Mycophenolate mofetil vs. sirolimus in kidney transplant recipients receiving tacrolimus-based immunosuppressive regimen

Abstract:  Mycophenolate mofetil (MMF) and sirolimus (SRL) are effective immunosuppressive drugs with distinct safety profile.
Methods:  Kidney transplant recipients receiving tacrolimus (TAC)-based immunosuppressive regimen were randomized to receive fixed daily doses of MMF (2 g/d, n = 50) or SRL (one loading dose of 15 mg, 5 mg/d till day 7 and 2 mg/d thereafter, n = 50) without induction therapy.
Results:  No differences were observed in the incidence of the composite (biopsy-confirmed acute rejection, graft loss or death) end-point (18% vs. 16%, p = 1.000), biopsy confirmed acute rejection (12% vs. 14%, p = 1.000), one-yr patient (94% vs. 98%, p = 0.308), graft (92% vs. 98%, p = 0.168), and death-censored graft survival (98% vs. 100%, p = 0.317) comparing patients receiving MMF or SRL respectively. Patients receiving SRL showed worse safety outcomes, higher mean creatinine (1.6 ± 0.5 mg/dL vs. 1.4 ± 0.3 mg/dL, p = 0.007), higher proportion of patients with proteinuria (52.0% vs. 10.7%, p = 0.041), higher mean urinary protein concentrations (0.3 ± 0.5 g/L vs. 0.1 ± 0.2 g/L, p = 0.012), higher mean cholesterol concentration (217 mg/dL vs. 190 mg/dL, p = 0.030), and higher proportion of patients prematurely discontinued from randomized therapy (26% vs. 8%, p = 0.031).
Conclusion:  In patients receiving TAC, MMF produced similar efficacy but superior safety profile compared with SRL.     

Relationship between renal resistance index and renal function in liver transplant recipients after cessation of calcineurin inhibitor

Abstract:  End stage renal disease is a major complication after orthotopic liver transplantation (OLT). Vasoconstriction of renal arterial vessels because of calcineurin inhibitor (CNI) treatment plays a pivotal role in the development of renal insufficiency following OLT. Renal resistance can be measured non-invasively by determining the resistance index (RI) of segmental arteries by color-coded duplex ultrasonography, a measure with predictive value for future renal failure. Sixteen OLT patients on long-term CNI therapy were recruited prospectively and randomly assigned either to receive the m-TOR inhibitor sirolimus (SRL) or to continue on CNI treatment, and were followed for one yr. Serum creatinine (crea) declined after conversion to SRL, whereas it tended to increase in patients remaining on CNI (meanΔ crea SRL: −27, −18, −18, −15 μmol/L; meanΔ crea CNI: 4, 5, 8, 11 μmol/L at 1, 3, 6, 12 months, p = 0.02). RI improved after switching to SRL and was lower on SRL than on CNI (meanΔRI SRL: −0.04, −0.04, −0.03, −0.03; meanΔRI CNI: −0.006, 0.004, −0.007, −0.01 after 1, 3, 6, 12 months, p = 0.016). Individual changes of RI correlated significantly with individual changes of crea ( r  = 0.54, p < 0.001). Conversion from CNI to SRL can ameliorate renal function accompanied by a reduction of intrarenal RI after OLT.     

Efficacy and Safety of Everolimus and Mycophenolic Acid With Early Tacrolimus Withdrawal After Liver Transplantation: A Multicenter Randomized Trial

