Steroid withdrawal in renal transplant recipients

The clinically important side effects of long-term steroid use are well known. We report the results of complete steroid withdrawal in 7 living-related renal transplants in HLA-identical (3) or one-haplotype match (4) recipients initially treated with azathioprine (5) or cyclosporine (2), and steroids. After the end of the second year, steroids were stopped if renal function was normal (serum creatinine below 2.0 mg/dl) and if no alterations were seen on renal biopsy. In 1 patient steroid had to be discontinued because of the complications of steroid immunosuppression. The study population consisted of 7 patients with a mean age of 32.4 years. The sex distribution was 6 males and 1 female. All patients had received a minimum of 3 blood transfusions prior to transplantation. Steroid was discontinued 34.0 +/- 18.1 months posttransplant. Oral azathioprine or cyclosporine were employed for long-term maintenance immunosuppression. Six patients (86%) have remained continuously off steroids for 52.2 +/- 50.5 months (range 4-150) with stable renal function. The mean serum creatinine was 1.1 +/- 0.4 mg/dl at the most recent follow-up. Reinstitution of steroid was required in 1 patient (14%) for rejection (36 months after steroid withdrawal). Thus, steroid withdrawal was successful in 6 of 7 patients. In HLA-identical recipients, all are currently steroid-free. In haplo-matched patients, 75% are steroid independent. Discontinuation of steroid resulted in a decrease in serum cholesterol concentration from 246 +/- 41 to 204 +/- 25 mg/dl (P less than 0.003). We conclude that steroid withdrawal may be accomplished in selected patient without increasing the rate of graft loss.(ABSTRACT TRUNCATED AT 250 WORDS)     

Steroid or tacrolimus withdrawal in renal transplant recipients using sirolimus

Background  

Calcineurin inhibitor (CNI) and steroid (ST) withdrawal are strategies under investigation to reduce long-term toxicities associated with current immunosuppressive regimens. We conducted a single center, prospective trial comparing the efficacy and safety of CNI or ST withdrawal in kidney transplant recipients receiving sirolimus-based immunosuppressive regimen.     

Tuberculosis in renal transplant recipients on various immunosuppressive regimens.

BACKGROUND: Mycophenolate mofetil (MMF) and tacrolimus (TAC) are more potent than conventional immunosuppressive drugs, i.e. azathioprine, cyclosporin and prednisolone, and may be associated with an increase in the incidence of infections in the post-transplantation (post-tx) period. The aim of this study was to determine if the use of either or both of MMF and TAC for immunosuppression in renal transplant recipients increases the prevalence or modifies the clinical presentation of tuberculosis (TB), when compared with conventional therapy. METHODS: The medical records of 443 adult patients who received a kidney transplant between 1994 and 2002 were reviewed retrospectively. Comparisons were made between patients who had conventional immunosuppressive treatments (cyclosporin, azathioprine and prednisolone) or an alternative regimen (including MMF, TAC or both). RESULTS: We found 20 patients (4.5%) to have post-tx TB. There were 13 cases of TB (age 38.9+/-10.6 years) among 328 patients who received conventional immunosuppressants (group I) (4.0%) and seven cases (age 24.2+/-7.4 years) among 115 (6.1%) who received an alternative immunosuppressive regimen (group II) (P>0.05). The patients in group II were younger than the patients in group I (P = 0.002). A significantly higher number of patients in group II developed TB within the first 6 months post-tx (P = 0.042). However, there was no significant difference between the two groups regarding clinical and radiographic presentations or outcomes. CONCLUSIONS: Immunosuppression with TAC or MMF is associated with the development of TB earlier in the post-tx period and in younger patients.     

Steroid withdrawal in pediatric and adult renal transplant recipients

Corticosteroids are still a cornerstone in the immunosuppressive regimen in pediatric renal transplant recipients despite their numerous side effects, such as inhibition of longitudinal growth, body disfigurement, arterial hypertension, cardiovascular complications, osteopathy, and others. Previous attempts to spare steroids in cyclosporine (CsA)-based protocols have been associated with an increased risk for acute rejection episodes. The recent introduction of more-potent immunosuppressive medications, such as mycophenolate mofetil (MMF), have, however, renewed interest in steroid-sparing protocols to avoid or ameliorate steroid-associated side effects. Recent studies in Caucasian adult renal transplant recipients receiving CsA and MMF have shown a beneficial effect of late (6 months post transplant) steroid withdrawal on steroid-associated side effects without the burden of an increased rate of acute rejection episodes. These favorable results compared with previous reports in patients on CsA and azathioprine (AZA) can be ascribed to the higher immunosuppressive potency of MMF compared with AZA. We have shown in a retrospective case control study in 40 pediatric renal transplant recipients that late steroid withdrawal is safe and successful in stable patients under an immunosuppressive maintenance therapy with CsA and MMF. The Mid-European Study Group on Pediatric Renal Transplantation and the Arbeitsgemeinschaft für Pädiatrische Nephrologie are currently performing a prospective randomized trial to validate these observations.This work was presented in part at the IPNA Seventh Symposium on Growth and Development in Children with Chronic Kidney Disease: The Molecular Basis of Skeletal Growth, 1–3 April 2004, Heidelberg, Germany     

