Simultaneous pancreas-kidney transplants in type I and type II diabetic patients with end-stage renal disease: similar 10-year outcomes.

INTRODUCTION: Herein we report 10- to 15-year results of simultaneous pancreas-kidney (SPK) transplants in 135 type I and type II insulin-dependent diabetes mellitus (IDDM) patients. METHODS: Diabetes type was defined by the absence (type I) or presence (type II) of C-peptide. The freedom from dialysis and need for insulin defined graft survival. Patient survival was verified by record review and the Social Security Death Registry. The mean follow-up exceeded 100 months. RESULTS: Type II IDDM present in 28% of the 135 cohort, predominately among African-Americans (AA). The type II group was two-thirds AA (43% of the total AA patients) and 17% of the non-African-American (nAA) group. The difference between the two groups by C-peptide level was significant (P = .001). Type II patients had a higher body mass index, were slightly older at the onset of DM, but had similar duration of IDDM before ESRD. At 5 and 10 years, pancreas survival for type 1 DM was 71% and 49%; for type II DM it was 67% and 56% (P = .52). Kidney survival for type I DM was 77% and 50%; for type II it was 72% and 56% (P = .65). Patient survival for type I DM was 85% and 63%; for type II DM it was 73% and 70% (P = .98). CONCLUSIONS: We conclude that the outcomes of SPK transplants are equivalent regardless of diabetes type. Accordingly, the decision whether to perform pancreas transplants in diabetic recipients of kidney allografts should be based on general acceptance criteria not diabetes type.

Kidney transplants in African Americans and non-African Americans: equivalent outcomes with living but not deceased donors.

BACKGROUND: The outcome differences between ethnic groups after kidney transplantation have led to the characterization of African Americans (AA) as having high immune risk. Several multicenter clinical trials have reported better outcomes when AA receive higher doses of immunosuppression (I/S), suggesting pharmacokinetic (PK) and pharmacodynamic (PD) differences. However, the donor source has not been cited as an risk factor for outcome. METHODS: Patient and graft survival rates of 469 AA were compared with 308 non-African Americans (nAA) who received kidney transplants between January 1, 1995 and December 31, 2002, and were followed-up through December 31, 2003. Gender, age, and I/S protocol were not different between the groups. Based on outcomes, open and laparoscopic donor groups were combined for analysis. Deceased donor kidneys comprised 49% of the AA kidneys but only 32% of the nAA kidneys (P < .000). Kaplan-Meier survival statistics were used for both patient and graft survival. RESULTS: Patient survival rates for AA compared with nAA at 1, 3, 5, and 7 years were not statistically different for living (log rank statistic, 1 df, P = .56) versus deceased donor kidneys (log rank statistic, 1 df, P = .15). Kidney graft survival rates for AA compared with nAA at 1, 3, 5, and 7 years for living donor were similar (log rank statistic, 1 df, P = .493), but significantly different for deceased donor kidneys (log rank statistic, 1 df, P = .026). CONCLUSIONS: The majority of living donation occurred between ethnically similar donor-recipient pairs, whereas deceased donors tended to be nAA. The difference demonstrated by donor source suggests that antigens may be more dissimilar or uniquely different between ethnic groups.

Multicenter survey of daclizumab induction in simultaneous kidney-pancreas transplant recipients.

