Summmary of this study:
Despite the advancement in immunsuppression but still there is high incidence of acute rejection
Tacrolimus is the corner stone in kidney transplantation immunosuppressive medications.
either low trough levels or high trough levels carries a risk on graft survival ,low levels are associated with acute rejection ,high levels are associated with diabetes after transplantation and Nephrotoxicity.
This study is retrospective observational study done on large number of patients>1000 to check the correlation between tacrolimus clearance and risk of BPAR (Biopsy proven acute rejection.
They divided patients to low clearance, below average ,above average and high clearance ,they used chemileuminescent micro particle immunoassay to test tacrolimus levels
they found that there is correlation between low trough levels (mostly because of high clearance) and acute rejection in the first 90 days after transplantation in standard risk and high immunological risk but they found no significant difference between clearance and BPAR .They defined a cut off value of 1.5 above which the patient could have acute rejection there is no explanation for this but CYP3A5 can be a cause but still cannot be used instead of clearance .
critical appraisal :
Adv.:
Retrospective Observational
large No of patients ,including high and low risk
Determination of cut off value that can clarify the patient that could have acute rejection
draw backs
:No ethinicity included
The test used in testing Tac level may give false high levels
No comment on comedic actions
CYP3A5 genotypes are not discussed
some patients were missed for follow up as transferred to other centers
saja Mohammed
3 years ago
Tacrolimus is one of the cornerstone immunosuppressive therapy since 1990s associated with improved graft survival but still early acute rejection reported in 10-20% post kidney transplantation ,tacrolimus characterized by narrow therapeutic index with underdosing can increase the chance of acute rejection at the same time prolong higher exposure can be associated with chronic nephrotoxicity and PTDM , also there is intra-individual and interindividual pharmacokinetics variation in tacrolimus trough level due to many factors ( drug interactions ,food, poor compliance)
This is a retrospective study from single center to assess the tacrolimus clearance effect on the rate of BPAR among adults kidney transplant recipients between the 2009-2013, they included > 600 adults’ patient on tacrolimus base maintenance immunotherapy
the study shows those with high tacrolimus clearance rate have higher risk of BPAR compared to lower clearance rate in both standard and high immunological risk groups
limitations
————–
Retrospective design from single center, ethnicity not mentioned in the patients’ characteristics,assume they are all white ethinic background .
follow up limited to 90 days in fact majority of patients followed to 8-10 weeks then referred to local nephrology units, dropping 79 patients during FU cannot rule out bias in sample size
the CYP3A4 genotype data are missing
concomitant medication and the compliance with medication not reported .
limitation related to the local method used with 18% of overestimation of tcarolimus trough level compared to standared chromotographic method.
Ben Lomatayo
3 years ago
Despite the advancement in immunosuppressive therapy, 10 to 20% of renal transplantation is associated with acute rejection(1,2). Tacrolimus is the primary drug in the immunosuppressive regimens and its blood levels has to be in therapeutic range. Higher and lower doses of tacrolimus are both not good for long-term graft survival. Patients with high Tacrolimus clearance are at increased risk of rejection compared to low clearance patients. Failure to take treatment in times result in low drug concentration in high clearance versus low clearance patients. This is retrospective study of 638 patients conducted between January 2009 to December 2013 in University Hospital Rikshopitalet, Norway. The objective was to find the relationship between estimated tacrolimus clearance{ daily tacrolimus dose in mg divided by trough concentration in microgram per litre > 1.5} and biopsy-proven acute rejection(BPAR) the first 90 days post transplant. Patients were divided to standard risk and high immunological risk( PRA >20%, ABO incompatible, DSA) and the induction was Basilixmab & methylprednisolone. ATG was given in patients with PRA >20%. Acute rejection was defined as unexplained rise in Cr > 20%. Steroids- resistant rejection were treated with ATG. Multivariate Cox-regression was done to evaluate the independent effect of potential risk factors on acute rejection & the clearance cuff off points was identified by Receiver operator characteristic curve analysis. This study demonstrated that 55 patients(13.3%) developed BPAR. Patients were divided into 4 group based on their estimated tacrolimus clearance( low, below average, high, above average). Patients with high clearance group experienced more incidence of BPAR (20.6%) with hazard ratio of 2.39 versus low clearance group. This due to lower trough concentration in high clearance group which triggers the immune system. Other risk factors for acute rejects were DGF, male sex, immunological risk & cold ischemia time. The median time to BPAR after transplantation was 8 days. Low oral bioavailability was associated with high clearance and other possible factors were P- glycoprotein and CYP enzyme. how ever CYP 3A5 was not measured in this study. Although liquid chromatography is the more accurate test to measure tacrolimus concentration, immunoassays was used to to measure the tacrolimus concentration. In conclusion, high tacrolimus clearance is important risk factor for for BPAR in first 3 months after transplantation
Critics ; a) Methodology is poor being retrospective analysis, b) Technique for measurement of Tacrolimus concentration; Immune assay is less accurate than liquid chromatography, c) Low PPV for estimated tacrolimus clearance(= 30%), d) Lack of CYP3A5 genotype in the study; CYP3A5 Is associated with tacrolimus clearance & patients expressing the functional protein requires a double dose to reach the same trough concentrations as the non-expresser
Assafi Mohammed
3 years ago
Please summarise this article.
Tacrolimus is very crucial as maintenance immunosuppression in renal transplantation in most of regimens. TAC clearance may vary between KTRs with consequences of variation in trough concentration and clinically targeted therapeutic level. In this cohort retrospective study of 638 KTRs, TAC clearance was evaluated in association with BPAR and patients were stratified into 4 groups (low, below average, above average, and high). In evaluating and analyzing KTRs, there was no difference in trough concentration of Tacrolimus between patients with BPAR and those without.The mean trough concentrations remain within the therapeutic range between KTRs groups. There was significant association between high TAC clearance and development of BPAR explained by variation in drug concentration between patients as time needed to reach the target trough concentration is different between patients’ groups of TAC-Clearnce .
Critically appraise this study This retrospective cohort study, first one in it’s type to search for the Association of BPAR as primary outcome with post transplant clearance of Tacrolimus. 638 KTRs were distributed into 4 groups, according to TAC clearance and results were analyzed using appropriate statistical and analytical methods to answer the study question and reach the primary outcome. Strength of the study:
include many patients transplanted at a single centre.
Study limitations:
There were lacking of adherence data of the patient although the authors considered the non-adherence is unlikely to be the main reason for the study finding.
The ethnicity of patients transplanted is not registered.
Very homogenous population(mostly of white origin).
No data on comedications.
No mention for the influence of CYP3A inducers or inhibitors as well as the patients’ ethnicity.
Ban Mezher
3 years ago
Inspire of improvement in IS regime, the risk of early AR still high(10-20%) of renal transplantation recipients. Tac considered as the corner stone in IS. But over- or under- dose is a problem that may cause AR( low dose) or nephrotoxicity (over dose), so close drug level monitoring is essential & should be done routinely.
There is high intra-individual & inter-individual pharmacokinetics variability due to many factors (e.g. co-medication, food, & non adherence).
Saint-Marcous et al found that missing one dose of Tac can lead to lower Tac exposure in recipients with high drug clearance when compared to low drug clearance recipients, & this can trigger immune response causing acute rejection or developing de novo DSA.
Aim of the study: prove the correlation between drug clearance with incidence of ABMR during first 3 months post-transplantation period.
Single-center study included 638 renal transplant recipients who receive Tac based regime through a period from Jan 2009-Dec 2012. The patients followed for 8-10 weeks.
High risk recipients ( DSA+ve, PRA>20%, & ABO incompatible recipient & donor) had induction with ATG & IVIG, Tac dose was 0.05 mg/kg with target trough level 8-12 microg/ml (0-30 days) & 6-10 micron/ml ( after 30 days).
Standard risk recipients had induction with 2 doses of basiliximab, Tac dose 0.04 mg/kg with target trough level 3-7 microg/ml. In addition to MMF & steroids for all recipients.
Tac level measured directly before morning dose, 3-4 times/ week tapering to once weekly monitoring at week 8.
Protocol biopsy done at 6 & 8 weeks in addition to graft biopsy when there was a suspicion of Ar ( unexplained increase in >20 % of GFR). drug clearance= mean of total daily dose/ morning trough level
According to clearance the recipients classified into low, below average , above average & high drug clearance.
The study found that recipients with high Tac clearance were associated with increased risk of ABMR in early post-transplantation period in both standard & high immunological risk patients. Recipients with low drug clearance can achieve target trough level faster than other groups.
Using of extended Tac formula to optimizing treatment in high risk patients. There are several factors can affect Tac pharmacokinetics as CYP3A5 genotype, ethnicity, & drugs that interact through CYP3A.
