Nghiên cứu mối liên quan giữa nồng độ mycophenolic acid và số lượng tế bào lympho t máu ngoại vi ở bệnh nhân ghép thận TT TIENG ANH

1 STUDY ON THE RELATIONSHIP BETWEEN MYCOPHENOLIC ACID CONCENTRATION AND PERIPHERAL BLOOD T LYMPHOCYTE COUNT IN KIDNEY TRANSPLANT PATIENTS ABSTRACT The advent of immunosuppressive drug has brought a new face to the transplant profession in general and kidney transplantation in particular However, the use of immunosuppressive drug after transplantation is highly complex In addition to the current common and routine immunosuppressive drug concentration tests such as Cyclosporin and Tacrolimus, the Mycophenolic acid test is a test deployed in numerous countries worldwide but has not been performed in Vietnam, while 100% of Post-transplant patients at Viet Duc hospital were assigned to use Mycophenolic acid (Cellcept or Myfotic) Nevertheless, this drug dosage adjustment merely follows the recommendations of manufacturers and the clinician’s experience but is not quantified According to the Vietnam Organ Transplantation Association, whether the habit of using a single dose of MPA for all patients is the target concentration, appropriate, safe, or not is still a controversial issue Many studies have shown that MPA affects the biosynthesis inhibition of the T lymphocyte, which is strongly involved in the rejection process Thus, this study is conducted with the following goals: 1) Investigating the Mycophenolic acid concentration and its area under the curve (AUC 0-12) on the 3rd day, 10th day, and months after the kidney transplantation 2) Evaluating the relationship between the Mycophenolic acid concentration and the immune response through the change in the number of TCD3, TCD4, TCD8 Lymphocyte in kidney transplant recipients New contributions to the thesis: For the first time in Vietnam, the author conducted a quantitative determination of mycophenolic acid (MPA) concentration The results indicated that the AUC0-12 value of MPA had a significant difference between patients who used the drug at days, 10 days, and months The study has suggested the role and practical significance of monitoring MPA levels, which helps to personalize the use of antirejection medicines for post-transplant kidney patients Thesis structure: Thesis with 113 pages; Abstract: pages; Overview: 38 pages; Objects and methods: 16 pages; Results: 23 pages; Discussion: 30 pages; Limitations of the study: page; Conclusion: page; Recommendations: page; 30 tables, 17 pictures, appendices CHAPTER OVERVIEW 1.2 Immunosuppressive drugs used in kidney transplantation 1.2.3 Several important parameters for drug absorption and concentration monitoring In fact, when we give the medication to patients, not all of the drug is taken into effect, but only a portion The active fraction is the fraction of the drug entering the circulation intact (not yet metabolized), which is called the bioavailability (BA), denoted by F (Fraction of dose), with the unit is % Bioavailability is a parameter representing the ratio of the drug entering the systemic circulation in the active form relative to the drug's administered dose (F%), time (Tmax), and concentration (Cmax) penetrated into the systemic circulation Therefore, we must have the number of drugs entering the circulation in order to have bioavailability Nonetheless, it is well-nigh impossible because the penetration of drugs into the circulation always simultaneously occurs as distribution and excretion, that is, the amount of drug entering the circulation fluctuates continuously over time That's why people utilize a parameter called AUC to assist AUC is the area under the curve (showing the variation of drug concentration in the blood over time); (Cp-t) represents the amount of drug which enters the circulation in the active form after time t The AUC is calculated as mg.h/L or µg.h/mL AUC0 - ∞ = AUC0 - t + AUCt - ∞ If we take a long enough sample, about - x t 1/2, then AUC0-t accounting for about 80% of the total drug intake is acceptable The rest can be ignored or extrapolated if desired 1.3 Mycophenolic Acid 1.3.1 Origin Mycophenolic acid (also known as mycophenolate) is a kind of immunosuppressive drug utilized to prevent post-transplant