We report an experience with 71 simultaneous kidney-pancreas transplant (SKPT) recipients receiving daclizumab induction in combination with tacrolimus (TAC), mycophenolate mofetil (MMF), and steroids. The mean follow-up time was 5.9+/-2.5 (SD) months (range 0.5-11 months). The study population included 47 males (65%) and 24 females (35%) with a mean age of 40+/-8 years. The mean pretransplant duration of diabetes and dialysis were 25+/-8 and 1.5+/-0.9 years (34 hemodialysis, 16 peritoneal dialysis), respectively. Mean HLA match was 1.2+/-1.5, with one patient receiving a second transplant. The mean cold ischemic times for the kidney and the pancreas were 15+/-5 and 16+/-4 hr, respectively. Six-month patient, kidney, and pancreas graft survival and rejection rates were 97, 96, 93, and 35%, respectively. There were two deaths, one due to fungal infection and the other due to a cardiac event. There were three kidney graft losses, two immunological, and one death with function. Of the five pancreas graft losses, two were due to infection, one immunological, one thrombosis, and one death with function. The patient population was then stratified according to the number of daclizumab doses: 4-5 doses (n=45) or 1-3 doses (n=26). There were no differences in patient and kidney graft survival rates, 98 vs. 96%, and 92 vs. 92%, respectively. However, there was a trend toward improved pancreas graft survival in the group receiving 4-5 doses (96%) compared with 1-3 doses (85%), P=0.07. Although more patients receiving 1-3 doses had rejection (54%) than patients receiving 4-5 doses (24%), there was no dose response relationship between the total number of doses or the adjusted total mg/kg dose and time to rejection. All patients with functioning grafts have good renal and pancreas allograft function at 6 and 12 months. The overall incidence of major infection was 27% and there were no differences in the incidence of infection between the two groups. No major adverse events were attributed to daclizumab use. In conclusion, excellent short-term outcomes were noted in this retrospective, multicenter survey of initial experience with daclizumab induction in combination with TAC, MMF, and steroids in SKPT recipients. Optimal dosing strategies for SKPT recipients remain to be determined.

A survey: the prevalence of laparoscopic donor nephrectomy at large U.S. transplant centers.

BACKGROUND: There is controversy whether laparoscopic donor nephrectomy (LDN) is the procedure of choice for live kidney donors. The purpose of this survey therefore was to determine the current practices, attitudes, and plans regarding LDN in high-volume renal transplant centers. METHODS: Medical directors of the 31 highest volume kidney transplant centers were surveyed via telephone. Kidney transplant data for 1998 and 1999 were collected. RESULTS: The surveyed centers performed 5213 transplantations in 1998, representing 43% of all kidney transplantations done nationally. Twelve (39%) of the 31 centers performed LDN in 1998, increasing to 20 (65%) of 31 in 1999. Of 1174 live donor operations performed by the 20 centers in 1999, 365 (31%) were LDNs. Among the surveyed centers, four had no plans to begin an LDN program. The most commonly cited incentive for LDN was "shorter recovery time," whereas the most common disincentive was "concern about graft quality." A combination of observation and animate laboratory was the most commonly reported method of learning the LDN procedure. Six-month follow-up interviews found that 26 (84%) of 31 centers had performed LDN; only 1 of the 31 centers had no plans to perform LDNs. CONCLUSIONS: LDN may be the de facto procedure of choice for live donors within the next year. Efforts should now focus on improving techniques for performing and teaching this procedure.

Successful long-term kidney-pancreas transplants regardless of C-peptide status or race.

BACKGROUND: We have previously shown that our patient population of 60% minority races has end-stage renal disease primarily as a result of diabetes mellitus and hypertension. It therefore was logical to explore the restoration of normal insulin production and renal function by simultaneous pancreas-kidney (SPK) transplantation, without regard to race. This study represents new analyses integrating race with C-peptide status and reports the outcome of 136 SPK transplantations performed over the last 10 years. RESULTS: Of the 49 African-Americans with diabetes mellitus and end-stage renal disease, 60% were type I and 40% were type II, based on C-peptide levels. In comparison, only 16% of Caucasians were type II. The average age at onset of diabetes mellitus was 15.7 years for type I compared with 20.7 years for type II (P>0.05). The actuarial 10-year survival rates for the 136 SPKs were 91.79% (patient), 85.07% (pancreas), and 83.58% (kidney). The type I and type II survival rates were similar in the two diabetic groups. CONCLUSIONS: The data strongly suggest that pretransplant C-peptide status does not influence the outcome of SPK transplantation in patients with renal failure from diabetes mellitus. SPK transplants should be offered to all suitable diabetic patients with renal failure regardless of C-peptide status or race.

A comparison of daclizumab to ATGAM induction in simultaneous pancreas-kidney transplant recipients on triple maintenance immunosuppression.

