Number Of Acute Rejection Episodes Research Articles

HIGHER CYCLOSPORINE LEVELS DECREASE KIDNEY REJECTION EPISODES WITHOUT INCREASING NEPHROTOXICITY

303 PURPOSE: Cyclosporine has become the mainstay of immunosuppression for renal transplant patients. Controversy persists, however, regarding the optimal level of cyclosporine that should be maintained for maximum immunosuppressive benefits and minimal toxicity. Because acute rejection episodes have been shown to be predictive of chronic rejection and graft loss, the goal of this study was to evaluate whether higher cyclosporine levels in the early post-transplant period would reduce the number of acute rejection episodes without significantly increasing nephrotoxicity. METHODS: This study retrospectively reviewed all patients who had living donor or cadaveric kidney transplants during a 5.5 year period. Cadaveric recipients were induced with low dose OKT3 (2 mg/day × 12 days). All patients were maintained on triple drug therapy and divided into three groups. Group 1 (n=62) was maintained at lower cyclosporine levels (150-250 ng/ml), prednisone, and azathioprine. Group 2 (n=32) and Group 3 (n=25) were maintained at higher cyclosporine levels (250-350 ng/ml), prednisone, and either azathioprine (Group 2) or MMF (Group 3). High, low, and mean cyclosporine levels and serum creatinine levels at 1, 3, 6, and 12 months were recorded. The frequency and severity of acute rejection episodes, all pre-treatment biopsy proven, were reviewed at 3 and 12 months. RESULTS: There were 119 kidney transplant patients entered into the study. There were no significant differences in race, sex, age, previous transplants, number of mismatches, or preformed antibodies between groups. There were significantly fewer rejection episodes in the groups maintained at higher cyclosporine levels (Groups 2 and 3) during the first 3 months (p<0.001) as well as the first 12 months (p<0.017). There was no significant difference in mean creatinine levels at any time interval between groups. No statistically significant difference was seen in the severity of rejection episodes as determined by Banff criteria. Patients with low cyclosporine levels (Group 1) tended to have an increased number of readmission days within the first 12 months following transplant compared with patients in Groups 2 and 3 (8.2 vs. 5.0, respectively). CONCLUSION: Maintenance of cyclosporine at higher levels can reduce the number of acute rejection episodes. This benefit can be achieved without increasing cyclosporine nephrotoxicity (as measured by serum creatinine levels) and may reduce the need for readmission to the hospital.

THE EFFECT OF PRAVASTATIN ON CHOLESTEROL LEVELS AND NK CELL ACTIVITY AFTER KIDNEY TRANSPLANTATION.

617 Introduction. Hyperlipidaemia is common after organ transplantation and is associated with an increased risk for cardiovascular disease. Administration of pravastatin (an HMG-CoA reductase inhibitor) early after transplantation successfully lowered cholesterol levels, while a reduced number of acute rejection episodes, accompanied by a decrease in natural killer (NK) cell activity has also been reported. If true, a consistent low NK cell activity due to pravastatin might impair tumour surveillance leading to an increased risk to develop cancer, thereby abrogating the beneficial lipid lowering effect of pravastatin. Therefore, we studied the effect of pravastatin on NK cell activity in stable renal transplant patients. Methods. From 10 cyclosporin treated patients with hypercholesterolaemia, 1 to 10 years after transplantation, we determined the number of NK cells by flowcytometry, (CD3−CD16+CD56+) and their cytotoxic activity (lysis of K562 cells) before, 6 weeks and 12 weeks after initiating pravastatin treatment. Results. Total cholesterol levels decreased from 8.7 mmol/L to 7.2 at 6 weeks and 7.1 at 12 weeks after initiation of pravastatin. LDL-levels decreased from 5.2 μmol/L to 3.6 and 3.8 at 6 and 12 weeks respectively (p<0.05), whereas HDL-levels had a tendency to increase from 1.4 to 1.6 at 6 weeks and 1.7 at 12 weeks. Although the number of NK cells remained the same, the cytotoxic activity of NK cells showed a significant (p=0.01) rise from 16.7% lysis (median, range 5.5-26.5) to 23.7% (10.0-37.7) during the first 6 weeks after administration of pravastatin. At 12 weeks NK cell activity was 19.2% (11.5-41.5). Conclusion. In contrast to previous reports on decreased NK cell activity due to pravastatin treatment early after transplantation, we can not confirm these results in stable kidney recipients. In our hands the cytotoxic activity of NK cells 12 weeks after starting pravastatin treatment was even slightly elevated. In view of the potential role of NK cells in tumour and virus surveillance these data are reassuring.

