Immunologic monitoring in lung allograft recipients

To identify patients with increased risk of chronic lung allograft rejection, we assessed the utility of an in vitro biopsy-derived lymphocyte growth assay and serum anti-HLA antibody screening as a complement to currently available methods of monitoring lung allograft recipients. Lymphocyte growth assay was performed on bronchoscopic fragments of tissue cultured in medium with rIL-2. Seventy-nine biopsies from 31 lung transplant recipients were tested by lymphocyte growth assay, and results were correlated with histopathology findings. Positive lymphocyte growth was found in 12/26 (46%) episodes of acute rejection, 5/44 biopsies without rejection (11%), and 0/9 episodes of bronchitis. Positive lymphocyte growth was seen in 7/16 (44%) grade A1 rejections and in 5/10 (50%) grade A2 rejections, as opposed to only 5/44 (11%) grade A0 (no rejection) biopsies (P < 0.01 for both A1 and A2 with respect to A0). Actuarial probability of remaining free from obliterative bronchiolitis (OB)* tended to be higher in patients who did not exhibit lymphocyte growth in biopsies. Sequential samples of sera obtained at the time of the biopsy were screened for lymphocytotoxic anti-HLA antibodies. Twenty-two of 44 recipients (50%) developed anti-HLA antibodies during the first postoperative year, exhibiting greater than 10% reactivity to an HLA reference panel of lymphocytes in four or more consecutive serum samples. Actuarial survival of lung allograft recipients with anti-HLA antibodies (n = 22) was lower than in those without anti-HLA antibodies (n = 22; P = 0.03). Of the 22 antibody producers, 7/12 died as a consequence of OB. Of the 22 non-antibody-producers, 1/2 deaths occurred as a consequence of OB. Anti-HLA antibodies were present in 9/11 instances of OB (82% sensitivity) and in 13/33 patients without OB (61% specificity; P = 0.03). These data indicate that lung transplant recipients with positive lymphocyte growth and anti-HLA antibodies are at an increased risk of chronic allograft rejection.     

Late acute rejection and subclinical noncompliance with cyclosporine therapy in heart transplant recipients

BACKGROUND: Although noncompliance with immunosuppressive medication is recognized as a critical behavioral risk factor for late acute rejection episodes and graft loss after transplantation, little is known about the degree of subclinical cyclosporine noncompliance, its associated risk for acute late rejection episodes (>1 year after transplantation), and its determinants in heart transplant recipients. METHODS: The convenience sample of this longitudinal study included 101 European heart transplant recipients (87 men and 14 women), with a median age of 56 (Q1 = 50, Q3 = 61) and a median posttransplantation status of 3 (range 1 to 6) years. Subclinical cyclosporine noncompliance was measured during a 3-month period with electronic event monitoring. Selected sociodemographic, behavioral, cognitive, emotional, health, and treatment-related determinants of medication noncompliance were measured by using instruments with established psychometric properties or by patient interviews. With the use of iterative partitioning methods of cluster analysis, including nonstandardized electronic event monitoring compliance parameters, patients were categorized by degree of subclinical cyclosporine noncompliance into a 3-cluster solution. RESULTS: Overall compliance was high, with a median medication taking compliance of 99.4%. The 3 derived clusters, that is, excellent compliers (84%), minor subclinical noncompliers (7%), and moderate subclinical noncompliers (9%), differed significantly by degree of subclinical noncompliance (p < .0001) and showed a 1.19%, 14.28%, and 22.22% incidence of late acute rejections (p = .01), respectively. The 3 groups also differed in terms of former medication noncompliance (p = .02), appointment noncompliance (p = .03), and perceived self-efficacy with medication taking (p = .04). CONCLUSIONS: Although in absolute numbers cyclosporine compliance in this sample was high, minor deviations from dosing schedule were associated with an increased risk for acute late rejection episodes. This suggests a pivotal role of patient compliance in successful long-term outcome after transplantation.     

Beneficial effects of treatment of early subclinical rejection: a randomized study

The prevalence of subclinical rejection, by the Banff criteria, is approximately 30% in the first 3 mo in renal transplant recipients. A randomized study was performed to determine whether the treatment of subclinical rejection with corticosteroids was associated with improved outcomes in these patients. Seventy-two patients, stratified by donor source, were randomized to biopsies at 1, 2, 3, 6, and 12 mo (Biopsy group), or to 6- and 12-mo biopsies only (Control group). Patients were analyzed by "intent to treat" and were followed for a minimum of 2 yr. Patients in the Biopsy arm of the study had a significant decrease in early (months 2 and 3) and late (months 7 to 12) acute rejection episodes, a reduced chronic tubulointerstitial score at 6 mo, and a lower serum creatinine at 24 mo than did patients in the Control arm. There was a trend toward an increase in infectious morbidity, but no increase in mortality, in the patients randomized to the Biopsy group. The results of this study suggest that early protocol biopsies and the treatment of subclinical rejection with corticosteroids may lead to better histologic and functional outcomes in renal transplant recipients.     