Outcome after steroid withdrawal in pediatric renal transplant patients receiving tacrolimus-based immunosuppression

BACKGROUND: Corticosteroids have always been an integral part of immunosuppressive regimens in renal transplantation. The primary goal of this analysis was to assess the safety of steroid withdrawal in our pediatric renal transplant recipients receiving tacrolimus-based immunosuppression. METHODS: Between December 1989 and December 1996, 82 renal transplantations were performed in pediatric patients receiving tacrolimus-based immunosuppression. Two of these patients lost their grafts within 3 weeks of transplantation (and were still on steroids at the time of graft loss), and were excluded from further analysis. Seventy-four patients (92.5%) were taken off prednisone a median of 5.7 months after transplantation. Of these 74, 56 (70%) remained off prednisone (OFF), and 18 (22.5%) were restarted on prednisone a median of 14.8 months after discontinuing steroids (OFF --> ON). 6(7.5%) were never taken off prednisone (ON). The mean follow-up was 59 +/- 23 months. RESULTS: The 1-, 3-, and 5-year actuarial patient survival rates in the OFF group were 100%, 98%, and 96%, respectively; in the OFF --> ON group, they were 100%, 100%, and 100%, and in the ON group, they were 100%, 83%, and 83%. The 1-, 3-, and 5- year actuarial graft survival rates in the OFF group were 100%, 95%, and 82%, respectively; in the OFF --> ON group, they were 100%, 89%, and 83%; and in the ON group, they were 100%, 50%, and 33%. Two of the six graft losses in the OFF group, three out of four in the OFF --> ON Group, and two out of five in the ON group, were to chronic rejection. A time-dependent Cox regression analysis showed that the hazard for graft failure for those who came and stayed off prednisone was 0.178 relative to those who were never withdrawn from prednisone (P=0.005). Patients who were 10 years of age or younger were withdrawn from prednisone earlier (median: 5 months) than those older than 10 years (median: 7.3 months, P=0.02). In addition, patients who never had acute rejection were withdrawn from steroids earlier (median: 5 months) than those who had one or more episodes of acute rejection (median: 7.6 months, P=0.001). There was no effect of donor age, race, sex, recipient race, sex, cadaveric versus living donor, 48-hr graft function, panel reactive antibody, and total HLA mismatches or matches on the likelihood of being weaned off steroids. Serum creatinine at most recent follow-up in the OFF group was 1.2 +/- 0.5 mg/dl; in the OFF --> ON group, it was 1.8 +/- 0.9 mg/dl, and in the ON group it was 2.0 mg/dl (P<0.003). The incidence of rejection in the OFF, OFF --> ON, and ON groups was 39%, 77%, and 100%, respectively (P<0.05). CONCLUSION: These data suggest that steroid withdrawal in pediatric renal transplant patients receiving tacrolimus-based immunosuppression is associated with reasonable short- and medium-term patient and graft survival, and acceptable renal function. Patients who discontinue and then resume steroids had patient and graft survival rates comparable with those in patients who discontinue and stay off steroids, but had a higher serum creatinine and a higher incidence of rejection.     

Steroid withdrawal in liver transplant recipients

Because of troublesome side effects associated with steroid use, many transplant centers have tried to withdraw steroids from stable, solid organ transplant recipients. The objective of this study was to evaluate the ability to wean liver transplant recipients off steroids, depending on both their primary immunosuppressive regimen and their primary disease state. This was a retrospective, single-center review of steroid weaning in adult orthotopic liver transplant recipients. Based on primary immunosuppression, patients could be weaned off steroids similarly if they were taking cyclosporine or tacrolimus (53.9% vs 61.4%). When triple immunosuppressive regimens were compared with dual regimens, a difference was found in ability to wean patients off steroids (52.4% vs 74.5%, P = .001). When steroid weaning was stratified for primary immunosuppression and primary disease state, patients with autoimmune-mediated diseases (autoimmune hepatitis, sclerosing cholangitis, and primary biliary cirrhosis) were less likely to be weaned if they were receiving cyclosporine-based immunosuppressants (36.8% vs 62.2%, P = .03). In conclusion, it appears that a large number of liver transplant recipients can safely be tapered off steroids.     

