|Year : 2020 | Volume
| Issue : 4 | Page : 298-305
A prospective study of correlation of blood levels of tacrolimus to graft function and adverse effect of tacrolimus in postrenal transplant patients
Krishna Asuri, Virinder Kumar Bansal, Sujoy Chatterjee, Omprakash Prajapati, Mahesh Chandra Misra
Department of Surgical Disciplines, All India Institute of Medical Sciences, New Delhi, India
|Date of Submission||24-Jun-2020|
|Date of Acceptance||25-Nov-2020|
|Date of Web Publication||30-Dec-2020|
Dr. Krishna Asuri
Department of Surgical Disciplines, All India Institute of Medical Sciences, Room No 5023, 5th Floor Teaching Block, Ansari Nagar, New Delhi - 110 029
Source of Support: None, Conflict of Interest: None
Introduction: There are limited data on the symptoms of immune-suppressive therapy after transplant on Indian patients and how tacrolimus blood level correlates with graft function and its adverse effects. This study was planned to study these factors. Materials and Methods: The study was conducted as a prospective longitudinal study. Adult patients who underwent the live renal transplant and matched the inclusion criteria from March 2018 to April 2019 were enrolled for the study. Trends of all the parameters were analyzed and their correlation was done with corresponding tacrolimus blood levels. Blood for tacrolimus level was collected at d1, 5, 15, 30, 90, and 180, and values of serum creatinine, diabetes status, hypertensive status, lipid profile, infection occurrence, and liver function tests were recorded at the same time. The subjective symptom occurrence was also recorded by Modified Transplant Symptom Occurrence and Symptom Distress Scale questionnaire at 3 months. Results: The mean age of the study population was 33.7 ± 10.1 years. The incidence of infection was highest at 48% in the 1–3 month period. The incidence of posttransplant diabetes mellitus (PTDM) was 13.7%. Patients requiring antihypertensive decreased from 93.1% immediate posttransplant to 51.5% after 6 months of transplant. There was an increase in posttransplant triglyceride levels, total cholesterol, and low-density lipoprotein level with only high-density lipoprotein showing a protective trend. Liver functions did not show any derangements during the study period. There was no significant correlation between any of the adverse effects and tacrolimus blood levels. Excessive appetite was the most commonly experienced symptoms whereas tremor was the most distressing one. There was a statistically significant increase in symptoms experienced in patients whose tacrolimus blood level was above the normal level for that period. Conclusion: Our study showed no significant correlation between blood levels of tacrolimus and graft function and also with hypertension, dyslipidemia, PTDM, and incidence of posttransplant infections. The incidence of adverse effects was significantly higher in patients who had tacrolimus blood levels higher than recommended.
Keywords: Adverse events, renal transplant, tacrolimus
|How to cite this article:|
Asuri K, Bansal VK, Chatterjee S, Prajapati O, Misra MC. A prospective study of correlation of blood levels of tacrolimus to graft function and adverse effect of tacrolimus in postrenal transplant patients. Indian J Transplant 2020;14:298-305
|How to cite this URL:|
Asuri K, Bansal VK, Chatterjee S, Prajapati O, Misra MC. A prospective study of correlation of blood levels of tacrolimus to graft function and adverse effect of tacrolimus in postrenal transplant patients. Indian J Transplant [serial online] 2020 [cited 2021 Mar 4];14:298-305. Available from: https://www.ijtonline.in/text.asp?2020/14/4/298/305430
| Introduction|| |
Renal transplant is the currently accepted standard of care in patients with end-stage renal disease. Immunosuppression has gone a long way from the days of high-dose radiation to the present era of monoclonal antibodies. The initial problems of rejection and graft loss have been substantially reduced with these novel immunosuppressive agents.
The current challenge to the transplant fraternity is to improve graft survival at the same time optimize the doses of immune-suppressant such that side effects of the drugs are minimum and well tolerated by the patients. Triple therapy, i.e., calcineurin inhibitors, steroids, and mycophenolate mofetil (MMF) is the standard immunosuppression therapy.
