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.     

Long-term outcome of sirolimus rescue in kidney-pancreas transplantation

The aim of this study was to evaluate long-term outcome of sirolimus (SRL) rescue in kidney-pancreas transplantation (KPTx). We reviewed 112 KPTx performed at our institution from 12/3/95 to 6/27/02. All patients received antibody (Ab) induction, tacrolimus (TAC), mycophenolate mofetil (MMF), and steroids. Thirty-five patients (31%) had SRL substituted for MMF for the following indications: (1) acute rejection (AR) of kidney or pancreas despite adequate TAC levels; (2) intolerance of full-dose MMF; (3) rising creatinine; and (4) TAC-induced hyperglycemia. Target SRL and TAC levels were 10 ng/mL and 5 ng/mL, respectively. Mean follow-up was 3 +/- 2 years overall and 1.2 +/- 0.5 years after SRL rescue. No patients died. One- and 3-year actuarial kidney and pancreas graft survival was 97%, 97%, and 95%, 90%, respectively. Of 10 patients switched to SRL for AR, 1 kidney failed from Ab-resistant AR, 1 kidney developed borderline AR, and the other 8 remain AR-free. Seven other patients developed AR despite therapeutic SRL levels; of these, 6 (86%) had mean TAC levels of <4.5 in the month preceding AR. Mean creatinine overall and for the rising creatinine group remained stable. All patients switched to SRL for TAC-induced hyperglycemia or MMF intolerance demonstrated biochemical or clinical improvement. Sirolimus-related infection or other serious adverse events (SAE) were uncommon. In conclusion, KPTx recipients can be safely switched to SRL with long-term stabilization of renal function, excellent graft and patient survival, and no increase in SAE. A minimum TAC level of 4.5 ng/mL may be necessary to prevent late AR.     

Concentration-controlled use of sirolimus associated with reduced exposure of cyclosporine in black recipients of primarily living renal allograft donors: 12-month results

AIM: This study was designed to identify optimal therapeutic sirolimus (SRL) concentrations in black kidney transplant recipients on reduced cyclosporine (CsA) exposure and prednisone. METHODS: Seventy patients (64 living/six deceased) received CsA (8-10 mg/kg/d), prednisone, and 15 mg loading dose followed by 5-mg fixed doses of SRL till day 7 when they were randomized to maintain SRL trough concentrations (high-performance liquid chromatography) of 8-12 (GI = 34) or 15-20 (GII = 36) ng/mL. RESULTS: Mean CsA concentrations were 109 +/- 53 vs. 89 +/- 41 ng/mL and 75 +/- 54 vs. 60 +/- 35 ng/mL (ns) at 2 and 6 months. Accordingly, mean SRL trough concentrations were 12.4 +/- 6.1 vs. 20.0 +/- 9.5 ng/mL (p < 0.001) and 10.8 +/- 5.8 vs. 18.0 +/- 6.1 ng/mL (p < 0.001). The incidence of biopsy-proven acute rejection [13% (GI: 18% vs. GII: 8%, ns)], graft loss or death was 16% (GI: 21% vs. GII: 11%, ns]. There were no deaths and three graft losses (GI = 1; GII = 2). Creatinine clearance was higher in GI (64.5 +/- 17 vs. 54.4 +/- 14.7 mL/min, p = 0.011). The incidence of post-transplant diabetes mellitus was 13% and no CMV disease was observed. CONCLUSION: In black recipients of primarily living renal allograft donors reduced CsA exposure and SRL concentration-controlled regimens produced low incidences of acute rejection, post-transplant diabetes mellitus and CMV disease, with no significant impairment in graft function.     

Conversion to low-dose tacrolimus or rapamycin 3 months after kidney transplantation: a prospective, protocol biopsy-guided study

