ABSTRACT. Calcineurin inhibitors (CNI) are an important componentof most immunosuppressive protocols utilized in renal transplantation.Both CNI available (cyclosporine and tacrolimus) have been usedfor many years. Studies comparing the efficacy of these twoagents in terms of long-term graft or patient survival havethus far failed to show an advantage for either agent. Thisfailure to show a difference could possibly be due to underpoweringof clinical trials. The authors used the SRTR database to analyze5-yr graft survival of the microemulsion formulation of cyclosporine(Neoral) as compared with tacrolimus. To minimize the donorvariability and bias, a paired kidney analysis was used. Deceaseddonors from the years 1995–2002 were analyzed from theSRTR database. All paired kidneys during this period, whereone kidney was allocated to a patient receiving initial Neoraltherapy and its mate allocated to a patient receiving initialtacrolimus therapy were evaluated. Multivariate and univariateanalysis were performed. Univariate analysis demonstrated equivalentgraft survival for Neoral compared with tacrolimus (66.9% versus65.9%, respectively). Multivariate analysis could not demonstratea difference in risk for 5-yr patient survival or graft loss.Renal function was superior for tacrolimus at all time points,whereas the slope of 1/Cr over time did not differ for the twoagents. In this paired kidney analysis, no difference in 5-yrrenal allograft survival could be found between the two agents.Renal function was superior in the patients receiving initialtacrolimus therapy; however, slope of 1/Cr did not differ betweenthe agents. E-mail kaplab@medicine.ufl.edu
Calcineurin inhibitor (CNI) therapy remains an important componentof current immunosuppressive protocols utilized in renal transplantation(1). Both cyclosporine and tacrolimus are used with excellentresults (2–4). These two immunosuppressive agents arethought to broadly exert their immunosuppression action by similarmechanisms (5,6). However, they do differ in chemical structure,binding proteins, and toxicity profiles (7–11). Studieshave been undertaken to compare the efficacy of these two agents.The majority of these studies have demonstrated lower acuterejection rates in regimens utilizing tacrolimus versus cyclosporine,even when the newer microemulsion formulation of cyclosporinewas utilized (12–17). Despite this decrease in acute rejectionrate, no statistical difference could be demonstrated betweenthe agents in 1-yr and 3-yr graft survival in these studies.A recent prospective study noted that a survival benefit oftacrolimus could be found when crossover was considered as anend point. However, it is important to note that even in thisstudy the intention-to-treat analysis could not demonstratea difference in 5-yr graft survival (17). Despite the lack ofa statistical difference in graft survival, this study did showa lower creatinine and presumed better renal function in thegroup of patients receiving tacrolimus.
It is possible that the failure of these clinical studies tostatistically demonstrate an improvement in graft survival wasrelated to the number of patients enrolled and the relativelyshort follow-up period assessed in these studies.
Registry analysis has the advantage of providing sufficientnumbers to adequately power an analysis for relatively rareendpoints (e.g., Graft survival). However, registry analysiscannot always account for subtle and hidden selection bias.To diminish any donor bias and to attempt to provide an analysisthat would minimize hidden bias, we utilized the ScientificRegistry of Transplant Recipients (SRTR) and compared long-termgraft survival and renal function in paired deceased donor kidneyswhere one kidney was allocated to a patient placed on Neoraltherapy and the other mate kidney allocated to a patient placedon tacrolimus therapy.
To examine the relative impact of Neoral and Prograf specifically,a paired-kidney analysis was conducted. Deceased donors from1995–2002 who allocated one kidney to a first transplantrecipient receiving Neoral therapy at baseline and one kidneyto a first transplant recipient receiving Prograf therapy atbaseline were identified, and outcomes were measured. Pairedkidney donations were identified by use of a donor identificationcode provided in the SRTR database. This type of analysis excludeddonor characteristic biases and era effects as confounding factorsand allowed us to examine the relative impact of the inhibitorsindependently of these. There were 3070 observations in eacharm of the analyses, and we analyzed the calcineurin inhibitoreffect on survival utilizing univariate Kaplan-Meier plots aswell as multivariate Cox models, adjusted for potential confoundingfactors. Covariates in the Cox models were assessed for adherenceto the proportional hazard assumption, and univariate analyseswere tested using log-rank tests. For the purpose of this study,medication regimen was defined as initial medication at dischargefrom the hospital from information immediately after transplantation.Patients with multiple listings of calcineurin inhibitor medicationswere eliminated from the analysis. The Efron method was usedfor tied values in the Cox models.