SIMCER was a 6‐mo, multicenter, open‐label trial. Selected de novo liver transplant recipients were randomized (week 4) to everolimus with low‐exposure tacrolimus discontinued by month 4 (n = 93) or to tacrolimus‐based therapy (n = 95), both with basiliximab induction and enteric‐coated mycophenolate sodium with or without steroids. The primary end point, change in estimated GFR (eGFR; MDRD formula) from randomization to week 24 after transplant, was superior with everolimus (mean eGFR change +1.1 vs. ?13.3 mL/min per 1.73 m² for everolimus vs. tacrolimus, respectively; difference 14.3 [95% confidence interval 7.3–21.3]; p < 0.001). Mean eGFR at week 24 was 95.8 versus 76.0 mL/min per 1.73 m² for everolimus versus tacrolimus (p < 0.001). Treatment failure (treated biopsy‐proven acute rejection [BPAR; rejection activity index score >3], graft loss, or death) from randomization to week 24 was similar (everolimus 10.0%, tacrolimus 4.3%; p = 0.134). BPAR was more frequent between randomization and month 6 with everolimus (10.0% vs. 2.2%; p = 0.026); the rate of treated BPAR was 8.9% versus 2.2% (p = 0.055). Sixteen everolimus‐treated patients (17.8%) and three tacrolimus‐treated patients (3.2%) discontinued the study drug because of adverse events. In conclusion, early introduction of everolimus at an adequate exposure level with gradual calcineurin inhibitor (CNI) withdrawal after liver transplantation, supported by induction therapy and mycophenolic acid, is associated with a significant renal benefit versus CNI‐based immunosuppression but more frequent BPAR.     

Two yr mycophenolate mofetil plus low-dose calcineurin inhibitor for renal dysfunction after liver transplant

Abstract:  We assessed the efficacy and outcome of low through level of calcineurin inhibitors (CNI) and introducing mycophenolate mofetil (MMF) in liver transplant (LT) patients with CNI-related renal dysfunction. Thirty LT patients were converted to combined therapy and compared with 30 patients used as a contemporary control group receiving CNI only. The two groups were matched for sex, age, months after LT, immunosuppressive treatment, creatinine level, presence of diabetes and calculated glomerular filtration rate (GFR) via Cockroft-Gault method. After two years, in the MMF serum creatinine decreased from 1.65 mg/dL (range 1.33–3.5) to 1.4 mg/dL (range 0.9–4.7) (p = 0.002) and GFR increased from 51 mL/min (range 18.9–72.2) to 57.6 mL/min (range 16–92.2) (p < 0.001), whereas the controls not showed any improvement. The logistic regression models employing improvement of creatinine and GFR of at least 10% with respect to baseline as dependent variables showed the use of MMF (p = 0.004 and p = 0.019, respectively) as the only statistically significant parameter. Multiple linear regression analysis identified only MMF as independent predictor of Δcreatinine and ΔGFR (p = 0.002 and p < 0.001, respectively). No rejection episode was observed (three in controls). This study demonstrates the medium-term efficacy and safety of MMF plus low dose CNI in reducing nephrotoxicity in LT recipients.     

Calcineurin inhibitor effects on glucose metabolism and endothelial function following renal transplantation

Abstract: Background:  Calcineurin inhibitors (CNI) are involved in the development of post-transplant diabetes mellitus (PTDM). Changes in insulin secretion and sensitivity contribute to the development of PTDM and are associated with endothelial function.
Methods:  In a pre-defined substudy of a previously published randomized trial in renal transplant recipients we compared the effect of CNI treatment (n = 23) with complete CNI-avoidance (n = 21) on insulin secretion and sensitivity (oral glucose tolerance test) as well as endothelial function (laser Doppler flowmetry), 10 wk and 12 months following transplantation.
Results:  Insulin sensitivity differed 10 wk post-transplant and was significantly better after 12 months in patients never treated with CNI drugs [0.091 (0.050) vs. 0.083 (0.036) μmol/kg/min/pmol/L, p = 0.043]. Insulin secretion tended to be higher in CNI treated patients at both time points (p = 0.068). Endothelial function was not significantly different at week 10 [540 (205) vs. 227 (565) arbitary units × minutes, p = 0.35] or month 12 [510 (620) vs. 243 (242), p = 0.33].
Conclusions:  Findings in the present study indicate that long-term CNI treatment negatively affects glucose metabolism and this may contribute to the increased risk for premature cardiovascular disease in CNI treated renal transplant recipients. Further studies to elucidate this hypothesis are, however, needed.     