Long-term survival of kidney allografts is primarily limited by a progressive decline in function characterized by the presence of interstitial fibrosis (IF) and tubular atrophy (TA) on biopsy. Since chronic calcineurin-inhibitor (CNI) drug toxicity has been implicated as a significant cause of IF/TA, a major effort in transplantation has been to decrease or eliminate CNI therapy. We now report the clinical and histological consequences of converting renal transplant recipients at 3 months to either very low levels of tacrolimus (TAC; 4-6 ng/mL) or sirolimus (SRL; 6-10 ng/mL) therapy. Fifty-eight enrollees in this prospective randomized trial received low-dose (2.9 ± 0.6 mg/kg) rabbit antithymocyte globulin induction followed by standard doses of TAC (10-15 ng/mL), mycophenolic acid, and low-dose steroids for 3 months. Protocol biopsies were performed at implantation and 3 and 12 months. Six patients had evidence of either borderline changes (n = 5) or grade 1A rejection (n = 1) on the 3-month protocol biopsy and were not randomized. Only one patient had clinically evident rejection that occurred after randomization to SRL. One patient in each group had borderline changes at 12 months. Renal function (estimated glomerular filtration rate) was equivalent in both groups at 12 months (TAC 74 ± 15 vs SRL 66 ± 18 mL/min, P = .22). Chronic allograft damage index scores at 1 year were similar in both groups (TAC 2.8 ± 2.4 vs SRL 2.0 ± 2.7, P = .71). The percentage of patients with IF/TA scores greater than 2 at 1 year was low in both groups (TAC 12% vs SRL 9%, P = .78). Therefore, in a low-risk population defined as having a normal 3-month protocol biopsy, TAC levels can be successfully decreased to very low concentrations. One-year graft function and histology were equally well maintained with either low-dose TAC or SRL immunosuppression.     

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.     

Long-term outcome of sirolimus rescue in kidney-pancreas transplantation

Sirolimus (SRL) rescue in kidney-pancreas transplantation has not been well described. We reviewed 112 KPTxs performed at our institution between December 3, 1995 and June 27, 2002. All patients received antibody induction, tacrolimus (TAC), mycophenolate mofetil (MMF), and steroids. In 35 patients, SRL was substituted for MMF for the following reasons: acute rejection (AR) of kidney or pancreas despite adequate TAC levels, MMF intolerance, increasing creatinine levels, and TAC-induced hyperglycemia. Three-year kidney and pancreas graft survivals were 97% and 90%, respectively. Of 10 patients who were switched to SRL because of AR, one kidney failed because of antibody-resistant AR, and one kidney developed borderline AR; the other eight patients remain AR-free. AR developed in seven other patients despite therapeutic SRL levels; six had TAC levels less than 4.5 ng/mL. The mean creatinine levels overall and for the group with increasing creatinine remained stable. All patients who were switched to SRL for TAC-induced hyperglycemia or MMF intolerance improved. Kidney-pancreas transplant recipients can be safely switched to SRL with excellent graft and patient survival.     

Mycophenolate Mofetil/Sirolimus Compared to Other Common Immunosuppressive Regimens in Kidney Transplantation

We evaluated outcomes with the sirolimus (SRL) and mycophenolate mofetil (MMF) combination regimen (SRL/MMF) in solitary kidney transplant recipients transplanted between 2000 and 2005 reported to the Scientific Registry of Renal Transplant Recipients. Three-and-a-half percent received SRL/MMF (n = 2040). Six-month acute rejection rates were higher with SRL/MMF (SRL/MMF: 16.0% vs. other regimens: 11.2%, p < 0.001). Overall graft survival was significantly lower on SRL/MMF. SRL/MMF was associated with twice the hazard for graft loss (AHR = 2.0, 95% C.I., 1.8, 2.2) relative to TAC/MMF, also consistent in both living donor transplants (AHR = 2.4, 95% C.I., 1.9, 2.9) and expanded criteria donor transplants (AHR = 2.1, 95% C.I., 1.7-2.5). Among deceased donor transplants, DGF rates were higher in the SRL/MMF cohort (47% vs. 27%, p < 0.001). However, adjusted graft survival was also significantly inferior with SRL/MMF in DGF-free patients (AHR = 1.9, 95% C.I., 1.6-2.3). In analyses restricted to patients who remained on the discharge regimen at 6 months posttransplant, conditional graft survival in deceased donor transplants was significantly lower with SRL/MMF compared to patients on TAC/MMF or CsA/MMF regimens at 5 years posttransplant (64%, 78%, 78%, respectively, p = 0.001) and across all patient subgroups. In conclusion, SRL/MMF is associated with inferior renal transplant outcomes compared with other commonly used regimens.     

