Mol Diagn Ther (2012) 16:331345 DOI 10.

1007/s40291-012-0012-5

CURRENT OPINION

Pharmacogenetics in Kidney Transplantation

Published online: 29 November 2012 Springer International Publishing Switzerland 2012

Abstract Every month, new releases on the relationship between pharmacogenetic biomarkers and immunosuppressive drug therapy in kidney transplantation are published. However, the systematic clinical application of these discoveries occurs at a very slow pace, and the usefulness of knowing a patients genotype remains an important matter of debate. This can be partially ascribed to the lack of consistency when looking at the different associations reported across several studies but also the need for a broadspectrum view and a rigorous analysis of the relevance of the different associations observed to date. For that purpose, we performed a comprehensive analysis of the strength of the different reported genetic associations, and in this article we discuss their potential for clinical implementation in kidney transplantation. For tacrolimus, it is likely that a genotype-based drug dosage can benet patient outcome, while for ciclosporin A, the data appear less convincing. For the mammalian target of rapamycin inhibitors, sirolimus
L. Elens R. H. N. van Schaik Department of Clinical Chemistry, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands L. Elens Louvain Centre for Toxicology and Applied Pharmacology catholique de Louvain (UCL), (LTAP), Universite Brussels, Belgium D. A. Hesselink T. van Gelder Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands T. van Gelder (&) Department of Hospital Pharmacy, Erasmus MC, University Medical Center Rotterdam, Rotterdam 3015 CE, The Netherlands e-mail: [email protected]

and everolimus given the lack of data and the absence of large prospective studies it is premature to implement pharmacogenetics, but some novel and promising leads have recently been reported. For mycophenolate mofetil, the complex metabolic pathways of its active moiety, mycophenolic acid, complicate analysis of the various published associations. However, at present, some interesting ndings can be highlighted and offer potential value to assist clinicians in decision making.

1 Introduction Patient survival and graft outcome after kidney transplantation have drastically improved in recent decades, mainly because of major improvements in immunosuppressive therapy and in medical care. Transplant physicians have the choice between several immunosuppressive agents. The current preferred regimen is based on the combination of calcineurin inhibitors (CNIs; ciclosporin A and tacrolimus) with anti-proliferative agents (mainly mycophenolate mofetil [MMF]) and glucocorticoids. In recent years, a new class of immunosuppressants, the mammalian target of rapamycin inhibitors (mTORi; sirolimus and everolimus), has become available. Despite excellent short-term patient and graft survival, optimal immunosuppression is difcult to achieve in an individual patient, as the majority of immunosuppressive agents are characterized by highly variable pharmacokinetics and a narrow therapeutic window. The use of immunosuppressive drugs is further complicated by their high toxicity prole, mainly represented by, but not limited to, nephrotoxic events with CNIs, hematologic and gastrointestinal side effects with MMF, and dyslipidemia and hematologic toxicity with mTORi. The susceptibility to developing adverse events or

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experiencing therapeutic failure varies strongly between individuals. An important part of this variability in drug response is thought to be the consequence of substantial inter-individual differences in drug metabolism. Some patients have relatively fast drug clearance, while others exhibit a slower drug elimination rate. This variation in drug clearance is of importance, since it might be related to an increased risk of under- or overexposure, which can ultimately lead to a higher frequency of acute graft rejection or adverse events, respectively. The proteins targeted by immunosuppressants may also display variable activities between individuals, providing alternative explanations for the observation that a drug can be more efcient and/or toxic for one patient compared with another, even when the patients experience equal exposure to the drug. Pharmacogenetic studies have provided interesting clues for unraveling the reason for the variability in pharmacokinetics and/ or clinical outcome (Tables 1, 2, 3). Most of the genetic associations are still controversial or await clear conrmation. Some ndings have, however, been validated across multiple studies. Nevertheless, the systematic application of pharmacogenetic testing in daily clinical practice is not universally accepted. To help the reader in the identication of relevant associations, we have dened a scale ranging from 0 to 6, which attempts to estimate the strength of each reported association (Table 4). This index aims to pool different aspects evaluating the relevance of the associations, including the quality/size of the studies, the consistency of the results, and the diverse in vitro-based evidence.

