Risk and benefit of coronary revascularization in renal transplant candidates.

The field of transplantation along with all of medicine has made tremendous progress in the past 30 years. Patients with end-stage renal disease are managed more effectively despite increasing chronic multisystemic comorbidities, particularly involving their cardiovascular system. These same patients are also undergoing renal transplant surgery with better short- and long-term results than any era previous. We will present some of the changing demographics encountered in today's renal transplant candidates along with the processes our institution is undertaking to optimize the patient's success with the renal allograft, particularly with respect to the diagnosis and therapeutics used to manage coronary artery disease.

Prediction of renal transplant survival from early postoperative radioisotope studies.

UNLABELLED: It has been routine at the University of Alabama Medical Center to obtain a radionuclide renal function study immediately after transplantation (usually within 3 d) that includes estimation of effective renal plasma flow (ERPF) from a single plasma sample in addition to imaging. We present here the correlation between baseline measurements and the 1-y graft survival. METHODS: Two cohort years were reviewed: 1988, when 131I-orthoiodohippurate (OIH) was used; and 1995, when 99mTc-mercaptoacetyltriglycine (MAG3) was used. ERPF was measured concurrently with gamma-camera imaging by previously published single-injection, single-sample methods (converting MAG3 clearance to ERPF by means of a correction factor). RESULTS: Graft survival during the first postoperative year improved significantly in the interval between cohort years, from 74% of 147 cadaver (CD) grafts in 1988 to 91% of 200 CD grafts in 1995 (log rank test, P < 0.05). In contrast, for living related donor (LRD) grafts there was no significant change, from 91% of 66 in 1988 to 91% of 83 in 1995. The baseline ERPF was a significant predictor of graft survival in both 1988 and 1995 (Wilcoxon test, P > 0.05). For LRD grafts the association was not significant in either year. Using MAG3 (1995), the peak time and the ratio of counting rate (R) at 20 min to that at 3 min (R20:3) were also significant predictors for CD graft survival. Using OIH (1988 cohort), the correlation with peak time did not reach significance, and the R20:3 measurement was not available. Although multivariate combinations (Cox proportional hazards model) did not have significantly more predictive value at the 95% confidence level than ERPF or R20:3 alone, some statisticians suggest a 75% confidence level for adding an additional covariate to a multivariate model. Use of this level led to a model including both ERPF and R20:3. CONCLUSION: Single-sample ERPF measured in the immediate post-transplant period, whether from OIH clearance or MAG3 clearance, was a statistical predictor of graft survival for CD transplants. For MAG3, the peak time and R20:3 were also significant predictors. These associations held only for CD transplants and not for LRD transplants.

Liver transplantation in the era of cost constraints.

BACKGROUND: The issue of containing cost has had a significant impact on organ transplantation. After our institution's 500th liver transplant, we critically examined the impact of the changing health care environment on liver transplantation. METHODS: We retrospectively analyzed 500 consecutive liver transplants done in the period of 1989 to 1998. RESULTS: Comparing the first 100 liver transplants to the last 100, patient demographics did not change significantly; however, mean waiting times increased significantly, from 30.4 days to 146.7 days, and median hospital stay decreased from 20.2 days to 10.9 days. One-year patient and graft survivals were not significantly different, 93.6% versus 96.5% and 88.0% versus 95.7%, respectively. CONCLUSIONS: Despite transplants in patients at higher risk and discharging patients sooner after transplantation, surgical results and patient survivals remained excellent. This was accomplished through improvements and modification of immunosuppression, outpatient treatment of uncomplicated acute rejection, and emphasis on close outpatient follow-up.

Improved outcomes in cadaveric renal allografts with pulsatile preservation.