Daclizumab (DAC) is a molecularly engineered humanized IgGa monoclonal Ab directed against the alpha chain of the interleukin-2 receptor (IL2R). Inhibiting the amplification of the immune response by blocking IL2R can reduce the frequency of acute rejection without the attendant risk of infection. The purpose of this retrospective study was to compare DAC to antithymocyte (ATGAM) induction in 24 simultaneous pancreas-kidney (SPK) transplants performed between September 1995 and September 1998. The primary endpoints were the incidence within 6 months posttransplant of: 1) biopsy-proven acute rejection; and 2) infection. The two groups (DAC, n = 12; ATGAM, n = 12) were matched on age, race, ESRD, number of HLA mismatches, PRA level, and cold ischemia time. DAC (1 mg/kg) was given on the day of transplant, then every other week (a total of five doses); ATGAM (15 mg/kg) was given on post-transplant day 1, then daily for 7-10 d. Immunosuppressive therapy consisted of cyclosporine (Neoral 8-10 mg/kg/d) or Prograf (0.16-0.2 mg/kg/d), mycophenolate mofetil (Cell- 2-3 g/d) and steroids. Of the 12 DAC patients, 3 patients (25%) had biopsy-proven acute rejection versus 8/12 (67%) of the ATGAM patients. The time to acute rejection was significantly different by group (DAC = 110 d; AT-GAM = 26 d). There was a reduction in the number of patients receiving antilymphocyte drugs for moderate to severe rejection (DAC = 2/12; ATGAM = 4/12), with 2 of the 4 ATGAM patients experiencing more than two episodes of biopsy-proven rejection. There was an increase in infection by group (DAC = 4/12; ATGAM = 7/12): total of three septic infections occurred in the ATGAM group opposed to none in the DAC group. Patient, pancreas, kidney 6-month survival rates were 100% for both groups. We conclude that DAC induction coupled with triple immunosuppressive therapy reduces the incidence of rejection in SPK transplant patients. The time to acute rejection was prolonged in the DAC group compared with the ATGAM group without the attendant risks of rejection.

Is laparoscopic donor nephrectomy the new criterion standard?

HYPOTHESIS: The posttransplantation renal function outcomes between consecutive open donor and laparoscopic donor nephrectomies (LDNs) are similar and affect living donation. DESIGN: Using the medical records of renal living donor-recipient pairs, 36 consecutive open donor nephrectomies were compared with the subsequent 100 LDNs. Data collected on donor characteristics included demographics (age, race, sex, weight, and height), renal vascular and ureteral anatomical features, surgical information (blood loss, number of blood transfusions, operating time, warm ischemia time, and renal injury), complications, and length of hospital stay. Recipients' data also included renal function information (serum creatinine level on postoperative days 7 and 30) and ureteral complications during the initial hospital stay. SETTING: A not-for-profit tertiary care teaching hospital in a metropolitan area. PATIENTS: Adults who had end-stage renal disease and received a living donation kidney. MAIN OUTCOME MEASURES: Operative time, warm ischemia time, blood loss, and posttransplantation serum creatinine level. RESULTS: Patient characteristics were not significantly different between the open donor nephrectomy and LDN groups. No right kidney LDNs were done because of the shortness of the right renal vein; and, after the initial experience, left kidneys with more than 2 arteries were excluded. Warm ischemia time was recorded only for LDN, and it was found that a warm ischemia time of 10 minutes or longer was associated with difficulty in extraction and was uniformly associated with elevated mean serum creatinine levels on postoperative day 7. CONCLUSIONS: The length of hospital stay was decreased and cosmetic result enhanced. The number of living donors has increased from 28 in 1997 to 53 in 1998 and to 63 in 1999 at our institution. The length of hospital stay, incidence of complications, and comparable kidney quality indicate that LDN should be the initiating procedure for most patients.

Evaluation of pre- and posttransplant donor-specific transfusion/cyclosporine A in non-HLA identical living donor kidney transplant recipients. Cooperative Clinical Trials in Transplantation Research Group.