Tacrolimus (formerly known as FK-506) was isolated in 1984 in Japan from soil fungus Streptomyces tsukubaensis and acts by inhibition of interleukin (IL)-2 gene expression and IL-2 production. This drug has wide inter- and intraspecific variability and risk of drug interaction with commonly used medications.
The therapeutic use of tacrolimus is complicated by its narrow therapeutic index (5–15 ng/ml). Tacrolimus doses should be such that its blood levels are maintained in the therapeutic range so that balance between the antirejection effect and its adverse effects is properly maintained. This requires therapeutic drug monitoring at regular intervals. The higher level of tacrolimus in blood has a deleterious effect on graft function and result in higher complication rates. The literature is very scanty about the correlation of tacrolimus blood levels and its various adverse effects including graft function, diabetes mellitus (DM), infections, lipid levels, and others.
As patients following renal transplant have to be on lifelong immune-suppressive therapy, it is important to assess the symptoms and distress caused by long-term side effects of these immune-suppressants which may further affect long-term drug adherence and have an important impact on the quality of life. The Modified Transplant Symptom Occurrence and Symptom Distress Scale (MTSOSD-R59) assesses the patient's appraisal of symptoms associated with side effects of immune-suppressive therapy and has been validated in previous studies.
This study was done to assess the correlation of tacrolimus blood levels to graft functions and outcomes at various time intervals and compare the pre- and post-transplant symptoms associated with adverse effects of immune-suppressive therapy using MTSOSD-R59.
| Materials and Methods|| |
The study was conducted in the Department of Surgical Disciplines, Nephrology, Psychiatry, and Ocular Pharmacology of All India Institute of Medical Sciences, New Delhi. It was a prospective longitudinal cohort study.
Seventy-seven patients who underwent live renal transplants from March 2018 to April 2019 were enrolled for the study.
All patients more than 18 years of age undergoing first live renal transplant and having tacrolimus based immunosuppression regime were included in the study.
Patients <18 years, not giving consent for the study, with other significant comorbidities like bronchial asthma, chronic obstructive pulmonary disease, coronary artery disease, hepatitis B or C positive patients, undergoing the second transplant, on nontacrolimus based regimen and deceased renal transplant recipients were excluded from the study.
The demographic characteristics, preoperative clinical details including primary renal pathology, intraoperative parameters, and postoperative outcomes were recorded in a prestructured proforma.
The induction of immunosuppression was started 1 day before transplant. Tacrolimus was given at a dose of 0.15 mg/kg in two divided doses on the day before transplant. MMF was given at a dose of 1 g twice daily before transplant and at the same dose on the day of transplant and continued posttransplant. Methyl-prednisolone 500 mg was given on the pretransplant day and 250 mg on the day of transplant followed by another dose on the evening of transplant. This was followed by tablet prednisolone from posttransplant day 1. If the patient had genetically unrelated donor or human leukocyte antigen mismatch ≥4/6 they were started on induction therapy with basiliximab at 20 mg for patients weighing more than 35 kg on the morning before transplant and posttransplant day 4.
In cases of acute cellular rejection, antirejection therapy, intravenous methylprednisolone pulse of 1000 mg once a day for 3 days was used.
For tacrolimus assay 3 mL of blood was collected at 8 o' clock in the morning before the patient had taken the morning dose of the drug in ethylenediaminetetraacetic acid vials and the sample was stored at –20°C. The tacrolimus levels were determined by Liquid Chromatography (Thermo scientific ACCELA, USA) and Mass Spectrometry (Applied Biosystem 4000 Triple Quadruple, USA) method in the Department of Ocular Pharmacology, AIIMS. Liquid chromatography–mass spectrometry or high-performance liquid chromatography-mass spectrometry (LC-MS, or alternatively HPLC-MS) is an analytical chemistry technique that combines the physical separation capabilities of liquid chromatography (or HPLC) with the mass analysis capabilities of mass spectrometry. This method involves solid-phase extraction of the biological samples (tacrolimus) and the use of liquid chromatography to separate various components, followed by the use of a mass spectrometer as a quantifier. Tacrolimus was separated from the blood by the HPLC technique and quantified by the mass spectrometric technique.
