Delayed graft function (DGF) after living donor kidney transplantation: A study of possible explanatory factors

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1 Ann Transplant, 2012; 17(3): PMID: Original Paper Received: Accepted: Published: Authors Contribution: A Study Design B Data Collection C Statistical Analysis D Data Interpretation E Manuscript Preparation F Literature Search G Funds Collection Delayed graft function (DGF) after living donor kidney transplantation: A study of possible explanatory factors Jamshid Salamzadeh 1 ACDEF, Zahra Sahraee 1 ABCDEF, Mohsen Nafar 2 ABDEF, Mahmoud Parvin 2 CD 1 Department of Clinical Pharmacy, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran 2 Shahid Labbafinejad Hospital, Urology and Nephrology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran Background: Material/Method: Result: Conclusions: Key words: Summary Delayed graft function (DGF), caused by failure of the kidney to function properly after transplantation, has a lower incidence rate in living donor transplantation compared to deceased donor transplantation. The aim of this study was to investigate the possible risk factors related to DGF in living donor transplantations. A prospective, observational cohort study of patients undergoing living donor renal transplantation was designed. The incidence of DGF was investigated; the urine levels of neutrophil gelatinase-associated lipocalin (NGAL) and interleukin 18 (IL-18) were measured on the 1 st and 3 rd day after transplantation, and the relationships of DGF incidence and potential explanatory factors were studied. DGF was observed in 16.2% of patients. Preliminary univariate analyses showed that older donors, retransplantation, previous blood transfusion, and low urinary output could be eligible predictors for DGF. Analysis of the urinary biomarkers revealed an association between DGF incidence with the level of NGAL on the 1 st day after transplantation, level of IL 18 on the 3 rd post-operative day, and with the differences in urine NGAL levels measured in 2 samplings. Multivariate logistic regression analysis showed that only the differences between the 1 st and 3 rd days of urinary NGAL levels could remain in the final model. Although, possibly due to living donor transplantation, none of the patient/donor characteristics could act as an explanatory factor for DGF; however, special attention is still required to target post-operation inflammation and oxidative stress, confirmed by relationship observed between DGF and urine NGAL levels on postoperative days. kidney transplantation delayed graft function neutrophil gelatinase-associated lipocalin (NGAL) interleukin 18 (IL-18) living donor Full-text PDF: Word count: 2865 Tables: 1 Figures: References: 44 Author s address: Jamshid Salamzadeh, Department of Clinical Pharmacy, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran. P.O. Box: , j.salamzadeh@yahoo.com 69

2 Original Paper Ann Transplant, 2012; 17(3): Background A comprehensive definition for delayed graft function (DGF) is the failure of the transplanted kidney to function properly in the early phase after transplantation due to ischemia-reperfusion and immunological injury [1]. The older definition of DGF (ie, requirement for dialysis in the first week after kidney transplantation) is not standardized and is very subjective, since the dialysis criteria vary among hospitals [2]. In recent years, serum creatinine levels (SrCr), rate of reduction in SrCr, and urine output (UO) are used to identify DGF on different days following transplantation. According to these criteria, reported rates of DGF are 20 40% [3], of which 4 10% are contributed to living donor transplants and 5 50% to deceased donor kidney transplants [1]. The main pathologic finding related to DGF is acute tubular necrosis (ATN) [4]. This may be because of the increase in oxidative stress phenomena after kidney transplantation. Studies have shown that the level of selected pro-inflammatory factors in blood serum may increase in the initial early phase after the kidney transplantation, especially in deceased donor kidneys [5,6]. There are also several risk factors found to be correlated to the DGF in deceased-donor renal transplantation. They are mainly classified into 3 groups related to the donor, the recipient, and the transplant procedure [7]. These risk factors have usually been considered as exclusion criteria for transplantation. In addition to recent reports on the association of some gene polymorphisms with DGF [8 10], there have also been several studies on the risk factors of DGF, such as donor and recipient age, body mass index (BMI), pre-sensitization, method and time of long-term renal