Late Acute Rejection Research Articles

Obliterative bronchiolitis after lung transplantation.

Despite marked improvements in early survival, long-term outcome after lung transplantation is still threatened by obliterative bronchiolitis (OB). Thought to be a manifestation of chronic allograft rejection, OB affects up to 65% of patients at 5 years after surgery and produces a relentless airflow obstruction. Early and late acute rejection are the primary risk factors for OB, but cytomegalovirus infection and airway ischemia may also play a role. In most patients, OB responds poorly to augmented immunosuppression and eventually leads to infectious complications and terminal respiratory failure. Because early diagnosis is associated with better prognosis, every effort should be made to detect OB in a preclinical stage. This may be best achieved by combining several techniques, such as surveillance transbronchial biopsy and bronchoalveolar lavage, measurements of ventilation distribution and exhaled nitric oxide, and expiratory computed tomography.

Daclizumab as escape therapy for late acute kidney rejection in the presence of FK506 nephrotoxicity

Daclizumab as escape therapy for late acute kidney rejection in the presence of FK506 nephrotoxicity

Transplantation for alcoholic cirrhosis

Abstract In recent years, alcoholic cirrhosis has been accepted as an indication for OLT, compliance of patients suffering from alcoholic cirrhosis is still under discussion, however. 118 patients who had undergone OLT for alcoholic cirrhosis were considered for analysis. The mean follow-up time of the study population was 53.7 ± 38.9 months. Compliance was defined by 3 parameters: 1. Sobriety. Fifteen (13%) out of 118 recipients suffered an alcohol relapse during the observation period. There was no difference between the groups with or without alcohol relapse concerning compliance with medication, incidence of rejection, or adherence to checkups. 2. Drug-compliance. Nineteen recipients (16%) were not within the target range with the immunosuppressive medication. Comparison of the compliant- and non-compliant groups produced a significant difference for late acute rejection, the other parameters being similar in the subgroups. 3. Adherence to appointments. Nearly all patients in the study population (>95%) were compliant with both transplant and psychological appointments in the outpatient clinic. In conclusion, analysis of our data indicates that patients with OLT for alcoholic cirrhosis are compliant, although alcohol relapse occurs in 13% of recipients.

The impact of acute rejection on chronic rejection: a report of the North American Pediatric Renal Transplant Cooperative Study.

The North American Pediatric Renal Transplant Cooperative Study (NAPRTCS) group has analyzed its database from January 1987 to October 1998. During this time we enrolled 6,395 transplants: of these, 5,323 were primary and 1,072 were repeat transplants. Overall, 30.8% (483/1,566) of the grafts failed as a result of chronic rejection. For living donor (LD) grafts, the failure rate as a result of chronic rejection was 32% (175/553), and it was 30% (308/1,013) for cadaveric donor (CD) transplants. A proportional hazards model identified first acute rejection, multiple rejections, and a late acute rejection as risk factors for the development of chronic rejection. Additional risk factors for the development of chronic rejection were African-American race, a repeat transplant, and a cyclosporin A (CsA) dose of < 5 mg/kg/day. Our analysis found that one acute rejection episode increases the risk of chronic rejection graft failure three-fold. Patients with two or more acute rejections have a 12-fold increased relative risk (RR) of chronic rejection graft loss (CRGL). A late acute rejection (> 365 days post-transplant) increases the RR by six-fold. Two or more acute rejections, when the first is a late initial rejection, increases the RR 26-fold. Based on this information we have initiated a multicenter trial of intervention in patients with one or more acute rejections.

