Calcineurin inhibitor (CNI) nephrotoxicity is a major concernafter renal transplantation. To investigate the safety and efficacyof a CNI-free immunosuppressive regimen, 132 live-donor renaltransplant recipients were included in a prospective, randomizedcontrolled trial. All patients received induction therapy withbasiliximab and steroids. The patients were randomized to amaintenance immunosuppression regimen that included steroids,sirolimus, and either low-dose tacrolimus or mycophenolate mofetil(MMF). Over a mean follow-up period of approximately 5 yr, patientand graft survival did not significantly differ between thetwo maintenance regimens. Patient survival was 93.8% and 98.5%in the tacrolimus/sirolimus and MMF/sirolimus groups, respectively,and graft survival was 83% and 88%, respectively. However, theMMF/sirolimus group had significantly better renal function,calculated by Cockcroft-Gault, from the second year post-transplantuntil the last follow-up. In addition, this group was less likelyto require a change in their primary immunosuppression regimenthan the tacrolimus/sirolimus group (20.8% versus 53.8%, P =0.001). The safety profile was similar between groups. In summary,after long-term follow-up, a CNI-free maintenance regimen consistingof sirolimus, MMF, and steroids was both safe and efficaciousamong low to moderate immunologic risk renal transplant recipients.
Avoidance or at least minimization of the nephrotoxic effectof the calcineurin inhibitors (CNIs) is indeed a worthy goal;however, it must be approached with great care.
The current CNIs in use, including cyclosporine (CsA) and tacrolimus(Tac), are, in addition to being nephrotoxic, associated withdetrimental effects on cardiovascular risk factors, such ashypertension, dyslipidemia, and glucose intolerance. Besides,development of chronic allograft nephropathy (CAN) is commonin recipients treated with CNI.1–3 Recently, it was foundthat especially long-term treatment with CNI drugs results infibrotic scarring of transplanted kidneys, an effect presentin about 25% of the patients already during the first 6 mo post-transplant.4
The introduction of potent immunosuppressive alternatives toCNI drugs, such as mycophenolate mofetil (MMF), mTOR inhibitors(mammalian target of rapamycin, sirolimus, everolimus), andthe anti-CD25 antibodies (anti-IL-2 receptor antibodies daclizumaband basilixiamb) challenge investigations of less toxic immunosuppressiveprotocols. MMF has been shown to be a well-tolerated and effectivealternative in patients with CsA-induced nephrotoxicity, notonly allowing CsA dose reduction but also full CsA withdrawalin selected patients resulting in significantly improved renalfunction.5–8 MMF also has a preferred profile on bloodpressure, lipids, and glucose metabolism.
CNI avoidance might translate into improved graft and patientsurvival as long as the overall immunosuppression is adequate.CNI-free regimens based on daclizumab induction followed byMMF and steroid maintenance have shown 1-yr graft survival ofmore than 95%; however, acute rejection rate was unacceptablyhigh in these patients with average immunogenic risk.9,10
The complementary properties of sirolimus (SRL) and MMF mayprovide the rationale for their combination in induction andmaintenance regimens. SRL, an mTOR inhibitor, inhibits cellproliferation driven by growth factors; and MMF, a reversibleinhibitor of inosine monophosphate dehydrogenase, acts as anantiproliferative drug. Early experiences with the use of theSRL, MMF, and steroid combination yielded insufficient prophylaxisof acute rejection.11,12 However, the introduction of inductiontherapy with monoclonal or polyclonal antilymphocyte antibodiesto the SRL/MMF and steroid combination brings an efficient acuterejection prophylaxis while improving renal function and/orreducing chronic allograft nephropathy.13,14
However, a recent review article of an organ-by-organ reviewof Organ Procurement and Transplantation Network and ScientificRegistry of Transplant Recipients data showed a decline in thenumber of renal transplant patients who were discharged on regimenscontaining SRL down to 16% in 2004. Moreover, the use of theSRL/MMF combination has remained less than 1%.15
We have previously reported on the safe and efficient use ofSRL/MMF combination regimen together with steroids and basiliximabinduction therapy in a short-term prospective randomized trial.14We hereby report on the safety and efficacy of the longer-termuse of such a regimen in living donor renal transplant recipients.
