Sunday, May 28, 2023
This activity is intended for transplant physicians and surgeons and other clinicians practicing in the field of heart and lung transplantation.
The goal of this activity is to define "state-of-the-art" treatment protocols and clinical strategies for the management of solid organ transplant recipients, to enhance the care of solid organ transplant recipients, and to support quality clinical practice of healthcare professionals involved in their care.
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Professor of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania; Director of Kidney, Pancreas & Islet Transplantation, Thomas E. Starzl Transplantation Institute, University of Pittsburgh Medical Center Montefiore, Pittsburgh, Pennsylvania
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Corticosteroids (steroids) and calcineurin inhibitors (CIs), traditional mainstays of immunosuppression for renal transplantation, are associated with important adverse effects that lead to long-term health problems and loss of native and kidney graft function, respectively. Therefore, eliminating these agents to the extent possible from maintenance immunosuppression regimens is an important goal in solid organ transplantation. Consequently, clinical protocols utilizing either steroid-sparing or CI-sparing regimens, as part of single- or multicenter pilot or randomized kidney transplant trials, were the focus of a number of investigators reporting at this meeting.
It is desirable to limit exposure of patients to steroids to avoid side effects that lead to health problems, poor quality of life, and patient noncompliance. Two approaches toward this end are regimens designed for systematic steroid withdrawal and complete steroid avoidance. Clinicians have been more reluctant to attempt complete avoidance of steroids for fear of exposing patients to acute rejection. However, recent evidence tells us that the potential for acute rejection must be carefully weighed in both approaches, especially in high-risk patients such as African Americans.
Steroids are associated with a multitude of side effects that ultimately contribute to infectious and cardiovascular morbidity and mortality in transplant recipients. However, all controlled trials of steroid elimination from the immunosuppressive regimen have shown an increased risk of acute and/or chronic rejection.[1] In particular, 2 large randomized trials have been conducted, one in the United States and one in Europe.[2,3] Especially troubling was the finding in the European trial that the risk of rejection increased 4-fold in African American patients. A number of smaller studies testing the various available immunosuppressive agents were presented at this meeting; the majority of study designs included tacrolimus (TAC) and mycophenolate mofetil (MMF).
A small, prospective, randomized trial of kidney transplant recipients compared steroid withdrawal at 1 week (n = 17) with continued prednisone therapy at a dosage of 5 mg daily (n = 10).[4] Immunosuppression was with basiliximab, cyclosporine (CsA), and MMF. The rates of acute rejection were 24% and 30%, respectively, and renal function was similar in both groups at 6 months. However, protocol biopsies at 1 month showed more subclinical rejection in African American patients (P = .02). Furthermore, the transforming growth factor beta levels were higher (NS) and there was more intrarenal cytotoxic gene expression (P = .05) in the steroid withdrawal group. By 6 months, protocol biopsies demonstrated a greater degree of fibrosis (NS) in the steroid withdrawal group. Although the authors suggested that steroid withdrawal is safe in selected patients, the findings on protocol biopsies and intrarenal cytotoxic and fibrogenic gene expression raise concerns, particularly if premature graft loss occurs in the steroid withdrawal group.
The outcomes of steroid withdrawal in African American patients receiving TAC and sirolimus (SRL) were reported from a single-center, ongoing, uncontrolled pilot study.[5] Thirty-one patients were eligible for the study, 28 were enrolled, and steroids were withdrawn in 21. Steroids were tapered over 8 weeks beginning at 12 weeks posttransplantation in patients with a serum creatinine level < 2.4 mg/dL and no acute rejection episodes. One-year patient and graft survival were 100% and 94%, respectively. The overall incidence of rejection was 16% in the cohort of 44 patients. A relatively high incidence (35%) of posttransplant diabetes mellitus (PTDM) was noted.
A multicenter, prospective, randomized trial compared 2 groups of patients: (1) patients receiving 2 doses of daclizumab (day 0 and day 10) in combination with maintenance TAC and MMF (n = 64), and (2) patients receiving 2 doses of perioperative steroids in combination with maintenance TAC and MMF plus a 4-month course of steroids (n = 66).[6] A total of 360 patients were entered into the trial; an interim analysis (median follow-up 11 months) of the first 130 patients was reported. Patient survival (94% and 95%), graft survival (88% and 89%), and rejection rates (14% and 16%) were comparable between the 2 groups. This study demonstrated that a 2-dose vs a 5-dose regimen of daclizumab was sufficient to suppress the IL-2R chain on T cells for at least 10 weeks.
