Clinical Kidney Journal, 2018, 1–11 doi: 10.1093/ckj/sfy020 CKJ Review CK J R E V I E W Genetic susceptibility to delayed graft function following kidney transplantation: a systematic review of the literature 1,2 1,2 1,2 Justine Huart , Jean-Marie Krzesinski and Franc ¸ois Jouret Division of Nephrology, Department of Internal Medicine, University of Lie ` ge Hospital (ULg CHU), Lie ` ge, Belgium and Groupe Interdisciplinaire de Ge ´ noprote ´ omique Applique ´ e (GIGA), Cardiovascular Sciences, University of Lie ` ge, Lie ` ge, Belgium Correspondence and offprint requests to: Franc ¸ois Jouret; E-mail: email@example.com ABSTRACT Delayed graft function (DGF) is deﬁned as the need for dialysis within 7 days following kidney transplantation (KTx). DGF is associated with increased costs, higher risk for acute rejection and decreased long-term graft function. Renal ischaemia/reperfusion (I/R) injury plays a major role in DGF occurrence. Single nucleotide polymorphisms (SNPs) in certain genes may aggravate kidney susceptibility to I/R injury, thereby worsening post-transplant outcomes. The present article proposes an extensive review of the literature about the putative impact of donor or recipient SNPs on DGF occurrence in kidney transplant recipients (KTRs). Among 30 relevant PubMed reports, 16 articles identiﬁed an association between 18 SNPs and DGF. These polymorphisms concern 14 different well-known genes and one not-yet-identiﬁed gene located on chromosome 18. They have been categorized into ﬁve groups according to the role of the corresponding proteins in I/R cascade: (i) oxidative stress, (ii) telomere shortening, (iii) chemokines, (iv) T-cell homeostasis and (v) metabolism of anti- inﬂammatory molecules. The remaining 14 studies failed to demonstrate any association between the studied SNPs and the occurrence of DGF. A better understanding of the genetic susceptibility to renal I/R injury may help prevent DGF and improve clinical outcomes in KTRs. Keywords: delayed graft function, ischaemia/reperfusion, kidney transplantation, polymorphisms, renal allograft INTRODUCTION immunosuppressive regimen of induction and maintenance and Delayed graft function (DGF) is a manifestation of acute kidney dialysis vintage. Expanded criteria donors (ECDs) in KTx lead to injury related to kidney transplantation (KTx). It has been defined an increased risk for DGF . Still, the incidence of DGF in ECD re- as the requirement for dialysis within 7 days following KTx . cipients has progressively decreased over time from 35.2% in DGF causes increased risk for acute rejection (AR) and has been 2003 to 29.6% in 2011 in the USA, probably related to a better associated with poor long-term graft outcomes and additional understanding of the donor risk profile along with improved allo- costs . Various immunological and non-immunological factors graft selection . Cardiac death donors have also shown a higher have been linked to DGF, including donor age, Human Leucocyte rate of DGF . Indeed, renal ischaemia/reperfusion (I/R) injury Antigen (HLA) compatibility, cold and warm ischaemia time, plays a critical role in DGF. I/R injury occurs when the blood Received: 28.11.2017. Editorial decision: 12.2.2018 V C The Author(s) 2018. Published by Oxford University Press on behalf of ERA-EDTA. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/ licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact firstname.lastname@example.org Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy020/4959286 by Ed 'DeepDyve' Gillespie user on 12 July 2018 2| J. Huart et al. supply to an organ is transiently disrupted and subsequently anti-inflammatory molecules. The remaining 14 studies failed restored . KTx necessarily conveys renal I/R, which prompts ac- to demonstrate any association between the studied poly- tive preclinical and clinical research focusing on the prevention morphisms and the occurrence of DGF. These data are summar- and/or attenuation of graft damage [6–9]. ized in Table 2. Besides the role of extrarenal factors in DGF, one may specu- late that intrarenal characteristics may predispose the kidney Oxidative stress allograft to injury. Global gene expression profiling captures such a complex process, thereby highlighting the putative im- GSTM1, GSTM3, GSTT1, GSTP1 and MnSOD polymorphisms. plications of particular genes and metabolic cascades in renal Glutathione S-transferases (GSTs) and manganese superoxide I/R injury and DGF [8, 10, 11]. DGF-associated genes are impli- dismutase (MnSOD) contribute to protection against xenobiotic cated in pathways of oxidative stress, vasospasm, cytokine sig- compounds, including immunosuppressive drugs in kidney nalling, endothelial and epithelial cell injury, as well as innate transplant recipients (KTRs). GSTs and MnSOD are also involved and adaptive immunity. Some of these genes harbour single nu- in antioxidative reactions