BACKGROUND: The beneficial effects of donor specific transfusion (DST) have become controversial in the cyclosporine era. This study was performed to evaluate the potential benefits of a new protocol for administering DSTs in the perioperative period. METHODS: Non-HLA identical living donor kidney transplant recipients were randomized prospectively to control or to receive a DST 24 hr before transplant and 7-10 days posttransplant. All patients received similar immunosuppression according to protocol. RESULTS: The protocol had 212 evaluable patients (115 transfused and 97 control). There were no differences in 1- and 2-year graft and patient survival, causes of graft failure, incidence and types of infection, repeat hospitalization, or the ability to withdraw steroids. Immunological hyporesponsiveness (by mixed lymphocyte culture) occurred more frequently in transfused patients (18%) than controls (3%) (P = 0.04). Blood stored for > or =3 days was associated with fewer early rejections than blood stored < or =2 days. Overall, class II antigen mismatches were associated with more rejection episodes than class I antigen mismatches. However, transfused patients, but not control patients, with more class I antigen mismatches were more likely to have rejections. CONCLUSIONS: Administration of DSTs by the method described had no practical influence on patient or graft survival for up to 2 years. However, donor-specific hyporesponsiveness was more common in transfused patients (18 vs. 3%). Longer follow-up will be needed to determine whether DST will be associated with long-term benefit.

Tacrolimus vs Neoral in renal and renal/pancreas transplantation.

In a retrospective analysis we compared the outcome of a group of 63 kidney or kidney/pancreas transplant recipients who were transplanted between June 1994 and February 1997 and received either tacrolimus (FK, n = 22) or Neoral (NEO, n = 41) as part of a triple immunosuppressive protocol. Ten patients in the NEO group has recurrent rejection episodes between 1 and 8 months post-transplant and were converted to FK. CellCept was the secondary immunosuppressive agent in about half the FK, three-quarters of the NEO, and in all but one in the conversion (CON) groups. Patients in all groups were on prednisone in equal amounts. Mean duration of follow-up for FK, NEO and CON groups was 32, 19 and 13 months, respectively. One-yr patient and graft survival was 100% in all groups. At 2 yr, graft survival was 95, 96 and 100% in FK, NEO and CON groups, respectively. Acute rejection at 1 yr was twice as high in the NEO group as the FK group. There were no rejection episodes among the FK patients who also received CellCept. The mean current serum creatinines (mg%) were: FK = 1.6, NEO = 1.8, CON = 1.9. Recurrent infection was more common with FK (8/22) than NEO (1/31) (p = 0.023). Our experience suggests there is less rejection but more infection in recipients treated with FK compared to NEO. In patients with recurrent rejection, conversion from NEO to FK stabilizes renal function and minimizes subsequent rejection episodes.

Ablating the ischemia-reperfusion injury in non-heart-beating donor kidneys.

BACKGROUND: The objective of this study was to determine if allopurinol (AL) and/or trifluoperazine (TFP) added to the Belzer machine preservation solution (MPS) improves the function of non-heart-beating donor (NHBD) canine kidneys. METHODS: Anesthetized canines underwent bilateral dissection of the renal vessels, obtaining baseline flow. After removing one kidney (heart-beating donor [HBD]), the dog was exsanguinated. After remaining in situ for 120 min (30-min warm ischemia time, 90-min cold ischemia time), the second kidney was removed (NHBD), flushed, biopsied, and weighed. The kidneys were machine-perfused separately for 20 hr, and pressure, flow, and resistance were measured serially. The kidneys were randomly assigned to a perfusate group (G): G1=MPS, G2=MPS+TFP, G3=MPS+AL, and G4=MPS+TFP+AL. Kidneys were implanted separately into a single recipient dog. Flow, resistance, and urine output were measured serially for 4 hr. Blood and urine samples and kidney biopsies were then obtained. All measurements were standardized to 100 g of kidney weight. RESULTS: HBD kidneys functioned better than NHBD kidneys in all groups, as expected. Although perfusate G1 was the most effective solution for HBD kidneys, the TFP additive (perfusate G2) more effectively reversed the vasospastic effects of ischemia/reperfusion for NHBD than the MPS solution (G1) with or without other additives. In HBD kidneys, the addition of AL resulted in the best creatinine clearance; however, AL was less effective than MPS alone in NHBD kidneys. TFP+AL together were completely ineffective in preserving renal function, regardless of whether the kidneys were from HBD or NHBD. CONCLUSIONS: MPS+TFP more effectively protected renal function against reperfusion injury in the NHBD than MPS alone, AL, or AL+TFP. AL exerts a salutary effect on creatinine clearance in HBD but not in the NHBD. The TFP and AL combination should not be used together with the MPS in machine preservation of kidneys.