The study had several limitation
didn’t identify CYP3A5 genotype
very homogenous population
co-medication used during study not identified
using a method with high Tac concentration than other methods.
Mohammed Sobair
3 years ago
Tacrolimus is the cornerstone in the immunosuppressive regimen after renal
transplantation.
Underdosing of tacrolimus increases the risk of acute rejection and development of de
novo donor-specific antibodies.3 Overdosing on the other hand is associated with side
effects, such as renal toxicity and post transplantation diabetes mellitus
Tacrolimus is a critical dose drug with a high intraindividual and interindividual
pharmacokinetic variability.
The high intrapatient variability may be due to many factors, such as comedication,
nonadherence, and food.
Nonadherence in renal transplant recipients is estimated to be approximately 20%-25%.
Aim of the analysis was to investigate the association between individual tacrolimus
clearance, controlled for actual trough concentrations obtained, and incidence of biopsy-
proven acute rejection (BPAR) the first 90 days after renal transplantation.
Finding in the study was that renal transplant recipients with high tacrolimus clearance
had a higher risk of having an acute rejection episode in the early phase after renal
transplantation. A plausible explanation could have been that patients with high
tacrolimus clearance had lower trough concentrations, but no such difference was
identified between recipients experiencing BPAR or no-BPAR in neither standard-risk
nor in high immunological risk patients.
multivariate analysis showed that a 1-unit higher estimated clearance resulted in an
independent doubling of the risk of BPAR the first 90 days post transplantation, for
example, a patient receiving a daily tacrolimus dose of 7.5 mg to reach a trough
concentration of 5.0 μg/L will have more than twice the risk of BPAR compared to a
patient receiving a dose of 2.5 mg to achieve the same trough concentration
multivariate analysis showed that a 1-unit higher estimated clearance resulted in an
independent doubling of the risk of BPAR the first 90 days post transplantation, for
example, a patient receiving a daily tacrolimus dose of 7.5 mg to reach a trough
concentration of 5.0 μg/L will have more than twice the risk of BPAR compared to a
patient receiving a dose of 2.5 mg to achieve the same trough concentration
A cutoff value of 1.5 units can identify patients with increased risk of acute rejection in
the early phase after transplantation.
1. Critically appraise this study.
Its retrospective study, investigate association between TAC clearance and incidence of
BPAR.
From January 2012, all patients received tacrolimus except recipients already receiving
cyclosporine therapy before retransplantation.
Concentrations OF TAC were determined using the chemiluminescen t micro particle
immunoassay AND BPAR done when suspected to measure outcome.
A KaplanMeier analysis with log-rank test and a Cox regression analysis comparing
hazard ratio (HR) of the below average, above average and high clearance groups
versus the low clearance group were performed.
To further assess the independent effect of potential risk factors on acute rejection, a
multivariate Cox-regression was performed using time to first BPAR as a main outcome.
Drawback of the study:
adherence data from our patients are lacking.
The ethnicity of patients transplanted at our center is not registered.
The population is very homogenous, with most patients being of white origin.
Similarly, we do not have data on comedication given to the patients included in the
current study.
The influence of CYP3A inducers or inhibitors is not recorded.
Ahmed Omran
3 years ago
Tacrolimus is considered the mainstay of maintenance IS .Its therapeutic range a is narrow .Under dosing can lead to allograft rejection while overdosing can lead to adverse effects .Drug-drug interaction ,food and nonadherence can cause intra individual variation ;while inter individual variation can occur difference in bioavailability and clearance. If non complianc; which is found in 20% of transplant recipients ,associated high tacrolimus clearance ,it could lead to higher risk of acute rejection due to subtherapeutic drug level.
CYP3A5 genotype is present in 15 % of transplant recipients and associated with increased tacrolimus clearance. In first year post transplantation, higher tacrolimus clearance was associated with increased AR .That risk is doubled if tacrolimus dose was more than 1.5 fold tacrolimus dose.
Critical appraisal
.Drug adherence was not evaluated
.Different methods in tacrolimus assay
.Different drug trough levels in different risk groups
.Short duration of follow up
.Glucocorticoid use affected the results
Mujtaba Zuhair
3 years ago
Low blood level of tacrolimus is associated with acute rejection and DSA development.
The study evaluate the association between tacrolimus clearance and the incidence of biopsy proven acute rejection in the first 90 days post transplantation .
This study is single center observational study. They divide patients to four groups ( low , low average , above average and high) depending on their tacrolimus clearances. They found that patients with high TAC clearance is associated with higher incidence of biopsy proven acute rejection. There were no significant difference in TAC trough concentration in first week post transplantation among patients who had acute rejection or not.
Dalia Eltahir
3 years ago
1. Please summarise this article. Patients with high tacrolimus clearance had low drug level compared with those with low clearance. Delays in dosing time will result in rejection. This study done to show association between individually estimated tacrolimus clearance and biopsy-proven acute rejection in the first 90 days post transplantation. It is a retrospective study of 638 patients . Patients were classified into 4 groups per their estimated clearance((low, below average, above average, and high). The conclusion was that patients with high tacrolimus clearance had a higher risk of acute rejection episode in the early phase after renal transplantation . The time to reach the target trough concentrations was less in the low clearance group which could explain the difference in risk of BPAR but there was no significant difference in time to reach the target concentrations between patients experiencing, and not experiencing BPAR. Critically appraise this study. It is retrospective observational. It was relevant and the question was answered at the end of the study. It included 638 patients (large number and represent almost all the patients who fulfilled the inclusion criteria in the study) who received similar treatment and underwent the same tests so the results of this study are valid, reliable and applicable. Limitation are here was no data on adherence of medication, ethnicity of patients, co-medications and CYP3A5 genotype of the patient .
.
Amit Sharma
3 years ago
1. Please summarise this article.
Tacrolimus use has improved graft results in kidney transplantation. The drug level has high interpatient and intra-patient variations. For optimal results, the serum drug levels have an important role. Even a short period of sub-therapeutic drug levels is detrimental for short-term and long-term graft survival. It was a retrospective study evaluating the effect of tacrolimus clearance (calculated by ratio of tacrolimus daily dose and tacrolimus trough level) on risk of biopsy proven acute rejection (BPAR) in 638 kidney transplant recipients over 5 years. A total of 13.3% developed BPAR (12.1 % of standard risk and 19.8% of high risk transplants). The risk factors associated with BPAR within first 90 days post-transplant included male gender, high immunological risk, presence of DGF and high tacrolimus clearance. The patients were divided into low, below average, above average and high tacrolimus clearance. The mean tacrolimus levels were in the therapeutic range in patients with or without BPAR. But the high tacrolimus clearance group had significantly high percentage of BPAR (20.6%) as compared to low clearance group. An increase in tacrolimus clearance by one unit doubled the risk of acute rejection and it was postulated that if the clearance is >1.5, there is high risk of BPAR. The study concluded that patients with high tacrolimus clearance have higher risk of acute rejection in early post-transplant period.
2. Critically appraise this study.
Looking at the various parameters:
Is the study question relevant?
The question here is whether post-transplant tacrolimus clearance is associated with BPAR in kidney transplantation. This is a relevant question as it has a bearing on the transplant outcomes.
Does the study add anything new to the evidence?
This study was one of the first published studies evaluating tacrolimus clearance in transplant recipients and its association with BPAR. It definitely added a new dimension in management of transplant recipients.
What type of research question is being asked?
The research question identifies the target population (transplant recipients), Studied parameter (tacrolimus clearance) and the outcome of interest (BPAR)
Was the study design appropriate for the research question?
This study was a retrospective cohort study, comparing BPAR incidence in kidney transplant recipients with respect to their tacrolimus clearance. This study design was appropriate.
Did the methodology address important potential sources of bias?
The methodology was simple with laboratory parameter follow-up of the patients. There were certain shortcomings like: all the transplanted patients in the transplant unit were not followed, all the patients were included together (both standard risk and high risk), there was no data on adherence of medication, ethnicity of patients, co-medications and CYP3A5 genotype of the patients. The tacrolimus trough level measurement was done using chemiluminescent microparticle immunoassay method while the standard method is liquid chromatography mass spectrometry method.
Was the study performed according to the original protocol?
Yes.
Does the study test a stated hypothesis?
Yes. The investigators were trying to find out the relevance of tacrolimus clearance with respect to BPAR in transplant recipients.
Is there a clear statement of what the investigators expect the study to find which can be tested, and confirmed or refuted?
Yes
Were the statistical analyses performed correctly?
Yes.
Do the data justify the conclusions?
Yes.
Are there any conflicts of interest?
No.