Automated information system for controlling the sociopsychological adaptation of junior grade schoolchildren during learning activities

Acute graft rejection and delayed function are considered to be the major risk factors of short-term as well as long-term graft survival. We studied the impact of these factors on graft outcome among 109 renal transplant recipients. All recipients were treated with triple drug protocol. The recipients were divided into two groups: I group included 57 patients with delayed graft function (DGF), II group included 52 patients with immediate graft function (IGF). We studied graft survival, incidence of acute rejection, serum creatinine levels and the cause of graft loss for patients in both groups. Acute rejection episodes occurred in 49% of patients from DGF group and 45% of patients from IGF group. Graft survival in IGF group was better than in DGF group. Actuarial graft survival at 1, 2, 3 and 4 years in examined groups was 84%, 82%, 72%, 65% vs. 92%, 86%, 84%, 84%, respectively. One-year graft survival in patients with acute rejection from DGF group and IGF group was significantly lower than in patients who remained rejection free (69%, 74% vs. 94%, 96%). We concluded that delayed graft function decreases long-term graft survival, while immediate graft function has an excellent impact on graft outcome. Acute graft rejection is the strongest risk factor of graft loss.     

Steroid withdrawal from long-term immunosuppression in liver allograft recipients

Corticosteroids were withdrawn from the immunosuppressive regimen of 168/197 (85%) of liver transplant patients who survived for more than three months. In 14, steroids were restarted for reasons other than rejection. The remaining 154 patients were evaluated for the occurrence of rejection and graft loss. Risk factors for the development of rejection after steroid withdrawal were assessed. There were 13 episodes of rejection in 12 (7.8%) grafts; 7 (4.5%) experienced acute cellular rejection, and 6 (3.9%) developed chronic ductopenic rejection. All cases of acute rejection resolved with high-dose steroids. Graft and patient loss due to chronic rejection was 3 (1.9%) and 2 (1.3%), respectively. Chronic rejection resolved in 1 patient, 1 was successfully retransplanted, and in the other 2 the principal cause of death was recurrent tumor. None of the risk factors examined (primary indication for transplant, severity of previous acute rejection, use of OKT3, retransplantation, ABO blood group donor/recipient match, CMV infection, and CsA mono versus CsA and AZA double therapy) were associated with the development of chronic rejection poststeroid withdrawal. The prevalence of side effects, after steroid withdrawal, was low; 66% of patients never required antihypertensive medication; 14% experienced a significant septic episode, and only 4 died with sepsis as the major factor. There were no fungal sepsis and no new cases of diabetes. Withdrawal of corticosteroids after 3 months can be successfully achieved in the majority of liver allograft recipients and is associated with a low rate of rejection, graft loss, and complications attributable to immunosuppressive medication.     

The dipsogen angiotensin II does not stimulate ethanol intake in mice

The Banff classification of acute rejection is based on histologic grades and scores for borderline changes, glomerular, vascular, interstitial and tubular lesions. We reviewed 56 episodes of acute rejection occurring in 44 kidney allograft recipients (30 cadaveric and 14 living donor transplants), comparing Banff classification to degree of reversibility of rejection. Rejection reversal was defined as complete if serum creatinine returned < or = 25% of baseline, partial if creatinine was > 25% to < 75% of baseline, and irreversible if creatinine was > or = 75% of baseline or graft loss occurred. Eight biopsies were classified as borderline (SUM score 1.6 +/- 0.5), 14 grade I (SUM score 3.3 +/- 0.4), 19 grade II (SUM score 4.2 +/- 0.3), and 15 grade III (SUM score 8.5 +/- 0.4). SUM distinguished borderline and grade III rejections, but not grades I and II. Clinically, grade and SUM score correlated with rejection reversal. Complete reversal of rejection occurred in 93% of patients with grade I rejection, while 47% of patients with grade III had irreversible rejection. The mean SUM for complete reversal was 3.9 +/- 0.34 and was different from SUM of partial (6.0 +/- 0.86) and irreversible (8.5 +/- 0.93), P < 0.006. Meanwhile, vascular scores were similar for rejections with complete (0.9 +/- 0.2) or partial (1.0 +/- 0.4) reversal, but significantly higher in those with irreversible rejection (3.0 +/- 0.4, P < 0.000). Likewise, mean scores for tubulitis and interstitial inflammation were significantly higher for irreversible rejection. Resolution of rejection by steroids was correlated to low vascular score (steroid sensitive 0.65 +/- 0.25 vs. steroid resistant 1.42 +/- 0.18, P < 0.01), and low SUM score (steroid sensitive 3.7 +/- 0.5 vs. steroid resistant 5.22 +/- 0.43, P < 0.04). Neither scores for tubulitis nor interstitial cellular inflammation were predictive of steroid sensitivity. These data demonstrate that Banff scoring has clinical relevance in predicting rejection reversal and has implications to first-line therapy of rejection episodes.     

