Everolimus with early withdrawal or reduced‐dose calcineurin inhibitors improves renal function in liver transplant recipients: A systematic review and meta‐analysis

Calcineurin inhibitors (CNI) are the mainstay of immunosuppression after liver transplantation (LT), but CNIs are associated with significant nephrotoxicity. Recently, mTOR inhibitors such as sirolimus and everolimus (EVR) have been used with or without CNIs in LT recipients for their renal‐sparing effect. We conducted a systematic review and meta‐analysis of randomized controlled trials (RCT) that examined the effect of EVR with CNI minimization or withdrawal on renal function in LT recipients. RCT of primary adult LT recipients with baseline GFR >30 mL/min who received EVR with CNI minimization or withdrawal were included. Four RCTs (EVR n=465, control n=428) were included. In three RCTs, EVR was initiated 4 weeks following LT; these studies were used to assess the primary outcome. All four studies were used to assess the secondary outcomes. Based on this study, EVR use with CNI minimization in LT recipients is associated with improved renal function at 12 months by GFR of 10.2 mL/min (95% CI: 2.75‐17.8). EVR use was not associated with an increased risk of biopsy‐proven acute rejection (RR 0.68, 95% CI: 0.31‐1.46), graft loss (RR 1.60, 95% CI: 0.51‐5.00), or mortality (RR 1.34, 95% CI 0.62‐2.90). However, it was associated with an increased risk of overall infections (RR 1.45, 95% CI: 1.10‐1.91).     

Steroid withdrawal in renal transplant patients on triple therapy with a calcineurin inhibitor and mycophenolate mofetil: a meta-analysis of randomized, controlled trials

BACKGROUND: Two previous meta-analyses of randomized, controlled trials of steroid withdrawal after renal transplantation have shown significant increases in acute rejection (both analyses) and graft failure rates (the last analysis). A new examination of this topic including only randomized, controlled trials based on currently used, new, potent therapy with calcineurin inhibitors and mycophenolate mofetil (MMF), avoiding early trials with azathioprine, is justified. METHODS: Steroid withdrawal in patients on triple therapy including a calcineurin inhibitor and MMF was assessed through meta-analysis of randomized, controlled trials in which intention-to-treat rates of acute rejection and renal allograft failure were established after steroid withdrawal or continuation. RESULTS: Six trials were included, four in patients receiving cyclosporine and two in patients receiving tacrolimus. The risk ratio (RR) for acute rejection was 2.28 (95% confidence interval [CI], 1.65-3.16; P < 0.00001) and the pooled risk difference (RD) was 0.08 (95% CI, 0.05-0.11; P < 0.001), indicating that the proportion of patients with acute rejection after prednisone withdrawal was significantly higher compared with controls. The RR for graft failure was 0.73 (95% CI, 0.42-1.28; P = 0.27) and the RD was -0.01 (95% CI, -0.03-0.01; P = 0.28), indicating that the proportion of patients with graft failure after withdrawal was not significantly different from that observed in controls. Total cholesterol was significantly lower after steroid withdrawal (weighted mean difference, -0.53 microM (95% CI, -0.70 to -0.36; P < 0.0001). CONCLUSIONS: Renal allograft recipients on triple therapy with a calcineurin inhibitor, MMF, and steroids are at low but significant risk of acute rejection after steroid withdrawal but do not suffer an increased risk of early graft failure. It is necessary to extend controlled follow-up to confirm graft function stabilization.     

Target of rapamycin inhibitors (sirolimus and everolimus) for primary immunosuppression of kidney transplant recipients: a systematic review and meta-analysis of randomized trials

