Eculizumab for the Treatment of Severe Antibody-Mediated Rejection: A Case Report and Review of the Literature

In renal transplantation, treatment options for antibody-mediated rejection are limited. Here, we report a case of severe AMR treated with eculizumab. A 50-year-old woman known for end stage kidney disease secondary to IgA nephropathy received a kidney transplant from a 50-year-old deceased donor. At 5 months after transplantation, she presented with acute graft dysfunction and biopsy showed a severe antibody-mediated rejection associated with thrombotic microangiopathy. Despite an aggressive conventional immunosuppressive regimen, signs of rejection persisted and the patient was treated with 3 doses of eculizumab. Following the therapy, markers of TMA improved and graft function stabilized. However, ongoing signs of rejection remained in the repeated biopsy. In kidney transplantation, eculizumab is an expensive treatment and its role in the treatment of antibody-mediated rejection remains to be determined.


Background
The management of antibody-mediated rejection (AMR) represents a challenge in kidney transplantation, as the treatment options are limited and sometimes ineffective [1]. Here, we report a case of severe AMR treated with eculizumab.

Case
A 50-year-old Asian woman known for end stage kidney disease secondary to IgA nephropathy received a kidney transplant from a 50-year-old deceased donor. The pretransplant crossmatch (CDC) was negative despite a PRA value of 25% and a complete HLA mismatch (in B and DR). The cold ischemia time was 7 hours and the patient was induced with basiliximab and methylprednisolone. Subsequent maintenance immunosuppression consisted of tacrolimus, mycophenolate, and prednisone.
After transplant, the recipient had delayed graft function requiring three dialysis sessions. Ultimately, the clinical course was favorable and she was discharged with a good renal function (creatinine value of 128 mol/L (1.48 mg/dL)).
One week after discharge, the patient was readmitted for graft dysfunction with a rise in creatinine to 194 mol/L. An urgent biopsy showed moderate glomerulitis and the presence of inflammatory cells in peritubular capillaries, but C4d was negative. As C4d-negative antibody-mediated rejection (AMR) was not a recognized entity in 2013; she was only treated with intravenous pulses of methylprednisolone and the creatinine stabilized at 160 mol/L. A few weeks later, an analysis revealed the presence of a donor specific antibody (DSA) (DQA0302) with MFI of 1800. This DSA was present before the transplant (MFI 1600) but we were not aware of its presence at the time of transplant. The DSA titers decreased mildly after initial treatment (MFI 900).
At 3 months after transplantation, despite a CMV infection treated with ganciclovir, renal function remained stable. However, after 5 months, the recipient presented again with severe acute graft dysfunction (creatinine up to 400 mol/L) but, this time, there were signs of thrombotic microangiopathy (TMA): thrombocytopenia, decreased haptoglobin, increased LDH, decreased fibrinogen, and hemolytic anemia. A second biopsy was performed and it showed an acute active type 2 AMR with lesions of TMA, peritubular capillaritis, and glomerulitis (negative Cd4) associated with a grade IA cellular rejection ( Figure 1). Immunohistochemistry for CMV was negative. She was then treated aggressively with a combination of pulse steroid therapy (3 doses), thymoglobulin (2 doses), plasmapheresis (3 exchanges), intravenous immune globulin (4 doses), and rituximab (4 doses). Two weeks after the intensive treatment, despite a stabilization of renal function (creatinine of 200 mol/L), signs of AMR (TMA) still persisted in a repeat biopsy (3rd biopsy) and DSA remained elevated (MFI 1300). We decided to treat the recipient with 3 doses of eculizumab (1200 mg, 900 mg, and 900 mg) (Figure 1). Following the therapy, blood markers of TMA significantly improved ( Figure 2). However, because of the heavy immunosuppressive state, the patient suffered from multiple infections: CMV reactivation, pulmonary aspergillosis, and Clostridium difficile colitis. DSA titers were not repeated after eculizumab treatment.
The last graft biopsy (8 months after transplant) showed ongoing AMR and progression of chronic lesions (moderate tubular atrophy and interstitial fibrosis) ( Figure 1). However, transplant glomerulopathy and peritubular capillary basement membrane multilayering were not seen in the electron microscopy (EM). One year after transplant, renal function declined progressively (creatinine up to 250 mol/L) and haptoglobin gradually decreased, but platelets were normal and there was only mild anemia. All infectious complications resolved.

Discussion
In AMR, the complement system is activated and constitutes one of the main mechanisms responsible for endothelial damage. Eculizumab is a monoclonal antibody that specifically binds to factor C5 and inhibits the terminal pathway of the complement cascade, preventing endothelial injury [2]. Clinically, it is mainly used for the treatment of paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome. In renal transplantation, there are few data on the use of eculizumab for the treatment of AMR.
In our case, the diagnosis of AMR was not done initially despite the presence of glomerulitis and peritubular capillaritis because C4d-negative AMR was not a recognized entity before 2014. Therefore, the patient was not aggressively treated after the first biopsy. Once the diagnosis of AMR was made, she had CMV infection that limited the immunosuppressive treatment. However, she probably could have benefited from a more aggressive and longer conventional treatment. By the time eculizumab was introduced, it was probably too late as AMR had become extremely severe. Furthermore, because eculizumab is an expensive medication and   [3]. These recipients who had a pretransplant positive crossmatch and DSA were treated with eculizumab in addition to plasmapheresis and thymoglobulin. When compared to a historical group (51 patients treated only with plasmapheresis and thymoglobulin), the incidence of AMR was significantly lower in patients treated with eculizumab (8% versus 41%).
Interestingly, at 1 year after transplant, the incidence of transplant glomerulopathy was also lower in the eculizumab group (7% versus 28%). Recently, Orandi et al. published a study using eculizumab alone or combined with splenectomy as rescue therapy for AMR. Of the 14 patients, 5 recipients treated with this combination had no graft loss. However, inquisitively, 80% of patients treated with eculizumab without splenectomy experienced graft loss [4].
In the literature, there are more than a dozen case reports on the use of eculizumab for treatment of AMR. In the majority of these cases, eculizumab is described as being effective in reversing the rejection and improving graft function [5][6][7][8][9][10][11]. However, in a minority of cases, eculizumab has failed to treat the rejection [12]. Interestingly, cases of cd4-negative AMR (including our case) do not seem to improve with eculizumab treatment. As c4d is a sign of complement activation, this suggests that there might be other mechanisms involved in AMR and eculizumab would be ineffective in this context. All cases are summarized in Table 1.
In kidney transplantation, eculizumab is an expensive treatment and its role in the treatment of antibody-mediated rejection remains to be determined.