Tacrolimus (FK506), a macrolide molecule that inhibits the expression of interleukin 2 by T lymphocytes, represents a potential major advance in the prevention of rejection following solid-organ transplantation (1). Tacrolimus has been shown to be an effective alternative to cyclosporine for the prevention of rejection and the treatment of refractory rejection after liver transplantation (2-6). Previous clinical trials in Japan, Europe, and the United States, including the University of Pittsburgh, also suggest that tacrolimus is an effective immunosuppressant in primary kidney transplantation (7-13).
In this article, the results at 12 months of a multicenter, randomized trial designed to compare the efficacy and safety of tacrolimus-based versus cyclosporine-based immunosuppression in patients receiving cadaveric kidney transplants are reported.
MATERIALS AND METHODS
This open-label study was conducted at 19 centers in the United States between November 1993 and August 1995. Patients were randomized after establishing renal allograft function to receive tacrolimus or cyclosporine and were stratified for the number of previous transplants and the study site. The protocol was approved by the institutional review board at each center, and the patients gave written informed consent before enrollment.
Male and female patients, 6 years of age or older, who had received a cadaveric kidney transplant (first or second transplant) were eligible. Transplant renal function was required to have improved postoperatively to the extent of achieving a serum creatinine concentration of ≤4 mg/dl after two successively declining daily determinations within 14 days after transplantation, without the need for interim dialysis. Patients were excluded if they had been recipients of a previous solid organ transplant and were still being administered immunosuppressive medication, were listed for any other solid organ transplant except a kidney transplant, or had received an ABO-incompatible transplant. Pregnant or nursing women were also excluded, as were patients who were seropositive for any of the human immunodeficiency viruses.
The first dose of study medication was administered within 1-15 days after transplantation. Patients assigned to tacrolimus (Prograf, Fujisawa USA, Deerfield, IL) received an initial oral dose of 0.10 mg/kg body weight every 12 hr. The target trough concentration of tacrolimus in whole blood was 10-25 ng/ml for the first 3 months after transplantation and 5-15 ng/ml thereafter. The dose of tacrolimus was titrated based on drug concentrations in whole blood, which were determined by using a microparticle enzyme immunoassay (IMx, Abbott Laboratories, Abbott Park, IL). Patients assigned to cyclosporine (Sandimmune, Sandoz Pharmaceuticals, East Hanover, NJ) received an initial oral dose of 5.0 mg/kg body weight every 12 hr. The target trough concentration of cyclosporine in whole blood was 150-400 ng/ml for the first 3 months after transplantation and 100-300 ng/ml for the duration of the study. The dose of cyclosporine was titrated based on drug concentrations in whole blood, which were determined by using high-performance liquid chromatography or by using a specific antibody to the parent compound. Subsequent dosing of tacrolimus or cyclosporine could be adjusted for the occurrence of adverse events or rejection.
All patients received combination immunosuppressive induction therapy with steroids, azathioprine, and an antilymphocyte antibody preparation before randomization. Intravenous methylprednisolone (500 mg) was administered on the day of transplantation. Oral methylprednisolone was administered at a daily dosage descending from 5.0 to 0.5 mg/kg for the first 14 postoperative days. The oral dosage was tapered to 25 mg/day by day 30 and to 10 mg/day during the first 180 days of the study. Intravenous azathioprine was administered on the day of transplantation at a dose of 2.0 to 4.0 mg/kg, followed by a daily oral dose of 1.5 mg/kg thereafter. The antilymphocyte antibody preparation was either muromonab-CD3 (OKT3, Orthoclone, Ortho Pharmaceuticals, Raritan, NJ) at a dose of 2.5-5.0 mg/day or antithymocyte globulin (ATGAM, Upjohn, Kalamazoo, MI) at a dose of 10-20 mg/kg/day. Antibody treatment was administered daily from the day of transplantation up to day 16 after transplantation, until patients had achieved stable target blood concentrations of study drug. Each center was required to use the same standard induction therapy for both treatment groups.
The design of the study permitted patients to cross over to the alternate study drug in cases of documented refractory rejection or after discontinuation from study drug because of an adverse event of grade 3 or greater according to World Health Organization toxicity criteria. Stringent guidelines for crossover were specified by the protocol, and compliance was enforced to minimize the potential impact of the extent of crossover between the two treatment groups.