BACKGROUND: Target of rapamycin inhibitors (TOR-I) have a novel mode of action but uncertain clinical role. We performed a systematic review of randomized trials where immunosuppressive regimens containing TOR-I were compared with other regimens as initial therapy for kidney transplant recipients. METHODS: Databases (inception, June 2005) and conference proceedings (1996-2005) were searched. Two independent reviewers assessed trials for eligibility and quality. Results at 1 year, are expressed as relative risk (RR), where values<1 favor TOR-I, or lower dose of TOR-I, and for continuous outcomes are expressed as weighted mean difference (WMD), both expressed with 95% confidence intervals (CI). RESULTS: Thirty-three trials (142 reports) were included (27 trials of sirolimus, 5 of everolimus, and 1 of head-to-head comparison). When TOR-I replaced calcineurin inhibitors (CNI) (8 trials with 750 participants), there was no difference in acute rejection (RR, 1.03; 95% CI, 0.74-1.44), but serum creatinine was lower (WMD, -18.31 micromol/L; 95% CI, -30.96 to -5.67) and bone marrow more suppressed (leukopenia: RR 2.02; 95% CI, 1.12-3.66; thrombocytopenia: RR, 6.97; 95% CI, 2.97-16.36; and anaemia: RR, 1.67; 95% CI, 1.27-2.20). When TOR-I replaced antimetabolites (11 trials with 3966 participants), acute rejection and cytomegalovirus infection (CMV) were reduced (RR, 0.84; 95% CI, 0.71-0.99; RR, 0.49; 95% CI, 0.37-0.65, respectively), but hypercholesterolemia was increased (RR, 1.65; 95% CI, 1.32-2.06). When low- was compared with high-dose TOR-I, with equal CNI dose (10 trials with 3,175 participants), rejection was increased (RR, 1.23; 95% CI, 1.06-1.43) but calculated glomerular filtration rate (GFR) higher (WMD, 4.27 mL/min; 95% CI, 1.12-7.41), and when lower-dose TOR-I and standard-dose CNI were compared with higher-dose TOR-I and reduced CNI, acute rejection was reduced (RR, 0.67; 95% CI, 0.52-0.88), but calculated GFR was also reduced (WMD, -9.46 mL/min; 95% CI, -12.16 to -6.76). There was no significant difference in mortality, graft loss, or malignancy risk for TOR-I in any comparison. CONCLUSIONS: TOR-I have been evaluated in four different primary immunosuppressive algorithms: as replacement for CNI and antimetabolites, in combination with CNI at low and high doses, and with a variable dose of CNI. Generally, surrogate endpoints for graft survival favor TOR-I (lower risk of acute rejection and higher GFR), and surrogate endpoints for patient outcomes are worsened by TOR-I (bone marrow suppression and lipid disturbance). Long-term hard-endpoint data from methodologically robust randomized trials are still required.     

Sirolimus rescue of renal failure in children after combined liver-kidney transplantation

Background: Calcineurin inhibitors (CNI) are the main immunosuppressive drugs in solid organ transplantation. However, their use is hampered by side effects like nephrotoxicity. We report an exceptional experience with three children treated with sirolimus after combined liver and kidney transplantation with prolonged renal failure and CNI-associated nephrotoxicity. Patients and results: Two girls experienced prolonged renal graft failure after combined liver-kidney transplantation for 11 and 12 weeks. Repeated biopsies did not show any rejection but did exhibit tubular damage and acute CNI-toxicity. A boy with hyperoxaluria after liver and (a third) renal transplantation experienced acute renal graft failure after an early steroid-resistant rejection. All children were switched to sirolimus-based immunosuppression and cessation of CNI therapy, which was followed by rapid improvement of renal function. Rejection of liver or kidney did not occur after CNI withdrawal. Sirolimus was commenced with 3 mg/m²/day in two doses and resulted in reasonable drug exposure. However, drug monitoring was required to adjust sirolimus dosage. Summary: Prolonged renal failure after transplantation with severe CNI toxicity may be salvaged successfully with sirolimus-based immunosuppression.     

A randomized controlled trial of late conversion from calcineurin inhibitor (CNI)-based to sirolimus-based immunosuppression in liver transplant recipients with impaired renal function.

Renal impairment is common in patients after liver transplantation and is attributable in large part to the use of calcineurin inhibitor (CNI)-based immunosuppression. We sought to determine whether conversion to sirolimus-based immunosuppression was associated with improved renal function. In a single-center, randomized, controlled trial, 30 patients at least 6 months post liver transplantation were randomized to remain on CNI-based immunosuppression or to switch to sirolimus-based immunosuppression. The primary outcome measure was change in measured glomerular filtration rate (GFR) between baseline and 12 months. Of 30 patients randomized, 3 were withdrawn at randomization, leaving 14 patients on CNI and 13 on sirolimus. There was a significant improvement in delta GFR following conversion to sirolimus at 3 months (7.7 mL/minute/1.73 m2; 95% confidence interval, 3.5-11.9) and 1 yr (6.1 mL/minute/1.73 m2; 95% confidence interval, 0.9-11.4). The difference in absolute GFR between the 2 study groups was significant at 3 months (P=0.02), but not at 12 months (P=0.07). The principal adverse events following conversion were the development of skin rash (9 of 13 patients, 69%) and mouth ulcers (5 of 13 patients, 38%). Two patients developed acute rejection at 2 and 3 months following conversion, 1 in association with low sirolimus levels and 1 having stopped the drug inadvertently. In conclusion, overall, this study suggests that conversion to sirolimus immunosuppression is associated with a modest improvement in renal function. Side effects were common, but tolerable in most patients and controlled with dose reduction.     

