Evaluation of cell CYCLE biomarkers in prediction of graft function after renal transplantation

It is very important to monitor closely graft functions for early diagnosis and treatment of graft dysfunctions in first week after renal transplantation. EGF (early graft function) is defined as a 70% or more decrease in serum creatinine levels of renal transplantation recipients within the first week, whereas SGF (slow graft function) is defined as less than 70% reduction. DGF (delayed graft function) is defined as performing hemodialysis at least once in the first week in a patient who has undergone renal transplantation. The aim of this study was to evaluate the possible relationship of urinary levels of TIMP-2 (Tissue Inhibitor of Metalloproteinase-2), IGFBP-7 (Insulin-like Growth Factor-Binding Protein-7), which are known as cell cycle biomarkers and NGAL(Neutrophil Gelatinase-Associated Lipocalin) with graft functions in the first week in renal transplantation recipients. Our study included 80 renal transplant recipients (19 women, 61 men; mean age ± SD: 41.48±12.93 years; 78 live, 2 cadaver donors). Serum and urine samples from renal transplant recipients were collected on the 1st and 7th days after transplantation. The analyzes of serum and urine creatinine were carried out by colorimetric (Jaffé), urine protein by turbidimetric, serum BUN by spectrophotometric, CRP by immunoturbidimetric, urine osmolality by cryoscopy (freezing point depression) methods. Urinary NGAL, TIMP-2 and IGFBP-7 levels were determined by using ELISA (Enzyme-Linked Immunosorbent Assay) method. Estimated GFR (glomerular filtration rate) values were calculated with serum creatinine-based CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) and MDRD (Modification of Diet in Renal Disease) formulas. Urinary NGAL, TIMP-2, IGFBP-7 and TIMP-2 x IGFBP-7 levels were given directly and in divided by urine creatinine and osmolality. DGF and SGF were not observed in the recipients within the first week. 1st day GFRCKD-EPI <20 (n= 20) and GFRCKD-EPI ≥20 (n=60), 7th day GFRCKD-EPI <60 (n=14) and GFRCKD-EPI ≥60 (n=66) groups were formed according to the GFR values of the recipients. Serum creatinine, BUN, CRP, and urine protein/creatinine levels significantly decreased on the 7th day after renal transplantation (p <0,0001). Furthermore, urinary NGAL (p <0,0001), TIMP-2 (p <0,003) and TIMP-2 x IGFBP-7 (p <0,008) levels significantly decreased on the 7th day. Positive and significant correlations were observed between 7th day urinary TIMP-2 and 7th day serum creatinine (r=0.283), CRP (r=0.233), serum BUN (r=0.373), urine protein (r=0.416) and urine protein/creatinine (r= 0,448) results. Similarly, positive and significant correlations were found between 7th day urinary TIMP-2 x IGFBP-7 and 7th day serum creatinine (r=0.284), serum BUN (r=0.350), urine protein (r=0.326) and urine protein/creatinine (r=0.360) results. ROC (receiver operating characteristic) analysis was used to evaluate the prediction of graft functions with these biomarkers on the 7th day after renal transplantation. The area under the receiver operator characteristic curve (AUC) for serum creatinine was 0,975. Urinary TIMP-2 (AUC=0.745), TIMP-2/creatinine (AUC=0.747), TIMP-2/osmolality (AUC=0.765), TIMP-2 x IGFBP-7 (AUC=0.746), ( TIMP-2 x IGFBP-7)/creatinine (AUC=0.740), (TIMP-2 x IGFBP-7)/osmolality (AUC=0.769) and [(TIMP-2/osmolality) x (IGFBP-7/osmolality)] (AUC=0.774) AUC values were between 0.740-0.774. Our results show that urinary TIMP-2 and TIMP-2 x IGFBP-7 levels may be useful in the evaluation of graft functions in the first week of renal transplant recipients. Reporting results as TIMP-2/creatinine, TIMP-2/osmolality, (TIMP-2 x IGFBP-7)/creatinine, and (TIMP-2 x IGFBP-7)/osmolality may improve standardization and reliability. Further investigation in multicentre and larger-scale are needed to emphasize the predictive values of these biomarkers. Keywords: Renal transplantation, graft function, TIMP-2, IGFBP-7, NGAL