Comparison of steroid avoidance in tacrolimus/mycophenolate mofetil and tacrolimus/sirolimus combination in kidney transplantation monitored by surveillance biopsy

BACKGROUND: Chronic steroid therapy in kidney transplantation has myriad side effects and steroid avoidance has become feasible. This prospective study compared the safety and efficacy of steroid avoidance in tacrolimus (TAC)/mycophenolate mofetil (MMF) and TAC/sirolimus (SRL) combinations in kidney transplantation. METHODS: In all, 150 kidney recipients were analyzed: 75 each in TAC/MMF and TAC/SRL groups. The primary endpoint was acute rejection. Surveillance biopsies were completed to analyze subclinical acute rejection (SCAR) and chronic allograft nephropathy (CAN). Acute rejection and SCAR were treated by methylprednisolone. Two-year patient and graft survival, renal function, and adverse effects were monitored. RESULTS: Acute rejection was seen in 12% of TAC/MMF and 8% of TAC/SRL patients. Two-year actuarial patient survival was 95% and 97%, and graft survival 90% and 90% in TAC/MMF and TAC/SRL groups, respectively. Surveillance biopsy showed cumulative incidence of SCAR was 27 % in TAC/MMF and 16 % in TAC/SRL groups at 2 years (P = 0.04). Overall, 33% of recipients in TAC/MMF and 20% in TAC/SRL received methylprednisolone for acute rejection/SCAR. Moderate/severe CAN was 10% in TAC/SRL group and 22% in TAC/MMF group(P = 0.06). New-onset diabetes mellitus (NODM) was 4% each in both groups. All recipients remain free of maintenance steroid therapy. CONCLUSIONS: Steroid avoidance in tacrolimus-based immunosuppression with MMF or SRL provides equivalent 2-year patient and graft survival with a low incidence of acute rejection and NODM. SCAR and CAN are lower in TAC/SRL compared to TAC/MMF group. The impact of decreased SCAR and CAN in TAC/SRL group on longer-term graft survival and function is to be evaluated.     

Comparison of four different immunosuppression protocols without long-term steroid therapy in kidney recipients monitored by surveillance biopsy: five-year outcomes

Induction and maintenance immunosuppression protocols with or without long-term steroid therapy in kidney transplant recipients are variable and are transplant center-specific. The aim of this prospective randomized pilot study was to compare 5-year outcomes in kidney recipients maintained on 4 different calcineurin inhibitor (CNI)-based immunosuppression protocols without long-term steroid therapy. Two hundred consenting patients who received kidney transplants between June 2000 and October 2004 were enrolled in 4 immunosuppression protocol groups, with 50 patients in each group: cyclosporine (CSA)/mycophenolate mofetil (MMF), CSA/sirolimus (SRL), tacrolimus (TAC)/MMF, and TAC/SRL. Induction therapy was done with basiliximab and methylprednisolone. Steroids were withdrawn on post-transplant day 2, and long-term steroid therapy was not used. Demographic characteristics among the four groups were comparable; approximately 50% of the recipients were African American and > or =80% of the kidneys transplanted were from deceased donors. Clinical acute rejection (CAR) was confirmed by biopsy and treated with intravenous pulse steroid therapy. Steroid-unresponsive CAR was treated with Thymoglobulin. Surveillance biopsies were performed at 1, 6, 12, 24, 36, 48, and 60 months to evaluate subclinical acute rejection (SCAR), chronic allograft injury (CAI), and other pathological changes per the Banff 2005 schema. The primary end point was CAR, and secondary end points were 5-year patient and graft survival rates, renal function, SCAR, CAI, and adverse events. In the first year post-transplant, the incidence of CAR was 18% in the CSA/MMF group, 8% in the CSA/SRL group, 14% in the TAC/MMF group, and 4% in the TAC/SRL group (CSA/MMF vs. TAC/SRL; p=0.05). The incidence of SCAR was 22% in the CSA/MMF group, 8% in the CSA/SRL group, 16% in the TAC/MMF group, and 6% in the TAC/SRL group (CSA/MMF vs. CSA/SRL and TAC/SRL; p=0.05). After the first year, the incidences of CAR and SCAR decreased and were comparable in all 4 groups. At 5 years post-transplant, cumulative CAI due to interstitial fibrosis/tubular atrophy (IF/TA), hypertension (HTN), and chronic calcineurin inhibitor (CNI) toxicity was observed in 54%, 48%, and 8% of the CSA/MMF group vs. 16%, 36%, and 12% of the CSA/SRL group vs. 38%, 24% and 6% of the TAC/MMF group vs. 14%, 25% and 12% of the TAC/SLR group (IF/TA: CSA/MMF vs. CSA/SRL and TAC/SRL; p=0.04, HTN: CSA/MMF vs. TAC/MMF and TAC/SRL; p=0.05, CNI toxicity: TAC/SRL and CSA/SRL vs. TAC/MMF; p=0.05). Five-year patient and graft survival rates were 82% and 60% in the CSA/MMF group, 82% and 60% in the CSA/SRL group, 84% and 62% in the TAC/MMF group, and 82% and 64% in the TAC/SRL group (p=0.9). Serum creatinine levels and creatinine clearances at 5 years were comparable among the groups. Our data show that the rates of CAR and SCAR in the first year post-transplant were significantly lower in the CSA/SRL and TAC/SRL groups and that cumulative CAI rates due to IF/TA and HTN at 5 years were significantly lower in the TAC/MMF, TAC/SRL, and CSA/SRL groups than in the CSA/MMF group. Despite significant differences in the incidences of CAR and SCAR and prevalence of different types of CAI at 5 years, renal function and patient and graft survival rates at 5 years were comparable among kidney recipients maintained on 4 different immunosuppression protocols without long-term steroid therapy.     

