© Ann Transplant, 2012; 17(3): 69-76 PMID: 23018258
Original Paper
Received: 2012.06.10 Accepted: 2012.08.15 Published: 2012.09.28
Delayed graft function (DGF) after living donor kidney transplantation: A study of possible explanatory factors
Authors’ Contribution: A Study Design B Data Collection C Statistical Analysis D Data Interpretation E Manuscript Preparation F Literature Search G Funds Collection
Jamshid Salamzadeh1 ACDEF, Zahra Sahraee1 ABCDEF, Mohsen Nafar2 ABDEF, Mahmoud Parvin2 CD 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 1
Summary
Background:
Material/Method:
Result:
Conclusions:
Key words:
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 1st and 3rd 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 1st day after transplantation, level of IL 18 on the 3rd 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 1st and 3rd 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
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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: 14155-6153, e-mail:
[email protected]
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Original Paper
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
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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].
Ann Transplant, 2012; 17(3): 69-76
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
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Ann Transplant, 2012; 17(3): 69-76
Table1. Distribution of the study variables and the univariate analyses results.
Number
DGF
IGF (non DGF)
11
57
41.18 (15.77)
35.84 (16.84)
P-value
Recipients age,years (s.d)
Donors age, year (s.d)
28 (3.31)
Recipients gender (%) Male Female
5 (45.45) 6 (54.55)
32 (56.14) 25 (43.86)
NS
Donor gender (%) Male Female
11 (100) 0
47 (82.45) 10 (17.55)
NS
Recipients BMI (s.d)
25.07 (4.23)
23.50 (4.60)
NS
Donor BMI (s.d)
23.99 (5.60)
25.21 (4.24)
NS
Recipient-donor body weight ratio
0.894 (0.204)
NS
TX number First TX Re-TX
8 (72.72) 3 (27.28)
Residual diuresis (%) 1000
25.19 (2.91)
0.717 (0.320)
NS 0.004
56 (98.24) 1 (1.76)
0.012
5 (45.45) 5 (45.45) 0 1 (9.1)
12 (21.05) 16 (28.07) 13 (22.81) 16 (28.07)
0.046
Blood transfusion (%)
6 (54.55)
15 (26.31)
0.082
Relationships between donor and recipient (%)
1 (9.09)
5 (8.77)
1st POD NGAL (ng/ml) IL 18 (pg/ml)
3.77 (1.93) 27.88 (23.18)
1.82 (1.75) 22.24 (33.05)
0.002 NS
3rd POD NGAL (ng/ml) IL 18 (pg/ml)
0.81 (0.89) 33.48 (30.26)
0.87 (1.24) 25.27 (27.25)
NS 0.096
Mean change in urine NGAL from 1st POD to 3rd POD
Mean change in urine IL 18 from 1st POD to 3rd POD
–5.59 (27.07)
2.96 (1.61)
1.02 (1.42)
–3.03 (29.01)
1
0.002
NS
DGF – delayed graft function; IGF – immediate graft function; NS – 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