FACTORS LEADING TO RENAL ALLOGRAFT CHRONIC DYSFUNCTION

318 The short-term renal allograft survival has improved after optimization of surgical and tissue typing techniques, the worldwide use of new immunosuppressants, and the better knowledge of rejection mechanisms. However, the annual rate of graft loss after the first year has remained virtually unchanged during the last 25 years. Chronic rejection or renal allograft chronic dysfunction, a complex and multifactorial process, is claimed as the leading cause of late graft failure. We performed a retrospective cohort study in order to identify risk factors associated with the development of chronic rejection. This study included 155 renal transplant recipients whose grafts had functionned for at least 12 months. Chronic rejection was clinically defined as deterioration of graft function, manifested by slowly progressive rising serum creatinine concentration of at least 25% from baseline values, after exclusion of other causes of graft dysfunction, and was histologically proved. Association between chronic rejection and donor and recipient-related factors, including cyclosporine doses and blood levels at 3, 6 and 12 months post-transplantation was investigated. Univariate analysis and multivariate Cox proportional hazard regression were used. Risk factors for chronic rejection were those reaching statistical significance below 5% under multivariate analysis. Chronic rejection was diagnosed in 47.7% of the recipients, and it was responsible for as many as 62.2% of graft losses after the first year of transplantation. The presence of chronic rejection had a significant impact on the 6-year graft survival (68.1% vs 93.2%; p=.0013). The number of acute rejection episodes (1 episode: RR = 2.39, 95% CI; 1.27-4.49; ≥ 2 episodes: RR = 5.18, 95% CI; 2.56-10.49), delayed graft function (RR = 2.57, 95% CI; 1.51-4.36) and donor age above 40 (RR = 2.07; 95% CI; 1.23-3.47) were identified by multivariate analysis as risk factors for chronic rejection. Cyclosporine A blood levels below therapeutic levels in the 3rd, 6th and 12th month after transplantation were associated with chronic rejection by univariate analysis. Results of this study point out the significant role of immunological and non-immunological mechanisms in the pathogenesis of chronic graft dysfunction. Our findings suggest that suboptimal immunosuppression may contribute to long-term graft loss and should thus be avoided.

Dacluzimab is Comparable to Antithymocyte Globulin (ATG) Induction in Preventing Acute Rejection (AR) Episodes in High Risk Renal Transplant Recipients

577 Dacluzimab has been shown to significantly reduce the incidence of AR in primary cadaveric renal transplants as compared to placebo [cyclosporine (CSA) and prednisone, or CSA, prednisone and azathioprine]. Its role in high risk renal transplant recipients has not been evaluated. Prior to the availability of Dacluzimab, we used ATG induction in these patients. Methods: In this pilot study we used variable doses of Dacluzimab (1-5 doses depending upon the status of graft function) in conjunction with CSA or FK 506, mycophenolate mofetil (MMF) and prednisone in 17 high risk renal transplant recipients. The indications for Dacluzimab induction included primary graft dysfunction in 5, post- transplant graft dysfunction in 4, prolonged cold ischemia time (>24 hours) in 4, and retransplants with high panel reactive antibodies (PRA) in 4. One patient had a combined liver kidney transplant. The number of AR episodes, need for OKT3 treatment, patient and graft survival and serum creatinines at 3 months were compared to 16 retrospective controls who received ATG induction along with CSA or FK 506, MMF and prednisone. The indications for ATG included primary graft dysfunction in 13 and post-transplant graft dysfunction in 3. Results: Both groups were comparable for age, sex, race, HLA mismatches, PRA, primary versus retransplants, cadaver versus living related transplants, number of patients receiving CSA or FK 506, dialysis and duration of dialysis. One patient died in each group (pseudomonas sepsis in the Dacluzimab group and myocardial infarction in the ATG group). The remaining patients are alive with functioning grafts. One patient in ATG group developed cytomegalovirus (CMV) infection. Three patients (17.6%) had AR in the Dacluzimab group. Of these, one had acute vascular rejection on day 3 after transplant and required treatment with OKT3. Four patients (25%) had AR in ATG group. None required treatment with OKT3. The number of Dacluzimab doses ranged from 1-5 (1.8 ± 1.3). The number of ATG doses ranged from 2-14 (8.9 ± 3.5). The length of stay in the hospital was longer in Dacluzimab group 12.6 ± 8.1 versus 8.4 ± 2.8. The difference was due to pseudomonas sepsis, pulmonary hemorrhage, and liver transplant related complications in three patients respectively. Serum creatinines at 3 months were comparable (1.9 ± 1.4 in Dacluzimab group versus 1.7 ± 1.7 in ATG group). The long term data is not yet available. Conclusions: 1) In this pilot study we show that Dacluzimab induction is comparable to ATG in high risk renal transplant recipients in preventing AR. 2) Patient and graft survival, incidence of CMV infections and serum creatinine at 3 months are comparable in both groups. 3) Since the cost of ATG per dose is equivalent to Dacluzimab dose, it is cost effective to use Dacluzimab (2 doses versus 9 doses of ATG). 4) Dacluzimab is also more convenient to administer avoiding a central line essential for ATG. These results need to be validated in a larger multicenter trial.