Steroid withdrawal in 60 kidney transplant recipients on a maintenance immunosuppression regimen of TAC, MMF, and steroids was examined in a 2-center study.[7] Eligible patients (N = 48) receiving either TAC plus MMF (n = 33) or TAC alone (n = 15) were randomized 6 months after transplantation to either steroid withdrawal or steroid continuation. At 2 years, 100% patient and graft survival rates were noted, with no documented episodes of acute rejection. Ninety-four percent of the TAC plus MMF and 87% of the TAC alone patients were maintained off steroids, with mean serum creatinine levels of 1.37 mg/dL and 1.53 mg/dL, respectively, and an incidence of PTDM of 6.5% and 4.3%, respectively.
A multicenter, prospective, placebo-controlled study randomized 157 patients to either basiliximab or matched placebo. Maintenance immunosuppression was with cyclosporine (CsA), azathioprine (AZA), and steroids.[8] Steroids were tapered over 10 weeks beginning at 5 months posttransplantation. In the placebo group, graft loss was more common (7 patients vs 1 patient, P < .05), the incidence of rejection was higher (39% vs 25.3%, P < .058), and the steroid withdrawal success rate was lower (40% vs 54%).
A single-center, 3-year, prospective, double-blind, placebo-controlled trial randomized 51 patients who were receiving CsA, MMF, and steroids to either continue or discontinue steroids.[9] At 3 months posttransplantation, patients were randomized either to continue steroids with a taper to 15 mg every other day by 1 year (n = 25) or to discontinue steroids completely by 6 months (n = 26). A total of 29 patients were able to continue in the study for 3 years. Outcomes were similar between the 2 groups with regard to renal function, PTDM, and hypertension. However, total serum cholesterol levels were higher in patients who continued to be maintained on steroids (200 vs 183 mg/dL, P = .05), highlighting one reason to spare or avoid steroids.
Three-year retrospective follow-up data were reported from the experience of a prospective multicenter pilot study of steroid avoidance. Fifty-seven renal transplant recipients received daclizumab, CsA, and MMF. The regimen contained no steroids.[10] One-year patient and graft survival rates were 95% and 89%, respectively, and a 25% incidence of rejection was reported from the pilot study. Subsequently, a retrospective review of 49 patients available for follow-up at 3 years was conducted. Three-year patient and graft survival were 92% and 89%, respectively. Thirty (65%) patients continued to be steroid-free, and 2 patients had experienced acute rejection episodes in the intervening 2 years.
A subgroup analysis of 192 patients transplanted under a protocol of basiliximab, TAC, MMF, and 3 perioperative doses of steroids was reported.[11] Overall patient and graft survival rates were 99.6% and the overall incidence of acute rejection was 14%. Eighty-nine percent of patients were steroid-free. Outcomes in high-risk groups -- African Americans (n = 37) and retransplant recipients (n = 10) -- were examined. The incidences of rejection in the African American and retransplant groups were not different from the incidence in the overall group. The authors concluded that these high-risk groups should not be excluded from steroid near-avoidance protocols.
CsA is undoubtedly beneficial in the early posttransplant period for the prevention of acute rejection, but the nephrotoxic side effect of CsA leads to chronic allograft nephropathy and graft loss. Randomized clinical trials of CsA elimination have shown that the risk of acute rejection is increased but that long-term graft survival is not adversely affected.[12] Several papers on CI-sparing regimens were presented at this meeting; most had small sample sizes, were single-center, and were designed for short-term follow-up.
Six-month interim data from a multicenter, prospective, randomized trial in 274 renal transplant recipients compared a triple-therapy regimen of reduced-dose CsA, SRL, and steroids with a double-therapy regimen of standard or full-dose CsA and steroids.[13] Patient (99%) and graft (98%) survival rates were similar in both groups, as were the incidences of rejection (13% vs 11%, respectively) and serum creatinine levels. The most common adverse event reported was peripheral edema, occurring in 59.3% of the reduced-dose CsA group and 58.1% in the full-dose CsA group. These short-term data suggest that the regimen of SRL and reduced-dose CsA is safe and effective. It should be noted that African American recipients and patients with panel reactive antibody levels greater than 50% were excluded from participation in this study.
