- Email: [email protected]
Cyclosporine C2 Levels in De Novo Renal Allograft Recipients: A German Multicenter Prospective Observational Study
Cyclosporine C2 Levels in De Novo Renal Allograft Recipients: A German Multicenter Prospective Observational Study W. Arns, F. Zantvoort, D. Abendroth, H. Seiter, E.-H. Scheuermann, U. Albert, R. Stahl, P. Fornara, L. Fricke, H.H. Neumayer, E. Nagel, U. Michel, and B. Ulbricht Abstract This ongoing multicenter prospective observational study was undertaken in de novo renal allograft recipients managed with cyclosporine (CsA) trough (C0) and 2-hour postdose (C2) level monitoring at defined times so as to assess the risk for an acute rejection episode or allograft dysfunction. The renal transplant recipients (n ⫽ 159) were enrolled at 11 German centers. The 6-month posttransplant data from 138 patients were evaluable for this interim analysis. Mean C2 levels (ng/mL), which were measured by liquid chromatography-tandem mass spectrometry at a central laboratory, were: days 3 to 5: 873.1 ⫾ 391.9; days 7 to 10: 939.1 ⫾ 422.8; days 14 to 28: 1116.3 ⫾ 497.6; 3 months: 905.0 ⫾ 316.8; and after 6 months: 787.0 ⫾ 276.5. To identify patients at higher risk for acute rejection or allograft dysfunction, we calculated the relative CsA absorption capacity (C2 [ng/mL]/ morning dose [mg/kg]; CsA-Abs), yielding mean values on days 3 to 5: 284.4 ⫾ 115.1; days 7 to 10: 306.7 ⫾ 134.8; days 14 to 28: 382.5 ⫾ 164.7; month 3: 501.5 ⫾ 168.8; month 6: 512.7 ⫾ 176.5. Three groups were distinguished by CsA-Abs at days 7 to 10: low absorbers (CsA-Abs ⬍ 200), normal absorbers (CsA-Abs 200 to 350), and high absorbers (CsA-Abs ⬎ 350). A between-group comparison of absorption level at 6 months posttransplant revealed the incidences of biopsy-proven acute rejection and Cockcroft-Gault formulabased mean glomerular filtration rates of 23.8% and 54.7 ⫾ 19.0 mL/min, 22.6% and 59.5 ⫾ 20.7 mL/min, and 17.6% and 67.7 ⫾ 23.5, respectively. In conclusion, mean C2 levels ⬎1000 ng/mL are attained within 2 to 4 weeks, with CsA-Abs increasing continuously over the first 6 posttransplant months. High CsA absorbers show a propensity toward good allograft function and lower acute rejection rates at 6 months after renal transplantation. VIDENCE IS MOUNTING that the 2-hour postdose (C2) levels of cyclosporine (CsA), the mainstay of immunosuppression in organ transplantation, are good predictors of the occurrence of an acute rejection epi-
E
sode.1– 6 Numerous international studies have shown that CsA profiling at C2 is an accurate measure of CsA exposure, possibly superior to trough level (C0) monitoring2–5,7 and more practicable5 than AUC-guided dose adjustments.