patients from transplant rejection MPA, derived from the fungus Penicillium brevicompactum, was discovered in the late 19th century Mycophenolic acid is known by the trade name Cellcept (Mycophenolate mofetil) in 250 mg and 500 mg; Myfortic is available in 180 mg and 360 mg MPA inhibits enzymes required for the development of B cell and T cells It primarily acts as an IMPDH – first noted in 1969 Figure 1.8 Mechanism of lymphocyte proliferation inhibition *Source: Antonio Perez-Aytes et al (2010) [33] 1.3.2 Pharmacokinetics Figure 1.9 Distribution and metabolism of MPA *Source: Antonio Perez-Aytes et al (2010) [33] 1.3.4 Drug efficacy In the mid-1990s, three large clinical trials were carried out in renal transplant recipients with a view to demonstrating the clinical efficacy of MMF The outcomes indicated superior efficacy of the combination with CsA and steroids in lowering the rate of acute rejection in months after kidney transplantation 1.4 Studies on MPA 1.4.1 Evaluating the relationship between the change of MPA concentration and the effects & changes of T lymphocyte A meta-analysis study published in 2019 analyzed over 27 studies globally and found that 20 studies (total 3382 out of 3,794 kidney recipients) demonstrated a strong association between the value of MPA AUC0-12 with rejection (Metz et al., 2019) According to the study of Jamali et al., the patients before and after four months of kidney transplantation both increased the proportion of TCD4 lymphocytes cell lines Nevertheless, the patients receiving Tac / MPA after transplantation indicated a more significant increase in the proportion of TCD4 lymphocytes compared with that of patients receiving TAC/Sirolimus Mahboob Lessan-Pezeshki et al., (2005) studied the evaluation of rejection in 16 first-time kidney transplant recipients without diabetes The results showed no significant difference among CD3, CD4, CD8 T-cell count, CD56 NK cell count, and CD20 B cells counted before and after transplantation 1.4.3 Several large clinical trials help evaluate the state of monitoring MPA concentration Van Gelder et al., studied 901 patients and indicated that MPA AUC0-12 values range of 30 to 60 mg/L.h is acceptable The patient’s dosing is based on the individuals, immunological risk assessments, and how AUC values fall into this optimal range Gaston et al, studied 720 patients and compared groups using fixed-dose MMF and calcineurin inhibitor dose adjustment The results showed no change in the desired effects between the groups * Currently, in Vietnam, the use of MPA is following the manufacturer’s instructions and the clinician’s experience No study evaluates the use of MPA and drug monitoring in renal transplant patients CHAPTER STUDY SUBJECTS AND METHODS 2.1 Place, Time, and Object of the study 2.1.1 Place of the study Biochemistry Department; Nephrology – Dialysis Department, Transplant Center, Viet Duc Friendship Hospital; Thai Ha Biomedical Center 2.1.2 Time of the study - The study was conducted from February 19, 2014 to May 24, 2016 2.1.3 Object of the study - The kidney transplant patient was at the transplant center of Viet Duc Hospital in the postoperative period and then was monitored and treated at the Nephrology - Dialysis Department for up to months - Control group: healthy people (blood donors and organ donors) 2.1.3.1 Criteria for selecting study subjects - Volunteer to participate in the study - Criteria for selecting patients: + All patients of all ages and both sexes received kidney transplants and were periodically monitored until the 6th month after transplantation at the Transplant Center and the Nephrology – Dialysis Department, Viet Duc Friendship Hospital + Use an immunosuppressive regimen with MPA twice a day (Cellcept or Myfortic both use tablets/time) - Criteria for selecting the control group: + Healthy people of all ages and both sexes are eligible to donate blood and organs 2.1.3.2 Exclusion criteria - The patient was converted to a regimen without MPA during follow-up (will be excluded at the time of converting to the respective treatment protocol) - The patient refused to participate in the study - The blood sample taken did not give results when testing for T