Rituximab for Humoral Rejection After Kidney Transplantation: An Update

Humoral/vascular rejection although rare after kidney transplantation, has a poor outcome, that is, 27% to 40% allograft losses within the first year (1). It is clearly defined with the Banff classification (2). Diagnosis is based on acute kidney allograft injury, circulating donor-specific alloantibodies (DSA), and immune-mediated immunopathologic lesions, for example, C4d deposits along the vascular walls. Therefore, in humoral/vascular rejection, treatment aims to eliminate DSA: this can be achieved by plasmapheresis (PP) or immunoadsorption in association with methylprednisolone (MP), mycophenolate mofetil, and tacrolimus (3), or by PP associated with intravenous immunoglobulins (IVIG) with or without antithymocyte globulins (ATG) (4). Becker et al. (5) showed that kidney transplant (KT) patients with vascular rejection with a possible humoral component responded to a single dose of rituximab therapy (RTx), when given in addition to MP pulses, PP, with or without ATG. This complex therapy renders it difficult to ascribe benefits specifically to rituximab. Recently, we have reported on eight KT patients with humoral/vascular rejection who were treated by PP+RTx and had good patient and graft survivals (6). Herein, we provide an update of this research on a larger series of 22 KT patients. Between March 2004 and June 2008, we performed 511 kidney transplantations; of these, 22 patients (4.3%) experienced humoral/vascular rejections, which were treated as previously described (6), that is, 6 (2–17) PP sessions and RTx (375 mg/m2, 4 {lsqb;2–5{rsqb; injections) in addition to MP pulses (n=22), ATG (n=9), OKT3 (n=4), IVIG (n=4), tacrolimus+mycophenolate mofetil (n=22). Patients (14 men, 63%), aged 48 (22–70) years, were recipients of a first (68%) or iterative (32%) KT. Pretransplant panel-reactive antibodies were negative in 11 (50%) patients, and ranged from 10% to 100% in the others. Pretransplant T- and B-cell crossmatches by microlymphocytotoxicity were negative in all patients. Humoral/vascular rejections occurred at 21 (21–455) days posttransplant: these were associated with acute renal failure (i.e., increased serum creatinine from 141 {lsqb;63–567{rsqb; to 231 {lsqb;143–849{rsqb; μmol/L), fever (n=5), oligoanuria (n=6), graft tenderness/pain (n=6), and occurrence of DSA (n=16). Allograft biopsies were classified according to the Banff 2007 classification (2). Diffuse C4d deposits were observed in 12 cases, and interstitial necrosis, hemorrhage, or edema in two, four, and eight cases, respectively. There were borderline changes in nine cases; and grade Ia or Ib acute cellular rejection in five cases. Within a median follow-up post-RTx of 9 (2–48) months, patient and graft survivals were 86.4% (cause of deaths: one encapsulating peritonitis, one disseminated tuberculosis, one cardiac tamponade) and 77.3%, respectively. Allograft losses occurred at 3.5 (n=2), 6.5 (n=2), and 11 months post-RTx, and serum creatinine at last-follow-up was at 180 (62–309) μmol/L. Profound B-cell lymphopenia was 0 (0–178)/mm3 compared with 52 (0–411)/mm3 before RTx, and there was no clearance of DSA. There were also numerous serious infections (86.4%) including four bacterial pneumopathies, two invasive aspergillosis, one pneumocystosis, one disseminated tuberculosis, one disseminated cryptococcosis, three acute pyelonephritis, two angiocholitis, two peritonitis, one spondylodiscitis, and three septic shocks complicating one of the aforementioned infections. In conclusion, PP+RTX therapy for humoral/vascular kidney rejection is efficient but is associated with serious infections. Lionel Rostaing Department of Nephrology, Dialysis and Multiorgan Transplantation Toulouse University Hospital Toulouse Cédex, France INSERM U563, IFR 30 Toulouse Cédex, France Céline Guilbeau-Frugier Department of Pathology, Toulouse University Hsopital, Toulouse, France Nassim Kamar Department of Nephrology, Dialysis and Multiorgan Transplantation Toulouse University Hospital Toulouse Cédex, France INSERM U858, IFR 31 Toulouse Cédex, France