Maintenance immunosuppressive regimens have routinely included corticosteroids since the combination of cyclosporine (CsA) and corticosteroids proved so successful in obtaining long-term graft and patient survival after kidney and liver transplantation. However, the dark side of chronic corticosteroid therapy in transplant recipients has been long recognized, and attempts at partial or complete withdrawal of corticosteroids date back to the early 1990s. Although controversial because of the inherent risk of rejection, total withdrawal of corticosteroids from transplant immunosuppressive regimens may be possible with the advent of a number of new agents.
The 1-year results of a prospective, randomized, open-label, single-center study comparing continuous corticosteroid therapy to corticosteroid withdrawal after pancreas transplantation were presented by Dr. Gruessner of the University of Minnesota, Minneapolis. Six-month interim results of this study were originally presented at Transplant 2000.
A total of 30 simultaneous pancreas-kidney (SPK) and 26 sequential pancreas after kidney (PAK) transplant recipients with functioning grafts at 6-36 months posttransplantation were randomized to either continued corticosteroid therapy or corticosteroid withdrawal. All patients had no episodes of rejection for at least 6 months prior to enrollment. The pre-enrollment immunosuppressive regimen consisted of quadruple therapy with antibody induction, tacrolimus (TAC), mycophenolate mofetil (MMF), and prednisone. Randomization criteria included the ability to tolerate TAC levels above 8 ng/mL and MMF at a minimum dose of 750 mg twice daily. In eligible patients, prednisone was decreased by 2.5 mg every other week; withdrawal was completed within 4-8 weeks.
Equal numbers of patients in the SPK and PAK groups were randomized to continued corticosteroids or corticosteroid withdrawal. Follow-up from the time of randomization ranged from 7-24 months in the SPK group and 13-24 months in the PAK group. There were no differences in demographics between the continuous corticosteroid and corticosteroid withdrawal groups for SPK and PAK. The SPK group however, had a significant increase in weight from the time of transplantation to the time of randomization. In the PAK group, 18 patients received kidneys from living donors and 8 from cadaveric donors.
Patient and pancreas graft survival rates were 100% in all groups. There were no episodes of rejection in either of the SPK groups. In the PAK group, there was 1 episode of rejection in a patient on corticosteroids and 1 episode in a patient randomized to corticosteroid withdrawal. There were 6 dropouts in the study, including 2 control and 4 corticosteroid withdrawal patients. When comparing patients continuing on corticosteroids vs those randomized to withdrawal, there were no differences in hemoglobin A1C levels, body weight, urine amylase, or serum creatinine levels. A significant decrease in total cholesterol was noted in the SPK patients randomized to corticosteroid withdrawal. Improved quality of life with fewer immunosuppressant side effects was noted in both SPK and PAK patients randomized to corticosteroid withdrawal.
The investigators concluded that corticosteroid withdrawal after SPK and PAK transplantation in selected patients on TAC plus MMF immunosuppression is safe and effective and did not result either in a decrease in graft survival or an increase in rejection rates.
A single-center experience with 40 consecutive SPK recipients (all with systemic-enteric drainage) enrolled over a 12-month period into a randomized study of rapid corticosteroid withdrawal was reported by Dr. Kaufman and associates of Northwestern University, Chicago, Illinois. Minimum and mean follow-up were 3 and 9 months, respectively. Patients were analyzed on an intent-to-treat basis. All patients received rabbit antithymocyte globulin (ATG) induction with 7-8 doses administered over 14 days in combination with TAC (target levels of 9-12 ng/mL). All patients also underwent a rapid corticosteroid taper with complete withdrawal on day 7. Twenty patients were randomized to TAC + sirolimus maintenance therapy and 20 were randomized to TAC + MMF at a dosage of 2 grams daily.
These 40 patients (the study group) were compared to a historical control group of 86 SPK transplant recipients who received TAC, MMF, and prednisone triple therapy in association with antibody induction (50 ATG, 36 daclizumab). The control group had a mean follow-up of 37 months, and no patients were withdrawn from corticosteroid therapy. Patient, kidney, and pancreas graft survival rates were 100% in the study group. None of the patients randomized to sirolimus experienced rejection, and only 1 patient randomized to MMF had a rejection episode (5% incidence). The incidence of acute rejection in the historical control group was 20%.