From the Transplant Center (W.A.), Kliniken der Stadt Koeln, Koeln, Germany; Medical Clinic III (F.Z.), Central Hospital Bremen, Bremen, Germany; Division of Visceral and Transplant Surgery (D.A.), University of Ulm, Ulm, Germany; Clinic and Policlinic for Urology (H.S.), University of Rostock, Rostock, Germany; Department of Nephrology (E.-H.S.), University Hospital Frankfurt/Main, Frankfurt/Main, Germany; Westpfalz-Klinikum Kaiserslautern (U.A.), Kaiserslautern, Germany; Clinic and Policlinic IV (R.S.), Nephrology, University of Hamburg, Hamburg, Germany; University Clinic and Policlinic for Urology (P.F.), Halle/Wittenberg, Germany; University of Luebeck School of
Medicine (L.F.), Luebeck, Germany; Department of Nephrology (H.H.N.), Charité Campus Mitte, Berlin, Germany; Transplant Center (E.N.), University of Augsburg, Augsburg, Germany; and Novartis Pharma GmbH (U.M., B.U.), Nuremberg, Germany. This study was sponsored by Novartis Pharma GmbH, Nuremberg, Germany. Address reprint requests to Wolfgang Arns, Kliniken der Stadt Koeln, Klinikum Koeln-Merheim, Medizinische Klinik I, Ostmerheimer Strasse 200, 51109 Koeln, Germany. Email: wolfgang. [email protected]
0041-1345/05/$–see front matter doi:10.1016/j.transproceed.2004.09.018
© 2005 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
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Transplantation Proceedings, 37, 1612–1615 (2005)
CYCLOSPORINE C2 LEVELS
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Table 1. Time Profiles for CsA Concentration, Neoral Dosing and Absorption, Creatinine, and GFR up to Month 6 Posttransplantation (mean ⴞ SD) Parameter
Days 3–5
Days 7–10
Days 14–28
Month 3
Month 6
C0 (ng/mL) C2 (ng/mL) AUC0–4 (ng · h/mL) CsA daily dose (mg) Relative CsA daily dose (mg/kg) CsA-Abs [(ng/mL)/ (mg/kg)] Serum creatinine (mg/dL) GFR (mL/min)
168.4 ⫾ 90.3 873.1 ⫾ 391.9 4778.1 ⫾ 1530.1 460.8 ⫾ 131.5 6.2 ⫾ 1.7
180.9 ⫾ 73.6 939.1 ⫾ 422.8 5076.2 ⫾ 1527.4 462.5 ⫾ 153.2 6.3 ⫾ 2.1
219.6 ⫾ 94.5 1116.3 ⫾ 497.6 5876.3 ⫾ 1931.6 407.1 ⫾ 138.5 5.8 ⫾ 2.1
177.7 ⫾ 64.0 905.0 ⫾ 316.8 4973.6 ⫾ 1240.5 275.1 ⫾ 82.7 3.8 ⫾ 1.3
151.7 ⫾ 59.8 787.0 ⫾ 276.5 4402.2 ⫾ 1093.7 251.4 ⫾ 80.1 3.4 ⫾ 1.2
284.4 ⫾ 115.1
306.7 ⫾ 134.8
382.5 ⫾ 164.7
501.5 ⫾ 168.8
512.7 ⫾ 176.5
4.8 ⫾ 3.5
3.6 ⫾ 3.1
2.5 ⫾ 2.1
1.7 ⫾ 0.8
1.7 ⫾ 0.7
31.2 ⫾ 23.4
41.8 ⫾ 27.4
49.4 ⫾ 25.2
55.0 ⫾ 23.4
56.6 ⫾ 20.9
Since C2 measurements have emerged as the best singlepoint, independent predictor of an acute rejection2 episode, they are regarded as an index for dose monitoring.7 Nevertheless, the exact C2 target level range has not been conclusively established. Recent data suggest that optimal CsA exposure early posttransplant significantly reduces the risk of an acute graft rejection episode.4 An international Consensus Conference held in 2002 delineated the CsA target levels to be attained within 3 to 5 days posttransplant.6 These recommendations were for the most part consistent with immunosuppressive strategies employed in North American countries.6 However, they may not be absolutely transferable to the German situation where it is common practice to adjust CsA doses to lower trough values.1 Herein we report a prospective observational study undertaken in Germany to determine C2 levels at specific posttransplant times for de novo renal allograft recipients, whose CsA levels were adjusted by trough level monitoring. We also assessed the relationship between C2 and the risk of an acute rejection episode and of allograft dysfunction.
PATIENTS AND METHODS Eleven renal transplant centers in Germany participated in this ongoing multicenter prospective observational study. Patients aged 19 to 71 were eligible if they received a cadaveric or living donor renal allografts and a de novo Neoral (cyclosporine microemulsion, Novartis Basel)-based immunosuppressive regimen that was adjusted by trough level monitoring. Among the 159 renal transplant enrolled recipients, the interim analysis included 138 patients with evaluable data at 6 months posttransplant. C2 was profiled on days 3 to 5; days 7 to 10; days 14 to 28; and at 3 and 6 months posttransplant. C0 and C2 concentrations were measured using liquid chromatography-tandem mass spectrometry (LC-MS/MS) at a central laboratory. Additionally, data on acute rejection rates and other relevant parameters were electronically recorded at given times for statistical analysis. The following two-point standard formula was employed to calculate CsA exposure as the area under the curve (AUC0 – 4): 990 ⫹ 10.74 ⫻ C0 ⫹ 2.28 ⫻ C2. Relative cyclosporine-absorption capacity (CsA-Abs), defined as C2 levels (ng/mL) divided by the morning dose (mg/kg), was calculated. The glomerular filtration
rate (GFR) as a marker of graft function was estimated using the Cockcroft-Gault formula.
