The rate of infection-related TEAEs was significantly higher at 24 months after SRL conversion (77.5% vs. 67.0%, P=0.002). These events included pneumonia, acne, presumptive herpes simplex, fever, and aphthous stomatitis, and stomatitis both of presumed infectious origin (Table 3). The higher infection rate in SRL conversion patients occurred primarily during the first few months after randomization. Specifically, between 0 and 6 months rates were significantly higher (59.3% vs. 39.6%, SRL conversion vs. CNI continuation, respectively, P<0.001); thereafter, rates were nearly identical through 24 months (58.8% vs. 56.4%, respectively, P=0.549).
The incidence of stomatitis was significantly higher for SRL conversion versus CNI continuation from randomization through 24 months (34.1% vs. 9.9%, P<0.001). However, most events were reported during the first 6 months (29.6% vs. 3.7%, P<0.001); from 6 through 24 months, stomatitis rates for SRL conversion patients were markedly lower (4.5%) and numerically lower versus CNI continuation (6.2%, P=0.315).
Overall malignancy rates, including the incidence of skin carcinomas, were significantly lower in SRL conversion versus CNI continuation through 24 months (ITT analysis, P<0.001, Table 3); the incidence was also significantly lower when patients with a prior history of malignancy at baseline were excluded (2.8% vs. 8.0%, P=0.002).
Of 743 patients randomized with baseline GFR more than 40 mL/min, baseline UPr/Cr was reported for 620 patients (74.7%). Mean and median UPr/Cr values for patients remaining on therapy are shown in Table 4. Baseline mean and median UPr/Cr values were similar between SRL conversion and CNI continuation patients. After randomization, these values increased among SRL conversion compared with CNI continuation patients (Table 4), primarily between baseline and 6 months, whereas median values were only slightly above the upper limit of normal (≤0.2). A categorical analysis stratified by baseline UPr/Cr showed that among SRL conversion and CNI continuation patients with UPr/Cr less than or equal to 0.2 at baseline, 72.9% and 87.3%, respectively, had UPr/Cr less than or equal to 0.5 at 24 months; among those with baseline UPr/Cr more than 1.0, a higher percentage of SRL conversion patients had UPr/Cr more than 1.0 at 24 months (66.7% vs. 57.1%, respectively, P<0.001 for stratified analysis). An unstratified analysis among patients with baseline and month 24 UPr/Cr revealed a significantly lower percentage of SRL conversion than CNI continuation patients had UPr/Cr less than or equal to 0.5 at 24 months (64.2% vs. 78.8%, respectively) and a higher percentage had UPr/Cr more than 1.0 (20.9% vs. 10.3%, respectively; P=0.001).
Mean on-therapy fasting lipid profiles were similar between groups at baseline. At one month, baseline-adjusted mean fasting serum total cholesterol levels were significantly higher among SRL conversion patients, peaking at month 2, then declining through month 24 such that corresponding differences between groups decreased from 1.31 mmol/L to 0.96 mmol/L (50.7 mg/dL to 33.3 mg/dL). Similar patterns were observed for low- and high-density lipoprotein cholesterol. At 24 months, adjusted mean low-density lipoprotein levels remained significantly higher (3.19 vs. 2.63 mmol/L), as did those for high-density lipoprotein (1.43 and 1.32 mmol/L, SRL conversion and CNI continuation, respectively [both P<0.001]). A similar pattern was observed for fasting triglyceride levels; at 24 months, adjusted mean values were 2.61 versus 1.77 mmol/L (SRL conversion vs. CNI continuation, respectively, P<0.001). In the GFR more than 40 mL/min stratum, fasting lipid profiles were similar to those for the overall treatment groups (data not shown).
A higher percentage of SRL conversion versus CNI continuation patients received lipid-lowering therapy; at 24 months, rates were 77.7% and 54.6%, respectively (P<0.001). The most frequently prescribed drugs were HMG-CoA reductase inhibitors (74.4% and 50.9%, SRL conversion and CNI continuation patients, respectively, P<0.001).