lymphocytes - Blood samples were taken in the wrong way: blood taken at the wrong time and blood clots 2.1.3.3 Specimens - Blood of study subjects was taken at time (right before taking the drug) and 1, 2, 3, hours after taking the medicines on the 3rd, 10th days, and 6th month after transplantation 2.2 Study Methods 2.2.1 Study design Descriptive and prospective study Convenient sampling according to purpose 2.2.2 Sampling method and sample size 2.2.2.2 Sample size The study had 35 patients who fully met the research criteria for days and 10 days after transplantation; 33 patients satisfied the research criteria for months post-transplant The control group consisted of 30 people 2.2.3 Methods and techniques 2.2.3.1 The method of data collection - Making the research medical record according to the designed medical record template 2.2.3.3 Implementation techniques Determining biochemical parameters: Creatinine, albumin, GOT, GPT on AU680 machine at Biochemistry Department, Viet Duc Friendship Hospital Determining the number of red blood cells and white blood cells on Unicel DxH600 machine at the Hematology Department, Viet Duc Friendship Hospital g Determining the number of T-CD3, T-CD4, T-CD8 lymphocytes By flow cytometry (Lympho T-CD3, -CD4, -CD8 enumeration by flow cytometry) at Thai Ha medical center m Quantifying the MPA in the blood: By CEDIA method on a Thermo Scientific Indiko - USA at the Biochemistry Department, Viet Duc Friendship Hospital * Principle: Based on Galactosidase Enzymes engineered into two inactive fragments (ED and EA), these fragments bind together to form an enzyme causing a color change in the medium that can be measured In the presence of the analyte in the sample, it binds to the antibody, leaving the inactive enzyme fragment free to form an active enzyme In the absence of the analyte in the sample, the antibody binds to the analyte conjugated on the inactive fragment inhibiting the reassociation of inactive fragments; and no active enzyme is formed The amount of active enzyme formed resulting in the absorbance change is proportional to the amount of analyte present in the sample 2.2.4.2 Formula We applied the trapezoidal rule of Hoang Thi Kim Huyen to calculate the AUC; Nonetheless, the drug concentration was quantified at time t0, t1, t2, t3, t6, while at t12, the drug concentration was equal to C0 Besides, we based on the chart of drug concentration to calculate S1 - S12 AUC0-12 = S1 + S2 + S3 + S4 + S5 + S6 + S7 +S8 +S9 +S10 +S11 +S12 The threshold value of AUC reached: 30 – 60 mg.h/L 10 2.4 Data processing: Using Stata program 2.5 Error handling: There was only research group conducted at the research facility 2.6 Study ethics - The study was approved by the Viet Duc Friendship Hospital, the Immunology Department and the Post-Graduate Office of the Military Medical Academy - The study had the voluntary participation of the patients All participants understand the purpose of the study and agree to participate in the study And, the patients have the right to withdraw from the study at any point without any coercion Explanations are also not required CHAPTER RESULTS 3.1 General characteristics of the research subjects Table 3.1 Distribution of subjects according to age and sex Female Total n % N % 19 – 29 30,8 10 28,6 30 – 39 46,1 11 31,4 40 – 49 7,7 14,3 50 – 61 15,4 25,7 Total 13 100,0 35 100,0 Min – Max 19 – 53 19 – 61 p-values 0,193c - The most common age group is from 30-39 years old, accounting Age groups for 31.4% Male N % 27,3 22,7 18,2 31,8 22 100,0 19 – 61 13 Drugs Cellcept (n=20) Prograf (n=20) adjustment (n, %) days (n, %) days (n, %) 0% 0% 5% 45% 15% 40% 11th outwards (n, %) 16 80% 15% On the first days, patient (5%) was adjusted the dose of Cellcept From to 10 days, there were patients (15%); and from the 11th day onwards, there were 16 patients (80%) When adjusting the dose of Prograf, there were patients (45%) on the first days, patients (45%) from to 10 days, and patients (15%) from the 11th day onwards 3.2.3 Group employing Myfortic + Prograf (n = 11) Table 3.9 Adjusting the dose of Myfortic + Prograf Time No adjustment The first From 3-10 From the (n, %) days days 11th day (n, %) (n, %) outwards Drugs Myfortic (n, %) 