Recurrent Acute Rejection Research Articles

OBLITERATIVE BRONCHIOLITIS

Obliterative bronchiolitis following lung transplantation is common and potentially devastating. Its exact cause is undefined, but multiple immune and nonimmune processes contribute to its pathogenesis. Severe acute rejection and recurrent acute rejection have been shown to confer the greatest risk for obliterative bronchiolitis, signifying the central importance of alloimmunity in the disease process. Treatment of established disease with intensification of immune suppression has been of limited benefit, so current clinical strategies include early detection and minimization of risk. As our understanding of the disease evolves, it is hoped that effective interventions targeted at specific pathogenetic steps will emerge. In the meantime, obliterative bronchiolitis remains the most important and sinister long-term complication of lung transplantation.

Posttransplantation Physiologie Features of the Lung and Obliterative Bronchiolitis

Obliterative bronchiolitis remains the major obstacle to long-term survival after lung transplantation. Herein we provide a brief review of the key literature as well as our own experience with this condition. Obliterative bronchiolitis has occurred in up to two-thirds of all lung transplant recipients. The characteristic physiologic changes include declines in (1) forced expiratory volume in 1 second, (2) forced vital capacity, and (3) diffusing capacity of the lungs for carbon monoxide. Lung biopsy in patients with obliterative bronchiolitis reveals occlusion of bronchioles in a patchy but extensive distribution. Mucous plugging and bronchiectasis may also be seen. Furthermore, intimal thickening of pulmonary vessels together with mild arteriosclerotic changes of the muscular and elastic pulmonary arterioles may be observed. To date, the main risk factor for the development of obliterative bronchiolitis is recurrent, severe, and persistent acute lung rejection. The recommended management is prevention because the established fibrotic condition may necessitate retransplantation.

Clinical and immunological characteristics of transplant recipients with recurrent acute rejection episodes

D ESPITE intense and repeated antirejective therapy with triple combinations of cyclosporine A (CyA), cortisone (CORT), antithymocyte globuline (ATG), and consecutive monoclonal CD3 antibodies (OKT3) in acute rejection episodes, still confront transplant recipients who have relapses of acute rejection (AR). In a patient subset after allogenic TX we asked (1). Can this recipient group be characterized by risk factors? and (2) Is there an efficacious regimen for safe therapy of recurrent rejection episodes?

The correlation of Banff scoring with reversibility of first and recurrent rejection episodes.

Recurrent acute rejection remains a significant problem for recipients of renal allografts, with a large proportion of patients progressing to graft loss. The newly introduced Banff schema was used to determine whether the histologic pattern of acute rejection (severity and renal compartment scoring) could discriminate recurring from nonrecurring rejections and to examine whether objective rejection scoring had predictive value for rejection reversal and outcome. A total of 67 biopsies obtained from 50 patients with acute rejection were examined for the occurrence of recurrent allograft rejection. All patients were maintained on a cyclosporine-based triple immunosuppressive protocol and had biopsy-proven acute rejection without chronic changes. Rejection recurred in 13 patients (26%), of whom 4 further developed a third rejection. The majority of the patients developed this first rejection within 2 months posttransplantation. Demographics, prebiopsy renal function, immunosuppression, and peak serum creatinine level at the time of biopsy were similar in patients with multiple and single rejection. Peak levels of reactivity to panel of lymphocytes seemed higher in the group of patients with recurrent rejection, whereas HLA matching was similar for all patients. Banff scores for acute rejection did not discriminate patients at risk of rejection recurrence who had lower vascular (0.6 vs. 1.2), tubular (0.6 vs. 1.1), and lower cumulative SUM (3.0 vs. 4.5) scores on their first rejection when compared with patients with one rejection. Histological scoring was, however, significantly different when first and third episodes were compared in the same patient, indicating increased rejection severity with recurrence. Moreover, the rate of reversal of recurrent rejection by anti-lymphocyte therapy was significantly less than that of first rejection (P<0.05). In conclusion, these data demonstrate that Banff scoring correlated with rejection reversal and steroid responsiveness, yet rejection recurrence was independent of histological score of the first rejection. Furthermore, Banff schema provided an objective histological correlation to the poor clinical outcome seen with recurrent rejection. The data also suggest that patients with early mild rejection continue to be at risk for recurrence and graft loss.