absorption, distribution, metabolism, and excretion (ADME) are well known. Many studies have investigated the possible links between various single nucleotide polymorphisms (SNPs) in genes implicated in the ADME of immunosuppressive drugs and the between-patient variability in pharmacokinetics. Comparison of the results of these studies is complicated by many factors. For instance, not all studies have looked at the same time points following transplantation and also, for most of them, pharmacokinetic data were limited to pre-dose concentrations, while very few studies performed extensive pharmacokinetic analysis. On the other hand, the majority of pharmacogenetic studies focused on pharmacokinetic data solely, and those that did report clinical outcome data were mostly underpowered. 2.1.1.1 Cytochrome P450 3A and Related Proteins While ciclosporin A, everolimus, and sirolimus are predominantly oxidized by cytochrome P450 (CYP) 3A4 with only a minor contribution from CYP3A5 [13], CYP3A5 is the main protagonist of CYP3A-mediated tacrolimus oxidation [4]. Among the multiple alleles that have been reported for CYP3A4, the CYP3A4*1B allele harbors an A-to-G substitution at position -392. Studies have suggested that this SNP results in increased promoter activity [5]. The CYP3A4*18B allele, corresponding to a G-to-A substitution at position 82266 in intron 10, has also been suggested to increase CYP3A4 activity but is only present in Asians [6]. The CYP3A4*22 allele is dened by the presence of the rs35599367C[T SNP in intron 6 (see http://www. cypalleles.ki.se/). Its allelic frequency is 5 % in the Caucasian population, and it is associated with reduced CYP3A4 hepatic expression and activity [7]. The CYP3A5*3 allele (i.e., 6986A[G, rs776746) introduces a cryptic splice site resulting in truncated messenger RNA (mRNA) and no functional CYP3A5 expression [8]. As a consequence, individuals carrying two CYP3A5*3 loss-of-function (LOF) alleles do not express CYP3A5 (non-expressers), while individuals with at least one functional CYP3A5*1 allele do express CYP3A5 (expressers). The CYP3A5*3 allele exhibits marked ethnic diversity, with allelic frequencies of about 35 % in African-Americans, 75 % in Asians, and 90 % in Caucasians. P450 oxidoreductase (POR) constitutes an indispensable element of all microsomal CYP enzymes [9]. The 1508C[T SNP (rs1057868; POR*28), is the most common SNP in POR and encodes the amino acid variant Ala503Val, which has been associated with differential CYP3A activity [10, 11]. Other factors regulate CYP3A activity and, recently, the rs4253728 PPAR-alpha SNP has been associated with the CYP3A4 phenotype, but its impact on immunosuppressive therapy remains to be investigated [12].

2 Past Evidence and New Highlights in Immunosuppressive Drug Pharmacogenetics Given all of the tracks that have been followed (Tables 1, 2, 3), it is difcult to disentangle the discrepancies and contradictions reported in pharmacogenetic studies. Frequently, the true meaning of the genetic associations is complicated by the fact that the results are potentially confounded by non-genetic factors. However, some evident observations may help the clinician to rene the present therapies or, at least, to clarify the reasons for variability in drug response. 2.1 Important Genes and Variants to Consider 2.1.1 Pharmacokinetics Every clinician prescribing an immunosuppressive regimen to transplant patients is aware of the wide variability in the dose required to reach target drug concentrations. For the currently employed drugs, the proteins involved in their

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2.1.1.2 Uridine 50 -Diphosphate-Glucuronosyltransferases The metabolism of mycophenolic acid (MPA) is mainly driven by glucuronidation via the uridine 50 -diphosphateglucuronosyltransferase (UGT) enzyme superfamily [13]. The major MPA metabolite is the inactive 7-O-MPA glucuronide (MPAG), which is formed mainly by the UGT1A subfamily, with a predominant role of UGT1A9 and a minor contribution from UGT1A8 [13, 14]. A quantitatively less important MPA, acylglucuronide (AcylMPAG), is mainly produced by UGT2B7 [13], with a minor contribution from UGT1A8 [14]. The pharmacologic potency of AcylMPAG is comparable to that of MPA [15] and is thought to be responsible for the toxic side effects [16, 17]. Two SNPs located in the UGT1A9 promoter, -275T[A and -2152C[T, have been associated in vitro with twofold higher MPA glucuronidation in human liver microsomes [18]. The UGT1A9*3 allele is dened by the 98T[C change, which has a low allelic frequency in the Caucasian population (2 %) but has been associated with 1.7-fold slower intrinsic clearance toward MPA glucuronidation when compared with the wild-type allele [19]. For UGT1A8, the UGT1A8*3 allele is associated with a 4.3-fold lower metabolic capacity of the enzyme toward MPA [14]. By contrast, the results are less clear for the UGT1A8*2 allele [14, 20]. As for the other UGTs, UGT2B7 is polymorphically expressed, and two frequent SNPs, the 802C[T (dening the UGT2B7*2 allele) and the -842G[A promoter SNPs, have been reported. Both SNPs are in complete reverse linkage disequilibrium (LD), and the -842G[A SNP has been linked to enhanced production of AcylMPAG in human liver microsomes [21, 22]. 2.1.1.3 Transporters or Carriers The ATP-binding cassette (ABC) family is a group of proteins responsible for the active transport of multiple compounds across cell membranes from the intra- to the extra-cellular matrix. ABC transporters are expressed at different sites in the body, but predominantly in excretory organs, where they play a key role in the absorption, distribution, and elimination of xenobiotics. ABCB1 (previously known as P-glycoprotein) is known to transport CNIs and mTORi [23, 24]. Several SNPs have been described for ABCB1. The three most common SNPs in the protein coding region are 1236C[T, 2677G[T/A (Ala893Ser/Thr), and 3435C[T. These three SNPs are in strong LD, and their allelic frequencies vary between different ethnic groups. Much attention has been focused on the 3435C[T SNP, located in exon 26 and characterized by an allelic frequency of approximately 50 % in Caucasians. The 3435T allele has been associated with reduced mRNA expression and stability and/or protein activity [25, 26] in various organs, including the kidney and lymphocytes [27, 28]. The 1199G[A SNP, located in exon