Analysis of time-dependent risks for infection, rejection, and death after pulmonary transplantation

Infection and rejection remain the greatest threats to the survival of pulmonary allograft recipients. Furthermore, a relationship may exist between these events, because the occurrence of one may predispose to the other. By using multivariate analysis for repeated events, we analyzed the risk factors for bacterial, fungal, and viral infection, grade II or greater acute rejection, and death among 239 lung transplant recipients who received 250 allografts between January 1988 and September 1993. A total of 90 deaths, 491 episodes of acute rejection, and 542 infectious episodes occurred during a follow-up of 6 to 71 months. The hazard or risk patterns of death, infection, and rejection each followed an extremely high risk during the first 100 days after transplantation, a second modest risk period at 800 to 1200 days, and a lower constant risk. Infection and graft failure manifested by diffuse alveolar damage were the major causes of early death (< 100 days), whereas infection and chronic rejection were primary causes of later death after pulmonary transplantation. By multivariate analysis, cytomegalovirus mismatching risk for primary infection was the most significant risk factor for death, rejection, and infection. Absence of cytomegalovirus prophylaxis was also a risk factor for early and late death and late infection. Survival of recipients who received cytomegalovirus prophylaxis was significantly improved. Immunosuppression based on cyclosporine versus FK 506 was a risk factor for late death and late infection. Graft failure manifested by diffuse alveolar damage/adult respiratory distress syndrome was a significant risk for death late after transplantation. These data suggest the following: (1) The hazard for death, infection, and rejection after pulmonary transplantation appears biphasic; (2) lower survival is associated with ischemia-reperfusion lung injury represented by diffuse alveolar damage/adult respiratory distress syndrome; (3) cytomegalovirus mismatch, absence of cytomegalovirus prophylaxis, and development of cytomegalovirus disease are significant threats for death, rejection, and infection after pulmonary transplantation; (4) prevention of cytomegalovirus disease should improve survival by decreasing the prevalence of infection and rejection.     

Prospective study of the value of transbronchial lung biopsy after lung transplantation

Transbronchial lung biopsy (TBB) has become the gold standard for the diagnosis of acute rejection and cytomegalovirus (CMV) pneumonia in lung transplant recipients. The aim of this study was to assess the value of regular surveillance TBB in stable asymptomatic patients and to establish the role of TBB as a follow-up procedure 1 month after a previous pathological biopsy result. We prospectively evaluated 76 TBBs performed in 17 lung transplant recipients. A definite pathological results was found in 14 of 15 TBBs performed for clinical indications: CMV pneumonia (5), acute rejection grade > or = A2 according to the criteria of the International Society for Heart and Lung Transplantation (ISHLT) (4), bronchiolitis obliterans (3), and desquamative interstitial pneumonitis (2). Fifteen of 45 surveillance TBBs performed in asymptomatic patients revealed significant abnormalities. Ten episodes of acute rejection ISHLT grade > or = A2 and three episodes of CMV pneumonia detected by TBB had direct therapeutic consequences. Nine of 16 follow-up TBBs performed 1 month after a pathological biopsy result again showed relevant pathological findings. With the exception of one severe haemorrhage, no life-threatening complications occurred. Our results suggest that transbronchial lung biopsies performed on a regular basis after lung transplantation are important for the detection of asymptomatic and/or persistent acute rejection or injection. In the long-term, this strategy might be the most effective tool in reducing the incidence of bronchiolitis obliterans, which is still the main obstacle for further improvement of long-term survival after lung transplantation.     