Pediatric Lung Transplant Outcomes Based on Immunosuppressive Regimen at Discharge: Retrospective Cohort Study Using Real-World Evidence From the US Scientific Registry of Transplant Recipients

BackgroundThis retrospective analysis of the US Scientific Registry of Transplant Recipients was undertaken to obtain real-world evidence concerning the efficacy and safety of tacrolimus-based immunosuppression in pediatric lung transplant recipients to support a supplemental New Drug Application.MethodsOverall, 725 pediatric recipients of a primary deceased-donor lung transplant between January 1, 1999, and December 31, 2017, were followed for up to 3 years post-transplant based on an immunosuppressive regimen at hospital discharge: immediate-release tacrolimus (TAC)+mycophenolate mofetil (MMF), TAC+azathioprine (AZA), cyclosporine (CsA)+MMF, or CsA+AZA. The primary outcome was the composite endpoint of graft failure or death (all-cause) at 1 year post-transplant, calculated by Kaplan–Meier analysis.ResultsThe use of TAC+MMF increased over time. During 2010 to 2017, 91.7% of pediatric lung transplant recipients were receiving TAC+MMF at the time of discharge. The proportion of recipients continuing their discharge regimen at 1 year post-transplant was 83.7% with TAC+MMF and 40.4% to 59.7% with the other regimens. Cumulative incidence of the composite endpoint of graft failure or death at 1 year post-transplant was 7.7% with TAC+MMF, 13.9% with TAC+AZA, 8.9% with CsA+MMF, and 9.1% with CsA+AZA. There was no significant difference in the risk of graft failure or death at 1 year post-transplant between groups from 1999 to 2005 (the only era when adequate numbers on each regimen allowed statistical comparison). No increase in hospitalization for infection or malignancy was seen with TAC+MMF.ConclusionThe real-world evidence from the US database of transplant recipients supported the Food and Drug Administration's approval of tacrolimus-based maintenance immunosuppression in pediatric lung transplant recipients.     

A Randomized Trial to Assess the Impact of Early Steroid Withdrawal on Growth in Pediatric Renal Transplantation: The TWIST Study

Minimizing steroid exposure in pediatric renal transplant recipients can improve linear growth and reduce metabolic disorders. This randomized multicenter study investigated the impact of early steroid withdrawal on mean change in height standard deviation score (SDS) and the safety and efficacy of two immunosuppressive regimens during the first 6 months after transplantation. Children received tacrolimus, MMF, two doses of daclizumab and steroids until day 4 (TAC/MMF/DAC, n = 98) or tacrolimus, MMF and standard‐dose steroids (TAC/MMF/STR, n = 98). Mean change in height SDS was 0.16 ± 0.32 with TAC/MMF/DAC and 0.03 ± 0.32 with TAC/MMF/STR. The mean treatment group difference was 0.13 (p < 0.005 [95% CI 0.04–0.22]), 0.21 in prepubertal (p = 0.009 [95% CI 0.05–0.36]) and 0.05 in pubertal children (p = ns). Frequency of biopsy‐proven acute rejection was 10.2%, TAC/MMF/DAC, and 7.1%, TAC/MMF/STR. Patient and graft survival and renal function were similar. Significantly greater reductions in total cholesterol and triglycerides but significantly higher incidences of infection and anemia were found with TAC/MMF/DAC (p < 0.05 all comparisons). Early steroid withdrawal significantly aided growth at 6 months more so in prepubertal than pubertal children. This was accompanied by significantly better lipid and glucose metabolism profiles without increases in graft rejection or loss.     

