Comparison of intravenous ganciclovir and cytomegalovirus hyperimmune globulin pre-emptive treatment in cytomegalovirus-positive heart transplant recipients.

BACKGROUND: We compared the use of intravenous ganciclovir and cytomegalovirus hyperimmune globulin (CMVIG) as a pre-emptive treatment for cytomegalovirus (CMV)-positive heart transplant recipients. METHODS: Of 59 CMV-seropositive adult heart transplant recipients enrolled in Group 1, 37 tested positive for pp65 antigen within 12 weeks post-transplantation. These patients were randomized to receive either intravenous ganciclovir (n = 23) or CMVIG (n = 14). Group 2 included 133 CMV-seropositive heart transplant recipients who were not tested for CMV antigenemia and who received no anti-CMV therapy. RESULTS: CMV disease developed in 0 of 59 patients from Group 1, and in 27 of 133 patients (20%) in Group 2 (p = 0.0001). The incidence of superinfections was lower in Group 1 (0.28 +/- 0.46) than in Group 2 (1.10 +/- 1.33) (p = 0.01). The 2 groups did not differ with regard to incidence of rejection (0.7 +/- 0.9 in Group 1 vs 1.0 +/- 1.2 in Group 2; p = NS), transplant coronary artery disease at 1 year (14% in Group 1 vs 16% in Group 2; p = NS) or post-transplant lymphoproliferative disease (0% in Group 1 vs 2% in Group 2; p = NS). Ganciclovir and CMVIG therapies were associated with similar rates of rejection (0.52 +/- 0.6 with ganciclovir vs 0.50 +/- 0.60 with CMVIG; p = NS), superinfection (0.30 +/- 0.48 with ganciclovir vs 0.25 +/- 0.46 with CMVIG; p = NS), and transplant coronary artery disease at 1 year (13% with ganciclovir vs 14% with CMVIG, p = NS). CONCLUSIONS: The pre-emptive anti-CMV approach is superior to prophylaxis in CMV-seropositive heart transplant recipients. Both ganciclovir and CMVIG are equally effective.     

Effect of the TNF-alpha-promoter polymorphism on cardiac allograft rejection.

BACKGROUND: A polymorphism exists in the tumor necrosis factor alpha (TNF-alpha) promoter (position -308, G/A = TNFA1/TNFA2). The TNFA2 allele is associated with increased TNF-alpha production in vitro and has been reported to increase the risk of allograft rejection in pediatric recipients of cardiac transplantation. We examined the effect of the TNFA2 allele on the risk of allograft rejection in adult cardiac transplant recipients. METHODS: We prospectively analyzed 57 subjects (aged 54 +/- 11 years, 84% men, 49% ischemic) who underwent cardiac transplantation between October 1996 and July 2001. Patients were observed after transplantation (mean, 910 +/- 605 days) and the frequency of allograft rejection (biopsy Grade > or =2) in patients with the TNFA2 allele (Group A, n = 15) was compared with TNFA1 homozygotes (Group B, n = 42). Overall survival and time to rejection episodes also were compared between groups. RESULTS: The frequency of allograft rejection was similar between groups (Group A, 8/15 [56%]; Group B, 22/42 [52%]; p = 0.77). Time to rejection also was comparable (Group A, 17 +/- 11 days; Group B, 20 +/- 20 days, p = 0.74). Overall post-transplant survival was similar between groups (1- and 2-year percentage survival: Group A, 87% and 78%, Group B, 88% and 82%, p = 0.35). CONCLUSION: The TNFA2 allele was not associated with increased risk of rejection in adult cardiac transplant recipients. The impact of this polymorphism on overall post-transplant outcomes will require investigation in larger multicenter studies.     

Total lymphoid irradiation for refractory rejection in pediatric heart transplantation

BACKGROUND: We evaluated the role of total lymphoid irradiation (TLI) in the management of refractory rejection among pediatric heart transplant patients. METHODS: Eleven of 298 patients underwent TLI at 6 to 195 months of age and were divided into subgroups: those who survived (group A, n = 7) and those who did not survive beyond 1 year after TLI (group D, n = 4). Non-TLI recipient data were considered as the controls. RESULTS: Six out of 11 patients died eventually (54%). TLI was initiated 3 to 107 months after transplantation with a dosage of 600 to 840 cGy. The pre-TLI rejection rate (0.62 +/- 0.40 per month) was higher (p < 0.0001); however, the post-TLI rejection rate (0.24 +/- 0.65 per month) showed no significant difference from the control rejection rate. The Cox proportional hazard model found significance for TLI as a risk factor for development of posttransplant coronary artery disease (relative risk, 4.8; 95% CI, 1.1 to 21.3) and posttransplant lymphoproliferative disease (relative risk, 47.9; 95% CI, 1.6 to 1,475.3), respectively. Although the rejection rate decreased after TLI in both groups (group A pre/post, 0.51 +/- 0.31/0.06 +/- 0.08 per month; group D pre/post, 0.82 +/- 0.49/0.57 +/- 1.09 per month), significance was obtained only in group A (p = 0.018). CONCLUSIONS: TLI was an effective adjunct for reversal of refractory rejection in pediatric heart transplantation by reducing the rejection rate. Great care must be taken for the risk of development of coronary artery disease or lymphoproliferative disease.     