Hinda Hassan
3 years ago
Please summarise this article. High tacrolimus clearance patients can have low trough level faster than low
clearance patients if they encounter a delay or missing of one dose which may end with acute rejection. This study assessed the association between individually estimated tacrolimus clearance and biopsy-proven acute rejection in the first 90 days post transplantation. It is a retrospective study of 638 patients from 2009 to 2013. Patients were classified into 4 groups per their estimated clearance((low, below average, above average, and high). The conclusion was that patients with high tacrolimus clearance had a higher risk of acute rejection episode in the early phase after renal transplantation.This study failed to correlate the high rejection rate in the high clearance group with low trough level.The time to reach the target trough concentrations was less in the low clearance group which could explain the difference in risk of BPAR but there was no significant difference in time to reach the target concentrations between patients experiencing, and not experiencing BPAR.
Critically appraise this study. study design was observational and it was retrospective. It has a well formulated research question which was relevant and it was answered by the end of the study. It included 638 patients (large number and represent almost all the patients who fulfilled the inclusion criteria in the study) who received similar treatment and underwent the same tests so the results of this study are valid, reliable and applicable. Limitation are lack of genetic studies which may play a cofounder factor as CYP3A5 gene expression is is associated with higher clearance and so twice as high dose to obtain the same trough concentrations . Another drawback is that some patients were followed in other centre which might give a chance for bias in collecting data.
Abdulrahman Ishag
3 years ago
VI. High Tacrolimus Clearance Is a Risk Factor for Acute Rejection in the Early Phase After Renal Transplantation Please summarise this article.
Tacrolimus is a critical dose drug with a high intra individual and inter individual pharmacokinetic variability. The high intra patient variability may be due to many factors, such as co medication, non adherence, and food .The target trough concentrations depend on the drug clearance . Patients with low clearance reached the target trough concentration range faster than the patients with high clearance .Patients with high tacrolimus clearance eliminate more drug within a dose interval compared with those with low clearance. Delays in dosing time will result in transient periods of lower concentrations in high versus low clearance patients. Transient sub therapeutic tacrolimus concentrations may induce acute rejection episodes.A potential for optimising therapy in high-risk patients identified by high clearance estimates may be intensified information and education on the importance of strict adherence, or even switching these patients to an extended release tacrolimus formulation to minimize episodes of under immune suppression .
A high estimated clearance may also be due to;
– A low oral bioavailability which generates a higher-dosage need to achieve target trough concentrations.
– There is a correlation between tacrolimus oral bioavailability and intra lymphocyte concentrations (site of immunosuppressive action).
-P-glycoprotein and CYP-enzymes are also present in lymphocytes and might lead to a low intra lymphocyte tacrolimus concentration.
CYP3A5 genotype is associated with tacrolimus clearance and patients expressing the functional protein need about twice as high dose to obtain the same trough concentrations as patients not expressing functional CYP3A5.
This study is aimed to investigate the association between individual tacrolimus clearance, controlled for actual trough concentrations obtained, and incidence of biopsy-proven acute rejection (BPAR) the first 90 days after renal transplantation .638 patients treated with oral tacrolimus were included in the analysis. Eighty-five (13.3%) of them experienced BPAR. Patients were stratified into 4 groups per their estimated clearance. The patients in the high clearance group had significantly higher incidence of BPAR (20.6%) with a hazard ratio of 2.39 (95% confidence interval, 1.30-4.40) compared with the low clearance group. Clearance estimate (as a continuous variable) showed a hazard ratio of 2.25 (95% confidence interval, 1.70-2.99) after adjusting for other risk factors. There were no significant differences in neither trough concentrations the first week after transplantation nor time to target trough concentration between patients later experiencing BPAR or not. The study found that , high estimated clearance is significantly associated with increased risk of BPAR the first 90 days post transplantation and may predict an increased risk of rejection in the early phase after renal transplantation.
Critically appraise this study.
The study design ;
A single-center, retrospective study
The study area ;
OsloUniversity Hospital Riks hospital, Norway Population; 638 patients included in the analysis . During the first 90 days post transplantation a total of 85 (13.3%) patients experienced BPAR.
The outcome
the association between tacrolimus clearance and BPAR the first 90 days after transplantation.
The prevalence of BPAR was used to calculate the positive predictive value (PPV) and negative predictive value (NPV). Conclusions. High estimated clearance is significantly associated with increased risk of BPAR the first 90 days post transplantation and may predict an increased risk of rejection in the early phase after renal transplantation.
The strengths of this study; It is generalized study , included all standard- and high-risk patients . Because the standard- and high-risk patients have different target trough concentrations, the Cox-regression analysis did not include trough concentration as a variable.
The weakness of the study ; -No CYP3A5 genotype data on the patients included in the present analysis .
-The ethnicity of transplanted patients not registered. The population is very homogenous, with most patients being of white origin. Similarly, no data on co medications given to the patients included in the current study.
-Glucocorticoid doses given for acute rejection treatment may have biased the results in the present analysis because on tacrolimus clearance via induction of CYP-enzymes.
-The majority of patients are followed at the transplant center for 8 to 10 weeks post transplant, but 79 patients were transferred to local hospitals at an earlier time. A bias in the data sample cannot rule out . -All tacrolimus concentrations used in this study were measured with the chemiluminescent microparticle immunoassay method . This immunoassay measure on average 18% higher tacrolimus concentrations than liquid chromatography combined with tandem mass spectrometry (which is considered the criterion standard), mainly due to cross reactivity withtacrolimus metabolites.
Professor Ahmed Halawa
Admin
3 years ago
THANK YOU All FOR YOUR CONTRIBUTION
Mohamad Habli
3 years ago
Summary
Tacrolimus based maintenance immunosuppression became the standard of care in kidney transplantation. Tacrolimus has narrow therapeutic range, where low level is associated with risk of acute rejection, and overdosing is associated with increase toxicity.
Tacrolimus level is intra- and inter-individually variable and depends on factors. As low levels are associated with increased risk of rejection, high Tacrolimus clearance has been the subject of study to assess the link with rejection.
For this purpose a retrospective study conducted in Norway between January 2009 and December 2013, evaluated 638 kidney transplant recipients who receive induction therapy either Basiliximab for standard risk or ATG for high risk patients, followed by maintenance therapy Tac/MMF/steroids.
In all patients, measurement of Tac level, mGFR, oral glucose tolerance test, estimation of tacrolimus clearance. The study group investigated the association between Tac clearance and biopsy proven acute rejection in the first 90 days post transplantation. The patients were divided into 4 groups according to their estimtated Tac clearance, high clearance group showed higher incidence of biopsy proven graft rejection. No significant differences in neither trough concentration in the first week posttransplant nor time to target trough concentration between patients experiencing biopsy proven acute rejection or not.
In conclusion. high estimated tacrolimus clearance is significantly associated with increased risk of biopsy proven acute rejection in the first 90 days post transplantation and may predict an increased risk of rejection in the early posttransplant period.
Critical appraisal
-Lack of data on CYP3A5 genotype, as liver metablism may be affected by inhibitors or inducers
-Lack of long periods of follow up, the study evaluated the short term risk of rejection
-Patients were investigated during hospitalization, while Tac concentration was collected giving 100% adherence to immunosuppressive treatment which can be different on outpatient basis.
-Lack of heterogenicity of studied population as most of them are white in origin
Weam Elnazer
3 years ago
summary:
The study’s main conclusion was that kidney transplant patients with high tacrolimus clearance had a greater risk of acute rejection early on. There was no difference between recipients experiencing BPAR or no-BPAR in either standard-risk or high immunological risk individuals. We discovered that DGF, male sex, and immunological high risk were independent risk factors for acute rejection in the early post-transplant period. 1
In the first 90 days after transplantation, a patient receiving a daily tacrolimus dose of 7.5 mg to achieve a trough concentration of 5.0 g/L would have more than double the risk of BPAR compared to a patient receiving a dose of 2.5 mg to achieve the same trough concentration.
The clearance groups took varying times to achieve target trough concentrations. They achieved their desired trough concentration range quicker than those in other clearance groups.
This might explain the difference in BPAR risk between the groups.
There was no significant difference in time to attain target concentrations between BPAR patients and non-BPAR patients. These early differences in goal accomplishment may be covered by basiliximab-based induction treatment.
In a real-life environment with both standard-risk and high immunological-risk patients, high tacrolimus clearance is related to an elevated risk of BPAR within 90 days following renal transplantation.
A 1.5 unit threshold value may identify individuals at risk of acute rejection soon after transplantation.
The causation of this link is unknown, while CYP3A5 expression may partially replace high estimated clearance as a risk factor.
Critically appraisal:
-patients were evaluated when admitted to the hospital while Tac concentration was obtained providing full adherence to immunosuppressive which may be different on an outpatient basis.
