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Tacrolimus (FK506) versus cyclosporin a microemulsion (neoral) maintenance immunosuppression: effects on graft survival and function, infection, and metabolic profile following kidney transplantation (KT)
Molecular Immunology 39 (2003) 1095–1100
Tacrolimus (FK506) versus cyclosporin a microemulsion (neoral) maintenance immunosuppression: effects on graft survival and function, infection, and metabolic profile following kidney transplantation (KT) Maroun M. Abou-Jaoude a , Imad Ghantous a , Wassim Y. Almawi b,∗ b
a Department of Surgery, St.-George Hospital, Beirut, Lebanon Department of Medicine, College of Medicine and Medical Sciences, Arabian Gulf University, PO Box 22979, Manama, Bahrain
Abstract We reviewed two groups of kidney transplant patients receiving neoral (Group I, 27 patients) or FK506 (Group II, 25 patients) as maintenance immunosuppression between December 1998 and May 2002. The recipient and donor demographics and induction therapy were comparable in both groups except for more highly sensitized patients in Group II. Acute rejection (AR) rate and timing were similar in both groups except for more steroid resistant AR in Group II (P = 0.04). Infections rate was similar in both groups (25.9% in Group I and 36% in Group II; P = N.S.), but there were less viral infections in Group I (0%) than Group II (29%; 4 CMV). CMV infections were related to the presence in Group II of more CMV-negative recipients getting kidneys from CMV-positive donors. The metabolic profile was comparable between the two groups, except for a better HDL in Group II (48.2 ± 7.6) versus Group I (45 ± 2.2; P = 0.021). Mean serum creatinine levels upon discharge, at 1, 3 and 6 months were: 1.62 ± 0.32, 1.4 ± 0.17, 1.39 ± 0.14 and 1.4 ± 0.14 in Group I and 2.15 ± 0.5, 1.48 ± 0.23, 1.41 ± 0.21 and 1.23 ± 0.11 in Group II, respectively. The 6 months actuarial patient and graft survival were identical in both groups (100 and 100%). Both calcineurin inhibitors are effective and safe in KT. The higher rate of AR in Group II was related to more highly sensitized patients and the higher CMV infections was due to the presence of more CMV-negative recipients receiving kidneys from CMV-positive donors. The same study will be continued to evaluate the long term effects of both drugs. © 2003 Elsevier Science Ltd. All rights reserved. Keywords: Tacrolimus; Cyclosporin; Kidney transplantation
1. Introduction Neoral and FK506 are potent immunosuppressive drugs used in inhibiting post-transplant AR (Almawi and Melemedjian, 2000). They act by antagonizing the function of the calcium dependent calcineurin, a phosphatase implicated in the dephosphorylation of cytosolic NFAT and hence its proper nuclear translocation, inhibiting the interleukin 2 expression necessary for T-lymphocyte proliferation (Almawi and Melemedjian, 2000). Although treatment with either drug resulted in comparable 1-year patient and graft survival (Trompeter et al., 2002; Pirsch et al., 1997), FK506 proved to be superior to neoral in reducing and reversing biopsy-confirmed AR (Trompeter et al., 2002; Pirsch et al., 1997; Vincenti et al., 2002; Mayer et al., 1997) including recurrent and steroid-resistant rejections as well as chronic rejection (Reyes et al., 2000; Blume et al., 2001). Moreover, ∗
Corresponding author. Tel.: +973-9292958; fax: +973-271090. E-mail address: [email protected] (W.Y. Almawi).
better 5-year graft survival (Vincenti et al., 2002) and function appear to be more frequent in FK506-treated patients compared to neoral-treated patients (Trompeter et al., 2002). The esthetic and metabolic side effects related to neoral therapy has limited its use (Graham, 1994; Mazariegos et al., 2001). Effectively, patients treated with neoral suffered more from hirsutism, gingival hyperplasia, hyperlipidemia (Thorp et al., 2000) as well as hypertension (Baan et al., 2001). All these immunological and non-immunological phenomena have prompted serious evaluation of switching patients from neoral to FK506-based maintenance immunosuppression following transplantation (Blume et al., 2001; Abouljoud et al., 2001). In fact, marked reversal of neoral toxicity was seen following conversion to FK506 (Verleden et al., 2002), hence recommending early conversion for the treatment of acute and chronic rejection, and for the improvement in the patients’ quality of life (Reyes et al., 2000), particularly in renal allograft recipients with delayed graft function (DGF) from severe acute tubular necrosis (ATN) (Jang et al., 2000),
0161-5890/03/$ – see front matter © 2003 Elsevier Science Ltd. All rights reserved. doi:10.1016/S0161-5890(03)00070-1
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or steroid-resistant rejections (Blume et al., 2001). While conversion did not improve renal function, there was marked improvement in blood pressure and lipid profile (Baan et al., 2001). In fact, cholesterol and triglycerides blood levels decreased while creatinine blood level remained stable (Israni et al., 2002). During this drug conversion, no AR was observed (Israni et al., 2002; Kohnle et al., 2000), making this switch a safe alternative in patients suffering from hyperlipidemia following KT (Thorp et al., 2000; Kohnle et al., 2000; Boots et al., 2001). Owing to the reduced requirement for treating hypertension and hyperlipidemia with minimal risk of rejection or allograft dysfunction (Thorp et al., 2000), the cardiovascular risk profile was more favorable in improving the patient and graft survival (Reyes et al., 2000, 8) and making a considerable proportion of patients benefit from FK506 monotherapy as compared to co-therapy (Boots et al., 2001). The aim of this study was to compare FK506 to neoral as maintenance immunosuppressive therapy by looking at the rate of AR, infection, graft and patient survival as well as the metabolic profile in patients following KT.