11 of ABCB1, results in a serine to asparagine transition at amino acid 400 (Ser400Asn) and has an allelic frequency of approximately 5.5 % in Caucasians. ABCC2 is involved in the biliary excretion of MPA glucuronides produced in hepatocytes [29]. The most common SNPs in ABCC2 consists of the -24C[T variant, located in the 50 -upstream ABCC2 promoter region, and the 1249G[A coding polymorphism. Human organic anion transporting polypeptide (OATP) carriers are expressed mainly in hepatocytes, where they mediate the uptake of a number of compounds from the blood, facilitating their biliary excretion. Recombinant expression of OATP1B3 and, to a lesser extent, OATP1B1 facilitates the cellular uptake of MPAG [30]. This information is of importance, as the hepatic uptake of MPAG is a prerequisite for MPA entero-hepatic recirculation, which is estimated to account for up to 61 % of total MPA exposure [31]. In vitro, the uptake of MPAG is markedly decreased by the presence of the 334G699A OATP1B3 variant haplotype [30]. By contrast, no in vitro experiment has yet investigated the impact of SLCO1B1 (solute carrier organic anion transporter family, member 1B1) SNPs on MPA/MPAG cellular uptake. In vivo, the most commonly studied SLCO1B1 SNPs are the 388A[G (SLCO1B1*1B allele) and 521T[C (SLCO1B1*5 allele) coding SNPs. They are in partial LD, and the presence of both variants is labeled as the SLCO1B1*15 allele.

2.1.2 Pharmacodynamics Several SNPs have been considered across different pharmacogenetic studies for their potential to explain differential susceptibility to adverse events or the risk of therapeutic failure. For instance, SNPs located in the TGFB1 (transforming growth factor, beta 1) and ACE [angiotensin I converting enzyme (peptidyl-dipeptidase A) 1] genes may inuence brogenesis during various nephropathies [32, 33], including CNI-related nephropathies. Also, it has been demonstrated that the polymorphically expressed CYP2C8 and CYP2J2 are involved in the synthesis of epoxyeicosatrienoic acids [34, 35], which have vasodilator properties and are thought to counterbalance the vasoconstrictive effect of CNIs that could eventually lead to nephrotoxicity. Other genes of the pharmacodynamic pathway have been considered, being mainly cyclophilin-A and NFATC4 (nuclear factor of activated T-cells, cytoplasmic, calcineurin-dependent 4) for CNIs, and IMPDH1 [IMP (inosine 50 -monophosphate) dehydrogenase 1], IMPDH2, IL12A [interleukin 12A (natural killer cell stimulatory factor 1, cytotoxic lymphocyte maturation factor 1, p35)], CYP2C8, and HUS1 [HUS1 checkpoint homolog (S. pombe)] for MMF.

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2.2 Ciclosporin A Although the CYP3A4*1B variant allele has been linked in some studies to faster oral ciclosporin A clearance [36], we do feel that its effect on ciclosporin A disposition is minor and probably not very clinically relevant (Table 1). This

allele is in strong LD with the CYP3A5*1 active allele, which complicates interpretation of the observations. Pooled data from clinical studies suggest that the CYP3A5*3 variant, like CYP3A4*1B, has, at best, a small effect on ciclosporin A blood concentrations and no impact on the incidence of acute rejection [37]. Genotyping of transplant

Table 1 Reported genetic associations between recipient/donor genotype and calcineurin inhibitor-based therapies Recipient/donor genotype, drug, and gene Recipient Ciclosporin A CYP3A4 CYP3A4*1B CYP3A4*18B CYP3A4*22 No effect or slightly : clearance : Clearance No effect or ; dose requirement; : doseadjusted drug concentrations No effect or slightly : clearance No effect, or ; or : drug concentrations or dose requirement; : PBMC concentrations ; PBMC concentrations No effect Slightly : dose requirement No effect; ; bioavailability No effect Not assessed : Risk of DGF; ; CLCR; no effect on BPAR 3 (weak) 1 (none) 4 (moderate) [36, 58, 70, 104106] [6, 107, 108] [38, 39] SNP Effects Pharmacokinetics Pharmacodynamics Estimated strength of association References

CYP3A5

CYP3A5*3

No effect on BPAR and nephrotoxicity; ; patient survival Mixed results

4 (moderate)

[36, 37, 55, 58, 64, 109112] Reviewed in [41, 42], [44]

ABCB1

3435C[T (2677G[T/A, 1236C[T)

2 (weak)

1199G[A ABCC2 POR -24C[T POR*28

Not assessed Not assessed No effect on BPAR, DGF, or creatinine clearance rs2276707 TT variant homozygous showed : risk of DGF

2 (weak) 1 (none) 2 (weak)

[44] [113] L. Elens et al., unpublished data [114, 115]

NR1I2

rs3814055, rs1523127, rs2276706, rs2276707, rs1464603, rs6785049, -205 to -200GAGAAG rs2228001 rs1057910 rs712704 rs1802059 rs2608555 rs1186672 CYP3A4*1B CYP3A4*22

1 (none)

XPC CYP2C9 PAX4 MTRR GAN ADH4 Tacrolimus CYP3A4

Not assessed Not assessed Not assessed Not assessed Not assessed Not assessed : Clearance or no effect ; Dose requirement; ; clearance; : risk of overexposure; : delay in achieving target blood concentrations ; Clearance; : risk of overexposure; : delay in achieving target blood concentrations