replacement therapy, residual diuresis, and sex compatibility. In addition, it is revealed that although ischemia time is minimal in living donors, prolonged cold and warm ischemia time can enhance the prevalence of DGF [11 14]. However, there have been only a few studies investigating the rate of DGF in living donor renal transplantation [15 18]; they have reported 1.6%, 7.1%, 8.8%, and 18.3% of DGF among study subjects. On the other hand, the risk factors for DGF in living donor transplantation have not been conclusively established. Moreover, DGF may convert into undesired post-transplantation events, including increased morbidity rate, prolonged patient hospitalization, and increased health care costs, and it may eventually dispose the graft to both acute and chronic rejection [1]. This makes the early detection and prevention of DGF a major target for both physicians and health care systems. When DGF becomes clinically diagnosable, the main management strategy is to support the patient with dialysis and to perform serial biopsies in order to monitor for rejection. Use of alternative immunosuppressive agents may also be required. At present no effective treatment for DGF is available [2]. Lack of therapeutic and preventive intervention may be due to delayed diagnosis of DGF by currently available clinical methods [1]. Research to determine a precise definition for and prediction of DGF have been presented in the last decade [2]. Amongst the most useful novel methods to diagnose DGF are urine biomarkers of neutrophil gelatinase-associated lipocalin (NGAL) and interleukin 18 (IL-18) [19]. NGAL is a product of NGAL expression genes in the tubular epithelia of the kidney [19]. NGAL prompts nephrogenesis by stimulating the conversion of mesenchymal cells into kidney epithelia, and has a role in proliferation and regeneration, and also in the repair process [19]. It has been shown that NGAL level, as a biomarker of DGF, increases in urine and biopsy samples taken early after deceased donor transplantation. Serum NGAL could also be a sensitive marker of kidney function, particularly in elderly patients [19 22]. IL-18 is a proinflammatory cytokine that belongs to the IL-1 superfamily of ligands and is produced by macrophages and immature dendritic cells. Reports confirm its role in many tissues such as lung, heart, bowel, and cartilage. In patients with ischemic ATN and acute kidney injury (AKI), urine concentrations of IL-18 and NGAL can increase [20,23,24]. Among current methods used to predict need for dialysis and graft recovery after kidney transplantation, measurement of NGAL and IL-18 are among the most promising ones, mainly because of their role on precise and prompt diagnosis of insufficient kidney function. It was shown, more evidently in deceased donor transplantations, that urinary levels of NGAL and IL-18 on the first day after transplantation are accurate predictors of the need for dialysis within the first week of kidney transplantation [20,21]. 70

3 Ann Transplant, 2012; 17(3): In the present study we analyzed the incidence, possible risk factors, and predictors of DGF in living donor transplanted patients. The hypothesis that appearance of NGAL and IL18 represents an early marker of DGF in living donor kidney transplants was also assessed. Material and Methods A prospective, observational cohort study of patients undergoing living donor renal transplantation at a specialty kidney transplant research center (Urology and Nephrology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran) was designed. All patients referred to this center between March 2010 and January 2012 were evaluated for inclusion in the study. The study was approved by the ethics committee of Shahid Beheshti University of Medical Sciences, and a written informed consent was obtained from all study subjects. Their demographic, medical, and medication history data, relevant laboratory test results (including renal function biomarkers, and applicable information from their donors) were gathered and examined for any relationship with DGF. DGF was defined by need for dialysis within the first week after transplantation, or when serum creatinine level increased, remained unchanged, or decreased by less than 10% per day immediately after surgery. These patients could be at risk of rejection and other poor long-term outcomes [25]. Inclusion and exclusion criteria The inclusion criteria were transplanted patients, over 18 years of age, who had received a kidney from living donors. Exclusion criteria were any condition that could interfere with measuring urine biomarkers (NGAL and IL18), such as neoplastic diseases, brain tumor, active inflammatory diseases, active