BACKGROUND: Early immunologic and non-immunologic injury of renal allografts adversely affects long-term graft survival. Some degree of preservation injury is inevitable in cadaveric renal transplantation, and, with the reduction in early acute rejection, this non-immunologic injury has assumed a greater relative importance. Optimal graft preservation will maximize the chances of early graft function and long-term graft survival, but the best method of preservation pulsatile perfusion (PP) versus cold storage (CS) is debated. METHODS: Primary cadaveric kidney recipients from January 1990 through December 1995 were evaluated. The effects of implantation warm ischemic time (WIT) ( < or = 20 min, 21-40 min, or > 40 min) and total ischemic time (TIT) ( < or > or = 20 h) on death-censored graft survival were compared between kidneys preserved by PP versus those preserved by CS. The effect of preservation method on delayed graft function (DGF) was also examined. RESULTS: There were 568 PP kidneys and 268 CS kidneys. Overall death-censored graft survival was not significantly different between groups, despite worse donor and recipient characteristics in the PP group. CS kidneys with an implantation WIT > 40 min had worse graft survival than those with < 40 min (p = 0.0004). Survival of PP kidneys and those transplanted into 2 DR-matched recipients was not affected by longer implantation WIT. Longer TIT did not impact survival. DGF was more likely after CS preservation (20.2% versus 8.8%, p = 0.001). CONCLUSIONS: Preservation with PP improves early graft function and lessens the adverse effect of increased warm ischemia in cadaveric renal transplantation. This method is likely associated with less preservation injury and/or increases the threshold for injury from other sources and is superior to CS.

Outcome after myocardial revascularization and renal transplantation: a 25-year single-institution experience.

BACKGROUND AND OBJECTIVE: Cardiac disease is a common cause of death in renal transplant recipients. This study retrospectively analyzes the results of myocardial revascularization procedures in these patients and makes recommendations for managing coronary atherosclerosis in patients with renal disease who already have a transplanted kidney or who may receive a kidney transplant. METHODS: Patients who had myocardial revascularization (coronary artery bypass grafting [CABG] or percutaneous transluminal coronary angioplasty [PTCA]) and renal transplantation at the authors' institution between 1968 and 1994 were analyzed. Patient, procedural, and institutional variables were used for actuarial analyses of survival, as well as multivariate analyses of risk factors for death. RESULTS: Eighty-three of 2989 renal transplant patients required myocardial revascularization either before or after their transplant, and diabetes mellitus was the cause of renal failure in 42% of these patients. Standard coronary angiography, CABG, and PTCA techniques were used without periprocedural renal allograft loss. Actuarial patient survival was 89%, 77%, and 65% at 1, 3, and 5 years after the last procedure (transplantation or revascularization). Cardiac disease was the most common mode of death. Early-phase risk factors for death by multivariate analysis included hypertension and revascularization before 1989. Late-phase risk factors for death included diabetes mellitus, higher number of pre-CABG myocardial infarctions, renal transplantation before 1984, older age, and unstable angina before CABG. CONCLUSIONS: Myocardial revascularization can be performed with acceptable short- and long-term results in patients with renal disease who have renal transplantation either before or after the revascularization procedure. Diabetes mellitus was a highly prevalent condition among these patients, and cardiac disease was their most common mode of death. PTCA and CABG, as performed at this institution, posed little risk for renal allograft loss. Modification of risk factors for coronary atherosclerosis, rigorous cardiac evaluation of patients at risk for coronary artery disease before renal transplantation, and aggressive use of revascularization procedures to decrease the incidence of myocardial infarction are proposed as ways to prolong the survival of renal transplant patients with ischemic heart disease.

Race: a critical factor in organ donation, patient referral and selection, and orthotopic liver transplantation?