and in the regulation of apoptosis cleotide polymorphisms (SNPs). By definition, SNPs correspond through direct protein–protein interactions. At the time of kid- to the variation of only one base pair in one given gene, which ney reperfusion, GSTs and MnSOD are rapidly induced to scav- may cause significant changes in the expression and/or activity enge reactive oxygen species (ROS) and prevent ROS-associated of the corresponding protein. By extension, polymorphisms cor- damage [13, 14]. St. Peter et al. genotyped 229 British KTRs respond to the coexistence of several distinct alleles in one with 24 h of cold ischaemia and 104 of their respective donors. given gene in a population. The haplotype is the combination of They focused on the polymorphisms of three classes of GSTs SNPs at multiple linked loci that are usually transmitted as a and MnSOD: GSTM1*A, GSTM1*B, GSTT1*1, GSTP1*A, GSTP1*B, group from parent to child. GSTP1*C, GSTP1*D, MnSOD aa14Ala and MnSOD aa14Val. In kid- In 2008, Kru ¨ ger et al. summarized the literature about ney donors, the presence of homozygous GSTM1*B or heterozy- genetic polymorphisms and the fate of the transplanted organ, gous GSTM1*B with GSTM1 null or GSTM1*A was associated with including the impact of both immunological and non- a lower risk for DGF. In KTRs, no association was found between immunological cascades on graft survival, AR and the occur- any enzyme polymorphism and DGF occurrence . Singh et al. rence of chronic allograft nephropathy. Our present review  enrolled 223 controls and 273 North Indian KTRs to study focuses on DGF and aims to systematically detail the published the impact of polymorphisms in three GST isoenzyme genes reports about potential associations between polymorphisms in (GSTM1, GSTM3, GSTT1 and GSTP1) on early graft function. The kidney donors and recipients and the occurrence of DGF. authors observed that recipients with the rs1695 genotype GG of GSTP1 were at higher risk of DGF . MATERIALS AND METHODS rs1001179 (-262 C/T) polymorphism in the CATALASE gene. We systematically searched PubMed for articles published from Catalase is an intracellular antioxidant enzyme effective in pro- the database’s inception date to May 2017 using the following tecting cells from hydrogen peroxide . Catalase is crucial in keywords: ‘delayed graft function’ or ‘DGF’ or ‘ischaemia- attenuating graft I/R injuries in the immediate phase after KTx reperfusion’ and ‘kidney’ or ‘renal’ and ‘allograft’ or ‘transplant- [42, 15]. Dutkiewicz et al. studied the impact of the -262 C/T ation’ and ‘polymorphisms’ or ‘SNP’. Furthermore, we reviewed (rs1001179) polymorphism in CATALASE on renal function out- the papers referenced in the ‘PubMed-related’ articles to iden- comes in 187 Polish KTRs. The T allele was associated with a tify additional candidate studies for which full-text English-lan- reduced risk of DGF, with increased blood levels of catalase guage articles were available. Bibliographic references of both found in the -262 T patients . original investigations and review articles were then scruti- nized. We included studies with the following quality criteria: NADPH oxidase p22(phox) C242T polymorphism. p22(phox) is a (i) 50 patients (kidney recipients, donors or both), (ii) well- polymorphic subunit of NAD(P)H oxidase that plays a critical defined evaluation of DGF occurrence and outcomes and (iii) role in its activation and stabilization. NAD(P)H oxidase is polymorphisms in molecules involved in I/R-related processes. involved in the production of superoxide that triggers the in- The articles that did not reach these criteria were excluded. flammation in ischaemic kidneys [43, 16]. Mandegary et al. Careful attention was given to the genetic background of enrolled 196 Iranian donor–recipient pairs to investigate the as- studied populations. sociation between donors’ and recipients’ NADPH oxidase p22(phox) C242T polymorphism and AR, DGF and blood pressure levels in KTRs. Recipient’s p22(phox) 242 T allele (CT þ TT) was RESULTS found to be a major risk factor for DGF, most probably via the We found 45 relevant articles in the PubMed database using the overproduction of superoxide at the time of I/R . above-defined keywords. Four of these were excluded because the studied polymorphisms concerned genes coding for pro- Telomere shortening teins involved in pharmacodynamics and pharmacokinetics of immunosuppressive drugs. Eleven articles were excluded be- A significant shortening in telomere length has been reported cause they did not strictly focus on DGF. Among the remaining in ischaemic kidneys, which suggests I/R-accelerated tissue 30 articles, 16 found an association between 18 polymorphisms senescence . Shorter telomeres have also been associated and DGF (Table 1). These polymorphisms were present in 11 dif- with a lower immune response . Polymorphisms in hTERT, ferent well-known genes and in one not-yet-identified gene BICD1 and chromosome 18 interfere with telomere shortening. located on chromosome 18. We categorized them into five Kłoda et al. studied rs2735940 hTERT, rs2630578 BICD1 and groups according to the role of the corresponding proteins in rs7235755 in chromosome 18 polymorphisms in 119 Polish kid- I/R cascade: (i) oxidative stress, (ii) telomere shortening, (iii) ney allografts  and corresponding recipients  as well as chemokines, (iv) T-cell homeostasis and (v) metabolism of in an independent cohort of Polish recipient–donor pairs . Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy020/4959286 by Ed 'DeepDyve' Gillespie user on 12 July 2018 SNPs and DGF | 3 Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy020/4959286 by Ed 'DeepDyve' Gillespie user on 12 July 2018 Table 1. Polymorphisms associated with DGF Polymorphism Gene Role of the molecule n donors versus recipients Nationality Outcome in DGF Reference Cascade of the oxidative stress GSTM1*B GSTM1 Anti-oxidative stress 229 recipients and 104 re- British Lower risk of DGF in donors  Anti-apoptotic spective donors rs1695genotype GG GSTP1 Anti-oxidative stress 223 controls and 273 North Indian Higher risk of DGF  Anti-apoptotic recipients Decrease toxicity of immunosuppressant rs1001179(-262C/T) Catalase Anti-oxidative stress 187 recipients Polish Lower risk of DGF with T allele  -262T increases blood level of catalase 242T allele NADPH Anti-oxidative stress 196 donor–recipient pair Iranian Higher risk of DGF in recipients  oxidase p22(phox) Telomere shortening rs2735940 hTERT Telomere length: I/R and immunity 119 kidney allografts Polish Lower risk of DGF  Polymorphism limits telomere shortening rs7235755 Unknown Telomere length: I/R and immunity 119 recipients Polish Higher risk of DGF  (chr 18) rs2735940 hTERT Telomere length: I/R and immunity 74 donor–recipient pairs Polish Higher risk of DGF in recipients  Polymorphism limits telomere Lower risk of DGF in donors shortening Chemokines Genotype 1/2 (410/240) in intron 2 IL-1Ra Inhibitor of IL-1 (inﬂammation and 136 controls and recipients Indian Higher risk of DGF  immunity) Genotype 1/2 leads to lower levels of IL-1Ra -308G>A TNF-a Pro-apoptosis 100 recipient–donor pairs Iranian Higher risk of DGF with A allele in  donors and lower risk with GG genotype in donors -1082G>A IL-10 Downregulation of inﬂammatory 100 recipient–donor pairs Iranian Higher risk of DGF with A allele when  responses associated with A allele in TNF-a -308G>A in donors rs3732379 CC genotype CX3CR1 Cell migration 270 recipients Caucasian Higher risk of DGF  T-cell homeostasis rs231775 (þ49A>G) CTLA4 Downregulation of T cell activation 269 renal transplant Caucasian Higher risk of DGF with G allele  rs231775 (þ49A>G), recipients Indian Higher risk of DGF with G allele rs3087243 350 controls and 190 Lower risk of DGF with A allele and recipients Higher risk of DGF with 110-bp and 3 -UTR dinucleotide AT repeat 116-bp alleles Lower risk of DGF with 102-bp allele (continued) 4| J. Huart et al. In their first publication in 2015, the authors showed that graft rs2735940 hTERT polymorphism was associated with a lower risk of DGF. rs2630578 BICD1 and rs7235755 chromosome 18 polymorphisms in the graft were associated with higher serum creatinine concentrations in the early period following KTx but not with DGF. These results suggest a negative correlation be- tween the length of telomeres and I/R injury severity . In 2016, the same authors reported that the presence of chromo- some 18 rs7235755 polymorphism in recipients was associated with higher risk for DGF. Polymorphism in BICD1 in recipients was also associated with higher serum creatinine concentra- tions in long-term follow-up after KTx. Polymorphisms in hTERT were not associated with kidney allograft outcomes . In 2017, Kłoda et al. studied 74 Polish deceased donor and re- cipient pairs. Both donors’ and recipients’ rs2735940 hTERT TT genotypes were associated with DGF but not with AR. The rs2735940 hTERT TT donor genotype decreases the risk for DGF, while the rs2735940 hTERT TT recipient genotype increases the risk for DGF. DGF occurrence was five times higher for a CX (CT or CC) donor genotype and TT recipient genotype. rs2630578 BICD1 and rs7235755 chromosome 18 polymorphisms in recipi- ents or donors were not associated with either DGF or AR . The limitation of telomere shortening in donors, as observed in the case of rs2735940 hTERT polymorphism, is thus regarded as protective against renal I/R injury. Chemokines Regulation of the interleukin-1 pathway: interleukin receptor antagonist intron 2 polymorphism. The interleukin (IL)-1 path- way is unique in having a natural inhibitor known as the IL-1 re- ceptor antagonist (IL-1Ra). Manchanda et al.studied 136 Indian KTRs from a related living donor and focused on three polymorphisms in the IL-1 gene cluster: IL-1b promoter