Severe Rejection Episodes Research Articles

Heart transplants--assessment of dental procedures.

The object of this study was to evaluate the effects of dental foci on survival rates and rejection episodes in heart transplant recipients. Therefore, in a retrospective longitudinal study we studied 74 heart transplant recipients at the Department of Maxillofacial Surgery and Department of Thoracic and Cardiovascular Surgery, University of Münster. Study patients were divided into groups: those in which dental foci had been verified (n = 31) and those without dental foci (n = 43). Statistical analysis was performed using the chi-square test, Kaplan-Meier life table analysis, and the log-rank test. Before heart transplantation, patients were screened clinically and radiographically to determine the extent of dental foci. Postoperatively, patients were evaluated dentally and medically to identify the impact of dental foci on the incidence of systemic and oral infections, frequency and severity of rejection episodes, mortality, and complications arising during dental treatment. By comparing the mortality, infection and rejection rates in the various groups no statistically significant differences (P > 0.05) were found between patients. Despite immunosuppression, extended inflammatory processes such as abscess formation or viral stomatitis were not found in the oral cavity. We therefore suggest that patients suffering from the symptoms of severe heart failure need not be subjected to rigorous preoperative dental treatment.

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.

GLUCOSE INTOLERANCE AS REFLECTED BY HEMOGLOBIN A1C IS SIGNIFICANTLY ASSOCIATED WITH A HIGH INCIDENCE OF TRANSPLANT CORONARY ARTERY DISEASE

994 Previous studies have shown that the factors associated with a higher incidence of developing transplant coronary artery disease (TxCAD) include glucose intolerance, hyperlipidemia, increased body weight, frequency and severity of rejection episodes and donor-age. Purpose: To determine the significance of each factor, including the severity of glucose intolerance as reflected by plasma hemoglobin A1c concentration (HbA1c), and its effect on the incidence of TxCAD. Methods: At 4 years post-Tx, plasma HbA1c (normal: 3.5-6.2%) was measured in 151 consecutive patients (88 male, 63 female, age; 16-68 years) undergoing routine annual coronary angiography. Total cholesterol level [TC] was also measured. By reviewing charts, donor-age, increase in body weight [ΔBW], and history of rejection [Rejection] were obtained. TxCAD was defined angiographically as stenosis in any vessel > 30%. History of cellular rejection was calculated by adding the score of each episode (ISHLT grading: 0=0, 1A=1, 1B=1.5, 2=2, 3A=3, 3B=3.5, 4=4). Patients with any history of humoral rejection were excluded. All variables above were subjected to multiple logistic regression analysis. Effect of accumulated amount of Cyclosporine, FK506 and Prednisone on HbA1c (total mg/BW) were analyzed by multiple liner regression. Results:Table 1 summarizes the result of regression analysis after placing all the variables together in a single model. HbA1c was found to be statistically associated with a high incidence of TxCAD. HbA1c was compared between patients with TxCAD and without TxCAD using ANOVA (Table 2). The drugs stated above had no significant effect on HbA1c.Table 1Table 2Conclusions: This retrospective analysis indicates that glucose intolerance as reflected by HbA1c is significantly associated with a high incidence of TxCAD. HbA1c is not related to the accumulated amount of immunosuppressants.

Cyclosporine plasma unbound fraction in heart and lung transplantation recipients.