Randomized trial of 3 maintenance regimens (TAC/SRL vs. TAC/MMF vs. CSA/SRL) with low-dose corticosteroids in primary kidney transplantation: 18-year results

A randomized trial of 150 primary kidney transplant recipients, initiated in May 2000, compared tacrolimus (TAC)/sirolimus (SRL) vs. TAC/mycophenolate mofetil (MMF) vs. cyclosporine microemulsion (CSA)/SRL (N = 50/group). All patients received daclizumab induction and maintenance corticosteroids. With current median follow-up of 18 years post-transplant, biopsy-proven acute rejection (BPAR) occurred less often in TAC/MMF (26% (13/50)), vs. the TAC/SRL (36% (18/50)) and CSA/SRL (34% (17/50)) arms combined (p = .23), with statistical significance favoring TAC/MMF (p = .05) after controlling for the multivariable (Cox model) effects of recipient age, recipient race/ethnicity, and donor age. First BPAR rate was clearly more favorable for TAC/MMF after stratifying patients by having 0–1 (N = 72) vs. 2–3 (N = 78) unfavorable baseline characteristics (recipient age <50 years, African American or Hispanic recipient, and donor age ≥50 years) (p = .02). Mean estimated glomerular filtration rate (eGFR), using the CKD-EPI formula, was consistently higher for TAC/MMF, particularly after controlling for the multivariable effect of donor age, throughout the first 96 months post-transplant (p ≤ .008). These differences were translated into an observed more favorable graft failure due to immunologic cause (CAI/TG) rate for TAC/MMF (p = .06), although no significant differences in overall death-uncensored graft loss were observed. Previously reported significantly higher study drug discontinuation and requirement for antilipid therapy rates in the SRL-assigned arms were maintained over time. Overall, these results at 18 years post-transplant more definitively show that TAC/MMF should be the gold standard for achieving optimal, long-term maintenance immunosuppression in kidney transplantation.     

Early steroid withdrawal in pediatric renal transplant: five years of follow-up

This prospective, comparative trial investigated the impact on mean change in height standard deviation score (SDS), acute rejection rate, and renal function of early steroid withdrawal in 96 recipients with 5 years of follow-up. Recipients under basiliximab induction and steroid withdrawal (SW: TAC/MMF; n = 55) were compared with a matched steroid control group (SC: TAC/MMF/STEROID, n = 41). SW received steroids until Day 6, SC decreased to 10 mg/m(2) within 2 months post-transplant. Five years after SW, the longitudinal growth (SDS) gain was 1.4 ± 0.4 vs. 1.1 ± 0.3 for SC group (p < 0.02). Height benefits in prepubertal and pubertal status in both groups were demonstrated in the delta growth trends (mixed model; p < 0.01). Biopsy-proven acute rejection in SW was 11% and 17.5%, SC (p: ns). Mean eGFR (ml/min/1.73 m(2)) at 5 years post-transplant was SW 80.6 ± 27.8 vs. 82.6 ± 25.1 for SC (p: ns). The death-censored graft survival rate at 1 and 5 years was 99 and 90% for SW; 98 and 96% for SC (p = ns). PTLD incidence in SW 3.3 vs. 2.5% in SC (p: ns). Five years post-transplant, early steroid withdrawal showed positive impacts on growth, stable renal function without increased acute rejection risk, and PTLD incidence.     

Efficacy of conventional immunosuppressive therapy in related and unrelated living renal transplantation

BACKGROUND: The application of antibody induction therapy in adult living-related kidney transplantation remains under discussion. The purpose of this study was to compare the outcome of living-related (LRT) and unrelated renal transplant recipients (LURT) using standardized immunosuppressive protocols. From October 2000 to October 2004, 72 adult LRT (TX) were performed at our institution. Thirty-nine LRT (group A) and 33 LURT (group B) recipients received a standardized immunosuppressive therapy consisting of tacrolimus (Tac), steroids and mycophenolate mofetil (MMF) without antibody induction therapy. This prolective analysis included immediate graft function, rejection rate and loss of the transplanted organ. The incidence of post-operative good graft function (>90%) was similar for both groups, as well as the rejection rate showed 57.8% for patients of group A and 58.8% for patients of group B (p < 0.5). However, the number of rejections (>1 rejection) was significantly higher in group B (11.8%) compared to patients in group A (4.4%). No difference concerning loss of transplanted kidney was observed for both groups. Conventional Tac, MMF and steroid-based immunosuppression therapy is equivalent in efficacy of therapy in living-related and unrelated renal transplants. In our opinion, induction therapy in patients without immunologic risk factors has no favourable effect.     

Steroid withdrawal in living donor renal transplant recipients using tacrolimus and cyclosporine: a randomized prospective study.