region 511, IL-1b exon-5 and IL-1Ra in intron 2. Five alleles of the IL-1Ra have been reported, corresponding to 2, 3, 4, 5 and 6 copies of an 86-base pair repeat located in intron 2. Genotype 1/2 (410/240) of IL-1Ra was associated with a higher risk of DGF in this cohort. A homozygous state of allele 2 is a greater producer of IL-1Ra than the heterozygous or wild-type homozygous states. Therefore genotype 1/2 of IL-1Ra may be considered as a ‘low producer’ of IL-1Ra, which in turn cannot counteract the pro-inflammatory re- sponse of IL-1 at the time of renal I/R injury . Apoptosis and inflammation: tumour necrosis factor-a -308 G > A and IL-10 -1082 G > A polymorphisms. Tumour necrosis factor-a (TNF-a) and IL-10 play a crucial role in the pathogenesis of renal I/R injury. Activated macrophages secrete TNF-a, which binds to TNF receptors on cells, leading them to apoptosis. IL-10 appears to limit and control inflammation . Deletion of the IL-10 gene accelerates kidney graft AR in mice . Mandegary et al.  enrolled a prospective single-centre cohort of 100 Iranian consecutive kidney recipient–donor pairs. Significant associ- ations were found between donors’ TNF-a polymorphism - 308 G> A and the occurrence of DGF, as well as between the combination of donors’ IL10 AA or GA and TNF-a AA or GA geno- types and DGF . McDaniel et al. studied cytokine poly- morphisms in 77 African American allograft recipients and 77 controls. TNF-a polymorphism in recipients was not associated with either DGF nor AR . Finally, Israni et al. recruited 965 recipients of deceased donor kidneys from 512 donors. Recipient’s ethnicities included African American, White, Asian and Native American. Donor’s ethnicities were African American and White. Donor’s TNF-a polymorphism was not Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy020/4959286 by Ed 'DeepDyve' Gillespie user on 12 July 2018 Table 1. Continued Polymorphism Gene Role of the molecule n donors versus recipients Nationality Outcome in DGF Reference Regulation of the immune responses F412L (rs3775291) TLR3 Pro-inﬂammation 265 recipients German Higher risk of DGF  Metabolization of anti-inﬂammatory molecules rs10509681 (CYP2C8*3) CYP2C8 Biosynthesis of ETTs, which are pro- 166 recipients Caucasian Higher risk of DGF  tective against I/R injuries CYP2C8*3 leads to lower levels of EETs Complement activation rs7851696 Ficolin-2 Activator of the complement system 270 recipients Caucasian Higher risk of DGF with T allele  via the lectin pathway NO pathway intron 4 VNTR eNOS3 Recovery of blood ﬂow after ischaemia 187 recipients Polish Higher risk of DGF with a allele  may reduce oxidative stress SNPs and DGF | 5 Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy020/4959286 by Ed 'DeepDyve' Gillespie user on 12 July 2018 Table 2. Polymorphisms non associated with DGF Polymorphism Gene Role of the molecule n donors versus recipients Nationality Reference Cascade of the oxidative stress GSTM1*A, GSTM1 Anti-oxydative stress 229 recipients and 104 re- British  GSTM1*B and GSTM1null phenotype GSTT1 Anti-apoptotic spective donors GSTM1null þ GSTT1null phenotype GSTP1 GSTT1*1 MnSOD GSTP1*A, GSTP1*B, GSTP1*C and GSTP1*D MnSOD aa14Ala and MnSOD aa14Val 239þ 34A/C 47C/T SOD1 Anti-oxidative stress 187 recipients Polish  SOD2 Telomere shortening rs2735940 hTERT Telomere length: I/R and 119 recipients Polish  immunity rs2630578 BICD1 Telomere length: I/R and 74 donor–recipient pairs Polish  immunity rs7235755 Unknown (chr 18) Telomere length: I/R and 74 donor–recipient pairs Polish  immunity Chemokines -308G>A TNF-a Inﬂammation 77 controls and recipients African American  rs1800629 and rs3093662 Pro-apoptosis 965 recipients and Recipients: African  -308G>A 512 donors American, White, Asian  100 recipient–donor pairs and Native American. Donors: African American and White Iranian -1082G>A, -819C>T and -592C>A IL-10 Downregulation of inﬂam- 77 controls and recipients African American  rs3024498 and rs2222202 matory responses 965 recipients and Recipients: African  -1082G>A Anti-apoptosis 512 donors American, White, Asian  100 recipient–donor pairs and Native American. Donors: African American and White Iranian -330 (T>G) IL-2 Immunity and 77 controls and recipients African American  inﬂammation þ869 T>C and þ915 G>C TGF-b1 Inﬂammation and 77 controls and recipients African American  rs1800472 and rs1982073 apoptosis 965 recipients and Recipients: African  512 donors American, White, Asian and Native American. Donors: African American and White (continued) 6| J. Huart et al. Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy020/4959286 by Ed 'DeepDyve' Gillespie user on 12 July 2018 Table 2. Continued Polymorphism Gene Role of the molecule n donors versus recipients Nationality Reference -174, a (C>G) IL-6 Pro-inﬂammation and 77 controls and recipients African American  apoptosis þ874 (CA) IFN-c Pro-inﬂammation and 77 controls and recipients African American  apoptosis FyB null genotype or FyB null alleles and DARC DARC binds to chemokines 222 recipients African American  polymorphism at position 535 and reduces their level. Limitation of systemic inﬂammation -511 (promoter region) and exon-5 IL-1b Pro-inﬂammation 136 controls and recipients Indian  IL12B 3 UTR IL-12p40 Stimulating IFN-c 253 recipients Caucasian  production CCR2-V64I CCR2 Receptors of chemokines, 100 donor–recipient pairs Iranian  CCR5-Delta32 CCR5 which play a role in inﬁl- tration and activation of macrophages rs6822844 IL2-IL21 cluster Regulation of T cells and NK 270 recipients Caucasian  cell functions 1188A>C IL-12B Pro-inﬂammation 267 recipients Caucasian  -295T>C IL-16 607C>A and 137G>C IL-18 Apoptosis rs 1042522 TP53 Pro-apoptosis 965 recipients and Recipients: African  512 donors American, White, Asian and Native American. Donors: African American and White (GT) repeat HMOX1 Anti-apoptosis 965 recipients and Recipients: African  512 donors American, White, Asian and Native American. Donors: African American and White Regulation of the innate and adaptive immune responses rs2476601 PTPN22 Negative regulation of T- 269 recipients Caucasian  cell reaction, negative regulatory kinase Csk and other signalling molecules rs5742909 CTLA4 Downregulation of T cells 350 controls and 190 Caucasian  rs11571317, activation recipients rs16840252 rs4553808, rs3087243 (continued) SNPs and DGF | 7 Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy020/4959286 by Ed 'DeepDyve' Gillespie user on 12 July 2018 Table 2. Continued Polymorphism Gene Role of the molecule n donors versus recipients Nationality Reference rs7574865 STAT4 Regulation of natural killer 270 recipients Polish  cells, CD8 T cells and Th1 function Differentiation of B cells and regulatory T cells Regulation of the innate immune responses R753Q (rs5743708) and R677W (del -196/-174) TLR2 Pro-inﬂammation 265 recipients German  T737S (rs5743318) TLR3 D299G (rs4986790) and T399I (rs4986791) TLR4 392STOP (rs5744168) TLR5 P545P (rs352140) and -1237T/C (rs5743836) TLR9 -159C/T (rs2569190) CD14 rs5498 ICAM1 Adhesion and transmigra- 270 recipients Caucasian  rs1041163 and rs3170794 VCAM1 tion of leucocytes Metabolization of anti-inﬂammatory molecules rs890293 (CYP2J2*7) CYP2J2 Biosynthesis of EETs, which 166 recipients Caucasian  are protective against I/R injury Complement rs11003125, rs7096206, rs7095891, MBL2 Immunity and 1271 donor–recipient pairs Netherlands  rs5030737, rs1800450 and MASP2 inﬂammation  rs1800451 rs72550870 C3F Complement C3 Immunity and 1265 donor–recipient pairs Netherlands  inﬂammation rs17549193 and rs4521835 FCN2 Immunity and 270 recipients Caucasian  rs3124952, rs3124953, rs17514136, inﬂammation 1271 donor–recipient pairs Netherlands  rs17549193 and rs7851696 NO pathway G894T substitution within exon 7 eNOS Recovery of blood ﬂow after 187 recipients Polish  ischaemia May reduce oxidative stress rs10918594 NOS1AP No pathway 75 recipients Polish  8| J. Huart et al. statistically associated with DGF, although a positive trend was T allele is known to be associated with increased affinity of observed . lectin-2 for carbohydrate structures presented by different pathogens . Dabrowska-Zamojcin et al. enrolled 270 Caucasian deceased-donor KTRs to evaluate the impact of Cell migration: CX3CR1 V249I polymorphism. Fractalkine, also FCN-2 gene rs7851696, rs17549193 and rs4521835 polymorph- known as CX3CL1, is a member of the chemokine family that isms in DGF, as well as in AR and chronic allograft dysfunction. acts as an adhesion molecule and as an extracellular chemo- The results showed an increased risk for DGF and AR in case of attractant promoting cell migration . Dabrowska-Zamojcin FCN-2 rs7851696 T allele, although these statistical associations et al. enrolled 270 Caucasian KTRs to study the impact of were not significant after Bonferroni correction . polymorphism V249I (rs3732379) in the Fractalkine receptor gene, Finally, nitric oxide (NO) plays a critical role in vascular tone CX3CR1. This polymorphism has been associated with a reduced and host defence [40, 28]. There are two distinct forms of NO number of CX3CL1 binding sites, reduced cell adhesion and synthases (NOSs): constitutive endothelial NOS (eNOS) and in- decreased signalling and chemotaxis. The rs3732379 CC genotype ducible NOS (iNOS). eNOS helps in tissue reperfusion and recov- in KTRs was associated with an increased risk for DGF . ery after ischaemia and may reduce oxidative stress . Dutkiewicz et al. enrolled 187 polish KTRs to study the im- T-cell homeostasis (CTLA-4 pathway) pact of polymorphisms of the eNOS gene (G894T substitution within exon 7 and intron 4 VNTR) on DGF, AR and chronic rejec- Cytotoxic T-lymphocyte antigen 4 (CTLA-4) is expressed at the tion and found an association between the a allele of the eNOS surface of