Mean hemoglobin concentrations were similar between groups at baseline but decreased after SRL conversion and remained significantly lower from 1 to 6 months. Thereafter, the differences were no longer significant; at 24 months, mean hemoglobin concentrations were 131.9 and 132.0 g/L (SRL conversion and CNI continuation, respectively, P= 0.955). Erythropoietic drug use was similar at baseline (4.7% and 4.8%, SRL conversion and CNI continuation, respectively), increased after SRL conversion to 14.7% at month 8, then remained relatively stable to 24 months (12.7% vs. 5.6% for CNI continuation).
Systolic blood pressure was significantly lower among SRL conversion patients at month 1 (132.4 vs. 135.5 mm Hg, P=0.008), as was diastolic blood pressure at 1, 2, 3 (P<0.001), and 19 (P=0.041) months after conversion. At 24 months, mean systolic blood pressure was 132 mm Hg in both groups (P=0.922); mean diastolic blood pressure was 79.9 and 80.9 mm Hg for SRL conversion and CNI continuation patients, respectively (P=0.225).
This is the first large, prospective, randomized, clinical trial assessing the safety and efficacy of converting maintenance renal allograft recipients from CNI- to SRL-based immunosuppression. The protocol eligibility criteria were designed to be broadly inclusive (patient age, 13 to 75 years; time since transplantation, 5 to 162 months; baseline GFR, 20 to more than 80 mL/min; preexisting histopathology, ranging from no CAN to severe [grade III] disease; no exclusion for de novo or recurrent glomerular disease and CNI toxicity).
The study results at 1 and 2 years showed no significant differences in primary safety outcomes. Enrollment in the GFR 20 to 40 mL/min stratum was halted prematurely, however, because of a higher incidence of safety endpoints among the SRL conversion patients in this stratum.
ITT analysis of the primary efficacy endpoint—change from baseline Nankivell GFR one year after randomization—failed to demonstrate a statistically significant advantage to SRL conversion over CNI continuation. This lack of difference may be partly attributable to the broad spectrum of severity of preexisting renal parenchymal injury in the study population. Additionally, the stabilization or improvement in renal function observed among CNI continuation patients was unexpected, an observation attributable to the closer monitoring of renal function and CNI blood levels than might otherwise have been the case had they not been participating in a controlled, clinical trial.
The 40-mL/min cutoff for the prospectively defined baseline GFR stratum was based on the consensus recommendation of participating study investigators and was intended to distinguish patients whom they considered more or less likely to benefit from conversion to SRL-based immunosuppression. Nonetheless, the higher baseline GFR stratum still included patients with a broad spectrum of preexisting injury and levels of residual renal function and diverse comorbid conditions and causes of end-stage renal disease, some of which had recurred before enrollment in this study. Thus, it is not surprising that some patients benefited from conversion, whereas others did not. Although ITT analyses failed to show a significant improvement for GFR more than 40-mL/min stratum, a subset of SRL conversion patients did show improvement from baseline GFR, as demonstrated by the retrospectively defined binary outcome analysis of clinically meaningful GFR improvements for the overall stratum (Fig. 3A) and for the subgroup with baseline UPr/Cr less than or equal to 0.11 (Fig. 3B). Moreover, patients who continued to receive SRL as assigned therapy showed significantly greater improvements in renal function that persisted from 12 through 24 months after conversion (Fig. 2).
The post hoc multiple regression analysis showed a significant interaction between baseline urinary protein excretion and SRL conversion. Accordingly, in the SRL conversion subgroup with baseline GFR more than 40 mL/min and UPr/Cr less than or equal to 0.11, the change in baseline-adjusted GFR was greater at 12 months than in the corresponding subgroup of CNI continuation patients and at a level (6 mL/min) that was both statistically significant and clinically important. Further, this significant treatment difference persisted through 24 months of follow-up at a level approaching 5 mL/min. Finally, in this subset of 297 patients, representing 40% of all patients with baseline GFR more than 40 mL/min, the safety profiles were similar for SRL conversion and CNI continuation. However, even in this subset, proteinuria increased and to a much greater extent than in those who remained on CNIs. The reasons for this may be hemodynamic but also may reflect podocyte injury and antagonism of vascular endothelial growth factor associated with SRL (12, 13).
