Extracorporeal Photopheresis as an Antirejection Prophylaxis in Kidney Transplant Recipients: Preliminary Results

doi:10.1016/j.transproceed.2011.08.061

Transplantation Proceedings

Volume 43, Issue 8, October 2011, Pages 2938-2940

https://doi.org/10.1016/j.transproceed.2011.08.061 Get rights and content

Abstract

Extracorporeal photopheresis (ECP) is considered a promising immunomodulatory therapy of acute allograft rejection in organ transplantation and graft-versus-host disease. Our aim was to investigate the biological responses of 10 patients who underwent kidney transplantation with ECP as prophylactic treatment. They received conventional immunosuppressive therapy plus ECP immediately after transplantation: 12 to 16 applications over the course of 2.5 months. ECP procedures were performed using an automated system for leukocyte separation and photoactivation with methoxsalen. All recipients were followed by estimated glomerular filtration rate (eGFR) and peripheral T, B, natural killer, T-regulatory (Treg) and dendritic cells (DC) counts and phenotypes. An acute rejection episode appeared in one control group recipient. The ECP group showed a positive trend to an higher GFR at months 3 (53 ± 11 vs 47.1 ± 9; P = .17) and 6 (67.5 ± 10 vs 53.6 ± 3; P = .03, Wilcoxon test). An increased percentage of Treg (CD3⁺ CD4⁺ CD25⁺) among the total CD3 cell count (4.9% ± 1% to 9.4% ± 15%) as well as inducible Treg (CD3⁺ CD8⁺ CD28⁻) was observed among CD3 cells (3.3% ± 3% to 11.8% ± 8%, P = .025) within 3 months of ECP treatment. A significant difference in the percentage of Treg was noted at month 3 (completed ECP) between the ECP and the control groups (9.4% ± 15% vs 3% ± 1%; P = .01). Addition of ECP to standard immunosuppression was associated with a significantly higher GFR at 6 months and with a significant increase in natural Treg among CD3 cells.

Section snippets

Selection and Description of Participants

Twenty consecutive kidney allograft recipients who received kidneys from 10 cadaveric donors (10 pairs) were assigned to the ECP-treated or the control group. Selection was based on ECP exclusion criteria and declared patient adherence to study visits over at least 12 months post-KTx. If both initial criteria were met, we performed a randomization. The ECP group underwent 12 to 16 ECP procedures in the first 3 months following KTx. Control and ECP subjects were prescribed mycophenolate mofetil

Results

Biopsy-proven acute rejection appeared in one control group recipient. The ECP group showed a positive tendency to a higher eGFR at months 3 (53 ± 11 vs 47.1 ± 9 mL/min/1.73 m²; P = .17) and a significant difference at 6 months (67.5 ± 10 vs 53.6 ± 3 mL/min/1.73 m²; P = .03 in Wilcoxon test; (Table 1).

Increased percentages of Treg (CD3⁺ CD4⁺ CD25⁺) in the total CD3 cell count (4.9% ± 1% to 9.4% ± 15%) as well as among inducible Treg (CD3⁺ CD8⁺ CD28⁻) among CD3 cells (3.3% ± 3% to 11.8% ± 8%; P

Discussion

Currently available immunosuppressive drugs are associated with severe complications such as hypertension, diabetes mellitus, infectious risk, and malignancies. Often they do not present episodes of rejection. New, less-toxic immunologic measures are needed to reduce the side effects. ECP has been shown to benefit patients with cardiac,³ but also kidney transplantations. A few reports have suggested that ECP serves as an effective “rescue” therapy for kidney rejection episodes resistant to

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Cited by (27)