Table 1 Characteristics of patients and donors P-valuea
Characteristic
Neoral
FK506
Number
27
25
Recipient age X ± S.D. Range (median)
44.5 ± 5.46 14–75 (44)
48.9 ± 4.0 31–68 (49.5)
N.S.b
Recipient gender (M:F)
22:5
17:8
N.S.b
Donor age X ± S.D. Range (median)
31.1 ± 3.3 18–51 (29)
28.0 ± 2.3 18–43 (28)
N.S.b N.S.b
Donor gender (M:F)
22:5
22:3
N.S.b
Donor type Cadaveric Living-related Emotionally-related
2 6 19
0 4 21
N.S.b N.S.b N.S.b
Blood group compatibility Identical 25 Compatible 2
22 3
N.S.b N.S.b
a b
Pearson’s χ2 -test. N.S.: not significant.
2. Materials and methods 2.1. Patient demographics Between December 1998 and May 2002, a total of 52 renal transplant patients were recruited into the study from St. George University Hospital, Beirut, Lebanon. The patients were randomized into Group I (n = 27) or Group II (n = 25), receiving neoral or FK506 as maintenance immunosuppression following KT, respectively. The causes for kidney failure were similar in both groups and consisted of: chronic glomerulonephritis (5 and 3) and chronic pyelonephritis (2 and 3) in Groups I and II. Kidney disease was unknown in 10 patients in Group I and 8 patients in Group II.
was performed on four patients in Group I and three in Group II. There were more highly sensitized patients in Group II (9/25) than in Group I (2/27; P = 0.011). These comprised previous transplants (0 versus 2), multiple transfusions (2 versus 3), and multiple pregnancies (0 versus 4) in Group I and Group II, respectively. Panel-reactive antibody (PRA) score was comparable between Group I and Group II. It was <20% in 13 patients in Group I and 11 patients in Group II. Six patients in Group I had a PRA score between 20 and 50% as well as three patients in Group II. PRA score higher than 50% was found in three patients in Group II but none in Group I (Table 2).
2.2. Characteristics of study participants
Table 2 Pre-transplant status of patients
The recipient mean age was comparable between Group I and Group II, and there was more males than females in both groups. Donor types were also comparable (cadaveric, living-related, and emotionally-related). The donor’s mean age and gender were also comparable between the two groups. Donor-recipient blood group matching was identical (25 and 22) and compatible (2 and 3) in Group I and Group II, respectively (P = N.S.). In addition, HLA-AB/DR matching was similar in Group I and Group II, and comprised no mis-matches (MM; 2 and 1), 3 MM (6 and 4), 4 MM (9 and 9), 5 MM (7 and 7), 6 MM (3 and 4) for Group I and Group II, respectively (Table 1).
Characteristic
Neoral
FK506
Number
27
25
Pre-transplant dialysis X ± S.D. Range (median)
12.8 ± 6.6 0–84 (8)
15.9 ± 5.9 0–60 (14.5)
2.3. Pre-transplant status
N.S.b
Pre-emptive dialysis
4
3
N.S.b
Sensitization Previous transplants Multiple transfusions Multiple pregnancies
0 2 0
2 3 4
0.011 0.011 0.011
13 6 0 8
11 3 3 8
N.S.b N.S.b N.S.b N.S.b
PRA scorec <20% 20–50% >50% Not determined
Pearson’s χ2 -test. N.S.: not significant. c Determined by ELISA method (lambda antigen tray). a
The requirement for pre-transplant dialysis (in months) was similar in Group I and Group II, and pre-emptive KT
P-valuea
b
M.M. Abou-Jaoude et al. / Molecular Immunology 39 (2003) 1095–1100 Table 3 Donors’ and receipients’ CMV status Characteristic
Neoral (disease)
FK506 (disease)
Na /Pb
4 23 0 0
3 20 0 2
P/P N/N P/N
(0) (0) (0) (0)
(0) (2) (0) (2)
Pearson’s χ2 -test (P-value = not significant). a P: IgM (−) and IgG (+) anti-CMV antibodies. b N: IgM (−) IgG (−) anti-CMV antibodies.
2.4. Donor and recipient CMV status Pre-transplant screening for anti-CMV antibodies was done for all patients, and the presence of a positive IgM anti-CMV antibody was confirmed by PCR; surgery was postponed in case of an active CMV infection. All patients in Group I had a previous but inactive CMV infection, and with the exception of four, have received a kidney from a CMV-positive donor (Table 3). Similarly, 23 of 25 patients in Group II received a kidney from a CMV-positive donor. The remaining two CMV-negative patients were transplanted from CMV-positive donors.