Demography
Demographic and baseline characteristics were previously outlined.14Both groups were homogeneous regarding recipients' age, sex,body weight, original kidney disease, pretransplant hypertension,urinary bilharziasis, hepatitis C virus antibody test, donors'age, and human leukocyte antigen matching.
Patient and Graft Outcome
Mean follow-up period was 62.6 ± 13 and 63.5 ±9.9 mo for group A and B, respectively (range, 55 to 75 mo).Higher patient and graft survivals were noted among group Bpatients, although it does not rank to statistical significance(Figures 1and 2; Table 1).
Group A.
Four patients died. The cause of death in 2 of them was miliarytuberculosis (TB), 3 and 6 mo post-transplantation. The causeof death in the others was most probably attributed to a cardiovascularcause being reported at home, 31 and 32 mo post-transplantation.Seven patients returned back to dialysis throughout the wholefollow-up period. Recurrence of original kidney disease (anti-glomerularbasement membrane nephritis and focal segmental glomerulosclerosis[FSGS]) was responsible for two graft failures, 4 and 7 mo post-transplantation.One patient had thrombotic microangiopathy complicated by transplantglomerulopathy and FSGS and put on dialysis 5 mo post-transplantation.Another patient had recurrent acute rejections (3 episodes)and complicated by transplant glomerulopathy resulting fromminimal change disease and returned to dialysis 24 mo post-transplantation.Chronic allograft nephropathy was responsible for graft failurein the last 3 cases (28, 42, and 60 mo post-transplantation).
Group B.
One patient died of septicemia caused by recurrent bacterialinfections secondary to multiple anal abscesses and fistulae7 mo post-transplantation. Similar to group A, 7 patients returnback to dialysis during the whole follow-up period. Recurrenceof original kidney disease (FSGS and membranoproliferative glomerulonephritis)was responsible for two graft failures, 8 and 43 mo post-transplantation,respectively. De novo glomerulopathy (FSGS) was responsiblefor one graft failure 21 mo post-transplantation. Chronic allograftnephropathy was responsible for graft failure in the last 4cases (19, 44, 57, and 60 mo post-transplantation).
Immunosuppressive Drugs
After the first 3 post-transplant months, mean SRL levels werekept within the targeted therapeutic windows throughout thewhole follow-up period. After the first 2 yr, there was no statisticallysignificant difference of SRL levels between either group asthe targeted window became the same (Figure 3). Subsequently,mean SRL doses were close to each other in both groups. Duringthe fifth year, mean SRL dose was 2.27 ± 1.14 mg/d and2.28 ± 1.11 mg/d in group A and B, respectively.
Figure 3. Sirolimus trough levels (ng/ml) in both groups.
Mean Tac doses and levels were kept within the targeted windowsamong group A patients. Fifth year mean Tac dose value was 2.37± 2.62 mg/d and mean level value was 3.82 ± 1.11ng/ml. Mean MMF doses were progressively reduced over time downto 1.5 ± 0.36 g/d during last follow-up year among groupB patients.
Secondary Immunosuppression
Statistically significant higher change rate of the primaryimmunosuppressive regimen was encountered among group A patientsas shown in Table 2. In 21 patients of group A, Tac was replacedby MMF, in essence cross over to group B, because of biopsy-provenacute Tac toxicity despite optimum level (2 cases), chronictubulointerstitial fibrosis of moderate degree (8 cases), recurrentsevere diarrhea complicated by marked body weight reductionand frequent hospital admissions (6 cases), and uncontrollednewly discovered diabetic state (5 cases).