Steroids have been a mainstay of immunosuppressive regimens in renal transplantation despite their adverse effects. The introduction of new immunosuppressant has improved the survival rates and prompted trials of steroid withdrawal. We conducted a randomized prospective study to compare steroid withdrawal at 6 months post-transplant between tacrolimus + mycophenolate mofetil (MMF) (FK group) versus cyclosporine A + MMF (CsA group). Steroid was withdrawn at 6 months post-transplant under the condition of no rejection episode proven by biopsy and maintenance of serum creatinine level <2.0 mg/dl. Fourteen recipients were excluded because of acute rejection within 6 months or protocol violation. Steroid could be tapered off in 62 in FK group and 55 in CsA. Three cases in FK group and five in CsA had acute rejection within another 6 months after steroid withdrawal (P > 0.05). At 12 months, the incidence of post-transplant diabetes was 18.6% vs. 8.0% in FK and CsA group. And hypercholesterolemia was presented in 8.5% vs. 2.0%, hypertension in 47.5% vs. 56.0%, and serum creatinine level 1.18 +/- 0.24 mg/dl vs. 1.18 +/- 0.20 mg/dl, respectively (P > 0.05). Steroid withdrawal may be carried out successfully using both FK and CsA with MMF, but long-term follow-up is necessary.     

Randomized trial of cyclosporine and tacrolimus therapy with steroid withdrawal in living‐donor renal transplantation: 5‐year follow‐up

The aim of this study was to compare the long‐term safety and efficacy of immunosuppressive regimens consisting of cyclosporine (CsA) plus mycophenolate mofetil (MMF) or tacrolimus (TAC) plus MMF after steroid withdrawal 6 months after kidney transplantation in low‐risk patients. One hundred and thirty‐one patients were randomized to receive either CsA (n = 63) or TAC (n = 68). Of these, 117 patients satisfied the criteria for steroid withdrawal (no biopsy‐proven rejection episode and serum creatinine level <2.0 mg/dl 6 months after transplantation). Fifty‐five recipients were of the CsA group, and 62 were of the TAC group. The 5‐year graft survival rate did not differ between groups (90.5% vs. 93.3% respectively; P = 0.55). The cumulative incidence of acute rejection 5 years after transplantation was 16.4% and 8.1% for the CsA and TAC groups respectively (P = 0.15). Post‐transplantation diabetes mellitus was more frequent in the TAC group than in the CsA group (P = 0.05), but the incidence of other side‐effects did not differ between groups. In conclusion, CsA‐ and TAC‐based regimens in conjunction with MMF have similar patient‐ and graft survival rates in low‐risk patients who underwent steroid withdrawal 6 months after kidney transplantation.     

Association of treatment with 15-deoxyspergualin and BK virus nephropathy in kidney allograft recipients

OBJECTIVE: BK virus nephropathy (BKVN) has been proposed as an important cause of allograft dysfunction and loss in kidney allograft recipient over the last decade. Intense immunosuppression and tubular injury have been shown to promote the replication of polyomavirus. 15-deoxyspergualin (DSG), an effective immunosuppressive agent, is used as a rescue drug for acute rejection in clinical renal transplantation in Japan. To determine whether DSG is a risk factor for BKVN and outline the relationship among BKVN, DSG, and other risk factors, we analyzed 88 patients who received living-related renal transplantation between January 1999 and April 2003. METHODS: A total of 114 biopsy specimens from 88 living-related kidney transplantation recipients (performed between January 1999 to April 2003) were retrospectively analyzed. Patients received immunosuppression therapy based on calcineurin inhibitors and corticosteroid [tacrolimus (TAC) 33 and cyclosporin (CyA) 55]. Additionally, mycophenolate mofeteil (MMF) was used in 21 patients; DSG was used in seven patients; and anti-CD3 monoclonal antibody was used in 16 patients. We analyzed the degree of donor/recipient human leucocyte antigen (HLA) compatibility assessed by the number of HLA-A, -B, and -DR-mismatched antigens in 88 patients. The diagnosis of BKVN was made by the light microscopic examination and a positive immunohistochemical staining of anti-40 antibody in biopsy specimens. Patients were divided into two groups of group A (mild histological change) and group B (moderate or severe histological change) to determine the risk factors in different histological staging. The clinical course of two typical patients in different histological stage is described briefly to outline the risk factors of BKVN. RESULTS: We identified seven cases of BKVN (8.0%) from 88 transplanted patients. Significantly higher incidence of combination regimen consisting of TAC and MMF in BKVN group was noticed compared with non-BKVN group (57.1% vs. 9.9%; p = 0.003). BKVN was associated with a significantly higher incidence of DSG administration compared with non-BKVN group (57.1% vs. 3.7%; p 相似文献   

Tacrolimus with Mycophenolate Mofetil (MMF) or Sirolimus vs. Cyclosporine with MMF in Cardiac Transplant Patients: 1-Year Report

