American Journal of Transplantation 2013; 13: 3155–3163 Wiley Periodicals Inc.
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Copyright 2013 The American Society of Transplantation and the American Society of Transplant Surgeons doi: 10.1111/ajt.12481
Planned Randomized Conversion From Tacrolimus to Sirolimus-Based Immunosuppressive Regimen in De Novo Kidney Transplant Recipients H. T. Silva Jr.1,*, C. R. Felipe1, V. D. Garcia2, E. D. Neto3, M. A. Filho4, F. L. C. Contieri5, D. D. B. M. de Carvalho6 and J. O. M. Pestana1 1
Nephrology Division, Hospital do Rim, Federal University of Sa~o Paulo, Brazil 2 Kidney and Pancreas Transplant Unit, Santa Casa de Misericordia, Porto Alegre, Brazil 3 Renal Transplant Service, Hospital das Clı´nicas, ~ Paulo School of Medicine, Sa~o Paulo, University of Sao Brazil 4 Instituto de Urologia e Nefrologia and Medical School~ Jose´ do Rio Preto, Sa~o FAMERP/HB-FUNFARME, Sao Paulo, Brazil 5 Renal Transplant Unit, Hospital Universita´rio Evange´lico de Curitiba, Curitiba, Parana, Brazil 6 Nephrology Service, Bonsucesso General Hospital, Rio de Janeiro, Brazil Corresponding author: Helio Tedesco Silva Jr., [email protected] Planned conversion from tacrolimus to sirolimus was evaluated in de novo kidney transplant recipients. In this multicenter, randomized, open-label study, 297 patients were initially treated with tacrolimus, mycophenolate sodium and prednisone. Of the 283 patients reaching 3 months, 97 were converted to sirolimus (SRL), 107 were maintained on tacrolimus (TAC) and 79 were patients receiving TAC without criteria to undergo intervention at month 3 (TACex). The primary objective was to show superior estimated glomerular filtration rate (eGFR) in the SRL group at month 24. Of the 258 patients who completed 24 months, 91 (94%) were in the SRL group, 101 (94%) in the TAC group and 66 (84%) in the TACex group. In the intention-to-treat population there were no differences in eGFR (66.2 25.3 vs. 70.7 25.1, p ¼ 0.817) or in the severity of chronic sclerosing lesions scores in 24-month protocol biopsies. Higher mean urinary protein-tocreatinine ratio (0.36 0.69 vs. 0.15 0.53, p ¼ 0.03) and higher incidence of treated acute rejection between months 3–24 (13.4% vs. 4.7%, p ¼ 0.047) were observed in SRL compared to TAC group. In this population planned conversion from TAC to SRL 3 months after kidney transplantation was not associated with improved renal function at 24 months. Keywords: Conversion, kidney transplantation, sirolimus, tacrolimus
Abbreviations: BCAR, biopsy-confirmed acute rejection; CMV, cytomegalovirus; CNi, calcineurin inhibitor; eGFR, estimated glomerular filtration rate; MPS, mycophenolate sodium; mTORi, mammalian target of rapamycin inhibitor; Pred, prednisone; SRL, sirolimus; TAC, tacrolimus; TACex, patients receiving TAC without criteria to undergo intervention at month 3 Received 29 March 2013, revised and accepted for publication 19 August 2013
Introduction Early conversion from calcineurin inhibitor (CNi) to mammalian target of rapamycin inhibitor (mTORi) is one of the immunosuppressive strategies that have been investigated to mitigate long-term CNi-associated adverse events. The growing interest for early conversion instead of ‘‘de novo’’ mTORi-based immunosuppressive regimen is based on four main findings. First, the lack of sufficient efficacy for the prevention of acute rejection observed with mTORi-based immunosuppressive regimens (1,2). Second, the initial difficulties in identifying nonnephrotoxic regimens combining mTORi and CNi (3,4). Third, the association of ‘‘de novo’’ use of mTORi with several important early adverse events such as wound healing and delayed graft function (5). Finally, the observation that late conversion, mainly 6 months after transplantation, was associated with minimal impact on renal function and with substantial incidence of adverse events (6). Early conversion studies published so far differ in baseline inclusion/exclusion criteria, induction agent, timing of conversion from CNi to mTORi, strategy for conversion (abrupt vs. stepwise) and mTORi—sirolimus (SRL) or everolimus. Among these trials, the incidence of acute rejection after conversion from CNi to mTORi and treatment discontinuation has shown different results. Although renal function has been used as primary end-point in all these trials, the timing posttransplant (12 or 24 months) and the criteria used to demonstrate statistically significant superior renal function among patients receiving mTORi-based regimen have not been standardized (7–14). Patients with known higher immunological risk and those prone to show poor response to mTORi-based immunosuppressive regimens have been systematically excluded, based on findings of a large late conversion study (6). Not surprisingly, outcomes have not been comparable. 3155
Silva et al
Because there are several demographic variables known to influence drug pharmacokinetics and pharmacodynamics, and ultimately kidney transplant outcomes, we sought to investigate the outcomes of a conversion strategy from tacrolimus to SRL in our population. The results of our study add more information to the debate related to the efficacy and safety of this strategy.
Methods Study design and patients This was a 24-month prospective, multicenter (five centers), randomized, controlled and parallel-group trial in de novo kidney transplant recipients. The study was conducted in compliance with Good Clinical Practice guidelines, in accordance with the Declaration of Helsinki and was approved by each independent ethic committee at centers. The trial is registered at ClinicalTrials.gov. (Identifier: NCT01802268). We screened patients older than 18 years, recipients of first kidney transplant from brain-dead deceased or living-related non-HLA identical donors not older than 65 years. Patients had to receive an ABO-compatible organ with a CDC-negative cross-match and a peak panel reactive antibody lower than 30%. All patients agreed to use contraceptive methods during the study and up to 3 months after study drug discontinuation. We excluded patients with chronic kidney diseases due to focal and segmental glomerulosclerosis and membranoproliferative glomerulonephritis, patients with active infection or positive for hepatitis B or C or human immunodeficiency viruses and with previous history of malignancy. Finally, we also excluded patients with significant hematological or severe metabolic laboratorial abnormalities. To be enrolled, willing patients first had to understand all trial-related objectives and procedures and then had to sign an IRB-approved informed consent. Enrolled patients could receive induction treatment with basiliximab and methylprednisolone before graft reperfusion according to local practice. Within 48 h after the transplant surgery patients received tacrolimus (TAC) (0.1–0.2 mg/kg/day), enteric-coated mycophenolate sodium (MPS; 1440 mg/ day) and prednisone (Pred). TAC doses were adjusted to maintain trough blood concentrations between 5 and 15 ng/mL. Patients were randomized after the transplant surgery either to be converted from TAC to sirolimus (SRL group) or to be maintained on tacrolimus (TAC group) 3 months after transplantation. Randomization was stratified according to donor source (deceased/living) and transplant center using computer-generated sequences. At conversion, patients who discontinued initial immunosuppressive regimen (TAC, MPS, Pred), with estimated glomerular filtration rate (eGFR) 30%, and another patient received induction therapy with thymoglobulin. The demographic characteristics are presented in Table 1. Induction therapy with basiliximab was used in 125 (42%) patients and 2 (0.7%) patients received thymoglobulin. At day 7, mean TAC concentrations were 10.6 5.4 ng/mL, mean MPS dose was 1438 92 mg/day and mean Pred dose was 31 9.8 mg/day (Table 2). During the first 3 months the cumulative incidence of first BCAR was 24.2%. Overall, there were 84 episodes of treated acute rejection, 10 clinical rejections, 15 borderline, 29 IA, 10 IB, 15 IIA and 5 IIB. There were five graft losses, five deaths and four lost to follow-up. At 24 months, the incidence of BCAR was 28.9% in patients converted to SRL, 22.4% in patients maintained on TAC and 50.6% in patients without criteria for intervention at 3 months (TACex; Table 3). American Journal of Transplantation 2013; 13: 3155–3163
Early Conversion From Tacrolimus to Sirolimus
Figure 1: Disposition of the study population.