Mycophenolate mofetil decreases rejection in simultaneous pancreas-kidney transplantation when combined with tacrolimus or cyclosporine

BACKGROUND: Historically, the acute rejection rates in simultaneous pancreas-kidney (SPK) recipients have been extremely high (50-80%), with many second and third rejection episodes despite the use of quadruple immunosuppression (antibody induction and cyclosporine [CsA]-azathioprine [AZA]-based maintenance immunosuppression). Although this acute rejection has rarely led to graft loss, it has been a great cause of morbidity and of significantly increased cost. In an attempt to decrease the acute rejection rate and related morbidity in SPK transplant recipients, we compared two "state-of-the-art" immunosuppression regimens in a prospective, randomized, single-center study. METHODS: Patients who received SPK transplants were randomized to receive either tacrolimus (TAC) and mycophenolate mofetil (MMF, n=18) or CsA (Neoral formulation) and MMF (n=18). All patients received OKT3 induction and prednisone, which was tapered to 5 mg/day by 6 months after transplantation. All rejection episodes were biopsy proven. In addition, metabolic control (HgbA1C, hypertension, serum cholesterol), drug toxicity, and infection also were measured. Data were compared with that of a historical group (n=18) who received conventional CsA (Sandimmune formulation) and AZA-based immunosuppression. RESULTS: The incidence of biopsy-proven acute rejection was 11% in both the TAC-MMF and CsA-MMF groups with only two patients in each group experiencing a rejection episode. This rejection rate was significantly decreased from that of the CsA-AZA historical group (77%, P<0.01). There were no significant differences in infection rates, including cytomegalovirus, or in metabolic control (HgbA1C, hypertension, and cholesterol levels). All patients remained on their initial immunosuppression regimen for the first 3 months after transplantation. Between 3 and 6 months after transplantation, three patients were switched from TAC to CsA for recurrent migraine headaches, posttransplant diabetes, and chronic cytomegalovirus infection. Two patients in the CsA-MMF group died of nonimmunologic causes (aspiration pneumonia and arrhythmia) between 3 and 6 months after transplantation. CONCLUSIONS: The data from this study show that MMF treatment significantly decreases the incidence of biopsy-proven acute rejection in SPK transplant recipients compared with AZA-treated historical controls. In addition, we conclude that TAC and CsA (Neoral), when combined with MMF, yield similar, low acute rejection rates with similar graft function and metabolic control.     

Monocytes-macrophages and cytokines/chemokines in fine-needle aspiration biopsy cultures: enhanced interleukin-1 receptor antagonist synthesis in rejection-free kidney transplant patients

BACKGROUND: Monocytes-macrophages are found within kidney allografts during the first days after surgery, where they perform "housekeeping" tasks, participate in postreperfusion injury, and act as antigen-presenting cells, as well as become involved in the effector phase of acute rejection. They also seem to play a prominent role in chronic rejection. We quantified their presence in fine-needle aspiration biopsies and studied the growth factors that, we hypothesized, would mark the different implications of the presence of monocytes-macrophages. METHODS: Fine-needle aspiration biopsies were obtained from 56 adult renal transplants and analyzed for CD14+ using the alkaline phosphatase-anti-alkaline phosphatase procedure. Thirty-three patients were studied on the production of interleukin (IL)-1 receptor antagonist (IL-1ra), IL-6, IL-8, macrophage colony-stimulating factor, monocyte chemotactic protein 1, and macrophage inflammatory protein 1alpha by aspiration biopsies cultures using enzyme-linked immunosorbent assay techniques. RESULTS: CD14+ cells were present at significantly higher numbers in steroid-resistant acute rejections but also during the first days after surgery, especially if acute tubular necrosis was present. We found a significantly higher production of IL-1ra by rejection-free patients compared with acutely rejecting patients, and this difference was already established on day 7 after surgery (10+/-10.5 days before rejection). CONCLUSIONS: Monocytes-macrophages are present at higher numbers in aspiration biopsies of kidney transplant patients suffering either acute tubular necrosis or steroid-resistant rejections, but they are present during the first days after transplant in stable patients, too. The production of IL-1ra is significantly up-regulated in stable patients, which suggests that monocytes-macrophages may constitute an early key factor in the down-regulation of the anti-allograft immune response.     