The most advantageous combination of immunosuppressive agents for cardiac transplant recipients has not yet been established. Between November 2001 and June 2003, 343 de novo cardiac transplant recipients were randomized to receive steroids and either tacrolimus (TAC) + sirolimus (SRL), TAC + mycophenolate mofetil (MMF) or cyclosporine (CYA) + MMF. Antilymphocyte induction therapy was allowed for up to 5 days. The primary endpoint of >/=3A rejection or hemodynamic compromise rejection requiring treatment showed no significant difference at 6 months (TAC/MMF 22.4%, TAC/SRL 24.3%, CYA/MMF 31.6%, p = 0.271) and 1 year (p = 0.056), but it was significantly lower in the TAC/MMF group when compared only to the CYA/MMF group at 1 year (23.4% vs. 36.8%; p = 0.029). Differences in the incidence of any treated rejection were significant (TAC/SRL = 35%, TAC/MMF = 42%, CYA/MMF = 59%; p < 0.001), as were median levels of serum creatinine (TAC/SRL = 1.5 mg/dL, TAC/MMF = 1.3 mg/dL, CYA/MMF = 1.5 mg/dL; p = 0.032) and triglycerides (TAC/SRL = 162 mg/dL, TAC/MMF = 126 mg/dL, CYA/MMF = 154 mg/dL; p = 0.028). The TAC/SRL group encountered fewer viral infections but more fungal infections and impaired wound healing. These secondary endpoints suggest that the TAC/MMF combination appears to offer more advantages than TAC/SRL or CYA/MMF in cardiac transplant patients, including fewer >/=3A rejections or hemodynamic compromise rejections and an improved side-effect profile.     

Prospective randomized study of azathioprine vs cyclosporine based therapy in primary haplo-identical living-donor kidney transplantation: 20-year experience

Background The achievements in short-term graft survival since the introduction of cyclosporine (CsA) have not been matched by improvements in long-term graft function. Chronic allograft nephropathy (CAN) remains the second most common cause of graft attrition over time, after patient mortality. We aimed to evaluate the long-term results of azathioprine vs CsA in live-donor kidney transplantation in a prospective randomized study. Methods We studied 475 renal transplant recipients who had had transplantations performed at the Urology and Nephrology Center, Mansoura University, before 1988 and who had received a primary immunosuppressive protocol consisting of either steroid and azathioprine (steroid/Aza; group 1, 300 patients) or steroid and CsA (steroid/CsA; group 2, 175 patients). Only adult primary renal transplant recipients aged between 18 and 60 years and with one haplotype HLA mismatch were included. All patients received kidneys from living-related donors, with previous donor nonspecific blood transfusions. The study was based on the long-term follow-up data of these renal transplant recipients. Comparative analyses included patient and graft survival rates, condition at last follow up, rejection (acute and chronic), and graft function (serum creatinine and creatinine clearance). Results The overall frequency of acute rejection episodes was not significantly different between the two groups. Graft survival rates were: group 1 vs group 2, 69% vs 58% at 5 years, and 52% vs 36% at 10 years, but at 20 years, graft survival rates had declined to 26% and 24%. No significant differences were encountered between the two groups regarding post-transplant malignancies, diabetes mellitus, hepatic impairment, or serious bacterial infections. Conclusions From this study we can conclude that the long-term result of historical conventional therapy (steroid/Aza) without induction therapy is effective for living-donor kidney transplants. In spite of the comparable graft function for the two groups, the steroid/CsA group experienced more hypertension, as well as many adverse reactions to CsA. Nowadays, since the introduction of induction therapy and the utilization of newer maintenance immunosuppressive agents – such as mycophenolate mofetil (MMF) and rapamycin – it is possible to achieve an excellent calcineurin inhibitors (CNI)-free regimen.     

A prospective randomized trial of mycophenolate mofetil in liver transplant recipients with hepatitis C