0 (n=11) 0% 0% 18,2% 81,8% Prograf 3 (n=11) 0% 45,4% 27,3% 27,3% No patient (0%) was adjusted the dose of Cellcept on the first days From to 10 days, there were patients (18.2%); and from the 11th outwards, there were patients (81.8%) 14 When adjusting the dose of Prograf, there were patients (45.4%) on the first days, patients (27.2%) from to 10 days, and patients (27.3%) from the 11th day onwards 3.3 Evaluation of the variability of MPA concentration Table 3.10 Kinetics of MPA concentration according to the time of transplant Concent days post-transplant 10 days post- months post- transplant transplant rate Mean Median Range ± SD C0 (mg/L) C1 (mg/L) C2 (mg/L) C3 (mg/L) C6 2,32 ± 6,26 ± 7,3 3,87 ± AUC 50,10 (mg.h/L) ± 3,45 Creatini 118,20 ± 35,70 0,1 – 1,57 ± 6,9 1,38 1,0 – 6,31 ± 16,0 5,15 0,80 – 7,83 ± 27,1 5,5 3,94 3,06 (µmol/L) 6,1 6,57 (mg/L) n 1,9 4,72 8,90 ± Range ± SD 1,47 6,69 ± Mean Median 16,1 2,9 45 1,4 3,8 7,2 5,7 4,27 0,20 – 2,51 ± 16,2 1,50 11,03 41,87 2,4 42,1 ± 94,45 ±14,50 116 59 – 123,69 240 ± 51,24 Range SD 4,25 0,80 - 6,51 ± Mean ± Median 112 0,2 – 2,29 ± 8,8 1,40 0,8 – 14,37 ± 16,9 12,32 1,0 – 9,00 ± 18,2 6,17 0,9 – 7,60 ± 18,7 5,80 0,6 – 3,43 ± 7,6 1,82 10,73 – 60,26 ± 82,3 25,87 69 – 109,27 298 ± 23,65 0,70 – 6,30 15,2 1,10 – 47,60 7,3 1,90 – 31,50 5,6 1,90 – 26,80 2,9 0,90 – 8,60 53,05 18,50 – 129,05 110 68 – 193 15 At all points: days, 10 days, and months after transplantation, MPA rose sharply in the first hour after oral administration MPA peaked at the second hour on days and 10 days posttransplantation and peaked at the first hour after months Table 3.13 Cmax achieved at days, 10 days and months according to median Time Cmax Cmax Cmax at days at 10 days at months n % n % N % C1 12 34,3 11 31,4 19 57,6 C2 13 37,1 14 42,8 21,2 C3 22,9 22,9 24,2 C6 5,7 5,7 0,0 Total 35 100,0 35 100,0 33 100,0 At days and 10 days, Cmax concentrated predominantly on C2 (37.1% - 42,8%); At months, Cmax focused mainly on C1 with the rate of 57.6% Table 3.14 C0 level at time points of post-transplant Time daysa 10 daysb monthsc P 0,95 ± 0,4 0,1 – 1,4 (n= 10) 0,96 ± 0,35 0,2 – 1,4 (n=20) 1,07 ± 0,23 0,7 – 1,4 (n=11) pa-b= 0,944 pa-c= 0,398 pb-c= 0,346 1,99 ± 0,33 1,5 – 2,5 (n=15) 1,94 ± 0,32 1,5 – 2,4 (n=14) 1,87 ± 0,28 1,5 – 2,3 (n=10) pa-b= 0,679 pa-c= 0,338 pb-c= 0,571 4,19 ± 1,33 2,6 – 6,9 (n=10) 8,8 3,75 ± 1,28 2,6 – 6,3 (n=12) pa-c= 0,402 C0 2,5 mg/L (n=1) 16 At all-time points: the difference in drug concentration C0 was not statistically significant Table 3.15 AUC0 – 12 level at time points of post- transplant a 3X days ± SD b 10 X days ± SD c Xmonths ± SD (min - max) (min - max) (min - max) 20,03 ± 3,45 23,88 ± 5,64 20,68 ± 3,08 pa-b= 0,305 11,03 – 29,05 10,73 – 28,9 18,5 – 22,85 pa-c= 0,917 (n= 5) (n=9) (n=2) pb-c= 0,469 42,79 ± 6,02 45,38 ± 7,43 45,11 ± 8,25 Pa-b= 0,238 33,05 – 54,4 32,45 – 57,6 30,7 – 59,05 Pa-c= 0,347 (n=18) (n=23) (n=17) Pb-c= 0,92 73,61 ± 10,62 69,02 ± 11,66 84,33 ± 97,98 Pa-b= 0.521 60,8 – 94,45 60,45 – 82,3 61,05 – 129,05 Pa-c= 0,109 (n=12) (n=3) (n=14) Pb-c= 0,227 Time AUC0 – 12 < 30 mg.h/L 30-60mg.h/L >60 mg.h/L P The levels of AUC0 – 12 at time points had no difference 3.4 Variability in TCD3, TCD4, TCD8 lymphocytes counts and the ratio of TCD4/TCD3 in kidney transplant patients Table 3.22 Variability in the number of T lymphocyte lines before and after transplantation Lymphocytes Pre-transplant Post-transplant pvalues TCD3 (cell/µL) 1690,31 ± 503,45 2069,14 ± 1374,4 0,222g TCD4 (cell/µL) 549,51 ± 211,72 729,46 ± 515,69 0,036g 33,36 ± 9,83 35,49 ± 13,77 0,413g Ratio TCD4/TCD3 (%) 17 TCD8 (cell/µL) 1134,37 ± 431,07 0,368g 1373,03 ± 1004,71 g Willcoxon signrank test The number of T lymphocytes cells post-transplant increased compared to pre-transplant, but only the TCD4 form had a statistically significant difference (p 0.05) Table 3.24 Relationship between AUC0 – 12 and the number of TCD4 cells at 10 days TCD4 AUC0 – 12 Increase Total Decrease (mg.h/L) At 10 days n % n % n % 18 60 mg.h/L 8,4 9,1 8,57 Total 24 100,0 11 100,0 35 100 χ2; p-values χ2=0,3854; p= 0,825 23 patients reached AUC0 – 12, of which 17 patients increased TCD4 CHAPTER 4: DISCUSSION 4.1 General characteristics of research subjects 4.1.1 Age and sex