To investigate the variability in the unbound fraction (fu) of cyclosporine in recipients of heart, heart-lung, and lung transplantation, cyclosporine fu was determined ex vivo in plasma by equilibrium dialysis. In a retrospective study, 260 samples of plasma (one to seven per patient) were obtained from 89 heart (86%), lung (9%), and heart-lung (5%) transplant patients. The unbound fraction (x100) of cyclosporine ranged from 0.52% to 3.94%, with an overall mean of 1.53%+/-0.375% (SD). The mean percentage unbound for individual patients ranged from 0.71% to 1.98%, giving a 2.8-fold interpatient variation. In heart transplant recipients (66 patients), the values of fu were significantly lower (p < 0.01) during more severe rejection episodes, which required antirejection treatment (endomycardial biopsy result of grade 3a and higher) than in the absence of rejection (grade 0) or during grade la rejections. The value of fu did not vary with organ transplanted (p = 0.35) or etiology of organ failure (p = 0.32). Cyclosporine fu was negatively correlated with the age of the patient (r = -0.18, p < 0.05). Correlations were not observed between fu and blood biochemical and cytologic indices. However, fu was significantly lower (p < 0.01) in hypercholesterolemic transplant recipients (1.37+/-0.52%) than in normocholesterolemic patients (1.60+/-0.63%). Administration of simvastatin resulted in a significant increase in the mean fu from 1.40+/-0.09%) to 1.82+/-0.13% (paired t test, n = 13; p < 0.01). In patients who received ketoconazole, fu was not different from controls. These findings suggest that the level of cyclosporine fu may be an important determinant of immunosuppressive activity of cyclosporine. Moreover, the variation in fu could be strongly related to the concentration of serum lipoproteins; interpretation of the results of cyclosporine monitoring thus requires consideration of the lipidemic status of the patient.

Mycophenolate Mofetil Improves Long Term Graft Survival Following Renal Transplantation in Patients Experiencing Delayed Graft Function

217 Delayed graft function (DGF) has been demonstrated to have a significant deleterious impact on long term graft survival. In fact, several studies have indicated it is second only to acute rejection in this regard. Additional investigations have suggested an immunologic basis for this decreased survival. Also, the coexistence of DGF and acute rejection has portended extremely poor graft survival. Three large prospective, randomized, double blind, controlled trials demonstrated a significant reduction in the frequency and severity of rejection episodes in renal transplant recipients treated with mycophenolate mofetil (MMF), (CellCept®, Hoffman- LaRoche), compared to those receiving azathioprine (AZA) or placebo (all in combination with cyclosporine and corticosteroids). The current study was undertaken to investigate any potential benefit of MMF in the setting of DGF, defined as the need for dialysis in the first week post-transplant. The incidence of DGF in each of the studies (∼10-30%) was too low to allow statistical conclusions within each study. As two of the studies (USA and Tri-Continental) had similar maintenance immunosuppressive protocols, a pooled risk factor analysis of graft and patient survival from these two studies was performed. DGF occurred in 48 of 326 patients in the combined AZA group and 67 of 336 and 65 of 330 patients in the MMF 2gm/day and MMF 3gm/day groups respectively. Regardless of treatment, DGF was a significant risk factor for both patient (p=0.0011) and graft (p=0.0001) survival. In patients experiencing DGF, graft survival was significantly improved in the MMF 2gm/day group vs. the AZA group (p=0.0370): incidence of graft loss or patient death at 3 years was 44% in the AZA group, 24% in the MMF 2gm/day group and 35% in the MMF 3gm/day group. Most graft losses were due to rejection. Conclusion: Improved graft survival was obtained in MMF treated patients with DGF (especially in the 2gm/day group).

Usefulness of Tacrolimus versus Cyclosporine after pediatric heart transplantation

This study compared the early clinical course of 9 pediatric heart transplantation recipients treated with cyclosporine A-based immunosuppression with 10 similarly aged recipients treated with tacrolimus-based therapy. One-year follow-up after transplantation revealed that tacrolimus-treated children had similar left ventricular function, experienced fewer episodes of severe rejection, were more rapidly weaned from corticosteroids, and had relatively few side effects from immunosuppression compared with cyclosporine A-treated children.

Anti-skeletal muscle glycolipid antibodies in human heart transplantation as predictors of acute rejection: comparison with other risk factors.