Total Lymphoid Irradiation for Refractory Acute Rejection in Heart-Lung and Lung Allografts

Persistent or recurrent acute allograft rejection (AR) refractory to high-dose steroid therapy can adversely affect long-term outcomes of heart-lung (HLT), bilateral-lung (BLT), and single-lung (SLT) transplantations. The use of total lymphoid irradiation (TLI) for the management of refractory acute AR in six transplant recipients (two men, four women; mean age, 29.8 +/- 3.8 years) is detailed. There are two HLT (primary pulmonary hypertension [PPH], cystic fibrosis [CF]), 1 BLT (pulmonary hypertension postventricular septal defect repair), and 3 SLT (sarcoid, PPH, congenital heart disease with atrial septal defect) recipients. Refractory AR is defined as persistent rejection unresponsive to high-dose steroid therapy in all cases. The BLT and SLT recipients had at least two moderate and one mild AR events per patient. The HLT recipients had at least two moderate acute heart and one severe and one mild asynchronous acute lung rejection events per patient. A total of 800 cGy of total lymphoid irradiation (TLI) was administered over a 5-week period. Mild and transient leukopenia was the only observed side effect. The patient with PPH received TLI 313 days after HLT for recurrent AR at another institution and died of ARDS 4 weeks after completing TLI. The patient with CF received TLI 707 days after HLT and died 457 days after TLI of severe obliterative bronchiolitis (OB) with multiorgan failure. The patient with BLT received TLI 176 days after transplant and died 372 days after TLI of respiratory failure related to severe rejection. One patient with SLT received TLI 78 days after transplant and died 679 days after TLI of severe acute AR. The two remaining patients with SLTs have been free from acute AR for more than 4 years. The patient with sarcoidosis received TLI 37 days after SLT following a clinical rejection event and two severe acute AR events. He is alive with normal lung function 5 years later. The patient with PPH received TLI 108 days after SLT following three moderate acute AR events and is alive with stable OB 4 years later. These limited preliminary results suggest that TLI has merit for the treatment of intractable acute AR following HLT and lung transplantation.

Acute rejection relapses posttransplant: definition of risk group and evaluation of potent therapeutic regimens.

A group of 113 patients were investigated after allogenic cadaver renal transplantation to analyse whether the small number of patients presenting acute rejection relapses could be defined by risk factors and whether there is an efficacious regimen for the safe therapy of recurrent rejection episodes. According to these results we are aware of a group of "highly reactive rejectors" especially within the younger recipients and there are further characteristics which can be identified as being associated with an elevated risk of recurrent acute rejection. By adequate antirejection therapy we can achieve a favourable transplant survival rate of 97% in the critical first year. An additional benefit may result from ALG consolidation related to suppression of the remaining CD8-positive human natural killer cells.

Enhanced risk of steroid-resistant acute rejection following pretransplant steroid therapy in liver graft recipients.

Most episodes of acute rejection will resolve after steroid therapy without detrimental consequences on the liver allograft. However, steroid-resistant acute rejection may induce irreversible lesions of the graft and is associated with an increased risk of chronic rejection. The aim of this study was to determine whether there were predictive factors for steroid-resistant acute rejection after liver transplantation. A total of 108 adult liver recipients with a follow-up of at least 2 years have been analyzed; sixty-two (57%) patients had at least one episode of acute rejection. The rates of steroid resistance were 35%, 52% and 83% after a first (n = 62), second (n = 25), or third (n = 7) episode of acute rejection, respectively. Steroid resistance of acute rejection was significantly associated with a past history of pretransplant steroid therapy (P = 0.004). High levels of ALT (P = 0.03) and serum bilirubin (P = 0.002) were also predictive of steroid-resistant acute rejection. Eight (7%) patients eventually developed chronic rejection. Predictive factors for chronic rejection included steroid-resistant acute rejection (P = 0.01), recurrent acute rejection (P = 0.03), and CMV infection (P = 0.01). In conclusion, this study suggests that pretransplant steroid administration or high levels of ALT and bilirubin in rejecting patients are risk factors for steroid resistance and should lead to aggressive antirejection therapy without delay.

