Multiple Rejection Episodes Research Articles

Flow cytometry crossmatching as a predictor of acute rejection in sensitized recipients of cadaveric renal transplants

Flow cytometry crossmatching (FCXM) was developed as a more sensitive assay than the standard complement-dependent cytotoxicity crossmatch (CDCXM) for the detection of anti-donor antibodies, that mediate hyperacute rejection and graft loss in the early post-transplant period in renal transplant recipients. The role of FCXM in predicting long-term clinical outcome in renal allograft recipients is unclear. This study examines the role of FCXM in predicting long-term clinical outcome in highly sensitized recipients of cadaveric renal transplants. All patients (n = 100) with peak panel reactive antibody (PRA) levels > 30%, who received cadaveric renal transplants between 1/1/'90 and 12/31/'95 at our institution, were divided into FCXM + and FCXM - groups. The incidence of acute rejection was determined for each group during the first yr after transplant. Graft survival rates at 1, 2, and 3 yr, and creatinine levels were also compared between groups. FCXM + patients experienced a higher incidence of acute rejection during the first yr after transplant (69 vs. 45%), and a higher percentage of FCXM + patients had more than one episode of acute rejection during the first yr after transplant (34 vs. 8%) when compared to FCXM - patients. There was no statistically significant difference in 1-, 2-, or 3-yr graft survival between FCXM + and FCXM - patients (76 vs. 83, 62 vs. 80, 62 vs. 72%, respectively). These results suggest that sensitized FCXM + cadaveric renal transplant recipients have a higher incidence of acute rejection episodes in the first yr after transplant. Given the association of multiple rejection episodes with poor long-term allograft survival, FCXM may be a useful predictor of long-term clinical outcome in this sub-group of renal transplant recipients.

Rejection with heart failure after pediatric cardiac transplantation

Background. Rejection associated with heart failure or death occurs after pediatric cardiac transplantation but has had limited analysis.Methods. We analyzed the records of 96 consecutive pediatric cardiac transplant recipients who survived to hospital discharge.Results. Eighteen patients (19%) experienced 23 episodes of heart failure or death associated with rejection. Univariate analysis demonstrated black race (p = 0.041), transplantation after 12 months of age (p = 0.032), later time after transplantation (p = 0.037), rejection episode in the first year after transplantation (p = 0.001), and history of two or more rejection episodes (p < 0.001) were significantly associated with rejection seen with heart failure. A multivariate regression analysis identified two or more rejection episodes to be the only independent risk factor for the development of rejection with heart failure (odds ratio 20; 95% confidence limits, 4–104; p < 0.0001).Conclusions. This study identified pediatric heart transplant recipients with a history of previous rejection episodes to be at a higher risk for symptomatic or fatal rejection. Further studies are needed to determine if intensification of maintenance immunosuppression, long-term rejection surveillance, or both in patients with multiple rejection episodes could reduce morbidity and mortality from rejection.

Long-term survival and function of intrahepatic islet allografts in baboons treated with humanized anti-CD154.

Clinical islet cell transplantation has resulted in insulin independence in a limited number of cases. Rejection, recurrence of autoimmunity, and impairment of normal islet function by conventional immunosuppressive drugs, e.g., steroids, tacrolimus, and cyclosporin A, may all contribute to islet allograft loss. Furthermore, intraportal infusion of allogeneic islets results in the activation of intrahepatic macrophages and endothelial cells, followed by production of proinflammatory mediators that can contribute to islet primary nonfunction. We reasoned that the beneficial effects of anti-CD154 treatment on autoimmunity, alloreactivity, and proinflammatory events mediated by macrophages and endothelial cells made it an ideal agent for the prevention of islet allograft failure. In this study, a nonhuman primate model (Papio hamadryas) was used to assess the effect of humanized anti-CD154 (hu5c8) on allogeneic islet engraftment and function. Nonimmunosuppressed and tacrolimus-treated recipients were insulin independent posttransplant, but rejected their islet allografts in 8 days. Engraftment and insulin independence were achieved in seven of seven baboon recipients of anti-CD154 induction therapy administered on days -1, 3, and 10 relative to the islet transplant. Three of three baboons treated with 20 mg/kg anti-CD154 induction therapy experienced delayed rejection episodes, first detected by elevations in postprandial blood glucose levels, on postoperative day (POD) 31 for one and on POD 58 for the other two. Re-treatment with three doses of anti-CD154 resulted in reversal of rejection in all three animals and in a return to normoglycemia and insulin independence in two of three baboons. It was possible to reverse multiple episodes of rejection with this approach. A loss of functional islet mass, as detected by reduced first-phase insulin release in response to intravenous glucose tolerance testing, was observed after each episode of rejection. One of two baboons treated with 10 mg/kg induction therapy became insulin independent post-transplant but rejected the islet graft on POD 10; the other animal experienced a reversible rejection episode on POD 58 and remained insulin independent and normoglycemic until POD 264. Two additional baboon recipients of allogeneic islets and donor bone marrow (infused on PODs 5 and 11) were treated with induction therapy (PODs -1, 3, 10), followed by initiation of monthly maintenance therapy (for a period of 6 months) on POD 28. Rejection-free graft survival and insulin independence was maintained for 114 and 238 days, with preservation of functional islet mass observed in the absence of rejection. Prevention and reversal of rejection, in the absence of the deleterious effects associated with the use of conventional immunosuppressive drugs, make anti-CD154 a unique agent for further study in islet cell transplantation.