activated CD8 and CD4 T cells. It plays an inhibitory intron 4 VNTR polymorphism and a higher risk for DGF . role in inflammation and helps maintain peripheral tolerance by suppressing T-cell proliferation and by inducting apoptosis of activated T-cells . Domanski et al. enrolled 269 Caucasian KTRs to study the impact of rs231775 (þ49 A> G) DISCUSSION polymorphism in CTLA4 and found an association with the G al- Among 30 studies in the literature, 16 reports suggest an associ- lele in rs231775 and a higher risk of DGF . Similarly, Misra et ation between polymorphisms and the occurrence of DGF al. enrolled 350 Indian patients with end-stage renal disease (Table 1), whereas 14 papers failed to find any relationship (ESRD) and 350 controls. Among the 350 ESRD patients, 190 (Table 2). As discussed below, it is interesting to note that genes underwent KTx. The CTLA-4 variants rs231775, rs3087243 and implicated in similar I/R-related pathways may or may not be 3 -UTR dinucleotide AT repeats in recipients were involved in involved in genetic susceptibility to DGF. Hence several genes genetic susceptibility to DGF. The A allele in both rs231775 connected to oxidative stress have been studied. I/R-related (þ49 A> G) and rs3087243 was considered as protective against ROS cause deleterious effects on kidney allografts by triggering DGF, while the G allele was associated with a higher risk of DGF. inflammatory injuries [13, 14]. High-producer polymorphisms in Concerning 3 -UTR dinucleotide AT repeats, the 102-bp allele genes coding for antioxidant proteins have been associated was protective against DGF, while 110-bp and 116-bp alleles with a lower risk of DGF, such as the presence of the -262 T allele increased the risk for DGF . in the KTR CATALASE gene  or the presence of the B allele in GSTM1 (GSTM1*B) in kidney donors . In contrast, low- Regulation of the immune response producer polymorphisms have been shown to be deleterious in The toll-like receptor (TLR) system is key in the innate immune I/R injury, including rs1695 genotype GG in GSTP1 in KTRs . system and participates in both acute and chronic allograft dys- Furthermore, high-producer polymorphisms in genes coding for function [25, 49]. Loss-of-function mutations of TLR4 in donors pro-oxidant proteins have been associated with a higher risk of have been associated with improved immediate kidney allograft DGF, like NADPH oxidase p22(phox) 242 T allele (CT þ TT) in KTRs outcomes . Therefore, Kru ¨ ger et al. hypothesized that . Still, other reports focusing on the oxidative cascade failed genetic variations in the TLR system may affect clinical out- to link gene polymorphisms and DGF. As an example, come after KTx, including DGF. They enrolled 265 German KTRs 239þ 34 A/C and 47 C/T polymorphisms in the SOD1 and SOD2 to evaluate the impact of selected polymorphisms in the TLR2, genes were not associated with DGF development (Table 2). TLR3, TLR4, TLR5, TLR9 and CD14 genes. The study showed that Superoxide dismutases (SODs) are regarded as the most import- the TLR3 F412L polymorphism had a significantly higher rate of ant enzymes against ROS, particularly against superoxide anion DGF in a univariate analysis but was not statistically significant radicals. after adjusting for known risk factors of DGF. Every other poly- Kidney aging may be notably reflected by telomere length morphism tested had no significant association with DGF . [17, 19, 55], and in the case of KTx, assessment of telomere Epoxieicosatrienoic acids (EETs) are vasodilatory factors with length in the early post-transplant period allows prediction of anti-inflammatory properties. They may play a protective role allograft long-term outcomes . In case of renal graft I/R, a against I/R-related damage [51, 52]. Several cytochrome P450 significant decrease in telomere length has been reported, thus (CYP450) isoforms mediate the biosynthesis of EETs . In suggesting accelerated kidney senescence [17, 44]. Conversely, humans, CYP2J2 and CYP2C8 are the most important isoforms. limitation of telomere shortening in recipients may favour the CYP2J2*7 (rs890293) and CYP2C8*3 (rs10509681) are the most com- deleterious immune response . Hence polymorphisms mon variants affecting enzymatic activity in Caucasians . rs2735940 hTERT (leading to limited telomere shortening) in Gervasini et al. studied these polymorphisms in 166 consecu- donors was associated with a lower risk for DGF [17, 19]. tive Caucasian adult KTRs. CYP2C8*3, which caused decreased However, this very same genotype in recipients was associated enzymatic activity and lower production of EETs, was associated with increased risk for DGF, most probably due to an amplified with a higher incidence of DGF in this cohort . immune trigger . Such a condition exemplifies the import- Ficolin (FCN)-2 is an activator of the complement system via ance of distinguishing the donor from the