To investigate the impact of the calcineurin inhibitor medicationon renal function, we examined the reported creatinine levelsat the given follow-up periods. Inverse serum creatinine (SCr)-1was utilized for tests involving renal function. To test forany difference in (SCr)-1, we conducted a t test paired by theoriginal donor. In addition to examining the magnitude of renalfunction, we also analyzed the change in renal function overtime by assessing the percent change in inverse creatinine froma 6-mo follow-up period to subsequent follow-up periods.
To further investigate the impact of the inhibitor medicationin the paired kidney subjects, we examined the rates and presenceof acute rejection in the posttransplant follow-up period. Acuterejection was indicated by reported acute rejection or treatmentfor acute rejection in the follow-up forms. We examined therates of acute rejection by medication regimen along with performinga multivariate logistic regression to assess the effect of theinhibitor medication on acute regression in the first year posttransplantadjusted for other potential confounding factors. In the caseof the logistic regression, observations were included thathad a minimum of 1 yr theoretical follow-up time. All analyseswere conducted with SAS software (version 8.02; SAS Institute,Cary, NC).
Demographic and recipient treatment information from the analysisare displayed in Table 1. Patients receiving Neoral at baselinehad slightly higher recipient ages (49 yr versus 47 yr), shorterwaiting times on dialysis (37 mo versus 43 mo), higher proportionof males (63% versus 57%), more patients using MMF antiproliferativemedication (79% versus 77%), and a lower proportion of African-Americanpatients (25% versus 29%) relative to recipients on Prografat baseline.
The Kaplan-Meier plot for overall graft survival revealed verysimilar survival curves (log-rank P = 0.4663), 5-yr graft survivalwas 66.9% and 65.9%, respectively, for Neoral and Prograf. Death-censoredgraft survival univariate results (see Figure 1) were very similar(log-rank P = 0.8309) and had similar 5-yr rates (Neoral, 77.7%;Prograf, 78.3%). Results were also not statistically significantfor the outcome of patient survival (log-rank P = 0.1767), with5-yr patient survival equal to 82.6% in the Neoral group and80.2% in the Prograf group. To address the degree of crossoverof inhibitor medication regiments, we also examined the registryfor follow-up information. At the 6-mo follow-up interval, recipientswho were on Neoral at baseline were reported (where 6-mo formswere present) to have remained on Neoral at a rate of 87.2%,while the Prograf baseline group reported 91.8% remaining onPrograf. At 1 yr, the proportion of those remaining on theirbaseline calcineurin inhibitor medication (where the 1-yr follow-upform were present) was 83.1% in the Neoral group and 91.7% inthe Prograf group. Of the 3070 recipient pairs, 674 (22.0%)received treatment at the same center, outcomes were not statisticallydifferent between these pairs and pairs (78.0%) of patientsreceiving treatment at different centers.
Figure 1. Kaplan-Meier plot of death censored graft survival for paired kidney analysis.
We also examined the effect of the calcineurin inhibitor medicationin multivariate Cox models. The adjusted overall graft survival(Figure 2) displayed very similar survival curves, including5-yr survival rates of 69.4 and 69.0 for Neoral and Prograf,respectively. The models were adjusted for induction and antiproliferativetherapies, cold ischemia time, PRA level, HLA-A, B, and DR mismatches,recipient age, recipient gender, recipient ethnicity, waitingtime on dialysis, and primary diagnosis. The hazard estimatesfor Neoral (with Prograf as the reference group) for overallgraft loss (see Table 2) and death censored graft loss were0.979 (0.861 to 1.112) and 1.097 (0.925 to 1.302), respectively.