A 6-month interim analysis of a prospective, randomized European trial comparing reduced-dose CsA, SRL, and steroids with full-dose CsA, SRL, and steroids in 313 patients was conducted to determine whether a regimen of reduced-dose CsA in combination with SRL would provide adequate immunosuppressive coverage and decrease nephrotoxicity.[14] In the reduced-dose CsA group (n = 130), patient and graft survival rates were 100% and 99% respectively, and the overall rejection rate was 9%. In the full-dose CsA group (n = 124), patient and graft survival rates were 99% and 98% respectively, and the rejection rate was 11%. Renal function was similar between the 2 groups, as were serum cholesterol and triglyceride levels. The most common adverse event requiring emergent treatment in both groups was hyperlipidemia (24.4%). The rates of lymphocele (14%) and urinary tract infection (15%) were high, but not significantly different between the 2 groups.
A multicenter (n = 57), tricontinental, prospective, randomized trial of 525 patients was conducted to determine which patients were most likely to benefit from CsA withdrawal after 3 months of maintenance immunosuppression with CsA, SRL, and steroids.[15] At 3 months posttransplantation, 430 eligible patients were randomized to either continue this regimen or taper and discontinue CsA therapy over a 6-week period. At 24 months, 67% of patients in both groups were still being treated per protocol. Seventy percent of patients who discontinued CsA had improved renal function, and this was true irrespective of the quality of their renal function at the time of randomization. Serum creatinine levels were significantly lower in the SRL plus steroid group (1.9 mg/dL vs 1.5 mg/dL, P < .001).
A single-center, prospective, randomized trial compared a CI-based (TAC) immunosuppressive regimen (n = 27) with a CI-free (SRL) regimen (n = 25).[16] All patients received induction therapy with Thymoglobulin (rATG) and maintenance immunosuppression with MMF and steroids. Seventy-nine patients (of a planned 300) were entered into this trial. Patient and graft survival rates in the SRL group were 100% and 97%, respectively, and 98% and 90% in the TAC group, respectively. Rejection rates (clinical and subclinical) were 7.5% in the SRL-treated patients and 5% in the TAC-treated patients; renal function was similar in both groups. Low acute rejection rates and excellent allograft function were achieved with a high degree of drug tolerability.
A single-center, prospective, randomized trial compared 2 induction strategies -- OKT3 vs a short course of daclizumab -- in 49 recipients of marginal kidneys who were therefore at high risk for development of delayed graft function (DGF), defined as the need for posttransplant hemodialysis.[17] Patients received MMF, steroids, and delayed introduction of TAC. The rate of DGF was similar in both groups; 52% of the OKT3-treated patients and 65% of the daclizumab-treated patients required hemodialysis within the first week after transplantation. Two-year patient and graft survival rates in the OKT3 group were 96% and 80%, respectively, and the incidence of rejection was 17%. Two-year patient and graft survival rates in the daclizumab group were 91% and 81%, respectively, and the incidence of rejection was 14%. These differences were not statistically significant. Notably, however, the cost of induction therapy with daclizumab was estimated to be $1200 less (P = .004) than the cost of induction therapy with OKT3 in this study. The authors concluded that a short course of an induction agent with no side effects, daclizumab, was just as effective as and less expensive than a longer course of an agent associated with more side effects, OKT3.
This collection of studies represents a wide range of immunosuppressive strategies ultimately aimed at minimizing complications of traditional therapies while improving patient outcomes. Steroid withdrawal or avoidance appears to be feasible in substantial numbers of patients receiving a number of different immunosuppressive regimens, with generally excellent outcomes. However, most studies are relatively small and uncontrolled, with short follow-up. The results from many such studies presented at this meeting diverge from the findings of earlier studies, suggesting that the risk of steroid elimination is lower in patients managed on MMF and TAC or SRL compared with CsA. Likewise, excellent short-term outcomes have been achieved with various CI-sparing regimens using MMF, SRL, rATG, and anti-CD25 monoclonal antibodies, suggesting that there are multiple paths to good graft survival and that using lower doses of CIs is generally feasible in low-risk patients.