; Risk of nephrotoxicity : Risk of nephrotoxicity : Risk of nephrotoxicity ; Risk of nephrotoxicity : Risk of nephrotoxicity : Risk of nephrotoxicity No effect No effect on BPAR or nephrotoxicity

2 (weak) 2 (weak) 2 (weak) 2 (weak) 2 (weak) 2 (weak) 3 (weak) 5 (moderate)

[116] [116] [116] [116] [116] [116] Reviewed in [41, 42] [38, 71]

CYP3A5

CYP3A5*3/*3

No effect on BPAR or nephrotoxicity; ; risk of early acute rejection

6 (strong)

[45, 5466]

Pharmacogenetics in Kidney Transplantation Table 1 continued Recipient/donor genotype, drug, and gene ABCB1 SNP Effects Pharmacokinetics 3435C[T (2677G[T/A, 1236C[T) No effect, or ; or : drug concentrations or dose requirement; : PBMC concentrations : PBMC concentrations No effect : Dose requirement Pharmacodynamics Mixed results Estimated strength of association 2 (weak) References

335

Reviewed in [41, 42], [43]

1199G[A ABCC2 POR -24C[T POR*28

Not assessed Not assessed No effect on BPAR, DGF, or creatinine clearance Not assessed No effect on nephrotoxicity : Risk of DGF; no effect on creatinine clearance; no effect on BPAR No effect on DGF; no effect on creatinine clearance; no effect on BPAR

2 (weak) 1 (none) 3 (weak)

[43] [117, 118] [72]

NR1I2 TGFB1 CYP2C8

rs3814055 -509C[T, 869T[C CYP2C8*3

; Clearance Not assessed Not assessed

0 (none) 1 (none) 1 (none)

[119] [120] [121]

CYP2J2

CYP2J2*7

Not assessed

1 (none)

[121]

Donor Ciclosporin A ABCB1 Tacrolimus ABCB1 CYP3A5 3435C[T 1199G[A CYP3A5*3/*3 Not assessed Not assessed Not assessed : Risk of nephrotoxicity : GFR ; Creatinine levels; no effect 2 (weak) 2 (weak) 3 (weak) [75] [76] [75, 76, 122124] 3435C[T Not assessed : Risk of nephrotoxicity 2 (weak) [50, 51]

ABC ATP-binding cassette, ADH4 alcohol dehydrogenase 4 (class II), pi polypeptide, BPAR biopsy-proven acute rejection, CLCR creatinine clearance, CYP cytochrome P450, DGF delayed graft function, GAN gigaxonin, GFR glomerular ltration rate, MTRR 5-methyltetrahydrofolatehomocysteine methyltransferase reductase, NR1I2 nuclear receptor subfamily 1, group I, member 2, PAX4 paired box 4, PBMC peripheral blood mononuclear cell, POR P450 oxidoreductase, SNP single nucleotide polymorphism, TGFB1 transforming growth factor, beta 1, XPC xeroderma pigmentosum, complementation group C, : increased, ; decreased

recipients for CYP3A4*1B and/or CYP3A5*3 is thus unlikely to help in dosing of ciclosporin A. The recent ndings of the impact of the decrease-of-function (DOF) CYP3A4*22 allele on ciclosporin A clearance [38] and its association with drug-related nephrotoxicity [39] offer a new candidate to explain the inter-individual differences in the therapeutic response to ciclosporin A. However, because these are recent ndings, we suggest exercising caution when interpreting these observations, as large prospective conrmatory studies are required. For CYP3A4, some studies have consistently associated the CYP3A4*18B allele with altered ciclosporin A pharmacokinetics in Asian subjects. However, the small sizes of the different studies lessened the strength of these associations (Table 1). Moreover, the clinical impact of these ndings still awaits investigation. A large number of genetic association studies investigating the

relationship between ABCB1 SNPs and ciclosporin A pharmacokinetics have been performed, but the results have been quite unsatisfactory, as they have identied only a limited (if any) effect of those SNPs on ciclosporin A blood concentrations (for a complete review, see references [4042]) (Table 1). However, some data suggest that ABCB1 activity strongly impacts on intra-cellular drug concentrations rather than on systemic exposure [27, 43 47]. Genetic variations in ABCB1 and its activity in lymphocytes may determine the amount of ciclosporin A available at the site of its immunosuppressive action. Of particular interest, the ABCB1 3435T and 1199A variant alleles have been associated with increased and decreased ciclosporin A concentrations, respectively, within peripheral blood mononuclear cells (PBMCs) [44]. A number of studies have, however, failed to consistently associate the