Among patients converted to SRL, the pattern of adverse events was consistent with the known safety profile of SRL. During the first 6 months after randomization, a significantly higher rate of investigator-reported TEAEs was observed in SRL conversion versus CNI continuation patients that did not continue during the ensuing 18 months of follow-up (Fig. 4). This early imbalance was most likely attributable to the fact that subjects randomly assigned to SRL conversion underwent a major change in immunosuppression, whereas those allocated to CNI continuation did not. Significantly fewer treatment-emergent malignancies were reported after SRL conversion, a finding that emerged early in the study and persisted through 24 months. Others have reported similar findings in SRL-treated patients (6, 14). Although the reasons for this difference are not known, it may be speculated that the similarity in observed AR rates between CNI continuation and SRL conversion cohorts, and the slightly higher rates of infection after SRL conversion, suggest that the difference in malignancies is more consistent with a mammalian target of rapamycin-specific effect on tumor biology than a reduction in net immunosuppression.
An unexpected finding in this study was the development of de novo proteinuria and progression of preexisting proteinuria after SRL conversion. Patients enrolled with more severe renal parenchymal injury (i.e., higher UPr/Cr) were more likely to experience (death-censored) graft loss or death. Moreover, in both treatment groups, graft loss after randomization was associated with significantly higher baseline UPr/Cr and significantly lower baseline GFR. These findings are consistent with earlier studies in which lower GFR (15) and abnormally increased urinary protein excretion (16) were shown to be risk factors for increased morbidity and mortality in renal allograft recipients. Further, conversion has been shown to be more successful in patients with less proteinuria at baseline (17). To the extent that proteinuria and reduced GFR are surrogate markers for renal parenchymal injury, those patients with the greatest degree of preexisting injury appeared to be at higher risk for suffering further damage, regardless of whether they underwent conversion to SRL. In this regard, patients in the subgroup with baseline GFR more than 40 mL/min and UPr/Cr less than or equal to 0.11 showed substantially less of an increment in UPr/Cr after SRL conversion, had significantly better renal function, and experienced fewer investigator-reported TEAEs, deaths, and graft losses than did the overall SRL conversion cohort. Thus, the overall safety profile associated with conversion from CNI- to SRL-based immunosuppression appears to be more favorable when conversion is initiated before or at an early stage in the progression of chronic renal allograft damage (GFR more than 40 mL/min and normal urinary protein excretion). Whether or not conversion can be accomplished safely and effectively in patients with higher UPr/Cr must await further study.
In conclusion, patients with more severely injured renal allografts were less capable of tolerating this major change in immunosuppression than those with healthier transplants at the time of conversion. These observations support the argument for conversion from CNI-based immunosuppression to SRL before a renal allograft has sustained substantial, permanent renal parenchymal injury, as imputed by decreasing GFR and the development of a persistent pattern of proteinuria. The results from this clinical trial suggest the target population for conversion should be those with baseline GFR more than 40 mL/min and urinary protein excretion that is well within normal limits.
The authors recognize Christine Innes (Wyeth Research, Collegeville, PA) and Karine Rutault (Wyeth Research, Paris, France) for their contributions to study coordination and data review; Bernadette Maida (Wyeth Research, Collegeville, PA) for her contribution to study design and data review; and Susan A. Nastasee (Wyeth Research, Collegeville, PA) for assistance in preparation of the manuscript.
