==== Front Clin Kidney JClin Kidney JckjClinical Kidney Journal2048-85052048-8513Oxford University Press 3009063010.1093/ckj/sfy020sfy020TransplantationGenetic susceptibility to delayed graft function following kidney transplantation: a systematic review of the literature Huart Justine 12Krzesinski Jean-Marie 12Jouret François 121 Division of Nephrology, Department of Internal Medicine, University of Liège Hospital (ULg CHU), Liège, Belgium2 Groupe Interdisciplinaire de Génoprotéomique Appliquée (GIGA), Cardiovascular Sciences, University of Liège, Liège, BelgiumCorrespondence and offprint requests to: François Jouret; E-mail: francois.jouret@ulg.ac.be8 2018 03 4 2018 03 4 2018 11 4 586 596 28 11 2017 12 2 2018 © The Author(s) 2018. Published by Oxford University Press on behalf of ERA-EDTA.2018This 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 journals.permissions@oup.comAbstract 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. delayed graft functionischaemia/reperfusionkidney transplantationpolymorphismsrenal allograftFonds National de la Recherche ScientifiqueFNRS10.13039/501100002661University of LiègeFonds Spéciaux à la Recherche, Fonds Léon Fredericq ==== Body INTRODUCTION Delayed graft function (DGF) is a manifestation of acute kidney injury related to kidney transplantation (KTx). It has been defined as the requirement for dialysis within 7 days following KTx [1]. DGF causes increased risk for acute rejection (AR) and has been associated with poor long-term graft outcomes and additional costs [2]. Various immunological and non-immunological factors have been linked to DGF, including donor age, Human Leucocyte Antigen (HLA) compatibility, cold and warm ischaemia time, immunosuppressive regimen of induction and maintenance and dialysis vintage. Expanded criteria donors (ECDs) in KTx lead to an increased risk for DGF [3]. Still, the incidence of DGF in ECD recipients has progressively decreased over time from 35.2% in 2003 to 29.6% in 2011 in the USA, probably related to a better understanding of the donor risk profile along with improved allograft selection [3]. Cardiac death donors have also shown a higher rate of DGF [4]. Indeed, renal ischaemia/reperfusion (I/R) injury plays a critical role in DGF. I/R injury occurs when the blood supply to an organ is transiently disrupted and subsequently restored [5]. KTx necessarily conveys renal I/R, which prompts active preclinical and clinical research focusing on the prevention and/or attenuation of graft damage [6–9]. Besides the role of extrarenal factors in DGF, one may speculate that intrarenal characteristics may predispose the kidney allograft to injury. Global gene expression profiling captures such a complex process, thereby highlighting the putative implications of particular genes and metabolic cascades in renal I/R injury and DGF [8, 10, 11]. DGF-associated genes are implicated in pathways of oxidative stress, vasospasm, cytokine signalling, endothelial and epithelial cell injury, as well as innate and adaptive immunity. Some of these genes harbour single nucleotide polymorphisms (SNPs). By definition, SNPs correspond to the variation of only one base pair in one given gene, which may cause significant changes in the expression and/or activity of the corresponding protein. By extension, polymorphisms correspond to the coexistence of several distinct alleles in one given gene in a population. The haplotype is the combination of SNPs at multiple linked loci that are usually transmitted as a group from parent to child. In 2008, Krüger et al. [12] summarized the literature about genetic polymorphisms and the fate of the transplanted organ, including the impact of both immunological and non-immunological cascades on graft survival, AR and the occurrence of chronic allograft nephropathy. Our present review focuses on DGF and aims to systematically detail the published reports about potential associations between polymorphisms in kidney donors and recipients and the occurrence of DGF. MATERIALS AND METHODS We systematically searched PubMed for articles published from the database’s inception date to May 2017 using the following keywords: ‘delayed graft function’ or ‘DGF’ or ‘ischaemia-reperfusion’ and ‘kidney’ or ‘renal’ and ‘allograft’ or ‘transplantation’ and ‘polymorphisms’ or ‘SNP’. Furthermore, we reviewed the papers referenced in the ‘PubMed-related’ articles to identify additional candidate studies for which full-text English-language articles were available. Bibliographic references of both original investigations and review articles were then scrutinized. We included studies with the following quality criteria: (i)  ≥ 50 patients (kidney recipients, donors or both), (ii) well-defined evaluation of DGF occurrence and outcomes and (iii) polymorphisms in molecules involved in I/R-related processes. The articles that did not reach these criteria were excluded. Careful attention was given to the genetic background of studied populations. RESULTS We found 45 relevant articles in the PubMed database using the above-defined keywords. Four of these were excluded because the studied polymorphisms concerned genes coding for proteins involved in pharmacodynamics and pharmacokinetics of immunosuppressive drugs. Eleven articles were excluded because they did not strictly focus on DGF. Among the remaining 30 articles, 16 found an association between 18 polymorphisms and DGF (Table 1). These polymorphisms were present in 11 different well-known genes and in one not-yet-identified gene located on chromosome 18. We categorized them 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 polymorphisms and the occurrence of DGF. These data are summarized in Table 2. 