Single-shot antithymocyte globuline and daclizumab induction in simultaneous pancreas and kidney transplant recipient: three-year results

Since 1996, preoperative single-shot dose antithymocyte globuline (ATG) with prednisolone (PRD), mycophenolate mofetile (MMF), and tacrolimus (TAC) is the favorite induction therapy in our center. In a series of 25 first simultaneous pancreas and kidney transplant (SPK) recipients, 5 doses of daclizumab were administered in addition to standard induction. Here we present our 3-year experience. Immunosuppression was started prior to reperfusion consisting of daclizumab (1 mg/kg body weight [bw]), ATG (4-6 mg/kg bw) and 250 mg PRD. After surgery, PRD was reduced gradually, TAC trough levels were between 8-15 ng/mL, MMF was given twice daily (2-3 g/d) as well as 4 further doses dacilzumab every 14 days. After 3 years, patient, pancreas, and kidney graft survival rates are 100%, 84%, and 92%, respectively. Four pancreas grafts were lost (chronic allograft dysfunction, n = 2; recurrent abdominal infection, n = 1; acute rejection [AR] without treatment, n = 1). Both patients suffering from severe infection and untreated AR lost their kidney graft too. During the first 3 months after SPK, 3 AR episodes were observed in 2 patients (8%). After a 3-year period, 8 AR episodes occurred in 7 recipients (28%). AR was treated using PRD (n = 5) or ATG (n = 1). In 1 case, immunosuppression was switched from TAC to sirolimus successfully. Overall, 8 AR episodes occurred in 7 patients (28%) during the first 3 years after SPK. One severe infection led to graft lost 13 months after SPK. In this series, the combination of ATG and daclizumab prevented AR episodes, successfully providing considerable 3-year survival rates.     

Improved renal function in sirolimus-treated renal transplant patients after early cyclosporine elimination

BACKGROUND: Sirolimus (Rapamune; SRL) in combination with cyclosporine (CsA) reduces the incidence of acute rejection episodes in renal allograft recipients. This study evaluated whether renal function could be improved by elimination of CsA from an SRL-based regimen. METHODS: This phase 2, open-label, controlled, randomized study was conducted at 17 centers in the United States and Europe. Two hundred forty-six first cadaveric renal allograft recipients were enrolled, and 197 were randomized to full-dose CsA (microemulsion) plus fixed-dose SRL (2 mg/day; group A, n=97) or reduced-dose CsA plus concentration-controlled SRL (troughs 10-20 ng/mL; group B, n=100). Most patients with acute tubular necrosis-delayed graft function that resolved later than posttransplantation day 7 were not randomized but were assigned to a third group (nonrandomized, n=49) and received up to 5 mg per day of SRL as part of their individualized treatment regimen. All patients received standard doses of corticosteroids. At the end of posttransplantation month 2, eligible patients (those not treated for rejection within 3 weeks) in group B had CsA tapered and eliminated over the subsequent 4 to 6 weeks. RESULTS: At 12 months after transplantation, renal function was significantly better in the CsA-elimination arm. In patients who were on therapy and who had not experienced an acute rejection episode before month 6, serum creatinine level was significantly lower (1.38 mg/dL vs. 1.82 mg/dL, P < 0.001) and calculated glomerular filtration rate (Nankivell method) was significantly higher (73.5 mL/min vs. 57.1 mL/min, P < 0.001) in group B than in group A. In the intention-to-treat population, rates of biopsy-confirmed acute rejection at 12 months were similar between groups A and B (18.6% vs. 22.0%, respectively; P = 0.598). In addition, graft survival (92.8% and 95.0%) and patient survival (96.9% and 96.0%) rates at 12 months were not significantly different between groups A and B, respectively. Furthermore, there were no significant differences between black and nonblack recipients within treatment groups in terms of rejection rates and graft survival at 12 months. Black recipients in group B had better serum creatinine levels at 12 months compared with black recipients in group A (1.55 mg/dL vs. 2.69 mg/dL, respectively, P = 0.011), as did nonblack recipients in group B compared with nonblack recipients in group A (1.53 mg/dL vs. 1.75 mg/dL, respectively, P = 0.055). Black patients in group A had higher mean serum creatinine levels (2.69 mg/dL) than nonblack patients in group A (1.75 mg/dL, P = 0.028). Hypertension, edema, hypomagnesemia, and dyspnea were reported significantly less frequently in patients randomly assigned to undergo CsA elimination compared with patients in group A (P < 0.05); group B patients had a significantly greater (P < 0.05) incidence of abnormal liver function tests, diarrhea, hypokalemia, and thrombocytopenia. CONCLUSION: Concentration-controlled SRL with early elimination of CsA is safe and results in improved renal function. Reduced exposure to CsA does not result in a clinically significant increase in the incidence of acute rejection episodes. This is true for both black and nonblack recipients. SRL may be used to reduce the exposure of renal allograft recipients to the nephrotoxic effects of CsA.     