A Randomized Controlled Trial of Late Conversion from CNI-Based to Sirolimus-Based Immunosuppression Following Renal Transplantation

Maintenance immunosuppression with calcineurin inhibitors (CNIs) following renal transplantation is associated with nephrotoxicity and accelerated graft loss. We aimed to assess whether conversion to sirolimus-based immunosuppression would affect the progression of renal impairment. In this single center, randomized controlled trial, 40 renal transplant recipients between 6 months and 8 years post-transplant were randomly assigned to remain on their CNI (cyclosporin or tacrolimus) or to switch to sirolimus. The primary outcome measure was change in glomerular filtration rate (GFR) measurement at 12 months. Analysis was by intention-to-treat. Of the 40 patients randomized, 2 patients never took the study drugs and were excluded, leaving 19 patients per group. There was a significant change in GFR at 12 months following conversion to sirolimus (12.9 mL/min, 95% CI 6.1-19.7; p < 0.001). Following conversion, the principal adverse events were the development of rashes (68%), particularly acne, and mouth ulcers (32%). No patient in either group experienced an acute rejection episode. In renal transplant recipients, a change in maintenance therapy from CNIs to sirolimus is associated with significant improvement in GFR at 12 months.     

Calcineurin Inhibitor Avoidance and Withdrawal for Kidney Transplantation: A Systematic Review and Meta-analysis of Randomized Controlled Trials

Objective

Many studies have compared the safety and efficacy of the calcineurin inhibitor (CNI) avoidance or CNI withdrawal regimens with typical CNI regimens, but the results remain controversial. The aim of this systematic review and meta-analysis is to make a profound review and an objective appraisal of the safety and efficacy of the CNI avoidance and CNI withdrawal protocols.

Methods

We searched PUBMED, EMBASE, and the reference lists of retrieved studies to identify randomized controlled trials (RCTs) that referred to CNI-free regimens, CNI avoidance, or CNI withdrawal for kidney transplantation. Eight publications involving 27 different RCTs and a total of 3953 patients were used in the analysis.

Results

Use of mammalian target of rapamycin inhibitors, namely sirolimus (SRL), in combination with mycophenolate, conserve graft function at 1 year (glomerular filtration rage [GFR]: mean difference MD 6.21, 95% CI 0.02–12.41, P = .05; serum creatinine: MD −0.11, 95% CI −0.19 to −0.03, P = .01, respectively) and 2 years post-transplant (GFR: MD 13.96, 95% CI 7.32–20.60, P < .0001). Similarly, early withdrawal (≤6 months) of CNIs protect graft function at 1 year after transplant (GFR: MD 7.03, 95% CI 4.84–9.23, P < .00001, serum creatinine: MD −0.21, 95% CI −0.22 to −0.19, P < .00001, respectively). CNI avoidance and withdrawal strategies are associated with higher incidence of acute rejection at 1 year post-transplant (odds ratio OR 1.74, 95% CI 1.08–2.81, P = .02; OR 1.78, 95% CI 1.35–2.34, P < .0001, respectively). At 2 years after transplant, there was no significant difference (OR 0.92, 95% CI 0.33–2.51, P = .86; OR 2.42, 95% CI 1.01–5.82, P = .05, respectively). Meanwhile, neither adverse events nor patient/graft survival differed significantly between the CNI-free and CNI protocols at 1 and 2 years. Referring to long-term results in the published RCTs, use of CNI-free and CNI withdrawal regimens achieve better renal function vs CNI regimens, with no significant difference in patient and graft survival, acute rejection, and most reported adverse events.

