EXPERIMENTAL AND CLINICAL TRANSPLANTATION

Introduction
Delayed graft function (DGF), presenting as poor renal function, is a common adverse outcome after renal transplant in pediatric recipients. Delayed graft function is defined as the need for dialysis intervention within the first week of transplant and/or creatinine reduction ratio less than 70% between day 0 and day 7 after transplant.^1,2 Risk factors include preoperative creatinine level, blood group, dialysis duration, donor type, and ischemia-reperfusion injury to the organ.³ Attempts for early prediction and prevention of DGF are often challenging and misleading.^3,4 Platelet-to-lymphocyte ratio (PLR) and neutrophil-to-lymphocyte ratio (NLR) have been shown to be useful indicators for outcome prediction in cardiac conditions and colorectal cancer and most recently for prediction of acute allograft rejection in kidney transplant recipients.^4-7 Varying levels of PLR and NLR have been used as prognostic indicators for the development of DGF in adult renal transplant recipients; however, the literature remains divided on their prediction.

In this retrospective study, we investigated the correlation between DGF and noninvasive hematologic parameters to predict the possible adverse outcomes prior to renal transplant. Herein, we aimed, for the first time, to assess and identify the best preoperative cutoff values for PLR and NLR for prediction of DGF in pediatric renal transplant recipients.

Materials and Methods
In this single-center retrospective study, we compared the preoperative hematologic parameters of 16 patients who developed DGF and 35 patients who did not develop DGF and assessed the role of these parameters for prediction of DGF outcomes. We included a total of 51 pediatric patients, aged between 1 and 18 years, who underwent renal transplant at Başkent University Hospital, Ankara, Turkey. We excluded adult (age >18 years) recipients, recipients of repeated kidney transplants, and recipients for whom preoperative full blood count data were not obtained within 10 days prior to the renal transplant. Demographic characteristics, preoperative features (primary disease, clinical presentation, panel reactive antibody, induction therapy, and complete blood count data), and donor characteristics (donor type and laterality of renal transplant) were obtained from an electronic medical record system. After the renal transplant procedure, all patients received steroid, calcineurin inhibitor, and mycophenolate mofetil as immunosuppressive agents.

Delayed graft function was defined as the need for dialysis within the first week of renal transplant. The PLR and NLR were defined as platelet-to-lymphocyte ratio and neutrophil-to-lymphocyte ratio, respectively. We calculated PLR and NLR from the most recent preoperative complete blood count data of 51 kidney transplant recipients. We performed the receiver operating characteristic (ROC) curve analysis to obtain the optimal cutoff values with highest sensitivity and specificity for PLR and NLR. After the cutoff values were validated by ROC curve analysis, the inflammation indexes for the patients were further categorized into groups with high and low ratios.

Statistical analyses
Continuous variables are presented as median values with interquartile ranges, and discrete variables are presented with frequencies and percentages. Normally distributed variables were compared with the t test, whereas the abnormally distributed variables were compared with the Mann-Whitney U test. We used the ROC curve analysis to classify the optimal cutoff values for PLR and NLR with highest sensitivity and specificity. We used the Pearson chi-square test and Fisher exact test for the categorized data and the Kruskal-Wallis test for continuous variables. Data were analyzed using the IBM SPSS statistics version 26.0. A 2-sided P < .05 was considered statistically significant.

Results
Baseline demographic and clinical features of the patients
A total of 51 pediatric kidney transplant recipients (male/female, 33/18) with median age of 12 (interquartile range, 8-18) years met the inclusion criteria. The main etiologies for chronic kidney disease were congenital anomalies of the kidney and urinary tract in 16 patients, obstructive anomalies in 13, nephronophthisis in 8, cystic kidney disease in 2, cystinosis in 3, oxalosis in 2, and other etiologies in 7. There were no significant differences in sex (P = .319), age at transplant (P = .847), donor type (P = .481), and laterality of kidney transplant (P = .100) between the patients with and without DGF.