Tacrolimus levels were maintained at 8–10 ng/ml in the first 3 months posttransplant and tapered to 5–8 ng/ml during 3–6 months posttransplant and a level of 3–5 ng/ml was maintained 6 months after of renal transplant. MMF was continued and steroids were tapered gradually after 3 months.
Posttransplant patient assessment
Tacrolimus levels were measured at 24 h, 5 days, 14 days, 28 days, 12 weeks, and 6 months. All levels were measured in ng/ml. Patients were closely monitored during their hospital stay. On discharge, they were taught to keep a weekly record of intake/output, blood sugar, blood pressure, and renal functions.
Close monitoring of patient's vitals including blood pressure, pulse rate and central venous pressure, intake and output chart, and blood biochemical investigations were done during the early posttransplant period. Graft function and the adverse effects of the drug were assessed by the following parameters. Intake and output recording was done during the hospital stay and after discharge. If there was any deterioration in urine output or clinical condition of the patient then appropriate treatment was started.
Serum urea and creatinine levels were measured daily during the hospital stay and then twice weekly for the next 3 months and every 15 days from 3 to 6 months after transplant. If there was a sustained rise in the above parameters then appropriate treatment in the form of tacrolimus dose adjustment, investigation for the cause of renal dysfunction like Ultrasound Doppler for renal blood flow of transplanted kidney, Diethylenetriaminepentaacetic acid (DTPA) radioisotope scan and graft biopsy were done and appropriate treatment was instituted.
Blood pressure was recorded 6 hourly during the hospital stay and thereafter daily. Any increase in blood pressure was treated with a combination of anti-hypertensive. During follow-up blood pressure was assessed on day 5, day 15, 1 month, 3 months, and 6 months.
Liver function tests were done pretransplant and posttransplant on day 1, day 5, day 15, 1 month, 3 months, and 6 months. If there was any derangement of the values then appropriate measures were taken.
Blood sugar monitoring was done for all patients. Patients with high blood sugar were started on insulin therapy as per the protocol of management. For nondiabetic patients, blood sugar monitoring was done on day 5, day 15, 1 month, 3 months, and 6 months posttransplant.
Infection screen was done by clinical examination for assessing wound infection, urine routine examination, culture and sensitivity, and chest X-rays during their follow-up visits. If any abnormality was detected then appropriate treatment was initiated. Further tests were guided by the patient's complaints. Routine screening of BK virus infection is not done at our institute as the test is costly and not feasible in a low resource setting like India. Recipients who have renal dysfunction or acute tubular injury of unknown cause with decoy cells are subjected to BK virus testing.
Lipid profile including total cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL), and triglycerides measured in mg/dl pretransplant, and at 1 month, 3 months, and 6 months posttransplant. If any abnormality was detected then appropriate treatment was started.
In case of graft dysfunction, as detected by decreased urine output, an acute rise in serum creatinine levels, graft tenderness, and fever or a combination of these symptoms following investigations were done.
Ultrasound Doppler to evaluate the vascular flow in the transplanted renal vessels, DTPA scan to note the functional status of the transplanted kidney, and renal biopsy. In every biopsy specimen, the state of glomeruli, tubules, blood vessels, and interstitium were analyzed and abnormal histology if any was recorded. The opinion of the most probable cause for the histological picture was taken with respect to various causes of graft dysfunction like acute rejection, tacrolimus toxicity, acute tubular necrosis, and chronic allograft nephropathy. Banff criteria were followed for reporting the biopsies.
Assessment of subjective symptoms
The subjective symptoms were assessed by The MTSOSD-59 at 3-month follow-up.