There were 283 patients completing 3 months (SRL ¼ 141, TAC ¼ 142). At this time, mean TAC trough blood concentration was 8.04 5.10 ng/mL, mean MPS dose was 1349 228 mg/day and mean Pred dose was 8.9 5.8 mg/day. Of them, 97 patients were converted to SRL, 107 were maintained on TAC and 79 (randomized either to SRL ¼ 44 or TAC ¼ 35) who did not fulfill criteria to undergo intervention were followed in a separate group (TACex). The demographic characteristics are shown in Table 1. There were no differences in the proportion of patients without criteria to intervention at 3 months when comparing patients initially randomized to SRL or TAC (31% vs. 25%, p ¼ 0.175). The reasons for exclusion were GFR < 40 mL/min in 42% (SRL ¼ 41% vs. TAC ¼ 43%), protein-to-creatinine ratio 0.5 g/mg in 20% (SRL ¼ 16% vs. TAC ¼ 26%), severe acute rejection or rejection within the last 4 weeks in 34% (SRL ¼ 41% vs. TAC ¼ 26%), wound healing event in 1% (SRL ¼ 0% vs. TAC ¼ 3%) and patient decision in 3% (SRL ¼ 2% vs. TAC ¼ 3%). After intervention, mean SRL trough concentrations were 9.0 4.2 ng/mL at month 4 and 7.6 2.9 ng/mL at month 24 and mean TAC trough concentrations were 8.0 4.5 ng/ American Journal of Transplantation 2013; 13: 3155–3163
mL at month 4 and 6.1 3.5 ng/mL at month 24. No differences were observed in mean MPS and Pred doses from month 4 (MPS 1348 224 vs. 1350 216 mg/day, p ¼ 0.67; Pred: 7.4 4.9 vs. 7.7 4.8 mg/day, p ¼ 0.92) to month 24 (MPS 1292 253 vs. 1306 256 mg/day, p ¼ 0.70; Pred: 5.7 1.6 vs. 5.8 2.1 mg/day, p ¼ 0.54), respectively (Table 2).
Efficacy The cumulative incidence of first BCAR was higher after conversion from TAC to SRL (7.2% vs. 2.9%, p ¼ 0.06, Table 3). At 24 months there were no differences in patient (95.9% vs. 97.2%, p ¼ 0.61) and graft survival (94.8% vs. 96.3%, p ¼ 0.62), respectively (Table 3). In the SRL group, 67% (4/6) of the patients who developed BCAR after 3 months also had an episode of BCAR before 3 months compared to none in the TAC and two in the TACex groups. While there was no difference in the incidence of treated acute rejection before month 3 (23.7% vs. 22.4%, p ¼ 1.0), after month 3 a higher incidence was observed in the SRL compared to TAC group (14.4% vs. 4.8%, p ¼ 0.047), respectively (Table 3). 3157
Silva et al Table 1: Demographic characteristics of the populations Parameters Age, years Gender Male Female Ethnicity Caucasian Black Mixed Other End-stage renal disease Hypertension Diabetes mellitus Unknown Other Past medical history Hypertension Diabetes mellitus Dyslipidemia Donor age, years Donor gender Male Female Donors ethnicity Caucasian Black Mixed Other Without information Type of donor Living Deceased Cold ischemia time2, h Panel reactive antibody, % HLA mismatches Locus A Locus B Locus DR CMV serology combination D/R D/Rþ Dþ/R Dþ/Rþ D or R missing
Total (n ¼ 297)
SRL (n ¼ 97 )
TAC (n ¼ 107)
TACex1 (n ¼ 79)
44.6 13.2
43.5 14.0
43.9 12.8
46.9 12.6
205 (69) 92 (31)
66 (68) 31 (32)
72 (67) 35 (33)
56 (71) 23 (29)
170 33 76 18
(57) (11) (26) (6)
52 11 29 5
(54) (11) (30) (5)
60 11 28 8
(56) (10) (26) (8)
47 10 17 5
(59) (13) (22) (6)
39 50 43 165
(13) (17) (15) (56)
17 18 16 46
(18) (19) (16) (47)
14 18 11 64
(13) (17) (10) (60)
7 12 14 46
(9) (15) (18) (58)
148 (50) 70 (24) 17 (6) 42.9 10.8
51 (53) 18 (19) 6 (6) 40.4 10.5
54 (50) 23 (22) 3 (3) 43.5 10.5
37 (47) 27 (34) 8 (10) 45.1 11.1
145 (49) 152 (51)
51 (53) 45 (47)3
53 (50) 54 (50)
35 (44) 44 (56)
184 35 61 6 11
60 15 19 1 2
69 11 21 3 3
45 8 20 1 5
(64) (12) (21) (2) (4)
(62) (15) (20) (1) (2)
(66) (11) (20) (3) (3)
(60) (11) (28) (1) (6)
151 (51) 146 (49) 21.7 7.2 1.54 5.4
50 (52) 47 (48) 22.0 7.0 1.4 4.8
61 (57) 46 (43) 21.4 8.2 1.2 4.2
37 (46) 42 (54) 21.7 6.1 2.2 7.1
1.2 0.6 1.1 0.6 0.9 0.7
1.2 0.7 1.2 0.6 0.9 0.8
1.2 0.6 1.1 0.6 0.9 0.7
1.2 0.6 1.2 0.6 0.9 0.7
7 11 21 214 44
1 1 10 70 15
(2) (4) (7) (72) (15)
(1) (1) (10) (73) (15)
4 5 7 79 12
(4) (5) (7) (73) (11)
2 5 4 56 12
(3) (6) (5) (71) (15)
CMV, cytomegalovirus; SRL, sirolimus; TAC, tacrolimus; TACex, patients receiving TAC without criteria to undergo intervention at month 3. p > 0.05 SRL vs. TAC comparing all parameters. 1 Patients without criteria for intervention at 3 months. 2 Deceased donor only. 3 One missing information.