FOUR YEAR FOLLOW-UP OF HIGH-DOSE DONOR BONE MARROW INFUSIONS TO ENHANCE ALLOGRAFT SURVIVAL

86 Donor bone marrow cell (DBMC) infusions have been proposed to enhance allograft survival. Aim of this clinical trial was to determine the effect of DBMC infusions on patient and graft survival after liver transplantation (LTX). DBMC (from vertebral bodies) were administered in 257 LTX recipients. In 432 LTX recipients donor vertebral bodies were not available (controls). Up to 1 × 109 DBMC/kg were infused in equal aliquots administered at day 5,11 (2 DBMC delayed; n=185), at day 5,14,21,28,90 (5 DBMC; n=36), or at day 0,11 (2 DBMC; n=36). Four year actuarial patient/graft survival (%) was 84.1/81.2 (2 DBMC delayed), 77.4/72.2 (5 DBMC), 74.8/69.2 (2 DBMC) and 79.0/66.1 (Controls). The 4 year results in controls were similar to the 3 year results reported by UNOS (77.4/66.4). Patient survival was not significantly different in all groups. Graft survival in the 2 DBMC delayed group was higher compared to the controls (p<0.001, Wilcoxon). Acute, biopsy proven, rejection was lower in the 2 DBMC delayed group (35.1%) vs. controls (43.3%; p<0.05). The incidence of multiple (3 or more) rejection episodes was 4.9% in the 2 DBMC delayed group, 11.6% in the control group (p=0.01), and 22.2% in the 5 DBMC group (p=0.001). Chronic rejection was 5.8% in the controls and 4.9% in the 2 DBMC delayed group (NS). Two or more biopsies positive for chronic rejection were observed in 0.5% in the 2 DBMC delayed group vs. 2.8% in the controls (NS). In contrast, a significantly higher incidence of chronic rejection was observed in the 5 DBMC group (27.8%). When the DBMC was infused at day 0,11 (2 DBMC group) the incidence of acute and chronic rejection was 50% and 13.9% respectively (NS vs. controls or 2 DBMC delayed). The incidence of EBV infections was higher in the controls and 2 DBMC group compared to the 2 DBMC delayed group (5.7 and 5.7 vs. 1.7 respectively; p<0.05). However PTLD was observed only in 3 cases (2 in the DBMC and 1 in the control groups, NS). The incidence of other infections (bacterial or viral) was not significantly different between groups. Similarly, no significant difference was observed in the distribution of causes of death or graft failure between groups. The incidence of GVHD was higher in the DBMC groups (3.1%) compared to the controls (0.5%; p=0.005), with the highest incidence observed in the 5 DBMC group (8.3%; p=0.001) compared to the 2 DBMC delayed (2.2%; p=0.05). The results indicate that timing of DBMC infusions can result in significantly different outcomes in LTX survival and can also affect the incidence of acute, chronic rejection as well as GVHD.

Pretransplant Plasmapheresis and Immunoglobulin G in Patients with an Elevated Panel Reactive Antibody.