Episodes of renal dysfunction defined either by an increased serum creatinine concentration of 0.5 mg/dl or greater or a doubling of serum creatinine concentration, as compared with baseline or serum nadir, were evaluated for possible rejection. All patients had kidney biopsies when rejection was suspected, unless the procedure was medically contraindicated. Kidney biopsies were reviewed by independent pathologists in a blinded fashion and scored according to the Banff working classification of kidney transplant pathology (14).
Rejection episodes were treated similarly for patients in both treatment groups. Intravenous methylprednisolone (7 mg/kg/day) was administered for 3 days, followed by oral prednisone, which was tapered as clinically indicated. Both steroid-resistant and severe, acute rejection were treated by the addition of muromonab-CD3 (5 mg/day i.v. for 7 to 14 days) or antithymocyte globulin (15-20 mg/kg/day i.v. for 7 to 14 days). Refractory rejection was treated by the most appropriate therapy as determined by the investigator.
The primary measures of efficacy were patient survival and graft survival at 1 year. Graft survival was defined as those patients who were alive at 1-year after transplantation with a functioning graft. The term graft loss was used to denote those patients who died or experienced graft failure. Secondary efficacy measures were graft failure (for any reason), acute rejection, and the use of antilymphocyte preparations for rejection. Graft failure, which excluded patients who died, was defined as a need for graft nephrectomy or permanent return to dialysis.
All patients were followed for 12 months after randomization or until death. Analysis was by intention to treat and included all patients who underwent randomization. Descriptive summaries for the time-to-event data for patient and graft survival were prepared by using the Kaplan-Meier product limit estimator. Multivariate Cox regression models were used to assess the consistency of the overall result. The comparison of the incidences of toxicity, graft failure, acute rejection, and the use of antilymphocyte preparations for rejection was based on Wilcoxon rank statistics and Fisher's exact tests. The consistency of the results for acute rejection was assessed by using the multivariate Cox regression model. Before data were pooled across sites, the potential interaction of treatment and study site was examined.
Characteristics of the Treatment Groups
A total of 412 patients were randomized after receiving a renal allograft: 205 patients entered the tacrolimus group and 207 entered the cyclosporine group. The median time from undergoing kidney transplantation to randomization was 4 days in both treatment groups. While overall the treatment groups were comparable with respect to patient demographic characteristics (Table 1), there were several differences in donor and recipient characteristics (Table 2). However, multivariate Cox regression analysis demonstrated no significant effect on patient and graft survival outcome or on the incidence of acute rejection.
While the mean dose of tacrolimus remained relatively constant during the study, the mean dose of cyclosporine was tapered over time, as is current clinical practice. After 1 year, the mean total daily dose of tacrolimus was 0.18 mg/kg compared with 5.50 mg/kg for cyclosporine-treated patients. Trough concentrations of tacrolimus and cyclosporine followed a similar trend (Fig. 1).
There were no significant differences between treatment groups in the mean dose of antilymphocyte antibody preparations used for induction therapy. Both treatment groups were comparable for azathioprine and oral steroid dose throughout the study.
Patient survival, graft survival, and graft failure. All patients were followed up for 1 year or to the time of death. The 1-year patient survival rate was 95.6% for tacrolimus-treated patients and 96.6% for cyclosporine-treated patients (P=0.576). The 1-year graft survival rate was 91.2% for tacrolimus-treated patients and 87.9% for cyclosporine-treated patients (P=0.289). Covariate analysis indicated that, regardless of treatment, the number of HLA mismatches, panel-reactive antigen grade, and the number of previous renal transplants had no effect on patient or graft survival.
Sixteen patients died during the study; nine patients (4.4%) were in the tacrolimus group, and seven patients (3.4%) were in the cyclosporine group. The most common cause of death in both groups was infection (Table 3). These deaths are reflected in the incidence of graft loss, which was 8.8% in patients treated with tacrolimus and 12.1% in patients treated with cyclosporine. There were fewer graft failures in patients treated with tacrolimus; 4.9% of the tacrolimus-treated patients experienced graft failure compared with 9.2% of the cyclosporine-treated patients, but this difference was not statistically significant (P=0.098, Table 3).
Acute rejection and use of antilymphocyte treatment. Ninety-five percent of all clinically diagnosed acute rejection episodes were confirmed by biopsy for both treatment groups. There was a significant reduction in the incidence of biopsy-confirmed acute rejection in the tacrolimus-treated patients (30.7%) compared with the cyclosporine-treated patients (46.4%, P=0.001) (Fig. 2). Blinded review of 97.7% of all biopsies by independent pathologists confirmed these results. The rates of acute rejection in the two treatment groups based on blinded review were 27.8% in tacrolimus-treated patients and 44.4% in cyclosporine-treated patients (P<0.001). Classification of acute rejection episodes according to severity indicated that significantly more cyclosporine-treated patients had moderate or severe acute rejections compared with tacrolimus-treated patients (P<0.001) (Table 4). Covariate analysis indicated that the occurrence of acute rejection was significantly correlated with graft loss.