An analysis of the effect of age on survival after heart transplant

Background Advances in immunosuppression and reports of improved survival after cardiac transplantation have led to a liberalization of traditional recipient eligibility criteria, especially age. While age alone is not a contraindication to transplantation, conflicting data exists regarding long-term survival of the older transplant recipient. Methods One hundred-fifty three patients undergoing consecutive first time cardiac transplantation from June 7, 1985 through February 1, 1997 were studied. For purposes of analysis, patients were stratified according to age (≤55 years vs >55 years) and hospital and late outcomes determined. Results The incidence of early and late acute cellular rejection was not different based up on age. The freedom from infection at 12 months was 54 ± 5% for patients ≤55 compared to 32 ± 8% for patients >55 years old ( p = .04). Five year estimated survival for patients >55 years old was only 56 ± 9% compared to 78 ± 5% for patients ≤55 years old ( p = .005). The hazard for death was highest within the first post-transplant year for older patients and was most commonly due to infection. Both advanced age and pre-transplant diagnosis of ischemic cardiomyopathy were found to be independently and additively predictive of reduced late survival. Conclusions In the present study, late survival was adversely influenced by advanced age. Older patients (>55 years) with pre-transplant diagnosis of ischemic cardiomyopathy were particularly at high risk (risk ratio 4.6:1) for death. Given little prospect of expanding the number of donor hearts, careful selection of patients over the age of 55 with pre-transplant ischemic cardiomyopathy is warranted.

Medication adherence and the transplant recipient: helping patients at each stage of change

THE posttransplant life of solid-organ recipients requires compliance with often complex medication and behavioral regimens. Failure to comply with immunosuppressive therapy, for example, may cause late acute rejection episodes, graft loss, and even death. Across all classes of medications, 24% to 50% of patients fail to comply with the medication as prescribed. While exact rates of noncompliance for posttransplant medications are difficult to gauge, studies have found noncompliance with immunosuppressive drugs to range from 22.3% to 36% of patients. Given the potentially lethal consequences of posttransplant medication noncompliance, new approaches to helping recipients manage their medication regimens are clearly required. This report describes the transtheoretical model of behavior change and explores its use for improving medication compliance in transplant recipients.

LIVER TRANSPLANTATION FOR ALCOHOLIC CIRRHOSIS WITH RESPECT TO COMPLIANCE

347 PURPOSE: Disagreement existed as to wether liver transplantation (OLT) should be provided to patients with alcohol induced cirrhosis. During the last years alholic cirrhosis has been accepted as indication for OLT, however, compliance of patients suffering from alcoholic cirrhosis is still under discussion. METHODS: 118 patients who received OLT for alcoholic cirrhosis were considered for analysis. Compliance was defined by 3 parameters: 1. Sobriety. Alcohol relapse was diagnosed by a specialist psychologist and supported by measurements of carbohydrate-deficient-transferrin (CDT). 2. Compliance with immunosuppresive medication. Whole blood trough levels of CyA or FK 506 were determined at each outpatient visit, routinely and on demand. Furthermore, late acute and chronic rejection were analyzed. 3. Adherence to appointed dates for check ups not only with transplant surgeons but also with the psychologist. RESULTS: The median follow up of the study population was 40 months. 1. Out of 118 patients. 103 (87%) remained abstinent during the observation period and 15 (13%) suffered an alcohol relapse. There was no difference between the group with and without alcohol relapse concerning compliance with medication (p=0.3787) or incidence of rejection (p=0.4410). 2. 99 recipients (84%) were compliant with the immunosuppressive medication and 19 patients (16%) were not within the target range. Comparing the compliant and non-compliant group a significant difference could be demonstrated for rejection (p<0.0079), the rate of alcohol relapse was similar in both groups (p=0.3787). 3. Nearly all patients of the study population (>95%) were compliant with both transplant and psychological appointments in the outpatient clinic. CONCLUSION: Non-compliance with immunosuppressive medication was found in 16% and had significant influence on late acute or chronic rejection. However, alcohol relapse (13%) did not show an effect on compliance with medication and did not increase the rate of late acute or chronic rejection. In conclusion, analysis of our data indicate that patients with OLT for alcoholic cirrhosis are compliant, although alcohol relapse occurs in 13% of recipients.

CYA WITHDRAWAL IN STABLE RENAL TRANSPLANT RECIPIENTS AFTER AZA - MMF SWITCH: A PILOT STUDY.