The association between MMF and risk of progressive renal dysfunction and death in adult liver transplant recipients with HCV

Abstract  The impact of a three-drug regimen including mycophenolate mofetil (MMF) vs. a two-drug (no MMF) regimen on progressive renal dysfunction (PRD) in liver transplant recipients with hepatitis C virus (HCV) infection has not been well described. Adults with HCV who received a primary liver transplant between January 1, 2000 and December. 31, 2005 and were discharged from the hospital on a three-drug regimen [CNI+MMF+steroids (S)] (n = 4 946) were compared with those discharged on two-drug regimen (CNI+S) (n = 3 884). Time to PRD (defined by a post-transplant 25% decline in estimated GFR, based on the four-variable MDRD equation) and recipient death were evaluated using Kaplan–Meier analysis. Cox proportional hazards regression was used to estimate the risk for post-transplant PRD and death after controlling for baseline characteristics and extended steroid use. The two groups were similar in baseline characteristics. The percentage of recipients on three- vs. two-drug regimen without PRD was higher, 36.8% vs. 31.9%, (p < 0.001), at three yrs post-transplant; three-drug therapy was associated with a 6% lower adjusted risk of PRD. The death rate and adjusted risk for death was lower for recipients on a three- vs. two-drug regimen. Liver transplant recipients with HCV on a MMF-containing regimen are at a lower risk for PRD and death compared with recipients on a regimen not including MMF.     

Long-term clinical outcomes of nocturnal hemodialysis patients compared with conventional hemodialysis patients post-renal transplantation

Abstract:  Nocturnal home hemodialysis (NHD) is a novel dialysis strategy associated with multiple advantages over conventional hemodialysis (CHD). Short- and long-term clinical outcomes of NHD patients after kidney transplantation are unknown. We hypothesized that the incidence of delayed graft function (DGF), patient and graft survival, and post-transplant estimated glomerular filtration rate (eGFR) is better among CHD-transplanted individuals than among those having received NHD. Of 231 NHD patients, 36 underwent renal transplantation between 1994 and 2006 and were matched to 68 transplanted CHD patients with a maximum follow-up of 11.7 yr. The incidence of DGF was not different between the two groups [NHD: 15/35 (42.9%) vs. CHD: 25/68 (36.8%) p = 0.43]. In modeling eGFR pre-transplant weight, donor age and recipient race were most predictive. Dialysis modality prior to transplantation influenced neither the level of eGFR post-transplantation (p = 0.34), nor the rate of eGFR decline. Patient survival was comparable between NHD and CHD groups (log-rank p = 0.91). Based on this analysis, it appeared that the incidence of DGF was similar between NHD- and CHD-transplanted patients and that pre-transplant modality did not impact on the level or rate of deterioration of post-transplant eGFR.     

Expanding the donor pool: use of renal transplants from non-heart-beating donors supported with extracorporeal membrane oxygenation

Abstract:  In response to organ shortage, we used the renal grafts from non-heart-beating donors (NHBDs). Extracorporeal membrane oxygenation (ECMO) was used to maintain NHBDs before organ procurement. We compared the results of renal transplantation from different donors, including heart-beating donors (HBDs), living-related donors (LDs), and NHBDs supported with ECMO. From February 1998 to June 2003, we recruited 219 patients receiving renal transplantation at National Taiwan University Hospital. Among them, 31 received kidneys from NHBDs supported with ECMO, 120 from HBDs, and 68 from LDs. Multiple organ transplant recipients were not included in this study. We compared the graft survival, serum creatinine levels, and estimated glomerular filtration rates of the three groups. The rate of delayed graft function was higher in NHBD recipients (41.9%) than in HBD recipients (27.0%) and LD recipients (10.9%) (p = 0.003). In the NHBD group, the recipients of grafts with delayed function had significantly longer ECMO runs (63.1 ± 3.0 min) than those without delayed function (53.7 ± 2.5 min) (p = 0.024). Estimated glomerular filtration rate (p = 0.472) and mean serum creatinine level (p = 0.286) were not significantly different between the three groups using a longitudinal approach. The 5-yr graft survival rates for NHBD (88.4%, 95% CI: 0.680–0.962), HBD (83.2%, 95% CI: 0.728–0.899), and LD transplant recipients (89.3%, 95% CI: 0.619–0.974) were not significantly different (p = 0.239). The 5-yr patient survival rates for NHBD, HBD, and LD transplant recipients were 100, 93.0 (95% CI: 0.859–0.966) and 100% respectively. The long-term allograft survival and function of kidneys from NHBDs supported by ECMO, HBD, and LD did not differ significantly. Long ECMO running time tended to delay graft function.     