Hepatitis C is the most common indication for liver transplantation (LT) in the United States. Recurrence of hepatitis C virus (HCV) infection post-LT remains a problem for which there is no completely satisfactory treatment. The aim of the present study is to evaluate mycophenolate mofetil (MMF), which has both immunosuppressive and antiviral properties, to determine whether it is associated with a difference in the rate of HCV recurrence and also examine its impact on patient and graft survival. Between August 1995 and May 1998, a total of 106 patients who were HCV positive before LT were randomized to tacrolimus (TAC) and prednisone versus TAC, prednisone, and MMF therapy. The rate of recurrence of HCV, patient and graft survival, incidences of rejection, and histological findings were examined. Fifty six patients were randomized to TAC and steroid therapy (double [D] drug; group D), and 50 patients were randomized to TAC, steroid, and MMF therapy (triple [T] drug; group T). Liver biopsies were performed when liver function was abnormal; protocol liver biopsies were not performed. Mean follow-up was 4.3 [plusmn] 0.8 years. Actuarial patient survivals at 4 years were 72.6% in group D and 73.8% in group T (P = not significant). Actuarial graft survivals at 4 years were 65.6% in group D and 65.4% in group T. One patient in group D and 2 patients in group T underwent a second LT for recurrent HCV. One patient in each group died of recurrent HCV without re-LT. Twenty-six patients in group D (46.4%) and 23 patients in group T (46.0%) showed signs of recurrent HCV. Mean hepatitis activity index (HAI) scores were 7.4 [plusmn] 2.7 in group D and 7.0 [plusmn] 3.4 in group T, and mean fibrosis scores were 2.9 [plusmn] 1.7 in group D and 2.6 [plusmn] 1.1 in group T. The rate of rejection was 0.57/patient in each group for the entire follow-up period. None of these values reached statistical significance. Rates of HCV recurrence, graft loss or death from recurrent HCV, and 4-year actuarial patient and graft survival were not different between the groups. In liver transplant recipients with HCV, MMF has no impact on patient survival, graft survival, rejection, or rate of HCV recurrence based on biochemical changes and histological findings. In addition, there was no difference in HAI or fibrosis score between the two groups. Either MMF has no anti-HCV effect or its immunosuppressive properties overwhelm its antiviral effect in the clinical setting. (Liver Transpl 2002;8:40-46.)     

Immunosuppressive treatment and progression of histologic lesions in kidney allografts

Renal transplantation is the best therapeutic option for patients with end-stage renal disease. Although short-term results are excellent, long-term graft survival has not improved substantially in recent times. Chronic allograft nephropathy (CAN) and death with a functioning graft are the most important causes of graft loss. Recent evidence shows that nephrotoxicity of calcineurin inhibitors contributes to CAN, and the introduction of non-nephrotoxic drugs such as mycophenolate mofetil (MMF) and mammalian target of rapamycin inhibitors may provide new immunosuppressive strategies to improve long-term results after renal transplantation. MMF decreases the risk of developing chronic allograft failure and is useful for treating established CAN, because it has a beneficial effect on allograft fibrosis. Treatment with sirolimus (SRL), a basic immunosuppressive drug given in association with MMF, may offer better renal function, decrease the prevalence of CAN, and downregulate expression of genes responsible for the progression of CAN than treatment with cyclosporine A (CsA). SRL also permits an early elimination of CsA from SRL-CsA-steroid regimens and shows better renal function and improved renal histology without risk of rejection. Notably, this approach improves graft survival at 4 years. Further multicenter studies are needed to determine whether both approaches produce similar results by comparing immunosuppression caused by SRL-based and tacrolimus (TAC)-based treatments. Because TAC is the most commonly used anticalcineurin drug, it is important to compare the effects of steroid-TAC-SRL treatment with and without elimination of TAC. Finally, although caution is needed, the use of non-nephrotoxic immunosuppressive treatment may change the natural history of CAN.     

Is simplification of immunosuppressive medication a way to promote medication adherence of kidney transplant recipients? Findings from a randomized controlled trial

After kidney transplantation, a strict immunosuppressive medication regimen is necessary for graft survival. However, nonadherence to medication has been shown to occur early after transplantation and to increase over time. Weaning the recipient off dual therapy onto monotherapy in order to reduce immunosuppressive burden may also be a way to promote adherence, although little is known about the impact of such a regimen on fear of rejection. We performed a cohort study on medication adherence and fear of rejection in a randomized, investigator-driven, open-label, single-centre pilot study. Recipients were randomized at 6-months post-transplant to either continue Tacrolimus and Mycophenolate mofetil (TAC/MMF) or to taper MMF at 6 months and discontinue MMF at 9 months (TAC monotherapy). Recipients completed questionnaires about medication adherence and fear of rejection at 6 and 12-months post-transplantation. Medication adherence was significantly higher in the TAC monotherapy group compared to dual TAC/MMF therapy group (χ² (1) = 4.582; P = 0.032). We found no difference in fear of rejection between the two groups of recipients (P = 0.887). Simplification of the medication regimen is a potential tool for increasing adherence in clinical practice (Netherlands Trial Register – NL4672).     