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between the third and the sixth month after KT. In Group II, FK506 was given at a dose of 0.1 mg/kg twice daily aiming for a trough blood level between 12 and 15 ng/ml the first month, 10–12 between the first and the third month and 8–10 between the third and the sixth month after KT. Four patients in the neoral group were converted later to FK506 because of slow graft function (two patients), or the development of neoral-associated hirsutism (two patients). 2.6. Anti-infection prophylaxis All patients received a second generation cephalosporine 1 i.v. dose upon induction and three doses after the transplant surgery. Anti-viral prophylaxis consisted of i.v. ganciclovir 10–14 days after the surgery followed by per os valacyclovir for a period of 3 months or 4 months for the patients who have received the extended regimen of ATG-F. Antiviral medication doses were adjusted based on the calculated glomerular filtration rate. Trimethoprim-sulfamethoxazole was given routinely in all patients for a period of 1 year as a prevention therapy against pneumocystis carinii infections. 2.7. Diagnosis of infections
2.5. Immunosuppressive regimen Induction and maintenance immunosuppressive regimens were comparable between the two groups. Induction therapy consisted of: two doses of Daclizumab (anti-low affinity IL-2 receptor antibody) (2 and 1), one dose of Daclizumab (6 and 2), intra-operative bolus of anti-thymocyte globulin-fresenius (ATG-F) (13 and 11), or the extended regimen of ATG-F (3 and 10) in Group I and Group II, respectively. No induction therapy was given in three patients in Group I and one patient in Group II. Maintenance immunosuppression consisted of triple therapy in which neoral or FK506 was combined with prednisone and an anti-metabolite: mycophenolate mofetil (MMF) or azathioprine (AZA). Intravenous methylprednisolone was given during the surgery at a dose of 500 mg and was tapered progressively to 0.2 mg/kg per day of oral prednisone by 1 month. MMF was started 2 days before the surgery at a dose of 1 g twice daily in Group I patients or half of the dose in Group II patients, and AZA was given in case of MMF intolerance or cost, at a dose of 2 mg/kg per day then tapered progressively to 1 mg/kg per day over 6-month period. Calcineurin inhibitors were given the day after transplantation if urine output was satisfactory. In case of DGF, their introduction was delayed until the graft recovery and the extended regimen of ATG-F was given. In Group I, neoral was started at a dose of 8 mg/kg per day in two divided doses aiming for a 2 h blood level of 1700 ng/ml during the first month, then 1500 ng/ml for the period between the first and the third month, then 1200 ng/ml
Urine culture was done routinely after the urinary catheter was removed on day 5 after transplantation. Thereafter, urine culture was obtained weekly on a routine basis and more frequently when indicated. The indwelling arterial and central venous monitoring catheters were removed in all patients as soon as possible and their tips were cultured. Similarly, central intravascular catheters used for hemodialysis access were also cultured when removed. Cultures were also taken from other sites (e.g. drains) when patients had persistently elevated leucocyte counts or episodes of fever. Bronchoscopy and bronchial lavage were performed when a pulmonary infiltrate was present and sputum samples were inadequate. Viral infections were diagnosed on the basis of positive PCR test, or histological proof of tissue invasion, or seroconversion or a four-fold rise in antiviral titres. All episodes of infections until 6 months post-transplant were analyzed. Intravascular catheters were regarded infected when the patient is symptomatic and the fever resolve upon catheter removal. The urine was considered infected if greater than 100,000 organisms/ml were present. 2.8. Diagnosis of AR AR diagnosis was based on graft biopsy or when an elevated serum creatinine responded to a 3 days bolus of intravenous Solumedrol therapy after excluding other causes of graft dysfunction. ATG-F was given in case of steroid-resistant AR or for grades II and III AR based on Banff histological classification (Schroeder et al., 1991).
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2.9. Follow-up
Table 4 Main outcome: neoral vs. FK506
After their hospital discharge, patients were followed on a routine outpatient basis. Besides the clinical profile, all patients were monitored for fasting blood glucose (FBG), creatinine, and lipid profile which included total cholesterol, triglycerides, HDL and LDL cholesterol.
Parameter
Neoral
FK506
P-valuea
Acute rejection Number of episodes Timing (days) ATG-F requirement
2/27 3–7 0/2
5/25 5–11 3/5
N.S.b N.S.b 0.04
Hospital stay (days) Mean ± S.D. Range Median
11.8 ± 1.2 8–20 11
12.8 ± 1.4 8–24 13
N.S.b N.S.b N.S.b
Post-transplant infections Patients Episodes Episodes per patient
7 8 1.1
9 14 1.5
N.S.b N.S.b N.S.b
Infection types Bacterialc Virald Fungal
8/7 (100%) 0 0
10/8 (71%) 4/4 (29%) 0
N.S.b 0.03 N.S.b
Serum creatinine Upon discharge 1 month post-discharge 2 months post-discharge 6 months post-discharge
1.62 ± 0.32 1.4 ± 0.17 1.39 ± 0.14 1.4 ± 0.14
2.15 1.48 1.41 1.23
± ± ± ±
0.06 N.S.b N.S.b 0.03
2.10. Statistical analysis When stated, data were presented as mean ± S.D., or as percent of total. Pearson’s χ2 -test was used to assess statistical significance.
3. Results 3.1. AR and infection rates AR occurred in 2 out of 27 patients (7.4%) in Group I and 5 out of 25 patients (20%) in Group II (P = N.S.). However, ATG-F bolus rescue therapy was provided to three (all highly sensitized) out of five rejected patients in Group II but none for the two AR patients in Group I (P = 0.04). This was related to more highly sensitized patients in Group II (nine patients) in comparison to Group I (2 patients) (Table 2). The onset of AR was similar in the two groups (P = N.S.). No statistically difference was noted between the 2 groups (25.93% in Group I and 36% in Group II) with regards to infection, a total of 8 infections in 7 patients in Group I was compared to 14 infections in 9 patients in Group II. Urinary (50%) and central line related infections (25%) were the most frequently encountered infections in Group I patients whereas urinary (30%), central line related (30%) and respiratory (20%) infections were mostly seen in Group II patients. In both groups, E. coli and Klebsiella were the most common isolated bacteria from the urinary infections. Respiratory infections were due mainly to Serratia. Of the intravascular catheter-related infections, 66% were due to S. aureus in Group II patients and 100% to S. epidermidis in Group I patients. Whereas infections were solely bacterial in Group I patients, four viral infections were seen in Group II patients (P = 0.03) (Table 4). These comprised CMV gastritis (n = 3) and CMV urethritis (n = 1). These CMV infections were related to the presence in Group II of more CMV-negative recipients receiving kidneys from CMV-positive donors. All these infections were diagnosed by tissue biopsy, except for the patient with CMV urethritis in whom the disease was diagnosed by a positive PCR in the urine. All of these infections were successfully treated by intravenous Ganciclovir during 2 weeks followed by an oral course of the same drug for a period of 6 weeks. No fungal infections were noted in both groups.