Table 2. Multivariate risk estimates for end point of overall graft loss
The 6-mo inverse creatinine values were statistically significantly(P < 0.0001) lower in the Prograf arm than the Neoral froma paired t test for a mean difference. While the magnitude ofthe renal function was statistically different at 6 mo, thechange in renal function (as measured by inverse creatinine)from 6 mo to 1, 2, 3, 4, and 5 yr follow-up periods were notsignificantly different between the calcineurin inhibitor groups.The overall mean levels and 95% CI of serum creatinine levelsat the applicable follow-up periods are displayed Figure 3.The creatinine levels and their respective SD can be seen onTable 3. The rate of any report of acute rejection within 1yr posttransplant for the medication regiments of Neoral/AZA,Neoral/MMF, Prograf/AZA, and Prograf/MMF were 27.2%, 21.5%,24.6%, and 21.9%, respectively. The multivariate logistic modeldid not find any significant effect of the inhibitor medicationon the presence of acute rejection in the first year posttransplant,the odds ratio for Neoral (with Prograf as reference) equalto 0.991 (0.867 to 1.132).
Our study failed to demonstrate a significant difference in5-yr graft survival between patients receiving initial tacrolimusversus those receiving Neoral as initial therapy. Baseline recipientdemographics were similar in both groups; as both the univariateand multivariate analysis were consistent in a lack of difference,it is unlikely that this lack of difference could be attributedto any major demographic differences in the respective groups.As this was a paired kidney analysis by design, no differencesin donor characteristics would be expected.
As the multivariate analysis corrected for concurrent immunosuppressivemedication and as the percent of patients receiving inductiontherapy or MMF therapy did not differ to any great extent, itis highly unlikely that this played a role in these findings.Opposed to the recent clinical trials, we could find no statisticaldifference in acute rejection rates between the agents. It ishighly unlikely that reporting of acute rejection is systematicallyover reported for one agent as opposed to the other. Also asthe secular trend is for both greater tacrolimus utilizationand lower acute rejection rates in the most proximate years,this finding is unlikely due to either an era effect or a systematicbias. In addition, as this lack of difference was confirmedby the multivariate analysis, we feel it is highly unlikelyto be due to differences in demographic characteristics. Asdose of medications are not known, it is possible that thiscontrary finding may be due to dosing differences other thanwhat was proscribed in clinical trials.
In essence, this analysis is similar to an intention-to-treatanalysis in that patients were assigned to each group accordingto the agent they were initially given. We felt this type ofanalysis would help avoid selection bias, as reasons for switchingare not available. It is important to note that the number ofpatients who switched off Neoral at 1 yr was 16.9%, while itwas 8.3% for tacrolimus. It is possible that this might accountfor our failure to detect a difference in survival in both groups.However, given these numbers, it is mathematically unlikelythat this would have influenced these results. As acute rejectionrates were equivalent, it is also unlikely that a switch secondaryto this reason would significantly alter these results. Still,as the effect of switching cannot be assessed by this type ofanalysis, we would like to make clear that this study can onlyaddress the issue of initial therapy.
In terms of renal function, initial tacrolimus therapy demonstratedimproved renal function over patients who received Neoral asinitial therapy. This was a paired kidney analyses; it is thereforeextremely unlikely that this difference reflected differencesin any donor variables. This difference in serum creatininewas statistically significant even in the earliest time periodmeasurement, and was sustained throughout the 5-yr period. Onthe other hand, the slope of 1/Cr or change in renal functiondid not appear to be different between the two agents. Thisis similar to findings noted in clinical trials (16–18).This improved renal function early, however, did not translatein to improved graft survival at 5 yr. Without a direct measureof renal function, it is possible that the lower creatinineobserved in patients who received tacrolimus might be reflectiveof a decrease in muscle mass in this group compared with patientsreceiving Neoral therapy. As a difference in muscle growth orcatabolism has not been seen in previous studies comparing thesetwo agents, we feel it is unlikely to explain the differencesin creatinine values observed in this study.
In summary, in this paired kidney analysis, we could find noevidence for any difference in 5-yr graft survival for patientsinitiated on either tacrolimus or Neoral therapy. Renal functionwas superior in the Tacrolimus group; however, there was nodifference in the slope of 1/Cr between the agents. Whetherinitial therapy with either calcineurin inhibitor is associatedwith improvement in even longer-term graft survival will needto be assessed by future studies.
United States Renal Data Service: USRDS services and data requests. Minneapolis, MN, USRDS Database, 2003
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Received for publication July 28, 2003.
Accepted for publication August 21, 2003.
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Abstract
Introduction