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 Anti-apoptotic 229 recipients and 104 respective donors British Lower risk of DGF in donors [13] rs1695genotype GG GSTP1 Anti-oxidative stress Anti-apoptotic Decrease toxicity of immunosuppressant 223 controls and 273 recipients North Indian Higher risk of DGF [14] rs1001179(-262C/T) Catalase Anti-oxidative stress -262T increases blood level of catalase 187 recipients Polish Lower risk of DGF with T allele [15] 242T allele NADPH oxidase p22(phox) Anti-oxidative stress 196 donor–recipient pair Iranian Higher risk of DGF in recipients [16] Telomere shortening rs2735940 hTERT Telomere length: I/R and immunity Polymorphism limits telomere shortening 119 kidney allografts Polish Lower risk of DGF [17] rs7235755 Unknown (chr 18) Telomere length: I/R and immunity 119 recipients Polish Higher risk of DGF [18] rs2735940 hTERT Telomere length: I/R and immunity Polymorphism limits telomere shortening 74 donor–recipient pairs Polish Higher risk of DGF in recipients Lower risk of DGF in donors [19] Chemokines Genotype 1/2 (410/240) in intron 2 IL-1Ra Inhibitor of IL-1 (inflammation and immunity) Genotype 1/2 leads to lower levels of IL-1Ra 136 controls and recipients Indian Higher risk of DGF [20] -308G>A TNF-α Pro-apoptosis 100 recipient–donor pairs Iranian Higher risk of DGF with A allele in donors and lower risk with GG genotype in donors [21] -1082G>A IL-10 Downregulation of inflammatory responses 100 recipient–donor pairs Iranian Higher risk of DGF with A allele when associated with A allele in TNF-α -308G>A in donors [21] rs3732379 CC genotype CX3CR1 Cell migration 270 recipients Caucasian Higher risk of DGF [22] T-cell homeostasis rs231775 (+49A>G) rs231775 (+49A>G), rs3087243 and 3′-UTR dinucleotide AT repeat CTLA4 Downregulation of T cell activation 269 renal transplant recipients 350 controls and 190 recipients Caucasian Indian Higher risk of DGF with G allele Higher risk of DGF with G allele Lower risk of DGF with A allele Higher risk of DGF with 110-bp and 116-bp alleles Lower risk of DGF with 102-bp allele [23][24] Regulation of the immune responses F412L (rs3775291) TLR3 Pro-inflammation 265 recipients German Higher risk of DGF [25] Metabolization of anti-inflammatory molecules rs10509681 (CYP2C8*3) CYP2C8 Biosynthesis of ETTs, which are protective against I/R injuries CYP2C8*3 leads to lower levels of EETs 166 recipients Caucasian Higher risk of DGF [26] Complement activation rs7851696 Ficolin-2 Activator of the complement system via the lectin pathway 270 recipients Caucasian Higher risk of DGF with T allele [27] NO pathway intron 4 VNTR eNOS3 Recovery of blood flow after ischaemia may reduce oxidative stress 187 recipients Polish Higher risk of DGF with a allele [28] 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*B and GSTM1null phenotype GSTM1null + GSTT1null phenotype GSTT1*1 GSTP1*A, GSTP1*B, GSTP1*C and GSTP1*D MnSOD aa14Ala and MnSOD aa14Val GSTM1 GSTT1 GSTP1 MnSOD Anti-oxydative stress Anti-apoptotic 229 recipients and 104 respective donors British [13] 239 + 34A/C 47C/T SOD1 SOD2 Anti-oxidative stress 187 recipients Polish [29] Telomere shortening rs2735940 hTERT Telomere length: I/R and immunity 119 recipients Polish [18] rs2630578 BICD1 Telomere length: I/R and immunity 74 donor–recipient pairs Polish [19] rs7235755 Unknown (chr 18) Telomere length: I/R and immunity 74 donor–recipient pairs Polish [19] Chemokines -308G>A rs1800629 and rs3093662 -308G>A TNF-α Inflammation Pro-apoptosis 77 controls and recipients 965 recipients and 512 donors 100 recipient–donor pairs African American Recipients: African American, White, Asian and Native American. Donors: African American and White Iranian [30] [31] [21] -1082G>A, -819C>T and -592C>A rs3024498 and rs2222202 -1082G>A IL-10 Downregulation of inflammatory responses Anti-apoptosis 77 controls and recipients 965 recipients and 512 donors 100 recipient–donor pairs African American Recipients: African American, White, Asian and Native American. Donors: African American and White Iranian [30] [31] [21] -330 (T>G) IL-2 Immunity and inflammation 77 controls and recipients African American [30] +869 T>C and +915 G>C rs1800472 and rs1982073 TGF-β1 Inflammation and apoptosis 77 controls and recipients 965 recipients and 512 donors African American Recipients: African American, White, Asian and Native American. Donors: African American and White [30] [31] -174, a (C>G) IL-6 Pro-inflammation and apoptosis 77 controls and recipients African American [30] +874 (CA) IFN-γ Pro-inflammation and apoptosis 77 controls and recipients African American [30] FyB null genotype or FyB null alleles and polymorphism at position 535 DARC DARC binds to chemokines and reduces their level. Limitation of systemic inflammation 222 recipients African American [32] -511 (promoter region) and exon-5 IL-1β Pro-inflammation 136 controls and recipients Indian [20] IL12B 3′UTR IL-12p40 Stimulating IFN-γ production 253 recipients Caucasian [33] CCR2-V64I CCR5-Delta32 CCR2 CCR5 Receptors of chemokines, which play a role in infiltration and activation of macrophages 100 donor–recipient pairs Iranian [34] rs6822844 IL2-IL21 cluster Regulation of T cells and NK cell functions 270 recipients Caucasian [35] 1188A>C -295T>C 607C>A and 137G>C IL-12B IL-16 IL-18 Pro-inflammation 267 recipients Caucasian [36] Apoptosis rs 1042522 TP53 Pro-apoptosis 965 recipients and 512 donors Recipients: African American, White, Asian and Native American. Donors: African American and White [31] (GT)n repeat HMOX1 Anti-apoptosis 965 recipients and 512 donors Recipients: African American, White, Asian and Native American. Donors: African American and White [31] Regulation of the innate and adaptive immune responses rs2476601 PTPN22 Negative regulation of T-cell reaction, negative regulatory kinase Csk and other signalling molecules 269 recipients Caucasian [2] rs5742909 rs11571317, rs16840252 rs4553808, rs3087243 CTLA4 Downregulation of T cells activation 350 controls and 190 recipients Caucasian [23] rs7574865 STAT4 Regulation of natural killer cells, CD8+ T cells and Th1 function Differentiation of B cells and regulatory T cells 270 recipients Polish [37] Regulation of the innate immune responses R753Q (rs5743708) and R677W (del -196/-174) T737S (rs5743318) D299G (rs4986790) and T399I (rs4986791) 392STOP (rs5744168) P545P (rs352140) and -1237T/C (rs5743836) -159C/T (rs2569190) TLR2 TLR3 TLR4 TLR5 TLR9 CD14 Pro-inflammation 265 recipients German [25] rs5498 rs1041163 and rs3170794 ICAM1 VCAM1 Adhesion and transmigration of leucocytes 270 recipients Caucasian [7] Metabolization of anti-inflammatory molecules rs890293 (CYP2J2*7) CYP2J2 Biosynthesis of EETs, which are protective against I/R injury 166 recipients Caucasian [26] Complement rs11003125, rs7096206, rs7095891, rs5030737, rs1800450 and rs1800451 rs72550870 MBL2 MASP2 Immunity and inflammation 1271 donor–recipient pairs Netherlands [38] [38] C3F Complement C3 Immunity and inflammation 1265 donor–recipient pairs Netherlands [39] rs17549193 and rs4521835 rs3124952, rs3124953, rs17514136, rs17549193 and rs7851696 FCN2 Immunity and inflammation 270 recipients 1271 donor–recipient pairs Caucasian Netherlands [27] [38] NO pathway G894T substitution within exon 7 eNOS Recovery of blood flow after ischaemia May reduce oxidative stress 187 recipients Polish [28] rs10918594 NOS1AP No pathway 75 recipients Polish [40] Oxidative stress GSTM1, GSTM3, GSTT1, GSTP1 and MnSOD polymorphisms Glutathione S-transferases (GSTs) and manganese superoxide dismutase (MnSOD) contribute to protection against xenobiotic compounds, including immunosuppressive drugs in kidney transplant recipients (KTRs). GSTs and MnSOD are also involved in antioxidative reactions and in the regulation of apoptosis through direct protein–protein interactions. At the time of kidney reperfusion, GSTs and MnSOD are rapidly induced to scavenge reactive oxygen species (ROS) and prevent ROS-associated damage [13, 14]. St. Peter et al. [13] genotyped 229 British KTRs with  ≥ 24 h of cold ischaemia and 104 of their respective donors. They focused on the polymorphisms of three classes of GSTs and MnSOD: GSTM1*A, GSTM1*B, GSTT1*1, GSTP1*A, GSTP1*B, GSTP1*C, GSTP1*D, MnSOD aa14Ala and MnSOD aa14Val. In kidney donors, the presence of homozygous GSTM1*B or heterozygous GSTM1*B with GSTM1 null or GSTM1*A was associated with a lower risk for DGF. In KTRs, no association was found between any enzyme polymorphism and DGF occurrence [13]. Singh et al. [14] enrolled 223 controls and 273 North Indian KTRs to study the impact of polymorphisms in three GST isoenzyme genes (GSTM1, GSTM3, GSTT1 and GSTP1) on early graft function. The authors observed that recipients with the rs1695 genotype GG of GSTP1 were at higher risk of DGF [14]. rs1001179 (-262 C/T) polymorphism in the CATALASE gene Catalase is an intracellular antioxidant enzyme effective in protecting cells from hydrogen peroxide [41]. Catalase is crucial in attenuating graft I/R injuries in the immediate phase after KTx [42, 15]. Dutkiewicz et al. [15] studied the impact of the -262 C/T (rs1001179) polymorphism in CATALASE on renal function outcomes in 187 Polish KTRs. The T allele was associated with a reduced risk of DGF, with increased blood levels of catalase found in the -262 T patients [15]. NADPH oxidase p22(phox) C242T polymorphism p22(phox) is a polymorphic subunit of NAD(P)H oxidase that plays a critical role in its activation and stabilization. NAD(P)H oxidase is involved in the production of superoxide that triggers the inflammation in ischaemic kidneys [43, 16]. Mandegary et al. [16] enrolled 196 Iranian donor–recipient pairs to investigate the association 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 + TT) was found to be a major risk factor for DGF, most probably via the overproduction of superoxide at the time of I/R [16]. Telomere shortening A significant shortening in telomere length has been reported in ischaemic kidneys, which suggests I/R-accelerated tissue senescence [44]. Shorter telomeres have also been associated with a lower immune response [45]. Polymorphisms in hTERT, BICD1 and chromosome 18 interfere with telomere shortening. Kłoda et al. studied rs2735940 hTERT, rs2630578 BICD1 and rs7235755 in chromosome 18 polymorphisms in 119 Polish kidney allografts [17] and corresponding recipients [18] as well as in an independent cohort of Polish recipient–donor pairs [19]. 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 between the length of telomeres and I/R injury severity [17]. In 2016, the same authors reported that the presence of chromosome 18 rs7235755 polymorphism in recipients was associated with higher risk for DGF. Polymorphism in BICD1 in recipients was also associated with higher serum creatinine concentrations in long-term follow-up after KTx. Polymorphisms in hTERT were not associated with kidney allograft outcomes [18]. In 2017, Kłoda et al. [19] studied 74 Polish deceased donor and recipient 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 recipients or donors were not associated with either DGF or AR [19]. 