0.54 0.23 0.21 0.11
Pearson’s χ2 -test. N.S.: not significant. c Bacterial infections included urinary, and central line related infections in Group I and urinary, central line related and pulmonary infections in Group II. d Viral infections comprised four CMV and one herpes virus. a
b
3.2. Metabolic effects No statistically significant differences were noticed between the two groups with regards to fasting blood glucose levels, since post-transplant FBG was 106.3 ± 9.9 and 122.2 ± 25.3 mg/dl for Group I and Group II, respectively (P = N.S.) (Table 5). Five patients in Group I and nine patients in Group II had a post-transplant FBG >110 mg/dl (P = N.S.). Post-transplant insulin therapy was required in three patients in each group. In addition, post-transplant serum lipid profile was generally comparable between the two groups. Total cholesterol (247.3±24.9 and 231.7±21.6), LDL (161.6 ± 13.7 and 146.3 ± 25.0), and triglycerides (280.2 ± 48.1 and 235.7 ± 69.5) blood levels were comparable between neoral and FK506-treated patients, while HDL were higher in the FK506 group (48.2 ± 7.6) compared with the neoral group (45.0 ± 2.2; P = 0.021) (Table 5). Seven patients in Group I and four patients in Group II needed anti-hypertensive therapy after KT (P = N.S.). 3.3. Patients and grafts outcomes The patient’s hospital stay for Group I (11.8 ± 1.2 days) was similar to that of Group II (12.8 ± 1.4 days). Upon discharge, mean serum creatinine level was higher but not statistically different in Group II compared to Group I
M.M. Abou-Jaoude et al. / Molecular Immunology 39 (2003) 1095–1100 Table 5 Metabolic effects: neoral vs. FK506 Neoral
FK506
P-valuea
98.7 ± 7.8 106.3 ± 9.9 5 3
96.5 ± 8.6 122.2 ± 25.3 9 3
N.S.c N.S.c N.S.c N.S.c
Cholesterolb Pre-transplant Post-transplant Post-transplant cholesterol >240
182.6 ± 20.6 247.3 ± 24.9 11
196.0 ± 20.1 231.7 ± 21.6 7
N.S.c N.S.c N.S.c
Triglyceridesb Pre-transplant Post-transplant Post-transplant triglyceride >200
209.1 ± 56.2 280.2 ± 48.1 14
222.3 ± 44.4 235.7 ± 69.5 8
N.S.c N.S.c N.S.c
45.0 ± 2.2
48.2 ± 7.6
0.021
161.6 ± 13.7
146.3 ± 25.0
N.S.c
Parameter Fasting glucoseb Pre-transplant Post-transplant Post-transplant FBG >110 Post-transplant insulin therapy
HDLb Post-transplant LDLb Post-transplant Pearson’s χ2 -test. Concentration in mg/dl. c N.S.: not significant. a
b
(2.15 ± 0.54 and 1.62 ± 0.32, respectively) (Table 4). This was related to more incidental slow graft function observed in that group. Thereafter, there was a pronounced progressive decline in serum creatinine in Group II to reach the value of 1.23 ± 0.11 at 6 months post-discharge as compared to 1.4 ± 0.14 in Group I (P = 0.03). The 6 months actuarial patient and graft survival were identical in both groups (100% and 100%).
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fected patient), viral infections were seen in the FK506 but not in the neoral-treated patients, in apparent disagreement with reports which indicated similar (Pirsch, 1999), or even lower (Hadley et al., 1995) frequency of viral (CMV) infections in FK506 compared to neoral-treated patients. This was largely the consequence of more CMV-negative recipients receiving renal grafts from CMV-positive donors. However, both 6 months patient and graft survival were excellent (100%) in both groups, which was better than previously reported studies (Mayer et al., 1997). Higher incidence of hyperglycemia and post-kidney transplant diabetes were previously reported with FK506 therapy (Mayer et al., 1997; Chand et al., 2001; Krentz et al., 1994). In contrast, requirement for anti-hypertension therapy was shown to be more frequent in neoral-treated patients (Selzner et al., 2001; Hohage et al., 1996). In our study, no differences on the incidence at 6 months of post-transplant diabetes (as manifested by increased FBG and requirement for Insulin therapy) or lipid profile (cholesterol, triglycerides, LDL, though not HDL) were seen in FK506 and neoral-treated patients. This was in agreement with other reports which demonstrated comparable metabolic profile between neoral and FK506 (Vincenti et al., 2002; Pirsch et al., 1997). This contradiction with earlier reports is most likely due to the small sample size in our study (Selzner et al., 2001; Hohage et al., 1996). In conclusion, both calcineurin inhibitors are effective and safe in KT with excellent patient survival as well as graft survival and function. With the exception of HDL, the metabolic profile was comparable among the two immunosuppressive regimens. However, FK506 therapy seems to be associated with a higher incidence of viral infections as compared to neoral. The same study will be continued to evaluate the long term effects of both drugs.