An open-label randomized trial of the safety and efficacy of sirolimus vs. azathioprine in living related renal allograft recipients receiving cyclosporine and prednisone combination

BACKGROUND: The ability of sirolimus (SRL), in combination with reduced exposure of cyclosporine, was investigated to prevent acute rejection and associated side effects. METHODS: Between June 1999 and February 2000, 70 recipients of primary one-haplotype living-related donor renal allografts were randomized to receive SRL (2 mg/d) or azathioprine (AZA) (2 mg/kg/d) combined with cyclosporine and prednisone. The primary end-point was a composite of first occurrence of biopsy-confirmed acute rejection, graft loss, or death during the first 3 months after transplantation. RESULTS: From week 4 to month 12, SRL patients received lower cyclosporine (week 4: 364 mg/d vs. 455 mg/d, p = 0.004; month 12: 195 mg/d vs. 255 mg/d, p = 0.038) doses and showed lower cyclosporine concentrations (week 4: 247 ng/mL vs. 309 ng/mL, p = 0.04; month 12: 143 ng/mL vs. 188 ng/mL, p = 0.045). Compared with AZA, SRL patients showed reduced 3-month primary end point (0% vs. 17.1%, p = 0.025), and reduced incidence of biopsy-confirmed acute rejection at 3 months (0% vs. 14.3%, p = 0.01) but not at 12 months (11.4% vs. 14.3%, NS). Mean creatinine at 12 months were not different (1.8 +/- 0.6 vs. 1.6 +/- 0.6, p = 0.23). Hyperlipidemia was the only adverse event more frequent among SRL patients (49% vs. 17%, p = 0.01). There were no differences in infections and no malignancies in both groups. CONCLUSIONS: The combination of 2 mg fixed doses of SRL, reduced cyclosporine exposure and prednisone was associated with a low incidence of acute rejection and did not result in significantly impaired graft function compared with patients receiving AZA, standard doses of cyclosporine and prednisone.     

The ORION Study: Comparison of Two Sirolimus‐Based Regimens versus Tacrolimus and Mycophenolate Mofetil in Renal Allograft Recipients

Safety and efficacy of two sirolimus (SRL)‐based regimens were compared with tacrolimus (TAC) and mycophenolate mofetil (MMF). Renal transplantation recipients were randomized to Group 1 (SRL+TAC; week 13 TAC elimination [n = 152]), Group 2 (SRL + MMF [n = 152]) or Group 3 (TAC + MMF [n = 139]). Group 2, with higher‐than‐expected biopsy‐confirmed acute rejections (BCARs), was sponsor‐terminated; therefore, Group 2 two‐year data were limited. At 1 and 2 years, respectively, graft (Group 1: 92.8%, 88.5%; Group 2: 90.6%, 89.9%; Group 3: 96.2%, 95.4%) and patient (Group 1: 97.3%, 94.4%; Group 2: 95.2%, 94.5%; Group 3: 97.0%, 97.0%) survival rates were similar. One‐ and 2‐year BCAR incidence was: Group 1, 15.2%, 17.4%; Group 2, 31.3%, 32.8%; Group 3, 8.2%, 12.3% (Group 2 vs. 3, p < 0.001). Mean 1‐ and 2‐year modified intent‐to‐treat glomerular filtration rates (mL/min) were similar. Primary reason for discontinuation was adverse events (Group 1, 34.2%; Group 2, 33.6%; Group 3, 22.3%; p < 0.05). In Groups 1 and 2, delayed wound healing and hyperlipidemia were more frequent. One‐year post hoc analysis of new‐onset diabetes posttransplantation was greater in TAC recipients (Groups 1 and 3 vs. 2, 17% vs. 6%; p = 0.004). Between‐group malignancy rates were similar. The SRL‐based regimens were not associated with improved outcomes for kidney transplantation patients.     

