The value of the relationship of neutrophil lymphocyte rate and platelet lymphocyte ratio with acute rejection and their role in determination of chronic alllogreft nephropathy in pediatric patients followed after renal transplantation

Despite advances in conservative treatments, chronic kidney disease (CKD) in children can progress into end-stage renal disease (ESKD). The best method of renal replacement therapy (RRT) for children is renal transplantation (RTx). In pediatric patients, RTx is associated with better outcomes in terms of both health-related quality of life measures and patient growth and development compared to peritoneal dialysis (PD) or hemodialysis (HD). Allograft loss is the most important complication that can develop after RTx. The two leading causes of graft loss are acute rejections and chronic allograft nephropathy. Acute rejection, which occurs days or weeks after RTx, is characterized by an inflammatory event manifested by specific pathological changes even in the absence of graft dysfunction. As clinical markers are usually insufficient to make a diagnosis of acute rejection, the gold standard method in the diagnosis of acute rejection is renal biopsy, which is an invasive procedure. Therefore, new markers are needed to predict acute rejection. Chronic allograft nephropathy (dysfunction) is a slow type of rejection and may occur within the first year after RTx, or graft loss may develop gradually over the years. It is a histopathological definition used to describe chronic interstitial fibrosis and tubular atrophy of the allograft which occur secondary to chronic inflammatory processes. Progressive decrease in the renal function tests, manifested by an increase in serum creatinine, proteinuria and hypertension are warning signs against chronic allograft nephropathy. Although the severity of these disorders varies from patient to patient, they are usually progressive and irreversible. Various blood and urine parameters, especially complete blood count, blood biochemistry and complete urinalysis, are used in routine patient follow-up after RTx. The neutrophil lymphocyte ratio (NLO) and thrombocyte lymphocyte ratio (TLO), which can be easily measured from peripheral blood, have been accepted as inflammation markers in the recent years and are currently used to evaluate disease activity in some diseases. In this study, the relationship of NLO and TLO with the acute rejections attacks in pediatric RTx patients aged 5-18 years, who were followed-up in our hospital for at least 5 years between 2000 and 2020, and their role in determining chronic allograft nephropathy was investigated. Demographic characteristics of the 58 patients included in the study were analyzed. Mean age of our patients was 16.1±2.1 years, and the majority of the patient group consisted of boys (62.1%, n=36). CAKUT group diseases were the most common cause of ESRD in the pre-RTx period,( 41.4%, n=24), and isolated VUR was the most common diagnosis in this group (27.7%, n=16). Pre-RTx CKD duration was 3.9±2.9 years, and 79% of the cases (n=46) received HD and/or PD treatment before RTx. The mean duration of dialysis was 1.8±1.6 years. PD application time was longer than HD (p<0.01). The age at RTx was 12.7±3.1 years. The majority of the patients were transplanted from a living donor(75.8%, n=44), and most of the living donors were first-degree relatives (72.7%, n=32). When the blood and urine parameters of the patients were evaluated before and after RTx, it was observed that serum creatinine, spot urine protein/creatinine ratio and 24-hour urinary protein excretion significantly decreased, and GFR and Hb values significantly increased, as expected (p=0,01 for 24-hour protein excretion and Hb, p=0,001 for the others). When compared to pre-RTx period, NLR was highest in post-RTx 1st month (1,98±0,84 vs 2,89±2,5, p=0,019), thereafter it decreased and stabilized to the basal values in 3 months. On the other hand, no significant change was observed in the course of TLO before and after RTx. Hyperacute rejection was not observed in any of the 58 patients included in the study. During the 5-year follow-up after RTx, 32.7% (n=19) of the patients had a total of 31 biopsy-proven acute rejection attacks. The mean time of acute rejection was 1.2±1.0 years after RTx. 61.2% of the acute rejections (n=19) were of cellular type. It was observed that recurrent acute rejection attacks could be of different histopathological types. During the acute rejection atttacks, the patients had an increase in serum creatinine, spot urinary protein/creatinine ratio, 24-hour urinary protein excretion, acute phase reactants (CRP and procalcitonin), and decreased GFR, as expected. Both NLR and TLR were also found to be significantly higher during acute rejection attacks (p=0.003 for NLR, p=0.002 for TLR). Chronic allograft nephropathy developed in 17,2% of the patients (n=10) mean 2,5±1,0 years after RTx in the 5-year follow-up. When the patients with and without chronic allograft nephropathy were evaluated, patients who developed chronic allograft nephropathy had increase in serum creatinine, spot urine protein/creatinine ratio, 24-hour urinary protein excretion and acute phase reactants, and a decrease in GFR at the end of the 5th year. Although both NLR and TLR were found to be higher in patients with chronic allograft nephropathy at the end of 5-year follow-up after RTx, the difference was not statistically significant (p=0.69 for NLR and p=055 for TLR). It was found that NLR was in the first 2 years and TLR was higher in the first 4 years in patients with chronic allograft nephropathy than the other patients. Among the patients who had acute rejection, NLR was found to be higher in the first 3 years and TLR was higher in all periods after RTx in those who developed chronic allograft nephropathy during the follow-up. In our study, chronic allograft nephropathy developed in all of the cases with multiple acute rejection attacks after 5-year follow-up. Patients with recurrent acute rejection had a significantly higher risk of developing chronic allograft nephropathy compared to patients with a single acute rejection (p=0.047). It was observed that 82.7% of the cases (n=48) in the study group developed viral and/or bacterial infections that required treatment during the 5-year follow-up. Urinary tract infections were the most common foci of infection (%54,1, n=26). However, no significant effect of previous infections on chronic allograft nephropathy was detected. In conclusion, we believe that NLR and TLR values can be used as easily accessible markers in the diagnosis of acute rejection and chronic allograft nephropathy, both of which can be considered as the most important causes of graft loss after RTx. No previous study exists in the literature that evaluate NLR and TLR parameters in pediatric patients who underwent RTx. Our study is the first study focusing on this subject. However, we believe that pediatric studies with larger populations are needed to support our findings.