Table 2. Secondary immunosuppression regimens in both groups
In another 14 patients of the same group, SRL was completelywithdrawn and replaced by either MMF, due to proteinuria (5cases), surgical complications (3 cases), high liver enzymes(1 case), or replaced by azathioprine in one female who wasseeking pregnancy. Two patients were maintained on steroidsand Tac only because of persistent leucopenia despite therapeuticSRL blood level; and finally, 2 patients were maintained onsteroids and MMF because of pulmonary TB.
Among group B patients, MMF was replaced by Tac in 3 patients,in essence cross over to group A, because of persistent leucopeniawith optimum SRL level.
In another 11 patients, SRL was withdrawn and replaced by Tacbecause of proteinuria (3 patients), interstitial pneumonitis(1 case), and intolerance (1 case). In 4 females, SRL and MMFwere replaced by Tac and azathioprine for the sake of gettingpregnant; and finally, 2 patients with pulmonary TB were maintainedon steroids and MMF only.
Graft Function
Based on intention-to-treat analysis, statistically significantbetter renal allograft function was encountered among groupB patients from the second post-transplant year until the lastfollow-up, as measured by calculated glomerular filtration rate(GFR), in comparison with group A (Figure 4).
Figure 4. Graft function based on intention-to-treat analysis (all cases are included) as estimated by calculated GFR (ml/min).
By exclusion of those with secondary immunosuppression (35 ingroup A and 14 in group B), no significant difference of renalfunction was found, although group B patients still have highercalculated GFRs at all time periods (Figure 5).
Figure 5. Graft function based on maintenance of primary immunosuppressive regimen (all cases with secondary immunosuppression are excluded) as estimated by calculated GFR (ml/min).
Histopathologic Findings
No acute rejection episodes were encountered beyond the secondyear of follow-up. Meanwhile, CAN of various degrees was diagnosedamong 11 and 9 patients of group A and B, respectively (Table 3).Two of those with moderate CAN and all of those with markedCAN returned back to dialysis.
On studying the impact of chronic allograft damage index (CADI)obtained from protocol graft biopsies (originally 86 cases)at the end of the first post-transplant year,14 we opted toclassify whole patients of the two groups together into nearlyequal two divisions: those with CADI score equal 0, 1, or 2and those whose the score equals 4, 5, 6, or 7. Table 4 showshigher calculated GFR values among the first group, which approachessignificance at the last follow-up.
Table 4. Impact of CADI score on calculated GFR (ml/min)
Among group B patients, studying the impact of each of the sixelements of the CADI score (mesangial matrix increase, glomerularsclerosis, tubular atrophy, interstitial inflammation, interstitialfibrosis, and vascular intimal proliferation) on subsequentrenal allograft function revealed that interstitial inflammation(which affected 30.2% of group B patients at 1 yr) was the onlyelement found to have significant impact on GFR throughout alltime points after the first year (Table 5).
Table 5. Impact of presence or absence of interstitial inflammation of 1-yr protocol biopsies on subsequent GFR (ml/min) among group B patients
Adverse Events
No significant difference was found regarding the incidenceor the number of antihypertensive medications used in each group,nor in the hematologic complications throughout the follow-upperiod (Table 6). The most significant infectious complicationwas the development of tuberculosis among 6 and 4 patients ingroup A and B, respectively. No significant difference was encounteredregarding the incidence of diabetes mellitus, elevated liverenzymes, osteonecrosis, proteinuria, or surgical complications.Group A shows significant higher incidence of chronic diarrhea,whereas group B shows significant higher incidence of hyperlipidemiaand herpes zoster infection. No single case of malignancy wasdiagnosed in either group.