-The chemiluminescent microparticle immunoassay technology used to quantify Tac concentration may overstate Tac concentration.
-The majority of patients are monitored for 8-10 weeks at our transplant facility, although 79 were sent sooner to local hospitals. We can’t rule out a bias in the data sample.
-They do not have CYP3A5 genotype data on the patients included in the present analysis.
-most patients are of white origin.
Huda Al-Taee
3 years ago
Tacrolimus is the cornerstone of IS regimen after transplantation, underdosing will lead to rejection and the development of de novo DSA, and overdosing associated with various side effects such as renal toxicity and PTDM. It is a critical drug with high intra and interindividual pharmacokinetic variability.
Aim of study:
to investigate the association between individual Tac clearance, controlled for actual trough concentrations, and incidence of biopsy proven acute rejection in the first 90 days after transplantation.
Methods:
Design and settings; single center retrospective study ( Oslo University Hospital Rikshospitalet, Norway), between January 2009 and December 2013.
Patients: 638 kidney transplant recipients, induction either basiliximab for standard risk or ATG for high risk patients, maintenance therapy Tac,MMF, and steroids.
intervention: measurement of Tac level, mGFR, oral glucose tolerance test, estimation of tac oral clearance( daily dose/trough concentration). the association between tac clearance and biopsy proven acute rejection in the first 90 days post transplant was investigated.
Ethical Approval: Regional Committee for Medical Research Ethics .
All patients signed written informed consent at the time of transplantation.
Results:
The patients were divided into 4 groups according to their Tac clearance,
high clearance group showed higher incidence of biopsy proven graft rejection.
no significant differences in neither trough concentration in the first week post transplant nor time to target trough concentration between patients experiencing biopsy proven acute rejection or not.
Conclusion:
High estimated tac clearance is significantly associated with increased risk of biopsy proven acute rejection in the first 90 days post transplantation and may predict an increased risk of rejection in the early post transplant period.
Critical Appraisal:
This is the first study investigating the association between tac clearance and transplant outcome.
This study has many limitations:
the patients were hospitalized, so there was low possibility on non adherence.
CYP3A5 genotype data is lacking.
both ethnicity and co medication used were not mentioned in the study.
glucocorticoid use biased the results
short duration of follow up.
Tac level measurement method known to give an overestimated result.
Doaa Elwasly
3 years ago
-underdosing of Tac increases rejection risk and high doses can lead to side effects as nephrotoxicity therefore monitoring its trough level is crucial.
The individual variation in it’s dose could be due to nonadherence , comedication and food intake,missing one dose of tac can lead to temporary low exposure to the drug specially in those with high Tac clearance compared to those with lower clearance, leading to acute rejection episodes and evolving of denovo DSA.
This study assessed the association between Tac clearance and the occurrence of BPAR. Methodology
They investigated retrospectively the patients reciveing Tac for nearly 5 y , patients recieved induction with basilixmab and maintenance with Tac , MMF and steroids and highly sensitizied cases were desnsitized.
Tac level was checked 3-4 times per week in the early post transplant period then once weekly later at week 8 post transplantation.
BPAR was discovered after suspicion depending on elevated creat and biopsy was done accordingly and classified by Banff criteria, treated with steroids or iv antithymocyte globulin.
Patients were divided into 4 groups according to estimated Tac clearance Results
The patients in the high clearance group had significantly higher incidence of BPAR.
No significant differences in trough concentrations the first week after transplantation or time to reach trough concentration between patients experiencing BPAR or not. Discussion
Patients with high tacrolimus clearance had a higher risk of acute rejection in the early post transplant period.
Also DGF, male sex and immunological high risk were crucial risk factor for acute rejection in the early period as well.
High estimated Tac clearance can be due to low bioavailability which indicated needing higher doses to reach trough level.
Optimising therapy in high-risk patients by high clearance estimates is an evidence on the importance of strict adherence.
Patients expressing CYP3A5 genotype had higher tacrolimus clearance and needed higher doses to reach trough levels. Conclusion
In the first 90 days after renal transplantation high tacrolimus clearance is accompanied by an increased risk of BPAR
-critical appraisal
· Lack of data on CYP3A5 genotype,
· lack of homgenicity of studied population as most of them are white in origin
· Lack of long periods of follow up
· patients were investigated while admitted in the hospital while Tac concentration was collected giving 100% adherence to immunosupressives which can be different on outpatient bases
· Possibility of biased results as steroids given for rejection management induces CYP enzyme affecting Tac clearance.
· chemiluminescent microparticle immunoassay method was used to measure Tac concentration which can overestimate Tac concentration but it did not cause much bias as it was applied all through the study
The advantage of this study is that
· it included cases whom received the same treatment protocol and investigation uniformly.
· Including standard and high risk patients
Was the first to address this topic
Riham Marzouk
3 years ago
10-20% of renal allograft recipients developed early acute rejection post-transplant even with immunosuppression coverage.
Tacrolimus is very potent CNI immunosuppressive drug which has narrow therapeutic index, its over and under dose can affect outcome, as under dose can predispose to rejection and overdose can leads to toxicity like PTDM and neurotoxicity, so TDM trough level is important in dose adjustment , but still there is intrapatient variation which can affects graft outcome and survival like comedications, food, compliance to dose and timing of dose.
Noncompliance to immunosuppressive medications accounts 20% of impaired graft outcome on long term. Any missed dose can shorten graft survival.
Also low clearance and high clearance patients are important determine in dose adjustment of tacrolimus to avoid toxicity or rejection , so we need to know.
High clearance patients are associated with higher incidence of acute rejection in standard risk and high risk patients than low clearance, this lower or higher clearance may be related to CYP3A5 genotype.
Sherif Yusuf
3 years ago
Please summarise this article.
Tacrolimus is the backbone of maintenance immunosuppression, it has a narrow therabiotic range with side effects that occur in overdosing, and rejection can occur with underdosing, moreover there is interpatient and intrapatient variability so drug monitoring is mandatory
Intrapatient variability can occur due to drug-drug interaction, food or nonadherence
Interpatient variability can occur due to different bioavailability and according to bioavailability patients are either have high or low tacrolimus clearance
20 % of transplant recipients are noncompliant with some times missing doses in this situation patients with high clearance of tacrolimus may have a higher risk of AR due to episodes of subtherapeutic range of tacrolimus
In this study it was found that patients with higher clearance of tacrolimus have a higher risk of developing AR in the first year post-transplant, the risk is double if tacrolimus dose divided by tacrolimus level was > 1.5
Functional CYP3A5 genotype is associated with higher tacrolimus clearance and is present in 15% of transplant patients
Critically appraise this study.
No assessment of adherence to the drug is done
Standard and high-risk recipients were included with different trough levels
Transfer of some patient to another center
Tacrolimus level was measured using chemiluminescent microparticle immunoassay method which overestimates level when compared to liquid chromatography combined with tandem mass spectrometry
Please summarise this article.
Aim- Investigate the association between individual tacrolimus clearance, controlled for actual trough concentrations obtained, and incidence of biopsy-proven acute rejection (BPAR) the first 90 days after renal transplantation. MATERIALS AND METHODS
A single-centre, retrospective study.
Data from all adult tacrolimus-treated renal recipients followed up for a minimum of 8 weeks post transplantation transplanted between January 2009 and December 2013 were included.
Oral tacrolimus was initiated on the day of transplantation
Dose – 0.04 mg/kg twice daily in standard-risk patients
0.05 mg/kg twice daily in high-risk patients.
Target whole blood trough concentrations –
5 to 7 μg/L in standard risk patients
8 to 12 μg/L (days 0-30) and 6 to 10 μg/L (after day 30) in high risk patients. High immunological risk –
Presence of donor-specific antibodies
panel-reactive antibodies (PRA) greater than 20% at transplantation
ABO incompatibility between donor and recipient.
Before 2012, patients with diabetes and those older than 55 years at the time of transplantation received cyclosporine. From January 2012, all patients received tacrolimus except recipients already receiving cyclosporine therapy before re transplantation. Induction treatment-
20 mg intravenous basiliximab on day 0 and 4 after transplantation
Patients with PRA greater than 20% which were DSA-negative were given antithymocyte globulin induction.
250 mg (standard risk) or 500 mg (high risk) intravenous methylprednisolone on day 0.
A single dose of 375 mg/m2 rituximab was given to DSA-positive and ABO-incompatible patients 4 weeks before transplantation (living donor) or at transplantation (deceased donor).
From day 0 to 4, 400 mg/kg IVIg were given to DSA-positive patients.
For ABO-incompatible patients were given a single dose of 500 mg/kg IVIg at transplantation.
