Treatment of chronic antibody mediated rejection with intravenous immunoglobulins and rituximab: A multicenter, prospective, randomized, double-blind clinical trial
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 1.73m2 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/m2 ) 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 m2 , 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.
CET Conclusion
| Reviewer: | Centre for Evidence in Transplantation |
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| Conclusion: | This small study investigates the role of rituximab, combined with IvIG, for renal transplant recipients with chronic antibody-mediated rejection (CAMR). The study is placebo-controlled. Despite being multicentre and spanning a 3-year period, only 25 of the planned 50 patients were recruited. The authors conclude that this regimen is unlikely to be useful in the management of CAMR, as no differences were seen in renal function, proteinuria, biopsy scores or MFI of donor-specific antibodies. The major limitation here is the small number of patients recruited, leading to a significant difference in baseline renal function between the groups. 95% confidence intervals for the outcomes are not presented, but it is likely that there is insufficient power to draw any firm conclusions on the basis of these data. |
Expert Review
| Reviewer: | Professor John Kanellis, Department of Nephrology, Department of Medicine, Monash University, Clayton, Melbourne. |
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| Conflicts of Interest: | No |
| Clinical Impact Rating | 3 |
| Review: | This double-blind, placebo controlled study examined the use of IVIG and rituximab to treat chronic antibody-mediated rejection (cAMR). Participants had donor specific antibody (DSA), transplant glomerulopathy and an eGFR of >20ml/min. No benefit was seen after analysis of change in eGFR and proteinuria, biopsy scores and DSA MFI. This study is of significant interest as it suggests no benefit from currently used treatments for cAMR. The use of IVIG and rituximab is onerous and has significant side effects, therefore it is important to have studies that reveal benefit. The results need to be interpreted with caution however, as the study was small with only half the planned participants being recruited. It is therefore significantly underpowered. Furthermore, as the authors also acknowledge, subjects already had significant injury present and the baseline eGFR differed in the two arms (placebo 45±18 ml/min vs treatment arm 35±17 ml/min). These issues may also have influenced the results. Further well designed and adequately powered studies in cAMR are desperately needed as there is a significant clinical challenge and few proven therapeutic options. It is hoped that new therapies being currently trialled (IL-6 blockade, IdeS therapy) will show significant benefit. |
Study Details
| Aims: | To evaluate the efficacy and safety of intravenous immunoglobulins (IVIG) combined with rituximab (RTX) in renal transplant patients with chronic antibody mediated rejection (ABMR), displaying transplant glomerulopathy and donor-specific antibodies (DSA). |
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| Interventions: | Participants were randomised to receive either four consecutive doses of IVIG (0.5 g/kg) every 3 weeks and one single dose of RTX (375 mg/m2), 1 week after the last IVIG dose (treatment group), versus an isovolumetric saline solution following the same schedule (control group). |
| Participants: | 25 stable renal transplant recipients aged ≥18 years with biopsy proven chronic ABMR diagnosed < 6 months prior to randomisation. |
| Outcomes: | The primary outcome measured was the delicine in estimated glomerular filtration rate. Secondary measured outcomes included proteinuria renal lesions, and DSA at 1 year. Adverse events, opportunistic infections and hospitalisations were also measured. |
| Follow Up: | 12 months |
Metadata
| Publication type: | Multicenter Study, Randomized Controlled Trial, Randomised Controlled Trial |
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| Organ: | Kidney |
| Language: | English |
| MeSH terms: | Adult; Allografts; Chronic Disease; Double-Blind Method; Female; Follow-Up Studies; Glomerular Filtration Rate; Graft Rejection; Graft Survival; HLA Antigens; Humans; Immunoglobulins, Intravenous; Immunologic Factors; Isoantibodies; Kidney Failure, Chronic; Kidney Function Tests; Kidney Transplantation; Male; Middle Aged; Postoperative Complications; Prognosis; Prospective Studies; Risk Factors; Rituximab; Tissue Donors |