Long-Term Management of Atypical Hemolytic Uremic Syndrome after Non-Renal Solid Organ Transplantation with Eculizumab

Thrombotic microangiopathy (TMA) defined as microangiopathic hemolytic anemia, thrombocytopenia and end organ damage has been described in the post transplant (PT) setting after solid organ and hematopoietic stem cell transplants (HSCT).  The true incidence among non-renal solid organ transplant (NRSOT) recipients is unknown.  Reported rates range from 2-30% (Verbiest 2014).  Despite standard interventions such as plasma exchange and/or reduction in calcineurin inhibitor (CNI) therapy, 3-month mortality rates remain as high as 40% in NRSOT patients who develop PT-TMA.

In HSCT and renal transplant recipients, it has been demonstrated that complement plays a central role in the development of PT-TMA, analogous to atypical hemolytic uremic syndrome (aHUS) (Zuber 2011; Jodele 2013).  Based on similar clinical manifestations and etiology, PT-TMA should be defined by the same laboratory criteria as aHUS and treated with eculizumab (ECU), a monoclonal antibody directed against C5 (Sheth, ASH 2014).  We previously reported the successful use of ECU for the acute treatment of PT-aHUS in NRSOT patients (Broome, ASH 2013).  We report the long-term data on this cohort of patients here.

Between January 2012-Novemeber 2013, 10 patients (8 small bowel, 2 liver), were diagnosed with PT-aHUS utilizing established clinical criteria for de novo aHUS.  All patients were on CNI therapy at the time of diagnosis.  The median time from transplant to TMA diagnosis was 10.5 months (range 1-53 months).  All patients received standard aHUS dosing of ECU (with meningococcal vaccinations and antibiotic prophylaxis).  By 1 month of ECU therapy, all patients demonstrated normalization of hematologic parameters and 4 of the 5 patients on hemodialysis (HD) at the time of ECU initiation were able to discontinue HD.  At a median follow-up of 24 months, 7 patients remain on therapy (range 18-43 months).  One patient had ECU discontinued at 3 months by the transplant team.  Two patients have died: one at 3 months of therapy due to sepsis/multi-organ failure and the other at 6 months of therapy due to PT lymphoproliferative disorder/graft failure (GF).  The 7 patients remaining on ECU had no clinical/laboratory evidence of recurrence of PT-aHUS (Table 1).  No new HD has been initiated in the follow-up period.  All remained on CNI therapy (tacrolimus) for prevention of transplant rejection.  One patient on ECU therapy developed GF.  No serious infections have been reported to date.  

ECU is an effective therapy for the long-term management of PT-aHUS in NRSOT recipients.  Prompt initiation of ECU appears to result in an increased likelihood of reversal of end organ damage related to TMA.  The 2 patients with GF (240 days, 572 days) and the 1 patient who remained on HD (180 days) had extended intervals from laboratory evidence of PT-aHUS to initiation of ECU, suggesting prolonged complement mediated TMA may contribute to irreversible organ damage.  With early ECU therapy, 86% of patients have healthy graft function and 80% of patients were able to discontinue HD.  Despite ongoing CNI therapy, renal function, as measured by serum creatinine, has continued to improve demonstrating the benefit of long-term ECU therapy.  The observed decline in haptoglobin, an acute phase reactant, at 12 and 18 months suggests a decrease in systemic inflammation with constant complement regulation mediated by ECU, illustrating the systemic nature of PT-aHUS.  All patients remained on both CNI and ECU without infectious complications, demonstrating the ability to successfully administer more than one immune mediator in NRSOT patients with PT-aHUS concurrently.   The mortality rate in our cohort of NRSOT recipients with PT-aHUS is 20%, significantly less than prior reports of up to 70%.  We propose treatment with ECU at the earliest clinical/laboratory signs of aHUS to prevent the morbidity and mortality associated with PT-aHUS in NRSOT patients.  Future studies should prospectively evaluate ECU therapy in PT-aHUS to better define the risks and benefits of this therapy in NRSOT patients.

Table 1: Median Laboratory Values Post ECU

	At diagnosis	1 month	3 months	6 months	12 months	18 months
Platelets k/uL	86	151 p=.01	175 p=.04	177 p=.01	191 p=.04	168 p=.07
Serum Creatinine mg/dL	2.26	1.54 p=.03	1.42 p=.05	1.28 p=.04	0.97 p=.13	1.18 p=.13
LDH units/L	369	302 p=.23	206 p=.17	186  p=.17	235 p=.23	158 p=.21
Haptoglobin mg/dL	<8	115 p=.00	154 p=.01	136 p=.02	67 p=.03	90 p=.04