408 It has been reported that an elevated PRA and a positive donor specific crossmatch is associated with an increased mortality and frequency of rejection. There may be a prolonged waiting time prior to transplantation, in the hopes of obtaining a negative prospective crossmatch. This may result in increased cost of care due to prolonged length of hospital stay and additional laboratory tests. There may be a higher mortality related to this prolonged wait. From July 1994 to June 1998, we transplanted nineteen (47% women) patients (32% on inotropes, 63% on mechanical circulatory assist devices, 95% Status 1, 84% with pulmonary hypertension) with a PRA >10% (15-89%, mean 51.8%). All patients underwent preoperative plasmapheresis (immediately prior to transplant), followed by 20 gm of intravenous Immunoglobin G (IV IgG). Patients were retrospectively crossmatched (68% positive). Post transplant, patients were treated with standard triple therapy (cyclosporine, azathiaprine, steroids) and the usual biopsy and prednisone tapering schedule. Mean length of stay 17.6±22.9 days (versus 17.8±17.5 days in the low PRA group). Seventeen patients are alive. Two died within two weeks of transplant. Of patients who were transplanted over twelve months ago, one-year (11/13) 85%. and two-year survival is (5/7) 71%. Of those, transplanted less then twelve months ago, survival is (6/6) 100%. Conclusions: Despite a positive crossmatch in a group of critically ill heart failure patients, one and two survival is comparable to the national average. Despite multiple episodes of mild cellular rejection, there were infrequent episodes of moderate to severe rejection (11 episodes). In light of these results, consideration of pre transplant plasmapheresis with IV IgG, in patients with an elevated PRA and/or a positive crossmatch, should be given. Long term follow-up to assess development of late rejection and transplant vasculopathy is necessary.

A PROSPECTIVE RANDOMIZED TRIAL OF NEORAL AND CELLCEPT WITH AND WITHOUT OKT3 INDUCTION

7 Does the use of new immunosuppressive medications, particularly mycophenolate mofetil (MMF), abrogate the benefits of induction therapy? We designed a prospective, randomized trial to address this question. Cadaveric (CD) and living donor (LD) renal allograft recipients were randomized to receive either OKT3/MMF/delayed Neoral/prednisone (Ind) or MMF/immediate Neoral/prednisone without OKT3 (no Ind). Patients with delayed graft function or those not surviving three months were excluded. All rejection episodes were identified by biopsy. All patients have been followed a minimum of six months and the preliminary results are outlined below. Table Four patients in the no OKT3 arms developed multiple rejection episodes while there were none in those receiving induction. Three patients had rejection episodes during the initial hospitalization in the no OKT3 groups, none in those receiving antibody therapy. Median time posttransplant to first rejection was 22 days in the no OKT3 groups and 23 days in the OKT3 groups. There was no difference in the incidence of CMV in any of the groups. Although the decreased incidence of rejection was not statistically significant, the clinical benefits of those patients not suffering a rejection episode are notable and has clinical relevance. Hospital costs tended to be higher in the OKT3 groups, although this was not significantly different either. The very low incidence of rejection in the OKT3 group is intriguing. If the difference in rejection frequency holds up over longer follow-up, the benefits from the use of OKT3 along with Neoral and MMF in the early posttransplant period may be validated. Research was funded in part by Ortho Biotech.Table

Cyclosporine microemulsion increases drug exposure and reduces acute rejection without incremental toxicity in de novo renal transplantation