Conclusions

In conclusion, this systematic review and meta-analysis suggests that renal recipients with early withdrawal of CNI drugs or avoiding CNI with SRL perform better to conserve graft function at 1 and 2 years post-transplant. Though the use of CNI regimens performs no better in 2-year acute rejection vs the contrast group, they greatly decrease the incidence of acute rejection at the first year after transplantation. CNI avoidance and withdrawal regimens improve the long-term renal function and perform similarly in the acute rejection, patient and graft survival, and adverse events. Due to the limited amounts of long-term studies, more high-quality RCTs are needed.     

Mycophenolate Mofetil Monotherapy for Severe Side Effects of Calcineurin Inhibitors Following Liver Transplantation

Withdrawal of calcineurin inhibitors (CNI) followed by mycophenolate mofetil (MMF) monotherapy after liver transplantation (LT) remains controversial due to the increased risk of acute rejection and graft loss. The aim of the present study, performed in a large cohort of liver-transplanted patients with severe CNI-induced side effects, was to assess renal function recovery, and safety in terms of liver function, of complete CNI withdrawal and replacement by MMF monotherapy. Fifty-two patients treated with MMF monotherapy for CNI-induced toxicity were analyzed. Mean estimated glomerular filtration rate (eGFR) increased significantly during the period of MMF monotherapy, from 37 ± 10 to 44.7 ± 15 mL/min/1.73 m² at 6 months (p = 0.001) corresponding to a benefit of +17.4% in renal function. eGFR stabilized or improved in 86.5%, 81% and 79% of cases, and chronic renal dysfunction worsened in 13.5%, 19% and 21% of cases, at 6, 12 and 24 months after CNI withdrawal, respectively. Only two patients experienced acute rejection. MMF monotherapy may be efficient at reversing/stabilizing CRD, and appears relatively safe in terms of liver graft function in long-term liver-transplanted patients. However, clinicians must bear in mind the potential risk of rejection and graft loss, and should be very cautious in the management of such 'difficult-to-treat patients'.     

Outcomes Following De Novo CNI-Free Immunosuppression After Heart Transplantation: A Single-Center Experience

Renal impairment at the time of heart transplantation complicates the choice of subsequent immunosuppressive therapy. Calcineurin (CNI)-free regimens utilizing proliferation signal inhibitors (PSI) may mitigate against nephrotoxicity in this group; however, their effectiveness remains unclear.
We present our 7-year experience with de novo CNI-free, PSI-based immunosuppression after heart transplantation. Of the 152 patients transplanted between July 1999 and July 2006, de novo immunosuppression regimens were 49 CNI-free, PSI-based, 88 CNI, 15 combination of CNI+PSI.
Pretransplant creatinine clearance improved within 6 months in the PSI group (0.69 ± 0.34 mL/s vs. 1.00 ± 0.54 mL/s, p < 0.05) but not the CNI (1.32 ± 0.54 mL/s vs. 1.36 ± 0.53 mL/s, p = ns) or CNI+PSI (1.20 ± 0.24 mL/s vs. 1.20 ± 0.41 mL/s, p = ns) groups. The PSI group had more episodes of early (≤6 months) acute rejection, bacterial or fungal infections and pleural effusions but less CMV infection (p < 0.05 for all comparisons). Early CNI addition occurred in 37% of the PSI group for acute rejection. 33% of the entire cohort changed immunosuppression regimens over 3.6 ± 2.2 years follow-up.
De novo CNI-free, PSI-based immunosuppression in patients with significant renal dysfunction allowed significant posttransplantation renal recovery but with increased early acute rejection, bacterial and fungal infections and pleural effusions.     

CNI withdrawal for post‐transplant lymphoproliferative disorders in kidney transplant is an independent risk factor for graft failure and mortality

Post‐transplantation lymphoproliferative disorders (PTLD) are associated with poor patient and graft survival. The risk of rejection and subsequent graft loss are increased by the reduction of immunosuppression therapy, the cornerstone of PTLD treatment. This multicentre, retrospective, nonrandomized cohort study includes 104 adults who developed PTLD after renal or simultaneous renal/pancreatic transplantation between 1990 and 2007. It examines the effect of calcineurin inhibitor (CNI) withdrawal on long‐term graft and patient survival. At 10 years postonset of PTLD, the Kaplan–Meier graft loss rate was 43.9% and graft loss or death with functioning graft was 64.4%. Cox multivariate analysis determined risk factors of graft loss as PTLD stage greater than I‐II and CNI withdrawal, and for graft loss and mortality, these remained risk factors along with age over 60 years. Type and location of PTLD, year of diagnosis, and chemotherapy regime were not independent risk factors. Multivariate analysis determined CNI withdrawal as the most important risk factor for graft loss (HR = 3.07, CI 95%: 1.04–9.09; P = 0.04) and death (HR: 4.00, CI 95%: 1.77–9.04; P < 0.001). While long‐term stable renal function after definitive CNI withdrawal for PTLD has been reported, this review determined that withdrawal is associated with reduced graft and patient survival.     