Mycophenolate mofetil--is it worth the cost? The in-favor opinion.

Since its introduction, mycophenolate mofetil (MMF) has rapidly gained acceptance among renal transplant physicians. Three large multicenter studies have shown that MMF decreased the incidence of acute rejection episodes by 50%. While clinical data supporting the long-term benefits of MMF are not available, there is some experimental evidence which demonstrates that MMF may play a role in the prevention of chronic allograft rejection. Furthermore, MM F is a potent immunosuppressive agent, which could result in a reduction of the dose of cyclosporin A (CsA) required and subsequently reduce its associated toxicity. Despite the fact that MMF is six to seven times more expensive than azathioprine (AZA), its introduction into maintenance immunosuppressive protocols may not increase renal transplant charges during the first year after renal transplant as its cost can be offset by the reduced number of acute rejection episodes (ARE). The long-term societal impact of MMF will need to be evaluated as the data related to graft and patient survival, as well as chronic rejection, become available.

Withdrawal versus continuous cyclosporine therapy in kidney transplant recipients of one-haplotype-matched donors

IT HAS BEEN widely recognized that the discovery of cyclosporine (CsA) and its clinical use represents one of the major advances in organ transplantation in the past 25 years. In the renal transplant setting, the most relevant effect of CsA is the reduction in the incidence of acute rejection episodes as well as an increase in 1-year graft survival to and beyond 90%; consequently, long-term graft survival rates have also improved. However, the annual rate of graft loss after the first year has not changed significantly. It seems as if the essential benefit obtained from CsA is related to the decrease in the number of acute rejection episodes during the first posttransplant year. A careful analysis of the literature raises reasonable questions regarding long-term vs temporary use of CsA during the first posttransplant months, mainly in those patients who have “immunologic advantages,” such as most of living related graft recipients. The main arguments against long-term use are the financial cost and the toxic effects associated with continued CsA therapy. On the other hand, the risk of temporary use involves the potential of acute rejection episodes following CsA withdrawal. Clinical data defending both points of view have been published. However, the bulk of information concerns mainly cadaveric allografts recipients and, to a lesser extent, living related donor recipients. In our country, the current ratio between living related to cadaveric kidney transplant recipients is 78% to 22%, and, as a developing country, generating policies regarding safe and cost-effective immunosuppression for the long term is a matter of great concern. Accordingly, we herein report the long-term impact of CsA withdrawal during the first year after kidney transplant versus continuous therapy, on graft survival of kidney transplant recipients of one-haplotype-matched donors.

Association of cytomegalovirus genotype with graft rejection after liver transplantation.

The envelope glycoprotein gB of human cytomegalovirus (CMV) occurs as one of four main genotypes. Some previous studies have proposed a relationship of CMV gB genotype to the frequency of symptomatic infection and to clinical outcomes in both transplant and human immunodeficiency virus-infected populations. Our aim was to define the distribution of CMV gB genotypes and the impact on acute cellular rejection and graft/patient survival after orthotopic liver transplantation (OLT). Between October 1988 and December 1996, 325 patients underwent cyclosporine-based OLT at our center. CMV infection was surveyed prospectively and defined as viral isolation from blood or urine; 53 (16%) patients had detectable CMV. Isolates were genotyped by polymerase chain reaction amplification and restriction digest analysis. The distribution of CMV genotypes was: gB1, 19 (36%) patients; gB2, 15 (28%) patients; gB3, 13 (24%) patients; and gB4, 4 (8%) patients. Two patients (4%) had mixed infection (1 + 3, 1 + 4). Age, preOLT diagnosis, use of ganciclovir prophylaxis, basal immunosuppression, mean number of HLA donor/recipient mismatches, and United Network of Organ Sharing status were comparable among patients with different genotypes. Patients with gBl had a significantly higher mean number of acute rejection episodes (1.52+0.30 vs. 0.67+0.22; P=0.027). However, there was no difference in rejection severity, including OKT3 usage or FK506 conversion, or development of chronic rejection among patients with different genotypes. The gB genotype did not affect the development of symptomatic or tissue-invasive CMV disease, detected in 15 patients. Actuarial rates of patient (odds ratio [OR] 3.0; confidence interval [CI] 1.49-6.0) and graft (OR 2.57; CI 1.25-5.22) survival were significantly diminished in the group with CMV infection versus those without CMV (P<0.0001 for both), but there was no association with CMV genotype. (1) Patients with CMV infection had significantly reduced patient and graft survival rates at 1 and 5 years after OLT as compared with OLT recipients without CMV infection. (2) CMV genotype gB1 was associated with a higher mean number of acute rejection episodes.