infectious diseases, sepsis, sickle cell, meningitis, pregnancy, cardio-renal syndrome, cushing syndrome, multiple sclerosis (MS), recent acute pancreatitis, long-term use of cimetidine, recent coronary artery bypass grafting (CABG), hepatitis C and cirrhosis, Alzheimer disease, recent stroke, hyperoxaluria, and mood disorder or schizophrenia (without treatment) [26 35]. In our study, for all living donor transplanted patients, cold and warm ischemia times were less Salamzadeh J et al Delayed graft function (DGF) after living donor than 1 hour and panel-reactive antibody (PRA) results were negative. Data collection The following data were recorded on the recipient: age, sex, weight, height, recipient-donor body weight ratio, blood transfusion and urine output before transplantation and retransplantation. The biochemical variables were determined and recorded daily before and after transplantation. Similarly, donors demographic information and their familial relation with their recipients were also gathered. All collected data were entered into an Excel worksheet (Microsoft Office 2007) and, after primary calculations, were transferred to the Statistical Package for Social Sciences (SPSS version 17.0) software for statistical analysis. The immunosuppressive regimen was similar in all patients, consisting of preoperative cyclosporine A and mycophenolate mofetil (MMF), continued postoperatively along with prednisolone. Patients who developed DGF (with or without need for dialysis) received a polyclonal antibody (thymoglobulin), and MMF was discontinued until normalization of SrCr [26]. Daily measurements of urine output and SrCr began on the day of transplantation and continued until discharge. On the first and third post-operative days, 10 ml urine samples were taken. Urine samples were centrifuged at 5000 RPM for 5 minutes to remove particulate matter and cell debris, and stored at 70 C. Elisa kits were utilized for measuring urine NGAL (ANTIBODYSHOP, Gentofte, Denmark) and IL18 (Medical and Biological Laboratories, Nagoya, Japan). Data analysis A 3-stage analysis was designed in order to build the final model of predictors related to DGF. In the first stage, any association between qualitative variables (urine biomarker levels, donors and recipients age and BMI, as well as recipient-donor body weight ratio) and occurrence of DGF was subjected to univariate evaluation using the Mann-Whitney U test and independent sample t test. Similarly, the chi-square and Fisher s exact tests were used for categorical variables (donors and recipients sex, first-degree familial relationship between donor and recipient, blood transfusion and categorically defined urine output of 71

4 Original Paper Ann Transplant, 2012; 17(3): Table1. Distribution of the study variables and the univariate analyses results. DGF IGF (non DGF) P-value Number Recipients age,years (s.d) (15.77) (16.84) Donors age, year (s.d) 28 (3.31) (2.91) Recipients gender (%) Male Female Donor gender (%) Male Female 5 (45.45) 6 (54.55) 11 (100) 0 32 (56.14) 25 (43.86) 47 (82.45) 10 (17.55) Recipients BMI (s.d) (4.23) (4.60) Donor BMI (s.d) (5.60) (4.24) Recipient-donor body weight ratio (0.204) (0.320) TX number First TX Re-TX Residual diuresis (%) < > (72.72) 3 (27.28) 5 (45.45) 5 (45.45) 0 1 (9.1) 56 (98.24) 1 (1.76) 12 (21.05) 16 (28.07) 13 (22.81) 16 (28.07) Blood transfusion (%) 6 (54.55) 15 (26.31) Relationships between donor and recipient (%) 1 (9.09) 5 (8.77) 1 1 st POD NGAL (ng/ml) IL 18 (pg/ml) 3 rd POD NGAL (ng/ml) IL 18 (pg/ml) Mean change in urine NGAL from 1 st POD to 3 rd POD Mean change in urine IL 18 from 1 st POD to 3 rd POD 3.77 (1.93) (23.18) 0.81 (0.89) (30.26) 1.82 (1.75) (33.05) 0.87 (1.24) (27.25) 2.96 (1.61) 1.02 (1.42) 5.59 (27.07) 3.03 (29.01) DGF delayed graft function; IGF immediate graft function; not significant; s.d. standard deviation; TX transplantation; POD post operation day recipients). Table 1 presents the distribution of the study variables and the results of the preliminary univariate analyses. Variables selected by univariate analysis (p<0.1) were evaluated in a multivariate logistic analysis. In the second stage, any collinearity between variables selected in the first stage was assessed, and significant interactions (p<0.05) were considered to be included in the multivariate analysis. At the end stage, selected risk factors and their significant interactions were entered into the multivariate logistic regression for the final model building and to indentify explanatory factors of DGF. A p value <0.05 was considered statistically significant. Results Sixty-eight living donor transplanted patients were included in the study. One patient died because of cardiac arrest 5 days after transplantation, and 72