The members of Sirolimus CONVERT Trial Study group are as follows: J. Alberu, Instituto Nacional de Ciencias, Mexico City, Mexico; R.R. Alloway, University Hospital, Cincinnati, OH; E. Ancona, Clinica Chirurgica General III, University of Padua, Padua, Italy; M. Arias, Hospital Marques de Valdecilla, Santander, Spain; P. Bachleda, Fakultni Nemocnice, Olomouc, Czech Republic; J.A. Bertolatus, University of Iowa Hospitals and Clinics, Iowa City, IA; J.L. Bosmans, University Hospital Antwerpen, Edegem, Belgium; B. Bourbigot, CHU La Cavale Blanche, Brest, France; D.C. Brennan, Washington University School of Medicine, St. Louis, MO; K. Brinker [deceased], Dallas Transplant Institute, Dallas, TX; S. Campbell, Princess Alexandra Hospital, Wooloongabba, Australia; J.M. Campistol, Hospital Clinic i Provincial, Barcelona, Spain; D.B. Monteiro de Carvalho, Hospital Geral de Bonsucesso, Rio de Janeiro, Brazil; J.A. Castillo-Lugo, Dallas Transplant Institute, Dallas, TX; S. Cho, Boston Medical Center, Boston, MA; S. Cockfield, University of Alberta Hospitals, Edmonton, Alberta, Canada; D.J. Cohen, Columbia University Medical Center, New York NY; D.J. Conti, Albany Medical Center, Albany, NY; F.L. de Carvalho Contieri, Hospital Universitario Evangelico de Curitiba, Curitiba, Brazil; F.G. Cosio, Rochester Methodist Hospital, Rochester, MN; P. Daloze, Hopital Notre Dame, Montreal, Quebec, Canada; M. Davalos Michel, CEMIC, Buenos Aires, Argentina; C.L. Davis, University of Washington Medical Center, Seattle, WA; D. del Castillo, Hospital Universitario Reina Sofia, Cordoba, Spain; M. del Carmen Rial, Instituto de Nefrologia, Buenos Aires, Argentina; H. Diliz, Centro Medico Nacional 20 de Noviembre, Colonia del Valle, Mexico; J. Dominguez, Hospital Dr. Sotero del Rio, Santiago, Chile; D. Durand, Hopital Rangueil, Toulouse, France; F. Egidi, Methodist University Hospital, Memphis, TN; J. Eris, Royal Prince Alfred Hospital, Camperdown, Australia; B. Fellstrom, Njurmedicinska Kliniken, Uppsala, Sweden; A. Flores, Hospital de Especialidades Num. 1 Leon, Guanajuato, Mexico; L. Gaite, Clinica de Nefrologia y Urologia y Sante Fe, Argentina; V.D. Garcia, Santa Casa de Porto Alegre, Porto Alegre, Brazil; M Glyda, Szpital Wojewodzki, Poznan, Poland; I. Gonzalez, Hospital Fray Junipero Serra ISSSTE de Tijuana, Tijuana Baja California, Mexico; J.M. Gonzalez Posada, Hospital Universitario de Canarias–La Laguna, Sta. Cruz de Tenerife, Spain; P.F. Gores, Carolinas Medical Center, Charlotte, NC; M.V. Govani, Clarian Health Partners, Indiana University School of Medicine, Indianapolis, IN; C. Gracida, Hospital de Especialidades Centro Medico Nacional Siglo XXI, Mexico; J.M. Grinyo, C.S.U. Bellvitge, Barcelona, Spain; G.C. Groggel, University of Nebraska Medical Center, Omaha, NE; J Halkett, Groote Schuur Hospital, Cape Town, South Africa; K. Hamawi, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia; A Holm, Hospital General Centro Medico Nacional La Raza, Mexico; I. Houde, Centre Hospitalier Univerisitaire de Quebec, Quebec, Quebec, Canada; D.E. Hricik, University Hospitals of Cleveland, Cleveland, OH; B. Hutchison, Sir Charles Gairdner Hospital, Nedlands, Australia; R. Jaramillo, Hospital Regional 1 de Octubre, Mexico; T.D. Johnston, University of Kentucky, Lexington, KY; J.F Juarez, Hospital de Especialidades 71 IMSS, Torreón Coahuila, Mexico; J. Kanellis, Monash Medicla Centre, Clayton, Australia; M. Klinger, Akademia Medyczna we Wroclawiu, Wroclaw, Poland; G. Knoll, Ottawa Hospital, Ottawa, Ontario, Canada; B. Kraemer, Klinikum der Universitat Regensburg, Regensburg, Germany; H. Kreis, Hopital Necker, Paris, France; M.R. Laftavi, Buffalo General