Acute rejection and cardiac allograft vascular disease is reduced by suppression of subclinical cytomegalovirus infection

BACKGROUND: Anticytomegalovirus (CMV) prophylaxis prevents the acute disease but its impact on subclinical infection and allograft outcome is unknown. We sought to determine whether CMV prophylaxis administered for three months after heart transplant would improve patient outcomes. METHODS: This prospective cohort study of 66 heart transplant recipients compared aggressive CMV prophylaxis (n = 21, CMV hyperimmune globulin [CMVIG] plus four weeks of intravenous ganciclovir followed by two months of valganciclovir); with standard prophylaxis (n = 45, intravenous ganciclovir for four weeks). Prophylaxis was based on pretransplant donor (D) and recipient (R) CMV serology: R-/D+ received aggressive prophylaxis; R+ received standard prophylaxis. Outcome measures were: CMV infection assessed by DNA-polymerase chain reaction on peripheral blood polymorphonuclear leukocytes, acute rejection, and cardiac allograft vascular disease (CAV) assessed by intravascular ultrasound. All patients completed one year of follow-up. RESULTS.: CMV infection was subclinical in all but four patients (two in each group). Aggressively treated patients had a lower incidence of CMV infection (73 +/- 10% vs. 94 +/- 4%; P = 0.038), and an independent reduced relative risk for acute rejection graded > or =3A (relative risk [95% CI] = 0.55 [0.26-0.96]; P = 0.03), as compared with the standard prophylaxis group. Aggressively prophylaxed patients also showed a slower progression of CAV, in terms of coronary artery lumen loss (lumen volume change=-21 +/- 13% vs. -10+/-14%; P = 0.05); and vessel shrinkage (vessel volume change = -15 +/- 11% vs. -3 +/- 18%; P = 0.03). CONCLUSIONS: Prolonged (val)ganciclovir plus CMVIG reduces viral levels, acute rejection, and allograft vascular disease, suggesting a role for chronic subclinical infection in the pathophysiology of the most common diseases affecting heart transplant recipients.     

Emergence of ganciclovir-resistant cytomegalovirus in lung transplant recipients

BACKGROUND: Since ganciclovir-resistant cytomegalovirus (CMV) disease was initially described in a patient with acquired immunodeficiency syndrome (AIDS) in 1986, the incidence of ganciclovir-resistant CMV disease appears to be increasing in immunocompromised patients. More recently, there have been sporadic reports of ganciclovir-resistant CMV disease in solid organ transplantation. METHODS: We retrospectively assessed the incidence of ganciclovir-resistant CMV disease in all lung transplant recipients transplanted between 6/93 and 6/01 at Loyola University Medical Center. All patients underwent routine CMV blood culture, shell vial assay as well as phenotypic and genotypic anti-viral susceptibility testing according to a pre-determined schedule. The number of CMV episodes, intravenous ganciclovir use, acute and chronic rejection and survival data were documented for all patients. RESULTS: Twelve of 212 (6%) transplant recipients developed ganciclovir-resistant CMV disease. Ganciclovir resistance was associated with a higher number of CMV episodes (3.4 +/- 2.3 episodes/patient vs 1.7 +/- 0.7 episodes/patient [p < 0.05]) and an increased exposure to cumulative intravenous ganciclovir in the primary CMV-mismatched (D(+)R(-)) population (22 +/- 10 vs 13 +/- 7 days [p < 0.05]) compared with patients who did not develop ganciclovir resistance. In addition, the use of daclizumab therapy was associated with a 7-fold greater likelihood of developing ganciclovir resistance (p < 0.0001). The presence of ganciclovir-resistant CMV disease in our population was associated with a decreased survival that could be attributed to CMV disease itself (p < 0.05). CONCLUSIONS: By screening all lung transplant recipients with CMV disease for ganciclovir resistance, we were able to detect a higher incidence of ganciclovir-resistant CMV disease (6%) than previously seen in solid organ transplantation. High-risk patients (D(+)R(-) CMV serostatus) who receive anti-lymphocytic therapy should be monitored aggressively and treated to prevent the development of ganciclovir resistance and avert a negative outcome.     