A Randomized,Controlled Study to Assess the Conversion From Calcineurin‐Inhibitors to Everolimus After Liver Transplantation—PROTECT

Posttransplant immunosuppression with calcineurin inhibitors (CNIs) is associated with impaired renal function, while mTor inhibitors such as everolimus may provide a renal‐sparing alternative. In this randomized 1‐year study in patients with liver transplantation (LTx), we sought to assess the effects of everolimus on glomerular filtration rate (GFR) after conversion from CNIs compared to continued CNI treatment. Eligible study patients received basiliximab induction, CNI with/without corticosteroids for 4 weeks post‐LTx, and were then randomized (if GFR > 50 mL/min) to continued CNIs (N = 102) or subsequent conversion to EVR (N = 101). Mean calculated GFR 11 months postrandomization (ITT population) revealed no significant difference between treatments using the Cockcroft‐Gault formula (?2.9 mL/min in favor of EVR, 95%‐CI: [?10.659; 4.814], p = 0.46), whereas use of the MDRD formula showed superiority for EVR (?7.8 mL/min, 95%‐CI: [?14.366; ?1.191], p = 0.021). Rates of mortality (EVR: 4.2% vs. CNI: 4.1%), biopsy‐proven acute rejection (17.7% vs. 15.3%), and efficacy failure (20.8% vs. 20.4%) were similar. Infections, leukocytopenia, hyperlipidemia and treatment discontinuations occurred more frequently in the EVR group. No hepatic artery thrombosis and no excess of wound healing impairment were noted. Conversion from CNI‐based to EVR‐based immunosuppression proved to be a safe alternative post‐LTx that deserves further investigation in terms of nephroprotection.     

Calcineurin-inhibitor-sparing immunosuppressive protocols

Calcineurin inhibitors (CNI) have played an important role in improving graft survival. However, the balance between preventing immunologic allograft losses and the management of CNI-related nephrotoxicity is still an issue in renal transplantation. There are three major CNI-sparing strategies. CNI MINIMIZATION: The advent of mycophenolate mofetil (MMF) allows cyclosporine (CsA) reduction to ameliorate renal function in patients with chronic renal allograft dysfunction, without increasing acute rejection rates. In combination with mTOR inhibitors, very low CNI levels may be sufficient to prevent acute rejection. However, in this association, CNI nephrotoxicity is magnified by pharmacokinetic interaction. CNI WITHDRAWAL: CNI withdrawal has been attempted in regimens containing MMF or sirolimus (SRL). Introduction of MMF in patients with chronic allograft nephropathy (CAN) followed by CNI withdrawal resulted in stabilization or improvement of renal function and hypertension profile, although there is some risk of acute rejection. In regimes based on SRL, CNI withdrawal is a safety strategy, achieving a sustained improvement of renal function, histology, and graft survival. There is not consensus at all whether MMF should be added or not in patients converted from CNI to mTOR inhibitor. CNI AVOIDANCE: Polyclonal-based regimens with MMF and steroids have shown acceptable acute rejection rates, but high rates of cytomegalovirus (CMV) and opportunistic infections. Conversely, anti-IL-2R in combination with MMF and steroids resulted in 50% incidence of acute rejection, thus suggesting that CNI avoidance is not feasible in a regimen based on MMF. Alternatively, a protocol based on anti-IL-2R induction therapy combined with SRL, MMF, and prednisone has shown an efficient prevention of acute rejection, higher creatinine clearance and lower rate of CAN in comparison with a group treated with CNI. New strategies using costimulation blockade may help in the development of safe CNI-free regimens. In summary, in renal transplantation the new immunosuppressive medications have made feasible old aspirations such as minimization, withdrawal, or even avoidance of CNI.     

