Solid Organ Transplant Rejection
Solid organ transplant rejection overview
Although steroids and immunosuppressant drugs are first line therapy for solid organ transplant (SOT) rejection, other adjunctive therapies have been used. One of these is extracorporeal photopheresis (ECP). Extracorporeal photopheresis has been used to help treat patients with heart, lung, kidney and liver transplant rejection; however, there are fewer studies in SOT rejection than in graft-versus-host disease (GVHD), partly due to the lower number of available patients.
The majority of published studies on photopheresis and SOT rejection in adults have aimed to assess the ability of ECP to help prevent or treat cardiac rejection.22,26,43-50 These include one multicentre, double-blind randomised trial on 60 patients.22 There have also been a reasonable number of studies in lung transplant, several of which have focused on the potential ability of photopheresis to improve lung deterioration associated with bronchiolitis obliterans (BO).221,27,31,32,51,52 As well as the cardiac and lung trials, there have been three small studies in renal rejection and one study in liver rejection.29,30,53,54
Photopheresis and heart transplant rejection – smaller studies
Several smaller studies have reported on a total (between all these studies) of 52 patients with cardiac transplant rejection who were treated with photopheresis.43-49 Fifty of the 52 patients were reported as benefitting from ECP therapy, with positive results ranging from a reduction in the number and severity of rejection episodes to rejection reversal.
The first cardiac rejection studies were published in the early/mid 1990’s. In 1992 Rose et al. published data on 4 cardiac patients who were at risk of rejecting their transplant.43 The researchers treated the patients with ECP alongside standard immunosuppression therapy and reported that, ‘high levels of panel reactive antibodies had been reduced, and patients suffered few rejection episodes and no infectious complications’.43 In the same year Costanzo-Nordin et al. published a small comparative trial of 16 heart transplant patients with International Society for Heart and Lung Transplantation (ISHLT) rejection grades 2, 3A, and 3B.44 The patients were randomised to receive either photopheresis (n = 9) or corticosteroid therapy (n = 7) and 8 of 9 patients had their rejection reversed in the photopheresis group compared to 7 of 7 in the corticosteroid group. The researchers concluded that, ‘photopheresis may be as effective as corticosteroids for treating ISHLT rejection grades 2, 3A, and 3B.44
Two further studies were published in 1994 and 1995.45,46 Meiser et al. treated 3 groups of 5 heart transplant patients for 6 months with triple-immunosuppression alone (as a control), 10 courses of single-day ECP, or 10 courses of 2-day ECP.45 Patients in both ECP arms had fewer rejection episodes (p = 0.007).45 In a non-comparative study Dall’Amico et al. used ECP as an adjunctive therapy to treat cardiac transplant patients with recurrent rejection.46 Severity and number of rejection episodes were reduced in 7 of 8 photopheresis-treated patients, as demonstrated by serial endomyocardial biopsies. The patients were also able to reduce the amount of immunosuppressive medication they were taking.46
In two other small studies 6 and 11 heart transplant patients were given photopheresis therapy for 6 months to treat recurrent rejection.47,48 In the first of these studies the number of rejection episodes decreased from 0.4 to 0.07 per patient per month during photopheresis, despite a reduction in immunosuppressive treatment.47 In the second of these studies the number of biopsies showing ISHLT grade 3A/3B rejection was reduced from 42% to 18% (pre-treatment).48 Doses of Immunosuppressive drugs were also lowered, and the authors concluded that, ‘ECP is a well tolerated treatment that allows better recurrent rejection control and a significant reduction in immunosuppressive therapy’.48 One further paper reported on 4 cardiac transplant patients with ISHLT grades 3A and 4 rejections who were successfully treated with photopheresis.49
Photopheresis and heart transplant rejection – larger studies
Three larger studies have examined the use of photopheresis in the treatment of cardiac transplant rejection. Barr et al. treated 23 cardiac transplant patients with photopheresis plus standard drug therapy (n = 10) or standard therapy alone (n = 13).50 The aim was to explore whether the addition of ECP to the standard immunosuppressive/steroid regimen was safe, and would result in decreased levels of panel reactive antibodies (PRA) and transplant arteriopathy. There was no difference between the two groups in regard to infection or acute rejection incidence, but the photopheresis group had a significant reduction in PRA levels at postoperative months 3 – 4 and 5 – 6 (p < 0.03/p < 0.05). Coronary artery intimal thickness was significantly reduced in the photopheresis group at 1-year (p < 0.04) and 2-year (p < 0.02) follow-up, and the authors concluded that, photopheresis is a safe, well-tolerated immunomodulatory technique that is capable of decreasing the severity of chronic rejection’.50