The use of antilymphocyte antibody therapy for rejection in each treatment group was consistent with the incidence and severity of acute rejection. The cyclosporine-treated group required more antilymphocyte treatment for rejection (10.7% of the tacrolimus-treated patients compared with 25.1% of the cyclosporine-treated patients; P<0.001).
Adverse events were reported for all patients. Impaired renal function (not associated with rejection), gastrointestinal disorders, and neurological complications were commonly reported in both treatment groups (Table 5). The majority of these events occurred early in the study (within the first 3 months after treatment) and in some cases required treatment or dose reduction. The most frequently reported events related to renal function were increased serum creatinine concentrations and oliguria that were of relatively brief duration. Long-term monitoring of serum creatinine concentrations suggested that there was no trend toward loss of renal function in either group. The mean serum creatinine concentration was 1.66 mg/dl in the tacrolimus group and 1.64 mg/dl in the cyclosporine group 1 year after transplantation. There was a trend toward the reporting of more dyspepsia, a vague gastrointestinal complaint, in the tacrolimus group (P=0.056); however, these events rarely lasted longer than 1-2 days and responded to dose reduction.
Tremor was the most commonly reported neurological complication in tacrolimus-treated patients, and the frequency of this adverse event was significantly greater than it was for patients receiving cyclosporine (Table 5). There was also a greater incidence of paresthesia in tacrolimus-treated patients; however, the incidence of both tremor and paresthesia that required a dosage change or treatment was similar between the treatment groups.
Hypertension was reported as an adverse event in 49.8% of tacrolimus-treated patients and 52.2% of cyclosporine-treated patients (Table 5). However, by 1 year, 39.4% and 30.2% of tacrolimus-treated and cyclosporine-treated patients, respectively, were off of all antihypertensive medications. Deep vein thrombosis was reported more frequently in the tacrolimus group (11 patients) compared with the cyclosporine group (1 patient); however, all of these patients had factors known to be associated with a predisposition to deep vein thrombosis, and 5 of the 11 cases were reported by a single study center.
Endocrine disorders. The initial incidence of posttransplant diabetes mellitus (PTDM*), which was defined as the use of insulin for 30 days or longer in patients who had no history of insulin-dependent diabetes mellitus or non-insulin-dependent diabetes mellitus, was 19.9% in tacrolimus-treated patients and 4.0% in cyclosporine-treated patients. Of the 36 patients who developed PTDM, seven tacrolimus-treated patients and one cyclosporine-treated patient were able to discontinue insulin treatment within the first year. Five of the tacrolimus-treated patients were weaned from insulin without discontinuing tacrolimus or steroid therapy, and two patients discontinued insulin after crossover to cyclosporine. Covariate analyses showed that patient race, steroid dose, and trough levels of tacrolimus were significant predictors for the development of PTDM. The risk of developing PTDM for black or Hispanic patients was 3.3 times that of white patients or other patients in both treatment groups. With regard to steroid dose, 75% of the patients who developed PTDM had maximum total daily steroid doses of 25 mg/day or greater within a 30-day period before the onset of PTDM.
The incidence of hyperlipidemia and hypercholesterolemia was substantially higher in cyclosporine-treated patients than in tacrolimus-treated patients. The mean total cholesterol level after 12 months of treatment was 193.9 mg/dl in the tacrolimus group and 229.8 mg/dl (P<0.001) in the cyclosporine group. Triglyceride and low-density lipoprotein levels were also significantly lower in tacrolimus-treated patients. The well-documented side effects of cyclosporine, including hirsutism, gingivitis, and gum hyperplasia, were rarely observed with tacrolimus treatment. However, alopecia and pruritus occurred more frequently in tacrolimus-treated patients.
Infections and malignancies. The overall infection rates were comparable between treatment groups: 72.2% of the tacrolimus-treated patients and 75.8% of the cyclosporine-treated patients reported infections. The incidence of opportunistic infections was also similar between tacrolimus- and cyclosporine-treated patients (Table 6). No cases of Pneumocystis carinii pneumonia were reported during the study.
