Results
Demographics and Immunosuppression
Of the 150 patients included prospectively between April 2002 and September 2003, 5 were excluded before randomization because they did not receive a transplant. The final population comprised 145 patients, 71 in Group I receiving sirolimus and 74 in Group II treated with CsA. There was no difference between the two groups regarding donor and recipient ages, gender, cold ischemia time, number of first transplantations and HLA missmatches ( Table 1 ). The proportion of patients with panel reactive antibodies and with high risk of cytomegalovirus infection (donor+/recipient-) tended to be higher in the sirolimus group but the differences were not significant. Immunosuppressive Regimen
Doses and duration of ATG were not different between the two groups. Mean sirolimus and CsA doses and trough levels are summarized in Table 2 . Of note, 13 patients (20.6%) had CsA trough levels at 12 months above the target level of 150 ng/mL. At month 12, the mean MMF dose was significantly lower in the sirolimus group. At 12 months, corticosteroids had been withdrawn in 82.8% of sirolimus-treated patients and in 84.1% of CsA-treated patients (p = 0.94), with only 11 patients still being treated with steroids in each group.
The reasons for maintaining patients on steroids in the sirolimus group included increased creatinine levels with chronic allograft dysfunction (n = 4) at kidney graft biopsy, borderline lesions observed at systematic renal biopsy performed in one center at month 3 (n = 2), previous acute rejection (n = 2), low dose of MMF (n = 2) and past medical history of sarcoidosis (n = 1). In CsA-treated patients, they included chronic allograft dysfunction (n = 2), previous acute rejection (n = 3), MMF withdrawal (n = 1), recurrence of membranoproliferative glomerulonephritis (n = 1), recurrence of focal and segmental glomerulosclerosis (n = 1), noncompliance (n = 1) and history of Sjogren's (n = 1) or Goodpasture's syndrome (n = 1).Patient and Graft Survival
Patient survival at 12 months was 97% in both groups. In Group I (sirolimus), a 56-year-old male patient died on day 1 posttransplantation due to cardiac arrest and a 60-year-old male patient died at month 1. Sirolimus was withdrawn for this patient because of vascular rejection and he died of hemorrhagic shock following kidney graft removal. In Group II (CsA), a 42-year-old male patient died suddenly on day 15 due to cardio-respiratory arrest and a 47-year-old male patient committed suicide 5 months after transplantation.
One-year death censored graft survival was 93% in the sirolimus group and 96% in the CsA group. One-year graft survival including death was 90% and 93%, respectively (Figure 1). Five patients lost their grafts in Group I due to renal artery thrombosis (n = 1), vascular rejection episodes at day 13 and 28 posttransplantation (n = 2), recurrent hemolytic and uremic syndrome (n = 1) and mycotic aneurysm of the renal graft artery at 3 months (n = 1). Three patients lost their grafts in Group II due to renal vein thrombosis (n = 1), primary nonfunction (n = 1) and recurrence of focal and segmental glomerulosclerosis (n = 1).
Figure 1. (click image to zoom)
Kidney graft survival at 1 year, including deaths, in patients treated with either a CNI-free immunosuppressive regimen including sirolimus (I) or cyclosporine (II).
Withdrawal of Study Medication
A total of 51 patients in Group I (71.8%) and 63 patients in Group II (85.1%) were still on study medication at month 12 posttransplantation. The causes of discontinuation are detailed in Table 3 . Study medication was withdrawn for most patients within 100 days posttransplantation (75.0% and 63.6% of the patients in Groups I and II, respectively).
Discontinuation was due to lack of efficacy in four patients receiving sirolimus (5.6%) and in three patients receiving CsA (4.1%). In the sirolimus group, two patients were switched to another immunosuppressive regimen because of acute rejection episodes and two patients were switched because serum creatinine levels increased. In the CsA group, one patient stopped study medication because of biopsy-confirmed CsA nephrotoxicity and two patients stopped because of vascular rejection.
Discontinuation was due to adverse events in 11 patients (15.5%) in Group I and in 5 patients (6.8%) in Group II (p = 0.09) ( Table 3 ). The adverse events leading to study withdrawal in Group I were: ongoing tubular necrosis (n = 2), lymphocytic cholangitis (n = 1), kidney hematoma (n = 1), infection (n = 2), pneumopathy (n = 1), proteinuria (n = 1) and brain lymphoma (n = 1); in two other patients, discontinuation of the study drug was followed by graft loss (one due to a mycotic aneurysm and one due to recurrence hemolytic and uremic syndrome).
Adverse events leading to study withdrawal in Group II included hemolytic and uremic syndrome (n = 1), hirsutism (n = 1) and gum hyperplasia (n = 1). Moreover two patients stopped CsA followed by graft loss one due to primary nonfunction and the other due to recurrence of focal and segmental glomerulosclerosis.Delayed and Slow Graft Function
The incidence of immediate graft function was similar in both groups (70.0% vs. 74.0% in Groups I and II, respectively, p = 0.6). Delayed graft function (18.6% vs. 12.3%) and SGF (11.4% vs. 13.7%) were not statistically different between the two groups. The duration of delayed graft function was 14.5 ± 10.6 days in Group I compared to 11.9 ± 4.6 days in Group II (p = 0.5).Acute Rejection Episodes
All patients with clinically suspected acute rejection underwent a renal graft biopsy. The proportions of patients with biopsy-proven acute rejection (Figure 2) were 14.3% in Group I (Grade I: n = 5; Grade II: n = 2; Grade III: n = 2) versus 8.6% in Group II (Grade I: n = 2; Grade II: n = 2; Grade III: n = 2) (Fisher t-test, p = 0.4). The acute rejection rate, including patients with borderline lesions, was 17.5% in Group I and 22.9% in Group II (p = 0.4). The mean interval between transplantation and the first episode of acute rejection was 75 ± 82 days and 87 ± 84 days in Groups I and II, respectively (n.s.). Only one rejection episode in each group occurred after steroid withdrawal, that 6 months after transplantation.