Chronic allograft damage In the intention-to-treat population reaching month 24 protocol biopsy was done in 70% and 64% of patients in the SRL and TAC groups, respectively (Table 4). The incidence of chronic allograft nephropathy according to the Banff 2003 was not different in both groups. There were also no clear differences in the severity of chronic sclerosing lesions scores or in the incidence of biopsies with positive C4d staining (9% vs. 6%) comparing patients in either group (Table 4). 3158
Safety Of the 258 patients who completed 24 months, 91 (94%) were in the SRL group, 101 (94%) in the TAC group and 66 (84%) in the TACex group (Figure 1). There were two graft losses (one due to acute rejection in SRL group and one due to chronic rejection in TAC group), six deaths (two due to infection and one due to cardiovascular event in each group) and four lost to follow-up (two in each group). In the TACex group there were three graft losses (due to rejection, hemolytic uremic syndrome and focal and segmental American Journal of Transplantation 2013; 13: 3155–3163
Early Conversion From Tacrolimus to Sirolimus Table 2: Mean drug dose and concentrations over 24 months of follow-up (n ¼ 283) Sirolimus group (n ¼ 141)
Day 7 Day 14 Day 21 Month 1 Month 2 Month 3
Tacrolimus group (n ¼ 142)
TAC (ng/mL)
MPS (mg/day)
Pred (mg/day)
TAC (ng/mL)
MPS (mg/day)
Pred (mg/day)
10.8 5.6 11.9 5.5 12.7 6.9 10.2 5.9 8.5 5.2 8.1 5.0
1434 104 1415 92 1365 201 1417 125 1368 206 1348 227
31.5 10.5 31.5 8.8 26.9 7.3 15.3 6.6 9.6 6.5 8.7 5.9
10.5 5.2 11.6 6.2 12.5 5.8 10.1 5.0 8.8 4.5 7.9 5.2
1443 78 1432 54 1432 54 1415 145 1372 201 1349 230
31.1 9.0 32.1 8.1 27.6 6.8 15.3 7.5 10.6 7.6 9.0 5.7
Sirolimus group (n ¼ 97)
Month Month Month Month Month
6 9 12 18 24
Tacrolimus group (n ¼ 107)
SRL (ng/mL)
MPS (mg/day)
Pred (mg/day)
TAC (ng/mL)
MPS (mg/day)
Pred (mg/day)
9.0 4.3 8.9 2.9 8.6 3.1 7.6 2.9 7.6 2.9
1294 270 1308 236 1287 250 1306 242 1292 253
7.1 4.3 6.1 2.0 5.8 1.8 5.6 1.6 5.7 1.6
6.9 4.4 6.4 4.0 5.7 2.6 6.3 2.6 6.1 3.5
1367 198 1368 196 1347 207 1356 199 1306 256
6.6 2.9 6.0 1.9 6.1 3.3 5.8 1.6 5.8 2.1
TAC, tacrolimus trough blood concentration; MPS, mycophenolate sodium; Pred, prednisone; SRL, sirolimus trough blood concentration.
glomerulosclerosis), six deaths (five due to infection and one due to malignancy) and four lost to follow-up.
tions compared to patients in TAC group at 24 months (Table 5).
During the first 3 months while all patients were receiving TAC, mycophenolate and steroids, the incidence of cytomegalovirus (CMV) and herpes zoster infections was 18% and 4%, respectively. After conversion, between months 4 and 24, the incidence of CMV (5% vs. 4% vs. 3%), herpes zoster (4% vs. 7% vs. 5%) and polioma virus (3% vs. 4% vs. 4%) infections was low and similar comparing patients in the SRL, TAC and TACex groups, respectively. Six patients showed CMV recurrent infection (4 patients had 2 episodes, 1 patient 3 and 1 patient 4). None of these recurrences occurred after conversion to SRL. One patient in the SRL group had a recurrence episode of herpes zoster infection. Four patients developed malignancies during the study period, two in the TAC group (Kaposi’s sarcoma and mixed embryonal testicular carcinoma, 12 and 8 months after transplantation, respectively) and two in the TACex group (squamous cell carcinoma and Kaposi’s sarcoma, 6 and 16 months after transplantation, respectively).
Renal function There was no difference in renal function (eGFR) at 24 months comparing patients in the SRL or TAC groups in the intention-to-treat (66.2 25.3 vs. 70.7 25.1, p ¼ 0.817, Figure 2A) or in the on-therapy population (69.0 24.2 vs. 74.1 23.7, p ¼ 0.162, Figure 2B). There were also no differences in eGFR in any study visit from month 1 to month 24 (Table 6). While at 3 months there were no differences in mean protein-to-creatinine ratios (0.14 0.24 vs. 0.17 0.62 g/mg, p ¼ 0.64) significant differences were observed at 12 (0.32 0.72 vs. 0.12 0.43 g/mg, p ¼ 0.02) and 24 months (0.36 0.69 vs. 0.15 0.53, p ¼ 0.03), for SRL and TAC groups, respectively. Also, at 24 months, the proportion of patients with a protein-to-creatinine ratio 0.5 g/mg was higher in the SRL group (19% vs. 7%, p ¼ 0.021). As expected the mean eGFR of 56.5 23.0 mL/ min/1.73 m2 at month 24 was significantly inferior in the TACex compared to the SRL and TAC groups.