5 Ann Transplant, 2012; 17(3): renal artery thrombosis occurred in 1 patient 3 days after surgery. DGF were observed in 11 (16.2%) of the 68 transplant patients under study, and only 3 (4.4%) of them needed dialysis. Mean DGF duration was 8.9±6.2 days. In 8 out of 11 patients (72.7%), DGF lasted less than 1 week, and in 2 patients (18.2%) DGF lasted more than 1 week. DGF lasted more than 2 weeks only in 1 out of 11 patients (9.1%). Time to control SrCr was significantly (P<0.0001) higher in DGF patients compared to immediate graft function (IGF) patients (15.2±5.1 vs. 8.2±3.5 days). According to the preliminary analyses, there were no associations between the incidence of DGF and donors and recipients BMI, sex, recipients age, recipient-donor body weight ratio and familial relationship between donor and recipient, even at a conservative significance level of p<0.1 (Table 1). However, univariate analyses revealed that donor age, second-time transplantation, blood transfusion, and urine output (recipients) before transplantation had a relationship with the incidence of DGF with p<0.1, making them eligible to be included in the multivariate logistic regression (Table 1). Urinary biomarkers analysis also demonstrated that urine NGAL level at the first day after transplantation (p=0.002) and mean changes in the urinary NGAL at the first to third post-operative days (p=0.002) are significantly associated with DGF. Urinary IL18 level at the third day after transplantation was also considered as a potential predictor for DGF (p=0.096) (Table 1). Multivariate logistic regression analysis revealed that except for the variable differences between the 1 st and 3 rd days of urinary NGAL levels, other predictors of the incidence of DGF could not remain in the final model (p=0.006; OR=2.05; 95% CI: ), so that there was an indirect relationship between this predictor and the risk of DGF. In other words, greater reduction in the urinary level of NGAL at the 3 rd postoperative day (POD) was related to less risk of DGF. Discussion Precise detection of patients with elevated DGF risk is important, since DGF can convert into undesired post-transplantation events and eventually Salamzadeh J et al Delayed graft function (DGF) after living donor disposes the graft to both acute and chronic rejection, leading to increased health care costs and patient morbidity and mortality [12,23,36,37]. The first descriptive finding of our study was the 16.2% (11 patients) incidence rate for DGF, of which 3 patients (4.4%) needed dialysis. These are at the lower limit of the reported dialysis frequencies after living kidney transplantation [3,15 17]; however, the DGF rate (1.6%) in the study by Park et al. was lower than our finding [18]. None of the patients faced graft rejection. This might be a result of the prompt administration of polyclonal antibody (thymoglobulin) as soon as patients developed DGF. Brennan et al. also demonstrated that among deceased donor transplanted patients who were at high risk for DGF, induction therapy with antithymocyte globulin could reduce the incidence and severity of acute rejection [38]. Prior history of transplantation and blood transfusion can sensitize the immune system, leading to increased activity of preformed antibodies. It has been shown that presensitization increases the risk of DGF in kidney transplant patients [13,39]. Nevertheless, in our study no relationship between history of blood transfusion and transplantation with DGF was shown. In a study at Carlos Van Buren Hospital in 2009, multivariate analysis of clinical parameters disclosed cold ischemia time (CIT) (>20 hours) and donor age (40±10.6 years) as 2 independent risk factors for DGF in living and deceased donor transplantation [14]. Similarly, another retrospective study in 2008 showed both older donor age (44.2±1.4 years) and longer CIT (21.5±0.7 hours) were significant risk factors for DGF [12]. Besides the study by Irish et al in the USA, findings of other investigations also confirmed donor age and CIT as highly significant risk factors for DGF in cadaver renal transplant recipients [40,41]. In our study, the range of donor age was between 20 to 36 years, and the mean donor age in DGF and non-dgf patients were 28.0±3.3 and 25.2±2.9 years, respectively. In addition, all of our patients had living donor transplantations, and cold or warm ischemia times for all of them were less than 1 hour. These differences could be possible explanations for different results obtained in our study compared to those mentioned above. Although recipient variables including age >55 years, weight >100 kg and body mass index (BMI) 73

