Treatment of chronic antibody mediated rejection with intravenous immunoglobulins and rituximab: A multicenter, prospective, randomized, double-blind clinical trial

Abstract

There are no approved treatments for chronic antibody mediated rejection (ABMR). We conducted a multicenter, prospective, randomized, placebo-controlled, double-blind clinical trial to evaluate efficacy and safety of intravenous immunoglobulins (IVIG) combined with rituximab (RTX) (EudraCT 2010-023746-67). Patients with transplant glomerulopathy and anti-HLA donor-specific antibodies (DSA) were eligible. Patients with estimated glomerular filtration rate (eGFR) <20 mL/min per 1.73m and/or severe interstitial fibrosis/tubular atrophy were excluded. Patients were randomized to receive IVIG (4 doses of 0.5 g/kg) and RTX (375 mg/m ) or a wrapped isovolumetric saline infusion. Primary efficacy variable was the decline of eGFR at one year. Secondary efficacy variables included evolution of proteinuria, renal lesions, and DSA at 1 year. The planned sample size was 25 patients per group. During 2012-2015, 25 patients were randomized (13 to the treatment and 12 to the placebo group). The planned patient enrollment was not achieved because of budgetary constraints and slow patient recruitment. There were no differences between the treatment and placebo groups in eGFR decline (-4.2 ± 14.4 vs. -6.6 ± 12.0 mL/min per 1.73 m , P-value = .475), increase of proteinuria (+0.9 ± 2.1 vs. +0.9 ± 2.1 g/day, P-value = .378), Banff scores at one year and MFI of the immunodominant DSA. Safety was similar between groups. These data suggest that the combination of IVIG and RTX is not useful in patients displaying transplant glomerulopathy and DSA.

Histopathologic Features that Predict Transplant Glomerulopathy Progression in a Chinese Cohort

“…Abreu et al [26] demonstrated in a retrospective study that C4d+ TG cases were more likely to be treated with intravenous Ig and/or rituximab. Nevertheless, in this study, we observed that these treating modalities did not improve TG prognosis, which is compatible with a recently published study [27]. Some have suggested that isolated TG with C4d-was associated with less severe active lesions (g, ptc) compared to C4d+ chronic AMR [28].…”

The relationship between pathologic lesions of active and chronic antibody-mediated rejection in renal allografts

“…, ct) but less glomerulitis (g) and no more peritubular capillaritis at the time of diagnosis, compared with the former.The apparent progression of glomerulitis to TG likely proceeds through 1 or more intermediate steps, and in many cases glomerulitis and TG are observed in the same glomerulus in biopsy specimens showing chronic active ABMR (Figure 3A). Furthermore, once detected by light microscopy, TG is associated with frequent and progressive loss of graft function,23 and a randomized placebo-controlled clinical trial of intravenous immunoglobulin plus rituximab failed to show an effect of the latter in slowing the rate of decline of graft function or the increase in proteinuria over 1 year in patients with TG and DSAs, most with (g + ptc) ≥2 24. Furthermore, once detected by light microscopy, TG is associated with frequent and progressive loss of graft function,23 and a randomized placebo-controlled clinical trial of intravenous immunoglobulin plus rituximab failed to show an effect of the latter in slowing the rate of decline of graft function or the increase in proteinuria over 1 year in patients with TG and DSAs, most with (g + ptc) ≥2 24.…”

“…Notably, in the majority of patients, the initial detection of TG by light microscopy, with or without concurrent glomerulitis, occurs ≥1 year posttransplant in recipients of +CM transplants and even later in recipients of conventional allografts 3,15,22,23. Furthermore, once detected by light microscopy, TG is associated with frequent and progressive loss of graft function,23 and a randomized placebo-controlled clinical trial of intravenous immunoglobulin plus rituximab failed to show an effect of the latter in slowing the rate of decline of graft function or the increase in proteinuria over 1 year in patients with TG and DSAs, most with (g + ptc) ≥2 24. A randomized placebo-controlled clinical trial of bortezomib in patients with active ABMR (median 5 years posttransplant; chronic active in 64%), yielded similar negative results,25 although some recent evidence suggests that the decline in graft function in patients with chronic active ABMR can be slowed or even halted (but not reversed) with newer therapeutic agent(s) 26.…”

The role of novel therapeutic approaches for prevention of allosensitization and antibody-mediated rejection

“…However, rituximab was given immediately after high-dose IVIG, which likely diminished the half-life and efficacy. 86 We recommend waiting 7-10 days after high-dose IVIG administration to proceed with monoclonal antibody therapy. Low-dose IVIG probably would not affect circulating monoclonal antibodies because inhibition of the FcRn system is less.…”