Based on data of the Organ Procurement and Transplantation Networkand Scientific Registry of Transplant Recipients, which identifiedtrends that have evolved over the past decade in the use ofimmunosuppression for recipients of solid organ transplants,Tac/MMF combination was found to be the most frequently usedmaintenance immunosuppression combination at 1 and 2 yr afterkidney transplantation. At 1 yr after transplantation in 2003,51% of patients were receiving Tac/MMF combination, 17% werereceiving CsA/MMF, 8% Tac/SRL, and only 1% on SRL/MMF combinationregimen. Moreover, a surprisingly low percentage of patientscontinued their original immunosuppressive discharge regimenthrough the first 3 yr following transplantation. Among patientstransplanted in 2001, the change rate for Tac/MMF combinationat 3 yr was 43% and that for SRL/MMF combination was up to 65%.15
We have previously reported on the 2-yr safety and efficacyprofile of SRL/steroids based regimens in combination with eitherlow-dose Tac (group A) or MMF (group B) together with basiliximabinduction therapy among live-donor renal allotransplant recipientsin a prospective randomized study, and it was shown that theSRL/MMF regimen was safe regarding patient and graft survivaland was associated with significant better renal function at2 yr than the Tac/SRL regimen.14 We hereby report on the long-termsafety and efficacy profile of the same randomized patients.
Throughout the follow-up period from the third to fifth year,2 group A patients had sudden death most probably secondaryto cardiovascular cause. During the same period, 3 and 4 patientsin group A and B, respectively, returned back to dialysis mostlysecondary to the development of CAN. Therefore, it was notedthat early causes of death among our patients were infectiousand late causes were cardiovascular, whereas early causes ofgraft failure were mostly the result of recurrent original kidneydisease and transplant glomerulopathy and late causes were theresult of CAN. Slightly lower rates of patient and graft survivalfor the SRL/MMF arm (87.1% and 83.9%, respectively) were obtainedby Flechner et al.16 in a 5-yr prospective randomized studyof either SRL/MMF or CsA/MMF with steroids and basiliximab inductionin adult renal allotransplant recipients.
Our group B patients show significant lower change rate of theprimary immunosuppression compared with group A through thewhole follow-up period, being observed in 14 patients (20.8%),4 of which were seeking pregnancy. This comes in accordancewith Flechner et al.16 about low change rates of primary SRL/MMFregimens. Our main indications for SRL withdrawal, in additionto pregnancy, were development of proteinuria in view of severalrecent reports linking SRL to proteinuria17,18 and tuberculousinfection, leukopenia, and surgical causes. Group A unique indicationsfor change of the primary regimen were mainly related to combinedSRL/Tac nephrotoxicity (e.g., pathologic diagnosis of acuteTac toxicity despite optimum blood level and/or moderate tubulointerstitialfibrosis), GIT toxicity (e.g., chronic diarrhea with markedweight reduction), and presumed islet cell toxicity19 (e.g.,newly discovered difficult controlled diabetes mellitus [DM]).
Based on intention-to-treat analysis, statistically significanthigher renal function obtained at 2 yr among SRL/MMF patients,14was maintained until the last follow-up period, a finding thatcomes in accordance with all short-term12,13,20 and long-termstudies16; however, more recently, Larson et al.,21 in a comparisonof TAC/MMF versus SRL/MMF, showed that the iothalamate clearanceat 1 mo was higher in the SRL/MMF than in the TAC/MMF group(67 ± 18 ml/min versus 58 ± 17 ml/min); however,this difference was lost at 1 yr because of the unexpected lossof GFR in the SRL/MMF group. Differences in renal function betweenLarson's and other studies may be explained by the differentanti-calcineurinic drugs used in the control group because itseems that CsA induces more profound renal hemodynamic changesthan TAC, at least at the current target levels for clinicalimmunosuppression.22
By exclusion of those with secondary immunosuppression, groupA patients could obtain comparable renal function with groupB patients after 5 yr, however, with high exclusion rate thatexceeds 50%.
By classification of patients according to stages of chronickidney diseases,23 it was found that about one half and onethird of SRL/MMF patients enjoyed quite normal renal functionby 3 and 5 yr, respectively.
Among our patients, who are of low to moderate immunologic risk,we reported reduced incidence of acute rejection among groupB patients, in the first post-transplant year down to13.5%,14a finding that comes in accordance with all trials using SRL/MMFwith steroids and induction therapy in which acute rejectionincidence varies from 6.5%,13 to 13%.21 Moreover, even in patientswith high immunologic risk, Lo et al.20 reported 12-mo incidenceof as low as 7%.