439 We investigated the efficacy and safety of CyA withdrawal after azathioprine (AZA)-mycophenolate mofetil (MMF) switch in stable kidney transplant recipients on triple therapy. Patients and methods: 28 first kidney transplant recipients (19M, 9F) were enrolled in an open, prospective, multicenter trial. They were selected because of a stable renal function for at least 6 months and a less than 12 months kidney biopsy exhibiting no acute rejection and at most, a Grade I chronic rejection according to Banff classification. Mean age was 45±10 years and mean time post-transplantation was 2.8±0.9 years. All patients were on triple therapy: CyA (239±57 mg/d), Aza (96±32mg/d) and steroids (11±5mg/d). Baseline mean serum creatinine was 109±20μmol/l and0000, mean inulin clearance was 71±20ml/min. Aza was interrupted and MMF introduced at 1.5g/d for 2 weeks increased to 1 g bid thereafter. CyA dosage was then decreased over a 3-month period and interrupted. At the end of follow-up (40 weeks), patients had a second kidney biopsy and inulin clearance measurement. Primary end-point was incidence of late acute rejections. Secondary end-points were renal function, graft survival and safety. Because of histologic deterioration seen on some end of follow-up kidney biopsies, we decided to interrupt the study and to review blindly all biopsies. CyA was therefore interrupted in 20 out of 28 patients during a mean of 4.6±1.2 months. Results: one patient (5%) experienced a reversible late acute rejection 36 days after CyA interruption. In the 19 patients who did not experience acute rejection, both serum creatinine and inulin clearance remained unchanged throughout the follow-up. Histologic data available in 18 patients were as follows: stability in 9 patients and deterioration in 9 patients (chronic in 4 patients, acute in one patient and both acute and chronic in 4 patients). Blood pressure decreased (138±20 versus 128±14mmHg and 80±13 versus 76±11 mmHg) as well as the number of required antihypertensive drugs. Conclusion: in stable kidney transplant recipients, CyA withdrawal with Aza-MMF switch was safe (5% of late acute rejection and stable renal function). The relevance of asymptomatic histologic deterioration and its relationship with CyA withdrawal deserves a controlled study.

Analysis of risk factors for the development of bronchiolitis obliterans syndrome.

Chronic rejection after lung transplantation, manifesting as bronchiolitis obliterans syndrome (BOS), has become the dominant challenge to long-term patient and graft survival. In order to elucidate risk factors for development of BOS we utilized the 1995 revision of the working formulation for the classification of lung allograft rejection (), and devised a quantitative method to retrospectively study lung transplant biopsies from all patients who survived at least 90 d. All transbronchial biopsies were regraded 0 to 4 for acute perivascular rejection and lymphocytic bronchitis/bronchiolitis (LBB), and the grades were totaled over a period of time to give two scores, respectively, for each patient. Also examined were timing of acute rejection and LBB episodes and decreased immunosuppression defined as two or more cyclosporine A levels < 200 ng/ml. Sixty-six patients with BOS and 68 with no BOS (NBOS) satisfied our criteria for inclusion in the study. Demographics including age, sex, and primary diagnoses were similar. The mean perivascular score for BOS was 6.2 over a mean follow-up of 822 d (range, 113 to 2,146) compared with 3.2 for NBOS over 550 d (range, 97 to 1,734) mean follow-up. Airway scores were 5.3 and 1.7, respectively, for the same follow-up periods. There was no correlation between length of follow-up and rejection or LBB scores, although mean length of follow-up for the two groups was significantly different. Late acute rejection and LBB were significantly associated with BOS as was decreased immunosuppression. In addition to perivascular rejection, LBB, late acute rejection, and decreased immunosuppression are significant risk factors for the development of BOS. Analysis of the current data leads us to believe that LBB, in the absence of infection, is in fact a manifestation of acute rejection, with similar implications for graft function as acute perivascular rejection.