Maintenance therapy –
Tacrolimus, 750 mg oral mycophenolate mofetil twice daily and prednisolone once daily, initiated at 20 mg (80 mg in high-risk patients), and tapered to 10 mg at 4 weeks in standard risk recipients and 8 weeks in immunologic high risk recipients.
The clinical follow-up after transplantation was performed at the transplant center for the first 8 to 10 weeks. Tacrolimus trough concentrations were measured 3 to 4 times per week early after transplantation and were gradually reduced to once a week after about 8 weeks. At 8 weeks post transplantation both measured glomerular filtration rate (iohexol plasma clearance) and oral glucose tolerance were assessed.
The ability of each patient to eliminate tacrolimus was estimated by dividing the total daily tacrolimus dose with the morning trough concentrations (daily dose [mg]/trough concentration [μg/L]). For this estimate the mean of all whole blood tacrolimus concentrations were used. Clearance in BPAR patients was estimated from 3 tacrolimus doses and trough concentrations before the day of initiation of acute rejection treatment. Independent risk factors for acute rejection in the early phase after transplantation are-
DGF
male sex
immunological high risk
Renal transplant recipients with high tacrolimus clearance had a higher risk of having an acute rejection episode in the early phase after renal transplantation. No difference was identified in trough concentration between recipients experiencing BPAR or no-BPAR in neither standard-risk nor in high immunological risk patients. A patient receiving a daily tacrolimus dose of 7.5 mg to reach a
Trough concentration of 5.0 μg/L will have more than twice the risk of BPAR compared to a patient receiving a dose of 2.5 mg to achieve the same trough concentration.
Patients in the low clearance group reached the target trough concentration range faster than the patients in the other clearance groups however There was no significant difference in time to reach the target concentrations between patients experiencing, and not experiencing BPAR. There is a correlation between tacrolimus oral bioavailability and intralymphocyte concentrations.
Patients having high clearance estimates may be educated on the importance of strict adherence, or even switching these patients to an extended release tacrolimus.
High risk of BPAR = Daily tacrolimus dose mg/Trough concentration μgL−1
If > 1:5 units CYP3A5 genotype is associated with tacrolimus clearance and patients expressing the functional protein need about twice as high dose to obtain the same trough concentrations as patients not expressing functional CYP3A5. CYP3A5 genotype data on the patients included in the present analysis. CONCLUSION
Estimated high tacrolimus clearance is significantly and independently associated with an increased risk of BPAR in the first 90 days after renal transplantation .
A cutoff value of 1.5 units can identify patients with increased risk of acute rejection in the early phase after transplantation.
Critically appraise this study.
DSA MFI not known , could be a confounding factor for rejection episode seen in sensitised patients.
In ABO incompatible transplant titres not known and protocol followed. Also in DSA positive patients pre transplant MFI not known and desensitisation protocol.
Summmary of this study:
Despite the advancement in immunsuppression but still there is high incidence of acute rejection
Tacrolimus is the corner stone in kidney transplantation immunosuppressive medications.
either low trough levels or high trough levels carries a risk on graft survival ,low levels are associated with acute rejection ,high levels are associated with diabetes after transplantation and Nephrotoxicity.
This study is retrospective observational study done on large number of patients>1000 to check the correlation between tacrolimus clearance and risk of BPAR (Biopsy proven acute rejection.
They divided patients to low clearance, below average ,above average and high clearance ,they used chemileuminescent micro particle immunoassay to test tacrolimus levels
they found that there is correlation between low trough levels (mostly because of high clearance) and acute rejection in the first 90 days after transplantation in standard risk and high immunological risk but they found no significant difference between clearance and BPAR .They defined a cut off value of 1.5 above which the patient could have acute rejection there is no explanation for this but CYP3A5 can be a cause but still cannot be used instead of clearance .
critical appraisal :
Adv.:
Retrospective Observational
large No of patients ,including high and low risk
Determination of cut off value that can clarify the patient that could have acute rejection
draw backs
:No ethinicity included
The test used in testing Tac level may give false high levels
No comment on comedic actions
CYP3A5 genotypes are not discussed
some patients were missed for follow up as transferred to other centers
Tacrolimus is one of the cornerstone immunosuppressive therapy since 1990s associated with improved graft survival but still early acute rejection reported in 10-20% post kidney transplantation ,tacrolimus characterized by narrow therapeutic index with underdosing can increase the chance of acute rejection at the same time prolong higher exposure can be associated with chronic nephrotoxicity and PTDM , also there is intra-individual and interindividual pharmacokinetics variation in tacrolimus trough level due to many factors ( drug interactions ,food, poor compliance)
This is a retrospective study from single center to assess the tacrolimus clearance effect on the rate of BPAR among adults kidney transplant recipients between the 2009-2013, they included > 600 adults’ patient on tacrolimus base maintenance immunotherapy
the study shows those with high tacrolimus clearance rate have higher risk of BPAR compared to lower clearance rate in both standard and high immunological risk groups
limitations
————–
Retrospective design from single center, ethnicity not mentioned in the patients’ characteristics,assume they are all white ethinic background .
follow up limited to 90 days in fact majority of patients followed to 8-10 weeks then referred to local nephrology units, dropping 79 patients during FU cannot rule out bias in sample size
the CYP3A4 genotype data are missing
concomitant medication and the compliance with medication not reported .
limitation related to the local method used with 18% of overestimation of tcarolimus trough level compared to standared chromotographic method.
Please summarise this article.
Tacrolimus is very crucial as maintenance immunosuppression in renal transplantation in most of regimens. TAC clearance may vary between KTRs with consequences of variation in trough concentration and clinically targeted therapeutic level.
In this cohort retrospective study of 638 KTRs, TAC clearance was evaluated in association with BPAR and patients were stratified into 4 groups (low, below average, above average, and high). In evaluating and analyzing KTRs, there was no difference in trough concentration of Tacrolimus between patients with BPAR and those without.The mean trough concentrations remain within the therapeutic range between KTRs groups. There was significant association between high TAC clearance and development of BPAR explained by variation in drug concentration between patients as time needed to reach the target trough concentration is different between patients’ groups of TAC-Clearnce .
Critically appraise this study
This retrospective cohort study, first one in it’s type to search for the Association of BPAR as primary outcome with post transplant clearance of Tacrolimus. 638 KTRs were distributed into 4 groups, according to TAC clearance and results were analyzed using appropriate statistical and analytical methods to answer the study question and reach the primary outcome.
Strength of the study:
Study limitations:
Inspire of improvement in IS regime, the risk of early AR still high(10-20%) of renal transplantation recipients. Tac considered as the corner stone in IS. But over- or under- dose is a problem that may cause AR( low dose) or nephrotoxicity (over dose), so close drug level monitoring is essential & should be done routinely.
There is high intra-individual & inter-individual pharmacokinetics variability due to many factors (e.g. co-medication, food, & non adherence).
Saint-Marcous et al found that missing one dose of Tac can lead to lower Tac exposure in recipients with high drug clearance when compared to low drug clearance recipients, & this can trigger immune response causing acute rejection or developing de novo DSA.
Aim of the study: prove the correlation between drug clearance with incidence of ABMR during first 3 months post-transplantation period.
Single-center study included 638 renal transplant recipients who receive Tac based regime through a period from Jan 2009-Dec 2012. The patients followed for 8-10 weeks.
High risk recipients ( DSA+ve, PRA>20%, & ABO incompatible recipient & donor) had induction with ATG & IVIG, Tac dose was 0.05 mg/kg with target trough level 8-12 microg/ml (0-30 days) & 6-10 micron/ml ( after 30 days).
Standard risk recipients had induction with 2 doses of basiliximab, Tac dose 0.04 mg/kg with target trough level 3-7 microg/ml. In addition to MMF & steroids for all recipients.
Tac level measured directly before morning dose, 3-4 times/ week tapering to once weekly monitoring at week 8.
Protocol biopsy done at 6 & 8 weeks in addition to graft biopsy when there was a suspicion of Ar ( unexplained increase in >20 % of GFR).
drug clearance= mean of total daily dose/ morning trough level
According to clearance the recipients classified into low, below average , above average & high drug clearance.
The study found that recipients with high Tac clearance were associated with increased risk of ABMR in early post-transplantation period in both standard & high immunological risk patients. Recipients with low drug clearance can achieve target trough level faster than other groups.
Using of extended Tac formula to optimizing treatment in high risk patients. There are several factors can affect Tac pharmacokinetics as CYP3A5 genotype, ethnicity, & drugs that interact through CYP3A.
The study had several limitation
Tacrolimus is the cornerstone in the immunosuppressive regimen after renal
transplantation.