RESULTS
Among the evaluable patients of age 51.9 ⫾ 12.9 years (56.6% men), 13.2% received a living donor graft and 22.6% experienced delayed graft function. Table 1 shows their time profiles for CsA concentration, Neoral dosing and absorption, serum creatinine, and graft function (GFR) up to 6 months posttransplant. Mean C2 levels increased continuously over the first 4 weeks after transplantation even though the average Neoral dose was lowered slightly. During the first posttransplant days, a dose of 1 mg/kg Neoral led to a mean C2 level of 284.4 ng/mL, whereas the same dose achieved a 1.8 times higher mean level after 6 months. To identify patients at higher risk for acute rejection or allograft dysfunction, patients were classified as low absorbers, normal absorbers, or high absorbers of cyclosporine based on their CsA-Abs.1,6 Poor absorbers were defined as patients who received a morning dose of 4 mg/kg body weight but did not attain C2 levels of 800 ng/mL by days 7 to 10 posttransplant, that is, their relative absorption capacity was less than 200 (ng/mL)/(mg/kg). High absorbers were defined as patients who, with a morning dose 2.3 mg/kg body weight, attained C2 levels greater than 800 ng/mL on days 7 to 10 posttransplant, that is, showed a relative absorption capacity ⬎ 350 (ng/mL/mg/kg). Figure 1 illustrates the incidence of acute rejection episodes and GFR (mean ⫾ SD) at 6 months posttransplant as a function of the relative CsA absorption capacity 7 to 10 days after transplantation. During the first 2 weeks posttransplant, a majority of our patients (75%) showed a relative cyclosporine absorption of ⬍ 350, while the value increased up to posttransplant month 3: namely, 78% had at least 350. The three groups of absorbers were also compared for a relationship between biopsy-proven acute rejection rates and mean GFR (⫾ SD). The results were 23.8% and 54.7 ⫾ 19.0 mL/min for the low absorber group: 22.6% and 59.5 ⫾ 20.7 mL/min for the normal absorber group; and 17.6% and
1614
Fig 1. Incidence of acute rejection and GFR (mean ⫾ SD) at 6 months after transplantation as a function of relative CsA absorption capacity 7 to 10 days posttransplantation.
67.7 ⫾ 23.5 mL/min for the high absorber group, respectively. Overall, biopsy-proven acute rejection episodes occurring in the first 6 months after transplantation were observed in 25 patients (21.4%). The differences in C2 levels and AUC0 – 4 observed in patients with versus without biopsy-proven acute rejection episodes was not significant: C2: 986.2 ⫾ 398.7 vs 922.5 ⫾ 431.7 ng/mL; AUC0 – 4: 5199.2 ⫾ 1236.3 vs 5032.7 ⫾ 1621.6 ng.h/mL, respectively. DISCUSSION
The interim results of this ongoing study demonstrated that mean C2 levels ⬎ 1000 ng/mL can be achieved within 2 to 4 weeks after transplantation. CsA-Abs risies continuously during the first 6 months posttransplant. Consistently, the high CsA absorbers tended to have good allograft function and lower acute rejection rates at 6 months posttransplantation. A comparison of these results with other studies are consistent across geographical regions.3 In 2002, an International consensus statement on C2 monitoring concluded that C2 monitoring is the optimal method to manage Neoral in adult de novo kidney transplant recipients, proposing guideline C2 targets.6 The proposed optimal C2 target to prevent an acute rejection episode, in adult de novo kidney transplant patients with good initial graft function was recommended to be 1500 to 2000 mg/mL within the first posttransplant month. Thereafter, 1100 ng/mL was set as the target for the first 4 to 6 months. The consensus concluded that achieving target levels by days 3 to 5 posttransplant optimizes the clinical benefit. These targets were proposed based on results obtained in patients managed by C2 monitoring. Based on the weight of evidence favoring C2 monitoring, another, North American center issued similar recommendations and target levels, drawing heavily upon the consensus statement’s conclusion.8 Target levels better reflecting the German practice were published in 2003.1 Based on their experience with C2 monitoring in renal transplant recipients, the German experts recommended lower C2 target levels of 800 to 1400 ng/mL up to 4 weeks posttransplant and 800 to 1200 ng/mL