Another study reported on 36 heart transplant patients who received at least 3 months of photopheresis for 2 days every 3 to 6 weeks.26 Some patients received prophylactic treatment in the presence of anti-donor antibodies (n = 4), and others received ECP after rejection (n = 12) or for recurrent/recalcitrant rejection (n = 20). Patients selected for photopheresis were at greater risk of rejection (p < 0.0001) but after 3 months of treatment, the rejection risk was decreased (p = 0.04) and the risk of subsequent rejection or rejection death was also significantly reduced (p = 0.006). The researchers concluded that photopheresis reduces the risk of rejection and/or death from rejection for patients with a high rejection risk.26
The largest study in cardiac rejection was carried out in 1998. In this multicentre, double-blind trial, 60 patients were randomised to receive either standard (triple-drug) immunosuppressive therapy together with ECP, or standard immunosuppressive therapy alone.22 After 6 months the group who were treated with immunosuppressive drugs and photopheresis had experienced fewer acute rejection episodes. In the photopheresis group the mean number of episodes of acute rejection per patient 0.91 (+/-1.0) in the photopheresis group compared to 1.44 (+/-1.0) in the standard-therapy group (p = 0.04). Significantly more patients in the photopheresis group had 1 or 0 rejection episode and significantly fewer patients in the photopheresis group had 2 or more rejection episodes (p = 0.02). The researchers concluded that, ‘the addition of photopheresis to triple-drug immunosuppressive therapy significantly decreased the risk of cardiac rejection without increasing the incidence of infection’.
Photopheresis and lung transplant rejection
Although fewer in number than the cardiac rejection studies, there have been several clinical papers published on the use of ECP in the treatment of lung rejection.21,27,31,32,51,52 These studies report varying degrees of success, and some of the trials focus particularly on the treatment of BO.21,27,32,52 Slovis et al. used ECP to treat 3 patients with biopsy-confirmed BO. All 3 patients had stabilisation or improvement in their pulmonary function after treatment.51
Two further studies were published in 1999. One of these reported on 5 patients treated with photopheresis after the failure of immunosuppression therapy for BO. This resulted in temporary stabilisation of airflow obstruction.27 The other study reported on 8 patients with progressively decreasing graft function and grade 3 BO (7 patients) who were all treated with photopheresis.31 After treatment with photopheresis there was stabilisation of the forced expiratory volume in 1 second (FEV1) in all 5 patients and histologic reversal of rejection in 2 patients.31
More recently, Villanueva et al. retrospectively reviewed the outcomes of 14 BO patients who had been treated with ECP.32 Results were mixed but 3 of the patients with BO and concurrent acute rejection experienced resolution of the acute rejection episode after photopheresis.32 Also, Benden et al reported on the treatment of 24 lung transplant patients with BO and recurrent acute rejection treated with ECP.52 After photopheresis there was a significant improvement in FEV1 (p = 0.011) and the median patient survival improved from 7.0 to 4.9. The authors concluded that, ‘ECP reduces the rate of lung function decline in recipients with BO and is well tolerated’.52
The largest study to date in lung rejection and ECP was undertaken on 60 lung transplant patients that had been treated with photopheresis for progressive BO.21 Improvements in FEV1 indicated that photopheresis had helped to reduce the rate of decline in lung function associated with BO.21
Photopheresis in kidney and liver transplant rejection
Although results have been quite promising for the small number of patients who have been treated with photopheresis for renal or liver transplant rejection, there haven’t been enough treatments carried out to indicate which, if any, renal or liver transplant patients may benefit from ECP therapy.29,30,52,53 In kidney transplant rejection, both Genberg et al. and Kumlien et al. reported on the use of ECP to treat 7 (in each study) patients with biopsy-proven acute rejection who were refractory to repeated pulses of high-dose steroids.30,53 Five patients in the Genberg et al. paper had significant improvement in renal function after photopheresis and 2 patients remained stable.30 In the Kumlien et al. paper all patients grafts were functioning at the most recent follow-up (9 – 43 months after transplantation).53
Dall’Amico et al. presented data on 4 adolescent patients treated with ECP after recurrent renal transplant rejection.54 Photopheresis was performed at weekly intervals during the first month, at 2-week intervals during the second and third months, and then monthly for another 3 months. A number of biochemical markers improved during the study, and all patients remained rejection-free during ECP, without infections or other complications. Clinical improvement allowed a progressive reduction in steroid therapy for 3 of 4 patients treated.54
In kidney rejection, Urbani et al. presented a retrospective review of 5 patients undergoing ECP for biopsy-proven rejection.29 At follow-up (median 7.9 months) 3 patients were off ECP with complete reversal and low-dose immunosuppression. Two patients were still receiving ECP with full-dose immunosuppression.29