The influence of ethnic origin on organ donation and renal allograft survival after renal transplantation has been controversial. Several large studies have reported inferior renal allograft survival in black recipients, whereas others have reported equal survival. However, the issue of race as it relates to organ donation, patient referral, and patient selection in orthotopic liver transplantation has not been investigated. We retrospectively reviewed our results of organ donation, patient referral and selection, and orthotopic liver transplantation since 1989. Because of a concerted educational effort by this organ procurement organization, the percentage of black donors has increased from 6.1% in 1988 to 21.9% in 1996. Since the inception of the Liver Transplant Program in 1989, 844 patients have been referred to our transplant center for organ transplant evaluation. Disproportionately fewer black patients (119; 14.1%) were referred for liver transplantation than white patients (725; 85.9%) based on the prevalence of end-stage liver disease in these populations. The acceptance rate for listing for transplantation was similar between the two groups. The percentage of patient referrals who actually underwent transplantation was similar across racial lines (43% black v 42% white patients). However, it appeared that black patients were referred for liver transplantation at a later stage and were more critically ill at the time of referral. Nevertheless, the patient and graft survival were similar between black and white patients. The 1- and 3-year survival rates in white recipients was 88% and 81%, respectively, versus 96% and 84% in black recipients. Within this organ procurement organization, black donation has increased over the past 10 years. Unfortunately, there may be a selection bias at the level of referral for liver transplantation. However, once patients are referred to this center for liver transplantation, the rate of transplantation and survival is similar between white and black patients.

Tacrolimus (FK506) and mycophenolate mofetil combination therapy versus tacrolimus in adult liver transplantation.

BACKGROUND: Mycophenolate mofetil (MMF) prolongs allograft survival in experimental animals, prevents acute rejection in humans, and has recently been approved for use in renal transplantation in combination with cyclosporine. Tacrolimus (Prograf) has been shown to be effective for the prevention and treatment of allograft rejection in liver transplantation. However, there has been limited experience with the combination of tacrolimus and MMF in liver transplantation. METHODS: This retrospective pilot study examined the results in 130 primary, consecutive, adult liver transplants under two separate immunosuppressive protocols. Patients in the study group received MMF (1 g p.o. b.i.d.), tacrolimus (0.1 mg/kg p.o. b.i.d.), and a standard steroid taper. MMF was also tapered and then discontinued within 3 months of transplantation. A historical control received tacrolimus (0.15 mg/kg p.o. b.i.d.) and the same steroid taper. RESULTS: Pretransplant demographics, including creatinine, were not significantly different between the groups. The 6-month patient and graft survivals of 96.3% (control) versus 92.0% (study) were not significantly different. The incidence of acute rejection was 45.0% in the control group versus 26.0% in the study group (P = 0.03). The study group had a lower incidence of rejection (mean episodes/patient +/- SEM): 0.28+/-0.07 vs. 0.61+/-0.10 (P = 0.007). All of the study group members responded to high-dose steroids. In the control group, three patients required monoclonal antibody therapy and two patients required the addition of MMF. The incidence of cytomegalovirus was similar in the study group and the control group (13.8% vs. 10.0%, P = NS). Early renal function was better preserved in the tacrolimus/MMF group (mean creatinine +/- SEM): 1.09 mg/dl +/- 0.05 vs. 1.51 mg/dl +/- 0.08 at 30 days, P = 0.0001. The study design required dosing with less tacrolimus (mean mg/day +/- SEM), which was achieved at 1 week (23.2+/-0.7 vs. 13.5+/-0.5); 1 month (18.7+/-0.8 vs. 11.4+/-0.5); 3 months (14.5+/-0.6 vs. 9+/-0.5); and 6 months (11.6+/-0.6 vs. 8.2+/-0.6); P = 0.0001, for all time points. CONCLUSION: Combination therapy with tacrolimus and MMF may significantly reduce the incidence of acute liver allograft rejection, allow a significant reduction in tacrolimus dosage, and decrease the incidence of nephrotoxicity. Long-term analysis will be necessary to assess any increased risk of opportunistic infections.

Impact of donor/recipient size matching on outcomes in renal transplantation.