ARNS, ZANTVOORT, ABENDROTH ET AL
up to month 6 posttransplantation. On days 7 to 10 of our study, 40% of evaluable patients remained below the C2 target lower range level of 800 ng/mL with 17% showing C2 levels above the upper range of 1400 ng/mL recommended for Germany. Importantly, we observed no significant differences in C2 levels and AUC0 – 4 between patients with versus without biopsy-proven acute rejection episodes. We attribute these results to the fact that our patients were not managed by C2 monitoring. The classification of patients as high, intermediate, and low CsA absorber categories1,6,8 was suggested by the International Neoral Renal Transplantation Study Group4,5 as an important variable to predict rejection risk. In that randomized trial,4,5 median CsA C2 levels rose slowly in low absorbers, reaching 728 ng/mL by day 3 and plateauing at 1255 ng/mL by day 7. In intermediate absorbers, C2 reached 1295 ng/mL by day 3, rising to 1602 ng/mL by day 7. High absorbers more rapidly attained a median C2 of 1918 ng/mL by day 2; however, this level declined to 1530 ng/mL by day 7. Presumably, this was due to dose overexposure.4 Consistent with those results,4,5 the initially poor cyclosporine absorbers in this study tended to have a higher risk of acute rejection episodes within the first 6 posttransplant months. The high absorbers showed a lower acute rejection rate accompanied by good allograft function during the first 6 months posttransplant, although there was no significant difference in renal function between absorber groups after 6 months. Relative cyclosporine absorption capacity of de novo renal transplant patients, adjusted by C0 monitoring, increased continuously over the first 6 months after renal allografting, by which time it had improved by a factor of 1.8. Thus, C2 monitoring adequately distinguishes poor Neoral absorbers, namely those at risk of underimmunosuppression, from high absorbers at risk of overexposure. The differences in the results between North American and German centers gives cause for further reflection about whether C2 monitoring is a more valuable tool to manage de novo renal transplant patients and whether a transition from trough level monitoring is justified. REFERENCES 1. Nashan B, Armstrong VW, Budde K, et al: Cyclosporine C2-monitoring for optimisation of immunosuppression in renal transplantation—recommendations according to first experiences in German centers. Transplantationsmedizin 15:15, 2003 2. Pescovitz MD, Barbeito R: Two-hour post-dose cyclosporine level is a better predictor than trough level of acute rejection of renal allografts. Clin Transplant 16:378, 2002 3. Nashan B, Cole E, Levy G, et al: Clinical validation studies of Neoral C(2) monitoring: a review. Transplantation 73(Suppl):S3, 2002 4. Keown P, for the International Neoral Renal Transplantation Study Group: Randomized International Study of Cyclosporine Microemulsion Absorption Profiling in Renal Transplantation with Basiliximab Immunoprophylaxis. Am J Transplant 2:157, 2002 5. International Neoral Renal Transplantation Study Group: Cyclosporine microemulsion (Neoral) absorption profiling and sparse-sample predictors during the first 3 months after renal transplantation. Am J Transplant 2:148, 2002
CYCLOSPORINE C2 LEVELS 6. Levy G, Thervet E, Lake J, et al: Patient management by Neoral C2 monitoring: an international consensus statement. Transplantation 73(Suppl):S12, 2002 7. Thervet E, Pfeffer P, Scolari MP, et al: Clinical outcomes during the first three months posttransplant in renal allograft
1615 recipients managed by C2 monitoring of cyclosporine microemulsion. Transplantation 76:903, 2003 8. Cole E, Midtvedt K, Johnston A, et al: Recommendations for the implementation of Neoral C(2) monitoring in clinical practice. Transplantation 73(Suppl):S19, 2002
E
sode.1– 6 Numerous international studies have shown that CsA profiling at C2 is an accurate measure of CsA exposure, possibly superior to trough level (C0) monitoring2–5,7 and more practicable5 than AUC-guided dose adjustments.