Long-term follow-up after total lymphoid irradiation in pediatric heart transplant recipients.

BACKGROUND: Total lymphoid irradiation (TLI) is used to treat recurrent allograft rejection. Short-term success and complication rates have been reported in pediatric and adult cardiac transplant populations. We report the long-term efficacy and safety of TLI in treating intractable rejection in pediatric patients. METHODS: Eight pediatric patients were treated with TLI (7 for recurrent rejection, 1 for risk of medication non-compliance). Therapy consisted of a mid-plane dose of 8 Gy administered with a 6-MeV linear accelerator using an anterior-posterior opposed technique. We reviewed outcomes for a total of 40 patient-years of follow-up. RESULTS: We encountered rejection (>Grade 2 by International Society for Heart and Lung Transplantation criteria) in 56.7% +/- 34.7% of biopsies performed within 90 days before TLI. Rejection rates dropped to 3.1% +/- 8.8% within the first 90 days (p < 0.005) after therapy and remained low at 5.6% +/- 1.3% (p < 0.05) during the first year after completion of TLI. Median time from TLI to the first subsequent rejection episode was 305 days (range, 77-1,920 days). Long-term follow-up (>3 years) of 5 patients demonstrated a continuing low incidence of rejection. Non-Hodgkin's lymphoma was diagnosed in 1 of 8 patients, graft coronary artery disease in 4 of 8 patients, and restrictive cardiomyopathy in 1 of 8 patients after TLI. CONCLUSIONS: Total lymphoid irradiation is an effective treatment for recurrent rejection and has short- and long-term efficacy. Morbid events may include cancer, graft coronary artery disease, and restrictive cardiomyopathy.     

Increased incidence of allograft rejection in stable heart transplant recipients after late conversion from mycophenolate mofetil to azathioprine.

Mycophenolate mofetil (MMF) is a safe and effective immunosuppressive agent in kidney and liver transplantation. Preliminary studies also support its use in heart transplantation. However, the cost of MMF is substantially greater than azathioprine (AZA), the current alternative. Since the majority of rejection episodes occur within the first few months of transplantation, using MMF early after transplantation and subsequently converting to AZA, after the risk of rejection has diminished, might be cost-effective. In order to evaluate the safety of such a strategy in heart transplant recipients, we reviewed the rejection profiles of a group of patients who were converted from MMF to AZA late after transplantation. Forty-three stable patients on chronic MMF therapy as part of an open-label, long-term safety study were converted to either commercially available MMF (CellCept) or AZA, at the conclusion of the study. Demographic variables, rejection histories before and after conversion, and immunosuppressive regimens were examined. Twenty-three patients were continued on commercial MMF and 20 were converted to AZA therapy. The average duration of MMF therapy prior to conversion was 41 months in each group. Baseline demographics were similar in the two groups. Treated allograft rejection occurred in 10 of 20 patients converting to AZA, as compared to only 1 of 23 patients remaining on MMF; p = 0.002. Additionally, mean scores (1-5 scale) for the three biopsies before and after conversion favored continued MMF therapy (1.5+/-0.6 before and 1.2+/-0.4 after conversion in MMF group vs. 1.3+/-0.5 before and 1.7+/-0.9 after conversion to AZA; p = 0.02). No allograft loss occurred as a result of conversion. These data suggest that conversion from MMF to AZA, even late after transplantation, can be associated with allograft rejection. The costs associated with these rejection episodes (the additional immunosuppressive agents, endomyocardial biopsies, and physician visits) may exceed the potential cost savings of converting stable heart transplant recipients from MMF to AZA.     

Early alterations of myocardial blood flow reserve in heart transplant recipients with angiographically normal coronary arteries.

