**5.2. What is a meta-analysis and what is the need of them?**

The number of publications is increasing every day in an accelerated manner to limit the ability of researchers and clinicians to assess critically and to assume the results of the studies. This, added to the fact that the knowledge about something is not born due to a single article, but to the integration of many, requires conducting systematic reviews of available evidence, of which there are two types:


Meta-analysis is a summary of different qualitative and quantitative studies (usually random‐ ized controlled trials) that evaluate one aspect whose results are combined using statistic resources to determine the directionality of the effect and the causes of variability between studies. It is the gold standard tool to assess the consistency of an evidence in the effect of a particular intervention, especially when studies are heterogeneous and discordant, when studies evaluating outcomes affect a low number of patients (as it happens when reporting adverse events), when conducting new clinical trials is expensive or when we want to know the existence of patient subgroups responding differently to the intervention analyzed.


CYP3A5 rs776746, has reached some kind of clinical recommendations. These have not been adopted by any of the regulatory agencies FDA nor EMA, but they already have a strong

The 3rd European Science Foundation- University of Barcelona (ESF-UB) Conference in Biomedicine on Pharmacogenetics and Pharmacogenomics, held in June 2010 in Spain, published a summary of their practical recommendations [43] which include the explained tacrolimus results. They recommend CYP3A5 rs776746 genotyping prior to grafting as it could help to reach steady state plasma tacrolimus concentrations earlier, and therefore prevent overdose (risk of nephrotoxicity) or underdose (risk of acute graft rejection). This recommen‐ dation is mainly based on Thervet's publication [23] and suggests the introduction of tacroli‐ mus at 0.15 mg/kg/day when the recpient's genotype is \*3/\*3, at 0.20 mg/kg/day when it is \*3/ \*1, and at 0.25 mg/kg/day when it is \*1/\*1; always taking into consideration that the patients

The Dutch Pharmacogenetics Working Group Guideline from the Royal Dutch Pharmacists Association have also evaluated therapeutic dose recommendations for tacrolimus based on our CYP3A5 SNP [44] and have found evidence to support an interaction between the drug and the gene. However, they do not make dosing recommendations adducing that in dutch

The number of publications is increasing every day in an accelerated manner to limit the ability of researchers and clinicians to assess critically and to assume the results of the studies. This, added to the fact that the knowledge about something is not born due to a single article, but to the integration of many, requires conducting systematic reviews of available evidence, of

**•** Quantitative systematic reviews or meta-analyses, which combine the results in a single

Meta-analysis is a summary of different qualitative and quantitative studies (usually random‐ ized controlled trials) that evaluate one aspect whose results are combined using statistic resources to determine the directionality of the effect and the causes of variability between studies. It is the gold standard tool to assess the consistency of an evidence in the effect of a particular intervention, especially when studies are heterogeneous and discordant, when studies evaluating outcomes affect a low number of patients (as it happens when reporting adverse events), when conducting new clinical trials is expensive or when we want to know the existence of patient subgroups responding differently to the intervention analyzed.

transplantation hospitals, the tacrolimus dose is titrated in response to TDM.

**•** Qualitative systematic reviews, where evidence is presented descriptively

endpoint and determine the causes of the variations between studies.

**5.2. What is a meta-analysis and what is the need of them?**

evidence as to be considered by expert doctors in the area.

298 Current Issues and Future Direction in Kidney Transplantation

will also require the regular TDM.

which there are two types:

**•** In this way the results allow us to:

**•** Plan future clinical trials on a related topic.


Calculate the sample size needed for future clinical trials about a similar topic.

Conducting such studies is cumbersome, it is really time-consuming, requires complex methodological knowledge and its performance is not free of trouble. The main difficulties are the presence of a small number of previously existing studies, the fact that the selected studies to be analysed are usually very heterogeneous and difficult to be combined, and in many of them the necessary information is absent or with low methodological quality. However, metaanalysis studies are low-cost and have high impact.

However, we must be careful as the name "meta-analysis" does not ensure a quality review and readers should critically evaluate it before accepting its results, for which there are currently accessible guides [47, 48]. Its validity largely depends on the quality of the included studies and the absence of bias in its execution [49]. The studies analyzed in the meta-analysis are mostly randomized trials, which are those that offer the best evidence, but there are scenarios where the information comes only from observational studies [50], as studies on etiological hypotheses or adverse events. This represents a challenge as this type of design has a higher risk of bias and lack of essential information for the integration of studies [51]. Furthermore, the inclusion of studies with a large heterogeneity or variability between them, hinders the results interpretation [52], requires the knowledge of statistical tools for proper interpretation [53] and one must know that it is a limitation for the applicability of the results. Meta-analysis is a retrospective process, so it is susceptible to errors of this type of design. It could have biases in any of its stages: in the search and selection of studies, analysis and synthesis of information.

The meta-analysis is the highest level of evidence and summarizes the studies available about a particular matter in a reliable way. Its implementation has its difficulties and limitations, so methodological rigor is required to help reduce the risk of bias and a critical and cautious view of its results.

As far as we know, two meta-analyses have been published regarding clinical implications of CYP3A5 and CNIs in renal transplantation. One is about tacrolimus [54] and its conclusion agrees with the data explained about CYP3A5 expressers/non-expressers dose requirements. The other one deals with cyclosporine [55], and also concludes that there is an association between our SNP and cyclosporine dose-adjusted concentration, where patients carrying \*3/\*3 genotype will require a lower dose of the drug to reach target levels, compared with \*1/ \*1 or \*1/\*3 carriers.