Treatment discontinuation occurred in 10% of patients in both SRL (10/97) and TAC (11/107) groups. Three study drug discontinuations occurred before graft loss or death in each group. The reasons to discontinue SRL were lack of efficacy, diarrhea, proteinuria (n ¼ 3), dyslipidemia, focal and segmental glomerulosclerosis, zygomycosis, CMV infection and pancreas transplantation. The reasons to discontinue TAC were diarrhea (n ¼ 2), renal dysfunction (n ¼ 2), poliomavirus nephropathy (n ¼ 2), pneumonia (n ¼ 2), malignancy (n ¼ 2) and pancreas transplantation. No differences were observed in blood pressure. Patients in the SRL group showed lower mean hemoglobin and glucose concentrations and higher mean total cholesterol, triglyceride, LDL- and VLDL-cholesterol concentraAmerican Journal of Transplantation 2013; 13: 3155–3163
Discussion This study showed that conversion from TAC to SRL-based immunosuppressive regimen at 3 months was not associated with improved renal function 24 months after transplantation in recipients of ‘‘de novo’’ kidney transplants. These findings are in agreement with that observed in the Spare-the-Nephron trial (7), where TAC was the CNi used in 80% of the patients and SRL was the mTORi. On the other hand, our results contrast with that observed in the Zeus trial, where cyclosporine and everolimus were used and a significant difference in eGFR was observed favoring the everolimus group at 12 (þ9.8 mL/min/1.73 m2) 3159
Silva et al Table 3: Key efficacy and safety parameters Parameters n, (%) Freedom from 1st episode of BCAR 0–3 months Freedom from 1st episode of BCAR 4–24 months Freedom from 1st episode of BCAR 0–24 months Patient survival Graft survival Death-censored graft survival Graft loss Death Lost to follow-up Study discontinuation Treatment discontinuation Lack of efficacy Adverse event Treated acute rejection 0–3 months Clinical rejection BCAR Borderline IA IB IIA IIB Treated acute rejection 4–24 months Clinical rejection BCAR Borderline IA IB IIA IIB Treated acute rejection 0–24 months Clinical rejection BCAR Borderline IA IB IIA IIB
Table 4: Protocol biopsies at month 24
SRL (n ¼ 97)
TAC (n ¼ 107)
TACex (n ¼ 79)
21 (79.4)
21 (81.9)
30 (62)
7 (92.8)
2 (98.1)
7 (91.1)
26 (74.5)
23 (80.2)
36 (54.4)
95.9 94.8 99.0
97.2 96.3 99.1
93.7 89.9 96.2
1 3 2 6 10
(1.0) (3.1) (2.1) (6.2) (10.0)
1 3 2 6 11
(0.9) (2.8) (1.9) (5.6) (10.3)
3 6 4 13
(3.8) (7.6) (5.1) (16.5) na
1 (9.2) 9 (9.3) 23 (23.7)
0 11 (10.3) 24 (22.4)
na na 37 (46.8)
2 (2.1) 21(21.6) 5 (5.1) 8 (8.2) 5 (5.1) 2 (2.1) 1 (1.0) 13 (14.4)
3 21 4 12 3 1 1 5
(2.8) (19.6) (3.7) (11.2) (2.8) (0.9) (0.9) (4.8)
5 (6.3) 32 (40.5) 6 (7.6) 9 (11.4) 2 (2.5) 12 (15.2) 3 (3.8) 10 (12.7)
(6.2) (7.2) (3.1) (2.1) (2.1) 0 0 36 (37.1)
(1.9) (2.9) (0.9) (0.9) 0 1 (0.9) 0 29 (27.1)
2 (2.5) 8 (10.1) 4 (5.1) 2 (2.5) 1 (1.3) 0 1 (1.3) 47 (59.5)
8 28 8 10 7 2 1
5 24 5 13 3 2 1
7 40 10 11 3 12 4
6 7 3 2 2
(8.2) (28.9) (8.2) (10.3) (7.2) (2.1) (1.0)
2 3 1 1
(4.7) (22.4) (4.7) (12.1) (2.8) (1.9) (0.9)
(8.9) (50.6) (12.7) (13.9) (3.8) (15.2) (5.1)
BCAR, biopsy-confirmed acute rejection; SRL, sirolimus; TAC, tacrolimus; TACex, patients receiving TAC without criteria to undergo intervention at month 3.
and 24 months (þ7.8 mL/min/1.73 m2) (8). Also, in the SMART trial, patients receiving cyclosporine and converted to SRL 10–24 days after transplantation showed a þ11.1 mL/min/1.73 m2 difference in eGFR at 12 months (13). The relative high proportion of patients receiving allograft from living donors, and the exclusion of those 3160
Parameter n (%) Patients with protocol biopsy Patients with chronic allograft nephropathy Grade I Grade II Grade III C4d positive C4d negative C4d not done Chronic/sclerosing lesions score Allograft glomerulopathy 0 1 2 3 Interstitial fibrosis 0 1 2 3 Tubular atrophy 0 1 2 3 Vascular fibrous intimal thickening 0 1 2 3 Mesangial matrix increase 0 1 2 3 Arteriolar hyalinosis thickening 0 1 2 3
SRL (n ¼ 91)
TAC (n ¼ 101)
64 (70) 42 (66) 30 (47) 10 (16) 2 (3) 3 (5) 29(45) 32 (50)
65 (64) 27 (42) 27 (42) 0 0 2 (3) 31 (48) 32 (49)
60 (98) 0 1 (2) 0
62 (100) 0 0 0
19 (31) 31 (51) 9 (15) 2 (3)
33 (53) 29 (47) 0 0
19 (31) 32 (52) 8 (13) 2 (3)
35 (56) 27 (44) 0 0
39 16 5 1
43 (70) 17 (28) 2 (3) 0
(64) (26) (8) (2)
57 (93) 4 (7) 0 0
45 11 5 1
(73) (18) (8) (2)
40 (65) 14 (23) 6 (10) 1 (2)
45 11 5 1
(72) (18) (8) (2)
SRL, sirolimus; TAC, tacrolimus.