In forty-five patients who underwent orthotopic heart transplantation, the titer of anti-human skeletal muscle glycolipid antibodies (AGA) present in the sera at the moment of transplantation was correlated with the number of histologically diagnosed cellular grade 3A and humoral acute rejection episodes during the first 120 days after transplantation. Determination of a cutoff value of 0.800 for the AGA level was determined by a receiver operating characteristic curve. Thirteen of 19 patients (68.4%) with an AGA titer above 0.800 developed 24 severe rejection episodes, and of the 26 patients with an AGA titer below 0.800, only 4 (15.3%) presented 6 severe rejection episodes during that time. This was especially evident for the humoral rejection episodes, which were diagnosed in only 1 of the 26 patients with AGA below 0.800 and in 7 of the 19 with AGA above 0.800. Comparison by univariate analysis of other well-known risk factors for a greater number of rejection episodes during the early posttransplant period with the AGA level at the moment of transplantation revealed that the latter distinguished a greater number of patients at risk than the other factors, such as a female donor, the lymphocyte direct cross-match, or the status of the patients at transplantation; the odds ratios were 6.33 for the AGA level, 3.17 for the direct cross-match, and 2.76 for the status at transplantation. By multiple logistic regression analysis, the only relevant risk factors in our group of patients were the AGA level (P=0.0009) and the status at transplantation (P=0.0285). These results indicate that determination of the AGA level at the moment of transplantation could represent a useful method for distinguishing which patients are at risk for a greater number of rejection episodes during the early posttransplant period, with a greater sensitivity than other risk factors.

Lung transplantation for pulmonary sarcoidosis

Patients with end-stage sarcoidosis have now undergone lung transplantation successfully with good short-term and intermediate-term results. Lung transplantation for sarcoidosis requires several considerations unique to this disease. Selection of pulmonary sarcoidosis patients for transplantation requires that medical therapy has been exhausted. This may involve the use of corticosteriods and alternative medications. Causes of pulmonary dysfunction other than pulmonary sarcoidosis, such as bronchiectasis and myocardial sarcoidosis, must be excluded before candidates are considered for transplantation. The extent and severity of extrapulmonary disease must also be assessed and may preclude lung transplantation. The presence of mycetomas is considered a relative contra-indication by some transplant centres and an absolute contra-indication by others. Relatively few patients with pulmonary sarcoidosis have undergone transplantation and, therefore, there are few data on outcome. Sarcoidosis frequently recurs in the allograft, but rarely causes symptoms or pulmonary dysfunction. More severe acute rejection episodes may occur in sarcoidosis transplant recipients, although at present there is no evidence of an increased risk of obliterative bronchiolitis or increased mortality.

Impact of early cyclosporin average blood concentration on early kidney transplant failure

Abstract This retrospective study served to examine the correlation between the degree of cyclosporin (CyA) exposure, as estimated by a single pharmacokinetic (PK) profile performed at 1 week post-transplant, and the outcome of 290 consecutive renal transplants performed over a 6-year period. For this retrospective analysis patients were stratified into four historical groups based on 12- versus 24-h PK studies and on the use of radioimmunoassay versus fluorescence polarization immunoassay methods for estimates of CyA concentrations. Four PK measures - trough concentration (C0), average concentration values (Cav; i.e., the dosing interval-corrected area under the concentration-time curve), maximum concentration (Cmax), and time to maximum concentration (tmax) - were examined as predictors of patient, graft, and rejection-free survival rates for each of the four groups individually and for all groups combined. Patients with an initial Cav > 550 ng/ml had higher 1-year (88 %) and 6-year (66 %) graft survival rates than patients with Cav < 550 ng/ml, who had 1- and 6-year graft survival rates of 80 % and 59 %, respectively (P = NS). Statistically significant differences were observed in graft survival rates between patients with Cav < 550 versus Cav > 550 ng/ml at 30 (88 % vs 96 %; P < 0.02), 60 (85 % vs 94 %; P < 0.007), 90 (85 % vs 94 %; P < 0.02), and 180 (83 % vs 92 %; P < 0.05) days. Moreover, patients with Cav < 550 ng/ml displayed more severe rejection episodes, as judged by Banff classification, than patients who displayed Cav > 550 ng/ml (grades II and III; 71 % vs 50 %; P = 0.036). In contrast, the C0, Cmax, and tmax values did not correlate with patient, graft, or rejection-free survival rates. The pharmacokinetic parameter of Cav correlated strongly with early graft survival and may, therefore, be a useful predictor of those renal transplant patients who may require more intensive post-transplant monitoring of CyA concentrations by serial PK studies to improve graft survival.