MACHINE PERFUSION PRESERVATION DOES NOT INCREASE THE RISK OF KIDNEY GRAFT REJECTION

221 Continuous hypothermic pulsatile perfusion (CHPP) is recently more widely used for preservation of kidneys harvested from "marginal donors". CHPP proved to be effective, allowing longer preservation time with no increase in ATN rate. It has been suggested that perfusion can damage vascular endothelium, therefore accelerating rejection. The aim of our study was to assess correlation of preservation method and frequency of rejection episodes. Material. From Jun '94 to Jan '97 seventy-six ESRD pts received kidneys harvested from 38 cadaveric donors (13 in UNOS group B and 25 group C). One kidney from each donor was stored in ViaSpan in simple hypothermia (CS), while the other was machine perfused (CHPP) with Belzer's UW Gluconate) using MOX 100 system (Waters Instr.). Standard perfusion parameters were used. Kidneys were transplanted using typical surgical technique. Two pts in CHPP group and five in CS received second or third kidney graft. Recipients factors (age, gender, cause of ESRD, pretransplant dialysis time, number of blood transfusion and maximum PRA) did not differ between the groups. Cold ischemia times were longer for kidneys stored using CHPP than in CS (30 h 32′ vs. 26h 31′; p<0.0001). The time of vascular anastomosis was similar (NS). Recipients received tripple immunosuppressive treatment. Mean mismatch number was 2.94 vs. 3.0 in CHPP vs CS (NS). Patients in CS group were slightly better matched for DR antigens: 0.67 vs. 0.76 mismatch in CHPP group (p<0.001). Graft function (serum creatinine and diuresis), incidence of ATN (with number of dialysis required), CMV infection and frequency of rejection (biopsy, duplex-scan Doppler or clinical signs) were monitored. Ethical Committee of Warsaw Medical School permission for this study was obtained. Results. No hyperacute rejection was observed in any case. Eleven pts from CHPP group had ATN requiring 1,54 ±2,84 hemodialysis procedures, in one case primary non-function occur and one patient died of myocardial infarction. Among controls, there were seventeen patients with ATN (p<0.05) requiring 2,8 ± 3,22 hemodialyses (p<0.05) and one graft never regain function. Significantly lower number of acute rejection episodes in CHPP group (0.57±0.88 rejections/patient) than in CS group (1.06±1.15) was observed (p=0.04). CS group patients required slightly higher doses of methylprednisolone for the treatment of rejection episodes (1.96 vs 1.32 g;), as well as more doses of ATG/OKT3 (0.86 vs. 0.45 doses/patient,) for steroid resistant rejection treatment. Chronic rejection affected graft function in 9.4% of recipients in CHPP group and 18.8% in the study group (p=0.04). After 24 months follow-up patients from CS group had significantly higher serum creatinine level: 1,68 mg% vs. 1,32 mg% (p<0,03). No kidney in the study group was lost due to rejection. Multivariate analysis shown no correlation between preservation method and acute rejection (F=1,67 beta=0,216 p<0,2). Acute rejection precedes accelerated chronic rejection (beta=0,47). Conclusions. Method of preservation has been found the risk factor for the allograft rejection. Patients who received kidneys stored using CHPP had less episodes of acute rejection. Therefore the suggestion that endothelial damage could induct rejection process has not been supported by our study. Moreover, the benefit of machine perfusion can be due to more efficient preservation of endothelium and/or better maintenance of whole organ integrity reflected by better postoperative function.

OPTIMALIZATION OF IMMUNOSUPPRESSION AFTER PULMONARY TRANSPLANTATION

742 Background: The successful use of tacrolimus (FK) and mycophenolic acid (MPA) after heart transplantation has persuaded us to assess this medication after lung transplantation. In this study, we compared three subsequent immunosuppressive protocols after single (SLTx) or bilateral(DLTx) lung transplantation using either cyclosporin (CyA) or FK in combination with azathioprine (aza) or MPA. Methods: A total of 80 lung transplantations were performed at our centre; 71 of these patients (pts) were included in this study. The first 34 pts were treated with CyA and aza (group I). Of the remaining 37 pts receiving FK (group II), 28 received FK and aza (group IIa), and 9 FK and MPA(group IIb). The dosage of all three drugs (CyA, FK and MPA) was adjusted according to trough levels. No meaningful differences were found in demographic or baseline characteristics. The mean recipient age was 41.9 and 41.3 years, the ratio of SLTx/DLTx 57.1/42.9% and 58.8/41.2% in groups I and II, respectively. All pts received additionally corticosteroids.Results: The discrepancy in mean observation periods (26.5 vs 14.7 months in groups I and II) led us to restrict the analysis of events to the first year post-transplantation only. The actuarial one-year survival rate was 70.6% for the CyA group and 94.3% for the FK group (p<0.02). Causes of death in the CyA group were sepsis (n=4), obliterative bronchiolitis(n=3), acute rejection (n=1), CMV infection (n=1), and pulmonary embolism(n=1), in the FK group liver failure (n=1), obliterative bronchiolitis (n=1), and sepsis (n=1). The number of acute rejection episodes (ARE) per patient was 1.5 for the CyA group versus 1.18 for the FK group (p<0.05). In the subgroup treated with FK and MPA (group IIb), only one mild acute rejection episode was observed (0.1 ARE/pt). The incidence of infection (CyA: 1.45 vs FK: 1.39 infections/patient) and their spectrum were comparable. The most frequently reported adverse events were diabetes mellitus (57% in the FK vs 23% the CyA group) and renal insufficiency (27% vs 15%) Conclusion: FK appears to be a more potent immunosuppressant after pulmonary transplantation when compared to CyA; the incidence of acute rejections is significantly reduced and the one year survival rate markedly improved. Since the frequency and severity of acute rejection episodes are the main risk factors for the development of obliterative bronchiolitis, further follow-up will be necessary to determine whether more potent immunosuppressive protocols, like the combination of tacrolimus and MPA, will also be able to reduce the incidence of chronic rejection.

