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.

Keywords: STEC-HUS; atypical haemolytic uraemic syndrome; complement; eculizumab; renal transplantation.

Fig. 1

Findings on brain imaging, histopathological examination and structural modelling of the C3 variant. (A) MRI of the brain was performed 11 days post-transplant due to evolving neurological symptoms (multiple generalized tonic–clonic seizures, severe headache, photophobia and cortical blindness) in the context of severe hypertension. Bilateral restricted diffusion abnormalities were seen within the cerebral hemispheres posteriorly, consistent with PRES. (B) Histopathological examination. A transplant biopsy performed 15 days post-operatively due to clinical manifestations of TMA showed (i) thrombotic occlusion of the arteriole at the glomerular hilum (silver, ×400) and (ii) ‘glomerular paralysis’ with markedly congested glomerular capillaries (haematoxylin and eosin, ×400); a transplant biopsy performed 5 months post-operatively due to an increase in serum creatinine showed tubulitis indicative of T-cell–mediated rejection (iii) (periodic acid–Schiff, ×400); there were no features of TMA and there was no evidence on immunofluorescence of eculizumb IgG kappa deposition. (C) (i) The p.S1619R genetic variant displayed on the FH/C3b co-crystal structure. An X-ray–derived co-crystal structure of fH/C3b was used to model the mutation and displayed with Pymol (Delano Scientific). The location of the S1619R variant (red sphere) is shown within the co-crystal structure of a FH CCPs1-4 (light grey):C3b (dark grey) complex. A previously reported, functionally significant genetic variant V1658A (yellow sphere) is also shown [12]. Neither of these variants is predicted to directly oppose FH (Protein Data Base ID code 2WII) [13]. (ii) The genetic variants were also displayed on the C3b (dark grey):FB (blue) co-crystal structure (Protein Data Base ID code 2XWJ) [14]. It can be seen that the V1658A variant directly opposed FB, in keeping with functional analysis demonstrating an increase in FB binding to C3b [12]. The S1619R variant is also in the C345C domain, suggesting that this variant may also lead to increased convertase formation. In silico analysis suggests that this rare genetic variant is conserved [genomic evolutionary rate profiling 4 (GERP 4)] and possible damaging (Polyphen2 0.834).