Figure 2. (click image to zoom)
Kaplan-Meier analysis of biopsy-proven acute rejection-free renal graft recipients treated with sirolimus (I) or cyclosporine (II) with steroid withdrawal at month 6.
Seven of the 12 biopsy-proven acute rejection episodes occurring in Group I (nine patients) were steroid-resistant and were treated with anti-T-cell polyclonal antibodies. Two episodes with vascular lesions led to graft loss. Another steroid-resistant rejection with vascular lesions was followed by death due to acute hemorrhage after kidney graft removal. In Group II, two of the six acute rejection episodes (six patients) were steroid-resistant and were treated with anti-T-cell polyclonal antibodies. The proportions of steroid-resistant episodes were not significantly different between the two groups (Fisher t-test, p = 0.62). In one center, protocol biopsies were performed at month 3. No acute rejection was detected but two patients had borderline lesions in the sirolimus group.Renal Function
eGFR at 12 months according to Nankivell's formula was the primary endpoint of the present study. As shown in Table 4 , eGFR was not significantly different comparing the two treatment groups in the ITT population. eGFR was significantly higher in the sirolimus group in those patients who continued to be treated according to the protocol (on treatment) (p = 0.01). In these patients, the difference appeared as early as 2 months after transplantation and remained significant throughout the study (Figure 3). Similar results were observed when the GFR was estimated according to the Cockcroft formula (data not shown).
Figure 3. (click image to zoom)
Glomerular filtration rate estimated according to Nankivell's formula in renal graft recipients treated with either sirolimus (Group I) or cyclosporine (Group II) during the first year posttransplantation (patients on treatment) (*p < 0.05).
In the sirolimus group, an eGFR of more than 60 mL/min at 12 months was significantly associated with immediate graft function (76% vs. 48%, p = 0.02) and absence of acute rejection episodes (74% vs. 35%, p = 0.02), but this was not the case in patients treated with CsA (67% vs. 51% for immediate graft function and 57% vs. 38% for acute rejection, respectively).Adverse Events
The most common adverse events are summarized in Table 5 . One case of posttransplant lymphoproliferative disease occurred during the study, and that was in the sirolimus group. Adverse events such as wound complications, acne, folliculitis, mouth ulcers, diarrhea, tachycardia, phlebitis and bronchopneumonia were significantly more common in sirolimus-treated patients. Hirsutism and gingival hypertrophy were events more often seen in CsA-treated patients. CMV infections were less frequent in Group I than in Group II (6% vs. 23%, respectively, p = 0.004).
At month 12, 24-h proteinuria was higher in Group I compared to Group II (0.64 ± 0.8 g/day vs. 0.18 ± 0.3 g/day, p < 0.001). The number of patients with 24-h proteinuria above 0.5 g/day was higher in Group I (38.8% vs. 5.6%, p < 0.001) (Figure 4). It is of note that the percentages of patients treated with an angiotensin converting enzyme inhibitor and/or angiotensin receptor blocker were not different in the two study groups (32.8% vs. 29.7%). High body mass index and the absence of immediate renal function were associated with proteinuria levels above 0.5 g/24 h at 12 months (p = 0.02 for each) in patients receiving sirolimus but not in those receiving CsA. In the sirolimus group, 30% of the patients with immediate graft function had proteinuria > 0.5 g/day compared to 67% of the patients with SGF or DGF.
Figure 4. (click image to zoom)
Protein excretion rate on 24-h urine output on month 12 posttransplantation in sirolimus- (Group I) and cyclosporine-treated patients (Group II) (*p < 0.01).
Hematology
Hemoglobin levels were not significantly different in Group I compared to Group II throughout the study period ( Table 6 ). There was a tendency to need more recombinant erythropoietin therapy in Group I (11.8% vs. 6.4%, p = n.s.). Erythrocyte counts were significantly higher and mean corpuscular volumes (MCV) were lower in sirolimus-treated patients. White blood cell counts tended to be lower in patients treated with sirolimus and platelet counts were not different between both groups. Lipids
As shown in Table 7 , serum triglyceride and cholesterol levels were significantly higher at month 3 in Group I compared to Group II. At 12 months, the mean cholesterol level was still significantly higher in Group I, whereas triglyceride levels were not statistically different between both groups. At this time more sirolimus-treated patients were receiving lipid-lowering medications (mainly statins) (70.5% vs. 51%, p = 0.03). Printer- Friendly Email This
Am J Transplant. 2007;7(11):2522-2531. ©2007 Blackwell Publishing
This is a part of article Sirolimus Versus Cyclosporine in Kidney Recipients Taken from "Bactrim Antibiotic" Information Blog