Steroid withdrawal in lung transplant recipients

OBJECTIVE: Many of the long-term complications in lung transplantations are secondary effects of immunosuppression. Corticosteroids are partially responsible for the development of osteoporosis, raised blood pressure, diabetes, muscular disorders, gastric ulcers, and other conditions. We analyzed the long-term result of steroid withdrawal in our lung transplant recipients. MATERIALS AND METHODS: When respiratory function stabilized, to avoid secondary effects, steroid treatment was withdrawn in 34 of the 375 lung transplant patients in our centers We evaluated the characteristics of the donors and recipients, their compatibility, the pre, and post-steroid withdrawal complications, and type of immunosuppressant. RESULTS: The mean age of patients was 42 +/- 7 years and of donors, 25 +/- 9 years. The primary diseases were: 15 emphysema, six pulmonary fibrosis, 10 cystic fibrosis, and three primary pulmonary hypertension. Twenty seven patients had double lung transplants and seven single lung. The mean steroid withdrawal period was 881 +/- 237 days posttransplantation. The most frequent treatment regimen at the time of steroid withdrawal was cyclosporine, azathioprine, and minimal steroid doses. Six recipients had to be restarted on steroids one patient who required a kidney transplant, three cases due to an infectious process with a differential diagnosis of rejection, and two cases due to loss of FEV1 (forced expiratory volume in 1 s), suggestive of chronic rejection. There was an improvement in blood pressure in five patients, in plasma cholesterol and triglyceride levels in eight patients, and insulin withdrawal in two diabetic patients. CONCLUSIONS: Steroid treatment may be suspended 2 to 3 years, posttransplant in selected lung transplant recipients. The usual patient profile shows few rejection episodes with cyclosporine and azathioprine immunosuppression. What is notable is the low mean age of donors. Close clinical monitoring and lung function testing are of major importance in the weeks following steroid withdrawal.     

Steroid withdrawal in pancreas transplant recipients

BACKGROUND: Numerous studies of steroid withdrawal have been carried out in kidney and liver transplant recipients, but only a few in pancreas transplant recipients. Yet, pancreas transplant recipients could have significant long-term benefits from steroid withdrawal. METHODS: We performed a retrospective analysis to determine the feasibility of steroid withdrawal in pancreas transplant recipients. RESULTS: Of 360 recipients who underwent a pancreas transplant between January 1, 1994 and June 30, 1998, 14 attempted steroid withdrawal (12 simultaneous pancreas-kidney [SPK]; 2 pancreas transplant alone [PTA]). Reasons for steroid withdrawal were bone fractures (n = 3), psychiatric disorders (n = 2), severe acne (n = 1), recurrent infections (n = 4), and problems with hypercholesterolemia or hypertension (n = 4). All 14 were maintained on tacrolimus and mycophenolate mofetil (MMF) immunosuppression, except for 1 who was on tacrolimus and azathioprine (AZA). Of the 14 recipients, 11 had no episodes of acute rejection before steroid withdrawal. The remaining 3 had one or more acute rejection episodes. Of the 14 recipients, 10 (72%) currently remain off steroids (mean follow-up 18 months, range 5-51 months). However, 4 recipients have resumed steroids: 2 after an acute rejection episode (at 2 and 21 months post-withdrawal) and 2 because of leukopenia (WBC < 3000) and an inability to tolerate full-dose MMF. Steroid withdrawal was unsuccessful in both PTA recipients and in 2 of the 12 SPK recipients. All 14 recipients currently have a functioning pancreas graft. However, 1 of the SPK recipients, in whom steroid withdrawal failed, has developed chronic kidney rejection and is now back on hemodialysis awaiting a retransplant. CONCLUSION: Steroid withdrawal is possible in up to 70% of pancreas transplant recipients. Further studies are necessary to define ideal candidates for steroid withdrawal. Based on the results of this analysis, we have launched a prospective, randomized trial of steroid withdrawal in pancreas transplant recipients.     

Comparing early withdrawal or avoidance of steroids with standard steroid therapy in kidney transplant recipients

This Practice Point commentary discusses the findings and limitations of an open-label, multicenter, prospective trial conducted by Vincenti et al., in which kidney transplant recipients receiving basiliximab, ciclosporin microemulsion, and enteric-coated mycophenolate sodium were randomized to standard corticosteroid therapy, steroid withdrawal 7 days after transplantation, or complete steroid avoidance. The trial failed to show noninferiority of the steroid-sparing arms in terms of calculated glomerular filtration rate at 12 months. In addition, the steroid-sparing groups had an increased cumulative incidence of biopsy-proven acute rejection at 12 months. This commentary highlights the issues to consider when interpreting and generalizing these results, including the under-representation of African Americans in the study population, the short duration of follow-up, and the switching of some patients between steroid-containing and steroid-sparing immunosuppressive regimens. The benefits of steroid-free immunosuppression versus low maintenance doses of steroids in kidney transplant recipients remain unclear.     