Comparison of clinical characteristics and laboratory features of patients with and without delayed graft function
There were no significant differences in preoperative creatinine level (P = .356), preoperative thrombocyte count (P = .626), white blood cell count (P = .366), and monocyte level between the patients with and without DGF. Median preoperative values for lymphocytes were significantly higher in the DGF group compared with the non-DGF group (2 vs 1 [P = .040]). Median preoperative values for neutrophils were significantly lower in DGF group when compared with the non-DGF group (4.2 vs 7.7 [P = .037]). Furthermore, the median value for PLR and NLR was significantly lower in the DGF group compared with the non-DGF group (145 vs 219 [P = .035] and 2.5 vs 8.2 [P = .015], respectively). We performed ROC curve analysis for PLR and NLR to assess the preoperative predictive value for DGF, which showed that the area under the curve (AUC) was 0.69 for PLR (P = .035) and 0.714 for NLR (P = .015) (Figure 1). Overall, NLR produced a larger AUC than PLR. According to the AUC values, we identified a cutoff value of 175 for PLR (sensitivity and specificity, 0.69 and 0.31, respectively) and a value of 5 for NLR (sensitivity and specificity, 0.75 and 0.31, respectively). After validation of cutoff values, the inflammatory indexes were further categorized into the following groups: PLR low (≤175) and high (>175), and NLR low (≤5) and high (>5). The cutoff values indicated that 11 of 16 patients who developed DGF had a low preoperative NLR (<5) compared with the non-DGF group (68.8% vs 34.3%, P = .023), and 11 of 16 patients who developed DGF had a low preoperative PLR (<175) compared with the non-DGF group (68.8% vs 31.4%, P = .014). Comparisons of demographic, clinical, and laboratory features of the patients with and without DGF are shown in Table 1.

Discussion
Delayed graft function is often associated with sys-temic inflammation, augmented by the disruption in hematologic cell lines. Several studies suggest that neutrophilia, thrombocytosis, and lymphocytosis are the main perpetrators, resulting in elevation of inflammatory biomarkers in patients with acute cellular rejection in solid-organ transplant, colorectal cancer, and cardiac conditions.^1,2,5-7 In our study, preoperative low PLR and NLR was significantly associated with the increased number of DGF when compared to non-DGF patients. The association between downstream activation of a recipient’s lymphocytes and immediate allograft injury leading to DGF is well documented.^8,9 Several studies on lymphocyte depletion strategies in kidney transplant recipients have demonstrated efficacious reduction in overall graft rejection, which has led to the use of lymphocyte depletion agents in both induction and maintenance therapies.^8,9 In our study, preoperative low levels of PLR and NLR were partly associated with a relative increased number of lymphocytes in peripheral blood, which is expected given the pathogenesis of DGF. It was previously reported in a case control study low average values for NLR and PLR were highly associated with the acute cellular rejection of adult kidney allografts.⁴ Similarly, Yildiz and Yildiz also found that low NLR level was significantly associated with corneal graft rejection after low-risk penetrating keratoplasty.¹⁰ However, several reports on the association between inflammatory biomarkers and an early graft injury found conflicting results regarding the optimal predictive cutoff value for the immune-inflammation index.^7,8,10 In our study, the optimal cutoff values for PLR and NLR were identified as 175 and 5, respectively.

To the best of our knowledge, this is the first study to evaluate the association between preoperative PLR and NLR with DGF in pediatric kidney transplant recipients. In this single-center study, the pretransplant low PLR and low NRL was inversely associated with DGF; therefore, these novel and noninvasive inflammatory biomarkers may contribute to an early prediction of DGF in kidney transplant recipients. We acknowledge the limitations of our study, ie, single-center retrospective, unknown timing for cold and warm ischemia, and small sample size. Therefore, more prospective, longitudinal, and multicenter studies are required to validate the role of PLR and NLR for prediction of DGF in renal transplant recipients.

Volume: 20 Issue: 5 May 2022 - Supplement - 3

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