Rapid Discontinuation of Steroids in Living Donor Kidney Transplantation: A Pilot Study

Steroids are associated with significant postoperative complications (hypertension, cosmetic changes, bone loss, hyperlipidemia, diabetes, and cataracts). Most develop early; in addition, late post-transplant steroid withdrawal in kidney transplant recipients has been associated with increased acute rejection (AR). To obviate these problems, we studied outcome of a protocol of rapid discontinuation of prednisone (RDS) (steroids stopped on POD6). Between November 1, 1999 and October 31, 2000, 51 adult living donor (LD) first transplant recipients (2 HLA-id, 28 non-id relative, 21 LURD) were immunosuppressed with thymoglobulin (1.25 mg/kg intraoperatively and then qdx4); prednisone (P) (500 mg methylprednisolone intraoperatively, 1 mg/kg x 1 day, 0.5 mg/kg x 2 days, 0.25 mg/kg x 2 days, then d/c); MMF, 1 g b.i.d.; and CSA, 4 mg/kg b.i.d. adjusted to achieve levels of 150-200 ng/mL (by HPLC). Exclusion criteria were delayed graft function or primary disease requiring P. Minimum follow-up was 5.5 months (range 5.5 to 17.5 months). Outcome was compared vs. previous cohorts of LD recipients immunosuppressed with P/AZA/CSA (n = 171) or P/MMF/CSA (n = 43) (both without antibody induction). RESULTS: For the RDS group, average CSA level (+/- S.E.) at 3 and 6 months was 190 +/- 12 and 180 +/- 9; avg. MMF dose, 1.7 +/- 0.1 g and 1.7 +/- 0.1 g. There was no significant difference in 6- and 12-month actuarial patient survival, graft survival and rejection-free graft survival between recipients on the RDS protocol vs. historical controls. For RDS recipients, actuarial 6- and 12-month rejection-free graft survival was 87%. Of the 51 RDS recipients, five (10%) have had AR (at 20 days, 1 month, 3 months, 3 months, and 3.5 months post-transplant). After treatment, all five were maintained on 5 mg P; there have been no second AR episodes. Two additional recipients were started on 5 mg P due to low white blood count (WBC) and low/no MMF. Of the 51 grafts, one has failed (death with function). Average serum Cr level (+/- S.E.) at 3 and 6 months for RDS recipients was 1.7 +/- 0.5 (NS vs. historical controls). CONCLUSION: For low-risk LD recipients, a kidney transplant with an RDS protocol does not increase risk of AR or graft loss. Future studies will need to be done to assess AR rates with an RDS protocol in cadaver transplant recipients and in recipients with delayed graft function.     

Optimizing tacrolimus therapy in the maintenance of renal allografts: 12-month results

BACKGROUND: The determination of optimal tacrolimus (TAC) trough levels is needed to prevent adverse effects of calcineurin inhibitors. METHODS: Stable transplant recipients currently receiving cyclosporine (CsA) were assigned randomly (1:1:1) to continue CsA (target trough level of 50-250 ng/mL); or convert to "reduced" TAC (target trough level 3.0-5.9 ng/mL) or "standard" TAC (target trough level 6.0-8.9 ng/mL). RESULTS: At 12 months, there was a significant improvement in renal function in the reduced TAC versus CsA group with lower serum creatinine (P=0.004) and cystatin C (P<0.001), and higher estimated creatinine clearance (P=0.017). However, there were no statistically significant differences in any renal parameter in the standard TAC versus CsA group. Total and low-density lipoprotein cholesterol were significantly reduced in both TAC groups versus the CsA group (P<0.001). Patient and graft survival and episodes of biopsy-confirmed acute rejection were similar for all treatment groups, and no statistically significant differences were observed between groups in the incidence of new-onset diabetes or cardiac conditions, or in the prevalence of hyperglycemia, hypertension, or hyperlipidemia among patients who did not have these conditions at baseline. Alopecia developed more commonly among TAC-treated patients than CsA-treated patients (P<0.001). CONCLUSIONS: Compared with CsA continuation, conversion to reduced TAC target trough concentrations resulted in significantly improved renal function without increasing the risk of rejection. Conversion to TAC, regardless of target concentration, resulted in improved serum lipid profiles in kidney transplant recipients at 12 months.     

