Effect of High Dose Erythropoietin on Early Graft Outcomes in NHBD and Ecd Kidney Recipients: A Randomised, Placebo-Controlled Trial

Abstract

Introduction: Neutrophil gelatinase-associated lipocalin (NGAL), interleukin-18 (IL-18) and kidney injury molecule-1 (KIM-1) have been suggested to be predictive of delayed graft function (DGF) following kidney transplantation. Studies to date have examined urine biomarker levels beginning post-operatively, without consideration for the contribution of residual renal function from the native kidneys. We performed a prospective study in recipients of ECD and NHBD kidneys, which examined the natural history of urine NGAL, IL-18 and KIM-1 levels from pre-engraftment until day 5 post-transplantation. Methods: In total, 39 patients were recruited into the study. Urine samples were collected longitudinally from the recipients preoperatively until day 5 post-transplantation. 21 out of the 39 recruited patients provided a native urine sample. NGAL, IL-18 and KIM-1 levels were measured by immunoassay and corrected for urine creatinine levels. All values relate to native urine biomarker levels in recipients prior to engraftment. Results: Urine NGAL (uNGAL) levels ranged from 0 -10367ng/mgCr and were inversely correlated with native urine output (Spearman r = -0.66, p=0.001). Urine KIM-1 (uKIM-1) levels ranged from 0 -9980pg/mgCr and were also inversely correlated with native urine output (Spearman r = -0.46, p=0.048). Urine IL-18 (uIL-18) levels were not correlated with urine output and ranged from 0 -2630pg/mgCr. Haemodialysis patients had higher uNGAL compared to peritoneal dialysis or pre-dialysis patients (ANOVA, p=0.004). uIL-18 and uKIM-1 levels did not correlate with dialysis modality. DGF, defined as the need for haemodialysis in the first week post transplantation, occurred in 9/21 patients and did not correlate with native uIL-18 or uKIM-1 levels. High uNGAL levels were present in native urine from patients who subsequently developed DGF (Mann Whitney, p=0.02). Finally, native biomarker levels of uNGAL and uKIM-1 were the strongest predictors of their posttransplant levels out to day 5, in a mixed effects model containing NGAL, IL-18, KIM-1 and donor type (p<0.004). Conclusions: The results from this study demonstrate that high levels of the biomarkers NGAL, IL-18 and KIM-1 can be found in native urine in the preoperative period. These levels were the strongest predictor of post-transplant levels, at all time points in the early post transplant period, irrespective of donor type. Thus native urine biomarker levels may confound early post operative measurements, which need to be viewed with caution when used in the prediction of AKI and DGF.