Few malignancies were reported during the study. Five patients (2.4%) in the tacrolimus group and eight patients (3.9%) in the cyclosporine group developed malignancies. Of these, three (1.5%) tacrolimus-treated patients and two (1.0%) cyclosporine-treated patients developed a lymphoma, and three (1.4%) cyclosporine-treated patients and no tacrolimus-treated patients developed posttransplant lymphoproliferative disease. Four of these eight patients lost their grafts, but all were alive at 1 year after transplant.
Crossover from study medication. Fourteen patients (6.8%) initially randomized to tacrolimus crossed over to treatment with cyclosporine, and 32 patients (15.5%) initially randomized to cyclosporine crossed over to tacrolimus (P=0.007). More patients randomized to tacrolimus crossed over to cyclosporine because of an adverse event, primarily because of neurologic (n=6) and gastrointestinal disorders (n=3). In contrast, more patients randomized to cyclosporine (n=27) crossed over to tacrolimus because of recurring or ongoing rejection. Twenty-one (77.8%) of the 27 refractory rejection episodes resolved after crossover to tacrolimus; the remaining six patients lost their grafts. One of the two refractory rejection episodes resolved after crossover to cyclosporine.
This was an open-label, randomized, multicenter study to assess the efficacy and safety of tacrolimus versus cyclosporine for primary immunosuppression in patients receiving cadaveric kidney transplants. The most clinically significant finding of this study was the dramatic reduction in the incidence and severity of biopsy-proven acute rejection in patients treated with tacrolimus. The rate of acute rejection was 46.4% in the cyclosporine group and 30.7% in the tacrolimus group. Moderate and severe rejection by the Banff criteria occurred 2.5 times more often in the cyclosporine-treated group, resulting in a significantly increased use of antilymphocyte antibody rejection therapy in these patients. It is noteworthy that the incidence of antilymphocyte antibody treatment in the cyclosporine (25.1%) and the tacrolimus (10.7%) groups was similar to that recently reported in the randomized double-blind trial of mycophenolate mofetil, in which 20.1% of the cyclosporine-azathioprine-treated control group versus 10.3% of the cyclosporine-mycophenolate mofetil group (2 g) received antilymphocyte antibody treatment for rejection (15). These findings suggest that a regimen consisting of tacrolimus, azathioprine, and corticosteroids is as effective as one consisting of mycophenolate mofetil, cyclosporine, and corticosteroids for preventing moderate to severe rejection that requires antilymphocyte treatment.
The ability of tacrolimus to reduce the incidence and severity of acute rejection in renal transplant recipients compared with cyclosporine-based immunosuppression raises important issues with regard to long-term patient and graft survival under tacrolimus-based immunosuppression. Several studies have shown that acute rejection is a major risk factor for graft loss, perhaps due to a subsequent predisposition to chronic rejection. Basadonna et al. (16), in a study of 219 primary living related kidney transplant recipients and 205 recipients of a cadaveric transplant, found that an acute rejection episode significantly increased the risk of developing biopsy-proven chronic rejection.
In an analysis of 665 consecutive primary cadaveric transplants, Ferguson (17) reported that the most important predictor of long-term graft survival was the presence or absence of one or more acute rejection episodes. Graft half-life in these patients without acute rejection was 16.9 years, compared with 3.9 years in patients who experienced acute rejection. Thus, the findings by Gjertson et al. (18), who reported a significant increase in the half-life of renal allografts in patients treated with tacrolimus (14 years) compared with cyclosporine-treated patients (8-9 years), may be related to the marked reduction in the incidence and severity of acute rejection afforded by tacrolimus, compared with cyclosporine.
The etiology of chronic rejection appears to be complex and includes risk factors such as histocompatibility, renal function in the preoperative period, donor age, frequency and intensity of acute rejection episodes, infections (particularly cytomegalovirus), and lipid abnormalities in the graft recipient (19, 20). Since there is no effective treatment for chronic rejection, prevention or the reduction in the intensity of acute rejection episodes may be of critical importance to improved long-term graft survival (20). To further evaluate this hypothesis, continued follow-up for a total of 5 years is planned in the present study.
In this study, the overall rates of nephrotoxicity, gastrointestinal disorders, cardiovascular events, malignancies, and infections were in general similar between treatment groups. There was a greater incidence of neurologic events in tacrolimus-treated patients, primarily tremor and paresthesia, which were typically mild and not treatment limiting.