Posttransplantation conversion to sirolimus-based immunosuppression: a single center experience

Sirolimus (SRL) has become an option in kidney transplantation, especially among patients who develop chronic allograft nephropathy (CAN). This study sought to evaluate the safety and efficacy of SRL in 103 kidney recipients of mean age 40 years, including 78 recipients of organs from deceased donors. The major reason for conversion was calcineurin inhibitor (CNI) nephrotoxicity (42.3%) followed by CAN (35.4%). A preconversion kidney biopsy was performed in 89 patients with CAN diagnosed in 51. Mean time to conversion was 40.5 months. The new therapy was: SRL/mycophenolate mofetil (MMF)/prednisone (Pred) in 79 patients; SRL/tacrolimus (TAC)/Pred in 15; and other SRL combinations in 9. The target SRL trough level was 5.0 to 8.0 ng/mL. To evaluate the impact of conversion on renal function, we compared the proteinuria and inverse serum creatinine at 3 months before conversion, at conversion, and at 1, 3, 6, 12, and 24 months postconversion. The overall mean follow-up time was 13.2 months. The analysis showed significant improvement in renal function at month 1 postconversion (P<.05) with stabilization thereafter. The SRL/MMF combination frequently induced anemia and/or leukopenia (n=23). Infections included pneumonia (n=10), herpes zoster (n=7), herpes simplex (n=3), cytomegalovirus (n=2), histoplasmosis (n=2), tuberculosis (n=2), and neurocryptococcosis (n=1). Reasons for SRL discontinuation were myelotoxicity (n=4), infection (n=3), nephrotoxicity (n=3), gastrointestinal intolerance (n=3), myopathy (n=1), pneumonitis (n=1), hyperlipidemia (n=1), and other reasons (n=3). Graft loss occurred in 29 patients due to CAN (n=21) followed by death (cardiovascular, n=2; infectious, n=2), acute rejection (n=3), and infection following immunosuppression withdrawal (n=1). We concluded that SRL represented an option but reducing associated immunosuppression should strongly be considered to minimize the frequent side effects, especially infections.     

A calcineurin antagonist-free induction strategy for immunosuppression in cadaveric kidney transplant recipients at risk for delayed graft function

BACKGROUND: Avoidance of calcineurin antagonists for a prolonged period de novo after cadaver donor renal transplantation may facilitate recovery from delayed graft function. The present study examined the benefit of prolonging the calcineurin antagonist-free interval by administering sirolimus (SRL) in combination with chimeric (c-) anti-interleukin-2 receptor (IL-2R) monoclonal antibodies (mAb). METHODS: Three contemporaneous but nonrandomized cohorts were compared for acute rejection episodes, patient and graft survival rates, renal function, and adverse reaction profiles for 12 months. Patients with delayed graft function were treated with either SRL/c-IL-2R mAb/prednisone (Pred) with inception of cyclosporine (CsA) once the serum creatinine value was < or =2.5 mg/dl (n=43; group 1) or anti-lymphocyte preparations/Pred/delayed CsA for 7 to 14 days (n=18; group 3). A third cohort displayed immediate function and was treated de novo with CsA/c-IL-2R mAb/Pred (n=21; group 2). RESULTS: The incidence of acute rejection episodes was significantly lower among group 1 (16%) compared with groups 2 (52%, P=0.004) or 3 (39%, P=0.05). Among the seven rejection episodes in group 1, six of seven occurred among African-American or retransplant recipients, and a separate cluster of six of seven occurred among patients who displayed SRL trough concentrations < or =9 ng/ml. Furthermore, additional antilymphocyte antibody treatment was required to reverse either steroid-resistant or Banff grades II or III acute rejection episodes among 14%, 55% (P=0.08), and 71% (P=0.03) of patients in each group, respectively. Patient and graft survival rates, as well as mean serum creatinine values, were similar at 12 months among the three groups. However, group 1 patients displayed higher serum cholesterol and triglyceride values, as well as lower hemoglobin, platelet, and leukocyte values compared with the other two groups. CONCLUSION: This pilot study suggests that a SRL/c-IL-2R mAb/Pred induction regimen provides excellent acute rejection prophylaxis.     