Use of HMG-CoA Reductase Inhibitors after Kidney and Heart Transplantation

Hypercholesterolaemia is common in patients treated with cyclosporin after kidney and heart transplantation; coronary vasculopathy, graft atherosclerosis or cardiovascular complications are the most frequent causes of mortality. Coronary heart disease has been attributed to hypercholesterolaemia and has been identified as a major risk factor of long term graft outcome in patients after kidney transplantation. HMG-CoA reductase inhibitors have been proven to be effective in lowering serum cholesterol concentrations in kidney and heart graft recipients receiving long term cyclosporin immunosuppression, and are therefore the drugs of choice in patients requiring treatment for hypercholesterolaemia after organ transplantation. The hydrophilic HMG-CoA reductase inhibitors, such as pravastatin and fluvastatin, should be distinguished from the lipophilic agents, lovastatin and simvastatin, with regard to toxicity and accumulation. Maximal doses of drugs in the latter group should be avoided, whereas the former have been administered at high dosages over prolonged periods of time without adverse effects. Recent preliminary data indicate that treatment with pravastatin not only decreases serum cholesterol but may have beneficial effects on the incidence, recurrence and severity of rejection episodes after kidney and heart transplantation.

Bile acid-independent bile flow is differently regulated by glucagon and secretin in humans after orthotopic liver transplantation.

The present study characterizes recovery of bile secretion after orthotopic liver transplantation (OLT) in humans with special regard to hormonal regulation of bile acid-independent bile flow by glucagon and secretin. Sixty-seven patients with an uncomplicated postoperative course were studied during the first 3 weeks after OLT to determine normalization of bile flow. A group of 7 and 10 patients, respectively, underwent a biliary stimulation test by either glucagon at days 7, 14, and 21 after OLT or by secretin at days 2, 10, and 21 after OLT. Secretin tests were similarly performed in patients with acute severe rejection during the first 10 days after OLT, while glucagon tests were performed in patients with acute allograft rejection occurring 2 weeks after OLT. Furthermore, hormone effects were studied in nontransplanted patients after cholecystectomy with indwelling biliary T tube. After OLT, bile secretory function recovered and stabilized within 14 days after surgery by reconstitution of both bile acid-dependent and -independent bile flow. Two weeks after OLT, bile secretion was comparable with nontransplanted patients after cholecystectomy. Glucagon and secretin stimulated bile acid-independent bile flow in transplanted and nontransplanted patients significantly, yet secretin choleresis, unlike glucagon choleresis, had already occurred during the first days after OLT and was unaffected by acute allograft rejection. These results allow the speculation that, in humans, glucagon and secretin exert their choleretic activity by different mechanisms and/or at different anatomical sites in the liver. Assuming that secretin acts at the bile duct cells, its secretory capacity was not altered by the transplantation procedure and during moderate or severe rejection episodes, as opposed to glucagon choleresis, which most likely originates in the hepatocytes and requires an entirely reconstituted canalicular transport system after OLT.

Bile acid-independent bile flow is differently regulated by glucagon and secretin in humans after orthotopic liver transplantation.