BACKGROUND: The evaluation of the coronary reserve provides valuable information on the status of coronary vessels. Therefore, we studied with positron emission tomography (PET) and 13N-ammonia the myocardial blood flow (MBF) reserve in heart transplant recipients free of allograft rejection and with angiographically normal coronary arteries early after heart transplantation (HTx). The MBF reserve was calculated as the ratio between MBF after dipyridamole injection and basal MBF normalized for the rate-pressure product. METHODS: Patients were studied within 3 months (group A, n = 12) or more than 9 months (group B, n = 12) after HTx. Five patients have been studied both during the early and late period after HTx. Results were compared to those obtained in 7 normal volunteers (NL). RESULTS: Group A recipients had a significantly lower dipyridamole MBF (in ml/min/100 gr of tissue) than that of group B recipients (142+/-34 vs 195+/-59, p<0.05). This resulted in a significant decrease in MBF reserve early after HTx (group A: 1.82+/- 0.33) and a restoration to normal values thereafter (group B: 2.52+/- 0.53 vs NL: 2.62+/-0.51, p = ns). Separate analysis of 5 patients studied twice is consistent with these results. CONCLUSION: This study shows that in heart transplant recipients free of allograft rejection and with normal coronary angiography, MBF reserve is impaired early after HTx. Restoration within one year suggests that this abnormality does not represent an early stage of cardiac allograft vasculopathy.     

Evidence that the soluble interleukin 2 receptor level may determine the optimal time for cystoscopically-directed biopsy in pancreaticoduodenal allograft recipients

In 18 consecutive pancreaticoduodenal allograft recipients (15 combined kidney/pancreas and 3 pancreas only after a prior successful kidney transplantation) operated on between December 1987 and February 1989, we studied the soluble interleukin 2 receptor (SIL-2R) level over time. All pancreaticoduodenal allografts were transplanted with exocrine drainage via a duodenocystostomy that allowed for cystoscopically directed needle biopsies of the pancreas. Of these 18 recipients, at 6 weeks after transplantation, 6 had had no rejection episodes or cytomegalovirus disease (control group), an acute allograft rejection had developed in 7, CMV disease developed in 4, and both rejection and CMV disease developed in 1 by 12 days after transplantation. SIL-2R level increased in all patients during immunosuppressive induction therapy (preoperative mean +/- SE, 1637 +/- 284 U/mL; maximum, 4367 +/- 687 U/mL). After induction therapy, the mean was 2768 +/- 432 U/mL. In all 6 recipients in the control group, SIL-2R level continued to decrease. However, SIL-2R level was significantly higher compared with controls, in those who had CMV disease (levels were increased at a mean of 7 days before diagnosis of CMV disease) and in those who had acute rejection episodes (levels were increased a mean of 7 days before the clinical diagnosis of rejection). Factors that did not cause an increase in SIL-2R level included acute pancreatitis, wound infection, operative procedures, and CsA nephrotoxicity. SIL-2R level can be useful for monitoring pancreaticoduodenal allograft recipients. Increases predict impending rejection or CMV disease, prior to the onset of organ dysfunction. When SIL-2R level increases, we recommend cultures of blood and urine to exclude CMV and pancreaticoduodenal allograft biopsy to confirm early rejection prior to the initiation of potentially dangerous antirejection therapy.     

Distribution and declines in cardiac allograft radionuclide left ventricular ejection fractions in relation to late mortality.

BACKGROUND: Cardiac allograft left ventricular ejection fraction (LVEF) is an important measure of left ventricular systolic function. Despite widespread use of LVEF after transplantation, its normal range and prognostic value in cardiac allografts has not been defined. METHODS: We conducted a retrospective cohort study among 292 consecutive adult heart transplant patients. Left ventricular ejection fractions were performed at 1, 3, 12, 24, and 48 months after transplantation using radionuclide ventriculography. Endomyocardial biopsies assessed rejection, right heart catheterization assessed loading conditions, and angiography assessed allograft coronary artery disease. We used Cox proportional hazards model to examine the predictive value of LVEF on late mortality. RESULTS: Of the patients who survived > or =4 years, the mean allograft LVEF decreased 4.7 units at 3 months, from 63.8 to 59.7; an additional 4.1 units at 12 months, from 59.7 to 55.6 (p < 0.001); and remained stable afterward. These changes were not associated with concurrent changes in loading conditions, episodes of rejection, or development of allograft coronary artery disease. Left ventricular ejection fraction lower than the 95% normal limit (<40%) at 12 months was inversely associated with risk for late cardiac mortality (relative risk = 3.5, 95% confidence interval = 1.0-12.2), while controlling for recipient age, sex, donor age, and rejection episodes. CONCLUSIONS: The cardiac-allograft LVEF frequently decreases in the first year after transplantation. The 95th percentile of allograft LVEF value (<40%) at Year 1 predicts late cardiac mortality among transplant recipients.     