Novel insights in the clinical management of hyperimmune patients before and after transplantation
2023, Current Research in Immunology
Despite improvements in anti-Human Leucocyte Antigens antibody detection, identification, and characterization offer a better in peri-operative management techniques, antibodies remain a serious cause of morbidity and mortality for patients both before and after organ transplantation. Hyperimmune patients are disadvantaged by having to wait longer to receive an organ from a suitably matched donor. They could benefit from desensitization protocols in both pre- and post-transplantation period. Clinical studies are underway to highlight which best desensitization strategies could be assure the best outcome in both heart and kidney transplantation. Although most clinical evidence about desensitization strategies by using anti-CD20 monoclonal antibodies, proteasome inhibitors, anti-CD38 monoclonal antibodies, interleukin-6 blockade, cysteine protease and complement inhibitors, comes from kidney transplantation studies, many of the debated novel concepts can be easily applied to desensitization also in heart transplantation.
Here, we discuss the candidates and recipients’ management by using most common standard of care and novel therapeutics, desensitization endpoints, and strategies for future studies.
Extracorporeal photopheresis and renal transplantation
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Extracorporeal photopheresis for the treatment of graft rejection in 33 adult kidney transplant recipients
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Citation Excerpt :
Studies with more intensive ECP regimens seemed to report better results. Of 28 cases of KT rejections, ECP seemed to help to stabilize renal function in 14 patients (50%) and to improve renal function in 8 patients (29%) [17–27]. The « French Haute Autorité de Santé (HAS) » recommended the use of ECP in the prevention of rejection in cardiac transplantation [33].
Background - Extracorporeal photopheresis (ECP) has shown encouraging results in the prevention of allograft rejection in heart transplantation. However, the role of ECP in kidney transplant (KT) rejection needs to be determined.
Methods - This multicentre retrospective study included 33 KT recipients who were treated with ECP for allograft rejection (23 acute antibody-mediated rejections (AMRs), 2 chronic AMRs and 8 acute cellular rejections (ACRs)). The ECP indications were KT rejection in patients who were resistant to standard therapies (n = 18) or in patients for whom standard therapies were contraindicated because of concomitant infections or cancers (n = 15).
Results - At 12 months (M12) post-ECP, 11 patients (33%) had a stabilization of kidney function with a graft survival rate of 61%. The Banff AMR score (g + ptc + v) was a risk factor for graft loss at M12 (HR 1.44 [1.01–2.05], p < 0.05). The factorial mixed data analysis identified 2 clusters. Patients with a functional graft at M12 tended to have cellular and/or chronic rejections. Patients with graft loss at M12 tended to have acute rejections and/or AMR; higher serum creatinine levels; DSA levels and histologic scores of AMR; and a longer delay between the rejection and ECP start than those of patients with functional grafts.
Conclusions - ECP may be helpful to control ACR or moderate AMR in KT recipients presenting concomitant opportunistic infections or malignancies when it is initiated early.
Role of photopheresis in the treatment of refractory cellular rejection in kidney transplantation
2016, Nefrologia
National Institutes of Health State of the Science Symposium in Therapeutic Apheresis: Scientific Opportunities in Extracorporeal Photopheresis
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Use of ECP was reported in the mid 1990s to be effective in stabilizing lung function in patients experiencing decline on other immune suppressive medications [88], and many groups have since reported similar findings [89-91]. A randomized, prospective study of 20 patients receiving cadaveric renal grafts showed no significant differences in acute rejection episodes, but patients in the ECP group had significantly higher glomerular filtration rates at the end of 6 months of therapy and a higher percentage of Treg cells [15,92]. Small studies have shown some promise in using ECP as an adjuvant or salvage antirejection therapy [93-95].
The clinical use of extracorporeal photopheresis (ECP) for accepted indications such as graft-versus-host disease, transplant rejection, and cutaneous T-cell lymphoma continues to increase. Expanded applications for ECP, such as the treatment of select autoimmune diseases, are being explored. Extracorporeal photopheresis's capacity to both immunotolerize in the autoreactive setting, while immunizing against a lymphoma is unusual and suggestive of a unique mechanism. It is likely that ECP's induction of dendritic cells is key to its efficacy in both of these settings, but exactly how ECP impacts other immune components and their interactions is not fully understood. Further basic science research is necessary to elucidate how these dissimilar cellular activities are functionally integrated. On the clinical side, collaborative multicenter trials designed to recognize the principal variables controlling therapeutic responses and improve prognostic indicators may enable tailoring devices, treatment schedules, and doses to the needs of the individual patients or diseases. This review describes our current understanding of how ECP influences the immune system, reviews the existing clinical applications of ECP, and explores areas for future basic science and clinical research as presented at the National Institutes of Health State of the Science Symposium in Therapeutic Apheresis in November 2012.
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No significant difference was seen between the two groups with regard to rates of biopsy proven acute rejection, time to rejection, nephrotoxicity, neurotoxicity, or mean duration of hospitalization but there was a statistically significant higher survival rate in the ECP cohort. In addition to a number of previously published case studies/series as of recent, Kusztal et al. [30,31] used ECP in combination with conventional immunosuppressive therapy as prophylactic treatment in a prospective randomized study of 10 kidney transplant patients compared to a control group of 10 with standard immunosuppressive therapy. 12–16 ECP treatments were performed over 2.5 months.
Since its introduction in photomedicine in 1983 ECP (extracorporeal photopheresis) has over the past decades been established as a safe and effective treatment approach for the palliative management of patients with cutaneous T-cell lymphoma, the Sezary syndrome variant in particular. Subsequently its effectiveness has been well documented in a number of additional T-cell–mediated diseases, particularly in the treatment and prevention of acute and chronic graft-vs. -host disease. More recently, ECP has been successfully used to treat acute heart allograft rejection and chronic allograft dysfunction after lung transplantation without increasing infectious complications. As recently documented ECP was also used as a part of CNI (calcineurin inhibitors) sparing or staggering protocols. For this group of patients it is proposed that its efficacy may be partly attributed through direct induction of lymphocyte apoptosis (Tambur et al., 2000) [1] and subsequent production of regulatory T cells (Treg) (Lamioni et al., 2007) [2], [3] without causing general immunosuppression. However, the exact indications for use of ECP within this framework are not yet finalized.

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: This work was supported by the Ministry of Science and Higher Education (MNiSW, Poland, Grant No. N402 178934).

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Renal transplantationImmunosuppresive therapyExtracorporeal Photopheresis as an Antirejection Prophylaxis in Kidney Transplant Recipients: Preliminary Results

Abstract

Section snippets

Selection and Description of Participants

Results

Discussion

Transpl Immunol

Transplant Proc

Intravenous infusion of syngeneic apoptotic cells by photopheresis induces antigen-specific regulatory T cells

J Immunol

Photopheresis for the prevention of rejection in cardiac transplantationPhotopheresis Transplantation Study Group

N Engl J Med

Successful treatment of recurrent rejection in renal transplant patients with photopheresis

J Am Soc Nephrol

Renal transplantation
Immunosuppresive therapy
Extracorporeal Photopheresis as an Antirejection Prophylaxis in Kidney Transplant Recipients: Preliminary Results