Evidence that human cardiac allograft acceptance is associated with a decrease in donor-reactive helper T lymphocytes

We have reported that acute cardiac allograft rejection is associated with increased numbers of donor-reactive helper T lymphocytes (HTL) in the peripheral blood of patients. Further, increased frequencies of circulating donor-reactive HTL may predict allograft rejection episodes diagnosed by endomyocardial biopsy. The present study evaluates the relationship between donor-reactive HTL and allograft "acceptance" in cardiac transplant recipients bearing long-term allografts (> 1 year). Patients were categorized as either long-term acceptors or persistent rejecters based on the number of rejection episodes and the ability to withdraw steroid therapy. Limiting dilution analysis for IL-2-producing HTL was utilized, with cadaver donor splenocytes as a source of donor alloantigens. Donor-reactive HTL frequencies were determined from peripheral blood samples obtained before transplant, and at 1 month and 1 year after transplant. Individuals who accommodated their allografts and were withdrawn from steroid therapy had reduced numbers of donor-reactive HTL at 1 year after transplant as compared with earlier time points. Further, PBMC obtained from these individuals at 1 year after transplant responded weakly to donor alloantigens in a mixed lymphocyte response (MLR). This relationship between donor-reactive HTL and allograft accommodation was exemplified in a cardiac/liver transplant patient who was diagnosed with progressive multifocal leukoencephalopathy and removed from all immunosuppression. No subsequent rejection episodes were diagnosed. Donor-reactive HTL were not detectable and this individual failed to mount an MLR to donor alloantigens. However, a vigorous donor-reactive response was observed when MLR cultures were supplemented with exogenous IL-2. Therefore, nonresponsiveness to the allograft appeared to be due to a deficit in IL-2 production. In contrast, patients who experienced persistent rejection episodes and required continued steroid therapy maintained large numbers of donor-reactive HTL at 1 year after transplant. PBMC from these individuals responded vigorously to donor alloantigens in an MLR. Hence, monitoring donor-reactive HTL may identify individuals who have accommodated their graft and may tolerate a reduction in immunosuppression.     

Validation of an in-office dental unit water monitoring technique

OBJECTIVE: Intestinal transplantation has become an option as a treatment for permanent intestinal failure. Endoscopy is an essential tool in assessing the intestinal allograft after intestinal transplantation. The aim of this study was to analyze our experience using endoscopy in intestinal transplant recipients. METHODS: This was a retrospective review of endoscopic and histological reports in 41 children who received an intestinal transplant between 1990 and 1995 at Children's Hospital of Pittsburgh. RESULTS: A total of 1273 endoscopies was performed of which 760 were ileoscopies via allograft ileostomy, 273 were upper endoscopies, and 240 were colonoscopies. One hundred four rejection episodes were documented histologically in 32 patients, 6 days to >4 yr after transplantation. Most episodes were mild and easily treated with increased immunosuppression; however, severe rejection with mucosal exfoliation was seen in nine patients. Rejection sometimes involved only part of the allograft. Endoscopic appearance alone without biopsies was sensitive enough to diagnose only 63% of the rejection episodes. Epstein-Barr and cytomegalovirus infections occurred in 11 and eight patients, respectively, and involved both native bowel and allograft in some. Complications of endoscopy were few: one perforation, three episodes of bleeding, and three episodes of transient respiratory compromise. CONCLUSIONS: Endoscopy is an essential tool in the postoperative assessment of intestinal transplant recipients. Frequent surveillance ileoscopies with biopsies should be performed after transplantation. If patients clinically deteriorate with fever, diarrhea, bacteremia, or gastrointestinal bleeding and a clear cause is not elucidated by ileoscopy, an upper endoscopy with biopsies is indicated.     

Positive selection driving the evolution of a gene of male reproduction, Acp26Aa, of Drosophila: II. Divergence versus polymorphism

BACKGROUND: Sirolimus, a novel immunosuppressant that inhibits cytokine-driven cell proliferation and maturation, prolongs allograft survival in animal models. After a phase I trial in stable renal transplant recipients documented that cyclosporine and sirolimus have few overlapping toxicities, we conducted an open-label, single-center, phase I/II dose-escalation trial to examine the safety and efficacy of this drug combination. METHODS: Forty mismatched living-donor renal transplant recipients were sequentially assigned to receive escalating initial doses of sirolimus (0.5-7.0 mg/m2/day), in addition to courses of prednisone and a concentration-controlled regimen of cyclosporine. We conducted surveillance for drug-induced side effects among sirolimus-treated patients and compared their incidence of acute rejection episodes as well as mean laboratory values with those of a historical cohort of 65 consecutive, immediately precedent, demographically similar recipients treated with the same concentration-controlled regimen of cyclosporine and tapering doses of prednisone. RESULTS: The addition of sirolimus reduced the overall incidence of acute allograft rejection episodes to 7.5% from 32% in the immediately precedent cyclosporine/prednisone-treated patients. At 18- to 47-month follow-up periods, both treatment groups displayed similar rates of patient and graft survival, as well as morbid complications. Although sirolimus-treated patients displayed comparatively lower platelet and white blood cell counts and higher levels of serum cholesterol and triglycerides, sirolimus did not augment the nephrotoxic or hypertensive proclivities of cyclosporine. The degree of change in the laboratory values was more directly associated with whole blood trough drug concentrations than with doses of sirolimus. CONCLUSIONS: Sirolimus potentiates the immunosuppressive effects of a cyclosporine-based regimen by reducing the rate of acute rejection episodes.     

