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Belatacept as Immunosuppression in Patient With Recurrence of Hemolytic Uremic Syndrome After Renal Transplantation

2009; Wolters Kluwer; Volume: 87; Issue: 12 Linguagem: Inglês

10.1097/tp.0b013e3181a991ca

1534-6080

Karsten Midtvedt, Jan Bitter, Christina Dørje, Rune Bjørneklett, Hallvard Holdaas,

Adenosine and Purinergic Signaling

Recurrence of hemolytic uremic syndrome (HUS) after renal transplantation is relatively common and remains a threat to long-term graft outcome. HUS is described as de novo if the disorder arises after renal transplantation in a patient with no previous history of HUS. Calcineurin inhibitors (CNIs; tacrolimus and cyclosporine) are considered to be major offenders in de novo posttransplant HUS (1–4). Finally, the mammalian target of rapamycin (mTOR) sirolimus also has been associated with development of posttransplant HUS (5, 6). We report a patient with recurrence of HUS after renal transplantation in two subsequent grafts, the first recurrence leading to graft loss. Retransplantation was performed but once again with recurrence of HUS. This time the patient was successfully treated with withdrawal of tacrolimus, intensive plasma exchange PE, and introduction of belatacept as part of maintenance immunosuppressive therapy. Case Presentation A 37-year-old white man was hospitalized on January 2005 with acute renal failure and anemia due to HUS. The first renal transplantation was performed on October 2005 with a living donor (mother, 59-years, human leukocyte antigen mismatch 1-1-0, cytomegalovirus +−+, panel reactive antibody negative). Because of previous HUS, the initial immunosuppression according to local guidelines consisted of rapamune (initial trough level 10–15 μg/L), prednisolone, mycophenolate mofetil, and basiliximab as induction therapy (2). There was immediate graft function and a decline in serum creatinine to approximately 120 to 130 μmol/L. Posttransplantation there were two biopsy verified rejections, one steroid resistant treated with intravenous (IV) antithymocyte globulin (375 mg total dose) (7). Serum creatinine eventually stabilized approximately 200 to 220 μmol/L. After this, the patient developed severe rapamycine side effects (joint pain and a burning sensation of the skin). He subsequently developed proteinuria and a further increase in serum creatinine level to 270 μmol/L. A transplant biopsy showed no acute rejection but interstitial fibrosis (IF) and tubular atrophy (TA) (IF grade 2/TA grade 2). Because of increasing proteinuria and severe side effects of rapamycine, the drug was withdrawn and low-dose tacrolimus (trough level 3–6 μg/L) in combination with low-dose everolimus (trough level 3–6 μg/L) was initiated 15 weeks posttransplantation. Serum creatinine stabilized at 180 to 200 μmol/L with a decline in proteinuria. Twelve months after transplantation, the patient was readmitted to the hospital because of an increase in serum creatinine level to 400 μmol/L. Immunosuppressive medication at that time consisted of tacrolimus (target level 5–10 μg/L), prednisolone, and mycophenolate mofetil. Everolimus had been stopped due to continued side effects believed to be mTOR related. A graft biopsy showed no histologic signs of acute rejection or recurrence of HUS. No change in immunosuppression was initiated. Shortly after this episode, the patient experienced a clinical recurrence of HUS (no graft biopsy performed). Graft function was lost, and the patient was re-established in hemodialysis. The second renal transplantation was performed on January 2008, also this time with a living-related donor (brother, 35 years, human leukocyte antigen mismatch 1-1-1, cytomegalovirus − to +, panel reactive antibody negative). Surgery was uneventful, and there was immediate graft function with a decline in serum creatinine level to100 μmol/L on day 7 posttransplant. Initial immunosuppression consisted of tacrolimus (trough levels 3–7 μg/L), prednisolone, mycophenolate mofetil, and induction with IV basiliximab. On day 10 posttransplant, there was an increase in serum creatinine and lactate dehydrogenase