recipient genotype at the lectin pathway. Complement activation plays a substantial the time of studying genetic susceptibility to renal I/R. role in I/R injury at the time of KTx [27, 39]. The FCN-2 rs7851696 Polymorphisms involved in I/R severity may be particularly Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy020/4959286 by Ed 'DeepDyve' Gillespie user on 12 July 2018 SNPs and DGF | 9 relevant in donors, whereas polymorphisms implicated in AR The pathophysiology of DGF is complex and multifactorial, and inflammation may rather concern the recipients. including immunological and non-immunological factors [8, 7]. Renal I/R triggers inflammation, which in turn favours cyto- Furthermore, there might be additive actions of both I/R and AR kine/chemokine secretion [22, 21, 31]. TNF-a is a pro-apoptotic in the immediate post-transplant period, which may synergistic- cytokine. High-producer polymorphism of the TNF-a gene (i.e. ally predispose to DGF. The actual role of genetic susceptibility to donor’s AA or GA at -308 G> A) appears to be deleterious and renal I/R may thus be difficult to appropriately ‘quantify’ . associated with a higher risk for DGF . Similarly, the combin- Genome-wide association studies (GWASs) are currently on- ations of donors’ IL10 AA or GA and TNF-a AA or GA genotypes going to test additional genes and SNPs in the particular settings were linked to DGF development, whereas TNF-a polymorph- of DGF. Confirmatory clinical trials are also required in validation isms in recipients were not associated with DGF [21, 30, 31]. In cohorts. As an example, two SNPs (rs3811321 and rs6565887 on contrast, low-producer polymorphism of the TNF-a gene chromosomes 14 and 18, respectively) have been initially identi- (donor’s GG at -308 G> A) has been associated with a lower risk fied by GWASs in 300 KTRs as predictive of serum creatinine lev- for DGF . However, this association between the donor’s els and hard clinical outcomes. However, Pihlstrøm et al. TNF-a gene polymorphisms and the occurrence of DGF failed to failed to confirm such an association between these two poly- be confirmed in a large cohort including 512 African American morphisms and post-transplant outcomes in 1638 recipients. and White donors . Besides TNF-a, other cytokines have Indeed, conflicting data may result from the number of recruited been genetically studied in DGF susceptibility, including IL-2 patients and from their ethnicity. Polymorphisms in the TNF-a [35, 30], IL-12 , transforming growth factor-b [31, 30, 21] and gene in 100 Iranian donors were associated with DGF occurrence IL-16 and IL-18 . None of these studies found an association  but failed to be confirmed in a large cohort including 512 with DGF susceptibility (Table 2). Conversely, polymorphisms of African American and White donors . genes coding for cytokine receptors may enhance their re- African American recipients have shown a higher risk of sponse to stimulation. Hence the CC genotype of rs3732379 DGF [60, 61]. Black ethnicity in recipients is a risk factor for DGF polymorphism (V249I) of CX3CR1 in recipients has been associ- , which is part of the nomogram established by Irish et al. ated with an increased risk for DGF. CX3CR1 is the receptor of  for predicting the likelihood of DGF. Nevertheless, CX3CL1, which is a chemokine acting as an adhesion molecule Palanisamy et al. showed that cardiovascular risk factors and as an extracellular chemoattractant promoting cell migra- contribute to disparities in graft outcomes in African American tion. V249I polymorphism causes changes in the number of KTRs. Furthermore, after correcting for cardiovascular risk fac- CX3CL1 binding sites, thereby favouring cell adhesion, signal- tors, race per se did not show an independent effect on graft out- ling and chemotaxis . Similarly, inflammation modulators comes . like CTLA-4, ETT and TLR may also attenuate or aggravate I/R In conclusion, several polymorphisms in either the donor or injury. High-producer polymorphisms of CTLA-4 [A allele in re- the recipient or both have been associated with DGF in KTRs. cipients’ rs231775 (þ49 A> G) and rs3087243, as well as the 102- These polymorphisms are involved in oxidative stress, telomere bp allele in 3 -UTR dinucleotide AT repeats] may prevent DGF. length, cytokine secretion and modulation, immunity and in- CTLA-4 is expressed on activated CD8 and CD4 T-cells and helps flammation. These processes are involved in I/R injury, which is maintain homeostasis by downregulating T-cells . In con- regarded as one of the most important causes of DGF. trast, since EETs possess vasodilatory and anti-inflammatory Identifying the polymorphisms linked to renal I/R may allow us properties , low-producer polymorphisms in the CYP2C8 to better understand its pathophysiology and find new thera- gene in recipients may increase the risk for post-transplant peutic targets. DGF. The