The new oral microemulsion formulation of cyclosporine (Neoral) possesses superior pharmacokinetics to the conventional formulation, Sandimmun (SIM), providing more complete and predictable absorption, and less pharmacokinetic variability. The safety and tolerability of Neoral, together with the incidence of acute rejection episodes and graft survival, were compared to the conventional cyclosporine formulation, SIM, in a prospective, randomized, double-blind multicenter trial. A total of 167 patients who received a first or second cadaveric renal transplant in 21 participating centers in six countries were randomized equally to two treatment groups and followed for three months after transplantation. Outcomes were analyzed across treatment, center and regional groups. In addition, a nested pharmacokinetic study was performed in four of these centers throughout the period of follow-up. No difference was detected between the safety or tolerability of the two formulations. Kidney function and other laboratory parameters remained comparable in Neoral- and SIM-treated patients throughout the study. However, the number of patients experiencing acute rejection was significantly reduced for the Neoral group (44.2% vs. 60.5%; P = 0.044), and significantly fewer patients experienced multiple episodes of rejection (12.8% vs. 22.2%, P = 0.028). The proportion of patients free of rejection at three months was significantly higher in patients treated with Neoral than in those receiving SIM (Kaplan-Meier estimated probability of remaining rejection-free at 3 months = 55% for the Neoral group, compared with 39% for the SIM group, P = 0.046, log rank test). Similar results were obtained when acute rejection, graft loss and death were used as a combined endpoint (Kaplan-Meier estimated probability for Neoral group = 54%, compared with 38% for the SIM group, P = 0.047, log rank test). Comparison of results by center or regional groups did not show any significant treatment interaction. A nested pharmacokinetic evaluation (four centers; 28 subjects) showed that the bioavailability of cyclosporine from Neoral was significantly higher than from SIM at all assessment times. Specifically, at weeks 2, 4 to 6, and 12, dose-normalized AUC was 49%, 63% and 32% higher for Neoral. Dose-normalized peak cyclosporine blood concentrations and AUC stabilized by weeks 4 to 6 in patients receiving Neoral, whereas these values increased slowly in SIM-treated patients without reaching the levels achieved in the Neoral group. These results suggest that the superior pharmacokinetic characteristics of the microemulsion formulation of cyclosporine lead to more efficient immunosuppression during the first critical months after transplantation, without a deleterious impact on clinical safety.

TACROLIMUS THERAPY FOR REFRACTORY ACUTE RENAL ALLOGRAFT REJECTION: DIFFERENTIAL RESPONSES IN AFRICAN-AMERICANS AND CAUCASIANS.

235 Significant differences have been reported between African-Americans (AA) and Caucasians (Cau) under primary tacrolimus (tac) immunosuppression in renal transplant. The effect of race on tacrolimus therapy for refractory acute renal allograft rejection (RARAR) has not been reported. We present a four year experience using tacrolimus therapy for RARAR with a comparison between AA and Cau in our study population. METHODS: RARAR was defined as biopsy-proven acute rejection occurring after a course of OKT3 or polyclonal antilymphocyte antibody therapy. Exclusion criteria consisted only of chronic rejection, defined as baseline serum creatinine (SeCr) > 3.0 mg/dl with biopsy showing chronic rejection. Tac therapy was initiated at 0.3 mg/kg/day with initial target levels of 15-25 ng/ml. Renal allograft biopsies were performed weekly until rejection reversal was documented. Long term target tac serum levels were 5-7 ng/ml. RESULTS: A total of 48 patients have been treated for RARAR since August 1993 including 32 AA, 13 Cau, 2 Hispanics, and 1 Asian. Mean follow-up for AA and Cauc. was 31 +/- 16 and 35 +/- 15 months. Median follow-up for AA and Cau was 30 and 40 months. Mean age of AA and Cauc. was 43 +/- 14 and 36 +/- 18 years. Immunologic risk factors included:TableCaucasians uniformly have done well following tac treatment for refractory rejection with a patient survival of 100% (13/13), a recurrent rejection incidence of only 15% (2/13), and both an overall incidence of graft loss, and incidence of graft loss due to chronic rejection of 8% (1/13). No Cau experienced multiple episodes of recurrent rejection. In contrast, while patient survival in AA was 94% (30/32), recurrent rejection occurred in 44%(14/32). The overall incidence of graft loss was 28% (9/32), and the incidence of graft loss to chronic rejection was 22% (7/32). 13% (4/32) of AA experienced multiple episodes of recurrent rejection and half of these lost their grafts. No episodes of RR in either AA or Cau occurred with a corticosteroid dose less than 0.15 mg/kg/day (prednisone equivalent), or serum tac levels less than 10.0 ng/ml, suggesting that RR did not occur due to inadequate dosing of immunosuppressive drugs. CONCLUSIONS: While the differences between AA and Cau do not reach statistical significance due to the number of patients in the study, the trend both to recurrent acute rejection and chronic rejection in AA is of concern and suggests that this group may not obtain as much benefit from tac therapy for RARAR.