Short-term outcomes of Thymoglobulin induction in pediatric renal transplant recipients

No data are currently available that describe the clinical outcomes associated with Thymoglobulin (rabbit polyclonal anti-thymocyte globulin) induction in pediatric renal transplant recipients. We report the outcomes of 17 pediatric renal transplant recipients (mean age 10.1+/-5.2 years) transplanted between 1 August 1999 and 31 July 2001. Eleven patients (65%) were Caucasian and 6 (35%) were African-American. Eleven (65%) recipients received cadaveric allografts. Two patients (12%) were second allograft recipients. One patient had primary allograft non-function secondary to vascular thrombosis. Two patients (12%) had delayed allograft function. Immunosuppression consisted of Thymoglobulin induction (mean number of doses 6+/-1.7) with tacrolimus (62%) or cyclosporine A (38%), mycophenolate mofetil, and prednisone. One year post transplant, patient and graft survival was 100% and 93%, respectively. No acute rejection episodes occurred during the first 6 months after transplantation in any of the recipients. Additionally, no rejection episode occurred among the 14 patients followed for 1 year after transplant. The incidences of asymptomatic cytomegalovirus (CMV) and Epstein-Barr virus (EBV) seroconversion at 1 year in seronegative recipients with a seropositive donor were 100% of 4 patients and 0% of 4 patients, respectively. No symptomatic CMV or EBV infections and no post-transplant lymphoproliferative disease have occurred in any patient. These short-term data suggest that Thymogobulin induction is safe and effective in combination with triple immunosuppressive therapy for preventing early rejection in pediatric renal transplant recipients.     

Percutaneous coronary intervention versus medical therapy for coronary allograft vasculopathy. One center's experience.

BACKGROUND: Coronary allograft vasculopathy, a rapidly progressive form of atherosclerosis, remains the limiting factor in the long-term survival of heart transplant recipients. Some centers have attempted percutaneous coronary intervention to slow the disease process and thereby reduce mortality in these patients, but long-term follow-up data are scarce. We compared clinical outcomes in heart transplant recipients with coronary allograft vasculopathy who were treated either with percutaneous coronary intervention or with aggressive medical therapy alone. METHODS: A retrospective analysis of all heart transplant recipients at our institution who underwent surveillance coronary angiography for coronary allograft vasculopathy between 1995 and 2000 was performed. Patients with coronary allograft vasculopathy were stratified according to whether they received medical therapy or percutaneous coronary intervention. Baseline demographics, results of re-vascularization procedures and outcomes were analyzed. RESULTS: From 1995 to 2000, 301 patients underwent 602 coronary angiograms. Of the 79 patients who had angiographic evidence of coronary allograft vasculopathy, 53 were treated with aggressive medical therapy, while 26 underwent percutaneous coronary intervention in addition to aggressive medical therapy. At baseline, patients treated with aggressive medical therapy tended to be younger (54.6 +/- 13.8 years) than patients treated with percutaneous coronary intervention (62.6 +/- 7.6 years; p = 0.0079). Ejection fraction at time of diagnosis of coronary allograft vasculopathy was similar for both groups (medical therapy group, 44.4 +/- 13.4% vs percutaneous coronary intervention group, 47.2 +/- 12.7%; p = 0.38). In our cohort, heart transplant recipients with coronary allograft vasculopathy demonstrated greater mortality than heart transplant recipients without coronary allograft vasculopathy (p = 0.016). Patients who underwent percutaneous coronary intervention had a 60% re-stenosis rate at 6 months if they were treated with coronary angioplasty and an 18% re-stenosis rate if they received a coronary stent. Kaplan-Meier analysis showed no significant difference in survival in either treatment group at 1 year (80% for medical therapy group vs 95% for percutaneous coronary intervention group) or 3 years (68% for medical therapy group vs 79% for percutaneous coronary intervention group) after the angiographic diagnosis of coronary allograft vasculopathy. CONCLUSION: In this non-randomized trial, heart transplant recipients with coronary allograft vasculopathy were less likely to survive than patients without it. In addition, we found no statistical difference in mortality in heart transplant recipients with coronary allograft vasculopathy, regardless of whether they received percutaneous coronary intervention or aggressive medical therapy alone.     