6 Original Paper Ann Transplant, 2012; 17(3): >25 kg/m 2 have been reported as risk factors associated with DGF [36,40,42], in our study none of them were recognized as predictors for DGF. Mean age (36.7±16.7 years) and BMI (23.8±4.6 kg/m 2 ) of our patients were less than in the previously mentioned studies (Table 1) and the recipient weight range was 40 to 87.5 kg. Few studies have examined risk factors for DGF in living donor transplantation. In these studies, it was shown that the recipient-donor body weight ratios were higher in the DGF group [15 17]. In our investigation, recipient-donor body weight ratio (0.894±0.204 in DGF and 0.717±0.320 in non- DGF patients) (Table 1) were less than in other studies. This might be the reason we could not find any association between DGF and this ratio. Ischemia reperfusion injuries (IRI) have a detrimental impact on graft tissue after transplantation, and may also lead to alteration in metabolism of micromolecules and production of biomarkers [43]. Some studies have found that patients who developed DGF can have higher values of urinary NGAL and IL-18 after cadaver transplantation. They concluded that these biomarkers could be predictive of DGF before the appearance of other clinical features [20,21]. Urine biomarker levels of our patients were much less than in the above-mentioned studies, very likely because all of our patients had living donors. Additionally, IRI and DGF are less prevalent and have lower severity in this type of graft. The biomarker levels of this study did not increase between 2 sampling times (first and third post-operative days), and even NGAL levels decreased, which may be a result of immediate control of patients by modifying immunosuppressant regimens and administration of thymoglobulin. Model building using logistic regression revealed that the rate of NGAL level alteration between the 1 st and 3 rd days after surgery was independently related to DGF. In DGF patients this reduction was significantly less than in non-dgf patients; however, urine NGAL levels decreased between the first to third post-operative days in all patients (Table 1). NGAL is described as a troponin-like biomarker for human acute kidney injury, especially after kidney transplantation, and urinary NGAL levels may serve as an early marker for ischemic renal injury [44]. According to earlier reports, NGAL levels could increase or remain unchanged from early hours to the second or third days after grafting in deceased donor transplantation [20], but in our study, probably because of the live donor transplantation, oxidative stress phenomena were less common than in other studies. Conclusions None of the demographic and patient/donor characteristics studied in this investigation could act as an explanatory factor for the development of DGF. This finding, apart from intense and thorough work-up tests and assessments prior to the kidney transplantation, could be a result of live kidney transplantation (in contrast to cadaver transplantation), which minimizes the potential negative impact of possible risk factors on transplanted kidney function. Our findings are in agreement with the results of a study published in 2012 by Park et al., in which they retrospectively investigated possible risk factors for DGF in 429 living donor renal transplantation recipients and did not report any significant risk factor for DGF occurrence [18]. However, as demonstrated by the considerable rate of DGF (16.2%) in study patients, special attention is still required to target post-operation inflammation and oxidative stress phenomena. This was established by the indirect relationship observed between DGF and urinary NGAL levels alterations on postoperative days. To obtain more comprehensive conclusion, another prospective study with a larger sample size is recommended. Acknowledgement The authors would like to thank the nursing staff of the nephrology ward of the Shahid Labbafinejad University Hospital. We also thank the School of Pharmacy, and the Urology and Nephrology Research Center of Shahid Beheshti University of Medical Sciences, Tehran, Iran, for their support of this research, which is a part of a thesis for clinical pharmacy specialty. Authorship and conflict of interest statement We, the authors of the article titled Delayed graft function (DGF) after living donor kidney transplantation: A study of possible explanatory factors, hereby declare that we have no conflict of interest in relation to this work. References: 1. Yarlagadda SG, Coca SG, Garg AX et al: Marked variation in the definition and diagnosis of delayed graft function: a systematic review. Nephrol Dial Transplant, 2008; 23:

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