Improvement in the Nutritional and Pulmonary Profiles of Cystic Fibrosis Patients Undergoing Bilateral Sequential Lung and Heart‐Lung Transplantation

Cystic fibrosis (CF) is the most common lethal genetic disease of the white population and is associated with malnutrition. In patients undergoing thoracic surgery, poor nutrition is a risk factor for postoperative complications. The aim of this study is to characterize the nutritional profiles of CF patients undergoing pulmonary transplantation (heart‐lung or bilateral lung) at our medical center between 1988 and 1996 and to assess the significance of their nutritional status on posttransplantation outcomes. We retrospectively reviewed the charts of the 31 CF patients who underwent lung transplantation. Body mass index (weight/height2) was calculated for the adult patients as an index of their relative body fat before transplantation. Preoperative biochemical nutritional parameters and pulmonary function tests were assessed. The data were then compared with data collected at 1 year after transplantation. Multivariate analysis was used to examine the relationship between preoperative parameters and transplantation outcomes. The outcome variables included initial length of hospital stay, the number of infections within the first 90 days, the number of acute rejection episodes within the first year; the occurrence of obliterative bronchiolitis within the first year; and the change in the forced expiratory volume in 1 second, forced expiratory flow between 25% and 75%, and the forced vital capacity, hematocrit, and cholesterol at 1 year. Significant differences were found in all parameters studied at the end of 1 year (p ≥ .002). An inverse correlation was demonstrated between the pretransplantation total protein/albumin ratio and the number of early infections (p = .029); however, albumin concentration alone showed no correlation. Preoperative diabetes mellitus did not correlate with any of the dependent variables. The multivariate analysis suggests that an increase in the globulin fraction of total protein may be associated with a decrease in early postoperative infections. The nutritional parameters and pulmonary function of the CF patients studied normalized by one year after transplantation. There was no increased risk of rejection or infection observed among the CF diabetic patients transplanted.

Pravastatin Increases Survival and Inhibits Natural Killer Cell Enhancement Factor in Liver Transplanted Rats

Pravastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, has been shown to decrease the number of acute rejection episodes in cardiac and renal transplant patients. This study evaluates the effects of pravastatin on survival of rats following liver transplant and attempts to elucidate the mechanisms of these effects. Both survival and natural killer cell enhancing factor (NKEF) studies utilized Dark Agouti rats for donor livers transplanted into Brown Norway rats as recipients. All rats received daily low-dose cyclosporine (CsA) 2 mg/kg/day by gavage. The treated groups also received gavage doses of pravastatin, 20 mg/kg/day. Survival data were analyzed by the method of Kaplan–Meier and log-rank χ2tests for statistical significance. For NKEF evaluation, rats were sacrificed at varying time points; total RNA was extracted from the liver and hybridized with32P-radiolabeled NKEF DNA probes in the Northern blot technique. Radiographs were quantitated using densitometry. Data were analyzed by two-way ANOVA. Actuarial survival was improved (P<< 0.05) in rats treated with pravastatin in addition to low-dose CsA (n= 41, CsA alonen= 74). Less fibrosis and chronic rejection was seen on histological section in the treated animal livers,P< 0.05. NKEF was seen maximally at Days 5–15 tapering off at Day 21. NKEF-a and NKEF-b levels were significantly decreased in the animals treated with CsA and pravastatin compared to CsA alone in the group of animals < 16 days postop (P<< 0.05). Pravastatin improves survival in rats following OLT and while the mechanism is still unknown, inhibition of natural killer cell enhancement factor may represent an alteration in the overall immune response.

