Absence of thrombocytopaenia and/or microangiopathic haemolytic anaemia does not reliably exclude recurrence of atypical haemolytic uraemic syndrome after kidney transplantation

Abstract

ABSTRACT:A 54-year-old man was diagnosed with atypical haemolytic uraemic syndrome (aHUS) with confirmed complement H mutation in 2012, requiring ongoing dialysis. He was commenced on eculizumab in 2014 once the pharmaceutical board approved this drug. After 4 months, he received a live unrelated donor renal transplant from his wife and continued eculizumab post-transplant. Three months later, there was a rise in his creatinine with no laboratory features of haemolysis and a kidney biopsy confirmed rejection, which was treated with increased immunosuppression. After completing 12 months of treatment with eculizumab, he opted for close monitoring rather than continuation with therapy. Five months post-cessation of the drug, there was a rise in creatinine, and once again, haematological parameters remained within reference range; however, his kidney biopsy showed features consistent with recurrence of aHUS; hence, eculizumab was recommenced with good effect. While there was no evidence of haemolysis, there was a gradual rise in LDH level and a drop in platelet count, although the parameters remained within the normal range. This suggests that aHUS can recur in the allograft in the absence of haematological abnormalities. Clinicians should have a low threshold for allograft biopsy if haematological parameters are not just outside the reference range, but possibly also if there are changes of at least >25% from baseline in platelet count and LDH levels, particularly in those patients who are no longer eligible for eculizumab. ). The plasma level of ADAMTS13 was over 10%, thereby excluding thrombotic thrombocytopaenic purpura and confirming the diagnosis of atypical haemolytic uraemic syndrome (aHUS). A kidney biopsy showed focal necrotizing lesions with capillary occlusion by red cell fragments, fibrin and neutrophils, indicative of thrombotic microangiopathy (TMA). Despite treatment with intravenous corticosteroids and alternate daily plasmapheresis (exchanged with fresh frozen plasma) over a 2 week period, there was ongoing evidence of MAHA, and he remained dialysis-dependent. Genetic screening performed in the Clinical Research Center for Rare Diseases in Italy identified the presence of a heterozygous complement factor H mutation, located at exon 23 (codon 3644G > A). Combined liverkidney transplantation was considered 12 months later, but given the presence of moderate-severe pulmonary hypertension, possibly related to his large arterio-venous fistula-related shunt, as well as concomitant cardiovascular disease, he was deemed unsuitable for dual transplantation. With Pharmaceutical Benefits Advisory Committee (PBAC) approving the use of eculizumab for aHUS from December 2014, CASE REPORT

Eculizumab in atypical hemolytic uremic syndrome: strategies toward restrictive use

“…In the patients who were treated prophylactically, eculizumab was discontinued in eight, all adults, at 1 to 28 months after transplantation [50, 53, 71–74]. Two patients, both recipients of a living donor kidney, developed aHUS recurrence after discontinuation of eculizumab (Online resource Table 1) [53, 74]. The remaining patients did well, without aHUS recurrence and serum creatinine ranged from 67 to 118 μmol L −1 after a follow-up of 4 to 26 months (Online resource Tables 1 and 4).…”

Complement gene variant effect on relapse of complement-mediated thrombotic microangiopathy after eculizumab cessation

“… 13 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 The 40 remaining publications were reviewed extensively. 3 , 5 , 6 , 7 , 9 , 10 , 11 , 12 , 14 , 15 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 Individual cases were excluded due to lack of eculizumab discontinuation, subsequent evidence of Shiga toxin-producing Escherichia coli , lack of information on eculizumab dosing, no complement genetic testing, case duplication, and eculizumab discontinuation in the setting of lack of a hematologic response.…”

Thrombotic microangiopathy after kidney transplantation: Expanding etiologic and pathogenetic spectra

“…In fact, in PT-TMA, often more than one acquired factors are implicated in the causation of the disorder, leading to a proposal by some researchers of three-hit mechanism. It is important to identify all the predisposing factors in order to optimally treat the condition[ 33 - 38 ]. It is, however, often impossible to pinpoint to a single etiologic factor in an individual patient.…”