At the end of the first post-transplant year, CADI score wasnot significantly different between either group.14 On studyingthe impact of CADI score on the subsequent renal function amongboth groups to define a cut off value, it was found that CADIscores of 0,1or 2 were associated with nearly significant betterrenal function at 5 yr. Moreover, on studying the impact ofeach of the 6 elements of the score24 on eventual renal functionin both groups, interstitial inflammation among group B patients(which affected 30.2% of patients at 1 yr) was the only elementfound to have significant impact on GFR throughout all timepoints after the first year.
The safety profile of both groups has markedly improved afterthe first 2 post-transplant years, as the immunosuppressivedoses were reduced as well as the targeted therapeutic windowof SRL. Therefore, low incidence of hematologic complications,apart from renal impairment induced anemia, and low surgicalcomplications were encountered. Similarly, the incidence ofinfectious complications was low apart from TB, which was encounteredamong 10 cases (7.6%) of our patients. In a previous reporton 1200 renal transplant population from the same locality,the incidence of post-transplant TB infection was 3.8%.25 Ahigher incidence among our series may be explained by the useof more potent immunosuppressive medications, improper pretransplantscreening, new epidemic, or combination of these factors. Early(before 1 yr) and aggressive presentation of TB (miliary form)was associated with higher mortality rates. In view of sucha life-threatening disease, a policy of handling immunosuppressivedrugs among recent cases could show some success, by which allgroup A or group B affected patients were converted to a dualregimen consisting of steroids and MMF so as to reduce net immunosuppressionand avoid drug interactions of SRL and Tac with anti-TB drugs.
No case of solid organ or skin cancer was diagnosed in eithergroup, a finding that supports the hypothesis of Luan et al.,26that SRL might prevent rather than promote tumor progression.
In summary, a calcineurin-inhibitor free immunosuppressive regimen,consisting of steroids, SRL, and MMF together with monoclonalantibody induction therapy, has proven to be both safe and effectiveamong low to moderate immunologic risk renal allotransplantpatients after long-term follow-up. Avoidance of early highchange rates of the regimen could be achieved by proper SRLdosages through strict follow-up of SRL blood levels. SRL administrationshould be delayed in certain patients at increased risk of sideeffects (e.g., high body mass index, delayed graft function).Administration of this regimen among high immunologic risk patientshas proved success on short term, awaiting longer-term follow-up.
Patients
Between May 2001 and January 2003, a total of 132 patients withend-stage renal disease, who received a live donor renal allo-transplantat the Urology and Nephrology Center, Mansoura University, Egypt,were the subjects of this study. Exclusion criteria includedpatients requiring second renal transplantation, patients youngerthan 18 yr, cases with pretransplant chemistries demonstratinga total serum cholesterol greater than 300 mg/dl, triglyceridesgreater than 400 mg/dl, white blood cell count less than 4000/mm3or platelets less than 150 000/mm3, patients with pretransplantpositive lymphocytotoxic cross-match test, and those with morethan 50% DR mismatch.
Immunosuppression Protocol
All patients in both groups received basiliximab (Simulect,Novartis, Basel, Switzerland) 20 mg intravenously at surgeryand on day 4 postoperative. Patients in both groups receivedintravenous methyl prednisolone 500 mg one day before and onday of surgery. Oral prednisolone was then given at a dose of1 mg/kg per day, which is then gradually tapered down to 0.1mg/kg by the 10th mo post-transplantation.
Group A patients received SRL solution (Rapamune, WyethAyerst,Princeton, NJ) within 24 h after completion of surgery in adose of 10 mg/d orally (single morning dose) for 3 d and thenmaintained on 5 mg/d. Further doses were concentration controlledto keep 24 h whole blood trough level between 6 and 12 ng/ml.Tacrolimus (Prograf, Fujisawa Pharmaceutical, Osaka, Japan)was also administered to this group of patients on the thirdday postoperative, provided that creatinine clearance is morethan 50 ml/min. Tacrolimus was started at a dose of 0.03 mg/kgper day in two equally divided doses targeting 12 h whole bloodtrough level of 3 to 7 ng/ml.