A randomized clinical trial of ursodeoxycholic acid as adjuvant treatment to prevent liver transplant rejection

Acute rejection following orthotopic liver transplantation is a common problem despite current immunosuppressive regimens. Ursodeoxycholic acid (UDCA) has been shown in small, open-labeled studies to prevent rejection episodes, although its effects on complications such as infections, length of hospital stay, and survival have not been evaluated. We conducted a randomized, placebo-controlled, double-blind trial to determine if UDCA (10-15 mg/kg/d) added to a cyclosporine-based immunosuppressive regimen was associated with a decrease in the incidence of at least one episode of acute cellular rejection. Secondary end-points included determining differences in the total number of rejection episodes, the use of muromonab-CD3, the incidence of infections, length of hospital stay, and survival at 90 days and 1 year. Fifty-two patients were randomized, 28 to the treatment group and 24 to the placebo group. During the 3 months of the trial, there was no difference between the placebo and UDCA groups in the number of patients who were rejection-free; however, there were significantly fewer patients in the treatment group who had multiple episodes of acute rejection (0 vs. 6; P = .007). Patients in the treatment group experienced a significantly lower incidence of bacterial infections (4% vs. 29%; P = .02), shorter hospital stay (25 days vs. 34 days; P = .03), and better 90-day survival (100% vs. 83%; P = .04) and 1-year survival (93% vs. 79%). The addition of UDCA to a cyclosporine-based immunosuppressive regimen results in significantly fewer patients experiencing multiple episodes of rejection and improved survival at 90 days and at 1 year. The use of UDCA as adjuvant therapy for patients undergoing liver transplantation who are treated with a cyclosporine-based immunosuppressive regimen should be considered. (Hepatology 1997 Oct;26(4):853-7)

Indirect recognition of donor HLA-DR peptides in organ allograft rejection.

To determine whether indirect allorecognition is involved in heart allograft rejection T cells obtained from peripheral blood and graft biopsy tissues were expanded in the presence of IL-2 and tested in limiting dilution analysis (LDA) for reactivity to synthetic peptides corresponding to the hypervariable regions of the mismatched HLA-DR antigen(s) of the donor. Serial studies of 32 patients showed that T cell reactivity to donor allopeptides was strongly associated with episodes of acute rejection. The frequency of allopeptide reactive T cells was 10-50-fold higher in the graft than in the periphery indicating that T cells activated via the indirect allorecognition pathway participate actively in acute allograft rejection. In recipients carrying a graft differing by two HLA-DR alleles the response appeared to target only one of the mismatched antigens of the donor. Indirect allorecognition was restricted by a single HLA-DR antigen of the host and directed against one immunodominant peptide of donor HLA-DR protein. However, intermolecular spreading was demonstrated in patients with multiple rejection episodes by showing that they develop allopeptide reactivity against the second HLA-DR antigen. These data imply that early treatment to suppress T cell responses through the indirect pathway of allorecognition, such as tolerance induction to the dominant donor determinant, may be required to prevent amplification and perpetuation of the rejection process.

Restricted V beta usage by T cells infiltrating rejecting human lung allografts.

TCR expression was evaluated in lung transplant patients to determine whether T cells infiltrating rejecting lung allografts employed restricted V beta elements. Serial bronchoalveolar lavage (BAL) specimens were obtained from six lung transplant recipients at approximately 3 wk, 6 wk, and 3 mo post-transplant. T cell lines were established by culturing lavage cells with irradiated donor splenocytes in the presence of low dose IL-2 for 3 wk, and TCR V beta usage was determined by quantitative reverse transcriptase-PCR. Patients were grouped into three categories based on TCR V beta profiles and the clinical status of the allograft. 1) In one patient, BAL-derived T cells expressed heterogeneous V beta repertoires at all time points evaluated. This patient did not experience graft rejection during the 16-mo period of observation, though respiratory infections were diagnosed. 2) In three patients, V beta usage by BAL-derived T cells was restricted during allograft rejection episodes, but was heterogeneous in the absence of rejection and during respiratory infections. In one of these patients, similar V beta repertoires were employed by BAL cells during multiple rejection episodes. 3) In two patients, restricted V beta usage by BAL-derived T cells was observed before and during rejection episodes. Collectively, these data illustrate that human lung allograft rejection, but not pulmonary infection, is associated with T cells expressing a limited number of V beta families. Restricted V beta usage by graft-reactive T cells may allow for the selective elimination of these cells using TCR-specific reagents, thereby promoting allograft-specific tolerance.