TLRs have a pivotal role in the innate immune system The present review highlights the state of knowledge in the and possess pro-inflammatory properties. The TLR3 F412L poly- field of genetic susceptibility to renal I/R. Although SNPs may morphism has been associated with a higher risk of DGF , so only have minor impacts per se on gene expression and protein this polymorphism likely attenuates the function of TLR3. function, interactions among multiple SNPs may have a major Focusing on the complement cascade at the time of renal impact on molecular cascades . Additionally, some SNPs I/R, Michielsen et al. recently summarized the impact of show very low frequency . Validation studies are lacking or complement polymorphisms on kidney graft outcomes without inadequately powered for most SNPs studied thus far , detailing their influence on DGF occurrence. Dabrowska- which may explain the controversial observations [21, 31]. Zamojcin et al. more recently reported an association be- Replication studies will need to include multivariate analyses to tween the FCN-2 rs7851696 T allele and a higher risk of DGF—al- isolate the putative effects of SNPs among other well- though this association was significant only without correction established risk factors of DGF. Most importantly, one must for multiple comparisons. The complement system, as part of clearly distinguish the impact of SNPs in donors versus in re- the innate immune system, is involved in protection against cipients versus in both. Polymorphisms involved in I/R severity foreign organisms and the clearance of apoptotic cells. may be particularly relevant in donors, whereas polymorphisms However, complement cascade may also aggravate I/R injury implicated in AR and inflammation may rather concern recipi- via antibody binding, which eventually leads to poor outcomes ents . Therefore, prospective multicentric studies including after KTx. In particular, a crucial role is suspected for mannose patients of various genetic backgrounds are required to clinic- binding lectin (MBL) in the early pathophysiology of renal I/R ally determine the benefits (and harms) of genotyping donors . Nevertheless, there was no significant difference in the in- and recipients before KTx [59, 12]. cidence of DGF in recipients with low MBL levels (400 ng/mL) compared to those with high MBL levels . C3 is the central ACKNOWLEDGEMENTS component of complement cascade and can be activated by The authors cordially thank the surgeons (M. Meurisse, C. all three complement pathways. In mice, the absence of local renal C3 in donor kidney significantly improves early Coimbra Marques, O.Detry,E.Hamoir, P. Honore ´ , L. Kohnen, N. post-reperfusion injury . In humans, the C3F allotype in both Meurisse and J-P Squifﬂet), the physicians (A. Bouquegneau, S. donors and recipients was not associated with DGF . Grosch,P. Vanderweckene,L. Vanovermeire and P. Xhignesse) Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy020/4959286 by Ed 'DeepDyve' Gillespie user on 12 July 2018 10 | J. Huart et al. 12. Kru ¨ ger B, Schro ¨ ppel B, Murphy BT. Genetic polymorphisms and the members of the local transplant coordination centre and the fate of the transplanted organ. Transplant Rev 2008; (Mme M.-H. Delbouille, M.-H. Hans, J. Mornard) for their commit- 22: 131–140 ment to kidney transplantation at the University of Lie `ge 13. St. Peter SD, Imber CJ, Jones DC et al. Genetic determinants of Hospital, Lie ` ge, Belgium. [32, 34, 37, 38]. delayed graft function after kidney transplantation. Transplantation 2002; 74: 809–813 14. Singh R, Manchanda PK, Kesarwani P et al. Inﬂuence of gen- FUNDING etic polymorphisms in GSTM1, GSTM3, GSTT1 and GSTP1 on allograft outcome in renal transplant recipients. Clin J.H. and F.J. are Fellows of the Fonds National de la Transplant 2009; 23: 490–498 Recherche Scientiﬁque (FNRS) and received support from 15. Dutkiewicz G, Domanski L, BINCZAK-KULETA A et al. The as- the University of Lie ` ge (Fonds Spe ´ ciaux a ` la Recherche, sociation of -262C/T polymorphism in the catalase gene and Fonds Le ´ on Fredericq) and the FNRS (Research Credit 2016). delayed graft function of kidney allografts. Nephrology (Carlton) 2010; 15: 587–591 16. Mandegary A, Rahmanian-Koshkaki S, Mohammadifar MA AUTHORS’ CONTRIBUTIONS et al. Investigation of association between donors’ and re- cipients’ NADPH oxidase p22(phox) C242T polymorphism J.H. performed the original research of the literature and and acute rejection, delayed graft function and blood pres- wrote the article. J.-M.K. wrote the article. F.J. supervised the sure in renal allograft recipients. Transpl Immunol 2015; 32: original research of the literature and wrote the article. 46–50 17. 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Clinical Kidney Journal – Oxford University Press
Published: Apr 3, 2018
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