The present study characterizes recovery of bile secretion after orthotopic liver transplantation (OLT) in humans with special regard to hormonal regulation of bile acid-independent bile flow by glucagon and secretin. Sixty-seven patients with an uncomplicated postoperative course were studied during the first 3 weeks after OLT to determine normalization of bile flow. A group of 7 and 10 patients, respectively, underwent a biliary stimulation test by either glucagon at days 7, 14, and 21 after OLT or by secretin at days 2, 10, and 21 after OLT. Secretin tests were similarly performed in patients with acute severe rejection during the first 10 days after OLT, while glucagon tests were performed in patients with acute allograft rejection occurring 2 weeks after OLT. Furthermore, hormone effects were studied in nontransplanted patients after cholecystectomy with indwelling biliary T tube. After OLT, bile secretory function recovered and stabilized within 14 days after surgery by reconstitution of both bile acid-dependent and -independent bile flow. Two weeks after OLT, bile secretion was comparable with nontransplanted patients after cholecystectomy. Glucagon and secretin stimulated bile acid-independent bile flow in transplanted and nontransplanted patients significantly, yet secretin choleresis, unlike glucagon choleresis, had already occurred during the first days after OLT and was unaffected by acute allograft rejection. These results allow the speculation that, in humans, glucagon and secretin exert their choleretic activity by different mechanisms and/or at different anatomical sites in the liver. Assuming that secretin acts at the bile duct cells, its secretory capacity was not altered by the transplantation procedure and during moderate or severe rejection episodes, as opposed to glucagon choleresis, which most likely originates in the hepatocytes and requires an entirely reconstituted canalicular transport system after OLT. (Hepatology 1997 Nov;26(5):1272-81)

Blood transfusions in liver recipients: a conundrum or a clear benefit in the cyclosporine/tacrolimus era?

Blood transfusions are common in patients with end-stage liver disease (ESLD), and their effects on sensitization, rejection, and liver graft survival are not well known. These effects were examined in 121 recipients of primary liver grafts, surviving > or = 30 days. Ninety-six (79%) patients received transfusions before transplantation. Transfusion recipients had significantly fewer severe or recurrent rejection episodes (18%), compared with patients who did not receive transfusions (42%, P=0.006), if the first transfusion was > or = 90 days before the transplant. Patients with alcoholic ESLD (n=49) had significantly fewer severe rejection episodes when compared with the nonalcoholic (n=72) patients (12% vs. 35%, P=0.004). The transfusion benefit was, however, more apparent and significant in the nonalcoholic (26% vs. 56% in nontransfused, P=0.02) than among the alcoholic recipients (6% vs. 25%, P=0.1). This finding is, most likely, due to a combination of a higher rate of severe rejection and the statistical power of the larger number of recipients in the nonalcoholic group. This finding is further corroborated by a multivariate analysis in which blood transfusions retained their benefit (P<0.05) independent of recipient's age and diagnosis. Graft and patient survival were not significantly different in the transfused versus nontransfused groups. Transfusion recipients had a higher panel antibody (11.4+/-23.4 vs. 2.7+/-8.1, P<0.02) but no increased risk of a positive crossmatch. In liver recipients, blood transfusions diminish the risk of rejection independent of recipient's age and the cause of ESLD.

Microchimerism and rejection in clinical transplantation

Haemopoietic microchimerism has been identified in recipients of solid-organ transplants and is thought by some to be critical for the development and maintenance of immunological tolerance. The aim of this study was to correlate prospectively the persistence of donor cells with clinical outcome in recipients of kidney, kidney and pancreas, and liver transplants. Persistence of donor cells in recipient peripheral blood was assessed at 3 days, and at 1, 3, 6, and 12 months after transplantation by a two-stage nested PCR technique to detect donor MHC HLA DR gene specifically. A pretransplant blood sample was collected from each patient to serve as an individual negative control. Seven liver, six kidney and pancreas, and 17 kidney patients were enrolled. 12 of the 17 kidney patients and all of the kidney and pancreas, and liver recipients were suitable for analysis. Exact matches for donors and recipients at the HLA DR loci (n = 1) or inability to obain primer pair specificity among similar HLA DR types (n = 4), meant that we were unable to analyse five patients. Donor DNA was detected in 20 (80%) of 25, ten (40%) of 25, seven (30%) of 23, five (22%) of 23, and six (32%) of 19 recipients at 3 days, and 1, 3, 6 and 12 months post-transplant, respectively. Within individuals, the detection of donor DNA varied over time; only two patients had detectable donor DNA at all times. Analysis of the whole group of transplant patients showed a similar frequency and severity of rejection episodes in patients with and without microchimerism as defined by detectable donor DR genes. These data suggest that a significant percentage of the recipients had persistent donor class II DNA in the peripheral circulation for at least 1 year after transplantation. We showed that a pretransplant blood sample is critical to avoid a false-positive result, and suggest that detectable chimerism may vary over time in individual patients. Therefore, analysis of microchimerism with a single, post-transplant analysis may not help in making clinical decisions for individual patients.