Long-term outcome of a prospective trial of steroid withdrawal after kidney transplantation

Background: Steroid withdrawal (SW) after kidney transplantation is desirable to avoid associated serious side effects. We studied the long-term outcome of a group of kidney transplant recipients who underwent SW. Methods: Between 1991 and 1993, kidney transplant recipients (N = 12) who had posttransplantation diabetes were entered in a prospective trial of SW. These patients were compared with a demographically similar comparison cohort (N = 66). End points of the study were patient and graft survival, incidence of late acute and chronic rejection, and changes in diabetes management. Results: Previously published data from the SW group at 15 months of follow-up indicated improvement in diabetes control without any adverse effect on patient or graft actuarial survival. At long-term follow-up (mean, 56 months) the improvement in diabetes management was not detectable. The incidence of late acute rejection in SW and cohort groups was 42% and 8%, respectively (P = .006). Likewise, the incidence of chronic rejection in the SW versus cohort group was 42% and 12%, respectively (P = .014). Conclusions: Although SW appeared to be successful initially, our long-term data indicate that SW significantly increases the risk of late acute rejection and chronic rejection episodes without benefits in posttransplantation diabetes management. Steroid withdrawal in patients with posttransplantation diabetes should be approached with caution. (Surgery 1999;125:155-9.)

Long-term outcome of a prospective trial of steroid withdrawal after kidney transplantation

Background: Steroid withdrawal (SW) after kidney transplantation is desirable to avoid associated serious side effects. We studied the long-term outcome of a group of kidney transplant recipients who underwent SW. Methods: Between 1991 and 1993, kidney transplant recipients (N = 12) who had posttransplantation diabetes were entered in a prospective trial of SW. These patients were compared with a demographically similar comparison cohort (N = 66). End points of the study were patient and graft survival, incidence of late acute and chronic rejection, and changes in diabetes management. Results: Previously published data from the SW group at 15 months of follow-up indicated improvement in diabetes control without any adverse effect on patient or graft actuarial survival. At long-term follow-up (mean, 56 months) the improvement in diabetes management was not detectable. The incidence of late acute rejection in SW and cohort groups was 42% and 8%, respectively ( P = .006). Likewise, the incidence of chronic rejection in the SW versus cohort group was 42% and 12%, respectively ( P = .014). Conclusions: Although SW appeared to be successful initially, our long-term data indicate that SW significantly increases the risk of late acute rejection and chronic rejection episodes without benefits in posttransplantation diabetes management. Steroid withdrawal in patients with posttransplantation diabetes should be approached with caution. (Surgery 1999;125:155-9.)

Promising new agents in the prevention of transplant rejection.

Promising immunosuppressive drugs designed to prevent rejection have been developed recently. Two monoclonal antibodies directed against the interleukin-2 (IL-2) receptor, daclizumab and basiliximab, have been shown to significantly reduce the incidence of acute rejection without increasing adverse events. Sirolimus (rapamycin), an agent that inhibits T- and B-response at a later stage than cyclosporin, has been shown to be synergistic with cyclosporin in experimental and clinical studies. Ongoing clinical trials have reported that in renal transplantation high doses of sirolimus are as effective as cyclosporin. SDZ-RAD, a derivative of sirolimus, is also under investigation. FTY-720 another promising drug, prolonged the survival of allografts and synergised with cyclosporin and sirolimus in experimental models. Gusperimus (deoxyspergualin), which inhibits IL-1 synthesis, was useful in reversing early and late acute rejection in clinical trials. Antisense oligonucleotides which interfere with intercellular adhesion molecules which are important in rejection, gave encouraging results in primate renal allografts. The availability of these new drugs will be able to further abate the risk of rejection in organ transplantation. However, caution is warranted with their use in order to avoid the risks of over immunosuppression. Today excellent results can be obtained with the available drugs. Newer immunosuppressive schedules should be designed, not only to reduce the risk of rejection, but also to obtain a better therapeutic index that allows a further improvement of the graft survival while minimising the comorbidity and drug-related toxicity.

Noncompliance causing late acute rejection in pediatric heart transplantation: JM Ringewald, SS Gidding, DF Wax, SE Crawford, S Rodgers, SR Shah, E Pahl, CL Backer, C Mavroudis. Children's Memorial Hospital, Northwestern University Medical School, Chicago, IL

Noncompliance causing late acute rejection in pediatric heart transplantation: JM Ringewald, SS Gidding, DF Wax, SE Crawford, S Rodgers, SR Shah, E Pahl, CL Backer, C Mavroudis. Children's Memorial Hospital, Northwestern University Medical School, Chicago, IL

Constrictive (obliterative) bronchiolitis.