Group B patients received SRL and maintained on single oralmorning dose of 10 mg/d targeting 24 h whole blood trough levelbetween 10 and 15 ng/ml. Mycophenolate Mofetil (Cellcept, Hoffman-LaRoche, Nutley, NJ) 1 g twice daily was begun the morning aftersurgery. Patients remained on this dose unless side effects,such as gastrointestinal toxicity or leucopenia, necessitateddose reduction.
No standard antimicrobial prophylaxis therapy was adopted inthis study.
Therapeutic Drug Monitoring
Serum trough levels of SRL were evaluated by high performanceliquid chromatography with mass spectroscopy detection throughthe first 2-yr transplant period, after which the microparticleenzyme immunoassay method was used.27 Two years post-transplantation,SRL trough level was maintained between 5 and 10 ng/ml in bothgroups. Tac trough levels were evaluated using a microparticulateenzyme immunoassay method and maintained between 3 and 7 ng/ml.
Clinical Assessment
The patients were assessed clinically with particular emphasison blood pressure measurement. Hypertension was defined accordingto the JNC vII report.28 The number of antihypertensive drugswas reported for every patient to express severity of hypertension.New-onset DM was defined as post-transplant hyperglycemia necessitatingtreatment with oral hypoglycemic agents or insulin injections.Clinical tolerance to the given medications was assessed, whichincluded the safety profile and the occurrence of any adverseevents.
Laboratory Investigations
These included complete urine analysis, serum electrolytes,liver function tests, fasting blood sugar, uric acid, calcium,phosphorus, complete lipid profile, and hematologic profile.Renal allograft function was evaluated by the estimation ofserum creatinine and calculated GFR using the Cockroft-Gaultformula.29
Evaluation of Graft Biopsies
Event (for cause) biopsy was carried out in case of nephroticrange proteinuria or episodes of renal dysfunction (25% increasein creatinine from baseline) for which histopathologic examinationwas performed according to the Banff Schema (1997).30
Study Outcomes
The study outcomes consisted of efficacy profiles, toxicityprofiles, and renal allograft pathology profiles. The efficacyprofiles were patient and graft survival, biopsy-confirmed acuterejection episodes, and graft function. The toxicity profilesincluded serious adverse events, malignancies, infections, woundcomplications, and metabolic complications. Renal allograftpathology was evaluated using the Banff schema (1997) for eventbiopsies.
Statistical Analysis t test was used to compare between the two groups in continuousdata. 2 was used to compare categorical variables. The survivalof the patients and the grafts was computed using the Kaplan-Meiermethod31 on an intention-to-treat basis. Differences in survivalwere calculated by the log-rank test.32 For all of the abovetests, a P value 0.05 was considered as significant.
Remuzzi G, Bertani T: Renal vascular and thrombotic effects of cyclosporine.
Am J Kidney Dis 13
: 261
–272, 1989[Medline]
Bennett WM, Houghton DC, Buss WC: Cyclosporine-induced renal dysfunction: Correlations between cellular events and whole kidney function.
J Am Soc Nephrol 1
: 1212
–1219, 1991[Abstract]
Nankivell BJ, Borrows RJ, Fung CL, O'squosquo; apos; yConnell PJ, Allen RD, Chapman JR: The natural history of chronic allograft nephropathy.
N Engl J Med 349
: 2326
–2333, 2003[Abstract/Free Full Text]
Ducloux D, Fournier V, Bresson-Vautrin C, Rebibou JM, Billerey C, Saint-Hiller Y, Chalpoin JM: Mycophenolate mofetil in renal transplant recipients with cyclosporine-associated nephrotoxicity: A preliminary report.