The authors noted leukopenia but no anemia in the study group. In patients receiving sirolimus, a slight decrease in platelet counts and an increase in triglyceride levels were noted. There were no differences in cholesterol levels in patients receiving sirolimus or MMF. Gastrointestinal symptoms were more prevalent in patients receiving the TAC + MMF. A total of 5 crossover patients experienced either leukopenia or GI symptoms.
They concluded that excellent early results can be achieved with rapid corticosteroid withdrawal in SPK transplant recipients using antibody induction therapy and either TAC + MMF or TAC + sirolimus maintenance therapy.
In the discussion of both of these papers, it was noted that since follow-up is relatively short, it is unclear whether corticosteroid withdrawal has a detrimental effect on kidney and/or pancreas graft half-lives. Moreover, it was emphasized that surveillance biopsy data is lacking and the intensity of monitoring must be increased after withdrawing patients from corticosteroid therapy. However, both of these studies reported encouraging early results with corticosteroid withdrawal using contemporary immunosuppression in transplant recipients who heretofore were not thought to be candidates for successful corticosteroid discontinuation.
Recent research has focused on the role of the interleukin-2 (IL-2) receptor in graft rejection as T-cell proliferation — a central event leading to graft rejection — is triggered by the interaction of IL-2 with its receptor on activated T cells. Anti-CD25 monoclonal antibodies (Mabs) that selectively block IL-2 receptors on activated T-helper cells have been used prophylactically as complementary immunosuppression with CsA and corticosteroids to allow reduced dosing of CsA in the early posttransplantation period.
The MAbs block the stimulation of T-cell IL-2 receptor sites by IL-2, and CsA prevents gene transcription activation by IL-2. Two types of anti-CD25 MAbs, chimerized (approximately 75% human and 25% murine protein) and humanized (approximately 90% human and 10% murine protein), have been used. Daclizumab is the humanized MAb and basiliximab is the chimeric MAb that bind specifically to the alpha or Tac subunit of the human high-affinity IL-2 receptor that is expressed on the surface of activated lymphocytes. Daclizumab and basiliximab are both clinically effective. Both have been shown to decrease the incidence of acute kidney allograft rejection when combined with a CsA-based triple therapy regimen. Both daclizumab and basiliximab have been shown in large, prospective, randomized, controlled, blinded trials to reduce the incidence of acute rejection and have been well tolerated without side effects or evidence of toxicity.[4-9]
Daclizumab is a genetically engineered human immunoglobulin G (IgG) monoclonal antibody that binds specifically to the alpha subunit (Tac/CD25) of the IL-2 receptor on the cell surface of activated lymphocytes. The interim 6-month results of an ongoing multicenter, open-label, comparative trial of 2 daclizumab dosing strategies vs no antibody induction in combination with TAC, MMF, and corticosteroids in SPK recipients was reported by Dr. Stratta of the University of Tennessee, Memphis, and the PIVOT Study Group. The PIVOT study group includes 24 US and 1 Canadian transplant center. Eligibility criteria are liberal and include nearly all potential SPK transplant recipients.
Patients were maintained on TAC, MMF, and prednisone triple therapy and then randomized to 1 of 3 study arms: (1) Group 1 – daclizumab 1 mg/kg every 2 weeks for a total of 5 doses; (2) Group 2 – daclizumab 2 mg/kg on days 0 and 14 for a total of 2 doses; or (3) Group 3, the control group — no antibody induction therapy. TAC levels were maintained above 10 ng/mL for the first month posttransplantation and greater than 8 ng/mL thereafter. MMF was dosed at 2-3 g daily according to patient tolerability. Corticosteroids were tapered to 30 mg daily on day 7 and 15 mg daily on day 30.
The target enrollment for the study is 290 evaluable patients with a follow-up of 36 months. A total of 182 patients with 6-month follow-up were analyzed, including 76 in Group 1, 81 in Group 2, and 25 in Group 3. Demographic characteristics were similar among the 3 groups.
Patients were analyzed on an intent-to-treat basis. The primary end point is a composite of the incidence of acute kidney or pancreas allograft rejection, kidney or pancreas allograft loss, and death in the first 6 months after transplantation.