From the Transplant Center (W.A.), Kliniken der Stadt Koeln, Koeln, Germany; Medical Clinic III (F.Z.), Central Hospital Bremen, Bremen, Germany; Division of Visceral and Transplant Surgery (D.A.), University of Ulm, Ulm, Germany; Clinic and Policlinic for Urology (H.S.), University of Rostock, Rostock, Germany; Department of Nephrology (E.-H.S.), University Hospital Frankfurt/Main, Frankfurt/Main, Germany; Westpfalz-Klinikum Kaiserslautern (U.A.), Kaiserslautern, Germany; Clinic and Policlinic IV (R.S.), Nephrology, University of Hamburg, Hamburg, Germany; University Clinic and Policlinic for Urology (P.F.), Halle/Wittenberg, Germany; University of Luebeck School of
Medicine (L.F.), Luebeck, Germany; Department of Nephrology (H.H.N.), Charité Campus Mitte, Berlin, Germany; Transplant Center (E.N.), University of Augsburg, Augsburg, Germany; and Novartis Pharma GmbH (U.M., B.U.), Nuremberg, Germany. This study was sponsored by Novartis Pharma GmbH, Nuremberg, Germany. Address reprint requests to Wolfgang Arns, Kliniken der Stadt Koeln, Klinikum Koeln-Merheim, Medizinische Klinik I, Ostmerheimer Strasse 200, 51109 Koeln, Germany. Email: wolfgang. [email protected]
0041-1345/05/$–see front matter doi:10.1016/j.transproceed.2004.09.018
© 2005 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
1612
Transplantation Proceedings, 37, 1612–1615 (2005)
CYCLOSPORINE C2 LEVELS
1613
Table 1. Time Profiles for CsA Concentration, Neoral Dosing and Absorption, Creatinine, and GFR up to Month 6 Posttransplantation (mean ⴞ SD) Parameter
Days 3–5
Days 7–10
Days 14–28
Month 3
Month 6
C0 (ng/mL) C2 (ng/mL) AUC0–4 (ng · h/mL) CsA daily dose (mg) Relative CsA daily dose (mg/kg) CsA-Abs [(ng/mL)/ (mg/kg)] Serum creatinine (mg/dL) GFR (mL/min)
168.4 ⫾ 90.3 873.1 ⫾ 391.9 4778.1 ⫾ 1530.1 460.8 ⫾ 131.5 6.2 ⫾ 1.7
180.9 ⫾ 73.6 939.1 ⫾ 422.8 5076.2 ⫾ 1527.4 462.5 ⫾ 153.2 6.3 ⫾ 2.1
219.6 ⫾ 94.5 1116.3 ⫾ 497.6 5876.3 ⫾ 1931.6 407.1 ⫾ 138.5 5.8 ⫾ 2.1
177.7 ⫾ 64.0 905.0 ⫾ 316.8 4973.6 ⫾ 1240.5 275.1 ⫾ 82.7 3.8 ⫾ 1.3
151.7 ⫾ 59.8 787.0 ⫾ 276.5 4402.2 ⫾ 1093.7 251.4 ⫾ 80.1 3.4 ⫾ 1.2
284.4 ⫾ 115.1
306.7 ⫾ 134.8
382.5 ⫾ 164.7
501.5 ⫾ 168.8
512.7 ⫾ 176.5
4.8 ⫾ 3.5
3.6 ⫾ 3.1
2.5 ⫾ 2.1
1.7 ⫾ 0.8
1.7 ⫾ 0.7
31.2 ⫾ 23.4
41.8 ⫾ 27.4
49.4 ⫾ 25.2
55.0 ⫾ 23.4
56.6 ⫾ 20.9
Since C2 measurements have emerged as the best singlepoint, independent predictor of an acute rejection2 episode, they are regarded as an index for dose monitoring.7 Nevertheless, the exact C2 target level range has not been conclusively established. Recent data suggest that optimal CsA exposure early posttransplant significantly reduces the risk of an acute graft rejection episode.4 An international Consensus Conference held in 2002 delineated the CsA target levels to be attained within 3 to 5 days posttransplant.6 These recommendations were for the most part consistent with immunosuppressive strategies employed in North American countries.6 However, they may not be absolutely transferable to the German situation where it is common practice to adjust CsA doses to lower trough values.1 Herein we report a prospective observational study undertaken in Germany to determine C2 levels at specific posttransplant times for de novo renal allograft recipients, whose CsA levels were adjusted by trough level monitoring. We also assessed the relationship between C2 and the risk of an acute rejection episode and of allograft dysfunction.