Prednisone metabolism in recipients of kidney or liver transplants and in lung recipients receiving ketoconazole

BACKGROUND: Actual prednisone exposure in low-dose prednisone regimens, in part determined by cytochrome P450 metabolism, has been shown to be important for allograft survival. METHODS: Prednisolone (the principal active metabolite of prednisone) metabolism was determined in eight nontransplant patients and in transplant recipients receiving oral prednisone maintenance therapy (20 kidney and 6 liver recipients receiving cyclosporine [CsA] and eight lung recipients receiving ketoconazole and CsA or tacrolimus [FK506]). RESULTS: Prednisolone area under the curve (AUC)-dose-normalized (PNAUCn) to 1 mg/kg was 8,288+/-1,513 ng.hr/mL in kidney recipients, versus 4,826+/-999 ng/mL per hr in healthy subjects (P<0.001); it was also increased in liver recipients versus healthy subjects (11,456+/-1,214 ng.hr/mL, P<0.001). Liver recipients also metabolized prednisolone more slowly than kidney recipients (P<0.001). PNAUCn in lung recipients was similar in kidney recipients despite the effect of ketoconazole to slow CsA metabolism. In kidney transplant recipients, the rate of CsA metabolism was correlated with the rate of prednisolone metabolism (r=0.54, P=.026). Basal cortisol levels in all transplant recipients were lower than in healthy subjects, suggesting more prednisolone exposure in transplant patients. CONCLUSIONS: Prednisolone metabolism is slower in solid-organ transplant recipients than in healthy subjects. The slower metabolism of prednisolone, particularly in liver recipients, may help explain the immunologic effectiveness of low-dose prednisone regimens in these patients.     

Prospective Clinical Trial Comparing Two Immunosuppressive Regimens, Tacrolimus and Mycophenolate Mofetil Versus Everolimus and Low-Dose Cyclosporine, in De Novo Renal Transplant Recipients: Results at 6 Months Follow-up

Objective

The aim of this study in renal transplant recipients was to compare a tacrolimus plus mycophenolate mofetil (MMF) immunosuppressive regimen with a combination of low dose of cyclosporine and everolimus.

Patients and Methods

Sixty consecutive patients were prospectively assigned to receive tacrolimus and MMF (TAC; n = 30) or everolimus and low-dose cyclosporine (EVL; n = 30). Tacrolimus was dosed seeking a trough blood level of 8 to 10 ng/mL by month 3 and 5 to 8 ng/mL thereafter. Everolimus was dosed seeking a trough blood level of 3 to 8 ng/mL by day 7. Cyclosporine was dosed aiming at a C2 blood level of 350 to 700 ng/mL in the first week and 150 to 400 ng/mL thereafter. All patients received induction with basiliximab and maintenance treatment with corticosteroids.

Results

At 6-months follow-up, patient survival rates (TAC 100% vs EVL 100%) and graft survival rates (TAC 96.7% vs EVL 93.3%) were not significantly different between the groups. Patients in the EVL group showed more acute rejection episodes, but serum creatinine concentrations and creatinine clearances were not significantly different from the TAC group. Among the observed side effects, hypercholesterolemia was significantly higher in the EVL group (total cholesterol: TAC 206 ± 38 vs EVL 250 ± 55 mg/dL; P < .003).

Conclusions

This study showed that the immunosuppressive association of tacrolimus and MMF produced similar acute rejection episodes, graft survivals, and renal function at 6 months after renal transplantation compared with an immunosuppressive combination of everolimus and low-dose cyclosporine. Dyslipidemia was significantly greater among patients who received everolimus.     

Long-term immunosuppression, without maintenance prednisone, after kidney transplantation