Cytomegalovirus seromismatching increases the risk of acute renal allograft rejection

BACKGROUND: There is an association between cytomegalovirus (CMV) infection or disease and acute allograft rejection in the setting of renal transplantation. There is, however, debate regarding the nature of this association, with evidence supporting both a "forward" relationship (CMV infection or disease precedes acute rejection) and a "backward" relationship (CMV infection or disease follows acute rejection). The objective of this study was to determine whether CMV matching had an independent effect on the risk of acute renal allograft rejection, which would support the view that CMV infection or disease is a risk factor for acute rejection. METHODS: Retrospective single center study (using a prospectively maintained database) of 333 first cadaveric transplant recipients from January 1st 1991 to December 31st 1997. Primary end-point was incidence of acute rejection, diagnosed clinically or by renal biopsy, for different groups formed on the basis of CMV seromatching. RESULTS: One hundred and ninety-four patients (58.3%) had at least one acute rejection episode. CMV seromismatched patients (donor +/recipient-) had a significantly higher rate of acute rejection than non-seromismatched patients (72.6% vs. 54.2%, P=0.005). Using multiple logistic regression, CMV seromismatch, delayed graft function, and biological induction were identified as independent predictors of acute rejection. The adjusted odds ratios for these were 2.28, 1.65, and 0.52, respectively. CONCLUSIONS: Patients who are CMV seromismatched are at higher risk of acute renal allograft rejection. This finding suggests that CMV infection or disease is a risk factor for acute rejection.     

Stability of right and left ventricular ejection fractions and volumes after heart transplantation.

BACKGROUND: The long-term stability of right ventricular (RV) and left ventricular (LV) volume and function after heart transplantation has not been well characterized. Accordingly, the objective of this study was to assess time- and rejection-dependent changes in RV and LV function and volume after cardiac transplantation by means of a recently validated 3-dimensional tomographic equilibrium radionuclide ventriculography approach. METHODS: A total of 71 consecutive patients (age, mean +/- SD, 57 +/- 12 years; 62 men; 9 women) were studied 5 +/- 4 years (range 1--16 years) after heart transplantation. The mean frequency of >Grade 2 rejection was 1.7 +/- 1.8 episodes (range 0--7 episodes). RV and LV ejection fraction (EF) and end-diastolic volume (EDV) in transplant patients were compared with data from 34 subjects at low likelihood for coronary artery disease. RESULTS: No significant differences in RV or LV EF or EDV compared with controls were observed (RV EF=54 +/- 9 vs 53 +/- 9; RV EDV [ml]=109 +/- 35 vs 120 +/- 32; LV EF=72 +/- 8 vs 73 +/- 9; and LV EDV [ml]=108 +/- 28 vs 98 +/- 20 for controls and patients with transplants, respectively; p=NS for all comparisons). There was no significant effect on RV or LV EF or volumes with rejection, or with time after transplantation. CONCLUSIONS: RV as well as LV EF and EDV are stable more than 1 year after heart transplantation for up to 16 years. Thus, changes in EF or EDV in the transplanted heart are abnormal and should prompt a clinical evaluation.     

Posttransplant tubulointerstitial nephritis: clinicopathological correlation

As a cause of graft dysfunction, tubulointerstitial nephritis (TIN) seems to be the third most common pathology after rejection and cyclosporine nephrotoxicity. Among 540 needle biopsies obtained from 280 renal transplant patients between 1996 and 1999, acute TIN was detected in 23 patients (8%). The cause of acute TIN was secondary to bacterial infection in 17 patients and secondary to cytomegalovirus (CMV) infection in three patients. The remaining three cases showed granulomatous pyelonephritis due to Mycobacterium tuberculosis (n = 2) and Candida albicans (n = 1). During follow-up, 13 of 23 patients (56.5%) showed at least one acute rejection episode. The average number of urinary tract infection (UTI) episodes in the 23 patients was 1.4 +/- 07. We observed that the number of UTI episodes showed a significant association with the development of chronic allograft nephropathy (P = .03) and graft loss (P < .01). Twelve patients (52.2%) lost their grafts during 5 years posttransplantation. Only 6 of 17 patients with bacterial TIN lost their graft at a mean time of 52.5 +/- 14 months. But all patients with CMV TIN or granulomatous TIN lost their grafts at a mean time of 31 +/- 3.1 months and 39 +/- 3 months, respectively (P < .05). In conclusion, these results support the pathological role of tubulointerstitial nephritis as a pathway of graft rejection or renal allograft deterioration among recipients after transplantation.     

The influence of rejection episodes on the development of coronary artery disease after heart transplantation