PATIENTS AND METHODS Eleven renal transplant centers in Germany participated in this ongoing multicenter prospective observational study. Patients aged 19 to 71 were eligible if they received a cadaveric or living donor renal allografts and a de novo Neoral (cyclosporine microemulsion, Novartis Basel)-based immunosuppressive regimen that was adjusted by trough level monitoring. Among the 159 renal transplant enrolled recipients, the interim analysis included 138 patients with evaluable data at 6 months posttransplant. C2 was profiled on days 3 to 5; days 7 to 10; days 14 to 28; and at 3 and 6 months posttransplant. C0 and C2 concentrations were measured using liquid chromatography-tandem mass spectrometry (LC-MS/MS) at a central laboratory. Additionally, data on acute rejection rates and other relevant parameters were electronically recorded at given times for statistical analysis. The following two-point standard formula was employed to calculate CsA exposure as the area under the curve (AUC0 – 4): 990 ⫹ 10.74 ⫻ C0 ⫹ 2.28 ⫻ C2. Relative cyclosporine-absorption capacity (CsA-Abs), defined as C2 levels (ng/mL) divided by the morning dose (mg/kg), was calculated. The glomerular filtration
rate (GFR) as a marker of graft function was estimated using the Cockcroft-Gault formula.
RESULTS
Among the evaluable patients of age 51.9 ⫾ 12.9 years (56.6% men), 13.2% received a living donor graft and 22.6% experienced delayed graft function. Table 1 shows their time profiles for CsA concentration, Neoral dosing and absorption, serum creatinine, and graft function (GFR) up to 6 months posttransplant. Mean C2 levels increased continuously over the first 4 weeks after transplantation even though the average Neoral dose was lowered slightly. During the first posttransplant days, a dose of 1 mg/kg Neoral led to a mean C2 level of 284.4 ng/mL, whereas the same dose achieved a 1.8 times higher mean level after 6 months. To identify patients at higher risk for acute rejection or allograft dysfunction, patients were classified as low absorbers, normal absorbers, or high absorbers of cyclosporine based on their CsA-Abs.1,6 Poor absorbers were defined as patients who received a morning dose of 4 mg/kg body weight but did not attain C2 levels of 800 ng/mL by days 7 to 10 posttransplant, that is, their relative absorption capacity was less than 200 (ng/mL)/(mg/kg). High absorbers were defined as patients who, with a morning dose 2.3 mg/kg body weight, attained C2 levels greater than 800 ng/mL on days 7 to 10 posttransplant, that is, showed a relative absorption capacity ⬎ 350 (ng/mL/mg/kg). Figure 1 illustrates the incidence of acute rejection episodes and GFR (mean ⫾ SD) at 6 months posttransplant as a function of the relative CsA absorption capacity 7 to 10 days after transplantation. During the first 2 weeks posttransplant, a majority of our patients (75%) showed a relative cyclosporine absorption of ⬍ 350, while the value increased up to posttransplant month 3: namely, 78% had at least 350. The three groups of absorbers were also compared for a relationship between biopsy-proven acute rejection rates and mean GFR (⫾ SD). The results were 23.8% and 54.7 ⫾ 19.0 mL/min for the low absorber group: 22.6% and 59.5 ⫾ 20.7 mL/min for the normal absorber group; and 17.6% and
1614
Fig 1. Incidence of acute rejection and GFR (mean ⫾ SD) at 6 months after transplantation as a function of relative CsA absorption capacity 7 to 10 days posttransplantation.