Impact of Calcineurin‐Inhibitor Conversion to mTOR Inhibitor on Renal Allograft Function in a Prednisone‐Free Regimen

Traditionally, chronic calcineurin inhibitor (CNI) nephrotoxicity has been considered to be one of the main nonimmune mechanisms causing chronic renal allograft dysfunction. CNI minimization and withdrawal strategies have yielded inconsistent results. Few studies address the feasibility of CNI elimination in a prednisone‐free regimen. We report a prospective, randomized trial in 200 patients evaluating the impact on renal function and incidence of acute rejection after conversion from tacrolimus (Tac) to sirolimus (SRL). Patients with recent (<3 months) acute rejection episodes or with >0.5 g/day of proteinuria were excluded. All were induced with alemtuzumab, underwent rapid steroid elimination and were maintained on mycophenolate mofetil and Tac. At 12 months posttransplant, patients were randomized 2:1 to SRL (n = 123) or maintained on Tac (n = 64). Mean follow‐up was 41.1 ± 15.8 months in the SRL group and 40.7 ± 14.4 months in the Tac group. Biopsy‐proven acute rejection at 24 months postrandomization was similar between the groups. Patient survival, graft survival and estimated GFR were also not statistically different. Our study demonstrates that in a prednisone‐free immunosuppressive regimen, conversion from Tac to SRL at 12 months posttransplantation is not associated with increased rates of acute rejection and graft loss. However, despite CNI elimination, renal allograft function is equally maintained in both groups.     

Optimal interventional treatment and long-term outcomes for biliary stricture after liver transplantation

Abstract:  We undertook an evaluation of the clinical outcomes of endoscopic cholangioplasty (ECP) and percutaneous cholangioplasty (PCP) for biliary strictures after liver transplantation. We compared success rates of intervention, patency after successful intervention and procedure-related morbidities in 79 patients with anastomotic stricture (n = 54) or non-anastomotic stricture (n = 25). Twenty-five ECP and 61 PCP procedures were performed; seven PCP procedures were consecutively performed after failure of ECP. Fifty-one (64.6%) patients were successfully treated by cholangioplasty. Successful intervention rates (60.0% in ECP vs. 59.3% in PCP, p = 1.00) and patencies after successful intervention (44.8 ± 7.4 months in ECP vs. 41.9 ± 3.4 months in PCP, p = 0.47) were no different for the two techniques. However, the number of intervention sessions for PCP (7.2 ± 0.6) was higher than for ECP (2.9 ± 0.6) (p < 0.01). Multivariate analysis showed that only an anastomotic stricture was found to be related with a longer patency with an estimated odds ratio of 5.74 (p = 0.04) and had a tendency to be associated with successful intervention with an estimated odds ratio of 3.12 (p = 0.07) irrespective of techniques. Endoscopic access should be the preferred first approach in patients with biliary stricture after liver transplantation irrespective of the type of stricture, in view of its less invasive nature and patient convenience.     

Factors associated with proteinuria in renal transplant recipients treated with sirolimus

Although sirolimus (SRL) use in renal allograft recipients (RTX) is associated with improved renal function, proteinuria develops in a significant proportion. 48 SRL-treated RTX were evaluated for development of proteinuria and stratified by level of proteinuria after SRL therapy. The Proteinuria Group ( n  = 25, 52.1%) had new-onset proteinuria or >25% increase in proteinuria following SRL conversion; the Nonproteinuria Group had stable proteinuria <0.5 g/day throughout. There was a higher proportion of male RTX and female donors to male recipients in the Proteinuria Group, (24% vs. 10%, P  = 0.008). Calcineurin inhibitor- and statin usage were significantly higher in the Nonproteinuria Group (8% vs. 17%, P  = 0.046; 28% vs. 83%, P  < 0.001 respectively) whereas biopsy-proven acute rejection was higher in the Proteinuria Group (68% vs. 33%, P  = 0.037). SDS-PAGE analysis of urine from 23 RTX in the Proteinuria Group demonstrated glomerular proteinuria in 100% and tubular proteinuria in 87%. While male gender and gender mismatch may impact on glomerular proteinuria through inadequate nephron dose and subsequent hyperfiltration, concurrent cyclosporine use may mitigate the development of proteinuria in SRL-treated patients, through afferent arteriolar vasoconstriction. Glomerular injury occurring following acute rejection may further contribute to glomerular proteinuria. Statins, through their anti-inflammatory and anti-fibrotic effects, may protect against development of proteinuria.     