Current thinking on chronic renal allograft rejection: issues, concerns, and recommendations from a 1997 roundtable discussion.

Chronic rejection accounts for most renal allograft losses after the first year posttransplantation. On March 24 and 25, 1997, a roundtable of five transplant surgeons, two nephrologists, and one pathologist assembled in Dallas, Texas, to review critical issues surrounding chronic renal allograft rejection. This article summarizes the presentations and relevant discussions of this meeting regarding the cause of chronic rejection, clinical diagnoses, risk factors, future prospects for intervention strategies, and general recommendations for the transplant community. Growing evidence indicates that chronic rejection is the aggregate sum of irreversible immunologic and nonimmunologic injuries to the renal graft over time. A history of acute rejection episodes and inadequate immunosuppression, likely attributable to inconsistent cyclosporine exposure or poor patient compliance, are among the most recognizable immunologic risk factors for chronic rejection. Donor organ quality, delayed graft function, and other donor and recipient variables leading to reduced nephron mass are nonimmunologic factors that contribute to the progressive deterioration of renal graft function. Clinical management of renal transplant recipients should incorporate both immunologic- and nonimmunologic-based intervention strategies aimed at minimizing risk factors to thwart the progression of chronic rejection and improve long-term allograft and patient survival.

Long-term graft survival after transplantation with kidneys from uncontrolled nonheartbeating donors.

BACKGROUND: Notwithstanding the widely acknowledged organ-donor shortage coupled with the expanded waiting list for organs, many transplant programs have been reluctant to use kidneys from nonheartbeating donors. Some reasons expressed by those programs include a higher rate of delayed graft function, additional dialysis requirements, more medication usage, and inferior graft survival rates. To refute the common misperceptions, we reviewed our 4-year experience with 31 nonheartbeating donor kidneys recovered from uncontrolled donors (Maashticht classification) at our institution. METHODS: After cardiac arrest and declaration of death, all donors underwent intravascular and intraperitoneal cooling. Immediately after bilateral en bloc nephrectomy, kidneys were placed on the Waters MOX pulsatile preservation machine. Preservation parameters were monitored hourly, using pharmacologic agents (Stelazine, dexamethasone, Humulin R) as indicated by those parameters. RESULTS: The nonheartbeating donors ranged in age from 15 to 53 years, 83% were males, and 60% of deaths were caused by trauma. For the 21 recovered and transplanted at our center, delayed graft function occurred with 16 kidneys; there was no primary nonfunction. There was no obvious correlation between functional status and donor age. It was noted that the immediate-function kidneys had shorter warm ischemia and total preservation times compared with the delayed graft function group. Nineteen of the 21 grafts continue to function. All patients are surviving. CONCLUSIONS: This series suggests that to obtain excellent results with nonheartbeating donor kidneys certain principles should be followed: use machine preservation to resuscitate and evaluate viability, choose immunologically low-risk recipients, avoid immediate exposure to immunophilin antagonists, and perform biopsy frequently for allograft dysfunction to exclude low-grade rejection.

Hyperacute rejection from antibody against class II HLA antigens.

The clinical significance of anti-B-cell antibodies in kidney and pancreas transplantation remains unresolved. Here, we report an isolated hyperacute rejection of the kidney, but not the pancreas, during a simultaneous kidney-pancreas (SKP) transplant. The hyperacute rejection was due to IgG antibodies directed against class II antigens expressed on B-cells. Antibodies directed against class II antigens are generally not thought to produce hyperacute rejection, since class II antigens allegedly are minimally expressed on vascular endothelium in the kidney. The pancreas was spared and continues to function normally, suggesting that class II antigens were not strongly expressed in this pancreas. The differential susceptibility to B-cell antibodies of the two transplanted organs is noteworthy and should call attention to the danger from IgG antibodies to class II antigens in kidney transplantation.