Constrictive bronchiolitis (CB), also termed in lung transplant patients obliterative bronchiolitis, is inflammation and fibrosis occurring predominantly in the walls and contiguous tissues of membranous and respiratory bronchioles with resultant narrowing of their lumens. CB is found in a variety of settings, most often as a complication of lung and heart-lung transplantation (affecting 34% to 39% of patients, usually in the first 2 years after transplantation) and bone marrow transplantation, but also in rheumatoid arthritis, after inhalation of toxic agents such as nitrogen dioxide, after ingestion of certain drugs such as penicillamine and ingestion of the East Asian vegetable Sauropus androgynous, and as a rare complication of adenovirus, influenza type A, measles, and Mycoplasma pneumoniae infections in children. In lung transplants, CB is the single most important factor leading to death thereafter. In one study, the overall mortality rate was 25%. However, at the same time, 87% of patients who were asymptomatic and diagnosed solely by transbronchial biopsy had resolution or stabilization of disease. Decreases in FEV1 from baseline can be used to clinically support CB in transplant patients; the term bronchiolitis obliterans syndrome is used to denote this clinical dysfunction, and a grading system has been established for it that is now widely used in the literature. Significant risk factors for the development of CB in lung transplants include alloantigen-dependent and -independent mechanisms. In the former group are late acute rejection and HLA mismatches at the A loci; in the latter are ischemia/reperfusion injuries to airways that result from the transplantation surgery and cytomegalovirus infection.

Long-term outcome of tacrolimus rescue therapy in late rejection after renal transplantation

REFRACTORY rejection episodes are major causes of graft failure after renal transplantation. It is well known that late acute rejections have a poor long-term prognosis. Tacrolimus (FK) is an immunosuppressant agent that acts by inhibition of calcineurin activity, similar to cyclosporine A (CyA). It is used as a therapeutic alternative to CyA and is considered to be more potent than CyA. FK has also demonstrated efficacy as rescue therapy in patients who experience persistent acute rejection with CyA-based therapy. A corticosteroid-sparing effect has been demonstrated in several studies with FK, which may be a particularly useful consideration in children receiving transplants. The differences in the tolerability profiles of FK and CyA may well be an influential factor in selecting the optimal treatment for patients undergoing organ transplantation. Although both drugs have a similar degree of nephrotoxicity, CyA has a higher incidence of significant hypercholesterolaemia, hirsutism, and gingival hyperplasia, while FK has a higher incidence of diabetes mellitus, some types of neurotoxicity (eg, tremor, paraesthesia), diarrhea, and alopecia. Conversion from CyA to FK in ongoing allograft rejection after renal transplantation has been shown to be effective in the early posttransplant period ( 6 months after transplantation). However, tacrolimus rescue therapy was performed in only a small number of patients with late acute rejection or chronic rejection. In our institution, FK was introduced for rescue therapy in 27 renal transplant recipients with late rejection between 1994 and 1996. We analyzed the 5-year outcome of FK rescue therapy in these patients.

Beneficial effects of 15-deoxyspergualin on late acute rejection occurring more than three months after renal transplantation

Beneficial effects of 15-deoxyspergualin on late acute rejection occurring more than three months after renal transplantation

Rescue FK506 Therapy for Acute Rejection and Early Chronic Rejection After Liver Transplantation: Report of 14 Cases