Transplantation 65
: 1504
–1506, 1998[CrossRef][Medline]
Hueso M, Bover J, Seron D, Gil-Vernet S, Sabate I, Fulladosa X, Ramos R, Coll O, Alsina J, Grynio JM: Low-dose cyclosporine and mycophenolate mofetil in renal allograft recipients with suboptimal renal function.
Transplantation 66
: 1727
–1731, 1998[CrossRef][Medline]
Keunecke C, Rothenpieler U, Zanker B, Schneeberger H, Illner WD, Theodorakis J, Stangl M, Land W: Mycophenolate mofetil monotherapy: an example of a safe nephrotoxicity/atherogenicity-free immunosuppressive maintenance regimen in a selected group of kidney-transplanted patients.
Transplant Proc 32
[Suppl]: S6
–S8, 2000[CrossRef][Medline]
Schrama YC, Joles JA, van Tol A, Boer P, Koomans HA, Hene RJ: Conversion to mycophenolate mofetil in conjunction with stepwise withdrawal of cyclosporine in stable renal transplant recipients.
Transplantation 69
: 376
–383, 2000[CrossRef][Medline]
Vincenti F, Ramos E, Brattstrom C, Cho S, Ekberg H, Grinyo J, Johnson R, Kuypers D, Stuart F, Khanna A, Navarro M, Nashan B: Multicenter trial exploring calcineurin inhibitors avoidance in renal transplantation.
Transplantation 71
: 1282
–1287, 2001[CrossRef][Medline]
Tran HT, Acharya MK, McKay DB, Sayegh MH, Carpenter CB, Auchincloss HJR, Kirkman RL, Milford EL: Avoidance of cyclosporine in renal transplantation: Effects of daclizumab, mycophenolate mofetil, and steroids.
J Am Soc Nephrol 11
: 1903
–1909, 2000[Abstract/Free Full Text]
Groth CG, Backman L, Morales JM: Sirolimus (rapamycin)-based therapy in human renal transplantation: similar efficacy and different toxicity compared with cyclosporine: Sirolimus European Renal Transplant Study Group.
Transplantation 67
: 1036
–1042, 1999[Medline]
Kreis H, Cisterne JM, Land W: Sirolimus in association with mycophenolate mofetil induction for the prevention of acute graft rejection in renal allograft recipients.
Transplantation 69
: 1252
–1260, 2000[CrossRef][Medline]
Flechner SM, Goldfarb D, Modlin C, Feng J, Krishnamurthi V, Mastorianni B, Savas K, Cook DJ, Novick AC: Kidney transplantation without calcineurin inhibitor drugs: A prospective randomized trial of sirolimus versus cyclosporine.
Transplantation 74
: 1070
–1076, 2002[CrossRef][Medline]
Hamdy AF, El-Agroudy A, Bakr MA, Mostafa A, El-baz M, El-Shahawy M, Ghoneim MA: Comparison of sirolimus with low-dose tacrolimus versus sirolimus-based calcineurin inhibitor-free regimen in live donor renal transplantation.
Am J Transplant 5
: 2531
–2538, 2005[CrossRef][Medline]
Meier-Kriesche HU, Li S, Gruessner RW, Fung JJ, Bustami RT, Barr ML, Leichtman AB: Immunosuppression: Evolution in practice and trends, 1994–2004.
Am J Transplant 6
: 1111
–1131, 2006[CrossRef][Medline]
Flechner S, Goldfarb D, Solez K, Modlin C, Mastroianni B, Savas K, Babineau D, Kurian S, Salomon D, Novick A, Cook DJ: Kidney transplantation with sirolimus and mycophenolate mofetil-based immunosuppression: 5-year results of a randomized prospective trial compared to calcineurin inhibitor drugs.
Transplantation 83
: 883
–892, 2007[CrossRef][Medline]
Diekmann F, Gutierrez-Dalmau A, Lopez S, Cofan F, Esforzado N, Ricart MJ, Rossich E, Saval N, Torregrosa J, Oppenheimer F, Campistol JM: Influence of sirolimus on proteinuria in de novo kidney transplantation with expanded criteria donors: Comparison of two CNI-free protocols.