Cytomegalovirus Keratitis After Penetrating Keratoplasty

We report the development of cytomegalovirus (CMV) keratitis in the penetrating keratoplasty of a 59-year-old human immunodeficiency virus-negative woman after uncomplicated corneal transplantation. Immunosuppression with topical cyclosporine A 2% in corn oil and topical prednisolone acetate 1% suspension was used postoperatively. The 15-month postoperative course was complicated by multiple episodes of endothelial rejection, medically controlled elevated intraocular pressure, polymicrobial bacterial (coagulase-negative staphlococcus and alpha-hemolytic streptococcus) keratitis, and endothelial plaque formation with associated hypopyon and epithelial defect. The graft failed and penetrating keratoplasty was repeated. Cytomegalovirus infection of superficial keratocytes in a region of scarring was identified in histological sections stained with hematoxylin and eosin and confirmed using mouse monoclonal anti-cytomegalovirus antibodies. Excision of the diseased corneal button with no additional treatment appears to have been curative. Low-grade keratitis was the only manifestation of the CMV infection, and it has not recurred 6 months postoperatively.

Frequency of hypoxanthine guanine phosphoribosyltransferase (HPRT-) T cells in the peripheral blood of cardiac transplant recipients. A noninvasive technique for the diagnosis of allograft rejection.

Histological evaluation of serial endomyocardial biopsies performed at fixed time intervals after cardiac transplantation is the universal method used for the detection of cardiac rejection and assessment of the adequacy of antirejection therapy. No noninvasive methodology thus far investigated has achieved a high enough sensitivity and predictive accuracy to be considered as a potential replacement for endomyocardial biopsy in the detection of rejection in adults. The present study exploited the finding that the rate of spontaneous mutation in the hypoxanthine guanine phosphoribosyltransferase (HPRT) gene is higher in proliferating human T cells than in resting cells. Thus, it was reasoned that in the posttransplantation setting, the frequency of HPRT- cells in peripheral blood may provide an indirect measure of alloactivated T lymphocytes. This study consisted of determining the clonal frequency of HPRT- mutant cells (FMC/10(6) peripheral blood mononuclear cells [PBMCs]) within a total of 293 peripheral blood samples representing various numbers of sequential samples from each of 27 transplant recipients. These sequential samples represented time periods when endomyocardial biopsy specimens showed either (1) no evidence of rejection (n = 5 patients), (2) a single initial episode after transplantation of early (< 1 year) or late (> 1 year) rejection (n = 12 patients), or (3) multiple rejection episodes (n = 10 patients). Statistical analyses were used to quantify the time profiles of FMC/10(6) PBMCs in serial samples among transplant recipients and to determine the association of these profiles with both the onset of first rejection episodes and, in appropriate patients, the recurrence of rejection episodes. Data showed that PBMCs from patients with no evidence of rejection uniformly gave low values of < 6 FMC/10(6) cells, a frequency similar to that seen in healthy nontransplanted volunteers. In contrast, 19 of the 22 PBMC samples that were obtained from patients whose corresponding biopsy sample was diagnosed with a histological rejection grade of > or = 3 gave values of > 6 FMC/10(6) cells, 11 of which gave values > 50/10(6) cells (range, 146 to 46,982 FMC/10(6) cells). A significant association between the onset of first rejection and an increased rate of FMC/10(6) values was noted (P = .0001). The ability of a rising trend in FMC/10(6) values to correctly identify the onset of rejection was 81.8% and to correctly identify no rejection, 100%. In addition, a significant association between recurrent rejection episodes and persistence of high FMC/10(6) values in the weeks after treated rejection episodes was noted (P = .0003). The ability of a persistently elevated trend in values of FMC/10(6) cells to correctly identify recurrent rejection was 90% and to correctly identify no rejection, 100%. Increasing frequencies of HPRT- mutant cells in peripheral blood correlated with the onset of first rejection, and persistently elevated HPRT- mutant cells in the weeks after a treated rejection episode correlated with recurrent rejection. This quantitative noninvasive assay may thus serve as a useful adjunct to endomyocardial biopsy for monitoring post-cardiac transplantation patients, and its use as a prospective diagnostic tool merits further study.