patients with eGFR lower than 40 mL/min/1.73 m2 and those with severe rejections may account for these observations. Notably, the use of TAC, instead of cyclosporine, maintained at relatively lower trough blood concentration may have influenced the outcome of our trial. Earlier trials already had suggested superior renal function in patients receiving standard doses of TAC as compared to cyclosporine. More recently, reduced TAC concentrations were associated with superior renal function compared to reduced cyclosporine concentration in the Symphony trial (2). Therefore, the differences in GFR seen when comparing cyclosporine with SRL may not be observed when comparing TAC with SRL. Contrasting with previous conversion trials, we were able to obtain protocol biopsies in the majority of patients American Journal of Transplantation 2013; 13: 3155–3163
Early Conversion From Tacrolimus to Sirolimus Table 5: Vital signs and laboratory data at 24 months Parameters Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) Hemoglobin (g/dL) White blood cell count (N/mm3) Platelets (N/mm3) Glucose (mg/dL) Urea (mg/dL) Creatinine (mg/dL) Total cholesterol (mg/dL) Triglycerides (mg/dL) HDL cholesterol (mg/dL) LDL cholesterol (mg/dL) VLDL cholesterol (mg/dL)
SRL
TAC
p-Value
136 19 81 12 13.6 1.6 7488 2546 216.380 64.510 87 20 41 14 1.4 0.4 219 48 231 212 46 12 131 39 37 17
132 17 80 11 14.1 1.7 7569 2381 210.540 59.495 100 45 45 15 1.3 0.3 181 48 170 114 44 12 101 32 30 14
0.157 0.630 0.038 0.820 0.516 0.013 0.092 0.178
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Copyright 2013 The American Society of Transplantation and the American Society of Transplant Surgeons doi: 10.1111/ajt.12481
Planned Randomized Conversion From Tacrolimus to Sirolimus-Based Immunosuppressive Regimen in De Novo Kidney Transplant Recipients H. T. Silva Jr.1,*, C. R. Felipe1, V. D. Garcia2, E. D. Neto3, M. A. Filho4, F. L. C. Contieri5, D. D. B. M. de Carvalho6 and J. O. M. Pestana1 1
Nephrology Division, Hospital do Rim, Federal University of Sa~o Paulo, Brazil 2 Kidney and Pancreas Transplant Unit, Santa Casa de Misericordia, Porto Alegre, Brazil 3 Renal Transplant Service, Hospital das Clı´nicas, ~ Paulo School of Medicine, Sa~o Paulo, University of Sao Brazil 4 Instituto de Urologia e Nefrologia and Medical School~ Jose´ do Rio Preto, Sa~o FAMERP/HB-FUNFARME, Sao Paulo, Brazil 5 Renal Transplant Unit, Hospital Universita´rio Evange´lico de Curitiba, Curitiba, Parana, Brazil 6 Nephrology Service, Bonsucesso General Hospital, Rio de Janeiro, Brazil Corresponding author: Helio Tedesco Silva Jr., [email protected] Planned conversion from tacrolimus to sirolimus was evaluated in de novo kidney transplant recipients. In this multicenter, randomized, open-label study, 297 patients were initially treated with tacrolimus, mycophenolate sodium and prednisone. Of the 283 patients reaching 3 months, 97 were converted to sirolimus (SRL), 107 were maintained on tacrolimus (TAC) and 79 were patients receiving TAC without criteria to undergo intervention at month 3 (TACex). The primary objective was to show superior estimated glomerular filtration rate (eGFR) in the SRL group at month 24. Of the 258 patients who completed 24 months, 91 (94%) were in the SRL group, 101 (94%) in the TAC group and 66 (84%) in the TACex group. In the intention-to-treat population there were no differences in eGFR (66.2 25.3 vs. 70.7 25.1, p ¼ 0.817) or in the severity of chronic sclerosing lesions scores in 24-month protocol biopsies. Higher mean urinary protein-tocreatinine ratio (0.36 0.69 vs. 0.15 0.53, p ¼ 0.03) and higher incidence of treated acute rejection between months 3–24 (13.4% vs. 4.7%, p ¼ 0.047) were observed in SRL compared to TAC group. In this population planned conversion from TAC to SRL 3 months after kidney transplantation was not associated with improved renal function at 24 months. Keywords: Conversion, kidney transplantation, sirolimus, tacrolimus
Abbreviations: BCAR, biopsy-confirmed acute rejection; CMV, cytomegalovirus; CNi, calcineurin inhibitor; eGFR, estimated glomerular filtration rate; MPS, mycophenolate sodium; mTORi, mammalian target of rapamycin inhibitor; Pred, prednisone; SRL, sirolimus; TAC, tacrolimus; TACex, patients receiving TAC without criteria to undergo intervention at month 3 Received 29 March 2013, revised and accepted for publication 19 August 2013
Introduction Early conversion from calcineurin inhibitor (CNi) to mammalian target of rapamycin inhibitor (mTORi) is one of the immunosuppressive strategies that have been investigated to mitigate long-term CNi-associated adverse events. The growing interest for early conversion instead of ‘‘de novo’’ mTORi-based immunosuppressive regimen is based on four main findings. First, the lack of sufficient efficacy for the prevention of acute rejection observed with mTORi-based immunosuppressive regimens (1,2). Second, the initial difficulties in identifying nonnephrotoxic regimens combining mTORi and CNi (3,4). Third, the association of ‘‘de novo’’ use of mTORi with several important early adverse events such as wound healing and delayed graft function (5). Finally, the observation that late conversion, mainly 6 months after transplantation, was associated with minimal impact on renal function and with substantial incidence of adverse events (6). Early conversion studies published so far differ in baseline inclusion/exclusion criteria, induction agent, timing of conversion from CNi to mTORi, strategy for conversion (abrupt vs. stepwise) and mTORi—sirolimus (SRL) or everolimus. Among these trials, the incidence of acute rejection after conversion from CNi to mTORi and treatment discontinuation has shown different results. Although renal function has been used as primary end-point in all these trials, the timing posttransplant (12 or 24 months) and the criteria used to demonstrate statistically significant superior renal function among patients receiving mTORi-based regimen have not been standardized (7–14). Patients with known higher immunological risk and those prone to show poor response to mTORi-based immunosuppressive regimens have been systematically excluded, based on findings of a large late conversion study (6). Not surprisingly, outcomes have not been comparable. 3155
Silva et al
Because there are several demographic variables known to influence drug pharmacokinetics and pharmacodynamics, and ultimately kidney transplant outcomes, we sought to investigate the outcomes of a conversion strategy from tacrolimus to SRL in our population. The results of our study add more information to the debate related to the efficacy and safety of this strategy.
Methods Study design and patients This was a 24-month prospective, multicenter (five centers), randomized, controlled and parallel-group trial in de novo kidney transplant recipients. The study was conducted in compliance with Good Clinical Practice guidelines, in accordance with the Declaration of Helsinki and was approved by each independent ethic committee at centers. The trial is registered at ClinicalTrials.gov. (Identifier: NCT01802268). We screened patients older than 18 years, recipients of first kidney transplant from brain-dead deceased or living-related non-HLA identical donors not older than 65 years. Patients had to receive an ABO-compatible organ with a CDC-negative cross-match and a peak panel reactive antibody lower than 30%. All patients agreed to use contraceptive methods during the study and up to 3 months after study drug discontinuation. We excluded patients with chronic kidney diseases due to focal and segmental glomerulosclerosis and membranoproliferative glomerulonephritis, patients with active infection or positive for hepatitis B or C or human immunodeficiency viruses and with previous history of malignancy. Finally, we also excluded patients with significant hematological or severe metabolic laboratorial abnormalities. To be enrolled, willing patients first had to understand all trial-related objectives and procedures and then had to sign an IRB-approved informed consent. Enrolled patients could receive induction treatment with basiliximab and methylprednisolone before graft reperfusion according to local practice. Within 48 h after the transplant surgery patients received tacrolimus (TAC) (0.1–0.2 mg/kg/day), enteric-coated mycophenolate sodium (MPS; 1440 mg/ day) and prednisone (Pred). TAC doses were adjusted to maintain trough blood concentrations between 5 and 15 ng/mL. Patients were randomized after the transplant surgery either to be converted from TAC to sirolimus (SRL group) or to be maintained on tacrolimus (TAC group) 3 months after transplantation. Randomization was stratified according to donor source (deceased/living) and transplant center using computer-generated sequences. At conversion, patients who discontinued initial immunosuppressive regimen (TAC, MPS, Pred), with estimated glomerular filtration rate (eGFR) 30%, and another patient received induction therapy with thymoglobulin. The demographic characteristics are presented in Table 1. Induction therapy with basiliximab was used in 125 (42%) patients and 2 (0.7%) patients received thymoglobulin. At day 7, mean TAC concentrations were 10.6 5.4 ng/mL, mean MPS dose was 1438 92 mg/day and mean Pred dose was 31 9.8 mg/day (Table 2). During the first 3 months the cumulative incidence of first BCAR was 24.2%. Overall, there were 84 episodes of treated acute rejection, 10 clinical rejections, 15 borderline, 29 IA, 10 IB, 15 IIA and 5 IIB. There were five graft losses, five deaths and four lost to follow-up. At 24 months, the incidence of BCAR was 28.9% in patients converted to SRL, 22.4% in patients maintained on TAC and 50.6% in patients without criteria for intervention at 3 months (TACex; Table 3). American Journal of Transplantation 2013; 13: 3155–3163
Early Conversion From Tacrolimus to Sirolimus
Figure 1: Disposition of the study population.