The impact of microsurgical hepatic arterial reconstruction on the outcome of liver transplantation for congenital biliary atresia

Hepatic artery thrombosis (HAT) after liver transplantation for biliary atresia (BA) is a serious complication that most often leads to retransplantation (re-OLT). The purpose of the present study was: (1) to identify risk factors associated with HAT and (2) to analyze the impact of recently introduced microsurgical hepatic arterial reconstruction (MHR) on the incidence of HAT, subsequent need for re-OLT, and patient survival. A retrospective review of 194 patients transplanted for BA was performed. One hundred and sixty-six patients (group 1) underwent conventional arterial reconstruction and 28 (group 2) had MHR. Actuarial survival for patients with HAT was significantly worse than for patients without HAT at 1, 2, and 5 years (71%, 61%, and 57% versus 85%, 85%, and 85%, P = 0.0007). Stepwise logistic regression analysis revealed that the risk of HAT correlated best with the type of arterial reconstruction (P = 0.007) followed by pretransplant bilirubin concentration (P = 0.04) and the number of acute rejection episodes (P = 0.03). In group 1, 32 patients developed HAT (19%), and of these, 18 underwent re-OLT for HAT. No patient in group 2 developed HAT (P = 0.006 versus group 1). One-year actuarial patient survival was 81% in group 1 and 100% in group 2 (P = 0.02). In OLT for BA, (1) the predominant risk factor for HAT is the technique of arterial reconstruction, and (2) MHR markedly reduces the incidence of HAT and the need for re-OLT while improving patient survival.

Acute versus chronic graft rejection: Related manifestations of allosensitization in graft recipients

I n the earlier years of clinical transplantation, there was a tendency among clinicians and investigators to focus on the immediate problem of acute graft rejection, which occurred soon arter transplantation in a large number or transplant recipients and was a major cause ofgraft loss. In the current clinical era, acute rejection can be pharmacologically controlled in most patients, and clinical concerns have begun to focus on the less immediate problem of chronic graft rejection. This phenomenon occurs in about half of all transplant patients, and is a majot cause of late graft loss. Chronic rejection is generally unresponsive to therapies that are effective against acute rejection, and to date, there is no accepted clinical therapy for chronic graft rejection. As a result, chronic rejection now claims more grafts than acute rejection. Chronic rejection is not simply delayed acute rejection. Indeed, acute and chronic rejection are diKerent in many ways. Acute rejection is histologically characterized by a rapid, intense and destructive leukocytic inliltration of graft tissues, and generally represents a pathologic inflammatory response.‘” In contrast, chronic rejection is characterized by a slower development within the graft or interstitial librosis and neointimal formation within the large1 vessels, and seems to represent a pathologic tissue remodeling response .+a For some time, these disparate characteristics led clinicians and investigators to consider acute and chronic rejection as separate and unrelated entities. However, there is developing cvidence that the two pathologies are closely related manifestations of post-transplant cellular and humoral sensitization to graft alloantigens. provided by several investigators,‘* who indcpendently showed that long-term (5-10 year) graft survival decreases signilicantly in direct relation to the number of acute rejection episodes experienced by the patients. For esample, Matas et al” have calculated that the half-life of kidney allografts in patients with no clinical acute rejection episodes is 733 years, compared with 5 1 years in patients with one rejection episode, and 6 years in patients with more than one acute rejection episode. Conversely, these data indicate that late graft loss due to chronic rejection is relatively rare among patients who do not esperience an early acute rejection episode. This suggests that the two types of graft rejection are somehow related. It also suggests that control of chronic rejection in transplant patients might be achieved by developing immunosuppressive strategies that efTectively avoid, rather than reverse, acute rejection episodes. Indeed, the current clinical tendency to accept acute rejection, because it is treatable, may indirectly promote chronic rejection development. The purpose of this discussion is to review some current concepts regarding the related mechanisms of acute and chronic grart rejection in the light of some key observations in experimental transplant models. This is not meant to be a comprehensive review of the subject, and many interesting studies will not be cited for the sake of clarity and brevity. What should emerge from this discussion is a broadened view of transplant biology, and a working model of the continuum of pathologic events associated with acute and chronic graft rejection.

Update on the status of pancreas-kidney transplantation.

Patient and graft survival rates after combined kidney and pancreas transplantation continue to improve. Percutaneous and cystoscopic pancreas biopsies are safe and aid in the diagnosis of acute rejection. Primary enteric drainage of pancreatic exocrine secretions is being re-evaluated to avoid the morbidity associated with bladder drainage. The use of FK506 might reduce the number of acute rejection episodes with no diabetogenic side effects. More studies have been presented which demonstrate that pancreas transplantation might improve diabetic microangiopathy and polyneuropathy and protect the transplanted kidney from diabetic nephropathy.