Pre-Transplant IFN-γ ELISPOTs Are Associated with Post-Transplant Renal Function in African American Renal Transplant Recipients

Final crossmatch testing is routinely used to assess the risk of antibody-mediated graft injury/rejection post-transplant. Analogously, we postulated that quantitative measurements of anti-donor effector/memory T cells pre-transplant would independently assess post-transplant risk. To address this hypothesis, we determined the frequencies of pre-transplant, donor-specific interferon-gamma (IFN-gamma) enzyme-linked immunosorbent spots (ELISPOTs) and correlated the results with post-transplant outcomes in 37 African American recipients of deceased donor kidney transplants treated with tacrolimus- and sirolimus-based immunosuppression. A positive ELISPOT test (>25 spots/300,000 cells) was detected in 14 (38%) of 37 patients. The incidence of biopsy-proven acute rejection was 50% (7/14) in ELISPOT-positive versus 17% (4/23) in ELISPOT-negative patients (p=0.036). Calculated glomerular filtration rate (MDRD) at 12 months was 37+/-16 mL/min in ELISPOT-positive versus 55+/-20 mL/min in ELISPOT-negative patients (p=0.01). ELISPOT status remained a correlate of allograft function at 12 months by linear regression analysis (p=0.001), independent of rejection and other contributing variables. Pre-transplant donor-directed IFN-gamma ELISPOT assessment of anti-donor cellular immunity may function as a 'cellular crossmatch' and independently correlates with renal allograft function in African Americans receiving tacrolimus- and sirolimus-based immunosuppression.     

Long-Term Use of Mycophenolate Mofetil is Associated With a Reduction in the Incidence and Risk of Late Rejection

To evaluate the association of long-term continuous (minimum 1 year) mycophenolate mofetil (MMF) vs. azathioprine (AZA) therapy with the incidence of late acute rejection, we analyzed 47 693 primary renal allograft recipients reported to the United States Renal Data System between 1988 and 1998. The primary study endpoint was acute rejection beyond 1 year after transplantation. Univariate Kaplan-Meier analysis and multivariate Cox proportional hazard models were used to investigate the risk of reaching the study endpoints. All multivariate analyses were corrected for potential confounding covariates. Mycophenolate mofetil was associated with a 65% decreased risk of developing late acute rejection as compared to AZA (RR = 0.35, CI 0.27-0.45, p < 0.001). The incidence of acute rejection episodes at 2 and 3 years post-transplantation was significantly lower in the MMF group (0.9% at 2 years, 1.1% at 3 years) than the AZA group (6.1% at 2 years, 9.3% at 3 years). In the primary vs. repeat late rejection analysis, MMF patients exhibited a decreased late acute rejection risk of 72% (RR = 0.28, p < 0.001) and 60%, respectively (RR = 0.40, p < 0.001). In African Americans, the late acute rejection risk was 70% lower in MMF patients than AZA patients (RR = 0.30, p < 0.001). Further study is indicated to determine the optimal duration of MMF therapy after renal allograft transplantation.     

A meta-analysis of immunosuppression withdrawal trials in renal transplantation

Since the publication of previous meta-analyses of cyclosporine (CsA) and prednisone withdrawal in renal transplant recipients, several additional randomized controlled trials with longer follow-up have been reported. Currently, in nine prednisone withdrawal trials (n = 1461), the proportion of patients with acute rejection was increased by 0.14 (95% confidence interval = 0.10 to 0. 17, P < 0.001). In nine prednisone withdrawal trials (n = 1899), the relative risk (RR; RR = 1.0 indicates no risk) of graft failure after withdrawal was also increased (RR = 1.40; range, 1.09 to 1.70, P = 0.012). There was no evidence of between-study heterogeneity for either acute rejection or graft failure in the prednisone withdrawal trials by a chi(2) test (P > 0.05). In 10 CsA withdrawal trials (n = 1049), the proportion of patients with acute rejection was increased by 0.11 (0.07 to 0.15, P < 0.001). In 12 trials (n = 1151), the RR of graft failure after CsA withdrawal was 1.06 (95% confidence interval, 0.82 to 1.29, P = 0.646), but a chi(2) test indicated that there was study heterogeneity. However, there was no evidence of heterogeneity in the six studies (n = 632) with at least 4.0 yr (5.8 +/- 1.7) of follow-up (RR = 0.92; range, 0.64 to 1.20, P = 0.569) or in the seven trials (n = 962) published in peer-reviewed journals (RR = 0.95; range, 0.70 to 1.20 P = 0.682). Finally, in three trials (n = 259) that compared CsA and prednisone withdrawal, there was a nonsignificant trend for less graft failure with CsA withdrawal (RR = 0.63; range, 0.08 to 1.16, P = 0.190). Thus, unlike prednisone withdrawal, CsA withdrawal in select patients seems to impart little risk of long-term graft failure.     