After discharge from the hospital, patients were reviewed after 15 days, 1 month, 3 months, and 6 months. Blood tests for various parameters including tacrolimus blood levels were done. Average values of variables like blood pressure and intake output were noted from the patient's daily records.
Data were collected and managed using Microsoft Excel (Microsoft, Seattle WA, USA). Demographic and clinical characteristics were described using mean values and standard deviation, median/interquartile ranges, and frequencies as appropriate. For qualitative data, the Chi-square test was used. P < 0.05 was considered as statistically significant.
RIDIT analysis was done on MTSOSD 59 to find the most distressing and the most commonly experienced symptoms. For correlating the tacrolimus levels with various aspects of graft function and adverse effects Pearson's product moment correlation coefficient was used.
Indian Council of Medical Research/Good Clinical Practice guidelines were followed. Patients were enrolled for the study after clearance from the institute ethics committee. (AIIMS/IEC/2018/28-4). Study was carried out as per Declaration of Helsinki.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given his consent for his images and other clinical information to be reported in the journal. The patient understand that name and initials will not be published and due efforts will be made to conceal identity, but anonymity cannot be guaranteed.
| Results|| |
The study was conducted in the Department of Surgical Disciplines, Nephrology, Psychiatry, and Ocular Pharmacology of All India Institute of Medical Sciences, New Delhi from March 2018 to April 2019. Out of the 110 renal transplants conducted during this period, 77 patients were enrolled for the study who met the inclusion criteria [Figure 1]. The demographic and preoperative clinical profile is as shown in [Table 1].
Correlation of graft function with tacrolimus level
There was no significant correlation between the serum creatinine level and the corresponding tacrolimus level (P > 0.05) [Table 2].
Correlation of diabetes occurrence with tacrolimus level
In the study population, 5 (6.8%) patients were diabetic pretransplant. Posttransplant at 1 month 17 (23.3%) patients required insulin and at 6 months after transplant 10 patients had posttransplant diabetes mellitus (PTDM). The incidence of new onset diabetes after transplant was 13.7%. Tacrolimus blood levels at different time intervals did not show any significant correlation with the incidence of PTDM [Table 3].
|Table 3: Correlation of adverse effects with tacrolimus level* on day 90|
Click here to view
Correlation of infection and tacrolimus levels
The overall incidence of infection during this period was 32.9%. Urinary tract infection (UTI) was the most common infection 19 (26%) in this time period. Surgical site infection was seen in 4 (5.5%) patients. Tacrolimus blood levels were assayed 4 times during this period and there was no significant difference (P > 0.05) in tacrolimus levels in patients with and without infections. The mean blood levels of those patients not having infection as compared to the mean tacrolimus level at corresponding intervals in those patients with infections were not significant statistically
During this period, 34 patients (46.5%) were diagnosed with infection, with one patient having two unrelated infections (UTI and Cryptosporidium) making a total of 35 infection-related admissions. UTI in 13 patients (17.8%) was the most common infection in this period also. Eleven (15.1%) patients presented with clinical Varicella Zoster Virus infection. Cytomegalovirus (CMV) infection was seen in 3 and pneumocystis pneumonia in 2 patients respectively. Tacrolimus blood levels were assayed once during this period and there was no significant difference (P > 0.05) in tacrolimus levels in patients with and without infections [Table 4].
Eighteen patients (24.7%) presented with evidence of infection in this time period. One patient had two events of infection at separate intervals (CMV and pyelonephritis). UTI in 8 (11%) patients remained the most common infection in this period also and diarrhea 6 (8.2%) was the second most common infection in this period. Tacrolimus blood levels were assayed once during this period and there was no significant difference (P > 0.05) in tacrolimus levels in patients with and without infections.
Correlation hypertension with tacrolimus level
Majority of patients, 67 (87.6%) were on anti-hypertensive medication pretransplant with 33 (45.5%) patients requiring more than 2 antihypertensive drugs for control of blood pressure.