Determinants of chronic renal allograft rejection in cyclosporine-treated recipients.

We analyzed the development of chronic rejection in 511 kidney-only renal transplants in 507 patients between July 1987 and November 1994. A database was established for recipients > or = 18 years old who received cyclosporine-based immunosuppression and demonstrated graft survival for a minimum of 12 months. The 347 recipients of cadaver transplants (67.9%) and 164 recipients of live donor transplants (32.1%) were followed for 12 to 102 months (mean 51 months). Chronic rejection was diagnosed in 124 transplants (24%), with a mean time to diagnosis of 23+/-18 months (range 3-92). Risk factors were identified in a multivariate analysis using the Cox model. The impact of the timing and severity of rejection episodes was analyzed in a univariate model. The presence of chronic rejection resulted in decreased (P=0.0001) 5-year graft survival for both cadaver graft (83.7% vs. 58.2%) and live donor graft (93.2% vs. 53.1%) recipients. Significant variables for the development of chronic rejection included an acute rejection episode (P=0.0001), a black recipient (P=0.0006), donor age > or = 50 years (P=0.006), and a serum creatinine level >2.0 mg/dl by 6 months after transplantation. Severity of rejection measured by peak serum creatinine or posttreatment return to baseline was not related to chronic rejection. However, acute rejection episodes lasting for more that 5 days (P=0.03) or occurring after 6 months (P=0.001) did influence time to chronic rejection. In addition, mismatching for donor-recipient race was a significant (P=0.008) risk factor for recipients of cadaver grafts. We conclude that acute rejection is the most significant risk factor for chronic rejection, and the long-term fate of grafts may be determined as early as the first 6 months. Racial matching of donor-recipient pairs may be useful to minimize chronic rejection risk. Future advances that diminish the incidence and severity of acute rejection may have the greatest impact on long-term survival.

Noninvasive diagnosis of cardiac allograft rejection in an orthotopic canine model

A decline in the R wave voltage obtained from surface electrocardiograms once correlated with cardiac allograft rejection. With cyclosporine therapy, however, these electrocardiographic findings became inconsistent, occurring only during severe rejection episodes. Despite cyclosporine use, intramyocardial unipolar peak-to-peak amplitudes obtained from plunge electrodes are reported to be highly sensitive and specific for diagnosing rejection. These reports are based on heterotopic grafts, which atrophy over time, making long-term voltage changes during rejection difficult to interpret. The purpose of this study was to use analysis of unipolar peak-to-peak amplitudes as a prospective monitoring tool for diagnosing orthotopic cardiac allograft rejection. Ten adult mongrel dogs underwent orthotopic heart transplantation with the attachment of four intramyocardial leads. The unipolar peak-to-peak amplitudes were measured daily and compared with endomyocardial biopsy results. We found that intramyocardial unipolar peak-to-peak amplitude analysis had a sensitivity and a specificity of 100% for diagnosing rejection. We also found that as the number of myocardial leads increased, the sensitivity of detecting rejection also increased. We conclude that unipolar peak-to-peak amplitude analysis is an accurate noninvasive means for early detection of cardiac allograft rejection in an orthotopic model. Its success should allow less frequent, more selective use of endomyocardial biopsy.