Benefits derivated from late steroid withdrawal in renal transplant recipients

Because corticosteroids have adverse metabolic effects, inducing bone-mineral imbalance and contributing to infections among renal transplant recipients, many withdrawal trials have been attempted to reduce adverse events and improve quality of life. We retrospectively analyzed the safety and efficacy of late steroid withdrawal, after the first posttransplant year, among a selected group of kidney allograft recipients. In 42 low immunological risk allograft recipients, among 382 patients transplanted during a decade, corticosteroids were progressively reduced and completely withdrawn. The evolution of clinical and biochemical parameters after the withdrawal were analyzed. Corticosteroid withdrawal was performed as a mean of 52.16 +/- 28.41 months posttransplant, with subsequent follow-up without steroid treatment of 18.13 +/- 16.11 months. Comparing the most recent evaluation with the data previous to steroid withdrawal, patients showed a significant decreases in diastolic pressure (P = .039), total cholesterol (P = .000), and low-density lipoprotein cholesterol levels (P = .039), but not in triglyceride levels (P = .33). Body weight did not change (P = .77), but increased fasting glucose levels were noted (P = .03), in absence of new diagnosed diabetes mellitus. A significant reduction in cyclosporine Neoral (P = .01) or tacrolimus doses were detected (P = .01). At the last visit, serum creatinine in the whole group remained stable (P = .06). Only five patients showed an increase in serum creatinine more than 20% (from 1.44 +/- 0.41 to 1.94 +/- 0.45 mg/dL P = .04) and proteinuria did not increase (P = .94). No patient was diagnosed with a rejection episodes or required corticosteroid resumption. Graft and patient survivals were 100% at the end of follow-up. In conclusion, our data showed that late corticosteroid withdrawal in renal transplant recipients of low immunological risk is safe and is followed by an improvement in their metabolic profile and in blood pressure.     

Steroid avoidance immunosuppression in low-risk kidney transplant recipients

Recent clinical trials have documented the short-term safety of steroid avoidance (SA) in kidney transplant recipients. Since July 2003, we have used a SA immunosuppression protocol for low-risk kidney transplant recipients. Eligibility criteria are age > or = 18, primary transplant (living or deceased donor), and tacrolimus started by postoperative day 3. Recipients were excluded if peak/current PRA was >50%/20%, or if they had a positive flow crossmatch, or if they had the recent use of corticosteroids (<6 months). All recipients received induction with rabbit anti-thymocyte globulin, total dose 6 mg/kg, or basiliximab. Recipients received 5 daily doses of corticosteroid and mycophenolate mofetil 1 gm twice daily starting on the day of transplantation. Tacrolimus was started when the serum creatinine level decreased by 20%, or by postoperative day 3. The goal for trough tacrolimus levels was 10-15 ng/mL for the first month, 8-12 ng/mL for months 2-3, and 5-10 ng/mL after month 3. Protocol biopsies (bx) were performed at reperfusion, 1 month, 4 months, and 12 months. Ninety-four kidney transplantations were performed during the study period. Sixty-seven recipients (71%) were eligible and enrolled in SA. Characteristics of the 67 SA recipients: mean age, 53 years (range, 26-70); 41% female; 67% Caucasian; 24% Hispanic; 15% African American; and 5% Native American. Also, 77% received a living donor kidney. The mean follow-up was 180 days (range, 10-360). At last follow-up, 91% remained steroid-free. Biopsy-proven acute rejection (BPAR) occurred in 5 recipients (7.5%). Three recipients (4.5%) had clinical BPAR and 2 had subclinical. One recipient died with pneumonia 4 months following transplantation. Posttransplantation diabetes mellitus (PTDM) occurred in 2 (5%) of 38 recipients. In the initial 41 recipients, 27 had protocol bx at 1 month and 13 at 4 months available for analysis. Chronic allograft nephropathy (CAN) was present on protocol bx in 48% at 1 month and 69% at 4 month. Actuarial (Kaplan-Meier method) patient and graft survival rates at 351 days were 97.8% and 96.8%, respectively. SA with anti-thymocyte globulin induction in low-immunologic risk kidney transplant recipients is safe and is associated with a low risk of BPAR. The incidence of PTDM appears to be lower.