[Table 3] shows the correlation of hypertension with tacrolimus levels at various time intervals. There was a decrease in the incidence and severity of hypertension with time after transplant, but there was no significant correlation with tacrolimus blood levels [Table 3].
Correlation of lipid abnormalities with tacrolimus level
There was a significant increase in the prevalence of lipid abnormalities from the pretransplant period to the posttransplant period. The prevalence of hypercholesterolemia increased from 0% to 17.8% 3 months posttransplant and to 39.7% after 6 months. There was a significant increase in the LDL cholesterol levels and a significant decrease in HDL cholesterol levels posttransplant. However, there was no significant correlation with tacrolimus level.
Correlation of tacrolimus level with liver functions
Liver functions did not show any derangements in the study population after transplant. Only one patient had a transient rise in serum glutamic-oxaloacetic transaminase and serum glutamic-pyruvic transaminase on day 5 which normalized without any intervention by day 15. Their correlation with tacrolimus blood level was also not significant [Table 3].
Assessment of symptom occurrence and symptom distress
Among the 59 possible symptoms, the most commonly experienced symptom was excessive appetite followed by tiredness and tremor. The most common distressing symptom was tremor, followed by anxiousness and tiredness [Table 5].
|Table 5: Most commonly experienced and most distressing symptoms in modified transplant symptom occurrence and symptom distress scale-59 questionnaire|
Click here to view
Four out of five symptoms namely tiredness, tremor, anxiousness, and sores on lips and/or mouth were both most commonly experienced and most distressing. Excessive appetite, though was the most commonly experienced symptom, was thirteen in the most distressing list. Excessive flatus which was fourth in the distressing list was the sixth most commonly experienced symptom.
The overall symptom experience and distress RIDIT score were compared with age, sex, and tacrolimus blood level at 3 months [Table 6].
|Table 6: Comparison of symptom occurrence and symptom distress based on gender, age, and tacrolimus level at 3 months|
Click here to view
The overall symptom occurrence score in males was 0.498 versus 0.524 in females. But this difference was not found to be statistically significant (P = 0.360). Twelve patients had tacrolimus blood level more than 8 ng/ml and these patients were found to have significantly more symptom experience score when compared with the 61 patients who had tacrolimus level at normal range (5–8 ng/ml) (0.532 vs. 0.493) (P = 0.04, Student's t-test).
The overall symptom distress score in males and females was 0.5. This was not statistically significant (P = 0.679, t-test). The symptom distress score in patients with normal tacrolimus blood level was 0.495 versus 0.52 in patients with tacrolimus level more than 8 ng/ml. This was not statistically significant (P = 0.109, Student's t-test).
Although there was a significant correlation of elevated tacrolimus blood level with the occurrence of subjective symptoms, the symptom distress scores in patients with normal and elevated tacrolimus blood levels did not show any statistical significance (P = 0.1).
| Discussion|| |
Close monitoring of the tacrolimus concentration is required to achieve an optimal efficiency and thus minimizing the risk of subtherapeutic or toxic blood concentrations. It has been shown that the efficacy and side effects of tacrolimus are highly correlated with the area under the curve (AUC 0–12). But recording a complete 12 h pharmacokinetic profile for every patient is not feasible in clinical practice and like most transplant centers we also use C0 concentration for drug measurement and monitoring which has been substantiated in many studies which have shown that C0 exposure is a good indicator for total systemic exposure.,
Based on the half-life of tacrolimus which is approximately 10 h, it is necessary to wait for at least 36 h (3.3 half-lives) to reach a steady-state tacrolimus concentration after initiation of therapy or after a change in the administration regime of tacrolimus. According to Braun et al. ideally, after starting the therapy, blood concentrations should be monitored on day 2 or 3 and then on average 3 times in the first few weeks after transplantation, and less frequently thereafter. The tacrolimus levels were measured in our study based on these recommendations.