Results of the double-blind, randomized, multicenter, phase III clinical trial of Thymoglobulin versus Atgam in the treatment of acute graft rejection episodes after renal transplantation.

BACKGROUND: Thymoglobulin, a rabbit anti-human thymocyte globulin, was compared with Atgam, a horse anti-human thymocyte globulin for the treatment of acute rejection after renal transplantation. METHODS: A multicenter, double-blind, randomized trial with enrollment stratification based on standardized histology (Banff grading) was conducted. Subjects received 7-14 days of Thymoglobulin (1.5 mg/kg/ day) or Atgam (15 mg/kg/day). The primary end point was rejection reversal (return of serum creatinine level to or below the day 0 baseline value). RESULTS: A total of 163 patients were enrolled at 25 transplant centers in the United States. No differences in demographics or transplant characteristics were noted. Intent-to-treat analysis demonstrated that Thymoglobulin had a higher rejection reversal rate than Atgam (88% versus 76%, P=0.027, primary end point). Day 30 graft survival rates (Thymoglobulin 94% and Atgam 90%, P=0.17), day 30 serum creatinine levels as a percentage of baseline (Thymoglobulin 72% and Atgam 80%; P=0.43), and improvement in posttreatment biopsy results (Thymoglobulin 65% and Atgam 50%; P=0.15) were not statistically different. T-cell depletion was maintained more effectively with Thymoglobulin than Atgam both at the end of therapy (P=0.001) and at day 30 (P=0.016). Recurrent rejection, at 90 days after therapy, occurred less frequently with Thymoglobulin (17%) versus Atgam (36%) (P=0.011). A similar incidence of adverse events, post-therapy infections, and 1-year patient and graft survival rates were observed with both treatments. CONCLUSIONS: Thymoglobulin was found to be superior to Atgam in reversing acute rejection and preventing recurrent rejection after therapy in renal transplant recipients.

Successful long-term kidney-pancreas transplants in diabetic patients with high C-peptide levels.

BACKGROUND: Pancreas transplants are rarely done in type 2 (noninsulin dependent) diabetic patients. Most researchers believe that in type 2 diabetic patients, peripheral insulin resistance plays a central role and also is associated with relative insulin deficiency or an insulin secretory defect. This suggests that in patients receiving transplants, the new beta cells will be overstimulated, leading to beta cell "exhaustion" and graft failure. METHODS: Early in our experience, simultaneous pancreas-kidney transplant candidates were selected using only clinical criteria for type 1 diabetes, i.e., early onset of diabetes and rapid onset of insulin use. Pretransplant sera were available for C-peptide analysis in 70 of 94 of those patients. Forty-four percent (31/70) were African American (AA). RESULTS: Thirteen patients (12 AA) with a nonfasting C-peptide level >1.37 ng/ml were identified. In these patients with high C-peptide levels, pancreas and kidney survival rates were 10O%. The results did not differ statistically from the low C-peptide group (< or =1.37 ng/ ml). There were no differences between patient and pancreas-kidney survival rates when the patients were separated into AA and non-AA groups. The follow-up was 1-89 months, with a mean of 45.5 months. CONCLUSIONS: Long-term pancreas graft function is attainable and beta cell "exhaustion" does not occur in patients with high preoperative C-peptide (>1.37 ng/ ml) levels. AA and non-AA patients have equivalent long-term patient, kidney, and pancreas-kidney graft survival rates.

Increased incidence of insulin-dependent diabetes mellitus in pediatric renal transplant patients receiving tacrolimus (FK506)

BACKGROUND: Use of tacrolimus (FK506), a potent immunosuppressive agent, has been reported to have a 10-20% incidence of insulin-dependent diabetes mellitus (IDDM) in adults, but the incidence of IDDM in pediatric renal transplant recipients treated with this agent is unknown. In this article, we report our single-center experience with FK506-induced IDDM in children. METHODS: Five consecutive living related donor pediatric renal transplants were reviewed retrospectively. RESULTS: All five patients developed IDDM lasting longer than 6 months. Mean follow-up time was 18.6 months. CONCLUSIONS: Pediatric patients may be at high risk for developing FK506-induced IDDM.