Influence of tacrolimus plus mycophenolate mofetil regimens on acute rejection rate and diabetes mellitus development in renal transplant recipients

In this study we investigated the influence of a tacrolimus (TAC) plus mycophenolate mofetil (MMF) immunosuppressive regimen on the acute rejection rate and side effect profile in renal transplant recipients. The study included 80 living-related and 40 cadaveric donor renal transplant recipients (82 men, 38 women) of mean age 35 +/- 10 years (range, 16 to 58) who were operated between August 1999 and September 2002. The mean HLA mismatches was 3 +/- 1 (range, 0 to 5). All patients received prednisolone, MMF (2 g/d for the first 14 days posttransplant and then 1 g/d) plus TAC (0.2 mg/kg/d). They were followed for the development of rejection attacks and side effects. Diabetes mellitus developed in 13 patients (9 men, 4 women; 10.8%). Initially, patients required insulin therapy but after 6 months, 5 recipients no longer needed insulin therapy and were switched to oral hypoglycermic agents and diet control. Hypertension was diagnosed in 58 patients (48.3%). Neither gender nor donor origin (P =.14; P =.79, respectively) produced a significant difference in diabetes mellitus development. Biopsy proven acute rejection episodes were observed in 16 out of 120 patients (13.3%). Six out of 120 patients lost their grafts throughout the study period including one death because of suicide, one because of cytomegalovirus disease and hemophagocytic syndrome, one due to posttransplant lymphoproliferative disease and two to a cardiac arrhythmia. Only one patient lost his graft due to acute accelerated vascular rejection. Biopsy-proven chronic rejection appeared in one patient. In conclusion, although the incidence of insulin-dependent diabetes mellitus during posttransplant 6 months, seems high it decreased to 1.6% upon reduction of the TAC dosage. TAC plus MMF immunosuppression seems effective and safe in terms of acute rejection rates and side effect profiles.     

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.     

Factors influencing outcome of simultaneous kidney and pancreas transplantation: a 23-year single-center clinical experience

Introduction

Simultaneous kidney and pancreas transplantation (SKPT) has become an effective treatment for patients who have diabetes mellitus type I with advanced nephropathy. This study assesses the progress of the SKPT program at Uppsala University Hospital, Sweden, and evaluates prognostic factors for graft survival.

Materials and Methods

Between February 1986 and September 2009, we performed 113 SKPT. The immunosuppression protocols changed over time and are defined as era 1, cyclosporine (CyA), atzathioprine (AZA) and steroids (C/A/S); era 2, C/A/S with antithymocyte globulin (ATG) induction (C/A/S/A); era 3, CyA, mycophenolate mofetic (MMF), steroids and ATG induction (C/M/S/A); era 4, tacrolimus (TAC), MMF, steroid, and ATG induction (T/M/S/A) and era 5, TAC, MMF, steroids and basiliximab induction (T/M/S/B). We analyzed donor/recipient/operative and postoperative variables to assess their influence on pancreas graft and patient survivals.

Results

The overall 1-, 5-, and 10-year patient survivals were 95.5%, 84.1%, and 65.5%, respectively. The 1-, 5-, and 10-year overall pancreas graft survivals were 77.6%, 58.4%, and 48.4%. The 1-, 5-, and 10-year pancreas graft survivals in SKPT patients transplanted between October 1997 and September 2009. (T/M/S/A and T/M/S/B; eras 4 and 5) were 95.3%, 72.7%, and 63.1%, respectively, which was significantly better than those of patients transplanted between February 1986 and September 1997 (era, 1 through 3) (P < 0.01, P < 0.0001, respectively). The quadruple regimen with TAC and MMF (eras 4 and 5) decreased the incidence of acute rejection episodes compared with eras 1 through 3 (P < 0.0001). Basiliximab induction (T/M/S/B; era 5) reduced the CMV infection rate compared with eras 1 through 4 (P < 0.01). Multivariate analysis revealed that donor age (younger than 40 years), immunosuppressive regimen with TAC and MMF (eras 4 and 5), and absence of acute rejection episodes independently affected pancreas graft survival.

Conclusions

We demonstrate a superiority of the quadruple protocol with T/M/S/B for graft and patient survival with a decreased incidence of CMV infection after SKPT.     