The incidence of delayed graft function ranged from 10% to 12% among the 3 groups. Actual 6-month patient survival rates ranged from 96% to 98%. Kidney and pancreas graft survival rates ranged from 92% to 97% and 84% to 88%, respectively. The incidence of serious infection was similar among the 3 groups, ranging from 11% to 14%. Additional outcomes related to rejection and graft loss are listed in the Table.
Group 1 Group 2 Group 3 Rate of acute renal allograft rejection (%) 21 12 36 Rate of acute pancreas allograft rejection (%) 4 5 16 Overall rate of acute rejection (%) 24 16 44 Median time to first rejection episode (days) 23 58 25 Actuarial probability of any rejection (%) 25 13 41 Actuarial event-free survival* 62 79 48
*No rejection, graft loss, or death
The 2-dose daclizumab regimen appears to be as effective as the 5-dose daclizumab regimen in preventing early acute rejection after SPK transplantation. In addition, the 2-dose regimen appears to be associated with the highest rate of event-free survival. However, the benefits of daclizumab compared with no antibody induction await larger sample size accrual.
The updated 1-year results of a prospective, randomized, multicenter study conducted to assess the effect of antibody induction in SPK transplant recipients receiving maintenance triple therapy with TAC, MMF, and corticosteroids was presented by Dr. Burke and colleagues of the University of Miami, Florida. A total of 174 patients were randomized at 18 centers to receive either antibody induction therapy (n = 87) or no induction therapy (n = 87). The induction agents used were based on standard practice at each investigational site and were as follows: daclizumab (39), OKT3 (17), ATGAM (17), basiliximab (12), and thymoglobulin (2).
Target TAC levels were greater than 12 ng/mL in the first 3 months after transplantation and greater than 10 ng/mL thereafter. MMF was dosed at 2-3 g/day. The corticosteroid taper was designed to achieve a prednisone dose of 5-10 mg daily by 3 months after transplantation. In contrast to the daclizumab multicenter study, this study was more exclusive with respect to SPK recipients. Exclusion criteria included a panel reactive antibody titer above 20%, retransplantation, and failure of the serum creatinine level to decrease by more than 20% in the first 24 hours after transplantation.
During the enrollment period, the incidence of delayed graft function in the 2 groups ranged from 15% to 18%, and these patients were subsequently excluded from the study. Approximately two thirds of patients received pancreas transplantation with enteric drainage and one third received bladder drainage. The incidence of African-American ethnicity among recipients ranged from 8% to 11%. Demographic variables were similar in both groups.
One-year patient, kidney, and pancreas graft survival rates were similar among groups. Patient survival was 97% in both groups, kidney graft survival rates ranged from 92% to 96%, and pancreas graft survival rates were 84% in both groups. The 12-month incidence of any treated rejection was 24% with antibody induction and 30% without induction (P = NS). The incidence of biopsy-proven kidney or pancreas rejection was 20% with antibody induction and 26% without induction (P = NS), whereas the incidence of biopsy-proven kidney rejection was 12.6% with antibody induction vs 21.8% without induction (P = .07). The mean time to first acute rejection was 104 days with vs 51 days without antibody induction.
In African-American recipients, the odds of a biopsy-confirmed and treated acute kidney rejection were 5.3 times greater than in Caucasian recipients, despite comparable doses of TAC and MMF. The incidence of acute kidney rejection in African-American recipients was 43% in patients with and 50% in patients without antibody induction, compared to 10% with vs 18.8% without antibody induction in non-African-American recipients. No significant differences in pancreas rejection rates were noted among the groups. Although the incidence of tissue-invasive cytomegalovirus (CMV) disease was similar, the incidence of CMV viremia was higher in patients receiving anti-T-cell antibody induction. Renal and pancreas allograft function was similar in both groups.
Triple therapy with TAC, MMF, and corticosteroids either with or without antibody induction therapy provides excellent safety, tolerability, and efficacy in SPK transplant patients. However, the likelihood of acute rejection is much higher in African-American recipients. Moreover, anti-T-cell antibody induction agents were associated with a slightly increased incidence of CMV viremia or syndrome (P = .08), but fewer biopsy-confirmed and treated acute kidney rejection episodes (P = .07) in the first year.