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ABCB1 genotype of the recipient with the risk of developing acute rejection (reviewed in reference [41]). Nevertheless, in a very large study of 832 renal transplant recipients treated with either ciclosporin A (n = 407) or tacrolimus (n = 425), it was found that the recipient ABCB1 haplotype pooling the 1236C, 2677G, and 3435T alleles predicted a higher risk of rejection [48]. The authors hypothesized that this haplotype causes increased ABCB1 activity, limiting the access of the drugs within immunocompetent cells. This statement is in line with the data of Capron et al. [43], who reported higher tacrolimus intra-lymphocyte accumulation in carriers of 2677T than in homozygous 2677GG wild-type patients; carriage of the 2677T allele is thus expected to protect against rejection. However, Crettol et al. [44] reported increased ciclosporin A intralymphocytic concentrations in carriers of 3435T. The 3435T allele would thus lead to more efcient immunosuppression and, like the 2677T variant allele, would protect against rejection, which is in contradiction to the increased risk of acute rejection associated with the C-G-T haplotype [48]. Alternatively, ABCB1 activity in the proximal tubular cells of the kidney may be important for accumulation of the drug within renal tissue. Higher ABCB1 activity in the kidney might protect the graft from CNI-induced nephrotoxicity. In kidney transplantation, the donor genotype would be relevant for ABCB1 expression in the graft, while, as explained above, the genetic prole of the recipient would be related to the PBMC compartment [49]. It has been reported that the donor genotype of ABCB1 3435C[T is connected to ciclosporin A-related nephrotoxicity, with the wild-type 3435C allele protecting against ciclosporin A-related nephrotoxicity [50, 51], but data showing a correlation with higher intrarenal ciclosporin A concentrations still need to be collected. Surprisingly, Cattaneo et al. [52] reported that the recipient genotype can also impact on the risk of CNI-related adverse events, as shown by impaired kidney function recovery in carriers of ABCB1 2677T and 3435T allelic variants. The authors hypothesized that this might be the consequence of more severe graft reperfusion due to oxidative stress and reactive oxygen species (ROS) released by inltrating host leukocytes, where ROS generation is sustained by increased intracellular ciclosporin A concentrations secondary to reduced ciclosporin A efux via ABCB1 transport in 3435T leukocytes. The importance of the donor genotype is not limited to ABCB1, as its expression and activity are regulated by multiple factors. For instance, the pregnane X receptor (PXR), which is encoded by the NR1I2 (nuclear receptor subfamily 1, group I, member 2) gene, is a key nuclear receptor controlling the expression of multiple transporters. The NR1I2 rs2276707C[T variant in donors has recently been associated with an increased risk of delayed graft function (DGF). This was explained by enhanced ABCB1 expression in recipients of kidneys from donors carrying the

rs2276707TT genotype, because of higher PXR protein levels [53]. The importance of ABCB1 activity in the transplanted kidney is thus assumed to be highly relevant to explain differences in graft outcome. 2.3 Tacrolimus It has been shown extensively by numerous studies that CYP3A5 expressers require about a two-fold higher tacrolimus dose to reach the same tacrolimus concentrations as those achieved by CYP3A5 non-expressers [45, 5466] (Table 1). The consistency of the association between the CYP3A5 genotype and the tacrolimus dose requirement, whatever the time post-transplantation or the ethnicity of the patient, has been validated in a recent meta-analysis [67]. The ascendancy of the explicative value of the CYP3A5*3 allele over those of other genes implicated in the tacrolimus ADME pathway has been recently illustrated by the fact that, among a panel of more than 2,000 SNPs in ADME genes, no variants other than CYP3A5*3 signicantly correlated with tacrolimus pharmacokinetics [68]. Of note, both the CYP3A4*22 and the POR*28 variants were not included in this SNP survey. Furthermore, the association between the tacrolimus dose requirement and the CYP3A5 genotype has also been observed among recipients of a non-renal organ transplant [42]. In light of the importance of the effect of the CYP3A5 recipient genotype on tacrolimus exposure, a randomized prospective study was performed to evaluate whether adaptation of the tacrolimus starting dose according to the CYP3A5*3 genotype led to faster achievement of target blood concentrations [69]. This study indeed did show that CYP3A5 genotype-guided dosing led to achievement of target tacrolimus concentrations more quickly and with fewer dose modications. However, the benet of reaching therapeutic tacrolimus concentrations earlier did not translate into better clinical outcomes. Important drawbacks of that trial were that the patients it included were at low immunologic risk and that tacrolimus was initiated only 7 days posttransplantation. These concerns could potentially explain why no clinical advantage of genotype-based dosing could be observed. Therefore, the results of this randomized trial do not rule out a clinical benet of consideration of a patients CYP3A5 genotype to adapt the initial tacrolimus dose when tacrolimus therapy is initiated at day 0. We suspect that most of the observed effects of the CYP3A4*1B allele on tacrolimus pharmacokinetics arise from its strong LD with the CYP3A5*1 active allele and not from a substantial functional change in CYP3A4-mediated tacrolimus metabolism. Nevertheless, some recent data have suggested that the CYP3A4*1B allele might still have an effect on tacrolimus dose requirements among CYP3A5 non-expressers [70] (Table 1). However, given the minor