It has been shown in the literature that adverse reactions of tacrolimus tend to occur most frequently in the first few months after transplantation and decrease with time possibly in line with reductions in tacrolimus concentration., Our results also show a similar trend with most of the adverse effects appearing within the first 3 months after transplant. There is a need to monitor drug levels of tacrolimus more frequently in the early posttransplant period.
The incidence of new-onset DM within 1 year posttransplant has been shown to be in the range of 8%–20% in cadaveric renal transplant patients and in liver transplant patients., The incidence of PTDM was 13.5% in our study which is comparable to the literature. The PTDM has been shown to be dependent on the dose of Tacrolimus and with time as the dose of Tacrolimus goes down the incidence and requirement of insulin also goes down. Although the number of patients in our study with DM was small, it showed a similar trend where 2 patients were weaned off insulin in the first 6 months after transplant. However, the tacrolimus drug levels did not show any correlation with the incidence of PTDM. This may be explained by the fact that corticosteroids which are also diabetogenic may have confounded the incidence of DM.
The posttransplant use of antihypertensive drugs was in 74% of patients after the 1st month of transplant which decreased to 54% after 6 months. In a review article by Fung et al. hypertension occurred in up to 50% of the liver and renal transplant patients treated with tacrolimus. It is further seen that it is difficult to determine with certainty an association between tacrolimus therapy and hypertension as hypertension may be caused by the excessive intravascular volume, intrinsic renal damage, or increased vasomotor tone. Moreover, corticosteroids may also lead to excess water retention and hypertension. Our study failed to show any correlation of tacrolimus blood level with the occurrence of hypertension.
We observed that dyslipidemia is a highly prevalent entity in the subgroup of renal transplant recipients, with a prevalence as high as 97.3% at 6 months posttransplant, of at least some form of dyslipidemia. This has been shown in many studies in the literature. Aakhus et al. and Kasiske et al. have shown that more than 80% of patients had total cholesterol levels above 200 mg/dl and more than 90% had LDL-Cholesterol levels above 100 mg/dl. In our study, the prevalence of hypercholesterolemia was 39.7% and high LDL-C was 86.3%, 6 months after transplant.
The predominant lipid abnormalities observed in our study were-marked elevations in serum triglycerides (78.1% vs. 97.2%) as well as LDL cholesterol (32.8% vs. 86.3%), moderate elevations of total cholesterol (0% vs. 39.7%) with an increase in serum HDL-cholesterol levels (93.15% vs. 60.2%). The typical pattern of posttransplant dyslipidemia as described by Kasiske et al., and Vathsala et al. in two separate studies was one of marked hypercholesterolemia and moderate hypertriglyceridemia along with increased apolipoprotein B. Other studies by Drüeke et al. and Cheung et al. have described a pattern consisting of increased levels of triglycerides, normal serum cholesterol, and decreased HDL cholesterol.
However, although there is a high prevalence of lipid abnormalities in the postrenal transplant period, it does not show any correlation with blood levels of tacrolimus which has been reported previously by Jiang et al. also.
The risk of infection in a renal transplant recipient is determined by the interaction of two key factors namely the epidemiological exposures of the patient, including the timing, intensity, and virulence of the organisms and the patient's “net state of immunosuppression,” which reflects a measure of all host factors contributing to the risk for infection.
In our study, the most common infection during the 1st month was UTI 26.03% followed by wound infection 5.48%. Both these infections are related to surgical procedures.
Fishman and Davis further reported that opportunistic infections are notable for their absence in the 1st month after transplantation, even though the daily doses of immunosuppressive drugs are at their highest during this time. This was also observed in our study with infections, where the incidence of opportunistic infections started rising after the 2nd month of transplant and was maximum in the period of 1–3 months after which there is an overall reduction in the immunosuppression (0% vs. 54.3% vs. 16.7%). This suggests that it is not only dose dependent but rather the cumulative dose of these drugs—the “area under the curve”—that determines the true state of immunosuppression and its side-effects.
Correlation of the blood levels of tacrolimus with the occurrence of infection was not found to be significant and this comparison has not been made previously in the literature.