Allograft rejection in pediatric recipients of living related liver transplants

The purpose of this study was to compare the incidence and severity of rejection episodes in a group of children receiving living related orthotopic liver transplants (LRLT) versus children receiving cadaveric liver transplants (CLT). Thirty-eight patients received primary LRLT and 54 patients received CLT during a 3-year period ending June 1993. Baseline immunosuppression consisted of cyclosporin, azathioprine, and corticosteroids. Rejection episodes were confirmed by liver histology and were treated initially with pulse intravenous methylprednisolone, 10 mg/kg/d for 3 days. Steroid-resistant rejection was treated with OKT3 or FK506. The median patient ages were 1.3 years for the CLT and .8 years for the LRLT recipients. Acute cellular rejection developed in 78% of the CLT grafts and 74% of the LRLT grafts (P = ns). However, steroid-resistant rejection was significantly less frequent in the LRLT recipients, 13% versus 43% in the CLT recipients (P < .01). Ductopenic rejection was diagnosed in 20% of CLT and 8% of LRLT grafts (P < .10), and graft loss caused by rejection was 9% in the CLT and 3% in the LRLT group (P = ns). In conclusion, the overall incidence of rejection is the same in LRLT and CLT recipients, but LRLT recipients are less likely than CLT recipients to develop steroid-resistant rejection or ductopenic rejection. (Hepatology 1996 Jan;23(1):40-3)

Antithymocyte globulin and methotrexate therapy of severe or persistent cardiac allograft rejection

The treatment of severe or persistent acute rejection remains difficult despite newer immunosuppressive agents available. To evaluate the effectiveness of rabbit antithymocyte globulin and methotrexate as therapy for severe or persistent acute cardiac allograft rejection, we conducted a retrospective analysis of clinical and laboratory data from 150 consecutive heart transplant recipients between 1983 and 1994. Thirteen episodes of severe or refractory acute rejection were treated with rabbit antithymocyte globulin in 10 patients. Rabbit antithymocyte globulin (125 mg/day for 3 consecutive days) was effective in 90% of patients. Therapy was well tolerated, and contributed to one infectious complication, no malignancy, and long-term survival in 8 of 10 patients. Recurrent rejection developed in 60% of patients. Methotrexate (7.5 to 15 mg/wk for 16 weeks) was administered to 8 patients with persistent rejection documented on three consecutive endomyocardial biopsies. Therapy was effective in 6 of the 8 patients, with one infectious complication and no malignancy on follow-up. White blood cell count decreased significantly during therapy (p = 0.008). Seven of the 8 patients in the methotrexate group are long-term survivors. Rabbit antithymocyte globulin is a valuable alternative in patients with severe or refractory acute rejection. Methotrexate is an important adjunct in patients with persistent rejection unresponsive to conventional immunosuppressive regimens.

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.

Extracorporeal photochemotherapy as adjuvant treatment of heart transplant recipients with recurrent rejection.

Recurrent rejection is an uncommon, severe complication after heart transplantation that is associated with a poor long-term prognosis. Photopheresis (ECP), a new form of extracorporeal photo-chemotherapy used for the treatment of cutaneous T cell lymphoma and several autoimmune diseases, has also been used for prevention and treatment of acute rejection in heart transplant recipients. It seems to induce specific suppression of both cellular and humoral rejection. In this study, we evaluated whether ECP added to standard therapies allowed better control of rejection and reduction of conventional immunosuppressive drugs in patients with repeated rejection episodes. Eight heart transplant recipients (6 men and 2 women, mean age 48 yr), with recurrent rejection were treated with ECP for 6 months. Endomyocardial biopsies (EMB) were performed monthly. As a result of treatment, 7 patients on ECP experienced a reduction of the number and severity of rejection episodes. The fraction of EMB negative for rejection increased from 13 to 41%, whereas the fraction of specimens with multifocal and/or diffuse moderate lymphocytes infiltration (grades 3A and 3B) decreased from 41 to 21%. ECP allowed reductions of daily immunosuppressive therapy: prednisone by 44% (16.9 vs. 9.4 mg), cyclosporine by 21% (366 vs. 291 mg), and azathioprine by 29% (137 vs. 97 mg). No major side effects were observed. We conclude that, although the number of patients is small, the use of ECP was safe and associated with improved control of recurrent rejection. This allowed tapering of immunosuppressive drugs, which was particularly useful in two patients with insulin-dependent diabetes and one with sternal wound osteomyelitis.