IVIG and Rituximab for Treatment of Chronic Antibody-Mediated Rejection in Pediatric Renal Transplantation: A Prospective Pilot Study with a 2 Year Follow-Up

Abstract

Background: Chronic antibody-mediated rejection (AMR) is the major cause of late renal allograft loss. There is, however, no established treatment for this condition. Here we report an update of our prospective study on an antihumoral regimen consisting of high-dose intravenous immunoglobulin G (IVIG) and rituximab in paediatric renal transplant recipients. Methods: Twenty patients with chronic AMR were treated with four weekly doses of IVIG (1 g/kg body weight per dose), followed by a single dose of rituximab (375 mg/m2 body surface area) 1 week after the last IVIG infusion. Response to antihumoral therapy was defined as a reduction of the rate of loss of GFR by at least 30%. Calculated eGFR (Schwartz) were smoothed by LOESS procedure (SAS 9.2) to reduce bias due to outliers. At least one serum creatinine value per month and patient was available. Donor-specific HLA antibodies (HLA DSA) were quantified with Luminex-based bead array technology. Results: Loss of eGFR decreased significantly from 7.6 ml/min/1.73 m2 (range, -29.2 to 1.9) during the 6 months prior to antihumoral therapy to 2.1 ml/min/1.73 m2 (range, -15.0 to 7.6; P=0.006) during the 6 months after intervention. Fourteen patients (70%) responded: 9 of 9 patients (100%) without and 5 of 11 (45%) with transplant glomerulopathy (P=0.014). During 2 years of follow-up, the respective median loss of eGFR in each of the four 6-month periods remained significantly lower than that prior to intervention.[Fig. 1]No patients had pre-existing anti-HLA DSA. At the time of index biopsy de novo anti-HLA DSA were found in 16 of 20 (80%) patients. In 13 of 20 patients (65%) the immunodominant DSA was directed against HLA class II antigens. HLA class I DSA declined in response to antihumoral therapy by 54.4% (p=0.027) and HLA class II DSA by 47% (p=0.040) at 12 months after intervention. The percentage of C4d positivity in peritubular capillaries decreased from 40 ± 18.5% in the index biopsy to 11.6 ± 12.2% (P=0.002) in the follow-up biopsy. In four of nine biopsies (44%) C4d staining turned completely negative. Conclusions: Antihumoral treatment with IVIG and rituximab significantly reduces or stabilizes the progressive loss of transplant function in paediatric patients with chronic AMR over an observation period of 2 years, apparently by lowering circulating DSA and reducing intrarenal complement activation. This treatment protocol may represent a significant advance in the management of this common and often difficult-to-treat posttransplant complication.