The role of tacrolimus levels and other factors such as sex and age with that of incidence of adverse symptom and the magnitude of distress caused by these symptoms at 3 months following renal transplant were also assessed.
There was a higher incidence of adverse symptoms experienced by patients with higher tacrolimus blood levels at 3 months (>8 ng/ml). However, the distress caused by these symptoms did not show any significant increase in patients with higher tacrolimus levels.
Wang et al. found that symptom occurrence and distress was more in females and younger age group which is in contrast to our results where symptom occurrence and distress did not have any correlation with age and sex. This may be explained by the fact that the study population was disproportionately distributed with more than 92% being male and 86% of patients lesser than 40 years.
Symptom occurrence is the cognitive pathway of symptom experience and is described by frequency, severity, and duration of a given symptom whereas symptom distress is the emotional pathway which demonstrates how the recipients are influenced daily by these symptoms. Our study population comprised of mostly males and the younger population who are more likely to endure symptoms without much distress. Hence though the symptom experienced is significant, distress caused by them is not significant.
The present study demonstrates excessive appetite, tiredness, anxiousness, tremor, and sores on mouth and lips as the five most commonly experienced symptoms and tremor, anxiousness, tiredness, wind, and sores on mouth and lips as the top five distressing symptoms. In a meta-analysis, Webster et al., showed that tacrolimus-treated patients were significantly more likely to report tremors, headache, dyspepsia, vomiting, and diarrhea. Older studies by Kugler et al., Moons et al. and de Barros and Cabrita showed moon's face, increased hair growth, and bruises as the most commonly occurring symptoms.
The difference with these studies can be attributed to the fact that the dominant immunosuppressive used at that time was cyclosporine with high dose steroids and hence the symptom occurrence profiles were dominated by the side effects of these drugs. A study by Wang et al. done in Chinese patients showed itching, concentration and memory problem, and fatigue as the most commonly reported symptoms.
This is the first time that this scale was used on the Indian population which differs culturally from the western population. The cultural dimension is also important while interpreting this scale as population comprising of the intellectual class would report concentration, memory, and fatigue among the commonly occurring symptoms while population with hard working and financially unstable people would report physical symptoms like tiredness and anxiety more frequently, as seen in our study.
Limitation of the study
Study had less number of patients and the follow up was short.
| Conclusion|| |
Our study showed no significant correlation between blood levels of tacrolimus and graft function and also with hypertension, dyslipidemia, PTDM, and incidence of posttransplant infections. There was a significant improvement in the quality of life of patients following transplant in all domains. The incidence of adverse effects was significantly higher in patients who had tacrolimus blood levels higher than recommended, though they were not causing significant distress. Further follow-up of these patients and the inclusion of more patients are required to assess the long-term graft function of these patients.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Basu A, Sharpio R. Tacrolimus in renal transplant. In: Morris PJ, editor. Kidney Transplantation. Principles and Practice. 6th
ed. Philadelphia: Saunders; 2008. p. 259-66.
Antignac M, Barrou B, Farinotti R, Lechat P, Urien S. Population pharmacokinetics and bioavailability of tacrolimus in kidney transplant patients. Br J Clin Pharmacol 2007;64:750-7.
Port FK, Wolfe RA, Mauger EA, Berling DP, Jiang K. Comparison of survival probabilities for dialysis patients vs cadaveric renal transplant recipients. JAMA 1993;270:1339-43.
Bross I. How to use Ridit analysis. Biometrics 1958;14:18-38.
Mahalati K, Kahan BD. Pharmacological surrogates of allograft outcome. Ann Transplant 2000;5:14-23.
Braun F, Schütz E, Peters B, Talaulicar R, Grupp C, Undre N, et al
. Pharmacokinetics of tacrolimus primary immunosuppression in kidney transplant recipients. Transplant Proc 2001;33:2127-8.