characteristics In this study, renal transplant patients were randomly selected; nevertheless, a higher proportion of male patients than female patients could be seen (with a rate of 62.9% and 37.1%) Various studies worldwide with the same random sampling method on renal transplant recipients have also shown that the proportion of men is higher than that of women, usually over 50% 4.1.3 Weigh and several biochemical indicators The average weight of our study group is moderate According to many studies globally, optimizing the dose of MPA by weight could help achieve the target SKD for the drug With this study, the selection of average weight is appropriate with a view to evaluating the concentration of a drug in a stable period post-transplantation, Our study indicated that the patient's albumin, GOT, GPT, red blood cells, and white blood cells counts had no significant change during the treatment; and the difference is not statistically significant; 19 According to Hariharan, creatinine/HT levels in the first year post-transplant had a predictive value for long-term results after transplantation Outcomes of the study demonstrated that the serum creatinine concentration at these time points showed no difference 4.2 Use of immunosuppressive drugs In our study, all patients received a regimen including a calcineurin inhibitor and a mycophenolic acid drug The percentage of study subjects receiving Tacrolimus (Prograf) is considerably higher, which is also consistent with the current trend of utilizing anti-rejection medicines in kidney transplant pathology Patients in our study were re-examined with a relatively high frequency (once a month), while patients' re-examination in developed countries could be once every to months Thus, when the variation in drug concentrations occurs, the dose adjustment for these patients may be delayed, affecting the long-term kidney transplant outcome Patients can still enjoy certain advantages in the long-term kidney transplant outcomes despite the inconvenience of more frequent follow-up visits In our study group of patients, Tacrolimus and Cyclosporin were quantified regularly; the treating physician based on that to adjust the dose to maintain trough concentrations within the target range Accordingly, the above drugs were adjusted to change the dose many times to reach the treatment goals In contrast, MPA was not regularly quantified and adjusted according to experience; in consequence, the treatment process of patients was not adjusted continuously 4.3 Evaluation of variability in drug concentration Individualized immunosuppressive therapy necessitates better strategies to avoid drug-related toxicity while maintaining efficacy 20 Few studies have prospectively evaluated the clinical effectiveness of MPA's therapeutic drug monitoring (TDM) in organ transplantation, and they have produced conflicting results MPA is a potent, selective, and reversible inhibitor of inosine monophosphate dehydrogenase (IMPDH), resulting in the eventual arrest of T- and B-lymphocyte proliferation Mycophenolate mofetil and EC-mycophenolate sodium are essentially completely hydrolyzed to MPA by esterases in the gut wall, blood, liver, and tissue MPA binds 97-99% to serum albumin in patients with normal kidney and liver function Following mycophenolate mofetil administration, MPA maximum concentration usually occurs within 1-2 hours A secondary peak in the concentration-time profile of MPA often appears 6-12 hours post-administration by virtue of the enterohepatic recirculation, contributing approximately 40% to the area under the plasma concentration-time curve (AUC) The mean elimination half-life of MPA ranges from to 17 hours Large between- and within-subject pharmacokinetic variability was displayed by MPA Because MPA has a narrow therapeutic window and large inter-individual variability, therapeutic drug monitoring (TDM) of the area under the time-concentration curve for 12h (hours) of exposure (AUC 0-12) of MPA (MPA-AUC 0-12) is crucial to improve clinical outcomes We studied the variability in MPA concentration at all 3-time points: days, 10 days and months post-transplant; all showed a sharp increase of MPA in the first hour after drug administration