BACKGROUND: Concern exists that prednisone-free maintenance immunosuppression in kidney transplant recipients will increase acute and/or chronic rejection. METHODS: From October 1, 1999, through February 29, 2004, at our center, 477 kidney transplant recipients (341 living donor, 136 cadaver) discontinued prednisone on postoperative day 6, per our protocol. Immunosuppression consisted of polyclonal antibody (Thymoglobulin) for 5 days, prednisone intraoperatively and for 5 days, a calcineurin inhibitor, and either sirolimus or mycophenolate mofetil. We compared outcome with that of historical controls who did not discontinue prednisone. RESULTS: The recipients on prednisone-free maintenance immunosuppression had excellent 4-year actuarial patient survival (92%), graft survival (90%), acute rejection-free graft survival (86%), and chronic rejection-free graft survival (95%). The mean serum creatinine level (+/- SD) at 1 year was 1.6 +/- 0.6; at 4 years, 1.6 +/- 0.6. We noted that 8% of recipients had cytomegalovirus (CMV) disease; 4.5%, fractures; 2.8%, cataracts; 1%, posttransplant diabetes; 0.2%, avascular necrosis; 0.2%, posttransplant lymphoproliferative disease; and 0%, polyomavirus. In all, 85% of kidney recipients with functioning grafts remain prednisone-free as of April 1, 2004.As compared with historical controls, the recipients on prednisone-free maintenance immunosuppression had better patient (P = 0.02) and graft survival (P < 0.0001) and lower rates of acute (P = 0.0004) and chronic (P = 0.02) rejection. In addition, they had a significantly lower rate of CMV disease (P < 0.0001), cataracts (P < 0.0001), posttransplant diabetes (P < 0.0001), and avascular necrosis (P = 0.0003). CONCLUSIONS: Prednisone-related side effects can be minimized without maintenance immunosuppression; our prednisone-free recipients do not have increased acute or chronic rejection.     

Long-term renal transplant function in recipient of simultaneous kidney and pancreas transplant maintained with two prednisone-free maintenance immunosuppressive combinations: tacrolimus/mycophenolate mofetil versus tacrolimus/sirolimus

BACKGROUND: It is not known how different steroid-free immunosuppressive combinations affect long-term kidney transplant function in recipients of simultaneous kidney and pancreas transplant (SPK). Here, we sought to evaluate, in SPK recipients, the impact on long-term renal allograft function of two Tac-based prednisone-free maintenance immunosuppressive protocols: tacrolimus (Tac)/mycophonelate mofetil (MMF) versus Tac/ sirolimus (SRL). METHODS: In this single-center, retrospective, sequential study, we analyzed 59 SPK transplant patients with at median follow up of 5 years. All patients received induction therapy with thymoglobulin and maintenance immunosuppression with Tac/MMF (n=22) or Tac/SRL (n=37). There were no differences between the two groups in regards to age, gender, race, panel reactive antibodies, degree of mismatch, donor age, incidence of delay graft function, and Tac trough levels at different time points after transplantation. RESULTS: Kaplan-Meier patient survival at 6 years after transplantation was not statistically different between the two groups. Rate of ACR was similar. Kidney survival, even if not statistically significant, was better in the Tac/MMF group than in the Tac/SRL (90.7% vs. 70.7%, P=0.09). The slope of glomerular filtration rate decline per month at 5 years after transplantation was not statistically different between the two groups. Both groups had the same decline over time in glomerular filtration rate of 0.40+/-0.06 mL/min/1.73/month. Pancreas survival at 6 years after transplantation was 100% in both treatment groups. CONCLUSIONS: Our data suggest that, in SPK recipients, long-term kidney allograft survival and function are not statistically different. A trend toward an increased rate of renal allograft loss was found in the Tac/SRL-treated group.     

Five‐Year Results of a Randomized Trial Comparing De Novo Sirolimus and Cyclosporine in Renal Transplantation: The Spiesser Study

Calcineurin inhibitors improve acute rejection rates and short‐term graft survival in renal transplantation, but their continuous use may be deleterious. We evaluated the 5‐year outcomes of sirolimus (SRL) versus cyclosporine (CsA) immunosuppressive treatment. This observational study was an extension of the SPIESSER study where deceased donor kidney transplant recipients were randomized before transplantation to a SRL‐ or CsA‐based regimen and followed up 1 year. Data from 131 (63 SRL, 68 CsA) out of 133 patients living with a functional graft at 1 year were collected retrospectively at 5 years posttransplant. Seventy percent of CsA patients versus 54% of SRL patients were still on the allocated treatment at 5 years (p = 0.091), most discontinuations in each group being due to safety issues. In intent‐to‐treat, mean MDRD eGFR was higher with SRL: 54.2 versus 45.3 mL/min with CsA (p = 0.019); SRL advantage was greater in on‐treatment analyses. There were no differences for patient survival (p = 0.873), graft survival (p = 0.121) and acute rejection (p = 0.284). Adverse events were more frequent with SRL (80% vs. 60%, p = 0.015). Results confirmed the high SRL discontinuation rate due to adverse events. Nevertheless, a benefit was evidenced on renal function in patients (more than 50%) still on treatment at 5 years.