The two prominent differences that were noted in the safety profiles of tacrolimus and cyclosporine were with respect to glucose metabolism and lipid metabolism. The initial incidence of PTDM in tacrolimus-treated patients (19.9%) was significantly greater compared with cyclosporine-treated patients (4.0%). The dose-dependent relationship of tacrolimus with the development and severity of impaired glucose metabolism has been demonstrated in animal models (21-24). In previous clinical studies, the incidence of PTDM in tacrolimus-treated patients has ranged from 5% to 20% (25-28). Historically, PTDM incidence rates for renal transplant patients treated with cyclosporine in combination with steroids (with or without azathioprine) have ranged from 3% to 30% (29-31). In the present study, the development of PTDM was correlated with steroid dose and tacrolimus blood levels and was reversible in a number of patients by the end of the 1-year follow-up assessment. Although no attempt was made to treat PTDM by the reduction of either the dose of corticosteroids or tacrolimus in this study, the data suggest that this strategy might be effective. Further studies and experience with tacrolimus-based immunosuppressive regimens are needed to determine the best strategy to minimize the risk of developing PTDM.
Unlike cyclosporine, tacrolimus does not appear to be associated with elevated serum lipid levels. Tacrolimus-treated patients had significantly lower mean levels of serum cholesterol, triglyceride, and low-density lipoprotein after 12 months of treatment. Since it has been reported that lipid abnormalities, particularly hypercholesterolemia, contribute to the development of chronic vascular rejection and graft loss, it might be speculated that tacrolimus therapy is potentially beneficial in this respect (32).
Adherence to the protocol was monitored closely for patients who crossed over from their primary treatment; however, it is likely that some bias occurred as a result of the open-label study design. More cyclosporine-treated patients discontinued randomized therapy and most patients were crossed over from cyclosporine to tacrolimus therapy because of efficacy, i.e., refractory rejection. On the other hand, more tacrolimus-treated patients discontinued treatment because of adverse events or presumed drug toxicity. The most common adverse event leading to crossover was neurologic in origin (6 out of 11, 54.5%, crossed over because of an adverse event). These events (seizure, headache, and weakness of the lower extremity) resolved after crossover.
In summary, this study demonstrates that tacrolimus is a safe and effective alternative to cyclosporine for primary immunosuppression in renal transplant recipients. Moreover, tacrolimus is superior to cyclosporine in its ability to reduce the incidence and severity of acute rejection. Tacrolimus is not associated with elevated serum lipid levels like cyclosporine; however, there is an increased risk of dose-related PTDM and neurotoxicity associated with its use. It is likely that these side effects can be better managed or further reduced with increasing clinical experience.
Acknowledgments. The authors acknowledge the efforts of the Data Monitoring Board: Tom Fleming, MD (University of Washington); Ron Shapiro, MD (University of Pittsburgh); and Leendert Paul, MD, PhD (University of Toronto). They also acknowledge Deborah M. Bellingham, PhD, and Shari R. Bodnoff, PhD, for their assistance in preparation of the manuscript and Jay Erdman and Mitsutoshi Mukai for programming and biostatistical support.
This study was sponsored by a grant from Fujisawa USA, Inc., Deerfield, IL.
Abbreviation: PTDM, posttransplant diabetes mellitus.
1. Goto T, Kino T, Hatanaka M, et al. FK506: historical perspectives. Transplant Proc 1991; 23: 2713.
2. US Multicenter FK506 Liver Study Group. A comparison of tacrolimus (FK506) and cyclosporine for immunosuppression in liver transplantation. N Engl J Med 1994; 331: 1110.
3. European FK506 Multicentre Liver Study Group. Randomised trial comparing tacrolimus (FK506) and cyclosporin in prevention of liver allograft rejection. Lancet 1994; 344: 423.
4. Fung J, Abu-Elmagd K, Jain A, et al. A randomized trial of primary liver transplantation under immunosuppression with FK506 vs cyclosporine. Transplant Proc 1991; 23: 2977.
5. Takaya S, Bronsther O, Todo S, et al. Retransplantation of liver: a comparison of FK506- and cyclosporine-treated patients. Transplant Proc 1991; 23: 3026.
6. Tzakis AG, Reyes J, Todo S, et al. FK506 versus cyclosporine in pediatric liver transplantation. Transplant Proc 1991; 23: 3010.
7. Shapiro R, Jordan M, Scantlebury V, et al. FK506 in clinical kidney transplantation. Transplant Proc 1991; 23: 3065.
8. Japanese FK506 Study Group. Clinicopathological evaluation of kidney transplants in patients given a fixed dose of FK506. Transplant Proc 1991; 23: 3111.