Nephrol Dial Transplant 22
: 2316
–2321, 2007[Abstract/Free Full Text]
Stephany B, Augustine J, Krishnamurthi V, Goldfarb D, Flechner S, Braun W, Hricik D, Dennis V, Poggio E: Differences in proteinuria and graft function in de novo sirolimus-based vs. calcineurin inhibitor-based immunosuppression in live donor kidney transplantation.
Transplantation 82
: 368
–374, 2006[Medline]
Hricik DE, Anton HA, Knauss TC, Rodriguez V, Seaman D, Siegel C, Valente J, Schulak JA: Outcomes of African American kidney transplant recipients treated with sirolimus, tacrolimus and corticosteroids.
Transplantation 74
: 189
–193, 2002[CrossRef][Medline]
Lo A, Egidi MF, Gaber L, Amiri H, Vera S, Nezakatgoo N, Gaber O: Comparison of sirolimus-based calcineurin inhibitor-sparing and calcineurin inhibitor-free regimens in cadaveric renal transplantation.
Transplantation 77
: 1228
–1235, 2004[CrossRef][Medline]
Larson TS, Dean PG, Stegall MD, Griffin MD, Textor SC, Schwab TR, Gloor JM, Cosio FG, Lund WJ, Kremers WK, Nyberg SL, Ishitani MB, Prieto M, Velosa JA: Complete avoidance of calcineurin inhibitors in renal transplantation: A randomized trial comparing sirolimus and tacrolimus.
Am J Transplant 6
: 514
–522, 2006[CrossRef][Medline]
Klein IH, Abrahams A, van Ede T, Hene RJ, Koomans HA, Ligtenberg G: Different effects of tacrolimus and cyclosporine on renal hemodynamics and blood pressure in healthy subjects.
Transplantation 73
: 732
–736, 2002[Medline]
National Kidney Foundation: K/DOQI clinical practice guidelines for chronic kidney disease: Evaluation, classification and stratification.
Am J Kidney Dis 39
[Suppl 1]: S1
–S266, 2002[CrossRef][Medline]
Isoniemi HM, Krogerus I, Von Willebrand E, Taskinen E, Ahonen J, Hayry P: Histopathological findings in well-functioning, long term renal allografts.
Kidney Int 41
: 155
–160, 1992[Medline]
El-Agroudy A, Refaie A, Moussa O, Ghoneim M: Tuberculosis in Egyptian kidney transplant recipients: Study of clinical course and outcome.
J Nephrol 16
: 404
–411, 2003[Medline]
Luan FL, Hojo M, Maluccio M, Yamaji K, Suthanthiran M: Rapamycin blocks tumour progression: Unlinking immunosuppression from antitumour efficacy.
Transplantation 73
: 1565
–1572, 2002[CrossRef][Medline]
Wilson DH, Book B, Brunet M, Engelmayer J, Gaulier JM, Luthe H, Marquet P, Moscato D, Mosso R, Oellerich M, Pescovitz M, Ramanathan L, Schmid R, Stickle D, Sarkozi L, Wallemacq P: Multicenter evaluation of an immunoassay for the measurement of sirolimus on the Abbott IMx analyzer.
Transplantation 78
[Suppl 1]: 477
–478, 2004
Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL Jr, Jones DW, Materson BJ, Oparil S, Wright JT Jr, Roccella EJ: The Seventh Report Joint National Committee on Prevention, Detection Evaluation and Treatment of High Blood Pressure: The JNC 7 Report.
JAMA 289
: 2560
–2572, 2003[Abstract/Free Full Text]
Cockroft DW, Gault MH: Prediction of creatinine clearance from serum creatinine.
Nephron 16
: 1227
–1236, 1976
Top
Abstract
Introduction
2 was used to compare categorical variables. The survival of the patients and the grafts was computed using the Kaplan-Meier method31 on an intention-to-treat basis. Differences in survival were calculated by the log-rank test.32 For all of the above tests, a P value 
0.05 was considered as significant. 