Donor cardiac troponin T: a marker to predict heart transplant rejection

BACKGROUND: Noninvasive methodologies have shown poor sensitivity in predicting rejection when compared to serial endomyocardial biopsies. We studied the potential role of donor blood troponin T (Tn-T) as a marker for predicting heart transplant rejection. METHODS: Blood cardiac Tn-T was measured from 16 heart donors. Transplant rejection and cardiac function in the recipients were monitored for 1 year. RESULTS: When data were analyzed based on donor blood Tn-T levels, 6 patients who received hearts from donors with low Tn-T (<0.45+/-0.1 ng/mL) showed no rejection, and patients whose hearts came from donors with higher Tn-T (6.01+/-0.81 ng/mL) developed episodes of high-grade rejection (3A) within 38.5+/-2.1 days after transplantation. Eight patients who received hearts from donors with intermediate levels of Tn-T (3.57+/-0.55 ng/mL) showed mild rejection (grade 1). All recipients had qualitatively normal left ventricular systolic function by serial echocardiography. The mean donor ischemic time was 169+/-47 minutes. CONCLUSIONS: The quality of the donor heart is an important prognostic factor in heart transplantation. It may be possible to identify severely damaged donor organs before transplantation and avoid their use or to develop more aggressive strategies for reducing recurrent acute rejection episodes in high-risk patients.     

Cell-mediated cytotoxicity: a predictor of chronic rejection in pediatric HLA haploidentical renal transplants

BACKGROUND: Recipient antidonor cytotoxic T-cell activity has been associated with graft loss and acute rejection in renal allograft recipients. The role of immunologic mechanisms in the development of chronic graft rejection is controversial. We analyzed all living related renal transplants performed at Children's Hospital (Boston, MA) from 1983 to 1995 to assess whether cell-mediated cytotoxicity, determined in vitro and measured before transplantation, was predictive of chronic rejection. METHODS: Eighty-three patients were studied retrospectively. Fifty-seven patients with one haplotype-matched renal transplants from living related donors were studied to determine the association between cell-mediated lympholysis (CML) level, acute rejection, chronic rejection, and graft failure. Acute rejection was defined by the decision to treat. Chronic rejection was defined by histology and/or the absolute serum creatinine value using an increasing serum creatinine level >1.0 mg/dl for children less than 3, a creatinine level >1.5 mg/dl for children between 3 and 10 years of age, and a creatinine level >2.0 mg/dl for children above 10 years of age. Return to dialysis or retransplantation was considered graft failure. RESULTS: Of the 57 haploidentical patients, there were 33 males and 24 females. The mean age at transplant was 11.1 years (SD=6.7). Twelve patients developed chronic rejection, 24 patients developed acute rejection, and 7 patients had graft failure. Pretransplant cytotoxic T lymphocyte activity was associated with chronic rejection (P=0.001) and graft failure (P=0.013) but only marginally with acute rejection (P=0.058). Controlling for age and sex, Cox's proportional hazards model revealed that CML level was predictive of time to chronic rejection (P<0.01) but not acute rejection (P=0.11). It was estimated that every 1-unit increase in CML level raises the monthly risk of chronic rejection by 7%. Ten children received HLA-identical kidneys from their siblings. There were no episodes of chronic rejection after 5 years. Two patients with high CML levels had episodes of acute rejection; both patients responded to treatment. CONCLUSION: Our data demonstrate an association between pretransplant cell-mediated cytotoxicity and the occurrence of chronic rejection in living related one-haploidentical renal transplants in pediatric patients.     