Immunosuppression with calcineurin inhibitors with respect to the outcome of HCV recurrence after liver transplantation: results of a meta-analysis.

A controversy exists over whether the outcome of a hepatitis C virus (HCV)-infection-related liver transplant differs based on the calcineurin inhibitor (CNI) used. We have performed a systematic review and a subsequent meta-analysis evaluating tacrolimus (Tac)-based vs. cyclosporine A-based immunosuppression in HCV-infected liver transplant recipients. Searches were conducted to locate randomized controlled trials comparing Tac vs. cyclosporine A. Data on HCV liver transplant recipients were obtained, independently of whether the study was specifically designed for patients with this disease or not. A fixed effects model was used for statistical pooling of the relative risks (RR) for the different outcomes. A total of 5 articles (366 patients) fulfilled the inclusion criteria. Statistically significant differences between Tac-based vs. cyclosporine A-based therapies were not found for mortality (P = 0.11; RR = 0.72; 95% confidence interval [CI], 0.49-1.08), graft survival (P = 0.37; RR = 0.86; 95% CI, 0.61-1.21), biopsy-proven acute rejection (P = 0.65; RR = 0.91; 95% CI, 0.61-1.36), corticoresistant acute rejection (P = 0.26; RR = 2.25; 95% CI, 0.55-9.29), and fibrosing cholestatic hepatitis (P = 0.92; RR = 0.96; 95% CI, 0.41-2.26). In 1 study, no differences were detected regarding severe fibrosis at 1 yr. In conclusion, patient and graft survivals in HCV-positive liver transplant patients are similar independently of the CNI selected as basic immunosuppressant. Unfortunately, data on the severity of recurrence and effect on viremia are scarce. Well-designed randomized prospective studies are needed to determine whether there are differences between the 2 CNIs regarding these specific variables.     

Updated metaanalysis of steroid withdrawal in renal transplant patients on calcineurin inhibitor and mycophenolate mofetil

During the 1990s two metaanalysis of randomized clinical trials of steroid withdrawal after renal transplantation showed significant increases in acute rejection episodes and graft failure rates. A recently published metaanalysis of steroid withdrawal in patients on a calcineurin inhibitor and MMF included randomized clinical trials. We have updated this study, searching more publications during the last 2 years. Finally, the same six trials were included, four in patients receiving cyclosporine and two tacrolimus. Risk ratio (RR) for acute rejection was 2.28 [95%CI 1.65-3.16, P < .00001], and pooled risk difference (RD) was 0.08 [0.05-0.11, P < .001], indicating that the proportion of patients with acute rejection episodes after prednisone withdrawal was significantly higher compared with controls. RR for graft failure was 0.73 [0.42-1.28, P = .27], and RD was -0.01 [-0.03-0.01, P = .28], indicating that the proportion of patients with graft failure after withdrawal was not significantly different from that of controls. Total cholesterol was significantly lower after steroid withdrawal (weighted mean difference -0.53 mumol/L [-0.70--0.36, P < .0001]). Renal allograft recipients on triple therapy with a calcineurin inhibitor, MMF, and steroids are at low but significant risk of acute rejection after steroid withdrawal, but do not suffer an increased risk of early graft failure. It is necessary to extend controlled follow-up to confirm graft function stabilization.     