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amplitude of the effect, the non-repeatability of the association when considering different time points, and the fact that the inuence was seen in CYP3A5 non-expressers solely and not in CYP3A5 expressers, it is unlikely that the CYP3A4*1B allele has clinical relevance. By contrast, the effects of the CYP3A4*22 allele and its signicant association with reduced tacrolimus clearance have been demonstrated to be unrelated to the effect of CYP3A5 expression [38, 71] (Table 1). Transplant recipients who carry the CYP3A4*22 variant allele require signicantly lower tacrolimus doses to reach the same concentrations as those achieved by non-carriers [38, 71]. Additionally, CYP3A5 non-expressers who carry a CYP3A4*22 allele have a higher risk of tacrolimus overexposure during the rst three days following transplantation [71]. This suggests that tacrolimus dosage adjustment based on CYP3A4*22CYP3A5*3 combined allelic status might be more informative than an algorithm taking into account the CYP3A5 genotype solely. Very recent data have suggested that CYP3A5 activity is also affected by POR*28, as a correlation was found with the tacrolimus dose requirement [72] (Table 1). If this observation is conrmed, this genetic variant may also need to be included in future pharmacogenetic studies. A recent meta-analysis has attempted to unravel the different controversial observations on the inuence of ABCB1 SNPs on tacrolimus pharmacokinetics [73]. The results of this meta-analysis suggest a limited impact of the 3435C[T SNP on tacrolimus blood concentrations. As was hypothesized for ciclosporin A, changes in ABCB1 activity could be more important to explain differences in tacrolimus drug tissue distribution than differences in tacrolimus

blood concentrations. Intuitively, intra-lymphocytic tacrolimus concentrations would correlate more closely with efcacy than whole-blood concentrations. A synergistic and protective action of the 3435T and 1199A alleles against low tacrolimus intracellular concentrations has been demonstrated [43]. As for ABCB1, CYP3A5 is expressed in the kidney [74], thus high CYP3A5 and ABCB1 activity would protect the kidney from tacrolimus accumulation/nephrotoxicity by locally metabolizing tacrolimus or extruding the drug from the renal parenchyma. It has been shown that patients engrafted with a kidney that was homozygous for the ABCB1 3435T variant allele were more at risk of histologic kidney damage [75], which again suggests that the 3435T allele might be related to increased local drug accumulation. Likewise, the mutated ABCB1 1199A allele in the donor was found to have a protective effect on renal function [76]. 2.4 Mammalian Target of Rapamycin Inhibitors It seems that the CYP3A5 genotype can account for part of the variability in sirolimus but only in CNI-free immunosuppressive regimens [2, 7781] (Table 2). The potential utility of that information is still unclear. Preliminary data demonstrated that human liver microsomes carrying CYP3A4*22 metabolized sirolimus at a signicantly slower rate than non-carriers [82]. Recently, we reported a trend toward higher dose-adjusted sirolimus concentrations in CYP3A4*22 carriers than in wild-type individuals [83], but this was not observed in the study performed by Woillard et al. [82]. By contrast, the ABCB1 genotype does not seem to be of relevance for mTORi therapy (Table 2) but, as for

Table 2 Reported associations between recipient genotype and mammalian target of rapamycin inhibitor-based therapies Drug and gene SNP Effects Pharmacokinetics Sirolimus CYP3A4 CYP3A4*1B CYP3A4*22 CYP3A5 ABCB1 IL10 Everolimus CYP3A5 ABCB1 CYP2C8 CYP3A5*3 3435C[T (2677G[T/A, 1236C[T) CYP2C8*3 No effect No effect No effect Not assessed Not assessed Not assessed 0 (none) 1 (none) 0 (none) [3, 126] [126] [126] CYP3A5*3/*3 3435C[T (2677G[T/A, 1236C[T) rs1800896 : Clearance; no effect if concomitant CNI was used ; Clearance; no effect ; Clearance; no effect if concomitant CNI was used ; Clearance; no effect ; Clearance Not assessed Not assessed No effect on BPAR No effect on toxicity events Not assessed 2 (weak) 3 (weak) 4 (moderate) 3 (weak) 1 (none) [2, 7780] [82] [2, 7781] [77, 80, 81, 125] [125] Pharmacodynamics Estimated strength of association References

ABC ATP-binding cassette, BPAR biopsy-proven acute rejection, CNI calcineurin inhibitor, CYP cytochrome P450, IL interleukin, SNP single nucleotide polymorphism, : increased, ; decreased

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CNIs, assessment of the impact of ABCB1 SNPs on intralymphocytic concentrations and tissue distribution may be of greater relevance. 2.5 Mycophenolate Mofetil Several studies have highlighted the fact that the UGT1A9 -275T[A and -2152C[T gain-of-function (GOF) SNPs inuence exposure to MPA [8490], but their impact on MMF treatment efcacy is not convincing [87, 90] (Table 3). Data retrieved from different clinical studies suggest a decrease in MPA glucuronidation associated with the UGT1A9*3 allele, but its low allelic frequency precludes any denitive conclusions with regard to its clinical relevance. Despite its involvement in AcylMPAG production, UGT2B7 activity appears to be not relevant in explaining differential susceptibility to side effects [9193]. By contrast, the UGT1A8*2 allele is presumably associated with less adverse gastrointestinal events [92], but how this information should be implemented in clinical practice remains unclear. Unlike SLCO1B1, SLCO1B3 activity seems to be implicated in MPA entero-hepatic cycle but, despite strong in vitro arguments showing that the SLCO1B3 334G699A variant haplotype is associated with decreased MPAG cellular uptake [30], the impact in vivo is less clear [30, 9496] and needs to be elucidated. SNPs in IMPDH1 [9799], and less obviously in IMPDH2 [92, 97, 99, 100], seem to impact on the therapeutic response to MMF, but it is still too premature to discern if those observations may be of clinical relevance, because of some contradictions in the results that are probably due to a lack of homogeneous study designs. In a multicenter study, Jacobson et al. [101] tested the possible association between MMF-related anemia and leukopenia and 2724 SNPs in 978 renal transplant patients. SNPs in the IL12A and CYP2C8 genes were associated with an increased hazard for the time to anemia, and one SNP in HUS1 (rs2037483) was associated with a reduced hazard. An analysis performed in 338 MMFtreated kidney transplant patients failed to replicate the results observed for the HUS1 and IL12A SNPs but conrmed that the CYP2C8 rs11572076A allele constitutes a risk factor for anemia [102]. In addition, a signicant association between the CYP2C8 genotype and the incidence of leukopenia was found. We do feel that this observation deserves further validation in studies.