The clinical significance of flow cytometry crossmatching in heart transplantation

BACKGROUND: Flow cytometry crossmatching is more sensitive than cytotoxic methods in identifying preformed antibodies to donor alloantigens. However, the significance of a positive flow crossmatch remains unknown for a recipient of a heart transplant who has a negative anti-human globulin crossmatch. METHODS: Flow crossmatching was performed retrospectively for 92 recipients of a primary cardiac allograft who underwent transplantation with a negative AHG crossmatch. RESULTS: Forty-six patients were flow crossmatch-positive for alloantibody: 20 were positive on both T and B lymphocytes, 12 were positive only on B lymphocytes, and 13 were positive only on T lymphocytes. Eleven had autoantibody invalidating the flow crossmatch with donor cells. Thirty-six patients had negative flow crossmatch. A significantly higher incidence of graft dysfunction with vascular rejection by 6 months was found for patients who had a positive flow crossmatch on B lymphocytes. This group also had an increased incidence of mortality within this same period. Patients who were flow crossmatch-positive on T and B lymphocytes were more likely to experience greater than two episodes of treated cellular rejection within the first 6 months. Flow crossmatch-positive patients stayed longer in the hospital in comparison to the other two groups, although the increases were not statistically significant. There were no differences between groups with regard to time to first rejection, absence of rejection episodes, episodes of decreased cardiac index (<2.3 L/m2), depressed left and right ventricular ejection fraction, or development of transplant atherosclerosis. CONCLUSION: A positive flow crossmatch identified a subset of patients who are predisposed to development of vascular rejection or are more likely to have frequent cellular rejection.     

Histological and clinical outcome after liver transplantation for hepatitis C

Hepatitis frequently recurs after liver transplantation for hepatitis C. However, the histological progression of disease, predictors of recurrence and disease severity, and patient survival remain uncertain. Fifty-five patients with cirrhosis caused by chronic hepatitis C underwent liver transplantation between January 1990 and December 1993. Hepatitis C genotype was determined, and liver biopsies were performed at frequent intervals posttransplantation. The median follow-up time was 40.4 months. The cumulative rate of survival was no different in liver transplant recipients for hepatitis C than in liver transplant recipients for other chronic liver diseases (P = .62). Histological recurrent hepatitis C developed in 33 of 50 patients assessable for disease recurrence; the median recurrence-free survival time was 13.4 months. Histological activity and stage were mild in most cases. Only 2 patients developed cirrhosis, and no patient required a second transplantation for recurrent disease. Patients with acute cellular rejection had a shorter recurrence-free survival (P = .0141). In patients with recurrent hepatitis, rejection also was correlated with increased histological grade 2 years after transplantation (P = .0061). Recurrence-free survival was decreased in patients infected with genotype 1 (1a and 1b combined) compared with genotypes 2 and 3 combined (P = .02), whereas there was no difference between genotypes 1a and 1b (P > .80). Only patients infected with genotype 1a or 1b developed bridging fibrosis or cirrhosis. In addition, patients who had an early recurrence had a greater risk of progressing to bridging fibrosis or cirrhosis (hazard ratio, 5.1; P = .0473). In our experience, recurrent hepatitiS C after liver transplantation in most cases is mild and survival is unaffected. Both acute cellular rejection and infection with genotype 1 are independent risk factors for reduced recurrence-free survival, and early recurrence is associated with a higher risk of disease progression.     

A study comparing mycophenolate mofetil to azathioprine in simultaneous pancreas-kidney transplantation

BACKGROUND: Mycophenolate mofetil (MMF; Cell-Cept) is a potent and selective inhibitor of B and T lymphocyte proliferation that has proven effective in reducing the incidence of acute rejection in cadaveric kidney transplant recipients in several randomized, blinded clinical studies. Because the frequency and characteristics of rejection episodes may be different and more severe after combined pancreas-kidney transplantation, we hypothesized that MMF would have a significant impact on pancreas-kidney rejection and graft outcome. Therefore, we compared the efficacy of MMF versus azathioprine (AZA) in cyclosporine-treated simultaneous pancreas-kidney transplantations. METHODS: A retrospective comparison of 358 consecutive primary SPK transplantations performed from 1990 to 1997 was conducted. Patients received either MMF (n=109, 3 g/day) or AZA (n=249, 2 mg/kg q.d.) in combination with cyclosporine-based immunosuppression. All patients received a quadruple-drug sequential induction protocol with either OKT3 or Atgam. Several outcome parameters, including patient and graft survival rates and frequency of rejection, were analyzed. RESULTS: MMF-treated patients demonstrated a markedly reduced rate of biopsy-proven kidney rejection (31 vs. 75% AZA, P=0.0001), clinically significant pancreas rejection (7 vs. 24% AZA; P=0.003), and steroid-refractory rejection (15 vs. 52% AZA; P=0.01). As a result, kidney and pancreas allograft survival was significantly better in MMF patients compared with AZA patients (2-year survival rates: kidney, 95 vs. 86%; and pancreas, 95 vs. 83%). Although surgical infections after transplantation were more frequent in MMF patients, MMF patients were more likely to have undergone enteric drainage. Importantly, we did not observe an increased incidence of any of the bacterial, fungal, or viral infections that typically plague immunosuppressed transplant recipients. CONCLUSIONS: This retrospective study demonstrates that MMF is a highly effective immunosuppressant in SPK transplantation. It is not associated with an increased risk of opportunistic infections when a balanced immunosuppressive management approach is used. MMF strikingly reduces the frequency of acute cellular and steroid-resistant rejection. As a result of this combined experience, it is not unexpected then that we observe significantly improved graft survival rates in MMF-treated SPK patients compared with patients receiving a more traditional immunosuppressive regimen.     

