Evaluation of the rate of TLR-4 ASP299GLY AND THRE399ILE polymorphisims and leukocyte TLR4 expression levels in patients with and without postpyelonephritic renal scarring

Background and Aim: TLR-4 is expressed in innate immune system cells, recognizes LPS of Gram (-) bacteria and initiates inflammatory cascade. This inflammatory process results in renal scarring during pyelonephritis. Children carrying TLR-4 polymorphisms have recurrent urinary tract infections. Leukocyte TLR-4 expression level is decreased in patients with recurrent urinary tract infections and in those with asymptomatic bacteriuria. In this study, we aimed to determine the rate of TLR-4 Asp299Gly and Thr399Ile polymorphisms and leukocyte TLR-4 expression level in children with acute pyelonephritis in order to evaluate the association of those parameters with renal scar development.Patients and Methods: The study was performed in children with pyelonephritis and without underlying urological anomalies other than primary vesicoureteral reflux (VUR) who have been followed up in Pediatric Nephrology Outpatient Clinic of Dokuz Eylul University Medical Faculty. Patients with and without renal scarring were classified as Group 1 and Group 2, respectively, while the control cases in our previous study were used as control group (Group 3). Furthermore, new control cases were enrolled to determine leukocyte TLR-4 expression levels. All three groups were compared for the rate of TLR-4 Asp299Gly and Thr399Ile polymorphisms determined in genomic DNA obtained from periperal blood samples, and for basal and LPS stimulated periperal blood myeloid cell TLR-4 expression levels. Statistical analyses were performed by SPSS 15.0 software.Results: There were 168 patients (86 in Group 1, 82 in Group 2) and 120 control cases. Myeloid cell TLR-4 expression levels were similar in Groups 1 and 2. However, both groups had lower basal and LPS stimulated TLR-4 expression levels than Group 3. While the rate of TLR-4 Asp299Gly polymorphism was not different among the three groups, the rate of TLR-4 Thr399Ile polymorphism was higher in Groups 1 and 2 than in Group 3. Group 1 and Group 2 were not different. On the other hand, the rate of TLR-4 Asp299Gly and Thr399Ile polymorphisms and TLR-4 expression levels were not different among VUR (-) vs VUR (+) and among single vs recurrent pyelonephritis.Conclusion: Patients with pyelonephritis had more frequent TLR-4 Thre399Ile polymorphism and lower leukocyte TLR-4 expression level compared to healthy controls. These findings indicate that children carrying TLR-4 Thre399Ile polymorphism and/or having low level of leukocyte TLR-4 expression have a tendency to develop pyelonephritis, probably due to difficulty in eradication of bacteria from the urinary system. However, we could not show the association of TLR-4 polymorphisms and of TLR-4 expression level to postpyelonephritic renal scarring.