There were 283 patients completing 3 months (SRL ¼ 141, TAC ¼ 142). At this time, mean TAC trough blood concentration was 8.04 5.10 ng/mL, mean MPS dose was 1349 228 mg/day and mean Pred dose was 8.9 5.8 mg/day. Of them, 97 patients were converted to SRL, 107 were maintained on TAC and 79 (randomized either to SRL ¼ 44 or TAC ¼ 35) who did not fulfill criteria to undergo intervention were followed in a separate group (TACex). The demographic characteristics are shown in Table 1. There were no differences in the proportion of patients without criteria to intervention at 3 months when comparing patients initially randomized to SRL or TAC (31% vs. 25%, p ¼ 0.175). The reasons for exclusion were GFR < 40 mL/min in 42% (SRL ¼ 41% vs. TAC ¼ 43%), protein-to-creatinine ratio 0.5 g/mg in 20% (SRL ¼ 16% vs. TAC ¼ 26%), severe acute rejection or rejection within the last 4 weeks in 34% (SRL ¼ 41% vs. TAC ¼ 26%), wound healing event in 1% (SRL ¼ 0% vs. TAC ¼ 3%) and patient decision in 3% (SRL ¼ 2% vs. TAC ¼ 3%). After intervention, mean SRL trough concentrations were 9.0 4.2 ng/mL at month 4 and 7.6 2.9 ng/mL at month 24 and mean TAC trough concentrations were 8.0 4.5 ng/ American Journal of Transplantation 2013; 13: 3155–3163
mL at month 4 and 6.1 3.5 ng/mL at month 24. No differences were observed in mean MPS and Pred doses from month 4 (MPS 1348 224 vs. 1350 216 mg/day, p ¼ 0.67; Pred: 7.4 4.9 vs. 7.7 4.8 mg/day, p ¼ 0.92) to month 24 (MPS 1292 253 vs. 1306 256 mg/day, p ¼ 0.70; Pred: 5.7 1.6 vs. 5.8 2.1 mg/day, p ¼ 0.54), respectively (Table 2).
Efficacy The cumulative incidence of first BCAR was higher after conversion from TAC to SRL (7.2% vs. 2.9%, p ¼ 0.06, Table 3). At 24 months there were no differences in patient (95.9% vs. 97.2%, p ¼ 0.61) and graft survival (94.8% vs. 96.3%, p ¼ 0.62), respectively (Table 3). In the SRL group, 67% (4/6) of the patients who developed BCAR after 3 months also had an episode of BCAR before 3 months compared to none in the TAC and two in the TACex groups. While there was no difference in the incidence of treated acute rejection before month 3 (23.7% vs. 22.4%, p ¼ 1.0), after month 3 a higher incidence was observed in the SRL compared to TAC group (14.4% vs. 4.8%, p ¼ 0.047), respectively (Table 3). 3157
Silva et al Table 1: Demographic characteristics of the populations Parameters Age, years Gender Male Female Ethnicity Caucasian Black Mixed Other End-stage renal disease Hypertension Diabetes mellitus Unknown Other Past medical history Hypertension Diabetes mellitus Dyslipidemia Donor age, years Donor gender Male Female Donors ethnicity Caucasian Black Mixed Other Without information Type of donor Living Deceased Cold ischemia time2, h Panel reactive antibody, % HLA mismatches Locus A Locus B Locus DR CMV serology combination D/R D/Rþ Dþ/R Dþ/Rþ D or R missing
Total (n ¼ 297)
SRL (n ¼ 97 )
TAC (n ¼ 107)
TACex1 (n ¼ 79)
44.6 13.2
43.5 14.0
43.9 12.8
46.9 12.6
205 (69) 92 (31)
66 (68) 31 (32)
72 (67) 35 (33)
56 (71) 23 (29)
170 33 76 18
(57) (11) (26) (6)
52 11 29 5
(54) (11) (30) (5)
60 11 28 8
(56) (10) (26) (8)
47 10 17 5
(59) (13) (22) (6)
39 50 43 165
(13) (17) (15) (56)
17 18 16 46
(18) (19) (16) (47)
14 18 11 64
(13) (17) (10) (60)
7 12 14 46
(9) (15) (18) (58)
148 (50) 70 (24) 17 (6) 42.9 10.8
51 (53) 18 (19) 6 (6) 40.4 10.5
54 (50) 23 (22) 3 (3) 43.5 10.5
37 (47) 27 (34) 8 (10) 45.1 11.1
145 (49) 152 (51)
51 (53) 45 (47)3
53 (50) 54 (50)
35 (44) 44 (56)
184 35 61 6 11
60 15 19 1 2
69 11 21 3 3
45 8 20 1 5
(64) (12) (21) (2) (4)
(62) (15) (20) (1) (2)
(66) (11) (20) (3) (3)
(60) (11) (28) (1) (6)
151 (51) 146 (49) 21.7 7.2 1.54 5.4
50 (52) 47 (48) 22.0 7.0 1.4 4.8
61 (57) 46 (43) 21.4 8.2 1.2 4.2
37 (46) 42 (54) 21.7 6.1 2.2 7.1
1.2 0.6 1.1 0.6 0.9 0.7
1.2 0.7 1.2 0.6 0.9 0.8
1.2 0.6 1.1 0.6 0.9 0.7
1.2 0.6 1.2 0.6 0.9 0.7
7 11 21 214 44
1 1 10 70 15
(2) (4) (7) (72) (15)
(1) (1) (10) (73) (15)
4 5 7 79 12
(4) (5) (7) (73) (11)
2 5 4 56 12
(3) (6) (5) (71) (15)
CMV, cytomegalovirus; SRL, sirolimus; TAC, tacrolimus; TACex, patients receiving TAC without criteria to undergo intervention at month 3. p > 0.05 SRL vs. TAC comparing all parameters. 1 Patients without criteria for intervention at 3 months. 2 Deceased donor only. 3 One missing information.