Hospital, Buffalo, NY; D. Landsberg, St. Paul’s Hospital, Vancouver, British Columbia, Canada; C. Legendre, Hopital Saint-Louis, Paris, France; M. Lorber, Yale-New Haven Hospital, New Haven, CT; F-L. Luan, University of Michigan Hospital, Ann Arbor, MI; D. Ludwin, St. Joseph’s Healthcare, Hamilton, Ontario, Canada; E.C. Maggiora, Sanatorio de la Trinidad Mitre, Buenos Aires, Argentina; E. Mancilla, Instituto Nacional de Cardiologia, Tlalpan, Mexico; R. Manfro, Hospital das Clinicas de Porto Alegre, Porto Alegre, Brazil; R. Mann, UMDNJ/Robert Wood Johnson University Hospital, New Brunswick, NJ; P.U. Massari, Hospital Privado-Centro Medico de Cordoba, Cordoba, Argentina; A.J. Matas, Fairview University Medical Center, Minneapolis, MN; G. Mayer, Universitatsklinik fur Innere Medizin, Innsbruck, Austria; J. Morales, Clinica Las Condes, Santiago, Chile; J.M. Morales, Hospital 12 de Octubre, Madrid, Spain; A. Mota, Hospitais da Univerisdade de Coimbra, Coimbra, Portugal; N. Muirhead, London Health Sciences Centre, London, ON, Canada; S. Naicker, Johannesburg Hospital, Parktown, South Africa; G. Nanni, Cattedra di Chirurgia Sostitutiva e dei Trapianti, Rome, Italy; I.L. Noronha, Hospital Sao Joaquim da Beneficencia Portuguesa, Sao Paulo, Brazil; R. Oberbauer, Allgemeines Krankenhaus der Stadt Wien, Wien, Austria; P.J. O’Connell, Westmead Hospital, Westmead, Australia; S.A. Ojeda, Centro Médico Nacional de Occidente, Hospital de Pediatria, Guadalajara, Jalisco, Mexico; M. Ostrowski, Klinika Chirurgii Ogolnej i Transplantacyjnej Pomorskiej, Szczecin, Poland; L. Paczek, Klinica Immunologii, Warszawa, Poland; S. Palekar, Newark Beth Israel Medical Center, Newark, NJ; G.E. Palti, Hospital Aleman, Buenos Aires, Argentina; M.D. Pascoe, Groote Schuur Hospital, Cape Town, South Africa; J. Paul, Hospital Miguel Servet, Zaragoza, Spain; J.R. Pinto, Hospital Curry Cabral, Lisboa, Portugal; C. Ponticelli, Ospedale Maggiore di Milano, Milano, Italy; B. Pussell, Prince of Wales Hospital, Randwick, Australia; P.R. Rajagopalan, Medical University of South Carolina, Charleston, SC; R. Reyes, Clinica San Cosme, Aguascalientes, Mexico; D. Roth, University of Miami/Jackson Memorial Medical Center, Miami, FL; G. Russ, Queen Elizabeth Hospital, Woodville, Australia; J. Cavaliere Sampaio, Hospital Universitario Pedro Ernesto, Rio de Janeiro, Brazil; J. Sanchez-Plumed, Hospital Universitario La Fe, Valencia, Spain; F.P. Schena, Univeristy of Bari, Policlinico, Bari, Italy; R.O. Schiavelli, Hospital General de Agudos Dr. Cosme Argerich, Buenos Aires, Argentina; S. Schwartz-Sorensen, Nefrologisk afdelning, Kobenhavn, Denmark; N. Shah, Saint Barnabas Medical Center, Livingston, NJ; A. Shoker, St. Paul’s Hospital, Saskatoon, Saskatchewan, Canada; H. Tedesco Silva, Jr., Hospital do Rim e Hipertensao-Fundacao Oswaldo Ramos, Sao Paulo, Brazil; J.P. Squifflet, University Hospital St. Luc, Brussels, Belgium; S. Steinberg, Sharp Memorial Hospital, San Diego, CA; B. Suwelack, Medizinische Klinik und Poliklinik D Universitatsklinikum Muenster, Muenster, Germany; A. Vathsala, Singapore General Hospital, Singapore, Singapore; J. Vella, Maine Medical Center, Portland, ME; S. Vitko, IKEM Transplantcenter, Prague, Czech Republic; R. Wali, University of Maryland Medical System, Baltimore, MD; R. Walker, Royal Melbourne Hospital, Parkville, Australia; S. Weinstein, Lifelink Transplant Institute, Tampa, FL; J. Welchel, Piedmont Hospital, Atlanta, GA; J.A. Yamamoto, Hospital de Pediatria del Centro Medico Nacional Siglo XXI, Mexico; H.C. Yang, Pinnacle Health Systems, Harrisburg Hospital, Harrisburg, PA; M. Zand, University of Rochester-Strong Memorial Hospital, Rochester, NY.