From January 1990 to May 1996, 148 male and 99 female patients had 265 liver transplantation (LTx) and 18 (6.7%) retransplantations. The mean age was 46.6 years. A cyclosporine-based immunosuppression was used. Ninety-four patients (38%) had 116 episodes of rejection. Thirty-seven of 86 patients treated by steroid bolus were steroid resistant, requiring orthoclone therapy. In eight (3.2%) other patients, orthoclone was used without previous steroid bolus. In 14 cases (6%), refractory rejection required rescue FK506 therapy. There were seven men and seven women with a mean age of 38 years (from 14 to 56). Indications for LTx were alcoholic cirrhosis (N 5 4), post-VHC cirrhosis (N 5 2), post-VHB cirrhosis (N 5 2), fulminant liver failure (N 5 3), giant liver hemangioma (N 5 1), hemochromatosis (N 5 1), and liver metastasis of pancreatic neuroendocrine tumour (N 5 1). Rescue FK506 was done for nine patients after failure of steroid bolus and orthoclone therapy, for three patients after failure of orthoclone therapy without previous steroid bolus, and for two patients after failure of steroid bolus without orthoclone therapy. Only oral formulation of FK506 was used in association with steroids and azathioprine. There were six cases of early chronic rejection (less than 50% of bile duct loss), each had a mean of three rejection episodes, 1.8 steroid bolus therapy, and 1.4 orthoclone therapy. Eight cases of acute rejection (four early rejection , 30 days post-LTx, and four late acute rejection . 1 month post-LTx) each had a mean of two rejection episodes, 1.5 steroid bolus therapy and 1.5 orthoclone therapy.

Late Acute Rejection is More Prevalent Among African-American Renal Allograft Recipients and is Frequently Associated With Allograft Loss

Late Acute Rejection is More Prevalent Among African-American Renal Allograft Recipients and is Frequently Associated With Allograft Loss

Late Acute Rejection Episodes After Vascularized Pancreas Transplantation

Late Acute Rejection Episodes After Vascularized Pancreas Transplantation

STEROID WITHDRAWAL MAY COMPROMISE LONG TERM OUTCOME AFTER KIDNEY TRANSPLANTATION

233 Background: Steroid use after renal transplantation is related to significant morbidity and mortality. Short term follow-up studies have suggested that slow steroid withdrawal (SW) is associated with a low risk of graft loss when patients are maintained on cyclosporine (CsA) and azathioprine(AZA). We studied the long-term outcome of a group of kidney transplant recipients who underwent SW. Methods: Between 1991 and 1993 we entered in a prospective trial 12 previously non-diabetic primary renal allograft recipients who developed PTDM (defined by the need for insulin therapy or HbA1c > 8%). Entry criteria included: 1) more than 1 year after transplant; 2) stable creatinine < 2.5 mg/dl; 3) at least 4 months after any prior rejection episode; and 4) known medication compliance. Mean age was 49 years. Nine were male and 3 female, with a racial profile of 6 blacks, 4 Hispanics, and 2 whites. Ten patients received cadaveric allografts while 2 received living related allografts. SW was accomplished over a mean of 5.7 months and patients were maintained on CsA and AZA. Endpoints of the study were patient and graft survival, and incidence of acute and chronic rejection(CR). We previously published a follow-up of these patients at 6 months post-SW which revealed several medical management benefits without adverse effects on patient or graft survival. Results: At long-term mean follow-up of 4 years (with a range of 32-65 months) patient and graft survival were 92% (11 of 12) and 58% (7 of 12) respectively. Forty-two percent (5 of 12) had at least 1 episode of late acute rejection (AR). Three of these patients lost their graft immediately; 1 resumed steroids, and 1 developed CR. Of the remaining 7 patients, one died from sepsis with a functioning grafts, 1 had CR with subsequent graft loss, 1 has CR with a functioning graft, and 4 are well and off steroids. Currently, only 7 patients have functioning graft, and 2 of these have biopsy proven CR. We compared the study population with 50 renal transplant recipients, matched for age, sex, primary renal disease, HLA-ABDR, with stable creatinine <2.5 mg/dl over 1 year after transplant but maintained on steroids. In the control group, the 4 year graft survival was significantly higher and the incidence of late AR lower.Conclusion: Long-term follow-up of PTDM patients who underwent SW reveals that early reductions in steroid-associated morbidity may be countered by an increase in late AR episodes and an increased overall rate of graft loss from CR when compared to a similar patient population from our center.