Underdosing of tacrolimus increases the risk of acute rejection and development of de
novo donor-specific antibodies.3 Overdosing on the other hand is associated with side
effects, such as renal toxicity and post transplantation diabetes mellitus
Tacrolimus is a critical dose drug with a high intraindividual and interindividual
pharmacokinetic variability.
The high intrapatient variability may be due to many factors, such as comedication,
nonadherence, and food.
Nonadherence in renal transplant recipients is estimated to be approximately 20%-25%.
Aim of the analysis was to investigate the association between individual tacrolimus
clearance, controlled for actual trough concentrations obtained, and incidence of biopsy-
proven acute rejection (BPAR) the first 90 days after renal transplantation.
Finding in the study was that renal transplant recipients with high tacrolimus clearance
had a higher risk of having an acute rejection episode in the early phase after renal
transplantation. A plausible explanation could have been that patients with high
tacrolimus clearance had lower trough concentrations, but no such difference was
identified between recipients experiencing BPAR or no-BPAR in neither standard-risk
nor in high immunological risk patients.
multivariate analysis showed that a 1-unit higher estimated clearance resulted in an
independent doubling of the risk of BPAR the first 90 days post transplantation, for
example, a patient receiving a daily tacrolimus dose of 7.5 mg to reach a trough
concentration of 5.0 μg/L will have more than twice the risk of BPAR compared to a
patient receiving a dose of 2.5 mg to achieve the same trough concentration
multivariate analysis showed that a 1-unit higher estimated clearance resulted in an
independent doubling of the risk of BPAR the first 90 days post transplantation, for
example, a patient receiving a daily tacrolimus dose of 7.5 mg to reach a trough
concentration of 5.0 μg/L will have more than twice the risk of BPAR compared to a
patient receiving a dose of 2.5 mg to achieve the same trough concentration
A cutoff value of 1.5 units can identify patients with increased risk of acute rejection in
the early phase after transplantation.
1. Critically appraise this study.
Its retrospective study, investigate association between TAC clearance and incidence of
BPAR.
From January 2012, all patients received tacrolimus except recipients already receiving
cyclosporine therapy before retransplantation.
Concentrations OF TAC were determined using the chemiluminescen t micro particle
immunoassay AND BPAR done when suspected to measure outcome.
A KaplanMeier analysis with log-rank test and a Cox regression analysis comparing
hazard ratio (HR) of the below average, above average and high clearance groups
versus the low clearance group were performed.
To further assess the independent effect of potential risk factors on acute rejection, a
multivariate Cox-regression was performed using time to first BPAR as a main outcome.
Drawback of the study:
adherence data from our patients are lacking.
The ethnicity of patients transplanted at our center is not registered.
The population is very homogenous, with most patients being of white origin.
Similarly, we do not have data on comedication given to the patients included in the
current study.
The influence of CYP3A inducers or inhibitors is not recorded.
Tacrolimus is considered the mainstay of maintenance IS .Its therapeutic range a is narrow .Under dosing can lead to allograft rejection while overdosing can lead to adverse effects .Drug-drug interaction ,food and nonadherence can cause intra individual variation ;while inter individual variation can occur difference in bioavailability and clearance. If non complianc; which is found in 20% of transplant recipients ,associated high tacrolimus clearance ,it could lead to higher risk of acute rejection due to subtherapeutic drug level.
CYP3A5 genotype is present in 15 % of transplant recipients and associated with increased tacrolimus clearance. In first year post transplantation, higher tacrolimus clearance was associated with increased AR .That risk is doubled if tacrolimus dose was more than 1.5 fold tacrolimus dose.
Critical appraisal
.Drug adherence was not evaluated
.Different methods in tacrolimus assay
.Different drug trough levels in different risk groups
.Short duration of follow up
.Glucocorticoid use affected the results
Low blood level of tacrolimus is associated with acute rejection and DSA development.
The study evaluate the association between tacrolimus clearance and the incidence of biopsy proven acute rejection in the first 90 days post transplantation .
This study is single center observational study. They divide patients to four groups ( low , low average , above average and high) depending on their tacrolimus clearances. They found that patients with high TAC clearance is associated with higher incidence of biopsy proven acute rejection. There were no significant difference in TAC trough concentration in first week post transplantation among patients who had acute rejection or not.
1. Please summarise this article.
Patients with high tacrolimus clearance had low drug level compared with those with low clearance. Delays in dosing time will result in rejection. This study done to show association between individually estimated tacrolimus clearance and biopsy-proven acute rejection in the first 90 days post transplantation. It is a retrospective study of 638 patients . Patients were classified into 4 groups per their estimated clearance((low, below average, above average, and high). The conclusion was that patients with high tacrolimus clearance had a higher risk of acute rejection episode in the early phase after renal transplantation . The time to reach the target trough concentrations was less in the low clearance group which could explain the difference in risk of BPAR but there was no significant difference in time to reach the target concentrations between patients experiencing, and not experiencing BPAR.
Critically appraise this study.
It is retrospective observational. It was relevant and the question was answered at the end of the study. It included 638 patients (large number and represent almost all the patients who fulfilled the inclusion criteria in the study) who received similar treatment and underwent the same tests so the results of this study are valid, reliable and applicable. Limitation are here was no data on adherence of medication, ethnicity of patients, co-medications and CYP3A5 genotype of the patient
.
.
1. Please summarise this article.
Tacrolimus use has improved graft results in kidney transplantation. The drug level has high interpatient and intra-patient variations. For optimal results, the serum drug levels have an important role. Even a short period of sub-therapeutic drug levels is detrimental for short-term and long-term graft survival. It was a retrospective study evaluating the effect of tacrolimus clearance (calculated by ratio of tacrolimus daily dose and tacrolimus trough level) on risk of biopsy proven acute rejection (BPAR) in 638 kidney transplant recipients over 5 years. A total of 13.3% developed BPAR (12.1 % of standard risk and 19.8% of high risk transplants). The risk factors associated with BPAR within first 90 days post-transplant included male gender, high immunological risk, presence of DGF and high tacrolimus clearance. The patients were divided into low, below average, above average and high tacrolimus clearance. The mean tacrolimus levels were in the therapeutic range in patients with or without BPAR. But the high tacrolimus clearance group had significantly high percentage of BPAR (20.6%) as compared to low clearance group. An increase in tacrolimus clearance by one unit doubled the risk of acute rejection and it was postulated that if the clearance is >1.5, there is high risk of BPAR. The study concluded that patients with high tacrolimus clearance have higher risk of acute rejection in early post-transplant period.
2. Critically appraise this study.
Looking at the various parameters:
The question here is whether post-transplant tacrolimus clearance is associated with BPAR in kidney transplantation. This is a relevant question as it has a bearing on the transplant outcomes.
This study was one of the first published studies evaluating tacrolimus clearance in transplant recipients and its association with BPAR. It definitely added a new dimension in management of transplant recipients.
The research question identifies the target population (transplant recipients), Studied parameter (tacrolimus clearance) and the outcome of interest (BPAR)
This study was a retrospective cohort study, comparing BPAR incidence in kidney transplant recipients with respect to their tacrolimus clearance. This study design was appropriate.
The methodology was simple with laboratory parameter follow-up of the patients. There were certain shortcomings like: all the transplanted patients in the transplant unit were not followed, all the patients were included together (both standard risk and high risk), there was no data on adherence of medication, ethnicity of patients, co-medications and CYP3A5 genotype of the patients. The tacrolimus trough level measurement was done using chemiluminescent microparticle immunoassay method while the standard method is liquid chromatography mass spectrometry method.
Yes.
Yes. The investigators were trying to find out the relevance of tacrolimus clearance with respect to BPAR in transplant recipients.
Yes
Yes.
Yes.
No.
Please summarise this article. High tacrolimus clearance patients can have low trough level faster than low
clearance patients if they encounter a delay or missing of one dose which may end with acute rejection. This study assessed the association between individually estimated tacrolimus clearance and biopsy-proven acute rejection in the first 90 days post transplantation. It is a retrospective study of 638 patients from 2009 to 2013. Patients were classified into 4 groups per their estimated clearance((low, below average, above average, and high). The conclusion was that patients with high tacrolimus clearance had a higher risk of acute rejection episode in the early phase after renal transplantation.This study failed to correlate the high rejection rate in the high clearance group with low trough level.The time to reach the target trough concentrations was less in the low clearance group which could explain the difference in risk of BPAR but there was no significant difference in time to reach the target concentrations between patients experiencing, and not experiencing BPAR.
Critically appraise this study.
study design was observational and it was retrospective. It has a well formulated research question which was relevant and it was answered by the end of the study. It included 638 patients (large number and represent almost all the patients who fulfilled the inclusion criteria in the study) who received similar treatment and underwent the same tests so the results of this study are valid, reliable and applicable. Limitation are lack of genetic studies which may play a cofounder factor as CYP3A5 gene expression is is associated with higher clearance and so twice as high dose to obtain the same trough concentrations .