Since 1981, 77 of 116 patients undergoing heart transplantation (HTx) have survived from 6 months to 8 years. Graft control involved a total of 871 endomyocardial biopsies (EMB) and 141 angiographies. Sixteen patients developed coronary artery disease (CAD) manifesting itself 7-60 months after HTx (20.7%). These patients (15 male, 1 female) experienced multiple rejection episodes (RE) and more than half suffered from hypercholesterolaemia and hypertension (n = 10). A mean rejection score (Billingham grading) of greater than 1 (mean = 1.6 +/- 1.1) was calculated in all patients with CAD at the time of angiography or autopsy. By contrast, the mean rejection score ranked less than 1 in patients with undetectable or resolved CAD (means = 0.4 +/- 0.38). This rate is not remarkably different from the rejection score in patients (n = 61) without CAD (mean = 0.2 +/- 0.4). The 8 patients alive (56 +/- 18 months) showed a low number of RE/year (mean = 1.1 +/- 0.4) compared with means = 1 +/- 0.9 in patients without CAD. Eight patients expired within a short period (mean = 31 +/- 26.9) and had a significantly higher number of RE/year (mean = 4.3 +/- 2.9; P less than 0.01 vs. no CAD, CAD alive). Autopsy (n = 6) and angiographic studies (n = 46) demonstrated diffuse, concentric, obliterative arterial disease in all vessels (type A) in 6 patients (RE/yr: mean = +/- 5.5 +/- 2.3), single stenoses in major coronary vessels (type B) in 7 patients and ordinary atherosclerosis (3-vessel disease) comparable to ischaemic heart disease (type C) in 3 patients.(ABSTRACT TRUNCATED AT 250 WORDS)     

Is bridging to transplantation with a left ventricular assist device a risk factor for transplant coronary artery disease?

BACKGROUND: Left ventricular assist device (LVAD) support is associated with coagulopathy, bleeding, increased blood transfusion, and increased anti-HLA antibody production. Increased anti-HLA antibody production is associated with early transplant rejection, transplant coronary artery disease (CAD), and decreased post-transplant survival rates. We asked whether bridging to transplantation with an LVAD increases the risk of transplant CAD. METHODS: We reviewed data for all adults (>18 years old) who underwent heart transplantation at our institution between 1988 and 2000. After exclusion of transplant recipients who survived <3 years, we divided the remaining cohort into 2 groups: those bridged to transplantation with LVADs (mean duration of support, 149 +/- 107 days, n = 29) and those in United Network for Organ Sharing Status 1 bridged to transplantation without LVADs (controls, n = 86). We compared groups in terms of disease cause, age, sex, donor age, panel-reactive antibody testing, crossmatching, pre- and post-transplant cholesterol concentrations, diagnosis of diabetes mellitus or treated hypertension, infections, calcium channel blocker use, transplant rejection, ischemic time, cytomegalovirus infection, pre-transplant transfusion, and incidence of transplant CAD (defined as any coronary lesion identified by coronary angiography). We considered p < 0.05 to be significant. RESULTS: The bridged and control groups were similar in all respects except mean ischemic time (217 +/- 58 minutes vs 179 +/- 67 minutes, p = 0.007), post-transplant cholesterol concentration (212 +/- 55 mg/dl vs 171 +/- 66 mg/dl, p = 0.007), and pre-transplant transfusion incidence (100% vs 22%, p < 0.001). The incidence of transplant CAD was similar in both groups during a 3-year follow-up period (28% vs 17%, p = 0.238) and during total follow-up (34% vs 35%, p = 0.969). Multivariate logistic regression analysis identified cholesterol concentration at 1 year after transplantation as a significant predictor of CAD at 3 years after heart transplantation (p = 0.0029, odds ratio = 0.984). CONCLUSIONS: Bridging to transplantation with an LVAD does not increase the risk of transplant CAD. Nevertheless, aggressive prophylactic therapy to minimize potential risk factors for transplant CAD, such as increased cholesterol concentration, is warranted in all transplant recipients.     

Factors predicting 10-year survival after heart transplantation.

BACKGROUND: We sought to identify factors predictive of long-term (>10-year) survival in heart transplant (HTx) recipients. METHODS: Four hundred fifteen adult patients underwent HTx at our institution between August 1982 and May 1997. The 158 patients who survived >10 years (Group A) and the 116 patients who died between 2 and 6 years (Group B) of HTx were compared in terms of gender, gender mismatch, ethnicity, age, height, weight, United Network for Organ Sharing status, type of induction therapy (OKT3 or anti-thymocyte globulin), infections (bacterial, viral, fungal and protozoal), cytomegalovirus (CMV) status, CMV mismatch, diabetes mellitus, hypertension and incidence of rejection episodes and transplant coronary artery disease within 2 years of HTx. RESULTS: Group A (135 men, 23 women; mean age 48 +/- 11 years) had significantly fewer post-HTx rejection episodes and viral, bacterial, fungal and total infections than did Group B (95 men, 21 women; mean age 49 +/- 12 years). Group A also had a significantly lower mean donor age, a lower incidence of pre-HTx diabetes, and a lower mean cholesterol level 1 year after HTx. In a multivariate analysis, fewer bacterial infections and rejection episodes after HTx, the absence of pre-HTx diabetes, and lower donor age were associated with longer survival. CONCLUSIONS: Pre-HTx diabetes, donor age and incidences of infection and rejection within 2 years of HTx predict long-term (>10-year) survival. Better control of infection and rejection during the first 2 years after HTx may improve survival.     