Total lymphoid irradiation in the treatment of early or recurrent heart transplant rejection

Recurrent acute cardiac allograft rejection is an important cause of repeat hospitalization and a major mode of mortality, particularly during the 6 months immediately following transplant. Total lymphoid irradiation (TLI) has been shown experimentally to induce a state of partial tolerance when administered prior to transplantation. Anecdotal reports of clinical experience have also suggested efficacy of TLI in treatment of recurrent cardiac rejection. The purpose of this study is to evaluate the safety and efficacy of TLI for treatment of early or recurrent heart transplant rejection. Between January 1990 and June 1992, 49 patients postallograft cardiac transplant were given courses of TLI for treatment of early or recurrent rejection after conventional therapy with Methylprednisolone, antithymocyte globulin, OKT3, and methotrexate. Two patients failed to complete their therapy and were not evaluated. Two other patients received a second TLI course, making a total of 49 courses delivered. Indications for TLI were early rejection (n = 5), recurrent rejection (n = 38), and recurrent rejection with vasculitis (n = 6). The dose goal of the TLI protocol was 8 Gy in 10 fractions given twice weekly. Three separate fields were used to encompass all major lymph node-bearing areas. The actual mean dose was 7 Gy (range 2.4-8.4 Gy), and the duration of treatment was 8 to 106 days. These variations were secondary to leukopenia or thrombocytopenia. The mean posttransplant follow-up is 15 +/- 1.2 months (maximum 27 months). Among patients initiating TLI within 1 month posttransplant (n = 15), the rejection frequency decreased from 1.83 episodes/patient/month pre-TLI to 0.13 episodes/patient/month post-TLI (p < 0.001). For those who began TLI 1-3 months after transplant (n = 21), rejection decreased from 1.43 to 0.10 episodes/patient/month (p < 0.001). When TLI was started more than 3 months posttransplant (n = 11), the pre-TLI and post-TLI rejection frequencies were 0.67 and 0.07/patient/month (p < 0.001), respectively. The reduced post-TLI rejection frequencies were maintained to 24 months. There was no increase in the frequency of infection after TLI, nor were there any deaths during or immediately following TLI. Total lymphoid irradiation is a safe and effective adjunct for prolonged control of early or recurrent cardiac rejection. Bone marrow suppression is transient in nearly all patients and is not associated with an increased incidence of infection. The long-term benefits, possible late deleterious effects, and the potential role of TLI as induction therapy remain to be elucidated.