After days and 10 days of transplantation, MPA peaked at the second hour and peaked at the first hour after months The patient’s 21 peak concentration ranges from 3.0 to 47.6 mg/L; 7/35 patients did not change the time to reach the peak concentration on different days of sampling At days and 10 days, Cmax concentrated predominantly on C2 (37.1% - 42.8%); at months, Cmax focused mainly on C1 with the rate of 57.6% In the study, we calculated the area under the curve over 12 hours using blood samples collected at 0, 1, 2, 3, and hours after drug administration Although monitoring the change of drug concentration over time within 12 hours is the best measure, there are still many obstacles in complying with the sampling time, the prolonged time interval betweensample collection causing many inconveniences to patients with a stable clinical condition, and especially insufficient economic conditions in the majority of patients Mathew et al in India studied patients using a combination of mycophenolate mofetil (MMF) and tacrolimus, producing fairly accurate results of the area under the curve AUC 0-12 by taking samples for the first hours after drug administration, including Cmax Fleming et al utilized MMF in combination with Cyclosporin on the group of patients and showed that the area under the curve in the first hours after drug administration accurately reflected the AUC within 12 hours Therefore, in this study, we chose the time when taking quantitative samples of MPA blood concentration in the first hours after oral administration, still ensuring the accurate reflection of the area under the curve AUC0-12 The choice of time to evaluate AUC also depends greatly on the half-life of the drug and the time to reach the maximum concentration (tmax) Various studies have shown that the time t max of renal transplant recipients using drugs in the first days post-transplant 22 often fluctuates considerably in the first to hours on average and stabilizes gradually Most of the time is in the first hours after drug administration from the first month onwards Thus, our study selected the time points of 0, 1, 2, 3, and hours, still ensuring the appropriateness of evaluating AUC0-12 in the periods up to months after transplantation The relationship between AUC 0-12 and rejection rates is clear Moreover, if fixed-dose MPA is used for all kidney transplants, the benefits and the undesirable effects will not be the same due to differences in numerous factors in each body, such as weight or drug metabolism Monitoring of AUC0-12 will assist in dose individualization Even in our study, the first days are the period of taking medicines with a fixed concentration The results show: Firstly, the AUC 0-12 value has a difference in the groups with different C concentrations Secondly, in the group not reaching the target concentration at C 0, the AUC value reaching the target range is up to 22.2%, while in the group reaching the target concentration at C 0, the AUC value not reaching the target range is up to 33.3% In addition, in the group that AUC value reaches the target range, there is a rate of 16.7% experiencing undesirable drug effects Accordingly, the oral dose for each individual to achieve the goals is different Other studies also showed similar results 4.3.1 The correlation between C0 concentration and AUC0-12 at days post-transplant The ratio of patients whose AUC concentration not reaching the target range is 10/35 = 28.57%, which is lower than various studies worldwide According to Arns W, Breuer S et al (2005), the AUC of 23 MPA not reaching the target range caused no inconvenience to the patient A study conducted by T van Gelder et al (2010) indicated that MPA levels were strongly associated with acute rejection rates in the first week post-transplant 4.3.2 The correlation between C0 concentration and AUC0-12 at 10 days post-transplant The first 10 days are in the period of rejection due to cytotoxicity (the role of T lymphocytes) This period lasts from days to months And we chose the 10-day period In our study, although no difference in AUC0-12 was observed in the three groups with different drug concentrations at C0, the ratio of patients reaching the target AUC0-12 