The impact of pharmacogenomic factors on acute persistent rejection in adult lung transplant patients

Persistent rejection in the face of treatment and multiple episodes of rejection are associated with the development of chronic rejection and graft loss in solid organ transplantation. The factors that create an environment for rejection that persists in the face of treatment are as yet not understood. The objective of this study was to evaluate the risk factors, including human multidrug resistance gene (MDR1), cytochrome P4503A5 (CYP3A5) and cytokine gene polymorphisms, associated with acute persistent rejection (APR) in lung transplant patients. One hundred and twenty-five adult lung transplant patients were studied. MDR1 G2677T, C3435T and CYP3A5 polymorphisms were assessed by direct sequencing of the polymorphic region in patient DNA. Cytokine genotyping for five cytokines was performed using the polymerase chain reaction-sequence specific primers (PCR-SSP) technique. Multivariate regression analysis was used to identify the predictors of acute persistent rejection. The dependent variable was the presence or absence of acute persistent rejection based on lung biopsies during the first postoperative year. The independent variables were MDR1 G2677T and C3435T, CYP4503A5 and cytokine polymorphisms, survival status, age, gender, survival days and HLA mismatches. The MDR1 C3435T polymorphism and age were independently associated with acute persistent rejection (p = 0.025, odds ratio = 0.29, 95% CI 0.1-0.86 and p = 0.016, odds ratio = 0.94, 95% CI 0.89-0.98, respectively). For the MDR1 C3435T polymorphism, 72% of patients with the C allele had acute persistent rejection in comparison to 52% for TT patients (p = 0.04). For age, a significant difference was found between the nonrejection group and the rejection group (mean+/-S.D. 52.1+/-11.2 vs. 44.4+/-12.3, p = 0.01). This is the first report of the association of a drug disposition genotype with drug-resistant acute rejection in organ transplant patients. The major predictor of acute persistent rejection in the first postoperative year for lung transplant patients was the MDR1 C3435T genotype. This association could be due to drug resistance, altered drug disposition or other immunologic effects associated with P-glycoprotein (P-gp) function. Future prospective treatment algorithms should be developed that will incorporate the knowledge of gene polymorphisms into treatment regimens to improve the outcome following lung transplantation.     

Hypogammaglobulinemia following cardiac transplantation: a link between rejection and infection.

BACKGROUND: Hypogammaglobulinemia (HGG) has been reported after solid organ transplantation and is noted to confer an increased risk of opportunistic infections. OBJECTIVES: In this study, we sought to assess the relationship between severe HGG to infection and acute cellular rejection following heart transplantation. METHODS: Between February 1997 and January 1999, we retrospectively analyzed the clinical outcome of 111 consecutive heart transplant recipients who had immunoglobulin G (IgG) level monitoring at 3 and 6 months post-transplant and when clinically indicated. RESULTS: Eighty-one percent of patients were males, mean age 54 +/- 13 years, and the mean follow-up period was 13.8 +/- 5.7 months. Patients had normal IgG levels prior to transplant (mean 1137 +/- 353 mg/dl). Ten percent (11 of 111) of patients developed severe HGG (IgG < 350 mg/dl) post-transplant. The average time to the lowest IgG level was 196 +/- 125 days. Patients with severe HGG were at increased risk of opportunistic infections compared to patients with IgG > 350 mg/dl (55% [6 of 11] vs. 5% [5 of 100], odds ratio = 22.8, p < 0.001). Compared to patients with no rejection, patients who experienced three or more episodes of rejection had lower mean IgG (580 +/- 309 vs. 751 +/- 325, p = 0.05), and increased incidence of severe HGG (33% [7 of 21] vs. 2.8% [1 of 35], p = 0.001). The incidence of rejection episodes per patient at 1 year was higher in patients with severe HGG compared to patients with IgG >350 (2.82 +/- 1.66 vs. 1.36 +/- 1.45 episodes/patient, p = 0.02). The use of parenteral steroid pulse therapy was associated with an increased risk of severe HGG (odds ratio = 15.28, p < 0.001). CONCLUSIONS: Severe HGG after cardiac transplantation may develop as a consequence of intensification of immunosuppressive therapy for rejection and hence, confers an increased risk of opportunistic infections. IgG level may be a useful marker for identifying patients at high risk.