"Eculizumab First" in the Management of Posttransplant Thrombotic Microangiopathy

Abstract

Introduction: Posttransplant thrombotic microangiopathy (PT-TMA) is an uncommon event that characterizes approximately 3% to 14% of kidney transplants (KTs), and that is associated with a higher risk of delayed graft function and graft loss. PT-TMA occurs more frequently within the first 3 months after transplant and can be a manifestation of de novo disease or the recurrence of previous atypical hemolytic uremic syndrome (aHUS). Abnormalities in complement regulation genes could explain the increased susceptibility of some patients to PT-TMA. Eculizumab is a humanized monoclonal antibody that inhibits the formation of the membrane attack complex C5b-9. The aim of this study is to evaluate the efficacy of eculizumab as treatment for PT-TMA.

Methods: We retrospectively analyzed clinical records of 45 KT patients who received eculizumab immediately after the clinical diagnosis of PT-TMA.

Results: Kidney biopsy was performed in 91.1% of patients, and complement genetic study was performed in 64.4%. Of the kidney biopsies, 85.4% showed signs of TMA; genetic analysis revealed 1 pathogenetic variant, 2 variants of uncertain significance, 1 likely benign variant, 8 risk polymorphisms, and 27 risk haplotypes. After 2 weeks from the treatment starting, hemoglobin and platelets significantly increased. A remarkable improvement in kidney function was also observed. After 6 months, 28.8% of patients had a complete renal recovery whereas 44.4% had a partial recovery.

Conclusion: This is, to our knowledge, the largest series of KT patients with PT-TMA treated with eculizumab. These data suggest that eculizumab is associated with a normalization of hemolysis indices and an important and progressive improvement of graft function.

Keywords: atypical hemolytic uremic syndrome; eculizumab; kidney transplant; thrombotic microangiopathy.

Graphical abstract

Figure 1

Changes in the distribution of hemoglobin, platelets, LDH, and eGFR values in patients treated with eculizumab after diagnosis of PT-TMA. Compared to baseline (day of transplant), the diagnosis of PT-TMA was associated with a worsening of hemoglobin, platelets and LDH values, whereas the eGFR value did not undergo significant changes with a median value of 5 ml/min per 1.73 m². The asterisks indicate the time point at which the difference became statistically significant. eGFR, estimated glomerular filtration rate; LDH, lactate dehydrogenase; PT-TMA, posttransplant thrombotic microangiopathy.

Figure 2

Graft and patients’ outcomes at 6 months of follow-up from the start of treatment and at the last follow-up visit.

Figure 3

Values of platelets, LDH, and tacrolimus trough levels at the starting of eculizumab in patients who achieved a complete or partial response and in those who continued dialysis treatment at 6 months of follow-up. The levels of these 3 parameters were not different among the 3 outcome groups. In the last picture of the panel is shown the duration of treatment with eculizumab (number of weeks of therapy) in the 3 outcome groups at 6 months of follow-up: a significant higher duration of eculizumab was found in patients with the worse renal function (hemodialysis group) (P = 0.04). LDH, lactate dehydrogenase.