Autori: Nicoletta Mancianti (1), Giulio Monaci (2), Paola Buracchi (2), Fabio Rollo (2), Andrea Guarnieri (2), Guido Garosi (2)
Affiliazioni: (1) Division of Nephrology, Sant’Andrea University Hospital, Rome (2) Nephrology, Dialysis and Transplantation Unit, AOU Senese
Introduction
Modern methods of desensitization in kidney transplantation ABO incompatible are based on the application of apheretic techniques combined with immunosuppressive drugs such as Rituximab. Severe infusion related reactions due to the administration of Rituximab are reported in approximately 10% of patients . Therefore, it is common practice to test alternative B cell depleting therapies. We reported on the first clinical case of a patient undergoing desensitization protocol for kidney disease transplantation AB0 incompatible with Ofatumumab, a fully humanized monoclonal anti-CD20 antibody.
Case report
A 41-year-old male diagnosed with end stage kidney disease was presented to our transplant center for live kidney donation accompanied by his mother: a potential, healthy, willing AB0 incompatible kidney donor. Immunological tests [complement-dependent cytotoxicity lymphocytotoxicity crossmatches (CDC-LT, CDC LB), luminex DSA, Match-HLA], were performed in the recipients. Table 1 gives demographic and immunological data of the donor and recipient.
After finding the donor and recipient eligible for transplantation, we proceeded with the desensitization protocol by using the Stockholm model (Tydel et al. AJ of Trasplantation 2005; 5:145-148) and the Johns Hopkins Hospital model (Montgomery et al. N Engl J Med 2011;365:318-326) as a guideline. This protocol states that all AB0 incompatible recipients must have received the anti-CD20 antibody (Rituximab) for four weeks before the transplant. Then, two weeks before the patients must have received plasmapheresis to reduce the anti-ABO antibody. Most recipients received plasmapheresis 4 to 5 times (range, 2–9 times) until the isoagglutinin anti-ABO antibody ratio was ≤1:8.
The qualifying patient was admitted to our department and administered Rituximab (375 mg/m2 i.v.) as part of the desensitization protocol but despite the premedication given prior (Methylprednisolone 250 mg, Chlorphenamine 10 mg and Paracetamol 1 g), he displayed an adverse infusion reaction: high fever, tremors, malaise and dyspnea. We decided to complete the procedure using another anti-CD20 antibody (Ofatumumab), after a period of clinical oversight. One month after the Rituximab reaction, the patient started a new desensitization therapy which consisted of Ofatumumab (300 mg i.v. 35 days before the transplant and 2000 mg i.v. 28 days before the transplant), six sessions of apheresis and a low dose intravenous immunoglobulin (0,5 g/Kg).
The intravenous dose of Ofatumumab was administered following Methylprednisolone 250 mg, Chlorphenamine 10 mg and Paracetamol 1 g. The patient tolerated the administration without reaction and it was possible to complete the cycle of desensitization without any side effects. The plasmapheresis sessions were performed on alternate days, up to the achievement of a sufficiently low antibody blood titer (≤1:8). In our clinical case six apheresis sessions (5 plasma-exchange and 1 cascade filtration) were necessary in order to achieve sufficiently low isoagglutinins levels and proceed to transplantation. The graphics 1 and 2 shows the pharmacological and apheresis procedural results: a progressive decrease in isoagglutinins levels.
The triple immunosuppressive therapy was started on the first day of the plasmapheresis through oral administration of Tacrolimus (0,15 mg/Kg/day), Mycophenolic Mophetil (1000 mg x 2/day) and Prednisone (25 mg/day). On the day of the renal transplantation Basiliximab, an anti-CD25 antibody, was administered at a dose of 20 mg i.v., then readministered on the fourth post-operative day as induction therapy.
After the desensitization protocol the patient underwent a renal transplant from an incompatible living donor with no surgical complications.
The clinical course was characterized by a good functional recovery with creatinine values that reached 1.6 mg/dl after 1 month.
Discussion
The percentage of severe infusion reactions following treatment with Rituximab is approximately 10%. The study of anti CD20 alternative is important in order to find alternative treatment options. Currently, three fully humanized anti-CD20 antibodies are available: Ofatumumab, Obinutuzumab and Ocrelizumab. There is no experience in the use of these drugs in renal transplantation.
Ofatumumab is a human monoclonal antibody (IgG1) that binds specifically to an epitope encompassing both the small and large extracellular loops of the CD20 molecule. The binding of Ofatumumab to the membrane-proximal epitope of the CD20 molecule induces recruitment and activation of the complement pathway at the cell surface, leading to complement-dependent cytotoxicity and resultant lysis of cells. It was also observed that Ofatumumab can induce lysis in cells Rituximab-resistant expressing CD20. As a fully humanized antibody, Ofatumumab may avoid immunogenic reactions.
Today Ofatumumab is approved and used in malignant haematological disorders with encouraging results especially in those patients resistant or intolerant to treatment with Rituximab. This is the first use of Ofatumumab in kidney transplantation protocol and our case report suggests that is a valid alternative B cell depleting agent, especially in patients who are intolerant to Rituximab due to infusion related reactions. Further studies are needed to secure and define the role of Ofatumumab and other emerging anti-B cell therapies in kidney transplantation.
Bibliografia: