Long-Term Comparative Results of C0 and C2 Monitoring of CyA in Renal Transplanted Patients

The purpose of this study was to evaluate the effects of CyA monitoring using Co monitoring (fasting level after 12 h from last dose), and C₂ monitoring (2 h after morning dose) on renal functions, lipid levels, CyA levels, and daily dosages of CyA in renal transplanted patients in the posttransplant period from the first month to the 36th month. In our center between 1992–2003, 37 of the 54 renal transplanted patients were treated with CyA, prednisolone, and mycophenolate mofetil or azathioprine. The mean age was 32.36 ± 10.32 and 35.00 ± 10.23 (p = 0.39) in Co (M/F: 18/7) and in C₂ (9/3), respectively. Cadaveric donor (d), living related d, and living unrelated d were in four patients (p), 17 p and four p in Co, and two p, seven p, and three p in C₂, respectively (p = 0.79). Chronic allograft nephropathy (CAN) developed in 13 p (52%) and one p (8.3%) in Co and in C₂, respectively (p = 0.013). Creatinine clearance values were 72.31 ± 23.10 mL/min and 78.73 ± 22.42 mL/min (p:0.621) at first month, 64.97 ± 22.58 mL/min and 78.00 ± 19.90 mL/min (p:0.065) at sixth month, 56.50 ± 19.62 mL/min and 76.62 ± 21.06 mL/min (p:0.006) at 12th month, 50.28 ± 24.79 mL/min and 80.87 ± 18.24 mL/min (p< 0.001) at 24th month, and 55.15 ± 19.21 mL/min and 86.65 ± 14.97 mL/min (p:0.004) at 36th month in C₀ and C₂, respectively. The mean daily dosages of CyA were 354.35 ± 122.63 and 266.67 ± 64.95 mg/d (p:0.031) at first month, 277.17 ± 77.94 and 250.00 ± 73.31 mg/d (p:0.228) at sixth month, 247.92 ± 58.48 and 211.36 ± 62.61 mg/d (p:0.09) at 12th month, 232.95 ± 56.90 and 170.45 ± 41.56 mg/d (p:0.003) at 24th month, and 240.63 ± 52.34 and 153.57 ± 46.61 mg/d (p:0.002) at 36th month in C₀ and C₂, respectively. In C₂, systolic and diastolic blood pressure, uric acid, total cholesterol (C), LDL-C, and triglyceride levels were lower than those monitored with C₀. In C₂, HDL-C levels were also higher than those monitored with C₀. None of these patients returned to dialysis or died in this period. In conclusion, during the first 36 months with monitoring C₂, preservation of renal function, control of blood pressure serum lipids and uric acid were better than those with monitoring C₀. In addition, daily dose of CyA was lower in C₂ method and, at the same time, this effect of C₂ can be accepted as cost effective.

Keywords: renal transplantation; cyclosporine; C0-C2 monitoring

Cyclosporine (CyA) has been using as a primary immunosuppressant agent in renal transplantation for 20 years. Its use in renal transplantation has resulted an improvement in graft survival. But nephrotoxicity is an important side effect of CyA in transplanted patients. The area under the concentration time curve (AUC) of CyA represents sensitive predictors for acute rejection (AR). It was realized that the level of C0 did not correlate well with AUC because of the individual absorption variability of CyA. Recently, the level of CyA 2 (C2) hours post dosing was found to correlate much better with AUC. In the literature, some investigators claimed that C2 levels were more appropriate for posttransplantation monitoring of CyA.[1] But, still, in most of the transplant centers, C0 monitoring is standard. In our center, we have been adjusting CyA dosage according to C2 monitoring in renal transplanted patients since the beginning of 2000. In this study, we investigated the effect of C0 and C2 monitoring on blood pressure, renal function serum glucose, serum uric acid, lipid profile, and CyA dosages.

Between 1992–2003, 54 renal transplanted patients using CyA were analyzed. It was noticed that the patients were on follow-up from the first posttransplantation month.

All patients were treated with CyA, azathioprine, or mycophenolate mofetil (MMF) and prednisone for immunosuppression. The number of patients who discontinued steroid administration was five for C0, one for C2. Physical examination and serum glucose, BUN, creatinine (Cr), creatinine clearance (Ccr), AST, ALT, uric acid, total protein, albumin, lipid levels, sedimentation rate, hematocrit, white blood count, and CyA dosage were recorded. Twelve patients who were converted to C2 monitoring from C0 monitoring were analyzed separately and the last levels of Ccr, uric acid, cholesterol, triglyceride, and blood pressure on C0 monitoring (36–48 months) were compared with the levels of the 12th and 36th months on C2 monitoring.

Serum levels of CyA were measured by CSA cobas integra (Roche). The blood samples were collected according to C0 monitoring (a fasting level at 9–11 h after evening administration) or C2 monitoring (2 h after morning administration). Target serum levels of CyA were 300–400 ng/mL at the first month, 100–300 ng/mL at sixth month, < 200 ng/mL at 12th month, and after 1 year < 200 ng/mL for C0 monitoring. They were 1700 ng/mL at first month, 1500 ng/mL at second month, 1300 ng/mL at third month, 1100 ng/mL between fourth and sixth months, 900 ng/mL between seventh and 12th month, and 800 ng/mL after 1 year for C2 monitoring.[2], [3]

Mann-Whitney-U test was used for statistical analysis.

The mean age was 32.3 ± 10.3 years and 35.0 ± 10.2 years in C0 group and in C2 group, respectively. There was no statistical difference between these two groups (p = 0.295) Sixteen patients who were treated at other centers previously were excluded from this study. One patient who was receiving antituberculosis treatment was also excluded. In total, 37 renal transplanted patients (25 in C0 group, 12 in C2 group) were analyzed. The characteristics of the patients were summarized in Table 1. Chronic allograft nephropathy developed in 13 p (52%) and one p (8.3%) in C0 and in C2, respectively (p = 0.013).

Table 1. Patient characteristics

Renal functions, serum glucose, CyA levels, and CyA dose were shown in Table 2. Uric acid, lipid profile, and blood pressure measurements were shown in Table 3. Mean daily dosages of CyA and Ccr of the patients were shown in Figures 1 and 2. Blood pressure, triglyceride, uric acid, and Ccr of 12 patients who were converted to C2 monitoring were compared to the last levels of C0 with the levels of the 12th and 36th months on C2 monitoring. Mean levels and significances were shown in Table 4. Ccr of the patients who converted to C2 from C0 were shown in Figure 3.

Table 2. Serum glucose, renal functions, CyA levels, and dosages of the patients

Table 3. Serum uric acid, lipid levels, and blood pressure of the patients

Table 4. Ccr, lipid levels, uric acid, and blood pressures of the patients who converted to C2 from C0

Graph: Figure 1 Mean dosages of the patients.

Graph: Figure 2 Ccr of the patients.

Graph: Figure 3 Ccr of the patients who converted to C2 from C0.

Gender, donation, systolic blood pressure, CCr, Serum Cr, and lipid profile were similar in the C0 and C2 groups. But, Ccr were higher and serum Cr levels were lower in the C2 group after the first month (6, 12, 24, 36 months) than in the C0 group.

The bioavailability of CyA shows wide intrapatient and interpatient variation in absorption.[4] Low oral bioavailability is associated with AR, and high exposure is a significant risk factor for CAN.[5], [6]

AUC is known to be the most accurate way to adjust CyA dosage.[1] However, this method is not practical. MOZART study showed that the microemulsion form of CyA with C2 monitoring was associated with excellent short-term efficacy and safety in renal transplant patients.[7] In our study, allograft functions of the patients were kept more reliable in patients monitored with the C2 monitoring than those with the C0 monitoring for long periods. This improvement was seen after the sixth month and continued for 36 months.

We obtained optimal target C2 levels with lower doses of CyA in C2 monitoring. There was no increase in the incidence of rejection or infection in C2 monitoring. In the literature, the comparison of C0 and C2 monitoring for posttransplantation in the first 6 months was investigated and the superiority of the C2 monitoring was claimed by some investigators. However, to achieve recommended C0 and C2 levels at the first month was not found to be expected. The incidence of cytomegalovirus (CMV) infections associated with C2 monitoring were demonstrated to be increased in C2 monitoring in the first month, probably reflecting the higher doses of CyA.[8] But, in this study, our patients were studied after the first month and increases in AR episodes or increases in the number of infections were not seen.

Also, when we evaluate all of the patients (n = 54), excluded and included, similar results were obtained. Another finding that supported superiority of the C2 method was that the renal functions were similar in 12 patients who converted to C2 monitoring from C0, even in succeeding years with transplantation. Also, in the follow-up period, there were no differences between the C0 method and the C2 method regarding Δcr and ΔCcr after 36 and 48 months.

This finding might show that lower and efficient doses of CyA achievement with C2 monitoring could improve allograft functions. Hyperlipidemia is very important in renal transplanted patients, and the major cause of death in posttransplantation period is cardiovascular disease.[9] In our study, we demonstrated significantly lower serum levels of LDL, triglyceride, total cholesterol in C2 group. An increase in HDL levels was not statistically important. Systolic and diastolic blood pressure measurements were lower in the C2 group than in those with the C0 monitoring.

In patients who converted to C2 from C0, serum levels of triglyceride, uric acid, and blood pressure measurements were decreased. In our study, lower serum levels of uric acid seem to be more related to lower doses of CyA and improvement in renal function. Finally, this might reduce the risk of cardiovascular disease, gout, and renal failure in transplanted patients.

In conclusion, C2 monitoring can be safer than C0 in renal transplanted patients, regarding improvement in renal functions. The best results for renal functions tests were found in patients who converted to C2 monitoring, especially after 36–48 months of transplantation. Blood pressure, LDL, triglyceride, and uric acid were lower. The optimal target level CyA was achieved with proper C2 monitoring. Also, the patients with the C2 monitoring had been treated with daily lower doses of CyA. Finally, monitoring of C2 to adjust CyA was found to be useful in regard to CyA nephrotoxicity, and it was also cost effective.