Cytomegalovirus infection-enhanced chronic kidney allograft rejection is linked with intercellular adhesion molecule-1 expression

In human kidney allografts, association of acute rejection and glomerulopathy with cytomegalovirus (CMV) infection has been demonstrated. To investigate the effect of CMV infection on the development of experimental chronic kidney allograft rejection, heterotopic kidney allografts from DA (Ag-B4, RT1a1) rat donors to WF (Ag-B2, RT1u) rat recipients were used. The animals received cyclosporine A (CsA) 5 mg/kg/day s.c. either for 1 or 12 weeks. Two groups of recipients were infected with 10(5) plaque-forming units of rat CMV (RCMV) and two other groups were left noninfected and used as controls. The grafts were removed 12 weeks after transplantation for histology and immunohistochemistry. RCMV infection significantly enhanced the development of chronic kidney allograft rejection in rats on continuous CsA the intensity of interstitial inflammation (P < 0.025), particularly the degree of pyroninophilic cells in the inflammatory infiltrate (P < 0.025), the glomerular mesangial matrix increase (P < 0.05) and capillary basement membrane thickening (P < 0.01), the extent of endothelial cell swelling (P < 0.025) and intimal proliferation (P < 0.025) in the graft vasculature, and the extent of tubular epithelial atrophy (P < 0.025). Chronic allograft damage index (CADI) was significantly increased to 4.3 +/- 0.8 in RCMV-infected allografts, compared to 0.8 +/- 0.4 in noninfected (P < 0.02). In addition, RCMV infection significantly increased the number of acute rejection episodes (serum creatinine > 200 mumol/liter, P < 0.05) and almost doubled the end-stage serum creatinine. RCMV infection significantly increased ICAM-1 expression on the vascular endothelium (P < 0.05) and tubular epithelial cells (P < 0.01), and was linked with enhanced interstitial, glomerular, and tubular inflammation. In 80% of allografts on continuous CsA, RCMV antigens could be observed in sporadic inflammatory cells one week after infection and in tubular epithelial cells at 12 weeks. In heavily inflamed allografts where the CsA treatment was discontinued at one week, enhancement of RCMV infection on the histological changes attributable to chronic kidney allograft rejection could not be demonstrated. Our results show that during CsA immunosuppression, RCMV infection enhances chronic kidney allograft rejection associated with increased interstitial inflammation as well as vascular endothelial and tubular epithelial ICAM-1 expression.

Development of bronchiolitis obliterans syndrome in recipients of heart-lung transplantation--early risk factors.

Given the internationally recognized definition of bronchiolitis obliterans syndrome (BOS) and longer follow up of heart-lung transplant recipients, it is possible to establish some of the major risk factors for development and progression of BOS. Between April 1984 and 31 December 1993, 157 patients underwent heart-lung transplantation; 126 survived at least six months after operation and so were at risk of developing BOS. The following early risk factors were assessed for development of BOS grade 1 (21-35% decline in FEV1) and progression from grade 1 to grade 2 (36-50% decline in FEV1): age, gender and underlying diagnosis of the recipient, evidence of acute rejection and cytomegalovirus (CMV) infection within 6 months of operation, peak FEV1 achieved, age and gender of the donor, cold ischemic time of the graft, and matching of CMV serological status and HLA antigens of donor and recipient. The number of acute rejection episodes observed remained the single most important determinant of development of BOS grade 1 (relative risk 1.17 (1.06, 1.29), P=0.002) and progression to BOS grade 2 (relative risk 1.58 (1.02, 2.46), P=0.03). No other factors were significantly related to development or progression of BOS, although both evidence of CMV infection and disease and the number of HLA mismatches increased the risk. Bronchiolitis obliterans syndrome is a major problem for medium-to-long-term survivors of cardiothoracic transplantation. Acute rejection early after transplantation is a sensitive prognostic indicator of subsequent functional decline and requires prompt attention.

Delayed hypersensitivity skin tests and subsequent renal transplant outcome.

Some studies in the literature have supported, while others have denied, the relationship between results of delayed hypersensitivity skin tests (DHST), renal allograft and patient survival rates. Several factors contribute to the unreliability of these studies. For example, most of these studies were performed in the precyclosporine era, furthermore, other variables which influence renal allografts and patient survival rates were not controlled in those studies. The purpose of this study was to investigate the relationship between results of DHST performed in the pretransplant period with the subsequent renal transplant outcome in the cyclosporine era. The study included 103 first cadaveric renal transplant recipients. DHST were performed during pretransplant evaluation by intradermal injections of a battery of recall antigens. Based on skin-test results, the patients were assigned to two groups--those with a positive skin test (STP+) and those with a negative (anergic) skin test. These two groups were compared with each other regarding allograft survival, patient survival, and other variables known to influence survival rates. The mean age, sex and racial distribution, degree of HLA matches between recipients and donors, number of acute rejection episodes, and number of patients with acute tubular necrosis were similar between the two groups. Renal allograft survival rates in the anergic group at 6 months, 1 year, 2 years, and 3 years were 97%, 90%, 84%, and 57%, respectively. The survival rate for renal allografts in the STP+ group for the same time points was 90%, 86%, 80%, and 72%, respectively. Patient survival rates for the anergic group at 6 months, 1 year, 2 years, and 3 years were 95%, 94%, 89%, and 85%, respectively, while those for the STP+ group were 98%, 98%, 98%, and 97% respectively. Differences between the STP+ and anergic groups, with regard to patient and allograft survival rates, were not significant. We conclude that DHST is not helpful in predicting outcome of patient or renal allograft survival rates over a 3-year time period.