Early Rejection of Human Cardiac Allografts Is a Risk Factor for Multiple Rejection Episodes

To determine the risk factors associated with development of acute cardiac allograft rejection during the first 3 months after transplant, data from 1,552 endomyocardial biopsies from 122 cardiac transplant recipients receiving their first graft were analyzed. An association (P&lt; .0001) between the onset of a first rejection episode and the frequency of rejection episodes in the first 90 days was established. Our findings suggest that patients presenting with an early onset of first cardiac allograft rejection episode are at risk for multiple rejection episodes and should therefore be more closely monitored. Int J Surg Pathol 3(I):9-16, 1995

CsA LEVELS IN THE EARLY POSTTRANSPLANT PERIOD—PREDICTIVE OF CHRONIC REJECTION IN LIVER TRANSPLANTATION?

The increasing success of clinical liver transplantation has brought rejection to the forefront as a cause of morbidity and graft loss. The relationship of immunosuppressive drug doses and levels to acute and chronic rejection remains a matter of debate. The effect of blood CsA levels and drug doses on the incidence of acute and chronic rejection and the impact of acute rejection episodes on the occurrence of chronic rejection were studied in 146 grafts in 132 patients. These patients were transplanted in the 4-year period from June 1989 using CsA-based immunosuppression (CsA, azathioprine, prednisolone). Liver grafts in patients maintained on median CsA levels (whole blood, trough level) of >175 μg/L in the first 28 days post-transplant had a significantly lower incidence of chronic rejection (2 out of 49 vs. 22 out of 97; P=0.002). There was no significant difference in incidence of graft loss due to fatal sepsis (6% vs. 5%) or nephrotoxicity between the high and low CsA level groups. The overall graft loss rate was lower in the higher CsA level group (22% vs. 37%). The total doses of the individual drugs did not correlate with the incidence of acute or chronic rejection. Although the occurrence of acute rejection itself did not determine later chronic rejection, late occurrence (P<0.00001) and multiple episodes (two or more; P=0.0002) of acute rejection were significant risk factors for the occurrence of chronic rejection. We conclude that to minimize graft loss to rejection, CsA levels should be maintained at greater than 175 μg/L in the early posttransplant period, and late and recurrent episodes of acute rejection should be prevented.

Severe or multiple rejection episodes are associated with early recurrence of hepatitis C after orthotopic liver transplantation

Recurrent hepatitis C causes significant morbidity after liver transplantation. Because immunosuppression is associated with enhanced viral replication, we postulated that clinical recurrence of the disease may be associated with augmented immunosuppression for rejection. In 96 patients with hepatitis C who received liver transplants, we recorded the interval from transplantation to recurrence, the episodes of steroid-resistant rejection (SRR) requiring OKT3, the number of rejection episodes, and the use of OKT3 induction. Recurrence was diagnosed based on elevated transaminases and characteristic histology. Hepatitis C recurred in 43 of 96 patients. Fifteen of 21 patients (71.4%) who previously had SRR had recurrence, versus 28 of 75 patients (37.3%) who either had no SRR (72 patients) or had it after recurrence was diagnosed (3 patients) ( P <.01). Mean time to recurrence was 127 ± 31 days in the 15 patients who had had SRR versus 246 ± 42 days in the other 28 patients ( P = .02). Recurrence and number of rejection episodes were clearly associated: 6 of 33 patients (18.2%) with no rejection had recurrence ( P < .05), versus 11 of 26 patients (42.3%) with one rejection episode ( P < .05) and 26 of 37 (70.2%) with more than 1 episode ( P < .05). OKT3 induction was used in 15 patients; 9 of 15 patients had recurrence (ns) at 337 ± 95 days. Of 72 patients who initially received triple immunosuppression, 30 patients had recurrence at 186 ± 25 days ( P = .05). Nine patients received primary FK506; 4 had recurrence at 68 ± 14 days. SRR requiring OKT3 is associated with a higher incidence and earlier presentation of recurrent hepatitis C. Multiple rejection episodes are also associated with a higher recurrence rate. Induction immunotherapy, by reducing the rate of early rejection, may delay the clinical recurrence of hepatitis C.