and the ratio of patients with MPA levels in the threshold that sharply decreased undesirable effects compared to the first days post-transplant showed a marked increase 4.3.3 The correlation between C concentration and AUC0-12 at months post-transplant At months after transplantation, there is a difference in the mean AUC0-12 in the groups with different C0 concentrations (p 0.05) ); Therefore, right after receiving a kidney transplant and taking medicines, hematopoietic function markedly improve A study conducted by Kamburova et al also showed an increase in CD4 cells in patients at all time points post-transplantation 3,6,12 and 24 months compared with pre-transplantation 25 A study concuted by Al-Akash et al also showed that the group of patients using MPA had decreased CD4 and CD8 T lymphocytes in the peripheral blood, which could be interpreted as a cumulative effect Accordingly, T lymphocytes cell counts should be examined at various time points and throughout the post-transplant period Mahboob Lessan-Pezeshki et al (2005) studied 16 first-time kidney transplant patients without diabets by monitoring peripheral blood Tlymphocytes In two groups based on rejection in weeks posttransplant: group I (n = 9) did not show rejection, and group II (n = 7) showed rejection The results indicated that the number of CD3, CD4, CD8 T cells pre- and post-transplantation had no significant difference, CD3 (62% versus 69.7%) and CD4 (35% versus 41.3%) counts increased in group II during the pre-transplant rejection The outcomes of our study indicated that the 23 patients achieved the target range of AUC 0-12 , of which 17 patients increased TCD4, 3/17 patients achieved AUC at 30-40 mg.h/L, 9/17 patients had AUC of 40 - 50 mg.h/L, and patients had AUC of 50 - 60 mg.h/L; 18 patients increased TCD8, and 13 patients increased both TCD4 and TCD8; in which patients did not achieve the target range of AUC 0-12 (29.16%) There were 22 cases without dose adjustment increasing TCD4 compared to pre-transplant, of which cases increased over 1300 cells/mL There were cases of dose adjustment in cases increasing TCD4 compared to pre-transplant Thus, we see that the treatment using MPA drugs on patients still increases TCD4, is not as effective as expected, and may give rise to rejection The current recommended use of drugs is not suitable for patients in Vietnam and necessitates the re-evaluation in a longer time, which, nonetheless, may also be due to the short follow-up 26 time, in consequence, the effect of the drug on the T-cell line has not been clearly shown Thus, in addition to calculating AUC 0-12, our study found that it is necessary to pay attention to the quantification of T-lymphocyte lines to have appropriate changes, avoid incorrect doses and the risk of transplant rejection LIMITATIONS - There are a small number of patients, not followed up for a long time - AUC has not taken at many time points - The group using MPA/Tac has not been compared with the group using MPA/CsA and group using Cellcept with group using Myfortic CONCLUSIONS Variability in concentrations of Mycophenolic acid (AUC 0-12) in patients after renal transplantation Mycophenolic acid drug concentration peaked at the first hour and the second hour after drug administration; The bioavailability of the drug largely did not satisfy the requirement at the time of posttransplant testing At days and 10 days, Cmax concentrated mainly on C2 (37.1% 42.8%), at months Cmax concentrated mainly on C1 with the rate of 57.6% AUC0-12 and C0 were not correlated at all time points AUC0-12 did not reach the target range at days: 17/35 cases (48.57%); at 10 days: 12/35 cases (34.29%); at months: 16/33 cases (48.48%) 27 The correlation between the concentration of Mycophenolic acid and the variability in the number of TCD3, TCD4, TCD8 lymphocytes in patients after kidney transplantation Currently, using MPA at the recommended concentration is not suitable for patients Consequently, the number of T lymphocytes (especially TCD4) still increases in the majority of patients posttransplantation - The number of TCD cells post-transplantation increased compared to pre-transplantation, but only the TCD4 form increased significantly (p