References 4. Discussion The results of this study support earlier findings pertaining to the effectiveness and safety of FK506 and neoral as maintenance immunosuppressive therapy following KT. While FK506 therapy was reportedly associated with reduced incidence of AR (Vincenti et al., 2002, Pirsch et al., 1997), higher number of steroid-resistant AR episodes requiring ATG-F rescue therapy was noted in Group II (FK506) patients. This was principally due to the higher number of highly sensitized patients in that group, thus explaining the apparent discrepancy between our results and previous findings. In spite of this, there was a progressive improvement in graft function (decline in serum creatinine) over a period of 6 months, which was significantly lower in the FK506 than the neoral group, similar to findings elsewhere (Vincenti et al., 2002; Mayer et al., 1997). While infection rate was comparable among the two groups (number of infected patients and infections per in-
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Tacrolimus (FK506) versus cyclosporin a microemulsion (neoral) maintenance immunosuppression: effects on graft survival and function, infection, and metabolic profile following kidney transplantation (KT) Maroun M. Abou-Jaoude a , Imad Ghantous a , Wassim Y. Almawi b,∗ b
a Department of Surgery, St.-George Hospital, Beirut, Lebanon Department of Medicine, College of Medicine and Medical Sciences, Arabian Gulf University, PO Box 22979, Manama, Bahrain
Abstract We reviewed two groups of kidney transplant patients receiving neoral (Group I, 27 patients) or FK506 (Group II, 25 patients) as maintenance immunosuppression between December 1998 and May 2002. The recipient and donor demographics and induction therapy were comparable in both groups except for more highly sensitized patients in Group II. Acute rejection (AR) rate and timing were similar in both groups except for more steroid resistant AR in Group II (P = 0.04). Infections rate was similar in both groups (25.9% in Group I and 36% in Group II; P = N.S.), but there were less viral infections in Group I (0%) than Group II (29%; 4 CMV). CMV infections were related to the presence in Group II of more CMV-negative recipients getting kidneys from CMV-positive donors. The metabolic profile was comparable between the two groups, except for a better HDL in Group II (48.2 ± 7.6) versus Group I (45 ± 2.2; P = 0.021). Mean serum creatinine levels upon discharge, at 1, 3 and 6 months were: 1.62 ± 0.32, 1.4 ± 0.17, 1.39 ± 0.14 and 1.4 ± 0.14 in Group I and 2.15 ± 0.5, 1.48 ± 0.23, 1.41 ± 0.21 and 1.23 ± 0.11 in Group II, respectively. The 6 months actuarial patient and graft survival were identical in both groups (100 and 100%). Both calcineurin inhibitors are effective and safe in KT. The higher rate of AR in Group II was related to more highly sensitized patients and the higher CMV infections was due to the presence of more CMV-negative recipients receiving kidneys from CMV-positive donors. The same study will be continued to evaluate the long term effects of both drugs. © 2003 Elsevier Science Ltd. All rights reserved. Keywords: Tacrolimus; Cyclosporin; Kidney transplantation
1. Introduction Neoral and FK506 are potent immunosuppressive drugs used in inhibiting post-transplant AR (Almawi and Melemedjian, 2000). They act by antagonizing the function of the calcium dependent calcineurin, a phosphatase implicated in the dephosphorylation of cytosolic NFAT and hence its proper nuclear translocation, inhibiting the interleukin 2 expression necessary for T-lymphocyte proliferation (Almawi and Melemedjian, 2000). Although treatment with either drug resulted in comparable 1-year patient and graft survival (Trompeter et al., 2002; Pirsch et al., 1997), FK506 proved to be superior to neoral in reducing and reversing biopsy-confirmed AR (Trompeter et al., 2002; Pirsch et al., 1997; Vincenti et al., 2002; Mayer et al., 1997) including recurrent and steroid-resistant rejections as well as chronic rejection (Reyes et al., 2000; Blume et al., 2001). Moreover, ∗
Corresponding author. Tel.: +973-9292958; fax: +973-271090. E-mail address: [email protected] (W.Y. Almawi).
better 5-year graft survival (Vincenti et al., 2002) and function appear to be more frequent in FK506-treated patients compared to neoral-treated patients (Trompeter et al., 2002). The esthetic and metabolic side effects related to neoral therapy has limited its use (Graham, 1994; Mazariegos et al., 2001). Effectively, patients treated with neoral suffered more from hirsutism, gingival hyperplasia, hyperlipidemia (Thorp et al., 2000) as well as hypertension (Baan et al., 2001). All these immunological and non-immunological phenomena have prompted serious evaluation of switching patients from neoral to FK506-based maintenance immunosuppression following transplantation (Blume et al., 2001; Abouljoud et al., 2001). In fact, marked reversal of neoral toxicity was seen following conversion to FK506 (Verleden et al., 2002), hence recommending early conversion for the treatment of acute and chronic rejection, and for the improvement in the patients’ quality of life (Reyes et al., 2000), particularly in renal allograft recipients with delayed graft function (DGF) from severe acute tubular necrosis (ATN) (Jang et al., 2000),
0161-5890/03/$ – see front matter © 2003 Elsevier Science Ltd. All rights reserved. doi:10.1016/S0161-5890(03)00070-1
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or steroid-resistant rejections (Blume et al., 2001). While conversion did not improve renal function, there was marked improvement in blood pressure and lipid profile (Baan et al., 2001). In fact, cholesterol and triglycerides blood levels decreased while creatinine blood level remained stable (Israni et al., 2002). During this drug conversion, no AR was observed (Israni et al., 2002; Kohnle et al., 2000), making this switch a safe alternative in patients suffering from hyperlipidemia following KT (Thorp et al., 2000; Kohnle et al., 2000; Boots et al., 2001). Owing to the reduced requirement for treating hypertension and hyperlipidemia with minimal risk of rejection or allograft dysfunction (Thorp et al., 2000), the cardiovascular risk profile was more favorable in improving the patient and graft survival (Reyes et al., 2000, 8) and making a considerable proportion of patients benefit from FK506 monotherapy as compared to co-therapy (Boots et al., 2001). The aim of this study was to compare FK506 to neoral as maintenance immunosuppressive therapy by looking at the rate of AR, infection, graft and patient survival as well as the metabolic profile in patients following KT.