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 pathway is unique in having a natural inhibitor known as the IL-1 receptor antagonist (IL-1Ra). Manchanda et al. [20] studied 136 Indian KTRs from a related living donor and focused on three polymorphisms in the IL-1 gene cluster: IL-1β promoter region  − 511, IL-1β 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 response of IL-1 at the time of renal I/R injury [20]. Apoptosis and inflammation: tumour necrosis factor-α -308 G > A and IL-10 -1082 G > A polymorphisms Tumour necrosis factor-α (TNF-α) and IL-10 play a crucial role in the pathogenesis of renal I/R injury. Activated macrophages secrete TNF-α, which binds to TNF receptors on cells, leading them to apoptosis. IL-10 appears to limit and control inflammation [46]. Deletion of the IL-10 gene accelerates kidney graft AR in mice [47]. Mandegary et al. [21] enrolled a prospective single-centre cohort of 100 Iranian consecutive kidney recipient–donor pairs. Significant associations were found between donors’ TNF-α polymorphism -308 G > A and the occurrence of DGF, as well as between the combination of donors’ IL10 AA or GA and TNF-α AA or GA genotypes and DGF [21]. McDaniel et al. [30] studied cytokine polymorphisms in 77 African American allograft recipients and 77 controls. TNF-α polymorphism in recipients was not associated with either DGF nor AR [30]. Finally, Israni et al. [31] 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-α polymorphism was not statistically associated with DGF, although a positive trend was observed [31]. Cell migration: CX3CR1 V249I polymorphism Fractalkine, also known as CX3CL1, is a member of the chemokine family that acts as an adhesion molecule and as an extracellular chemoattractant promoting cell migration [48]. Dabrowska-Zamojcin et al. [22] enrolled 270 Caucasian KTRs to study the impact of polymorphism V249I (rs3732379) in the Fractalkine receptor gene, CX3CR1. This polymorphism has been associated with a reduced number of CX3CL1 binding sites, reduced cell adhesion and decreased signalling and chemotaxis. The rs3732379 CC genotype in KTRs was associated with an increased risk for DGF [22]. T-cell homeostasis (CTLA-4 pathway) Cytotoxic T-lymphocyte antigen 4 (CTLA-4) is expressed at the surface of activated CD8 and CD4 T cells. It plays an inhibitory role in inflammation and helps maintain peripheral tolerance by suppressing T-cell proliferation and by inducting apoptosis of activated T-cells [24]. Domański et al. [23] enrolled 269 Caucasian KTRs to study the impact of rs231775 (+49 A > G) polymorphism in CTLA4 and found an association with the G allele in rs231775 and a higher risk of DGF [23]. Similarly, Misra et al. [24] enrolled 350 Indian patients with end-stage renal disease (ESRD) and 350 controls. Among the 350 ESRD patients, 190 underwent KTx. The CTLA-4 variants rs231775, rs3087243 and 3′-UTR dinucleotide AT repeats in recipients were involved in genetic susceptibility to DGF. The A allele in both rs231775 (+49 A > G) and rs3087243 was considered as protective against DGF, while the G allele was associated with a higher risk of DGF. Concerning 3′-UTR dinucleotide AT repeats, the 102-bp allele was protective against DGF, while 110-bp and 116-bp alleles increased the risk for DGF [24]. Regulation of the immune response The toll-like receptor (TLR) system is key in the innate immune system and participates in both acute and chronic allograft dysfunction [25, 49]. Loss-of-function mutations of TLR4 in donors have been associated with improved immediate kidney allograft outcomes [50]. Therefore, Krüger et al. [25] hypothesized that genetic variations in the TLR system may affect clinical outcome after KTx, including DGF. They enrolled 265 German KTRs to evaluate the impact of selected polymorphisms in the TLR2, TLR3, TLR4, TLR5, TLR9 and CD14 genes. The study showed that the TLR3 F412L polymorphism had a significantly higher rate of DGF in a univariate analysis but was not statistically significant after adjusting for known risk factors of DGF. Every other polymorphism tested had no significant association with DGF [25]. Epoxieicosatrienoic acids (EETs) are vasodilatory factors with anti-inflammatory properties. They may play a protective role against I/R-related damage [51, 52]. Several cytochrome P450 (CYP450) isoforms mediate the biosynthesis of EETs [53]. In humans, CYP2J2 and CYP2C8 are the most important isoforms. CYP2J2*7 (rs890293) and CYP2C8*3 (rs10509681) are the most common variants affecting enzymatic activity in Caucasians [26]. Gervasini et al. [26] studied these polymorphisms in 166 consecutive Caucasian adult KTRs. CYP2C8*3, which caused decreased enzymatic activity and lower production of EETs, was associated with a higher incidence of DGF in this cohort [26]. Ficolin (FCN)-2 is an activator of the complement system via the lectin pathway. Complement activation plays a substantial role in I/R injury at the time of KTx [27, 39]. The FCN-2 rs7851696 T allele is known to be associated with increased affinity of lectin-2 for carbohydrate structures presented by different pathogens [54]. Dabrowska-Zamojcin et al. [27] enrolled 270 Caucasian deceased-donor KTRs to evaluate the impact of FCN-2 gene rs7851696, rs17549193 and rs4521835 polymorphisms in DGF, as well as in AR and chronic allograft dysfunction. The results showed an increased risk for DGF and AR in case of FCN-2 rs7851696 T allele, although these statistical associations were not significant after Bonferroni correction [27]. Finally, nitric oxide (NO) plays a critical role in vascular tone and host defence [40, 28]. There are two distinct forms of NO synthases (NOSs): constitutive endothelial NOS (eNOS) and inducible NOS (iNOS). eNOS helps in tissue reperfusion and recovery after ischaemia and may reduce oxidative stress [28]. Dutkiewicz et al. [28] enrolled 187 polish KTRs to study the impact of polymorphisms of the eNOS gene (G894T substitution within exon 7 and intron 4 VNTR) on DGF, AR and chronic rejection and found an association between the a allele of the eNOS intron 4 VNTR polymorphism and a higher risk for DGF [28]. DISCUSSION Among 30 studies in the literature, 16 reports suggest an association between polymorphisms and the occurrence of DGF (Table 1), whereas 14 papers failed to find any relationship (Table 2). As discussed below, it