Determinants of Immunosuppressive Dose Requirements in Children After Solid Organ Transplantation
Condition: Transplantation Infection
Study type: Observational

Summary: 
      The long-term success of solid organ transplantation is largely dependent on the efficacy of
      immunosuppressive medication. Unfortunately, for the most important agents the correct drug
      levels are difficult to attain, with potential severe consequences of drug under- or
      overexposure. In addition there is a large variation in dose requirements within and between
      different subjects. Clinical studies have demonstrated that a better control of drug exposure
      can improve outcome. A large set of patient characteristics appear important in determining
      dose requirements in adults, in particular genetic variation in genes involved in drug
      metabolism. In children relative dose requirements are increased compared to adults, but is
      not known why and the role of pharmacogenetic variation has not been described.

      Our study aims to describe relative dose requirements in children after solid organ
      transplantation with the help of clinical and laboratory data obtained during regular
      hospital visits (retrospective). In addition we will assess their genotype for genes involved
      in the metabolism of immunosuppressives.
    

Detailed description: 
      The success of solid organ transplantation is for an important part determined by the potency
      of the immunosuppressive regime to prevent allograft rejection. Depending on the type of
      organ transplanted current 5-year graft survival for liver is circa 70% and for kidney almost
      80% (1-3). Although acute rejection has become less a problem, analyses of data on the
      follow-up of solid organ recipients has demonstrated that long-term allograft survival has
      not improved much in the last decade. The life expectancy of a donor organ appears limited
      due to phenomena such as chronic, antibody mediated, rejection and the toxic effects of
      immunosuppressive medication.

      Unfortunately, the most commonly applied immunosuppressive agents (in particular the
      calcineurin-inhibitors) possess a narrow therapeutic index with potential severe consequences
      of drug under- or overexposure. Furthermore, in clinical practice optimal dosing is difficult
      to achieve due to important inter- and intraindividual variation in drug pharmacokinetics.
      Consequently attention has shifted towards designing a "tailored immunosuppressive
      maintenance therapy", aimed at optimization of drug efficacy and the prevention of these
      unintended and possible deleterious side effects in the individual recipient. For a "perfect
      fit" this entails a fundamental knowledge of the individual characteristics of the recipient
      and its graft in relation to the pharmacodynamic and -kinetic properties of the agent.

      A complex and often interdependent set of factors appears relevant in determining drug
      exposure. These include recipient characteristics such as age, race, body composition, organ
      function (intestine-liver-kidney), food and concomitant medication intake, but also
      graft-related characteristics such as: seize, donor-age, and time after transplantation.
      Longitudinal and cross-sectional analysis of clinical and genetic co-variables in allograft
      recipient cohorts has identified several single nucleotide polymorphisms (SNPs) in genes
      encoding for enzymes and transporters involved in drug metabolism(CYP3A4, CYP3A5, MDR1),
      which were associated with differences in dosing and toxicity (4-10). In particular carriers
      of a common polymorphism in CYP3A5 (designated CYP3A5*1) demonstrate a 25-40% increase in
      tacrolimus clearance and a 2-3 fold increase in dose requirements.

      In children the dose requirements per kg bodyweight to attain desired blood concentrations
      are approximately 2.7 fold higher for patients under 5 years and 1.9 fold higher for patients
      aged 5 to 12 years when compared to older patients11-14. Age-related differences in
      expression of enzymes or transporters involved in drug metabolism might play an important
      role. Fakhoury et al demonstrated an increase in intestinal CYP3A4/5 mRNA and protein
      expression from childhood to adulthood (15). In addition other factors such as intestinal
      transit time and length, body composition, protein binding, body metabolism and organ
      function, might be important in determining dose requirements in children (16-18). The
      importance of the aforementioned genetic polymorphisms on long-term dose requirements have
      not been studied in children.

      Objective:

      To describe dose requirements of immunosuppressive medication in relation to a set of
      clinical and non-clinical (genetic) factors in a cohort of pediatric recipients of a solid
      organ allograft.

      Methods:

      A retrospective study in a single center (University Hospitals Leuven) with an active program
      for pediatric kidney, liver and intestinal transplantation. The study population consists of
      subjects who received a solid organ transplant (liver, kidney, intestine, combined) between 0
      and 18 years of age.

      As a part of their standard care patients are admitted to the department for a yearly
      check-up after transplantation. During this admission a set of investigations are performed
      to evaluate the current medical situation, including an elaborate pharmacokinetic (PK)
      assessment. Patient characteristics and clinical data (age, bodyweight, sex, type of graft,
      cause of organ failure, co-medication, laboratory results, PK data) will be retrieved from
      the patient files concerning these follow-up admissions. In addition patients and/or their
      parents will be requested permission to collect one extra tube of whole blood (ca 8 ml) for
      DNA analysis during a standard blood collection at a regular hospital/outpatient visit.

      After collection patient data will be given a code for further anonymous storage and
      analysis. DNA SNP analysis will take place at our laboratory for pediatric nephrology with
      PCR.
    

Intervention name(s): Blood withdrawal for DNA
Intervention type(s): Procedure
Intervention description(s): Single withdrawal of 8 ml whole blood for DNA analysis, during a "standard" blood collection as part of standard clinical follow up.
Other intervention name(s): not applicalble
Observational model: Cohort
Time perspective: Retrospective
Sampling method: Non-Probability Sample
Study population: 
        Pediatric recipients of a solid organ transplantation
      
Biospecimen description: 
      tube of whole blood (8 ml) to be processed for DNA extraction and storage
    
Keywords: Pediatric transplantation; Pharmacogenetics; Pharmacokinetics; Calcineurin inhibitors; CYP3A; Pgp