TAC is a macrolide antibiotic isolated from Streptomyces tsukubaensis, which forms a complex with an intracellular-binding protein (FKBP12). A complex of TAC-FKBP12, calcium, calmodulin, and calcineurin is formed, inhibiting the phosphatase activity of calcineurin required for T-cell signaling.
Although the use of TAC with corticosteroids has markedly improved outcomes following pancreas transplantation, islet cell toxicity resulting in glucose intolerance occurs in some patients. Dr. Philosophe and colleagues, of the University of Maryland, Baltimore, presented their results with a management algorithm for the diagnosis and treatment of hyperglycemia after successful pancreas transplantation. It was noted that the use of calcineurin inhibitors such as TAC or CsA may result in a dose-related, reversible islet cell toxicity characterized by the histologic findings of cytoplasmic swelling, vacuolization, and loss of secretory granules in the beta, but not the alpha, cells. The study included 28 Type 1 diabetic patients with negligible C-peptide levels prior to surgery who underwent successful transplantation (8 SPK, 8 pancreas alone, 5 PAK, and 7 simultaneous cadaver pancreas and living donor kidney transplant recipients) and then developed hyperglycemia at a mean of 13 months posttransplantation. These episodes of posttransplant diabetes were characterized as Type 2 diabetes or insulin resistance. Their initial approach to posttransplant hyperglycemia included measuring a C-peptide level, calculating the increase in body mass index (BMI) posttransplantation, performing a pancreas biopsy, and reducing the corticosteroid dose. Following these maneuvers, the authors reported on 4 possible treatment options:
Overall, islet cell toxicity was confirmed histologically in 50% of patients. In some patients, histologic resolution of islet cell toxicity was documented with regression of cytoplasmic swelling and vacuolization and an increase in the number of secretory granules in beta cells. Conversion from TAC-based to sirolimus-based therapy in combination with MMF may be the single best treatment option for the management of drug-induced hyperglycemia following pancreas transplantation.
Although the mechanism of action of TAC closely parallels that of CsA, tacrolimus is a more potent calcineurin inhibitor. Randomized, multicenter trials comparing tacrolimus and CsA have shown tacrolimus to be a more effective primary agent than CsA for the prevention of acute kidney allograft rejection.[13-16] Here, results of TAC-based vs CsA-based immunosuppressive therapy in pancreas transplantation are reported.
The preliminary results of a multicenter, open-label, prospective, randomized, parallel-group study were presented by Dr. Saudek of Brussels, Belgium, representing the EUROSPK Study Group. This study was designed to enroll 200 SPK transplant recipients from 10 centers in Europe and 1 in Israel. All patients in the study are Type 1 diabetic individuals undergoing primary SPK transplantation. The 2 groups were similar for numerous demographic characteristics except that portal venous drainage was more common in the TAC group. Approximately 82% of patients underwent pancreas transplantation with enteric drainage in both arms. Following induction with ATG for 4 doses, patients were randomized to either TAC or CsA (Neoral)-based therapy in combination with MMF and corticosteroids. Target TAC levels were 8-15 ng/mL and target CsA levels were 150-250 ng/mL. MMF dosing was at 2-3 g/day. Corticosteroids were gradually tapered with complete withdrawal at 6 months after transplantation. At present, 102 patients have been enrolled in the Neoral arm and 103 have been enrolled in the TAC arm. The authors reported 1-year outcomes on 71 patients receiving Neoral and 70 patients receiving TAC.
At 1-year follow-up, patient survival was 96% in both groups. Kidney graft survival rates were 95.5% in the TAC-treated group vs 92.4% in the CsA-treated group. Pancreas graft survival rates were 90% and 73% for the TAC and CsA-treated groups, respectively (P = .002). In the TAC group, there were 2 episodes of vascular thrombosis resulting in early pancreas graft loss, in contrast to the CsA group, in which there were 10 episodes (P = .02). If pancreas graft loss due to technical therapy is censored, there were no significant differences in 1-year outcomes. A significant reduction in MMF dosing was noted in the TAC group. At 6 and 12 months, the mean MMF doses were 1.8 g/day and 1.7 g/day, respectively, in the CsA group and 1.5 g/day and 1.3 g/day, respectively, in the TAC group (P < .05).