MEDICATION COMPLIANCE AFTER RENAL TRANSPLANTATION

Noncompliance is known to be an important cause of late graft failure after renal transplantation. We investigated prospectively the degree of compliance with immunosuppressive and antihypertensive drugs during the first year after renal transplantation by monthly pill counts. In addition, we examined whether noncompliance was related to a number of demographic and clinical variables or to the occurrence of rejections. The study population consisted of 127 patients who were involved in a randomized trial comparing cyclosporine monotherapy with azathioprine-prednisone treatment. Average compliance rates approximated 100%, although considerable variability within and between subjects was observed. Using an arbitrary limit to classify patients as compliers or noncompliers, the following frequencies of noncompliance were observed during the study year: cyclosporine, 23%; azathioprine, 13%; prednisone, 23%; atenolol, 36%; and nifedipine, 32%. Average compliance scores for all immunosuppressive drugs were superior to those of antihypertensive medication (P < 0.001). Except for a better compliance for prednisone in men as compared with women, we found no consistent relationship between compliance on the one hand and several demographic variables, graft function, or quality of life on the other hand. Patients who developed one or more acute rejection episodes showed a higher degree of undercompliance, especially for prednisone, than patients without rejections (P < 0.01). Following the occurrence of a rejection episode, compliance scores improved significantly. Keeping in mind the limitations of the pill count method, we conclude that noncompliance with immunosuppressive drugs is not a huge problem during the first year after renal transplantation. However, it is likely that noncompliance contributes to a certain number of acute rejection episodes.

Significance of pericardial effusion after heart transplantation

The aim of this study was to evaluate the clinical significance of pericardial effusion after heart transplantation and to assess its correlation with acute rejection. One hundred fifty transplanted patients were followed up for the first year: serial echocardiographic studies were performed on the same day as were the endomyocardial biopsies; hemodynamic studies and coronary angiographies were performed 1 year after transplant. Ten days after surgery, pericardial effusion was absent in 77 patients, small in 52, moderate in 14, and large in 7, and was significantly related to severe postoperative bleeding (p <0.001). Patients were classified according to the presence and the course of pericardial effusion in group A (absence or disappearance of previous pericardial effusion within 1 month, 107 patients) and in group B (onset, persistence, or increase in pericardial effusion, 43 patients). One hundred nineteen patients experienced ≥1 acute rejection episode. The evolution of pericardial effusion was different (p <0.0001) according to the number of acute rejection episodes and biopsy specimens showing acute rejection, histologic grading and time of the first episode, and histologic grading of the most severe acute rejection episode. Furthermore, there was a significant correlation with the cumulative duration of acute rejection episodes (p <0.005) and the presence of previous cardiac surgical history (p <0.007), but no correlation with cardiac transplant vasculopathy or with a positive weight mismatch. This study suggests that pericardial effusion in transplant recipients is associated with a higher incidence and more severe histologic grading of acute rejection episodes; its presence indicates the need for stricter monitoring of acute rejection.

Racial differences in renal allograft survival: The role of systemic hypertension

The rate of decline in the number of functioning renal allografts beyond the first year after transplantation has changed little in the last 25 years, and during long-term follow-up most allografts are lost due to chronic transplant rejection or patient death. The recipient race correlates with allograft survival, and African American recipients have a lower allograft survival than Caucasians. The goal of the present study was to identify clinical variables present during the first six months after transplantation that predict the loss of renal allografts beyond six months after transplantation, and in particular to determine the role of systemic hypertension on renal allograft survival in black and white recipients. This study includes 547 recipients of first cadaveric renal allografts performed at The Ohio State University. All patients were treated with a uniform immunosuppressive protocol and had a follow-up of at least three years. By multivariate analysis the following variables correlate with poor allograft survival: an elevated serum creatinine concentration measured six months after transplantation (SCr6mo) (P < 0.0001); black race (P < 0.0001); increasing numbers of acute rejection episodes (ATR) (P = 0.002); and young recipients (P = 0.026). Allograft survival is significantly worse in black (mean allograft half-life of 7.7 +/- 1.3 years) than in white recipients (24 +/- 3 years) (P < 0.0001). Black recipients also have a significantly higher six month average mean arterial blood pressure (MAP) (105 +/- 8 mm Hg) than white recipients (102 +/- 7 mm Hg) (P = 0.002). However, the prevalence of hypertension is not significantly different in black (33%) than in white recipients (26%).(ABSTRACT TRUNCATED AT 250 WORDS)