Table 1 Characteristics of patients and donors P-valuea
Characteristic
Neoral
FK506
Number
27
25
Recipient age X ± S.D. Range (median)
44.5 ± 5.46 14–75 (44)
48.9 ± 4.0 31–68 (49.5)
N.S.b
Recipient gender (M:F)
22:5
17:8
N.S.b
Donor age X ± S.D. Range (median)
31.1 ± 3.3 18–51 (29)
28.0 ± 2.3 18–43 (28)
N.S.b N.S.b
Donor gender (M:F)
22:5
22:3
N.S.b
Donor type Cadaveric Living-related Emotionally-related
2 6 19
0 4 21
N.S.b N.S.b N.S.b
Blood group compatibility Identical 25 Compatible 2
22 3
N.S.b N.S.b
a b
Pearson’s χ2 -test. N.S.: not significant.
2. Materials and methods 2.1. Patient demographics Between December 1998 and May 2002, a total of 52 renal transplant patients were recruited into the study from St. George University Hospital, Beirut, Lebanon. The patients were randomized into Group I (n = 27) or Group II (n = 25), receiving neoral or FK506 as maintenance immunosuppression following KT, respectively. The causes for kidney failure were similar in both groups and consisted of: chronic glomerulonephritis (5 and 3) and chronic pyelonephritis (2 and 3) in Groups I and II. Kidney disease was unknown in 10 patients in Group I and 8 patients in Group II.
was performed on four patients in Group I and three in Group II. There were more highly sensitized patients in Group II (9/25) than in Group I (2/27; P = 0.011). These comprised previous transplants (0 versus 2), multiple transfusions (2 versus 3), and multiple pregnancies (0 versus 4) in Group I and Group II, respectively. Panel-reactive antibody (PRA) score was comparable between Group I and Group II. It was <20% in 13 patients in Group I and 11 patients in Group II. Six patients in Group I had a PRA score between 20 and 50% as well as three patients in Group II. PRA score higher than 50% was found in three patients in Group II but none in Group I (Table 2).
2.2. Characteristics of study participants
Table 2 Pre-transplant status of patients
The recipient mean age was comparable between Group I and Group II, and there was more males than females in both groups. Donor types were also comparable (cadaveric, living-related, and emotionally-related). The donor’s mean age and gender were also comparable between the two groups. Donor-recipient blood group matching was identical (25 and 22) and compatible (2 and 3) in Group I and Group II, respectively (P = N.S.). In addition, HLA-AB/DR matching was similar in Group I and Group II, and comprised no mis-matches (MM; 2 and 1), 3 MM (6 and 4), 4 MM (9 and 9), 5 MM (7 and 7), 6 MM (3 and 4) for Group I and Group II, respectively (Table 1).
Characteristic
Neoral
FK506
Number
27
25
Pre-transplant dialysis X ± S.D. Range (median)
12.8 ± 6.6 0–84 (8)
15.9 ± 5.9 0–60 (14.5)
2.3. Pre-transplant status
N.S.b
Pre-emptive dialysis
4
3
N.S.b
Sensitization Previous transplants Multiple transfusions Multiple pregnancies
0 2 0
2 3 4
0.011 0.011 0.011
13 6 0 8
11 3 3 8
N.S.b N.S.b N.S.b N.S.b
PRA scorec <20% 20–50% >50% Not determined
Pearson’s χ2 -test. N.S.: not significant. c Determined by ELISA method (lambda antigen tray). a
The requirement for pre-transplant dialysis (in months) was similar in Group I and Group II, and pre-emptive KT
P-valuea
b
M.M. Abou-Jaoude et al. / Molecular Immunology 39 (2003) 1095–1100 Table 3 Donors’ and receipients’ CMV status Characteristic
Neoral (disease)
FK506 (disease)
Na /Pb
4 23 0 0
3 20 0 2
P/P N/N P/N
(0) (0) (0) (0)
(0) (2) (0) (2)
Pearson’s χ2 -test (P-value = not significant). a P: IgM (−) and IgG (+) anti-CMV antibodies. b N: IgM (−) IgG (−) anti-CMV antibodies.
2.4. Donor and recipient CMV status Pre-transplant screening for anti-CMV antibodies was done for all patients, and the presence of a positive IgM anti-CMV antibody was confirmed by PCR; surgery was postponed in case of an active CMV infection. All patients in Group I had a previous but inactive CMV infection, and with the exception of four, have received a kidney from a CMV-positive donor (Table 3). Similarly, 23 of 25 patients in Group II received a kidney from a CMV-positive donor. The remaining two CMV-negative patients were transplanted from CMV-positive donors.