Interest in nonimmunologic factors affecting longterm graft survival has focused on adequacy of nephron dosing. Body surface are (BSA) is a reliable surrogate for nephron mass. In a retrospective study of 378 primary recipients of paired kidneys from 189 cadaveric donors, we assessed the impact of matching donor and recipient BSA on outcome over 7 years. BSA of donors was 1.82 +/- 0.26 m2. Initially, paired recipients of kidneys from a single donor were divided into two groups. Group 1 included the recipient with the larger BSA of the pair (1.97 +/- 0.17 m2), while group 2 consisted of smaller BSA recipients (1.69 +/- 0.19 m2). Although early function was better in group 2 patients, graft survival at 1 year (77% vs. 79%) and 5 years (54% vs. 55%) was identical between groups, as were most recent serum creatinine levels (2.0 +/- 0.1 vs. 2.1 +/- 0.1 mg/dl). A second analysis divided patients with a functioning allograft at discharge from initial transplant hospitalization (n = 345) into three groups based solely on donor to recipient BSA ratio: the ratio of group A (n = 30) was < or = 0.8, that of group B (n = 255) was between 0.81 and 1.19, and that of group C (n = 51) was > or = 1.2. Graft survival and kidney function over 5 years did not differ among groups. In multivariate analysis of 17 variables, donor:recipient BSA, independent of other risk factors, did not affect risk allograft loss. These data indicate that including nephron mass as a criterion for cadaveric organ allocation is unlikely to improve long-term results in renal transplantation.

Iron overload in African Americans.

PURPOSE: Iron overload unexplained by dietary or medicinal iron excess, transfusion, or sideroblastic anemia has been described infrequently in Americans of African descent. The purpose of this study was to characterize iron overload attributable to excessive iron absorption in African Americans. PATIENTS AND METHODS: In a community hematology and medical oncology practice during the interval 1990 to 1993, we identified and evaluated a series of cases comprised of 6 men and 1 woman, with a mean age of 55 +/- 14 (SD) years (range 33 to 69). Data on clinical features, serum iron parameters, liver and body iron stores, evaluations of anemia, human leukocyte antigen (HLA) typing, and family studies were analyzed. RESULTS: Among our patients, the serum iron parameters were: iron concentration 26 +/- 13 mumol/L, transferrin saturation 59 +/- 21%, and ferritin concentration 1,588 +/- 1,053 micrograms/L. Clinical abnormalities observed included weakness and fatigue, decreased libido and impotence, hepatopathy, arthropathy, diabetes mellitus, hypogonadotrophic hypogonadism, and hyperpigmentation. Hepatic parenchymal cell iron deposits were increased in each of the 6 patients studied, and Kupffer cell iron deposits were prominent in 4. The occurrence of iron overload was verified by liver iron quantification and therapeutic phlebotomy. Four subjects had alpha-thalassemia minor; 2 others had hemoglobin S and C traits. No proband had HLA-A3 positivity. Four probands had other family members with iron overload. CONCLUSIONS: In comparison with Caucasians with hemochromatosis, our patients have slightly lower mean values of serum iron concentration and transferrin saturation, more Kupffer cell iron deposits, a higher incidence of thalassemia and hemoglobinopathy, and infrequent positivity for HLA-A3. Iron overload in African Americans appears to be more similar to that in certain sub-Saharan African natives than to hemochromatosis.

Risk factors affecting second renal transplant outcome, with special reference to primary allograft nephrectomy.