Chronic allograft damage In the intention-to-treat population reaching month 24 protocol biopsy was done in 70% and 64% of patients in the SRL and TAC groups, respectively (Table 4). The incidence of chronic allograft nephropathy according to the Banff 2003 was not different in both groups. There were also no clear differences in the severity of chronic sclerosing lesions scores or in the incidence of biopsies with positive C4d staining (9% vs. 6%) comparing patients in either group (Table 4). 3158
Safety Of the 258 patients who completed 24 months, 91 (94%) were in the SRL group, 101 (94%) in the TAC group and 66 (84%) in the TACex group (Figure 1). There were two graft losses (one due to acute rejection in SRL group and one due to chronic rejection in TAC group), six deaths (two due to infection and one due to cardiovascular event in each group) and four lost to follow-up (two in each group). In the TACex group there were three graft losses (due to rejection, hemolytic uremic syndrome and focal and segmental American Journal of Transplantation 2013; 13: 3155–3163
Early Conversion From Tacrolimus to Sirolimus Table 2: Mean drug dose and concentrations over 24 months of follow-up (n ¼ 283) Sirolimus group (n ¼ 141)
Day 7 Day 14 Day 21 Month 1 Month 2 Month 3
Tacrolimus group (n ¼ 142)
TAC (ng/mL)
MPS (mg/day)
Pred (mg/day)
TAC (ng/mL)
MPS (mg/day)
Pred (mg/day)
10.8 5.6 11.9 5.5 12.7 6.9 10.2 5.9 8.5 5.2 8.1 5.0
1434 104 1415 92 1365 201 1417 125 1368 206 1348 227
31.5 10.5 31.5 8.8 26.9 7.3 15.3 6.6 9.6 6.5 8.7 5.9
10.5 5.2 11.6 6.2 12.5 5.8 10.1 5.0 8.8 4.5 7.9 5.2
1443 78 1432 54 1432 54 1415 145 1372 201 1349 230
31.1 9.0 32.1 8.1 27.6 6.8 15.3 7.5 10.6 7.6 9.0 5.7
Sirolimus group (n ¼ 97)
Month Month Month Month Month
6 9 12 18 24
Tacrolimus group (n ¼ 107)
SRL (ng/mL)
MPS (mg/day)
Pred (mg/day)
TAC (ng/mL)
MPS (mg/day)
Pred (mg/day)
9.0 4.3 8.9 2.9 8.6 3.1 7.6 2.9 7.6 2.9
1294 270 1308 236 1287 250 1306 242 1292 253
7.1 4.3 6.1 2.0 5.8 1.8 5.6 1.6 5.7 1.6
6.9 4.4 6.4 4.0 5.7 2.6 6.3 2.6 6.1 3.5
1367 198 1368 196 1347 207 1356 199 1306 256
6.6 2.9 6.0 1.9 6.1 3.3 5.8 1.6 5.8 2.1
TAC, tacrolimus trough blood concentration; MPS, mycophenolate sodium; Pred, prednisone; SRL, sirolimus trough blood concentration.
glomerulosclerosis), six deaths (five due to infection and one due to malignancy) and four lost to follow-up.
tions compared to patients in TAC group at 24 months (Table 5).
During the first 3 months while all patients were receiving TAC, mycophenolate and steroids, the incidence of cytomegalovirus (CMV) and herpes zoster infections was 18% and 4%, respectively. After conversion, between months 4 and 24, the incidence of CMV (5% vs. 4% vs. 3%), herpes zoster (4% vs. 7% vs. 5%) and polioma virus (3% vs. 4% vs. 4%) infections was low and similar comparing patients in the SRL, TAC and TACex groups, respectively. Six patients showed CMV recurrent infection (4 patients had 2 episodes, 1 patient 3 and 1 patient 4). None of these recurrences occurred after conversion to SRL. One patient in the SRL group had a recurrence episode of herpes zoster infection. Four patients developed malignancies during the study period, two in the TAC group (Kaposi’s sarcoma and mixed embryonal testicular carcinoma, 12 and 8 months after transplantation, respectively) and two in the TACex group (squamous cell carcinoma and Kaposi’s sarcoma, 6 and 16 months after transplantation, respectively).
Renal function There was no difference in renal function (eGFR) at 24 months comparing patients in the SRL or TAC groups in the intention-to-treat (66.2 25.3 vs. 70.7 25.1, p ¼ 0.817, Figure 2A) or in the on-therapy population (69.0 24.2 vs. 74.1 23.7, p ¼ 0.162, Figure 2B). There were also no differences in eGFR in any study visit from month 1 to month 24 (Table 6). While at 3 months there were no differences in mean protein-to-creatinine ratios (0.14 0.24 vs. 0.17 0.62 g/mg, p ¼ 0.64) significant differences were observed at 12 (0.32 0.72 vs. 0.12 0.43 g/mg, p ¼ 0.02) and 24 months (0.36 0.69 vs. 0.15 0.53, p ¼ 0.03), for SRL and TAC groups, respectively. Also, at 24 months, the proportion of patients with a protein-to-creatinine ratio 0.5 g/mg was higher in the SRL group (19% vs. 7%, p ¼ 0.021). As expected the mean eGFR of 56.5 23.0 mL/ min/1.73 m2 at month 24 was significantly inferior in the TACex compared to the SRL and TAC groups.