9. Japanese FK506 Study Group. Japanese study of FK506 on kidney transplantation: results of an early phase II study. Transplant Proc 1991; 23: 3071.
10. Japanese FK506 Study Group. Japanese study of FK506 on kidney transplantation: results of late phase II study. Transplant Proc 1993; 25: 649.
11. Shapiro R, Jordan ML, Scantlebury VP, et al. A prospective, randomized trial of FK506/prednisone vs FK506/azathioprine/prednisone in renal transplant patients. Transplant Proc 1995; 27: 814.
12. Schleibner S, Krauss M, Wagner K, et al. FK506 versus cyclosporine in the prevention of renal allograft rejection-European pilot study: six-week results. Transplant Int 1995; 8: 86.
13. Laskow DA, Vincenti F, Neylan J, et al. Phase II FK 506 multicenter concentration control study: one-year follow-up. Transplant Proc 1995; 27: 809.
14. Solez K, Axelsen RA, Benediktsson H, et al. International standardization of criteria for the histologic diagnosis of renal allograft rejection: the Banff working classification of kidney transplant pathology. Kidney Int 1993; 45: 411
15. Sollinger HW for the U.S. Renal Transplant Mycophenolate Mofetil Study Group. Mycophenolate mofetil for the prevention of acute rejection in primary cadaveric renal allograft recipients. Transplantation 1995; 60: 225.
16. Basadonna GP, Matas AJ, Gillingham KJ, et al. Early vs late acute renal allograft rejection: impact on chronic rejection. Transplantation 1993; 55: 993.
17. Ferguson R. Acute rejection episodes: best predictor of long-term primary cadaveric renal transplant survival. Clin Transplant 1994; 8: 328.
18. Gjertson DW, Cecka JM, Terasaki PI. The relative effects of FK506 and cyclosporine on short- and long-term kidney graft survival. Transplantation 1995; 60: 1384.
19. Häyry P. Chronic allograft rejection: an update. Clin Transplant 1994; 8: 160.
20. Matas AJ. Chronic rejection: definitions and correlates. Clin Transplant 1994; 8: 162.
21. Hirano Y, Fujihara S, Ohara K, et al. Morphological and functional changes in islets of Langerhans in FK506-treated rats. Transplantation 1992; 53: 889.
22. Tze WJ, Tai J, Murase N, et al. Effect of FK506 on glucose metabolism and insulin secretion in rats. Transplant Proc 1991; 23: 3158.
23. Ericzson BG, Wijnen RMH, Kobota K, et al. FK506-induced impairment of glucose metabolism in the primate: studies in pancreatic transplant recipients and in non-transplanted animals. Transplantation 1992; 54: 615.
24. Carroll PB, Boschero AC, Li MY, et al. Effect of the immunosuppressant FK506 on glucose-induced insulin secretion from adult rat Islets of Langerhans. Transplantation 1991; 51: 275.
25. Jordan ML, Shapiro R, Vivas CA, et al. FK506 “rescue” for resistant rejection of renal allografts under primary cyclosporine immunosuppression. Transplantation 1994; 57: 860.
26. Scantlebury V, Shapiro R, Fung J, et al. New onset diabetes in FK506 vs cyclosporine-treated kidney transplant recipients. Transplant Proc 1991; 23: 3169.
27. Shapiro R, Jordan M, Fung J, et al. Kidney transplantation under FK506 immunosuppression. Transplant Proc 1991; 23: 920.
28. Shapiro R, Jordan ML, Scantlebury VP, et al. A prospective, randomized trial of FK506/prednisone vs FK506/azathiprine/prednisone in renal transplant patients. Transplant Proc 1995; 27: 814.
29. Yamamoto H, Akazawa S, Yamaguchi Y, et al. Effects of cyclosporine A and low dosages of steroids on posttransplantation diabetes in kidney transplant recipients. Diabetes Care 1991; 14: 867.
30. Von Kiparski A, Frei D, Uhlschmid G, et al. Post-transplant diabetes mellitus in renal allograft recipients: a matched pair control study. Nephrol Dial Transplant 1990; 5: 220.
31. Krentz AJ, Dmitrewski J, Mayer D, Nattrass M. Effects of immunosuppressive agents on glucose metabolism: implication for the development of post-transplant diabetes mellitus. Clin Immunother 1995; 4: 103.
32. Dimeny E, Fellstrom B, Larsson E, et al. The role of lipoprotein abnormalities in chronic vascular rejection after kidney transplantation. Transplant Proc 1995; 27: 2036.