Calcineurin inhibitor-sparing regimens in solid organ transplantation: focus on improving renal function and nephrotoxicity

Abstract: Background: The calcineurin inhibitors (CNIs), cyclosporine and tacrolimus, have had a revolutionary effect on the overall success of renal transplantation through reduction in early immunologic injury and acute rejection rates. However, the CNIs have a significant adverse impact on renal function and cardiovascular disease, and extended long-term graft survival has not been achieved. The recognition of these effects sparked interest in CNI-sparing strategies. Strategies to limit CNI exposure include CNI minimization, avoidance, and withdrawal. We sought to review the impact of CNI-sparing strategies in kidney, liver, and heart transplantation. Materials and methods: A PubMed search 1966 to August 2006 was conducted to identify relevant research articles, and the references of these articles as well as the authors’ personal files were reviewed. Results: Calcineurin inhibitor minimization using mycophenolate mofetil or sirolimus may be associated with a modest increase in creatinine clearance (CrCl) and a decrease in serum creatinine (SCr) in the short term. Despite improvement in CrCl or SCr, CNI nephrotoxicity and chronic allograft nephrotoxicity are progressive over time when CNI exposure is maintained. In kidney transplantation, the tubulo-interstitial and glomerular damage are irreversible. Mycophenolate mofetil may improve renal outcomes during CNI minimization more than sirolimus, and antibody induction may be effective to limit CNI exposure, but longer-term follow-up data are required. Use of sirolimus with mycophenolate mofetil or azathioprine to avoid CNI exposure de novo has improved glomerular filtration rate for at least two yr in most studies in kidney transplantation; however, experience is limited in liver and heart transplantation, and reports of delayed graft function and wound healing with sirolimus may have dampened enthusiasm for de novo use. Late CNI withdrawal has achieved variable results, possibly because withdrawal was attempted after the kidney damage was too extensive. Early CNI withdrawal, prior to significant graft damage, has generally improved CrCl and markers of fibrosis and decreased chronic allograft lesions, a finding also observed with sirolimus in most CNI avoidance studies. Successful withdrawal appears to be more effective than CNI minimization. Conclusions: Calcineurin inhibitors are associated with significant nephrotoxicity and chronic kidney damage. Minimization is associated with a modest increase in renal function, but persistent damage is observed on biopsies as long as the CNIs are continued. Avoidance is hampered by lack of experience and possible sirolimus-induced side effects. CNI withdrawal may be the best option by delivering CNIs during the early period of immunologic graft injury and then converting them to less nephrotoxic agents before significant renal damage occurs.     

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.     