67.7 ⫾ 23.5 mL/min for the high absorber group, respectively. Overall, biopsy-proven acute rejection episodes occurring in the first 6 months after transplantation were observed in 25 patients (21.4%). The differences in C2 levels and AUC0 – 4 observed in patients with versus without biopsy-proven acute rejection episodes was not significant: C2: 986.2 ⫾ 398.7 vs 922.5 ⫾ 431.7 ng/mL; AUC0 – 4: 5199.2 ⫾ 1236.3 vs 5032.7 ⫾ 1621.6 ng.h/mL, respectively. DISCUSSION
The interim results of this ongoing study demonstrated that mean C2 levels ⬎ 1000 ng/mL can be achieved within 2 to 4 weeks after transplantation. CsA-Abs risies continuously during the first 6 months posttransplant. Consistently, the high CsA absorbers tended to have good allograft function and lower acute rejection rates at 6 months posttransplantation. A comparison of these results with other studies are consistent across geographical regions.3 In 2002, an International consensus statement on C2 monitoring concluded that C2 monitoring is the optimal method to manage Neoral in adult de novo kidney transplant recipients, proposing guideline C2 targets.6 The proposed optimal C2 target to prevent an acute rejection episode, in adult de novo kidney transplant patients with good initial graft function was recommended to be 1500 to 2000 mg/mL within the first posttransplant month. Thereafter, 1100 ng/mL was set as the target for the first 4 to 6 months. The consensus concluded that achieving target levels by days 3 to 5 posttransplant optimizes the clinical benefit. These targets were proposed based on results obtained in patients managed by C2 monitoring. Based on the weight of evidence favoring C2 monitoring, another, North American center issued similar recommendations and target levels, drawing heavily upon the consensus statement’s conclusion.8 Target levels better reflecting the German practice were published in 2003.1 Based on their experience with C2 monitoring in renal transplant recipients, the German experts recommended lower C2 target levels of 800 to 1400 ng/mL up to 4 weeks posttransplant and 800 to 1200 ng/mL
ARNS, ZANTVOORT, ABENDROTH ET AL
up to month 6 posttransplantation. On days 7 to 10 of our study, 40% of evaluable patients remained below the C2 target lower range level of 800 ng/mL with 17% showing C2 levels above the upper range of 1400 ng/mL recommended for Germany. Importantly, we observed no significant differences in C2 levels and AUC0 – 4 between patients with versus without biopsy-proven acute rejection episodes. We attribute these results to the fact that our patients were not managed by C2 monitoring. The classification of patients as high, intermediate, and low CsA absorber categories1,6,8 was suggested by the International Neoral Renal Transplantation Study Group4,5 as an important variable to predict rejection risk. In that randomized trial,4,5 median CsA C2 levels rose slowly in low absorbers, reaching 728 ng/mL by day 3 and plateauing at 1255 ng/mL by day 7. In intermediate absorbers, C2 reached 1295 ng/mL by day 3, rising to 1602 ng/mL by day 7. High absorbers more rapidly attained a median C2 of 1918 ng/mL by day 2; however, this level declined to 1530 ng/mL by day 7. Presumably, this was due to dose overexposure.4 Consistent with those results,4,5 the initially poor cyclosporine absorbers in this study tended to have a higher risk of acute rejection episodes within the first 6 posttransplant months. The high absorbers showed a lower acute rejection rate accompanied by good allograft function during the first 6 months posttransplant, although there was no significant difference in renal function between absorber groups after 6 months. Relative cyclosporine absorption capacity of de novo renal transplant patients, adjusted by C0 monitoring, increased continuously over the first 6 months after renal allografting, by which time it had improved by a factor of 1.8. Thus, C2 monitoring adequately distinguishes poor Neoral absorbers, namely those at risk of underimmunosuppression, from high absorbers at risk of overexposure. The differences in the results between North American and German centers gives cause for further reflection about whether C2 monitoring is a more valuable tool to manage de novo renal transplant patients and whether a transition from trough level monitoring is justified. REFERENCES 1. Nashan B, Armstrong VW, Budde K, et al: Cyclosporine C2-monitoring for optimisation of immunosuppression in renal transplantation—recommendations according to first experiences in German centers. Transplantationsmedizin 15:15, 2003 2. Pescovitz MD, Barbeito R: Two-hour post-dose cyclosporine level is a better predictor than trough level of acute rejection of renal allografts. Clin Transplant 16:378, 2002 3. Nashan B, Cole E, Levy G, et al: Clinical validation studies of Neoral C(2) monitoring: a review. Transplantation 73(Suppl):S3, 2002 4. Keown P, for the International Neoral Renal Transplantation Study Group: Randomized International Study of Cyclosporine Microemulsion Absorption Profiling in Renal Transplantation with Basiliximab Immunoprophylaxis. Am J Transplant 2:157, 2002 5. International Neoral Renal Transplantation Study Group: Cyclosporine microemulsion (Neoral) absorption profiling and sparse-sample predictors during the first 3 months after renal transplantation. Am J Transplant 2:148, 2002
CYCLOSPORINE C2 LEVELS 6. Levy G, Thervet E, Lake J, et al: Patient management by Neoral C2 monitoring: an international consensus statement. Transplantation 73(Suppl):S12, 2002 7. Thervet E, Pfeffer P, Scolari MP, et al: Clinical outcomes during the first three months posttransplant in renal allograft
1615 recipients managed by C2 monitoring of cyclosporine microemulsion. Transplantation 76:903, 2003 8. Cole E, Midtvedt K, Johnston A, et al: Recommendations for the implementation of Neoral C(2) monitoring in clinical practice. Transplantation 73(Suppl):S19, 2002