Severe or multiple rejection episodes are associated with early recurrence of hepatitis C after orthotopic liver transplantation

Recurrent hepatitis C causes significant morbidity after liver transplantation. Because immunosuppression is associated with enhanced viral replication, we postulated that clinical recurrence of the disease may be associated with augmented immunosuppression for rejection. In 96 patients with hepatitis C who received liver transplants, we recorded the interval from transplantation to recurrence, the episodes of steroid-resistant rejection (SRR) requiring OKT3, the number of rejection episodes, and the use of OKT3 induction. Recurrence was diagnosed based on elevated transaminases and characteristic histology. Hepatitis C recurred in 43 of 96 patients. Fifteen of 21 patients (71.4%) who previously had SRR had recurrence, versus 28 of 75 patients (37.3%) who either had no SRR (72 patients) or had it after recurrence was diagnosed (3 patients) (P < .01). Mean time to recurrence was 127 +/- 31 days in the 15 patients who had had SRR versus 246 +/- 42 days in the other 28 patients (P = .02). Recurrence and number of rejection episodes were clearly associated: 6 of 33 patients (18.2%) with no rejection had recurrence (P < .05), versus 11 of 26 patients (42.3%) with one rejection episode (P < .05) and 26 of 37 (70.2%) with more than 1 episode (P < .05). OKT3 induction was used in 15 patients; 9 of 15 patients had recurrence (ns) at 337 +/- 95 days. Of 72 patients who initially received triple immunosuppression, 30 patients had recurrence at 186 +/- 25 days (P = .05). Nine patients received primary FK506; 4 had recurrence at 68 +/- 14 days.(ABSTRACT TRUNCATED AT 250 WORDS)

Frequency and significance of conduction defects early after orthotopic heart transplantation

To define the clinical significance of conduction defects after orthotopic heart transplantation sequential electrocardiograms (ECG) of 124 patients were analyzed during their postoperative hospital stay. The first ECG was abnormal in 90 patients (73%), with a predominance of right bundle branch block, and normal in 34 (27%). Sex, age, mean donor ischemic time, duration of aortic cross clamping and use of previous antiarrhythmic therapy were not significantly different in the 2 groups. During hospital follow-up, patients were grouped according to evolution of the initial electrocardiographic abnormalities. In group 1, 25 patients continued to have an initially normal ECG. In groups 2 and 3, 30 and 48 patients, respectively, had evidence of transient and permanent conduction defects. The 21 patients in group 4 showed progressive deterioration of conduction with either a new (9 patients) or worsening preexisting conduction defect (12 patients). The evolution of the initial ECG was strongly dependent on the duration of the donor heart ischemic time and the severity of the in-hospital cardiac rejection. Patients with persistent conduction abnormalities had a statistically longer ischemic time than either patients with normal or transient conduction defects (182 ± 84 vs 144 ± 68 and 130 ± 66 minutes, p = 0.04). Although the overall percentage of patients with histologic evidence of moderate to severe rejection was similar across the groups, 66.6 and 46.1% of patients in groups 3 and 4, respectively, had multiple episodes of rejection compared with 16.6 and 0% in the remaining 2 groups (p = 0.044). The in-hospital mortality was greater in patients with an abnormal ECG than in patients with a transient conduction defect or a normal ECG (21.7 vs 5.4%, p = 0.01).

Severe or multiple rejection episodes increase the incidence of clinically recurrent hepatitis C . The Mount Sinai Medical Center, NY, NY

Severe or multiple rejection episodes increase the incidence of clinically recurrent hepatitis C . The Mount Sinai Medical Center, NY, NY

Subcutaneous Nodule in a Cardiac Transplant

REPORT OF A CASE A 50-year-old black man received an orthotopic cardiac transplant for alcoholic cardiomyopathy. The postoperative course was complicated by multiple episodes of rejection confirmed by cardiac biopsy and treated with immunosuppressive agents including OKT3, azathioprine, prednisone, and cyclosporine. Infectious complications included gastric toxoplasmosis, cytomegalovirus colitis, septicemia, and a toe abscess without osteomyelitis. The patient had a Hickman central venous catheter. Five months postoperatively, the patient remained hospitalized; at that time, an asymptomatic nodule in the midanterior thigh was noted. Physical examination revealed a subcutaneous nodule on the right thigh with a superficial component measuring 0.75 cm and an easily palpable deeper component measuring 2.0 cm ( Figure 1 ). The nodule was deep brown, soft, and fixed to the subcutaneous tissue. There were no pustules. There was no increased warmth or tenderness in the region of the nodule, and the patient was afebrile. Chest roentgenogram was without significant