肝移植后因药物不良反应暂停及转换钙调磷酸酶抑制剂的单中心经验

目的 研究肝移植术后暂停及转换钙调磷酸酶抑制剂(CNI)对控制感染和改善受损肾功能的作用.方法 回顾性分析单中心施行的947例原位肝移植的资料,分为2个阶段,第1阶段(2002年1月至2007年12月)有234例肝移植术后发生感染的患者,第2阶段(2008年1月至2010年12月)有101例.2个阶段共有329例受者因CNI肾毒性而造成肾功能损害,其中将CNI转换为SRL者40例(转换组),其余289例采取CNI减量+吗替麦考酚酯(MMF)加量方案(减量组).结果 肝移植术后存活超过1、3和5年者CNI的应用率分别为95.8%、95.3%和97.5%.第2阶段共有17例受者短期停用免疫抑制剂,停药的主要原因是细菌(部分合并真菌)感染(88.2%);2个阶段共有48例患者将CNI转换为SRL,换药主要原因是肾功能损害(83.3%).第2阶段感染患者中短期暂停CNI者15例,占14.9%(15/101),CNI暂停后感染控制的有效率为73.3%(11/15),排斥反应发生率为6.7%(1/15).第2阶段感染患者的累积存活率明显高于第1阶段(P＜0.05).转换组CNI转换前肾小球滤过率为(0.82±0.24)ml/s,CNI转换后6周时为(1.28±0.31)ml/s,6个月时为(1.36±0.32)ml/s,转换后6周和6个月时高于转换前(P＜0.05).CNI调整后6个月时,转换组患者存活率为85.0%,减量组为83.7%(P＞0.05).结论 肝移植术后患者发生感染及肾功能损害时可采取CNI减量甚至短时间停用CNI,或转换使用SRL,此方案是安全、有效的.

Abstract：

Objective To report the results of a single-center, retrospective study on the effect of calcineurin inhibitors (CNI) withdraw for controlling infections and conversion to sirolimus (SRL)for ameliorating renal dysfunction. Methods A total of 947 liver transplant cases from 2002 to 2010were divided into two eras (Jan. 2002 to Dec. 2007 and Jan. 2008 to Dec. 2010). There were 234cases of infections after liver transplantation (LT) in the first era and 101 cases in the second era. And of 329 cases of CNI-related renal dysfunction after LT in two eras, 40 cases (converting group) had converted CNI to SRL, while 289 cases (reducing group) adopted protocol of CNI reducing and mycophenolate mofetil (MMF) raising. Results CNI-based IS took up 95.8 %, 95. 3 %, 97. 5 % of the IS protocols with recipient survival time longer than 1, 3, and 5 years. The primary cause for CNI withdraw was infection (88. 2 %, 15/17) in the second era, and renal dysfunction for conversion to SRL in the two eras (83. 3 %, 40/48). In the second era, 14. 9% (15/101) of the cases of infections after LT experienced CNI withdraw. Of the 15 patients, 11 had effectively controlled the infection (77. 3 %) while rejection rate was 6. 7 % (1/15). The cumulative survival rate of the second era was significantly higher than the first era (P＜0. 05). The glomerular filtration rate (GFR) of converting group at 6th week and 6th month was statistically elevated as compared with that before conversion,respectively (1.28 ± 0. 31, 1.36 ± 0. 32 mL/s vs. 0. 82 ± 0. 24 mL/s, P＜0. 05). Six months after CNI adjustments, survival rate of converting group and reducing group was 85. 0% and 83. 7 %,respectively (P＞0. 05). Conclusion Reducing or even short-term withdraw of CNI may allow the better control of infections after LT, and the conversion from CNI to SRL can ameliorate the CNIrelated nephrotoxicity. These individually tailored IS protocols will benefit the long term survival for LT.     

Timing of sirolimus conversion influences recovery of renal function in liver transplant recipients

Abstract: The long‐term use of calcineurin inhibitors (CNI) leads to renal dysfunction in many liver transplant (LT) recipients. The purpose of this analysis is to evaluate renal function in patients converted from CNI to sirolimus (SRL). From May 2002–November 2006, 137 LT were performed in 125 patients, 72 of which were converted to SRL. Evaluation of SRL conversion was stratified by early conversion (<90 d from LT) (EC) vs. late conversion (LC). Renal function was evaluated using the six‐point modification of diet in renal disease formula (estimated glomerular filtration rate [eGFR]). Forty‐two patients on SRL and 40 on CNI had at least three months of follow‐up and are included in the eGFR evaluation. At all time points after conversion, the EC group demonstrated a significantly higher mean eGFR than those in the LC group. A significant improvement in eGFR was seen within the EC group when comparing eGFR at time of conversion to eGFR at three, six, nine, and 12 months after conversion and last follow‐up. The only improvement in the LC group was from conversion to the three‐month time point. We conclude that EC to SRL results in a profound improvement in eGFR that begins at three months and is sustained beyond one yr.     