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between the third and the sixth month after KT. In Group II, FK506 was given at a dose of 0.1 mg/kg twice daily aiming for a trough blood level between 12 and 15 ng/ml the first month, 10–12 between the first and the third month and 8–10 between the third and the sixth month after KT. Four patients in the neoral group were converted later to FK506 because of slow graft function (two patients), or the development of neoral-associated hirsutism (two patients). 2.6. Anti-infection prophylaxis All patients received a second generation cephalosporine 1 i.v. dose upon induction and three doses after the transplant surgery. Anti-viral prophylaxis consisted of i.v. ganciclovir 10–14 days after the surgery followed by per os valacyclovir for a period of 3 months or 4 months for the patients who have received the extended regimen of ATG-F. Antiviral medication doses were adjusted based on the calculated glomerular filtration rate. Trimethoprim-sulfamethoxazole was given routinely in all patients for a period of 1 year as a prevention therapy against pneumocystis carinii infections. 2.7. Diagnosis of infections
2.5. Immunosuppressive regimen Induction and maintenance immunosuppressive regimens were comparable between the two groups. Induction therapy consisted of: two doses of Daclizumab (anti-low affinity IL-2 receptor antibody) (2 and 1), one dose of Daclizumab (6 and 2), intra-operative bolus of anti-thymocyte globulin-fresenius (ATG-F) (13 and 11), or the extended regimen of ATG-F (3 and 10) in Group I and Group II, respectively. No induction therapy was given in three patients in Group I and one patient in Group II. Maintenance immunosuppression consisted of triple therapy in which neoral or FK506 was combined with prednisone and an anti-metabolite: mycophenolate mofetil (MMF) or azathioprine (AZA). Intravenous methylprednisolone was given during the surgery at a dose of 500 mg and was tapered progressively to 0.2 mg/kg per day of oral prednisone by 1 month. MMF was started 2 days before the surgery at a dose of 1 g twice daily in Group I patients or half of the dose in Group II patients, and AZA was given in case of MMF intolerance or cost, at a dose of 2 mg/kg per day then tapered progressively to 1 mg/kg per day over 6-month period. Calcineurin inhibitors were given the day after transplantation if urine output was satisfactory. In case of DGF, their introduction was delayed until the graft recovery and the extended regimen of ATG-F was given. In Group I, neoral was started at a dose of 8 mg/kg per day in two divided doses aiming for a 2 h blood level of 1700 ng/ml during the first month, then 1500 ng/ml for the period between the first and the third month, then 1200 ng/ml
Urine culture was done routinely after the urinary catheter was removed on day 5 after transplantation. Thereafter, urine culture was obtained weekly on a routine basis and more frequently when indicated. The indwelling arterial and central venous monitoring catheters were removed in all patients as soon as possible and their tips were cultured. Similarly, central intravascular catheters used for hemodialysis access were also cultured when removed. Cultures were also taken from other sites (e.g. drains) when patients had persistently elevated leucocyte counts or episodes of fever. Bronchoscopy and bronchial lavage were performed when a pulmonary infiltrate was present and sputum samples were inadequate. Viral infections were diagnosed on the basis of positive PCR test, or histological proof of tissue invasion, or seroconversion or a four-fold rise in antiviral titres. All episodes of infections until 6 months post-transplant were analyzed. Intravascular catheters were regarded infected when the patient is symptomatic and the fever resolve upon catheter removal. The urine was considered infected if greater than 100,000 organisms/ml were present. 2.8. Diagnosis of AR AR diagnosis was based on graft biopsy or when an elevated serum creatinine responded to a 3 days bolus of intravenous Solumedrol therapy after excluding other causes of graft dysfunction. ATG-F was given in case of steroid-resistant AR or for grades II and III AR based on Banff histological classification (Schroeder et al., 1991).
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2.9. Follow-up
Table 4 Main outcome: neoral vs. FK506
After their hospital discharge, patients were followed on a routine outpatient basis. Besides the clinical profile, all patients were monitored for fasting blood glucose (FBG), creatinine, and lipid profile which included total cholesterol, triglycerides, HDL and LDL cholesterol.
Parameter
Neoral
FK506
P-valuea
Acute rejection Number of episodes Timing (days) ATG-F requirement
2/27 3–7 0/2
5/25 5–11 3/5
N.S.b N.S.b 0.04
Hospital stay (days) Mean ± S.D. Range Median
11.8 ± 1.2 8–20 11
12.8 ± 1.4 8–24 13
N.S.b N.S.b N.S.b
Post-transplant infections Patients Episodes Episodes per patient
7 8 1.1
9 14 1.5
N.S.b N.S.b N.S.b
Infection types Bacterialc Virald Fungal
8/7 (100%) 0 0
10/8 (71%) 4/4 (29%) 0
N.S.b 0.03 N.S.b
Serum creatinine Upon discharge 1 month post-discharge 2 months post-discharge 6 months post-discharge
1.62 ± 0.32 1.4 ± 0.17 1.39 ± 0.14 1.4 ± 0.14
2.15 1.48 1.41 1.23
± ± ± ±
0.06 N.S.b N.S.b 0.03
2.10. Statistical analysis When stated, data were presented as mean ± S.D., or as percent of total. Pearson’s χ2 -test was used to assess statistical significance.
3. Results 3.1. AR and infection rates AR occurred in 2 out of 27 patients (7.4%) in Group I and 5 out of 25 patients (20%) in Group II (P = N.S.). However, ATG-F bolus rescue therapy was provided to three (all highly sensitized) out of five rejected patients in Group II but none for the two AR patients in Group I (P = 0.04). This was related to more highly sensitized patients in Group II (nine patients) in comparison to Group I (2 patients) (Table 2). The onset of AR was similar in the two groups (P = N.S.). No statistically difference was noted between the 2 groups (25.93% in Group I and 36% in Group II) with regards to infection, a total of 8 infections in 7 patients in Group I was compared to 14 infections in 9 patients in Group II. Urinary (50%) and central line related infections (25%) were the most frequently encountered infections in Group I patients whereas urinary (30%), central line related (30%) and respiratory (20%) infections were mostly seen in Group II patients. In both groups, E. coli and Klebsiella were the most common isolated bacteria from the urinary infections. Respiratory infections were due mainly to Serratia. Of the intravascular catheter-related infections, 66% were due to S. aureus in Group II patients and 100% to S. epidermidis in Group I patients. Whereas infections were solely bacterial in Group I patients, four viral infections were seen in Group II patients (P = 0.03) (Table 4). These comprised CMV gastritis (n = 3) and CMV urethritis (n = 1). These CMV infections were related to the presence in Group II of more CMV-negative recipients receiving kidneys from CMV-positive donors. All these infections were diagnosed by tissue biopsy, except for the patient with CMV urethritis in whom the disease was diagnosed by a positive PCR in the urine. All of these infections were successfully treated by intravenous Ganciclovir during 2 weeks followed by an oral course of the same drug for a period of 6 weeks. No fungal infections were noted in both groups.