环孢素A转换为他克莫司对慢性移植肾肾病患者的治疗效果

目的 探讨由环孢素A(CsA)转换为他克莫司(Tac)为主的免疫抑制方案对慢性移植肾肾病(CAN)患者的治疗效果.方法 选择接受同种肾移植后发生CAN的患者153例,患者肾移植后均采用CsA、吗替麦考酚酯(MMF)及泼尼松(Pred)的免疫抑制方案.根据是否以Tac替换CsA将患者分为两组.(1)CsA组:45例,进入研究后患者维持原免疫抑制方案.(2)Tac组:108例,进入研究后将CsA转换为Tac,停用CsA后立即开始服用Tac,MMF和Pred的用法同CsA组.对所有患者随访12个月,观察人/移植肾存活率、急性排斥反应发生率、移植肾功能、24 h尿蛋白定量、移植肾穿刺病理学活检及免疫抑制剂的不良反应等指标.结果 随访12个月时,CsA组和Tac组患者存活率均为100%,移植肾存活率分别为86.6%和93.5%(P＜0.05);急性排斥反应发生率分别为4.4%(2/45)和3.7%(4/108)(P＞0.05),6例发生急性排斥反应的患者均经甲泼尼龙冲击治疗3 d后逆转.Tac组患者移植肾功能明显改善,并且出现重度蛋白尿、重度肾间质纤维化和肾小管萎缩的患者比例较CsA组显著减少(P＜0.05).Tac组有13.8%(15例)的患者出现轻度血糖增高,发生率显著高于CsA组的4.4%(2例)(P＜0.05);Tac组有22.2%(24例)的患者发生高血压,发生率显著低于CsA组的55.6%(25例)(P＜0.05);17例因使用CsA而出现牙龈增生和多毛症者,经转换治疗后,症状均明显好转.结论 由CsA转换为Tac为主的免疫抑制方案能够显著改善CAN患者的移植肾功能,延缓CAN的发展,转换过程中未发生严重Tac不良反应并且改善了使用CsA时出现的不良反应.

Abstract：

Objective To investigate the effect of conversion from cyclosporine A (CsA) to tacrolimus (Tac) on chronic allograft nephropathy (CAN). Methods 153 CAN patients undergoing kidney transplantation received CsA, mycophenolate mofetil (MMF) and prednisone (CsA-MMF-Pred) regimen after kidney transplantation, and divided into 2 groups according to whether CsA were maintained in the immunosuppressive regimen: CsA + MMF + Pred group (CsA group, n = 45); Tac + MMF + Pred group (Tac group, n = 108). The patients were followed up with patient/kidney survival rate, acute rejection incidence, renal function, 24-h proteinuria and adverse events of immunosuppressive drugs for 12 months. Results Compared with CsA group, the transplanted kidney survival rate was significantly higher in Tac group (93. 5 % vs 86.6 %, P＜0. 05). Acute rejection (AR) was diagnosed in 4. 4 % (2/45) of recipients in CsA group and 3. 7 % (4/108) in Tac group (P＞0. 05) respectively. Acute rejection (2 cases in CsA group and 4 in Tac group) was reversed by 500 mg of methylprednisolone for consecutive 3 days, and the patients in Tac group showed a significantly lower degree of interstitial fibrosis and tubular atrophy (IF/TA) (P＜0. 05).Renal allograft functions and 24-h proteinuria during a follow-up period of 12 months were significantly improved in Tac group (P ＜ 0. 05). Incidence of mild hyperglycemia in Tac Group (13.8 %, 15/108) was significantly higher than in CsA group (4.4 %, 2/45), and that of hypertension in Tac group (22. 2 %, 24/108) was significantly lower than in CsA group (55.6 %,25/45). CsA-related side effects (such as hirsutism and gingival hypertrophy) in 17 patients were greatly improved after conversion from CsA to Tac treatment. Conclusion The conversion from CsA to Tac on the patients with CAN can improve renal allograft function, retard the progression of renal allograft dysfunction, reduce the incidence of CsA-related side effects and not generate serious adverse effects of Tac.     

Randomized prospective trial of early steroid withdrawal compared with low-dose steroids in renal transplant recipients using serial protocol biopsies to assess efficacy and safety

BACKGROUND: Corticosteroid therapy after renal transplantation is associated with many adverse effects. Newer immunosuppressive agents may allow for safe and effective reductions in dose or early steroid withdrawal. METHODS: In this prospective, single-center clinical trial, 60 patients were randomized into 2 groups: control patients (n = 28), who received low doses of prednisone throughout, and study patients (n = 32), who were withdrawn from steroids 7 days posttransplant. Patients received a limited course of rabbit antilymphocyte globulin (rALG) induction therapy, tacrolimus (TAC), and mycophenolate mofetil (MMF). Patients were followed for clinical outcomes and renal function. Protocol biopsies were performed at 1, 6, and 12 months. RESULTS: Clinical rejections occurred in 11% of controls and 13% of study patients. Renal function was well maintained and equivalent in both groups. In all, 111 protocol biopsies were performed without complications. Subclinical rejection was noted in only 2 protocol biopsies, and borderline changes were seen in 12 biopsies, all of which were distributed equally between both groups. Unsuspected acute TAC toxicity was seen in 8 biopsies. Protocol biopsies led to changes in therapy in 10% of patients. In both groups, serial protocol biopsies demonstrated increased allograft fibrosis over time, which was significant at 1 year in the steroid withdrawal group. CONCLUSION: The immunosuppressive combination of rALG, TAC, and MMF prevents subclinical rejection and the need for high doses of steroids after transplantation. However, continual low-dose steroid therapy may aid in preventing chronic allograft fibrosis. Protocol biopsies help define the short-term and long-term risks of steroid withdrawal therapy.