Randomized Controlled Trial of Sirolimus Conversion in Cardiac Transplant Recipients With Renal Insufficiency

This randomized, comparative, multinational phase 3b/4 study of patients 1–8 years postcardiac transplantation (mean 3.9 years) evaluated the effect of conversion from a calcineurin inhibitor (CNI) to sirolimus on renal function in patients with renal insufficiency. In total, 116 patients on CNI therapy with GFR 40–90 mL/min/1.73m² were randomized (1:1) to sirolimus (n = 57) or CNI (n = 59). Intent‐to‐treat analysis showed the 1‐year adjusted mean change from baseline in creatinine clearance (Cockcroft‐Gault) was significantly higher with sirolimus versus CNI treatment (+3.0 vs. ?1.4 mL/min/1.73 m², respectively; p = 0.004). By on‐therapy analysis, values were +4.7 and –2.1, respectively (p < 0.001). Acute rejection (AR) rates were numerically higher in the sirolimus group; 1 AR with hemodynamic compromise occurred in each group. A significantly higher treatment discontinuation rate due to adverse events (AEs; 33.3% vs. 0%; p < 0.001) occurred in the sirolimus group. Most common treatment‐emergent AEs significantly higher in the sirolimus group were diarrhea (28.1%), rash (28.1%) and infection (47.4%). Conversion to sirolimus from CNI therapy improved renal function in cardiac transplant recipients with renal impairment, but was associated with an attendant AR risk and higher discontinuation rate attributable to AEs.     

Effect of early conversion from CNI to sirolimus on outcomes in kidney transplant recipients with allograft dysfunction

Background: Studies evaluating the effect of conversion from calcineurin inhibitor (CNI) to sirolimus (SRL) in renal transplant recipients (RTRs) have shown conflicting results, and only few short-term uncontrolled studies are available in patients with chronic allograft dysfunction. This is the first controlled study to evaluate long-term survival and both renal and cardiac outcomes in nondiabetic RTRs with allograft dysfunction who were converted from CNI to SRL. Methods: We evaluated 13 RTRs with biopsy-proven allograft dysfunction who underwent early conversion from CNI to SRL, and 26 controls with normal graft function taking CNI. All continued both steroids and mycophenolate mofetil. SRL was titrated to trough levels of 4-8 ng/mL. Outcome measures included 3-year event-free survival, acute rejection rate and 3-year changes in Modification of Diet in Renal Disease (MDRD) Study equation estimated glomerular filtration rate (eGFR) and left ventricular mass index (LVMi) as assessed by echocardiography. Results: Compared with controls, patients on SRL showed better 3-year event-free survival (p=0.024; log-rank test), significant eGFR increase (+5.5 ± 8.9 vs, -6.4 ± 14.7 ml/min per 1.73 m2, p=0.011), LVMi regression (-9.0 ± 7.6 g/m2.7 vs. 1.0 ± 10.1 g/m2.7, p=0.0038) and similar acute rejection rate. Three-year change in eGFR was the only significant predictor of event-free survival by Cox regression analysis (hazard ratio = 0.96; 95% confidence interval, 0.93-0.99; p=0.017), whereas SRL was the strongest predictor of both eGFR increase (beta coefficient, 0.342; p=0.01) and LVM reduction (beta coefficient, -0.609; p=0.0001) by multivariate regression analysis. Conclusions: Conversion from CNI to SRL in RTRs with allograft dysfunction proved to be associated with better survival, improved renal graft function and regression of cardiac hypertrophy.     

Calcineurin Inhibitor Minimization,Conversion, Withdrawal,and Avoidance Strategies in Renal Transplantation: A Systematic Review and Meta‐Analysis

Despite their clinical efficacy, concerns about calcineurin inhibitor (CNI) toxicity make alternative regimens that reduce CNI exposure attractive for renal transplant recipients. In this systematic review and meta‐analysis, we assessed four CNI immunosuppression strategies (minimization, conversion, withdrawal, and avoidance) designed to reduce CNI exposure and assessed the impact of each on patient and allograft survival, acute rejection and renal function. We evaluated 92 comparisons from 88 randomized controlled trials and found moderate‐ to high‐strength evidence suggesting that minimization strategies result in better clinical outcomes compared with standard‐dose regimens; moderate‐strength evidence indicating that conversion to a mammalian target of rapamycin inhibitor or belatacept was associated with improved renal function but increased rejection risk; and moderate‐ to high‐strength evidence suggesting planned CNI withdrawal could result in improved renal function despite an association with increased rejection risk. The evidence base for avoidance studies was insufficient to draw meaningful conclusions. The applicability of the review is limited by the large number of studies examining cyclosporine‐based strategies and low‐risk populations. Additional research is needed with tacrolimus‐based regimens and higher risk populations. Moreover, research is necessary to clarify the effect of induction and adjunctive agents in alternative immunosuppression strategies and should include more comprehensive and consistent reporting of patient‐centered outcomes.