is interesting to note that genes implicated in similar I/R-related pathways may or may not be involved in genetic susceptibility to DGF. Hence several genes connected to oxidative stress have been studied. I/R-related ROS cause deleterious effects on kidney allografts by triggering inflammatory injuries [13, 14]. High-producer polymorphisms in genes coding for antioxidant proteins have been associated with a lower risk of DGF, such as the presence of the -262 T allele in the KTR CATALASE gene [15] or the presence of the B allele in GSTM1 (GSTM1*B) in kidney donors [13]. In contrast, low-producer polymorphisms have been shown to be deleterious in I/R injury, including rs1695 genotype GG in GSTP1 in KTRs [14]. Furthermore, high-producer polymorphisms in genes coding for pro-oxidant proteins have been associated with a higher risk of DGF, like NADPH oxidase p22(phox) 242 T allele (CT + TT) in KTRs [16]. Still, other reports focusing on the oxidative cascade failed to link gene polymorphisms and DGF. As an example, 239 + 34 A/C and 47 C/T polymorphisms in the SOD1 and SOD2 genes were not associated with DGF development (Table 2) [29]. Superoxide dismutases (SODs) are regarded as the most important enzymes against ROS, particularly against superoxide anion radicals. Kidney aging may be notably reflected by telomere length [17, 19, 55], and in the case of KTx, assessment of telomere length in the early post-transplant period allows prediction of allograft long-term outcomes [56]. In case of renal graft I/R, a significant decrease in telomere length has been reported, thus suggesting accelerated kidney senescence [17, 44]. Conversely, limitation of telomere shortening in recipients may favour the deleterious immune response [45]. Hence polymorphisms rs2735940 hTERT (leading to limited telomere shortening) in donors was associated with a lower risk for DGF [17, 19]. However, this very same genotype in recipients was associated with increased risk for DGF, most probably due to an amplified immune trigger [19]. Such a condition exemplifies the importance of distinguishing the donor from the recipient genotype at the time of studying genetic susceptibility to renal I/R. Polymorphisms involved in I/R severity may be particularly relevant in donors, whereas polymorphisms implicated in AR and inflammation may rather concern the recipients. Renal I/R triggers inflammation, which in turn favours cytokine/chemokine secretion [22, 21, 31]. TNF-α is a pro-apoptotic cytokine. High-producer polymorphism of the TNF-α gene (i.e. donor’s AA or GA at -308 G > A) appears to be deleterious and associated with a higher risk for DGF [21]. Similarly, the combinations of donors’ IL10 AA or GA and TNF-α AA or GA genotypes were linked to DGF development, whereas TNF-α polymorphisms in recipients were not associated with DGF [21, 30, 31]. In contrast, low-producer polymorphism of the TNF-α gene (donor’s GG at -308 G > A) has been associated with a lower risk for DGF [21]. However, this association between the donor’s TNF-α gene polymorphisms and the occurrence of DGF failed to be confirmed in a large cohort including 512 African American and White donors [31]. Besides TNF-α, other cytokines have been genetically studied in DGF susceptibility, including IL-2 [35, 30], IL-12 [33], transforming growth factor-β [31, 30, 21] and IL-16 and IL-18 [36]. None of these studies found an association with DGF susceptibility (Table 2). Conversely, polymorphisms of genes coding for cytokine receptors may enhance their response to stimulation. Hence the CC genotype of rs3732379 polymorphism (V249I) of CX3CR1 in recipients has been associated with an increased risk for DGF. CX3CR1 is the receptor of CX3CL1, which is a chemokine acting as an adhesion molecule and as an extracellular chemoattractant promoting cell migration. V249I polymorphism causes changes in the number of CX3CL1 binding sites, thereby favouring cell adhesion, signalling and chemotaxis [22]. Similarly, inflammation modulators like CTLA-4, ETT and TLR may also attenuate or aggravate I/R injury. High-producer polymorphisms of CTLA-4 [A allele in recipients’ rs231775 (+49 A > G) and rs3087243, as well as the 102-bp allele in 3′-UTR dinucleotide AT repeats] may prevent DGF. CTLA-4 is expressed on activated CD8 and CD4 T-cells and helps maintain homeostasis by downregulating T-cells [24]. In contrast, since EETs possess vasodilatory and anti-inflammatory properties [26], low-producer polymorphisms in the CYP2C8 gene in recipients may increase the risk for post-transplant DGF. The TLRs have a pivotal role in the innate immune system and possess pro-inflammatory properties. The TLR3 F412L polymorphism has been associated with a higher risk of DGF [25], so this polymorphism likely attenuates the function of TLR3. Focusing on the complement cascade at the time of renal I/R, Michielsen et al. [39] recently summarized the impact of complement polymorphisms on kidney graft outcomes without detailing their influence on DGF occurrence. Dabrowska-Zamojcin et al. [27] more recently reported an association between the FCN-2 rs7851696 T allele and a higher risk of DGF—although this association was significant only without correction for multiple comparisons. The complement system, as part of the innate immune system, is involved in protection against foreign organisms and the clearance of apoptotic cells. However, complement cascade may also aggravate I/R injury via antibody binding, which eventually leads to poor outcomes after KTx. In particular, a crucial role is suspected for mannose binding lectin (MBL) in the early pathophysiology of renal I/R [39]. Nevertheless, there was no significant difference in the incidence of DGF in recipients with low MBL levels (≤400 ng/mL) compared to those with high MBL levels [57]. C3 is the central component of complement cascade and can be activated by all three complement pathways. In mice, the absence of local renal C3 in donor kidney significantly improves early post-reperfusion injury [58]. In humans, the C3F allotype in both donors and recipients was not associated with DGF [58]. The pathophysiology of DGF is complex and multifactorial, including immunological and non-immunological factors [8, 7]. Furthermore, there might be additive actions of both I/R and AR in the immediate post-transplant period, which may synergistically predispose to DGF. The actual role of genetic susceptibility to renal I/R may thus be difficult to appropriately ‘quantify’ [30]. Genome-wide association studies (GWASs) are currently ongoing to test additional genes and SNPs in the particular settings of DGF. Confirmatory clinical trials are also required in validation cohorts. As an example, two SNPs (rs3811321 and rs6565887 on chromosomes 14 and 18, respectively) have been initially identified by GWASs in 300 KTRs as predictive of serum creatinine levels and hard clinical outcomes. However, Pihlstrøm et al. [59] failed to confirm such an association between these two polymorphisms and post-transplant outcomes in 1638 recipients. Indeed, conflicting data may result from the number of recruited patients and from their ethnicity. Polymorphisms in the TNF-α gene in 100 Iranian donors were associated with DGF occurrence [21] but failed to be confirmed in a large cohort including 512 African American and White donors [31]. African American recipients have shown a higher risk of DGF [60, 61]. Black ethnicity in recipients is a risk factor for DGF [62], which is part of the nomogram established by Irish et al. [63] for predicting the likelihood of DGF. Nevertheless, Palanisamy et al. [61] showed that cardiovascular risk factors contribute to disparities in graft outcomes in African American KTRs. Furthermore, after correcting for cardiovascular risk factors, race per se did not show an independent effect on graft outcomes [61]. In conclusion, several polymorphisms in either the donor or the recipient or both have been associated with DGF in KTRs. These polymorphisms are involved in oxidative stress, telomere length, cytokine secretion and modulation, immunity and inflammation. These processes are involved in I/R injury, which is regarded as one of the most important causes of DGF. Identifying the polymorphisms linked to renal I/R may allow us to better understand its pathophysiology and find new therapeutic targets. The present review highlights the state of knowledge in the field of genetic susceptibility to renal I/R. Although SNPs may only have minor impacts per se on gene expression and protein function, interactions among multiple SNPs may have a major impact on molecular cascades [39]. Additionally, some SNPs show very low frequency [31]. Validation studies are lacking or inadequately powered for most SNPs studied thus far [39], which may explain the controversial observations [21, 31]. Replication studies will need to include multivariate analyses to isolate the putative effects of SNPs among other well-established risk factors of DGF. Most importantly, one must clearly distinguish the impact of SNPs in donors versus in recipients versus in both. Polymorphisms involved in I/R severity may be particularly relevant in donors, whereas polymorphisms implicated in AR and inflammation may rather concern recipients [19]. Therefore, prospective multicentric studies including patients of various genetic backgrounds are required to clinically determine the benefits (and harms) of genotyping donors and recipients before KTx [59, 12]. ACKNOWLEDGEMENTS The authors cordially thank the surgeons (M. Meurisse, C. Coimbra Marques, O. Detry, E. Hamoir, P. Honoré, L. Kohnen, N. Meurisse and J-P Squifflet), the physicians (A. Bouquegneau, S. Grosch, P. Vanderweckene, L. Vanovermeire and P. Xhignesse) and the members of the local transplant coordination centre (Mme M.-H. Delbouille, M.-H. Hans, J. Mornard) for their commitment to kidney transplantation at the University of Liège Hospital, Liège, Belgium. [32, 34, 37, 38]. FUNDING J.H. and F.J. are Fellows of the Fonds National de la Recherche Scientifique (FNRS) and received support from the University of Liège (Fonds Spéciaux à la Recherche, Fonds Léon Fredericq) and the FNRS (Research Credit 2016). AUTHORS’ CONTRIBUTIONS J.H. performed the original research of the literature and wrote the article. J.-M.K. wrote the article. F.J. supervised the original research of the literature and wrote the article. CONFLICT OF INTEREST STATEMENT The authors declare no conflict of interest. ==== Refs REFERENCES 1 Mallon DH , Summers DM , Bradley JA et al Defining delayed graft function after renal transplantation: simplest is best . Transplantation 2013 ; 96 : 885 –889 24056620 2 Domański L , Bobrek-Lesiakowska K , Kłoda K et al Lack of association of the rs2476601 PTPN22 gene polymorphism with transplanted kidney function . Ann Transplant 2011; 16 : 63 –68 3 Rege A , Irish B , Castleberry A et al Trends in usage and outcomes for expanded criteria donor kidney transplantation in the United States characterized by kidney donor profile index . Cureus 2016 ; 8 : e887 28018757 4 Lafuente O , Sánchez-Sobrino B , Pérez M et al Midterm results of renal transplantation from controlled cardiac death donors are similar to those from brain death donors . Transplant Proc 2016 ; 48 : 2862 –2866 27932093 5 Erpicum P , Detry O , Weekers L et al Mesenchymal stromal cell therapy in conditions of renal ischaemia/reperfusion . Nephrol Dial Transplant 2014 ; 29 : 1487 –1493 24516234 6 Niemann CU , Feiner J , Swain S et al Therapeutic hypothermia in deceased organ donors and kidney-graft function . N Engl J