However, in spite of lower overall MMF doses, patients in the TAC arm had a significant reduction in the incidence of rejection (P = .025). In the TAC group, there was only 1 episode of Grade 2-3 rejection vs 9 episodes in the Neoral group. Mean length of stay was 40 days with CsA vs 32 days with TAC (P < .05). There were no significant differences in the incidence of infection or in hemoglobin A1C levels. The overall rates of rejection were 29% in the TAC group vs 42% in the CsA group. The authors noted an increased risk of urinary tract infections in patients undergoing pancreas transplantation with bladder drainage and an increased risk of intra-abdominal infections in patients who were on pretransplant peritoneal dialysis. Based on this preliminary analysis of interim results, pancreas graft survival at 12 months was improved in patients receiving TAC-based therapy. Length of hospital stay and the incidence of acute rejection were both lower in patients receiving TAC. However, definitive conclusions await further patient accrual.
Sirolimus (rapamycin and Rapamune) is a potent immunosuppressant with a mechanism of action different from CsA or TAC. Sirolimus is an immunophilin-binding agent that is structurally similar to TAC and binds to the same intracellular binding protein. The actual mechanism of action of sirolimus is uncertain. It is postulated, however, that whereas CsA and TAC block IL-2 transcription, sirolimus blocks IL-2-dependent proliferation and the stimulation caused by cross-linkage of CD-28. In a large, randomized, controlled, blinded, multicenter trial, sirolimus decreased the incidence of biopsy-proven rejection in nonblack kidney transplant recipients. Experience with sirolimus in pancreas transplantation is reported here.
A single-center experience with the use of sirolimus in pancreas transplant recipients was reported by Dr. Odorico and colleagues of the University of Wisconsin, Madison. Their experience to date consists of 31 patients, including 18 SPK and 13 solitary pancreas (9 PAK, 4 pancreas alone) transplant recipients. Within this group, 11 patients underwent second transplants, 5 of which were pancreas retransplants. The authors considered this group to be at high immunologic risk. Mean follow-up after sirolimus conversion was 10 months.
Three clinical settings in which sirolimus was utilized were discussed. Eleven patients received sirolimus as primary therapy after pancreas transplantation, including 6 patients in whom sirolimus was added as a fifth agent posttransplantation. Four of these cases were patients with renal insufficiency (mean creatinine clearance 41 mL/min) after solitary pancreas transplantation. Sirolimus was added so that a TAC-sparing regimen could be implemented. In 2 other patients with a history of MMF intolerance, sirolimus was added as an MMF-sparing agent immediately after transplantation. In the other 5 cases, delayed renal allograft function occurred after SPK transplantation, resulting in the use of sirolimus as a bridge to therapeutic dosing.
The second clinical situation involved 7 patients switched to sirolimus as rescue therapy for recurrent rejection. Two of these patients had multiple recurrent rejection episodes and biopsy evidence for chronic allograft nephropathy. The other 5 patients exhibited an inadequate response to thymoglobulin therapy.
The third clinical setting involved 16 patients undergoing sirolimus conversion for a variety of indications including renal insufficiency in 11, diarrhea and gastrointestinal toxicity in 4, glucose intolerance in 3, neurotoxicity in 1, and other side effects in 1. The mean sirolimus dose was 3.2 mg/day with a range of 2-8 mg/day. Target levels were 5-15 ng/day. In the entire group, there were 3 deaths, 1 kidney graft loss due to chronic rejection, and 3 pancreas graft losses. There were 4 episodes of acute rejection occurring on sirolimus therapy, and 1 patient developed posttransplantation lymphoproliferative disorder. Sirolimus was ultimately discontinued in 10 patients, including 3 that were planned because the patients were subsequently tolerant of TAC. Other reasons for discontinuation of sirolimus included leukopenia, poor wound healing, and acute rejection. The authors concluded that their initial experience with sirolimus was favorable, particularly in patients who were unable to tolerate full-dose calcineurin inhibitors or antimetabolite therapy.