0.54 0.23 0.21 0.11
Pearson’s χ2 -test. N.S.: not significant. c Bacterial infections included urinary, and central line related infections in Group I and urinary, central line related and pulmonary infections in Group II. d Viral infections comprised four CMV and one herpes virus. a
b
3.2. Metabolic effects No statistically significant differences were noticed between the two groups with regards to fasting blood glucose levels, since post-transplant FBG was 106.3 ± 9.9 and 122.2 ± 25.3 mg/dl for Group I and Group II, respectively (P = N.S.) (Table 5). Five patients in Group I and nine patients in Group II had a post-transplant FBG >110 mg/dl (P = N.S.). Post-transplant insulin therapy was required in three patients in each group. In addition, post-transplant serum lipid profile was generally comparable between the two groups. Total cholesterol (247.3±24.9 and 231.7±21.6), LDL (161.6 ± 13.7 and 146.3 ± 25.0), and triglycerides (280.2 ± 48.1 and 235.7 ± 69.5) blood levels were comparable between neoral and FK506-treated patients, while HDL were higher in the FK506 group (48.2 ± 7.6) compared with the neoral group (45.0 ± 2.2; P = 0.021) (Table 5). Seven patients in Group I and four patients in Group II needed anti-hypertensive therapy after KT (P = N.S.). 3.3. Patients and grafts outcomes The patient’s hospital stay for Group I (11.8 ± 1.2 days) was similar to that of Group II (12.8 ± 1.4 days). Upon discharge, mean serum creatinine level was higher but not statistically different in Group II compared to Group I
M.M. Abou-Jaoude et al. / Molecular Immunology 39 (2003) 1095–1100 Table 5 Metabolic effects: neoral vs. FK506 Neoral
FK506
P-valuea
98.7 ± 7.8 106.3 ± 9.9 5 3
96.5 ± 8.6 122.2 ± 25.3 9 3
N.S.c N.S.c N.S.c N.S.c
Cholesterolb Pre-transplant Post-transplant Post-transplant cholesterol >240
182.6 ± 20.6 247.3 ± 24.9 11
196.0 ± 20.1 231.7 ± 21.6 7
N.S.c N.S.c N.S.c
Triglyceridesb Pre-transplant Post-transplant Post-transplant triglyceride >200
209.1 ± 56.2 280.2 ± 48.1 14
222.3 ± 44.4 235.7 ± 69.5 8
N.S.c N.S.c N.S.c
45.0 ± 2.2
48.2 ± 7.6
0.021
161.6 ± 13.7
146.3 ± 25.0
N.S.c
Parameter Fasting glucoseb Pre-transplant Post-transplant Post-transplant FBG >110 Post-transplant insulin therapy
HDLb Post-transplant LDLb Post-transplant Pearson’s χ2 -test. Concentration in mg/dl. c N.S.: not significant. a
b
(2.15 ± 0.54 and 1.62 ± 0.32, respectively) (Table 4). This was related to more incidental slow graft function observed in that group. Thereafter, there was a pronounced progressive decline in serum creatinine in Group II to reach the value of 1.23 ± 0.11 at 6 months post-discharge as compared to 1.4 ± 0.14 in Group I (P = 0.03). The 6 months actuarial patient and graft survival were identical in both groups (100% and 100%).
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fected patient), viral infections were seen in the FK506 but not in the neoral-treated patients, in apparent disagreement with reports which indicated similar (Pirsch, 1999), or even lower (Hadley et al., 1995) frequency of viral (CMV) infections in FK506 compared to neoral-treated patients. This was largely the consequence of more CMV-negative recipients receiving renal grafts from CMV-positive donors. However, both 6 months patient and graft survival were excellent (100%) in both groups, which was better than previously reported studies (Mayer et al., 1997). Higher incidence of hyperglycemia and post-kidney transplant diabetes were previously reported with FK506 therapy (Mayer et al., 1997; Chand et al., 2001; Krentz et al., 1994). In contrast, requirement for anti-hypertension therapy was shown to be more frequent in neoral-treated patients (Selzner et al., 2001; Hohage et al., 1996). In our study, no differences on the incidence at 6 months of post-transplant diabetes (as manifested by increased FBG and requirement for Insulin therapy) or lipid profile (cholesterol, triglycerides, LDL, though not HDL) were seen in FK506 and neoral-treated patients. This was in agreement with other reports which demonstrated comparable metabolic profile between neoral and FK506 (Vincenti et al., 2002; Pirsch et al., 1997). This contradiction with earlier reports is most likely due to the small sample size in our study (Selzner et al., 2001; Hohage et al., 1996). In conclusion, both calcineurin inhibitors are effective and safe in KT with excellent patient survival as well as graft survival and function. With the exception of HDL, the metabolic profile was comparable among the two immunosuppressive regimens. However, FK506 therapy seems to be associated with a higher incidence of viral infections as compared to neoral. The same study will be continued to evaluate the long term effects of both drugs.
References 4. Discussion The results of this study support earlier findings pertaining to the effectiveness and safety of FK506 and neoral as maintenance immunosuppressive therapy following KT. While FK506 therapy was reportedly associated with reduced incidence of AR (Vincenti et al., 2002, Pirsch et al., 1997), higher number of steroid-resistant AR episodes requiring ATG-F rescue therapy was noted in Group II (FK506) patients. This was principally due to the higher number of highly sensitized patients in that group, thus explaining the apparent discrepancy between our results and previous findings. In spite of this, there was a progressive improvement in graft function (decline in serum creatinine) over a period of 6 months, which was significantly lower in the FK506 than the neoral group, similar to findings elsewhere (Vincenti et al., 2002; Mayer et al., 1997). While infection rate was comparable among the two groups (number of infected patients and infections per in-
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