Abstract
Complement dysregulation is central to the pathogenesis of atypical hemolytic uremic syndrome (aHUS). Mutations in genes encoding complement regulatory proteins (CRPs) can be identified in 61% of aHUS patients (Fremeaux-Bacchi 2013). In hematopoietic stem cell transplant (HSCT) recipients, all 6 children who developed post-transplant thrombotic microangiopathy (PT-TMA) were found to have a mutation in complement factor (CF) H related genes and/or the presence of CFH autoantibodies. In contrast, 18 children without evidence of PT-TMA had no mutations detected suggesting a strong role for complement dysregulation in the development of PT-TMA (Jodele 2013). Similarly, 30% of renal transplant patients who develop de novo PT-TMA had a mutation identified in CFH and/or CFI related genes, which were lacking in matched transplanted controls (Le Quintrec 2008).
In non-renal solid organ transplant (NRSOT) recipients, the role of complement in PT-TMA is less well-understood. A lack of established diagnostic criteria makes PT-TMA in NRSOT recipients difficult to recognize. The overall rate of renal failure (RF) in NRSOT recipients ranges from 7-21% (Ojo, NEJM 2003). RF is often attributed to endothelial damage triggered by calcineurin inhibitors (CNI), infection, or ischemia, all of which activate the alternative complement pathway. We propose a contributor to NRSOT related RF is PT-TMA, which develops in a subset of patients with underlying mutations in genes encoding CRPs.
From January 2012-Novemeber 2013, 10 patients were clinically diagnosed with PT-TMA (8 small bowel (SB), 2 liver) and treated with eculizumab at our institution. The 7 patients remaining on therapy at 1 year underwent testing for mutations in genes encoding CRPs via a commercially available assay at Washington University School of Medicine in St Louis. Identified mutations are depicted in table 1.
Table 1. Gene Mutations Patient 1SB CFHR3-CFHR1 heterozygous deletion CFH: 2808G>T, 1204C>TCFI: 898A>G Patient 2SB C3: p.T647M (1940C>T) heterozygous CFH: 2808G>T, 1204C>T, 184G>A, CFI: 898A>G, 1217G>ATHBD: 1418C>T Patient 3L CFH: p.Y402H, 1204C>T, 184G>A CFI: 898A>GTHBD: 1418C>T Patient 4SB CFI: 898A>G Patient 5L CFHR3-CFHR1 heterozygous deletion CFI: 898A>GCFB:1693A>G, 95G>A Patient 6SB CFB p.I242L (724A>C) heterozygous CFH: 184G>A, 1204C>TCFI: 898A>G Patient 7SB CFH: p.Y402H, 1204C>T, 184G>ACFI: 898A>G CF: Complement Factor, THBD: Thrombomodulin, SB: Small Bowel, L: Liver
All patients clinically diagnosed with PT-TMA had at least one non-synonymous mutation identified in genes encoding CRPs, which supports the role of complement dysregulation in the pathogenesis of PT-TMA in NRSOT patients. CFI898A>G, CFH1204C>T, and the combination of CFH1204C>T and CFH184G>A were found in 100%, 71%, and 57% of our patients, suggesting clinical significance. CFHR3-CFHR1 heterozygous deletion was seen in 29% of our cohort and has been correlated with an increased risk of aHUS and presence of CFH autoantibodies as reported in HSCT-TMA (Zipfel 2007). Two patients were heterozygous for either C3 p.T647M or CFB p.I242, which have been noted in aHUS cohorts (Schramm 2015; Noris 2010). Although seen in 35% of the normal population, CFH p.Y402H was observed in 29% of our cohort. Its presence has been reported to affect CFH related binding and has been associated with complement mediated disorders of the eye and kidney (Mullins 2011; Hageman 2005; Abrera-Abeleda 2006).
The identification of one or more CRP mutations in NRSOT patients with PT-TMA strongly suggests they harbor a predisposition to an impaired ability to regulate complement. Upon exposure to complement activating stimuli, these individuals develop PT-TMA or more accurately termed aHUS. We previously linked spontaneous thrombosis, as the underlying cause for SB transplant, to an increased risk of PT-TMA. The 3 patients with spontaneous thrombosis as the etiology for SB transplant that were tested were found to have CRP mutations, supporting our hypothesis that SB ischemia may be the presenting feature of aHUS. To better define the underlying PT-TMA-related risks associated with CRP mutations, we propose a study involving pre-transplant screening of all NRSOT recipients with ongoing prospective evaluation for the development and clinical course of PT-TMA.
Disclosures
Broome: Alexion Pharmaceuticals: Consultancy, Honoraria, Research Funding.
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