Tacrolimus in pediatric heart transplantation: ameliorated side effects in the steroid-free, statin era

Abstract:  Due to concerns over the side effects of cyclosporine, tacrolimus is widely used in pediatric heart transplantation. However, tacrolimus therapy is also accompanied by potentially serious side effects. This paper examines the side effect profile of tacrolimus in a large group of pediatric heart recipients. Data on renal function, diabetes, hyperlipidemia and hypertension were collected by case-note review of 100 patients who had received ≥ 12 months treatment with tacrolimus. Forty-two patients received tacrolimus from the time of transplant ( de novo ), and 58 were initially treated with cyclosporine (switch). Mean estimated glomerular filtration rate improved in the first six months post transplant in the de novo group (66.7–84.6 mL/min/1.73 m², p = 0.002). Conversely, it decreased in those initially treated with cyclosporine (82.1–68.8, p = 0.032), but improved after switch to tacrolimus (77.3–85.6, p = 0.006). Twenty-one percent exhibited glucose intolerance, and 2% had diabetes. Borderline or elevated fasting cholesterol levels were present in 4.4%. Hypertension was seen in 67% at the point of switch from cyclosporine, which fell to 36% at latest follow-up (p = 0.001). These results present an encouraging outlook for this cohort of patients. The relatively low levels of complications shown may be due to early weaning of steroids, and concomitant statin therapy.     

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.     

An analysis of renal dysfunction in 1511 patients with fractured neck of femur: the implications for peri-operative analgesia

Following two deaths from respiratory failure secondary to opioid toxicity in patients admitted for surgical repair of fractured neck of femur, we retrospectively studied the serum urea and electrolyte concentrations of 1511 consecutive patients requiring surgery for proximal femoral fracture, and calculated their glomerular filtration rate. Five hundred and forty-five (36.1%) patients had renal dysfunction on admission (glomerular filtration rate < 60 ml.min⁻¹.1.73 m⁻²); 435 (28.8%) had grade 3 chronic kidney disease (moderate; glomerular filtration rate 30–59 ml.min⁻¹.1.73 m⁻²), 82 (5.4%) had grade 4 disease (severe; glomerular filtration rate 15–29 ml.min⁻¹.1.73 m⁻²) and 28 (1.9%) had grade 5 (renal failure; glomerular filtration rate < 15 ml min⁻¹.1.73 m⁻²). The 30-day mortality for patients with renal dysfunction (62/536; 11.6%) was significantly greater (p = 0.004) than for patients with normal renal function (68/958; 7.1%), although median (IQR [range]) postoperative lengths of stay were similar 15 (10–22 [1–125]) vs 14 (9–22 [1–120]) days respectively; p = 0.06). Renal impairment is common in patients admitted for fixation of fractured neck of femur, who are consequently at risk of opioid toxicity.     

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-based immunosuppression with sirolimus in renal transplantation: a randomized, controlled Spare-the-Nephron trial

As part of the Spare-the-Nephron trial, we evaluated the combination mycophenolate mofetil (MMF) and sirolimus (SRL) as a calcineurin inhibitor (CNI)-free regimen for the preservation of renal function in renal allograft recipients. This 2-year, open-label, multicenter trial randomized 299 patients of which 151 were maintained on MMF and a CNI, 148 on MMF plus SRL (n=120, tacrolimus; n=31, cyclosporine). Baseline characteristics including measured (iothalamate) glomerular filtration rate (GFR) were similar between groups. After 1 year, the mean percentage change from baseline in the primary end point of measured GFR was significantly higher in the MMF/SRL group compared with the MMF/CNI group. After 2 years, the change was indistinguishable. Calculated creatinine clearance and GFR were significantly greater with MMF/SRL at 2 years within which biopsy-proven acute rejection (BPAR) occurred in 14 MMF/SRL-treated patients (3 graft losses) and in 17 receiving the MMF/CNI (6 graft losses). Significantly, no patients receiving MMF/SRL but five treated with MMF/CNI died. Thus, compared with MMF/CNI treatment, a 2-year regimen of MMF/SRL resulted in similar measures of renal function but with fewer deaths and a trend to less BPAR and graft loss.