Rare genetic variants in Shiga toxin-associated haemolytic uraemic syndrome: genetic analysis prior to transplantation is essential

Abstract

We present a case of haemolytic uraemic syndrome (HUS) in a 16-year-old female with serological evidence of acute Escherichia coli O157:H7 infection. She progressed to established renal failure and received a deceased donor kidney transplant. Shiga toxin–associated HUS (STEC-HUS) does not recur following renal transplantation, but unexpectedly this patient did experience rapid and severe HUS recurrence. She responded to treatment with the terminal complement inhibitor eculizumab and subsequent genetic analysis revealed a rare variant in a complement gene. This highlights the importance of genetic analysis in patients with STEC-HUS prior to renal transplantation so that management can be individualized.

Complement Gene Variants and Shiga Toxin–Producing Escherichia coli–Associated Hemolytic Uremic Syndrome

“…Still, when we focused our analysis on very rare pathogenic variants with minor allele frequency ,0.1%, we showed that such very rare pathogenic variants were associated with a fivefold higher risk of developing Shiga toxin-positive HUS. Thus, although Shiga toxin-associated HUS is mostly driven by the infectious agent, our study highlights that in rare cases, genetic abnormalities may contribute to complement activation in Shiga toxin-associated HUS, consistent with published data (9,10,(20)(21)(22)(23)(24)(25)(26)(27)(28). However, our study did not include patients with Shiga toxin infection who did not develop HUS (a study difficult to complete outside of large epidemics) and thus cannot prove the role of genetics in the risk of developing HUS after Shiga toxin infection.…”

“…However, the role of hereditary complement abnormalities needs to be confirmed by a large international study. Finally, considering our data and prior case reports of STEC infection unmasking complement deficiency, genetic screening does not appear justified for all patients with postdiarrheal HUS, but should be considered in patients with a fulminant course to death or ESKD (19,20,22,27), progression to ESKD within ,3 years (patient 1, Table 5), a family history of HUS (23) (patient 6, Table 5), relapse of HUS (21,23,26), or post-transplant recurrence (22,27).…”

“…Altogether, 17 children with postdiarrheal/Shiga toxin-producing Escherichia coli (STEC) HUS were subsequently reported who carried rare variants in complement genes (9,10,20-28). In nine of them, genetic screening was motivated by an unusually severe outcome, relapses, or post-transplant recurrence, suggesting that STEC infection triggers aHUS onset and/or preexisting complement variants amplify Shiga toxin-induced complement activation and endothelial/podocyte damage, and worsen disease severity (20)(21)(22)(23)(24)(25)(26)(27). However, seven reported patients who had complement variants had a favorable outcome (9,10,28), leaving the issue of the role of genetics in Shiga toxinassociated HUS unclear.…”

Thrombotic Microangiopathy and the Kidney

“…Therefore, all individuals with TMA should be investigated for STEC-HUS (Figure 3). Rarely, complement gene mutations are detected, and in these cases the clinical picture is unusually severe (13,65). In STEC-HUS resulting in ESRD, it is recommended to screen for mutations before transplantation.…”

Complement C5-inhibiting therapy for the thrombotic microangiopathies: accumulating evidence, but not a panacea

“…In addition to infection complications, other concerns may emerge as use of complement-inhibiting therapy in clinical practice increases. Eculizumab-associated hepatotoxicity has been reported in children [ 19 ], and glomerular deposition of eculizumab in individuals with C3 glomerulopathy (C3G) [ 20 ], though not complement-mediated aHUS [ 21 ], has been reported although the long-term clinical consequences are as yet unclear.…”