Transcriptional regulation of aquaporin-2 water channel gene by cAMP

In patients awaiting heart transplantation, end-stage disease of a second organ may occasionally require consideration of simultaneous multiorgan transplantation. Outcome statistics in multiorgan transplant recipients are needed to define optimal utilization of scarce donor resources. Incidence of cardiac allograft rejection, actuarial recipient survival, and cardiac allograft rejection-free survival were evaluated in 82 recipients of 84 simultaneous heart and kidney transplants. Twenty-three of the 82 dual-organ recipients have died with 1, 6, 12, and 24-month actuarial survival rates of 92%, 79%, 76%, and 67%, respectively. The actuarial survival rates in the heart-kidney recipients were similar to those observed in 14,340 isolated heart recipients (United Network for Organ Sharing Scientific Registry) during the same period (92%, 86%, 83%, and 79%, respectively; P=0.20). Clinical data on all episodes of treated rejection in either organ and on immunosuppressive regimens were available on 56 patients; 48% of these patients have had no rejection in either organ, 27% experienced heart rejection alone, 14% experienced kidney rejection alone, and 11% had both heart and kidney allograft rejection. Heart allograft rejection was less common in heart-kidney recipients, as compared with isolated heart transplant recipients; 0, 1, and > or = 2 treated cardiac allograft rejection episodes occurred in 63%, 20%, and 18% of heart-kidney recipients compared with 46%, 27%, and 28% of 911 isolated heart recipients reported by Transplant Cardiologists' Research Database (P=0.02). The rejection-free survival rates at 1, 3, and 6 months were 88%, 74%, and 71% in the double-organ recipients, as compared with 66%, 44%, and 39%, respectively, in the single-organ recipients. Compared with isolated heart transplantation, combined heart-kidney transplantation does not adversely affect intermediate survival and results in a lower incidence of treated cardiac allograft rejection. The findings suggest that combined heart-kidney transplantation may be an acceptable option in a small subset of potential heart transplant recipients with severe renal dysfunction.     

Increased expression of mRNA for the long form of the leptin receptor in the hypothalamus is associated with leptin hypersensitivity and fasting

BACKGROUND: Graft coronary artery disease (CAD) is an increasingly important problem during long-term survival after heart transplantation, but the importance of cellular rejection, in particular late after transplantation, remains undetermined. METHODS and RESULTS: We analyzed 492 coronary angiographies (967+/-705 days after transplantation; range, 49 days to 9.4 years) and 5201 endomyocardial biopsies (518+/-648 days after transplantation) from 156 patients (age, 47+/-11 years). Patients with angiographically detectable graft CAD had significantly more episodes of rejection requiring augmentation of immunosuppressive therapy (i.e., International Society of Heart and Lung Transplantation score > or = 3A) than those without graft CAD during the first (3.7+/-2.6 vs. 2.2+/-2.0, P<0.001) as well as subsequent years after transplantation (1.2+/-1.9 vs. 0.4+/-0.9, P<0.01). Multivariate logistic regression analysis including established risk factors for CAD, ischemic time, gender and age of donors and recipients, number of mismatches, cytomegalovirus infection, and drug therapy showed that the number of rejections during the first [odds ratio (OR)=1.39, P<0.005] as well as subsequent years (OR=1.49, P<0.05), previous cytomegalovirus infection (OR=3.21, P<0.05), donor age >40 years (OR=2.97, P<0.05), and current or former smoker status (OR=2.76, P<0.05) were independent predictors of graft CAD. In patients without angiographically detectable graft CAD 1 year after transplantation, the number of rejections after the first year was even more strongly related to graft coronary artery disease than in the total patient population, underlining the importance of late cellular rejection (OR=1.74, P<0.005). CONCLUSION: Rejection requiring augmentation of immunosuppression early and late after transplantation is an independent risk factor for the development of angiographically detectable graft CAD. Hence, the search for and treatment of moderate or severe rejection seems to be prudent even late after transplantation.