Another drawback is that some patients were followed in other centre which might give a chance for bias in collecting data.
VI. High Tacrolimus Clearance Is a Risk Factor for Acute Rejection in the Early Phase After Renal Transplantation
Please summarise this article.
Tacrolimus is a critical dose drug with a high intra individual and inter individual pharmacokinetic variability. The high intra patient variability may be due to many factors, such as co medication, non adherence, and food . The target trough concentrations depend on the drug clearance . Patients with low clearance reached the target trough concentration range faster than the patients with high clearance .Patients with high tacrolimus clearance eliminate more drug within a dose interval compared with those with low clearance. Delays in dosing time will result in transient periods of lower concentrations in high versus low clearance patients. Transient sub therapeutic tacrolimus concentrations may induce acute rejection episodes.A potential for optimising therapy in high-risk patients identified by high clearance estimates may be intensified information and education on the importance of strict adherence, or even switching these patients to an extended release tacrolimus formulation to minimize episodes of under immune suppression .
A high estimated clearance may also be due to;
– A low oral bioavailability which generates a higher-dosage need to achieve target trough concentrations.
– There is a correlation between tacrolimus oral bioavailability and intra lymphocyte concentrations (site of immunosuppressive action).
-P-glycoprotein and CYP-enzymes are also present in lymphocytes and might lead to a low intra lymphocyte tacrolimus concentration.
CYP3A5 genotype is associated with tacrolimus clearance and patients expressing the functional protein need about twice as high dose to obtain the same trough concentrations as patients not expressing functional CYP3A5.
This study is aimed to investigate the association between individual tacrolimus clearance, controlled for actual trough concentrations obtained, and incidence of biopsy-proven acute rejection (BPAR) the first 90 days after renal transplantation . 638 patients treated with oral tacrolimus were included in the analysis. Eighty-five (13.3%) of them experienced BPAR. Patients were stratified into 4 groups per their estimated clearance. The patients in the high clearance group had significantly higher incidence of BPAR (20.6%) with a hazard ratio of 2.39 (95% confidence interval, 1.30-4.40) compared with the low clearance group. Clearance estimate (as a continuous variable) showed a hazard ratio of 2.25 (95% confidence interval, 1.70-2.99) after adjusting for other risk factors. There were no significant differences in neither trough concentrations the first week after transplantation nor time to target trough concentration between patients later experiencing BPAR or not. The study found that , high estimated clearance is significantly associated with increased risk of BPAR the first 90 days post transplantation and may predict an increased risk of rejection in the early phase after renal transplantation.
Critically appraise this study.
The study design ;
A single-center, retrospective study
The study area ;
Oslo University Hospital Riks hospital, Norway
Population;
638 patients included in the analysis . During the first 90 days post transplantation a total of 85 (13.3%) patients experienced BPAR.
The outcome
the association between tacrolimus clearance and BPAR the first 90 days after transplantation.
The prevalence of BPAR was used to calculate the positive predictive value (PPV) and negative predictive value (NPV).
Conclusions.
High estimated clearance is significantly associated with increased risk of BPAR the first 90 days post transplantation and may predict an increased risk of rejection in the early phase after renal transplantation.
The strengths of this study;
It is generalized study , included all standard- and high-risk patients . Because the standard- and high-risk patients have different target trough concentrations, the Cox-regression analysis did not include trough concentration as a variable.
The weakness of the study ;
-No CYP3A5 genotype data on the patients included in the present analysis .
-The ethnicity of transplanted patients not registered. The population is very homogenous, with most patients being of white origin. Similarly, no data on co medications given to the patients included in the current study.
-Glucocorticoid doses given for acute rejection treatment may have biased the results in the present analysis because on tacrolimus clearance via induction of CYP-enzymes.
-The majority of patients are followed at the transplant center for 8 to 10 weeks post transplant, but 79 patients were transferred to local hospitals at an earlier time. A bias in the data sample cannot rule out .
-All tacrolimus concentrations used in this study were measured with the chemiluminescent microparticle immunoassay method . This immunoassay measure on average 18% higher tacrolimus concentrations than liquid chromatography combined with tandem mass spectrometry (which is considered the criterion standard), mainly due to cross reactivity with tacrolimus metabolites.
THANK YOU All FOR YOUR CONTRIBUTION
Summary
Tacrolimus based maintenance immunosuppression became the standard of care in kidney transplantation. Tacrolimus has narrow therapeutic range, where low level is associated with risk of acute rejection, and overdosing is associated with increase toxicity.
Tacrolimus level is intra- and inter-individually variable and depends on factors. As low levels are associated with increased risk of rejection, high Tacrolimus clearance has been the subject of study to assess the link with rejection.
For this purpose a retrospective study conducted in Norway between January 2009 and December 2013, evaluated 638 kidney transplant recipients who receive induction therapy either Basiliximab for standard risk or ATG for high risk patients, followed by maintenance therapy Tac/MMF/steroids.
In all patients, measurement of Tac level, mGFR, oral glucose tolerance test, estimation of tacrolimus clearance. The study group investigated the association between Tac clearance and biopsy proven acute rejection in the first 90 days post transplantation. The patients were divided into 4 groups according to their estimtated Tac clearance, high clearance group showed higher incidence of biopsy proven graft rejection. No significant differences in neither trough concentration in the first week posttransplant nor time to target trough concentration between patients experiencing biopsy proven acute rejection or not.
In conclusion. high estimated tacrolimus clearance is significantly associated with increased risk of biopsy proven acute rejection in the first 90 days post transplantation and may predict an increased risk of rejection in the early posttransplant period.
Critical appraisal
-Lack of data on CYP3A5 genotype, as liver metablism may be affected by inhibitors or inducers
-Lack of long periods of follow up, the study evaluated the short term risk of rejection
-Patients were investigated during hospitalization, while Tac concentration was collected giving 100% adherence to immunosuppressive treatment which can be different on outpatient basis.
-Lack of heterogenicity of studied population as most of them are white in origin
summary:
The study’s main conclusion was that kidney transplant patients with high tacrolimus clearance had a greater risk of acute rejection early on. There was no difference between recipients experiencing BPAR or no-BPAR in either standard-risk or high immunological risk individuals. We discovered that DGF, male sex, and immunological high risk were independent risk factors for acute rejection in the early post-transplant period. 1
In the first 90 days after transplantation, a patient receiving a daily tacrolimus dose of 7.5 mg to achieve a trough concentration of 5.0 g/L would have more than double the risk of BPAR compared to a patient receiving a dose of 2.5 mg to achieve the same trough concentration.
The clearance groups took varying times to achieve target trough concentrations. They achieved their desired trough concentration range quicker than those in other clearance groups.
This might explain the difference in BPAR risk between the groups.
There was no significant difference in time to attain target concentrations between BPAR patients and non-BPAR patients. These early differences in goal accomplishment may be covered by basiliximab-based induction treatment.
In a real-life environment with both standard-risk and high immunological-risk patients, high tacrolimus clearance is related to an elevated risk of BPAR within 90 days following renal transplantation.
A 1.5 unit threshold value may identify individuals at risk of acute rejection soon after transplantation.
The causation of this link is unknown, while CYP3A5 expression may partially replace high estimated clearance as a risk factor.
Critically appraisal:
-patients were evaluated when admitted to the hospital while Tac concentration was obtained providing full adherence to immunosuppressive which may be different on an outpatient basis.
-The chemiluminescent microparticle immunoassay technology used to quantify Tac concentration may overstate Tac concentration.
-The majority of patients are monitored for 8-10 weeks at our transplant facility, although 79 were sent sooner to local hospitals. We can’t rule out a bias in the data sample.
-They do not have CYP3A5 genotype data on the patients included in the present analysis.
-most patients are of white origin.
Tacrolimus is the cornerstone of IS regimen after transplantation, underdosing will lead to rejection and the development of de novo DSA, and overdosing associated with various side effects such as renal toxicity and PTDM. It is a critical drug with high intra and interindividual pharmacokinetic variability.
Aim of study:
to investigate the association between individual Tac clearance, controlled for actual trough concentrations, and incidence of biopsy proven acute rejection in the first 90 days after transplantation.
Methods:
Design and settings; single center retrospective study ( Oslo University Hospital Rikshospitalet, Norway), between January 2009 and December 2013.
Patients: 638 kidney transplant recipients, induction either basiliximab for standard risk or ATG for high risk patients, maintenance therapy Tac,MMF, and steroids.
intervention: measurement of Tac level, mGFR, oral glucose tolerance test, estimation of tac oral clearance( daily dose/trough concentration). the association between tac clearance and biopsy proven acute rejection in the first 90 days post transplant was investigated.