Treatment discontinuation occurred in 10% of patients in both SRL (10/97) and TAC (11/107) groups. Three study drug discontinuations occurred before graft loss or death in each group. The reasons to discontinue SRL were lack of efficacy, diarrhea, proteinuria (n ¼ 3), dyslipidemia, focal and segmental glomerulosclerosis, zygomycosis, CMV infection and pancreas transplantation. The reasons to discontinue TAC were diarrhea (n ¼ 2), renal dysfunction (n ¼ 2), poliomavirus nephropathy (n ¼ 2), pneumonia (n ¼ 2), malignancy (n ¼ 2) and pancreas transplantation. No differences were observed in blood pressure. Patients in the SRL group showed lower mean hemoglobin and glucose concentrations and higher mean total cholesterol, triglyceride, LDL- and VLDL-cholesterol concentraAmerican Journal of Transplantation 2013; 13: 3155–3163
Discussion This study showed that conversion from TAC to SRL-based immunosuppressive regimen at 3 months was not associated with improved renal function 24 months after transplantation in recipients of ‘‘de novo’’ kidney transplants. These findings are in agreement with that observed in the Spare-the-Nephron trial (7), where TAC was the CNi used in 80% of the patients and SRL was the mTORi. On the other hand, our results contrast with that observed in the Zeus trial, where cyclosporine and everolimus were used and a significant difference in eGFR was observed favoring the everolimus group at 12 (þ9.8 mL/min/1.73 m2) 3159
Silva et al Table 3: Key efficacy and safety parameters Parameters n, (%) Freedom from 1st episode of BCAR 0–3 months Freedom from 1st episode of BCAR 4–24 months Freedom from 1st episode of BCAR 0–24 months Patient survival Graft survival Death-censored graft survival Graft loss Death Lost to follow-up Study discontinuation Treatment discontinuation Lack of efficacy Adverse event Treated acute rejection 0–3 months Clinical rejection BCAR Borderline IA IB IIA IIB Treated acute rejection 4–24 months Clinical rejection BCAR Borderline IA IB IIA IIB Treated acute rejection 0–24 months Clinical rejection BCAR Borderline IA IB IIA IIB
Table 4: Protocol biopsies at month 24
SRL (n ¼ 97)
TAC (n ¼ 107)
TACex (n ¼ 79)
21 (79.4)
21 (81.9)
30 (62)
7 (92.8)
2 (98.1)
7 (91.1)
26 (74.5)
23 (80.2)
36 (54.4)
95.9 94.8 99.0
97.2 96.3 99.1
93.7 89.9 96.2
1 3 2 6 10
(1.0) (3.1) (2.1) (6.2) (10.0)
1 3 2 6 11
(0.9) (2.8) (1.9) (5.6) (10.3)
3 6 4 13
(3.8) (7.6) (5.1) (16.5) na
1 (9.2) 9 (9.3) 23 (23.7)
0 11 (10.3) 24 (22.4)
na na 37 (46.8)
2 (2.1) 21(21.6) 5 (5.1) 8 (8.2) 5 (5.1) 2 (2.1) 1 (1.0) 13 (14.4)
3 21 4 12 3 1 1 5
(2.8) (19.6) (3.7) (11.2) (2.8) (0.9) (0.9) (4.8)
5 (6.3) 32 (40.5) 6 (7.6) 9 (11.4) 2 (2.5) 12 (15.2) 3 (3.8) 10 (12.7)
(6.2) (7.2) (3.1) (2.1) (2.1) 0 0 36 (37.1)
(1.9) (2.9) (0.9) (0.9) 0 1 (0.9) 0 29 (27.1)
2 (2.5) 8 (10.1) 4 (5.1) 2 (2.5) 1 (1.3) 0 1 (1.3) 47 (59.5)
8 28 8 10 7 2 1
5 24 5 13 3 2 1
7 40 10 11 3 12 4
6 7 3 2 2
(8.2) (28.9) (8.2) (10.3) (7.2) (2.1) (1.0)
2 3 1 1
(4.7) (22.4) (4.7) (12.1) (2.8) (1.9) (0.9)
(8.9) (50.6) (12.7) (13.9) (3.8) (15.2) (5.1)
BCAR, biopsy-confirmed acute rejection; SRL, sirolimus; TAC, tacrolimus; TACex, patients receiving TAC without criteria to undergo intervention at month 3.
and 24 months (þ7.8 mL/min/1.73 m2) (8). Also, in the SMART trial, patients receiving cyclosporine and converted to SRL 10–24 days after transplantation showed a þ11.1 mL/min/1.73 m2 difference in eGFR at 12 months (13). The relative high proportion of patients receiving allograft from living donors, and the exclusion of those 3160
Parameter n (%) Patients with protocol biopsy Patients with chronic allograft nephropathy Grade I Grade II Grade III C4d positive C4d negative C4d not done Chronic/sclerosing lesions score Allograft glomerulopathy 0 1 2 3 Interstitial fibrosis 0 1 2 3 Tubular atrophy 0 1 2 3 Vascular fibrous intimal thickening 0 1 2 3 Mesangial matrix increase 0 1 2 3 Arteriolar hyalinosis thickening 0 1 2 3
SRL (n ¼ 91)
TAC (n ¼ 101)
64 (70) 42 (66) 30 (47) 10 (16) 2 (3) 3 (5) 29(45) 32 (50)
65 (64) 27 (42) 27 (42) 0 0 2 (3) 31 (48) 32 (49)
60 (98) 0 1 (2) 0
62 (100) 0 0 0
19 (31) 31 (51) 9 (15) 2 (3)
33 (53) 29 (47) 0 0
19 (31) 32 (52) 8 (13) 2 (3)
35 (56) 27 (44) 0 0
39 16 5 1
43 (70) 17 (28) 2 (3) 0
(64) (26) (8) (2)
57 (93) 4 (7) 0 0
45 11 5 1
(73) (18) (8) (2)
40 (65) 14 (23) 6 (10) 1 (2)
45 11 5 1
(72) (18) (8) (2)
SRL, sirolimus; TAC, tacrolimus.
patients with eGFR lower than 40 mL/min/1.73 m2 and those with severe rejections may account for these observations. Notably, the use of TAC, instead of cyclosporine, maintained at relatively lower trough blood concentration may have influenced the outcome of our trial. Earlier trials already had suggested superior renal function in patients receiving standard doses of TAC as compared to cyclosporine. More recently, reduced TAC concentrations were associated with superior renal function compared to reduced cyclosporine concentration in the Symphony trial (2). Therefore, the differences in GFR seen when comparing cyclosporine with SRL may not be observed when comparing TAC with SRL. Contrasting with previous conversion trials, we were able to obtain protocol biopsies in the majority of patients American Journal of Transplantation 2013; 13: 3155–3163
Early Conversion From Tacrolimus to Sirolimus Table 5: Vital signs and laboratory data at 24 months Parameters Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) Hemoglobin (g/dL) White blood cell count (N/mm3) Platelets (N/mm3) Glucose (mg/dL) Urea (mg/dL) Creatinine (mg/dL) Total cholesterol (mg/dL) Triglycerides (mg/dL) HDL cholesterol (mg/dL) LDL cholesterol (mg/dL) VLDL cholesterol (mg/dL)
SRL
TAC
p-Value
136 19 81 12 13.6 1.6 7488 2546 216.380 64.510 87 20 41 14 1.4 0.4 219 48 231 212 46 12 131 39 37 17
132 17 80 11 14.1 1.7 7569 2381 210.540 59.495 100 45 45 15 1.3 0.3 181 48 170 114 44 12 101 32 30 14
0.157 0.630 0.038 0.820 0.516 0.013 0.092 0.178