Removal of a failed primary renal allograft was found by some groups to adversely affect the outcome of a second kidney transplant. Recent data does not support this view and fail to show any such effect. Such data, however, are limited by small numbers or univariate analysis. The records of 192 patients receiving a primary and a subsequent kidney transplant between January 1980 and July 1992 were retrospectively reviewed. Immunosuppression initially included azathioprine and prednisone; cyclosporine was introduced in December 1983 with Minnesota antilymphocyte globulin (MALG) added for induction in May 1987. Regraft survival rates were 66% at one year and 60% at two years. Using Kaplan-Meier survival analysis patients having primary transplant nephrectomy had a worse second allograft outcome than patients who kept their failed grafts (P = 0.0003). Multivariate analysis showed a significant relationship between primary allograft survival and retransplant outcome. To eliminate this influence, patients whose first graft failed within six months of transplantation were excluded from the analysis. This resulted in 90 patients whose first graft functioned for more than 6 months. Graft survival was 80% at one year and 73% at 2 years in this select population. Patients with prior transplant nephrectomy still had a worse retransplant outcome than those who kept their failed grafts (P = 0.05). Multivariate analysis identified primary allograft nephrectomy, older donor age, longer interval from nephrectomy to retransplant, and lack of MALG at induction as negative risk factors. In conclusion, primary allograft nephrectomy may have a negative influence on second renal transplant outcome. This result may be improved by reducing donor age and the time interval from nephrectomy to retransplantation, and using MALG at induction.

Progress in renal transplantation. A single center study of 3359 patients over 25 years.

OBJECTIVE: The study analyzed 3359 consecutive renal transplant operations for patient and graft survival, including living related, cadaveric, and living unrelated patients. The analysis was separated into three groups according to immunosuppression and date of transplant. SUMMARY BACKGROUND DATA: Improvements in renal transplantation in the past 25 years have been the result of better immunosuppression, organ preservation, and patient selection. METHODS: A single transplant center's experience over a 25-year period was analyzed regarding patient and graft survival. Potential risk factors included patient demographics, tissue typing, donor characteristics, number of transplants, acute and chronic rejection, acute tubular necrosis, primary disease, and malignancy. RESULTS: The primary cause of graft loss was rejection. Improvement in cadaveric graft survival since 1987 with quadruple therapy was not apparent in living donor patients. Race continued to be a negative factor in graft survival. Avoiding previous mismatched antigens and the use of flow cytometry improved allograft survival. The leading cause of death in the past 7 years in cadaveric recipients was cardiac (52%). CONCLUSIONS: Improved graft survival in the past 25 years was related to 1) advances in immunosuppression, 2) better methods of cytotoxic antibody detection, and 3) human lymphocyte antigen match.

A rapid flow cytometry assay for HLA antibody detection using a pooled cell panel covering 14 serological crossreacting groups.

Many studies have demonstrated the usefulness of flow cytometry crossmatching (FC-XM) for selection of regraft recipients, and more recently this assay has been shown to correlate with allograft survival in primary cadaveric transplant patients. The need now exists for a practical antibody screening procedure which uses the same methodology. We describe here a simple and sensitive method to screen for HLA antibodies by FC using a pool of 6 cells selected to cover the 14 serological crossreacting groups defined by Rodey. Screenings of 367 sera (255 primary transplant sera, 112 regraft sera) received for monthly antibody testing were performed by both pooled cell FC and complement-dependent cytotoxicity (CDC) assays. Forty of these sera were also FC-screened using a panel of 16 individual cells for comparison with the pooled cell FC screenings. Analysis indicated a strong correlation between the pooled FC-PRA and the individual cell panel FC-PRA (P = .0001) with mean values of 60% and 73%, respectively. Only 2 of the 40 sera screened by both FC methods resulted in PRAs that differed by > 40%. The majority (82%) of the primary patients did not exhibit HLA antibodies by CDC--however, 22% of the CDC negative patients were positive by flow cytometry. Females were more likely to be positive by FC (35%) than males (16%) (P = .0001). Similarly, black patients were more likely to have FC-demonstrable antibodies (28%) than white candidates (14%) (P = .014). The regraft patients who tested positive by either or all methods had a mean PRA for CDC, pooled FC-PRA, and individual cell FC-PRA of 40, 75, and 85, respectively. FC-PRA proved to be a more sensitive technique in both primary and regraft patients.

Renal retransplantation: the role of race, quadruple immunosuppression, and the flow cytometry cross-match.