and clinical signs of recurrence of HUS (Table 1). There was presence of red cell fragmentation in a blood smear, and hemoglobin was below 0.2. Tacrolimus treatment was discontinued and PE started immediately. Six daily PE were performed, and then an additional 13 PEs were performed over the next 4 weeks. Plasma was exchanged for 2 L albumin and 3 L Octaplas (Octopharma PPGmbH, Vienna, Austria). With only mycophenolate mofetil and prednisolone as immunosuppression, we feared the development of an acute rejection. Because of intolerance for mTOR and recurrence of HUS during CNI therapy compassionate us of belatacept was instituted. The treatment regimen was approved by the Norwegian Medical Agency. The patient received written and oral information regarding belatacept. An additional dose of 20 mg of basiliximab IV was administered 10 days after the recurrence of HUS, and the first dose of belatacept (10 mg/kg) was given 8 days later (28 days after transplantation). There were no detectable side effects. Belatacept 10 mg/kg IV was repeated 2 and 6 weeks after the initial dose. Thereafter, 5 mg/kg belatacept IV has been given on a monthly basis (Fig. 1).TABLE 1: Changes in hemoglobin, platelet count, lactate dehydrogenase, and serum creatinineFIGURE 1.: Timeline for events after first and second renal transplantation. HUS, hemolytic uremic syndrome; MMF, mycophenolate mofetil.Twelve months after transplantation, an ultrasound guided surveillance renal biopsy was taken. The biopsy showed no signs of development of IF, TA, drug induced toxicity, or thrombotic microangiopathy. The patient is currently on 7.5 mg prednisolone, mycophenolate mofetil 500 mg twice daily, and belatacept 5 mg/kg body weight IV ever 4 weeks. At latest control, serum creatinine was 78 μmol/L. DISCUSSION Rate of recurrence of HUS after renal transplantation varies considerably in the literature, but when occurring it represents a serious threat to long-term graft function. In patients with non-Shiga toxin-associated HUS, the rate of recurrence has been reported to be as high as 50% to 60% with most of the recipients developing graft failure (1, 8). De novo HUS is considerably less common and occurs in only 0.8% to 5% (7, 9) of renal transplant recipients. It is usually believed to be drug induced. Major offenders are CNIs and mTORs. There are no treatment guidelines for recurrence or de nove HUS after renal transplantation. Most case reports focus on plasma exchange with substitution by albumin and fresh frozen plasma or Octaplas in addition to a change or withdrawal of part of basic immunosuppression. Treatment is often unsuccessful, and reduced immunosuppression leaves the patient at considerable risk of developing acute rejections. Belatacept (LEA29Y) is a second generation cytotoxic T-lymphocyte–associated antigen immunoglobulin (CTLA4-Ig), which blocks the interaction between CD80/86 and CD28 costimulatory pathways. In studies performed with belatacept, patients with recognized HUS have not been included. To our knowledge, treatment of HUS recurring posttransplant with belatacept has not been reported previously. Recently, Ashman et al. (10) reported successful treatment of drug-induced de novo HUS with introduction of belatacept. Contrary to their publication, we used PE and additional IV basiliximab as “bridging” to start of belatacept therapy. Introduction of belatacept gave us the possibility to avoid CNIs and mTORs, which both may induce HUS posttransplant, and at the same time give the patient adequate immunosuppression. Belatacept is a drug that might be promising for patients with de novo drug induced or recurrent posttransplant HUS after renal transplantation. Karsten Midtvedt Section of Nephrology Medical Department Rikshopitaler, Oslo University Hospital Oslo, Norway Jan Bitter Department of Medicine Vest-Agder Sentralsykehus Kristiansand, Norway Christina Dørje Section of Nephrology Medical Department Oslo University Hospital Oslo, Norway Rune Bjørneklett Department of Medicine Haukeland University Hospital Bergen, Norway Hallvard Holdaas Section of Nephrology Medical Department Oslo University Hospital Oslo, Norway