3 Expert Opinion and Clinical Applications An important factor that undermines the potential contribution of pharmacogenetics is that for most of the immunosuppressive agents, therapeutic drug monitoring (TDM)

is used to correct blood concentrations. Adequate concentrations of the drugs are achieved in most cases within 2 weeks after transplantation. The use of TDM limits the potential usefulness of genotype-based dosing in daily clinical practice, as TDM compensates for the betweenpatient variability caused by pharmacogenetic changes in pharmacokinetics. However, it is important to minimize the time needed to achieve target concentrations, which may still offer a chance for genotype-based dosing to improve clinical outcomes. Unlike the use of TDM with CNIs and mTORi, the use of TDM with MMF-based therapy is not generally accepted. However, it is difcult to establish how knowledge of the genotype may be conducive to better management of MMFbased therapy. Indeed, even if the clinician knows that, given his/her genotype, a patient might be more at risk of graft rejection or side effects, the true value of that kind of information still needs to be proven. The pharmacogenetics of mTORi is still in its infancy, but data reported up to now underline the potential utility of the CYP3A5*3 allele for sirolimus-based therapy. In view of the recent preliminary ndings, evaluation of the CYP3A4*22 allele warrants additional studies. For CNIs, we have highlighted the importance of local ABCB1 and CYP3A5 activities for drug tissue distribution and accumulation. Although it is still premature to base clinical decisions on these associations, recent data have suggested that knowledge of the (donor) genotype may assist in decision making. Potentially, it would become possible to identify patients at high risk of toxicity and consequently to prescribe a CNI-free regimen or to choose quick withdrawal of these agents from their treatment scheme. Other studies have suggested that ABCB1 SNPs might also be important for drug efcacy, as they have been correlated with the amount of drug reaching the therapeutic target, i.e., the lymphocyte. This important lead still needs validation. At present, the best candidate for implementing genotype-based dosing is the CNI tacrolimus. The potential usefulness of dosing based on the CYP3A5*3 genotype of the patient has already been tested [69]. Patients receiving a CYP3A5 genotype-based tacrolimus dosage reached target concentrations more rapidly and with fewer dose modications than the control group [69]. However, this did not translate into improved clinical outcomes. As has already been stressed previously [63], the study population consisted of patients at low immunologic risk of acute rejection, and the large majority of patients received induction therapy combined with high MMF doses. Therefore, the introduction of tacrolimus into the immunosuppressive regimen was delayed for 1 week, possibly explaining the lack of clinical benet of the genotype-adjusted dosage. Another factor that limits the contribution of genotype-based dosing

Table 3 Reported associations between recipient genotype and mycophenolate mofetil Effects Pharmacokinetics ; (Dose-adjusted) MPA concentrations; uctuating results if concomitant CNI was used 4 (moderate) : Dose-adjusted MPA concentrations; no effect No effect No effect ; Incidence of diarrhea 3 (weak) 4 (moderate) 4 (moderate) No effect ; Incidence of gastrointestinal side-effects; no effect 4 (moderate) 1 (none) ; Clearance : MPA concentrations; uctuating results if concomitant CNI was used No effect : MPA concentrations; : dose-adjusted AcylMPAG concentrations in CNI-free patients; no effect on MPA or AcylMPAG concentrations No effect : MPA exposure in ciclosporin A-free patients; ; MPA clearance; no effect No effect ; Dose-adjusted MPAG concentrations; no effect Not assessed Not assessed : Dose-adjusted MPA concentrations; ; MPA:MPAG ratio; no effect; no difference in MPAG concentrations ; Or : dose-adjusted MPA concentrations; no effect when concomitant ciclosporin A was used Not assessed Not assessed Not assessed Not assessed Not assessed Not assessed Not assessed Not assessed : Incidence of diarrhea; no effect on hematologic disorders; no effect on gastrointestinal disorders No effect : Risk of BPAR but not in ciclosporin Atreated patients; no effect [8490] Pharmacodynamics Estimated strength of association References

Gene

SNP

UGT1A9

-275T[A, 2152C[T

440C[T/-331T[C

[30, 84, 127] [8490] [30, 85, 88, 90, 128] [85, 88, 90] [21, 84, 88, 90, 98, 129]

UGT1A9*3

Pharmacogenetics in Kidney Transplantation

UGT1A8

UGT1A8*2

UGT1A8*3

UGT2B7

-842G[A/802T[C

-79[A

3 (weak) 2 (weak)

[90, 91] [30, 84, 90, 96, 129, 130] 1 (none) 2 (weak) 2 (weak) [30, 96] [30, 96] [30, 96]