Outcomes of 85 pancreas transplant recipients with pancreas graft function at 10 years after transplantation were reported by Dr. Gruessner and colleagues. This group represented approximately 20% of pancreas transplants performed during the study period and included 43 SPK, 24 pancreas alone, and 18 PAK transplant recipients. In patients with a functioning pancreas graft at 10 years, the 15-year patient survival rates were 89% for PAK and 84% for pancreas alone recipients. None of the SPK recipients had 15-year follow-up. The corresponding 15-year pancreas survival rates were 69% for PAK and 76% for pancreas alone recipients.
Death with a functioning graft was the most common cause of late graft loss, with 9 deaths occurring more than 10 years after transplantation. The next most common cause of late graft loss was chronic rejection. If death with a functioning graft is censored, the 15-year graft survival rate was 78% in PAK and 91% in pancreas alone recipients. In the 43 SPK recipients, the 10-year kidney graft survival rate was 86%. The most common cause of graft loss in the SPK group was chronic rejection followed by death with a functioning graft. In the pancreas alone group, the rate of kidney transplantation after pancreas transplantation was 29%. However, most of these patients had impaired renal function at the time of their initial pancreas alone transplant.
A number of malignancies occurred in the total population, including 19 skin cancers, 1 melanoma, and 8 solid organ tumors. In patients with functioning grafts, stable metabolic function occurred long-term with euglycemia and normal hemoglobin A1C levels. Serum creatinine, total cholesterol, and triglyceride levels likewise remained stable long term. Long-term survival rates were higher in primary vs retransplants, in living donor vs cadaver donor pancreas transplants, and in pancreas alone vs either PAK or SPK transplants. Fifteen-year graft survival rates ranged from 70% for PAK to 76% for pancreas alone recipients. A total of 9 late deaths occurred from malignancies, suicide, trauma, and other causes. The authors concluded that in patients with greater than 10-year pancreas graft function, excellent graft and patient survival rates as well as excellent metabolic long-term function can be obtained.
Comparative outcomes of SPK (n = 193) and PAK (n = 205) recipients transplanted between 1994-2000 were reported by Dr. Humar and colleagues at the University of Minnesota, Minneapolis. The mean waiting times were 167 days vs 244 days for for a PAK vs SPK transplant (P = .01). The waiting time for the kidney transplant in PAK recipients was difficult to estimate because most had received a kidney from a living donor. The mean length of hospital stay was 10.7 days vs 17.5 days for PAK vs SPK transplantation (P < .001). The mean length of stay after the living donor kidney transplant was 6.2 days, so the combined length of stay for the sequential transplant procedures was comparable to the length of hospital stay for the simultaneous procedure. The rates of early readmissions (first 3 months after transplantation) to the hospital were comparable between groups with a mean of 1 readmission per patient. The average cost of the PAK transplantation, including the living donor kidney transplant, was approximately $9000 more than that of the SPK procedure. Using the Short Form (SF)-36 Health Survey, no significant differences in patient-reported health-related quality of life were noted between the groups.
The advantages of a PAK transplant are the ability to use a living donor kidney, the ability to perform a preemptive transplant, and superior long-term kidney graft survival. However, the disadvantages include the fact that the patient must undergo 2 operations and that slightly inferior results are achieved, from a pancreas transplant perspective. Patient survival rates are comparable regardless of whether the patient undergoes simultaneous or sequential transplantation. The rate of immunologic pancreas graft loss is approximately 5% following SPK vs 15% following PAK transplantation. However, PAK patients have a shorter waiting time, decreased length of hospital stay, and perhaps a lower overall surgical complication rate.
It was concluded that PAK transplantation is a viable option for uremic diabetic patients. Performing a sequential vs simultaneous procedure does not significantly increase total length of hospitalization or cost. Quality of life is similar. Thus, the uremic diabetic patient should be counseled regarding 4 potential treatment options: (1) a cadaver donor SPK transplant, (2) a living donor SPK transplant, (3) a living donor kidney transplant followed by a cadaver donor PAK transplant, and (4) a simultaneous living donor kidney and cadaver donor pancreas transplant. Depending on individual preferences and circumstances, any of these treatments are potential therapeutic options for the diabetic patient with advanced nephropathy.