**1. Introduction**

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286 Current Issues and Future Direction in Kidney Transplantation

Optimizing balance between therapeutic efficacy and the occurrence of adverse events is the main goal of individualized medicine. This takes even more importance in narrow therapeutic index drugs such as immunosuppressants. These drugs are highly effective in preventing acute graft rejection but tacrolimus, cyclosporine and mycophenolic acid show highly variable pharmacokinetics and pharmacodynamics. Still nowadays the fragile equilibrium between the risks and benefits of immunosuppression makes the management of immunosuppressive pharmacotherapy a challenge.

Therapeutic drug monitoring (TDM) is an essential and indispensable instrument for calci‐ neurin inhibitors dosing, reducing the pharmacokinetic component of variability by control‐ ling drug blood concentrations. But TDM is only possible once the drug is administered and steady state and patient's compliance are achieved, so complementary strategies are needed. Moreover, despite correct TDM, it may take several days or even weeks to reach target blood concentrations. For many patients this time periods are not appropriate in order to achieve sufficiently high concentrations to prevent graft rejection or adverse reactions or, on the other hand, without exposing the patient to excessive toxicity. In this sense, Pharmacogenetics is an interesting approach, helpful to manage immunosuppressant drugs. Changes in expression or function of proteins and enzymes involved in drug transport, metabolism or mechanism of action will cause changes in drug's absorption, metabolism and distribution and, therefore, can lead to changes in the response and toxicity of the treatment. Characterization of these genetic variants, mainly Single Nucleotide Polymorphisms (SNPs), can help to establish

© 2013 Herrero et al.; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

effective doses and to minimize adverse effects. Many publications, including our own, have found statistically significant correlations between (SNPs) and tacrolimus and/or cyclosporine dose-corrected blood levels. There are also works correlating certain variants in SNPs with safety and efficacy of the treatment. Even some researchers, working groups and consortia recommend guidelines for initial dosing adjust regarding this SNPs.

icals that discusses technical and scientific aspects about the products registries. One of its aims is to reach a better harmonization in the interpretation and application of technical guides and requirements for the registries. ICH defines Pharmacogenomics as the study of variations in DNA and RNA characteristics regarding the response to drugs and it defines Pharmacoge‐ netics as a subset inside pharmacogenomics, that studies the variations in the DNA sequence

Practical Pharmacogenetics and Single Nucleotide Polymorphisms (SNPs) in Renal Transplantation

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There is another term that is also frequently found: biomarker, genetic or genomic biomarker, whose definition is "a measurable characteristic of DNA and/or RNA which is an indicator of a biological process that can be normal, pathogenic and/or a response to a therapeutic (or other kind) intervention. A genomic biomarker could be, for instance, the measuremente of a gene expression or of its regulation. It can consist in one or more DNA and/or RNA characteristics, as for instance, in DNA, its single nucleotide polymorphisms (SNPs); the variability in the repetition of short sequences; the haplotypes; DNA modifications as methilation; the deletions or insertions of a single nucleotide; the copy number variation; or the cytogenetic rearange‐ ments as translocations, duplications, deletions or inversions. Regarding RNA, it could be a particular trait of its sequence; the levels of expression; the processing (as splicing and editing); or the levels of microRNAs. A deeper explanation of some of these terms will be done in the

The aim of pharmacogenomics is to identify the most important genetic elements in the instauration and/or evolution of a pathological process in order to create new strategies for drug evaluation and optimization of the drug development process. These are usually high throughput studies, regarding the simple number and statistical signification but also very exigent with the study subject: the final goal is finding correlation with the disease at a genomic level, not with one single nucleotide but with genes or groups of related genes instead. On the other side, pharmacogenetics studies the influence of genetic factors on the activity of a drug, making attention in concrete changes inside a gene that somehow has already been postulated as a candidate gene, by previous knowledge or by pharmacogenomic studies. Subject of pharmacogenetic studies are especially, the variants in genes related with transport and metabolism of drugs, with the aim that specific drugs can be given to specific groups of

To summarize, pharmacogenetics has to be considered as one of the mainstays of personalized medicine, which will let us correlate good or bad response to a drug in a specific population with genetic aspects. It will also let us know which drugs will offer greater therapeutic benefit

We also must review some other basic concepts in genetics and, extensively, pharmacogenetics in order to understand the following information. The most relevant one is Polymorphism, which is defined as a mendelian monogenic character that appears in the population with the presence of more than one allele in the same genetic locus. Applying the term to pharmaco‐

or lower risk of adverse reactions development for a given population.

regarding the response to drugs [1-5].

genetically defined (or "stratified") patients [6, 7].

**3. What are genetic polymorphisms?**

next paragraph.

Pharmacogenetic tests are becoming cheaper every day, so the cost of performing these assays is getting more assumable, especially when clinically relevant complications are demonstrated. The incorporation of pharmacogenetic studies to the real clinical practice will depend on the creation of well-designed sets of SNPs that, in a cost-effectiveness manner, could correlate clinical complications with genotypes, taking into consideration the whole and complicated treatment in polymedicated patients. Many results contribute to highlight the need of prospective controlled studies, with pharmacogenetic analysis prior to transplantation. This will probably be the critical point for the regulatory agen‐ cies to settle the most relevant polymorphisms as validated biomarkers to be widely used in the clinical transplantation setting.

For all this reasons, our aim in this chapter is to provide an easy explanation about what a polymorphism is and an updated view of the most relevant SNPs with evidence of their implication in safety and efficacy of immunosuppressive treatment in renal transplantation. The final goal is to give a summary from basic knowledge to concrete examples that help to improve the medical doctors' knowledge of the clinical impact of Pharmacogenetics in their daily practice.