To assess the impact of quadruple immunosuppression in black and white recipients of cadaver kidney retransplants, we reviewed data from 178 second or subsequent renal allografts performed at our center between 1985 and 1991. Sixty-six black and 102 white recipients were divided into 3 groups: groups 1 and 2 consisted of patients with a negative complement-dependent cytotoxicity (CDC) T cell cross-match, receiving triple drug therapy (CsA-AZA-prednisone) and quadruple immunosuppressive therapy (quad therapy; Minnesota antilymphoblast globulin-CsA-AZA-prednisone), respectively. Group 3 patients also received quad therapy, but, in addition to a negative CDC cross-match, had a negative T cell flow cytometry cross-match (FCXM). Black and white patients in groups 1 and 2 experienced similar graft survival at 1 year, ranging from 47% to 63% (P = NS). In group 3, 1-year graft survival in whites, but not blacks, improved to 82%, with fewer grafts lost to immunologic causes in the first 90 days after transplant. A parametric analysis of potential risk factors identified a significant effect of better HLA-DR matching (P = 0.0005) on improved graft survival, with previous mismatched antigens (P = 0.04), female donor (P = 0.002), and short duration of previous graft (P = 0.05) as risk factors for graft loss. Race and immunosuppressive protocol did not affect graft survival. In group 3, blacks received fewer well-matched kidneys than whites (P = 0.05), which may have contributed to poorer outcomes for black recipients. Nine of 10 patients undergoing retransplantation with a negative CDC cross-match and a positive T cell FCXM suffered graft loss at a median of 26 days after transplant. Thus, quad therapy did not enhance graft survival for either black or white patients undergoing cadaveric retransplantation. Immunologic considerations, including HLA-DR matching and the FCXM, continue to exert a strong influence on outcomes in these high-risk recipients.

Experience with mycophenolate mofetil (RS61443) in renal transplantation at a single center.

OBJECTIVE: Mycophenolate mofetil (MM) is a new immunosuppressive agent that reversibly inhibits guanine nucleotide synthesis and DNA replication. Its activity is highly selective for T and B lymphocytes. Two open-label multicenter trials of MM in renal transplantation have been performed. This report summarizes the results from one center involved in these two trials. METHODS AND RESULTS: The initial trial of MM was an open-label dose-ranging trial in primary cadaveric renal transplantation. Mycophenolate mofetil was included in the maintenance immunosuppression regimen from the day after transplantation. Of the 21 patients enrolled in this trial, one (5%) was withdrawn for side effects. There was one graft loss due to recurrent renal disease and two patients were withdrawn for difficulty with follow-up. Mean follow-up is 26 months, and patient and graft survival at 2 years are 100 and 95% respectively. The second trial was designed to study the efficacy of mycophenolate in reversing refractory renal allograft rejection. Patients enrolled in the trial had biopsy-proven acute rejection and had previously received at least one course of high-dose corticosteroids and/or OKT3. Of the 26 patients enrolled in this trial, one (4%) was withdrawn for side effects. There were two deaths. Mean follow-up is 20 months, and patient and graft survival at 12 months was 91 and 54%. The incidence of infections in the two groups was 38% and there were no deaths in either group attributable to infection. CONCLUSIONS: The results of these two studies indicate that mycophenolate mofetil could be administered safely to renal allograft recipients for periods up to 2 years. It appears to be effective in reversing acute rejection in a high percentage of patients refractory to other forms of therapy.

Pediatric renal transplantation at the University of Alabama at Birmingham, 1968 to 1993.

From May 5, 1968 through January 31, 1993, 272 renal allografts were performed in 233 children at the University of Alabama at Birmingham. Graft survival has improved since 1983 with the addition of cyclosporine. Acute and chronic rejections continue to be the major causes of graft failure. The use of living-related donor renal allografts optimizes long-term graft function, allows early transplantation, and minimizes potential long-term dialysis complications in children.