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High Incidence of Paralytic Ileus After Bortezomib Treatment of Antibody-Mediated Rejection in Kidney Transplant Recipients

2015; Wolters Kluwer; Volume: 99; Issue: 11 Linguagem: Inglês

10.1097/tp.0000000000000930

1534-6080

Erika De Sousa–Amorim, Ignacio Revuelta, Fritz Diekmann, Frederic Cofán, Joan Cid, Miquel Lozano, Josep M. Campistol, F Oppenheimer,

Drug-Induced Adverse Reactions

Bortezomib a proteasome inhibitor, approved by the Food and Drug Administration for the treatment of multiple myeloma (MM), capable of eliminating plasma cells responsible for the synthesis of antibodies, has recently been shown to be useful in the treatment of antibody-mediated rejection (AMR) in kidney transplantation (KT).1-3 Mild to moderate gastrointestinal (GI) toxicity associated with Bortezomib is a frequent adverse event (AE), commonly presenting as nauseas and diarrhea,1 with exceptional cases of paralytic ileus described in MM patients.4-7 From 2010, bortezomib has been used in our center as a rescue therapy for patients with refractory AMR, defined as the persistence of histological signs of AMR and renal dysfunction, despite standard therapy consisting of rituximab (400 mg), 5 or 6 sessions of plasma exchanges (PE) and IVIG (100 mg/kg after each PE). Patients with refractory AMR received 1.3 mg/m2 of bortezomib intravenous post-PE in days 1, 4, 8, and 11, IVIG (100 mg/kg) and a total of 5 to 6 sessions of PE. So far, a total of 7 patients have been treated, and 2 patients have developed paralytic ileus immediately after treatment. Case 1 was a 49-year-old woman, diagnosed with end-stage renal disease of unknown etiology, who received an ABO-incompatible living donor KT in February 2014. Biopsy-proven AMR was diagnosed early after transplantation without the presence of donor-specific antibodies and was treated with rituximab, IVIG, and PE plus maintenance immunosuppression with tacrolimus extended release 2.5 mg every day, mycophenolate mofetil 180 mg twice a day and low dose prednisone 15 mg every day. After 1 month, renal dysfunction and histological signs of AMR persisted despite treatment, and bortezomib was started. After 3 doses, the patient developed abdominal distension, pain, and diarrhea. Case 2 was a 62-year-old man with IgA nephropathy, who received a second living donor KT in the paired exchange program in December 2013, with pretransplant desensitization due to a positive flow cytometry crossmatch, receiving rituximab, IVIG, and PE. Six months later, AMR was diagnosed on protocol biopsy, without detectable donor-specific antibodies, receiving a new course of rituximab, IVIG, and PE. After 6 months, a new biopsy showed persistence of AMR, and bortezomib was started. Maintenance immunosuppression was tacrolimus 1 mg twice a day, mycophenolate sodium 500 mg twice a day and prednisone 10 mg every day. After completion of 1 cycle consisting of 4 doses, the patient progressively developed constipation, abdominal distension, and pain. In both cases abdominal X-rays showed marked small bowel dilatation (see Figure 1). Blood and stool cultures were negative, cytomegalovirus and clostridium difficile infections and other causes of paralytic ileus were ruled out. There was no history of abdominal surgery or surgical complications related to the KT, diabetes, or gastroparesis. The use of concomitant drugs was ruled out (including narcotics, anti-fungal agents, anticholinergics, opiates and loperamide). Hospital admission was required, and bortezomib was discontinued. Supportive treatment with intravenous hydration and nasogastric decompression led to progressive increased of bowel movements and complete resolution after 5 to 7 days.FIGURE 1: Abdominal radiography in case 1 (A) and 2 (B), showing marked distension of small intestine.Our center started using bortezomib in January 2010 for rescue therapy of refractory AMR. Between that time and April 2015, a total of 7 patients were treated with bortezomib for refractory AMR. Therefore, the incidence of paralytic ileus in this cohort was 28% (2/7), which is higher than reported in the treatment of MM.4 Previous experience with Bortezomib in KT showed a high incidence of mild to moderate GI AE, but no cases of paralytic ileus,8 and to date, these are the first cases reported in this population. The GI symptoms are very common after bortezomib affecting up to half of all patients,9 but the rate of severe GI complications is below 1%.4-7 Unlike the transplant-related cases reported, cases in MM patients occurred after multiple cycles and more frequently with subcutaneous administration. Furthermore, dose density (ie, weekly vs biweekly administration) and concomitant treatment with antifungal azols agents seemed to increase the likelihood of this complication. All but one of paralytic ileus cases resolved spontaneously after supportive care, with 1 case resulting in death from sepsis.4 The exact mechanism responsible for GI toxicity associated to Bortezomib is unknown, but it has been suggested that a drug-induced acute autonomic dysfunction could be the cause. In the KT population, it is possible that the interaction of bortezomib with other drugs, also presenting potential GI side effects as immunosuppressive agents, may lead to increase susceptibility to GI symptoms. Moreover, the cumulative prednisone dose has been previously associated with an increased incidence of paralytic ileus in KT,10 although more evidence is needed to confirm this finding. Although GI AE in our cohort were severe and required hospital admission, the paralytic ileus responded well to therapy and resolved rapidly. Given that bortezomib appears to be a promising strategy for AMR and pretransplant desensitization in KT, increased awareness of this potential complication is mandatory. Careful and frequent assessment for GI signs and symptoms could lead to prevention and in cases of mild to moderate AEs, effective management with supportive measures, antiemetics, antidiarrheal medications and in some cases bortezomib dose reductions or discontinuation could be helpful. ACKNOWLEDGMENT This study is included in the framework of Redes Tematicas De Investigacion Cooperativa En Salud, REDINREN (RD06/0016/1002 and RD12/0021/0028), from Instituto de Salud Carlos III - Ministerio de Ciencia e Innovación and cofounded by Fondo Europeo de Desarrollo Regional (FEDER) “Una manera de hacer Europa”.