ABCC2

-24C[T

SLCO1B1

SLCO1B1*1B

SLCO1B1*5

SLCO1B1*15

SLCO1B3

334T[G/699G[A

4 (moderate)

[30, 94, 96]

IL12A

rs568408

: Risk of anemia; no effect : Risk of anemia; : risk of leukopenia ; Risk of anemia; no effect ; Risk of BPAR; : risk of leukopenia ; Risk of BPAR; no effect No effect on BPAR; : risk of BPAR

2 (weak) 3 (weak) 2 (weak) 3 (weak) 2 (weak) 2 (weak)

[101, 102] [101, 102] [101, 102] [9799] [97, 99] [97, 100, 131, 132]

CYP2C8

rs11572076

HUS1

rs2037483

IMPDH1

rs2278293 rs2278294

IMPDH2

rs11706052

ABC ATP-binding cassette, AcylMPAG acylglucuronide, BPAR biopsy-proven acute rejection, CNI calcineurin inhibitor, CYP cytochrome P450, HUS1 HUS1 checkpoint homolog (S. pombe), IL interleukin, IMPDH IMP (inosine 50 -monophosphate) dehydrogenase, MPA mycophenolic acid, MPAG 7-O-MPA glucuronide, SLCO solute carrier organic anion transporter family, SNP single nucleotide polymorphism, UGT uridine 50 -diphosphate-glucuronosyltransferase, : increased, ; decreased 339

340 Table 4 Strength of association estimation index Feature considered for the genetic association quality assessment In vitro effect Category Well demonstrated Controversial No effect or not assessed Study characteristics At least one large-scale study ([1000 subjects) and/or a well-conducted prospective study Studies of moderate size (1001000 subjects) Studies of small size (\100 subjects) Replication Multiple replications (n C 3), existence of a well conducted meta-analysis with a clear conclusion and/or an effect demonstrated in multiple diverse populations (ethnicities, type of transplantation, adults, children, etc.) Limitations or moderate inconsistencies in studies No replication, major inconsistencies, no effect reported, scattered studies

L. Elens et al.

Associated scorea 2 1 0 2 1 0 2

1 0

a When the scores for the different features are added together, the total score is graded as follows: 01 = no association; 23 = weak association; 45 = moderate association; 6 = strong association

is the systematic application of TDM in the early phase after transplantation. Tacrolimus concentrations are monitored on a daily basis and followed by dosage adjustments. With this strategy, transplant clinicians are able to bring the majority of patients within the tacrolimus target concentration range, despite the large variability in pharmacokinetics. The main contribution of genotype-based dosing would therefore be the avoidance of inadequate tacrolimus exposure in the rst few days or the rst week post-transplantation. As demonstrated, this delay is longer for CYP3A5 expressers and puts those patients at risk of early acute rejection [103]. In order to get convincing evidence for implementation of CYP3A genotype-based tacrolimus dosing, studies comparable to the trial conducted by Thervet et al. [69] should be conducted in patients at intermediate or high risk of rejection, without induction therapy and with tacrolimus being started on the day of transplantation. We know of at least one such clinical trial which is currently ongoing (Hesselink DA, unpublished data). Additionally, recent data have suggested that an additional value can be credited to the knowledge of CYP3A4*22 allelic status, and possibly POR*28 allelic status, for renement of the starting dose in CYP3A5 non-expressers.

4 Conclusions Numerous studies have found clear correlations between SNPs in genes involved in the ADME of immunosuppressive drugs and their concentrations in plasma or whole blood. Nevertheless, implementation of such data in clinical practice is still scarce. An important reason is the fact that only a few studies have been sufciently large and/or well conducted to allow evaluation of clinical outcome with respect to genotype. Only one randomized trial has studied

the added value of genotype-based dosing and, although there was a signicant impact in achievement of target concentrations more efciently, the incidence of acute rejection was not modied [69]. Even if that original randomized clinical trial failed to demonstrate a clinical benet of CYP3A5 genotype-based tacrolimus dosage, the study provided a good landscape to conduct a more adequately designed trial that could eventually lead to more robust conclusions. Importantly, that trial considered only one variant for one immunosuppressive drug and hence does not exclude the possibility that an alternative immunosuppressive regimen, when considering other genetic variants, might benet from genotype consideration. Indeed, for tacrolimus, it seems likely that the use of genetic information on either the donor (i.e., CYP3A5*3 and ABCB1) or the recipient (i.e., CYP3A5*3 and possibly CYP3A4*22 and POR*28) will assist physicians in treating their patients accurately. The genotype of the recipient will help to optimize the denition of the tacrolimus starting dose, resulting in quicker achievement of target concentrations. The donor genotype may identify kidneys at increased risk of CNI nephrotoxicity, and this may lead to sequential immunosuppressive regimens. TDM limits the usefulness of pharmacogenetic information, as concentration-based dose adjustment corrects for the variability caused by SNPs in ADME enzymes. When TDM is not performed or when it can only be done occasionally (e.g., for measurement of tissue concentrations), pharmacogenetics may have a stronger impact on decision making.
Acknowledgments Laure Elens is a post-doctoral researcher with the Fonds de la Recherche Scientique, Belgium (FRS-FNRS). No sources of funding were used to prepare this article. The authors have no conicts of interest that are directly relevant to the content of the article.

Pharmacogenetics in Kidney Transplantation

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