Ethical Approval: Regional Committee for Medical Research Ethics .
All patients signed written informed consent at the time of transplantation.
Results:
The patients were divided into 4 groups according to their Tac clearance,
high clearance group showed higher incidence of biopsy proven graft rejection.
no significant differences in neither trough concentration in the first week post transplant nor time to target trough concentration between patients experiencing biopsy proven acute rejection or not.
Conclusion:
High estimated tac clearance is significantly associated with increased risk of biopsy proven acute rejection in the first 90 days post transplantation and may predict an increased risk of rejection in the early post transplant period.
Critical Appraisal:
This is the first study investigating the association between tac clearance and transplant outcome.
This study has many limitations:
-underdosing of Tac increases rejection risk and high doses can lead to side effects as nephrotoxicity therefore monitoring its trough level is crucial.
The individual variation in it’s dose could be due to nonadherence , comedication and food intake,missing one dose of tac can lead to temporary low exposure to the drug specially in those with high Tac clearance compared to those with lower clearance, leading to acute rejection episodes and evolving of denovo DSA.
This study assessed the association between Tac clearance and the occurrence of BPAR.
Methodology
They investigated retrospectively the patients reciveing Tac for nearly 5 y , patients recieved induction with basilixmab and maintenance with Tac , MMF and steroids and highly sensitizied cases were desnsitized.
Tac level was checked 3-4 times per week in the early post transplant period then once weekly later at week 8 post transplantation.
BPAR was discovered after suspicion depending on elevated creat and biopsy was done accordingly and classified by Banff criteria, treated with steroids or iv antithymocyte globulin.
Patients were divided into 4 groups according to estimated Tac clearance
Results
The patients in the high clearance group had significantly higher incidence of BPAR.
No significant differences in trough concentrations the first week after transplantation or time to reach trough concentration between patients experiencing BPAR or not.
Discussion
Patients with high tacrolimus clearance had a higher risk of acute rejection in the early post transplant period.
Also DGF, male sex and immunological high risk were crucial risk factor for acute rejection in the early period as well.
High estimated Tac clearance can be due to low bioavailability which indicated needing higher doses to reach trough level.
Optimising therapy in high-risk patients by high clearance estimates is an evidence on the importance of strict adherence.
Patients expressing CYP3A5 genotype had higher tacrolimus clearance and needed higher doses to reach trough levels.
Conclusion
In the first 90 days after renal transplantation high tacrolimus clearance is accompanied by an increased risk of BPAR
-critical appraisal
· Lack of data on CYP3A5 genotype,
· lack of homgenicity of studied population as most of them are white in origin
· Lack of long periods of follow up
· patients were investigated while admitted in the hospital while Tac concentration was collected giving 100% adherence to immunosupressives which can be different on outpatient bases
· Possibility of biased results as steroids given for rejection management induces CYP enzyme affecting Tac clearance.
· chemiluminescent microparticle immunoassay method was used to measure Tac concentration which can overestimate Tac concentration but it did not cause much bias as it was applied all through the study
The advantage of this study is that
· it included cases whom received the same treatment protocol and investigation uniformly.
· Including standard and high risk patients
10-20% of renal allograft recipients developed early acute rejection post-transplant even with immunosuppression coverage.
Tacrolimus is very potent CNI immunosuppressive drug which has narrow therapeutic index, its over and under dose can affect outcome, as under dose can predispose to rejection and overdose can leads to toxicity like PTDM and neurotoxicity, so TDM trough level is important in dose adjustment , but still there is intrapatient variation which can affects graft outcome and survival like comedications, food, compliance to dose and timing of dose.
Noncompliance to immunosuppressive medications accounts 20% of impaired graft outcome on long term. Any missed dose can shorten graft survival.
Also low clearance and high clearance patients are important determine in dose adjustment of tacrolimus to avoid toxicity or rejection , so we need to know.
High clearance patients are associated with higher incidence of acute rejection in standard risk and high risk patients than low clearance, this lower or higher clearance may be related to CYP3A5 genotype.
Please summarise this article.
Critically appraise this study.
Please summarise this article.
Aim- Investigate the association between individual tacrolimus clearance, controlled for actual trough concentrations obtained, and incidence of biopsy-proven acute rejection (BPAR) the first 90 days after renal transplantation.
MATERIALS AND METHODS
A single-centre, retrospective study.
Data from all adult tacrolimus-treated renal recipients followed up for a minimum of 8 weeks post transplantation transplanted between January 2009 and December 2013 were included.
Oral tacrolimus was initiated on the day of transplantation
Dose – 0.04 mg/kg twice daily in standard-risk patients
0.05 mg/kg twice daily in high-risk patients.
Target whole blood trough concentrations –
5 to 7 μg/L in standard risk patients
8 to 12 μg/L (days 0-30) and 6 to 10 μg/L (after day 30) in high risk patients.
High immunological risk –
Presence of donor-specific antibodies
panel-reactive antibodies (PRA) greater than 20% at transplantation
ABO incompatibility between donor and recipient.
Before 2012, patients with diabetes and those older than 55 years at the time of transplantation received cyclosporine. From January 2012, all patients received tacrolimus except recipients already receiving cyclosporine therapy before re transplantation.
Induction treatment-
20 mg intravenous basiliximab on day 0 and 4 after transplantation
Patients with PRA greater than 20% which were DSA-negative were given antithymocyte globulin induction.
250 mg (standard risk) or 500 mg (high risk) intravenous methylprednisolone on day 0.
A single dose of 375 mg/m2 rituximab was given to DSA-positive and ABO-incompatible patients 4 weeks before transplantation (living donor) or at transplantation (deceased donor).
From day 0 to 4, 400 mg/kg IVIg were given to DSA-positive patients.
For ABO-incompatible patients were given a single dose of 500 mg/kg IVIg at transplantation.
Maintenance therapy –
Tacrolimus, 750 mg oral mycophenolate mofetil twice daily and prednisolone once daily, initiated at 20 mg (80 mg in high-risk patients), and tapered to 10 mg at 4 weeks in standard risk recipients and 8 weeks in immunologic high risk recipients.
The clinical follow-up after transplantation was performed at the transplant center for the first 8 to 10 weeks. Tacrolimus trough concentrations were measured 3 to 4 times per week early after transplantation and were gradually reduced to once a week after about 8 weeks. At 8 weeks post transplantation both measured glomerular filtration rate (iohexol plasma clearance) and oral glucose tolerance were assessed.
The ability of each patient to eliminate tacrolimus was estimated by dividing the total daily tacrolimus dose with the morning trough concentrations (daily dose [mg]/trough concentration [μg/L]). For this estimate the mean of all whole blood tacrolimus concentrations were used. Clearance in BPAR patients was estimated from 3 tacrolimus doses and trough concentrations before the day of initiation of acute rejection treatment.
Independent risk factors for acute rejection in the early phase after transplantation are-
DGF
male sex
immunological high risk
Renal transplant recipients with high tacrolimus clearance had a higher risk of having an acute rejection episode in the early phase after renal transplantation. No difference was identified in trough concentration between recipients experiencing BPAR or no-BPAR in neither standard-risk nor in high immunological risk patients. A patient receiving a daily tacrolimus dose of 7.5 mg to reach a
Trough concentration of 5.0 μg/L will have more than twice the risk of BPAR compared to a patient receiving a dose of 2.5 mg to achieve the same trough concentration.
Patients in the low clearance group reached the target trough concentration range faster than the patients in the other clearance groups however There was no significant difference in time to reach the target concentrations between patients experiencing, and not experiencing BPAR. There is a correlation between tacrolimus oral bioavailability and intralymphocyte concentrations.
Patients having high clearance estimates may be educated on the importance of strict adherence, or even switching these patients to an extended release tacrolimus.
High risk of BPAR = Daily tacrolimus dose mg/Trough concentration μgL−1
If > 1:5 units
CYP3A5 genotype is associated with tacrolimus clearance and patients expressing the functional protein need about twice as high dose to obtain the same trough concentrations as patients not expressing functional CYP3A5. CYP3A5 genotype data on the patients included in the present analysis.
CONCLUSION
Estimated high tacrolimus clearance is significantly and independently associated with an increased risk of BPAR in the first 90 days after renal transplantation .
A cutoff value of 1.5 units can identify patients with increased risk of acute rejection in the early phase after transplantation.
Critically appraise this study.
DSA MFI not known , could be a confounding factor for rejection episode seen in sensitised patients.
In ABO incompatible transplant titres not known and protocol followed. Also in DSA positive patients pre transplant MFI not known and desensitisation protocol.