma exchange), is sufficient to prevent recurrence of aHUS and to maintain long-term graft function American Journal of Transplantation 2012; 12: 1938–1944 American Journal of Transplantation 2012; 12: 3337–3354
Live-related donation in patient with aHUS and identified mutation is a possible option, provided that complete genotyping of the donor is performed excluding the mutation identified i the patient or other possibly predisposing mutation American Journal of Transplantation 2010; 10: 1517–15238
It is therefore evident that genetic mutations should be identified prior transplantation in order to stratify the risk of recurrence and guide the best treatment.