1. Meier-Kriesche HU, Schold JD, Kaplan B. Long-term renal allograft survival: Have we made significant progress or is it time to rethink our analytic and therapeutic strategies? Am J Transplant
2004; 4: 1289.
2. Nankivell BJ, Borrows RJ, Fung CL, et al. The natural history of chronic allograft nephropathy. N Engl J Med
2003; 349: 2326.
3. Paul LC. Chronic allograft nephropathy: An update. Kidney Int
1999; 56: 783.
4. Sehgal SN. Rapamune (RAPA, rapamycin, sirolimus
): Mechanism of action immunosuppressive effect results from blockade of signal transduction and inhibition of cell cycle progression. Clin Biochem
1998; 31: 335.
5. Terada N, Lucas JJ, Szepesi A, et al. Rapamycin blocks cell cycle progression of activated T cells prior to events characteristic of the middle to late G1 phase of the cycle. J Cell Physiol
1993; 154: 7.
6. Campistol JM, Eris J, Oberbauer R, et al. Sirolimus
therapy after early cyclosporine withdrawal reduces the risk for cancer in adult renal transplantation. J Am Soc Nephrol
2006; 17: 581.
7. Gonwa TA, Hricik DE, Brinker K, et al.; Sirolimus
Renal Function Study Group. Improved renal function in sirolimus
-treated renal transplant patients after early cyclosporine elimination. Transplantation
2002; 74: 1560.
8. Mota A, Arias M, Taskinen EI, et al. Sirolimus
-based therapy after early cyclosporine withdrawal results in significantly better renal histology and function at 3 years following kidney transplantation
. Am J Transplant
2004; 4(suppl 8): 566.
9. Oberbauer R, Hutchison B, Eris J, et al. Three-year assessment of health-related quality of life in sirolimus
-treated kidney transplant patients after cyclosporine elimination. Am J Transplant
2003; 3(suppl 5): 215.
10. Oberbauer R, Segoloni G, Campistol JM, et al. Early cyclosporine withdrawal from a sirolimus
-based regimen results in better renal allograft survival and renal function at 48 months after transplantation. Transpl Int
2005; 18: 22.
11. Racusen LC, Solez K, Colvin RB, et al. The Banff 97 working classification of renal allograft pathology. Kidney Int
1999; 55: 713.
12. Izzedine H, Brocheriou I, Frances C. Post-transplantation proteinuria and sirolimus
. N Engl J Med
2005; 353: 2088.
13. Mathieson PW. How much VEGF do you need [comment]? J Am Soc Nephrol
2006; 17: 602.
14. Kauffman HM, Cherikh WS, Cheng Y, et al. Maintenance immunosuppression
with target-of-rapamycin inhibitors is associated with a reduced incidence of de novo malignancies. Transplantation
2005; 80: 883.
15. Meier-Kriesche HU, Baliga R, Kaplan B. Decreased renal function is a strong risk factor for cardiovascular death after renal transplantation. Transplantation
2003; 75: 1291.
16. Roodnat JI, Mulder PG, Rischen-Vos J, et al. Proteinuria after renal transplantation affects not only graft survival but also patient survival. Transplantation
2001; 72: 438.
17. Diekmann F, Budde K, Oppenheimer F, et al. Predictors of success in conversion from calcineurin inhibitor
in chronic allograft dysfunction. Am J Transplant
2004; 4: 1869.
Keywords:© 2009 Lippincott Williams & Wilkins, Inc.
Sirolimus; Immunosuppression; Calcineurin inhibitor; Kidney transplantation