Med 2015 ; 373 : 405 –414 26222557 7 Kłoda K , Domanski L , Pawlik A et al Effect of the ICAM1 and VCAM1 gene polymorphisms on delayed graft function and acute kidney allograft rejection . Ann Transplant 2010 15 : 15 –20 21183871 8 Siedlecki A , Irish W , Brennan DC. Delayed graft function in the kidney transplant . Am J Transplant 2011 ; 11 : 2279 –2296 21929642 9 Rowart P , Erpicum P , Detry O et al Mesenchymal stromal cell therapy in ischemia/reperfusion injury . J Immunol Res 2015 ; 2015 : 602597 26258151 10 Grigoryev DN , Cheranova DI , Heruth DP et al Meta-analysis of molecular response of kidney to ischemia reperfusion injury for the identification of new candidate genes . BMC Nephrol 2013 ; 14 : 231 24152794 11 Wilflingseder J , Sunzenauer J , Toronyi E et al Molecular pathogenesis of post-transplant acute kidney injury: assessment of whole-genome mRNA and miRNA profiles . PLoS One 2014 ; 9 : e104164 25093671 12 Krüger B , Schröppel B , Murphy BT. Genetic polymorphisms and the fate of the transplanted organ . Transplant Rev 2008 ; 22 : 131 –140 13 St. Peter SD , Imber CJ , Jones DC et al Genetic determinants of delayed graft function after kidney transplantation . Transplantation 2002 ; 74 : 809 –813 12364860 14 Singh R , Manchanda PK , Kesarwani P et al Influence of genetic polymorphisms in GSTM1, GSTM3, GSTT1 and GSTP1 on allograft outcome in renal transplant recipients . Clin Transplant 2009 ; 23 : 490 –498 19486347 15 Dutkiewicz G , Domanski L , BINCZAK-KULETA A et al The association of -262C/T polymorphism in the catalase gene and delayed graft function of kidney allografts . Nephrology (Carlton) 2010 ; 15 : 587 –591 20649881 16 Mandegary A , Rahmanian-Koshkaki S , Mohammadifar MA et al Investigation of association between donors’ and recipients’ NADPH oxidase p22(phox) C242T polymorphism and acute rejection, delayed graft function and blood pressure in renal allograft recipients . Transpl Immunol 2015 ; 32 : 46 –50 25173715 17 Kłoda K , Domanski L , Kwiatkowska E et al hTERT, BICD1 and chromosome 18 polymorphisms associated with telomere length affect kidney allograft function after transplantation . Kidney Blood Press Res 2015 ; 40 : 111 –120 25792135 18 Kłoda K , Domański L , Kwiatkowska E et al BICD1 and chromosome 18 polymorphisms associated with recipients’ telomere length affect kidney allograft function after transplantation . Transplant Proc 2016 ; 48 : 1451 –1455 27496426 19 Kłoda K , Mierzecki A , Domański L et al Joint assessment of donor and recipient hTERT gene polymorphism provides additional information for early kidney transplantation outcomes . Med Sci Monit 2017 ; 23 : 1812 –1818 28410362 20 Manchanda PK , Bid HK , Kumar A et al Genetic association of interleukin-1β and receptor antagonist (IL-1Ra) gene polymorphism with allograft function in renal transplant patients . Transpl Immunol 2006 ; 15 : 289 –296 16635751 21 Mandegary A , Azmandian J , Soleymani S et al Effect of donor tumor necrosis factor-alpha and interleukin-10 genotypes on delayed graft function and acute rejection in kidney transplantation . Iran J Kidney Dis 2013 ; 7 : 135 –141 23485538 22 Dabrowska-Zamojcin E , Dziedziejko V , Safranow K et al Association between the CX3CR1 gene V249I polymorphism and delayed kidney allograft function . Transpl Immunol 2015 ; 32 : 172 –174 25898802 23 Domański L , Bobrek-Lesiakowska K , Kłoda K et al The impact of rs231775 (+49AG) CTLA4 gene polymorphism on transplanted kidney function . Ann Transplant 2012; 17 : 29 –35 24 Misra MK , Kapoor R , Pandey SK et al Association of CTLA-4 gene polymorphism with end-stage renal disease and renal allograft outcome . J Interferon Cytokine Res 2014 ; 34 : 148 –161 24313821 25 Krüger B , Banas MC , Walberer A et al A comprehensive genotype–phenotype interaction of different Toll-like receptor variations in a renal transplant cohort . Clin Sci 2010 ; 119 : 535 –544 20604744 26 Gervasini G , Garcia M , Macias RM et al CYP2C8*3 polymorphism and donor age are associated with allograft dysfunction in kidney transplant recipients treated with calcineurin inhibitors . J Clin Pharmacol 2013 ; 53 : 427 –434 23426640 27 Dabrowska-Zamojcin E , Czerewaty M , Malinowski D et al Ficolin-2 gene rs7851696 polymorphism is associated with delayed graft function and acute rejection in kidney allograft recipients . Arch Immunol Ther Exp (Warsz) 2018 ; 66 : 65 –72 28536887 28 Dutkiewicz G , Domanski L , Binczak-Kuleta A et al The association between eNOS intron 4 VNTR polymorphism and delayed graft function of kidney allografts . Clin Transplant 2010 ; 24 : E130 –E136 20047617 29 Dutkiewicz G , Domanski L , Binczak-Kuleta A et al Lack of association of polymorphisms 239+34A/C in the SOD1 gene and 47C/T in the SOD2 gene with delayed graft function and acute and chronic rejection of kidney allografts . Transplant Proc 2009 ; 41 : 3701 –3703 19917371 30 McDaniel DO , Barber WH , Nguyan C et al Combined analysis of cytokine genotype polymorphism and the level of expression with allograft function in African-American renal transplant patients . Transpl Immunol 2003 ; 11 : 107 –119 12727482 31 Israni AK , Li N , Cizman BB et al Association of donor inflammation- and apoptosis-related genotypes and delayed allograft function after kidney transplantation . Am J Kidney Dis 2008 ; 52 : 331 –339 18640487 32 Mange KC , Prak EL , Kamoun M et al Duffy antigen receptor and genetic susceptibility of African Americans to acute rejection and delayed function . Kidney Int 2004 ; 66 : 1187 –1192 15327416 33 Hoffmann TW , Halimi JM , Büchler M et al Impact of a polymorphism in the IL-12p40 gene on the outcome of kidney transplantation. Transplant Proc 2009 ; 41 : 654 –656 34 Azmandian J , Mandegary A , Saber A et al Chemokine receptor 2-V64I and chemokine receptor 5-Δ32 polymorphisms