MONOTHERAPY WITH CYCLOSPORINE FOR CHRONIC IMMUNOSUPPRESSION IN PEDIATRIC LIVER TRANSPLANT RECIPIENTS

Children who survive liver transplantation (LT) suffer the adverse effects of life-long immunosuppression. In an attempt to minimize these effects, we have instituted a program of tapering immunosuppression, resulting in chronic monotherapy for children after LT. Seventy-three children ages 4 months to 19 years received LT between January 1987 and December 1992. Patient survival was 85% (62/73), with graft survival of 73%, at one year. Triple therapy with prednisone, cyclosporine, and azathioprine begun at transplant was tapered as follows: 1-2 mg/kg prednisone at discharge was reduced by .2 mg/kg every 2 months until a .2 mg/kg total was reached. Alternate-day steroids (.2 mg/kg) were begun at 1 year and discontinued at 1.5 years. AZA (1 mg/kg) was begun posttransplant and discontinued after any serious viral illness or by 1 year. Currently 37 survivors are > 18 months post-LT and were considered candidates for monotherapy. Monotherapy was attempted in 28 (76%), and 25 of these remain on monotherapy an average of 2 years later. All have normal liver function. After monotherapy and alternate-day steroids were achieved, 66% of children < 5th percentile for height at the time of transplant improved to greater than the 5th percentile. There were 3 (11%) patients who rejected while on monotherapy an average of 1.15 years after it was started. These patients had the following predisposing factors that decreased cyclosporine levels and led to rejection: common bile duct stricture, chronic and intermittent antibiotic administration for urinary tract infection, and noncompliance. In the 9 potential candidates not tapered to monotherapy, 6 have had recurrent acute or chronic rejection; 2 of these now receive FK506. We conclude that the majority of stable pediatric LT recipients may be safely tapered to chronic cyclosporine monotherapy. Increased growth is a major benefit of decreased steroid dosing in these children. Cyclosporine absorption and adequate levels are crucial for success of this approach.

Acute liver allograft rejection--is treatment always necessary?

A group of 195 consecutive adult patients who received a primary orthotopic liver allograft were reviewed retrospectively to analyze the incidence of rejection, the response to antirejection therapy, and the impact of acute rejection on the development of ductopenic rejection. The diagnosis of acute rejection (AR) was based on a combination of clinical and histological criteria, and 69.7% of the patients had at least one episode of acute rejection. Only 6.7% of the patients failed to respond to steroids and were treated with OKT3. Four (2.3%) patients developed acute vanishing bile duct syndrome (within 60 days) and 6 (3.5%) patients developed chronic rejection. Eight patients who spontaneously recovered from AR without additional immunosuppression are described in detail. In addition to histological damage, all developed significant hepatic dysfunction. Except for one patient who died from disseminated fungal infection, the 7 remaining patients are alive with excellent graft function 7 to 21 months posttransplant. While severe AR and recurrent AR should be treated without delay, some patients with mild-to-moderate rejection and hepatic dysfunction may resolve without additional immunosuppression.

Orthotopic liver transplantation: a pathological study of 63 serial liver biopsies from 17 patients with special reference to the diagnostic features and natural history of rejection.

The histopathological features of orthotopic liver transplants were evaluated in 63 serial biopsy specimens from 17 patients. Biopsies were taken at the time of insertion of the liver (six biopsies), at the time of development of liver function abnormalities (11 biopsies) and as follow-up to previously abnormal biopsies (46 biopsies). The biopsies taken at the time of insertion all showed diffuse hepatocellular ballooning with confluent areas of necrosis in one case. Biopsies taken at the time of onset of rejection (nine cases) all showed a mixed portal inflammatory infiltrate, bile duct damage and central or portal vein endothelialitis (i.e., attachment of lymphocytes to the vein endothelium). Follow-up biopsies showed several patterns including: (i) resolution of changes of acute rejection with subsequent development of recurrent acute or chronic rejection (four cases); (ii) prolonged acute rejection simulating extrahepatic biliary obstruction (four cases); (iii) prolonged acute rejection with predominance of eosinophils simulating a drug reaction (one case); and (iv) rapidly progressive acute rejection leading to death (one case). Biopsy of the transplanted liver at the time of transplantation is useful to provide a baseline for comparison with later biopsies. Biopsy at the time of onset of changes in liver function is essential to confirm the presence of rejection prior to alteration of immunosuppression.

VASCULAR CHANGES IN RENAL HOMOGRAFTS.

Renal vascular changes were seen in six patients after renal homotransplantation. A deposition of fibrinous material on the intimal surface and in the vessel wall was found in three cadaver kidneys where extensive areas of necrosis had occurred. Necrotizing arterial lesions were seen in two transplanted kidneys and may have represented acute rejection. Severe obliteration of the vessel walls in four patients was considered to be the end result of recurrent acute rejections or of chronic rejection. It is hoped that vigorous immunosuppressive therapy may prevent vascular rejection.