Colvin R, Mauyyedi S. Pathology of renal transplant. In: Morris PJ, editor. Kidney Transplantation. Principles and Practice. 6th
ed. Philadelphia: Saunders; 2008. p. 385-86.
Buchwald A, Winkler K. Validation of an LC-MS/MS method to determine five immunosuppressant with deuterated internal standards including MPA. BMC Clin Pharmacol 2012;12:2-11.
Pirsch JD, Miller J, Deierhoi MH, Vincenti F, Filo RS. A comparison of tacrolimus (FK506) and cyclosporine for immunosuppression after cadaveric renal transplantation. FK506 Kidney transplant study group. Transplantation 1997;63:977-83.
Williams R, Neuhaus P, Bismuth H, McMaster P, Pichlmayr R, Calne R, et al
. Two-year data from the European multicentre tacrolimus (FK506) liver study. Transpl Int 1996;9:S144-50.
Fung JJ, Todo S, Tzakis A, Demetris A, Jain A, Abu-Elmaged K, et al
. Conversion of liver allograft recipients from cyclosporine to FK 506-based immunosuppression: benefits and pitfalls. Transplant Proc 1991;23:14-21.
Aakhus S, Dahl K, Widerøe TE. Cardiovascular morbidity and risk factors in renal transplant patients. Nephrol Dial Transplant 1999;14:648-54.
Kasiske B, Cosio FG, Beto J, Bolton K, Chavers BM, Grimm R Jr., et al
. Clinical practice guidelines for managing dyslipidemias in kidney transplant patients: A report from the managing dyslipidemias in chronic kidney disease work group of the national kidney foundation kidney disease outcomes quality initiative. Am J Transplant 2004;7:13-53.
Vathsala A, Weinberg RB, Schoenberg L. Lipid abnormalities in cyclosporine-prednisolone-treated renal transplant recipients. Transplantation 1989;48:37-47.
Drüeke TB, Abdulmassih Z, Lacour B, Bader C, Chevalier A, Kreis H. Atherosclerosis and lipid disorders after renal transplantation. Kidney Int Suppl 1991;31:S24-8.
Cheung AK, Wu LL, Kablitz C, Leypoldt JK. Atherogenic lipids and lipoproteins in hemodialysis patients. Am J Kidney Dis 1993;22:271-6.
Jiang Y, Xie X, Peng LK. Dyslipidemia in human kidney transplant recipients receiving cyclosporine and tacrolimus is associated with different expression of cd 36 on peripheral blood monocytes. Transplant Proc 2011;43:1612-15.
Fishman J, Davis J. Infections in renal transplant recipients. In: Morris PJ, editor. Kidney Transplantation. Principles and Practice. 6th
ed. Philadelphia: Saunders; 2008. p. 492-98.
Wang C, Wang G, Yi H, Tan J, Xu C, Fang X, et al
. Symptom experienced three years after liver transplantation under immunosuppression in adults. PLoS One 2013;8:e80584.
Dobbels F, Moons P, Abraham I, Larsen CP, Dupont L, de Geest S. Measuring symptom experience of side-effects of immunosuppressive drugs: The modified transplant symptom occurrence and distress scale. Transpl Int 2008;21:764-73.
Webster AC, Woodroffe C, Taylor RS. Tacrolimus versus cyclosporine as primary immunosuppression for kidney transplant recipients: Meta-analysis and meta-regression of randomized trial data. BMJ 2005;98:810.
Kugler C, Fischer S, Gottlieb J, Tegtbur U, Welte T, Goerler H, et al
. Symptom experience after lung transplantation: impact on quality of life and adherence. Clin Transplant 2007;21:590-6.
Moons P, de Geest S, Versteven K, Abraham I, Vlaminck H, Moens G, et al
. Psychometric properties of the “modified transplant symptom occurrence and symptom distress scale”. J Nurs Meas 2001;9:115-34.
de Barros CT, Cabrita J. Self-report of symptom frequency and symptom distress in kidney transplant recipients. Pharmacoepidemiol Drug Saf 1999;8:395-403.
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]