and clinical risk factors of delayed graft function and acute rejection in kidney transplantation . Iran J Kidney Dis 2012 ; 6 : 56 –62 22218121 35 Kwiatkowska E , Domanski L , Kłoda K et al IL2-IL21 gene cluster polymorphism is not associated with allograft function after kidney transplantation . Int Urol Nephrol 2014 ; 46 : 2415 –2420 25377634 36 Pawlus J , Sierocka A , Tejchman K et al The impact of interleukin 12B (1188A>C), interleukin 16 (-295T>C), and interleukin 18 (607C>A, 137G>C) gene polymorphisms on long-term renal transplant function and recipient outcomes. Transplant Proc 2014 ; 46 : 2079 –2082 37 Dąbrowska-Żamojcin E , Dziedziejko V , Safranow K et al. STAT4 gene polymorphism in patients after renal allograft transplantation . Cent J Immunol 2016 ; 41 : 255 –259 38 Damman J , Kok JL , Snieder H et al Lectin complement pathway gene profile of the donor and recipient does not influence graft outcome after kidney transplantation . Mol Immunol 2012 ; 50 : 1 –8 22173059 39 Michielsen LA , van Zuilen AD , Muskens IS et al Complement polymorphisms in kidney transplantation: critical in graft rejection? Am J Transplant 2017 ; 17 : 2000 –2007 28097805 40 Zukowski M , Kotfis K , Biernawska J et al Association of the rs10918594 of nitric oxide synthase 1 adaptor protein (NOS1AP) polymorphisms with the graft function after kidney transplantation . Ann Transplant 16 : 72 –76 41 Belda-Antolí M , Padrón-Sanz C , Cejalvo-Lapeña D et al Antioxidant potential of Himanthalia elongata for protection against ischemia-reperfusion injury in the small bowel . Surgery 2017 ; 162 : 577 –585 28666685 42 Johnson KJ , Weinberg JM. Postischemic renal injury due to oxygen radicals . Curr Opin Nephrol Hypertens 1993 ; 2 : 625 –635 7859026 43 Zhou J , Zhang YH , Song HZ et al 5d, a novel analogue of 3-n-butylphthalide, decreases NADPH oxidase activity through the positive regulation of CK2 after ischemia/reperfusion injury . Oncotarget 2016 ; 7 : 39444 –39457 27276705 44 Chkhotua A , Abendroth D , Schelzig H. Renal ischemia/reperfusion and its influence on telomere length and expression of cell cycle regulatory genes . Georgian Med News 2006 ; 130 : 22 –26 45 Blanco JR , Jarrin I , Martinez A et al Shorter telomere length predicts poorer immunological recovery in virologically suppressed HIV-1–infected patients treated with combined antiretroviral therapy . JAIDS J Acquir Immune Defic Syndr 2015 ; 68 : 21 –29 25321176 46 Daemen MA , van de Ven MW , Heineman E et al Involvement of endogenous interleukin-10 and tumor necrosis factor-alpha in renal ischemia-reperfusion injury . Transplantation 1999 ; 67 : 792 –800 10199725 47 Cornell LD , Smith RN , Colvin RB. Kidney transplantation: mechanisms of rejection and acceptance . Annu Rev Pathol Mech Dis 2008 ; 3 : 189 –220 48 Liu YZ , Wang C , Wang Q et al Role of fractalkine/CX3CR1 signaling pathway in the recovery of neurological function after early ischemic stroke in a rat model . Life Sci 2017 ; 184 : 87 –94 28624392 49 Alegre ML , Leemans J , Le Moine A et al The multiple facets of toll-like receptors in transplantation biology . Transplantation 2008 ; 86 : 1 –9 18622268 50 Krüger B , Krick S , Dhillon N et al Donor toll-like receptor 4 contributes to ischemia and reperfusion injury following human kidney transplantation . Proc Natl Acad Sci USA 2009 ; 106 : 3390 –3395 19218437 51 Node K , Huo Y , Ruan X et al Anti-inflammatory properties of cytochrome P450 epoxygenase-derived eicosanoids . Science 1999 ; 285 : 1276 –1279 10455056 52 Alkayed NJ , Goyagi T , Joh HD et al Neuroprotection and P450 2C11 upregulation after experimental transient ischemic attack . Stroke 2002 ; 33 : 1677 –1684 12053011 53 Zeldin DC , Moomaw CR , Jesse N et al Biochemical characterization of the human liver cytochrome P450 arachidonic acid epoxygenase pathway . Arch Biochem Biophys 1996 ; 330 : 87 –96 8651708 54 Hummelshoj T , Munthe-Fog L , Madsen HO et al Polymorphisms in the FCN2 gene determine serum variation and function of Ficolin-2 . Hum Mol Genet 2005 ; 14 : 1651 –1658 15879437 55 Melk A , Ramassar V , Helms LM et al Telomere shortening in kidneys with age . J Am Soc Nephrol 2000 ; 11 : 444 –453 10703668 56 Kłoda K , Domański L , Mierzecki A. Telomere length assessment for prediction of organ transplantation outcome. Future or failure: a review of the literature . Med Sci Monit 2017 ; 23 : 158 –162 28076340 57 Berger SP , Roos A , Mallat MJK et al Association between mannose-binding lectin levels and graft survival in kidney transplantation . Am J Transplant 2005 ; 5 : 1361 –1366 15888042 58 Damman J , Daha MR , Leuvenink HG et al Association of complement C3 gene variants with renal transplant outcome of deceased cardiac dead donor kidneys . Am J Transplant 2012 ; 12 : 660 –668 22176838 59 Pihlstrøm HK , Mjøen G , Mucha S et al Single nucleotide polymorphisms and long-term clinical outcome in renal transplant patients: a validation study . Am J Transplant 2017 ; 17 : 528 –533 27483393 60 Moore J , Tan K , Cockwell P et al Predicting early renal allograft function using clinical variables . Nephrol Dial Transplant 2007 ; 22 : 2669 –2677 17556406 61 Palanisamy AP , Schiltz CE , Pilch NA et al Cardiovascular risk factors contribute to disparities in graft outcomes in African American renal transplant recipients: a retrospective analysis . Blood Press 2015 ; 24 : 14 –22 25048253 62 Willicombe M , Rizzello A , Goodall D et al Risk factors and outcomes of delayed graft function in renal transplant recipients receiving a steroid sparing immunosuppression protocol . World J Transplant 2017 ; 7 : 34 28280693 63 Irish WD , McCollum DA , Tesi RJ et al Nomogram for predicting the likelihood of delayed graft function in adult cadaveric renal transplant recipients . J Am Soc Nephrol 2003 ; 14 : 2967 –2974 14569108