IL-18 and Urinary NGAL Predict Dialysis and Graft Recovery after Kidney Transplantation

Current methods for predicting graft recovery after kidney transplantation are not reliable. We performed a prospective, multicenter, observational cohort study of deceased-donor kidney transplant patients to evaluate urinary neutrophil gelatinase-associated lipocalin (NGAL), IL-18, and kidney injury molecule-1 (KIM-1) as biomarkers for predicting dialysis within 1 wk of transplant and subsequent graft recovery. We collected serial urine samples for 3 d after transplant and analyzed levels of these putative biomarkers. We classified graft recovery as delayed graft function (DGF), slow graft function (SGF), or immediate graft function (IGF). Of the 91 patients in the cohort, 34 had DGF, 33 had SGF, and 24 had IGF. Median NGAL and IL-18 levels, but not KIM-1 levels, were statistically different among these three groups at all time points. ROC curve analysis suggested that the abilities of NGAL or IL-18 to predict dialysis within 1 wk were moderately accurate when measured on the first postoperative day, whereas the fall in serum creatinine (Scr) was not predictive. In multivariate analysis, elevated levels of NGAL or IL-18 predicted the need for dialysis after adjusting for recipient and donor age, cold ischemia time, urine output, and Scr. NGAL and IL-18 quantiles also predicted graft recovery up to 3 mo later. In summary, urinary NGAL and IL-18 are early, noninvasive, accurate predictors of both the need for dialysis within the first week of kidney transplantation and 3-mo recovery of graft function.Kidney allograft function after transplantation varies from a rapid increase in GFR, causing brisk reductions in serum creatinine (Scr), to primary allograft failure. Defined as the need for dialysis within 1 wk of transplantation, delayed graft function (DGF) occurs in 20 to 33% of deceased-donor kidney transplants (DDKTs).^1–4 Recent strategies for increasing the donor pool include using “extended-criteria donor” (ECD) and “donation after cardiac death” (DCD) kidneys. Both types are associated with higher rates of DGF compared with standard-criteria kidneys.⁵ Thus, with more ECD/DCD transplants, as a strategy to reduce waiting lists, physicians will encounter DGF more frequently.DGF, predominantly caused by ischemia-reperfusion injury (IRI) from allograft procurement, occurs infrequently in living-donor kidney transplants (LDKTs).The role of IRI in graft survival was first highlighted by Terasaki et al.,⁶ who showed that graft survival was better in LDKTs than DDKTs, regardless of antigen mismatches. Moreover, they showed six-antigen mismatched grafts that functioned on day 1 had better 3-yr survival than perfectly matched grafts with delayed function. Investigators have actively sought preventative/therapeutic techniques aimed at reducing IRI and the need for post-transplant dialysis; however, apart from using hypothermic machine allograft perfusion and minimizing cold ischemia time,⁷ results have been disappointing.The deleterious effects of DGF in the immediate post-transplant period include increased lengths of stay and total hospital costs primarily because of the need for dialysis.^8,9 We examined the long-term role that DGF plays in patient and graft survival in a recent meta-analysis and showed more than 40% increased risk of graft loss at 1 yr with DGF.¹⁰ Even in patients not dialyzed after transplant, studies have shown poorer long-term outcomes with “slow graft function (SGF)” compared with “immediate graft function (IGF).”^3,11,12Although most studies agree that DGF is associated with poorer outcomes, multiple DGF definitions are used.^13–17 Current means of diagnosing DGF or SGF, using Scr and urine output (UOP), require knowledge of previous values to interpret, are affected by diuretic use, and can take a number of days to confirm.¹⁸ As in other forms of acute kidney injury (AKI) caused by IRI, this lag in diagnosis has greatly hampered efforts to prevent or treat renal injury in human trials.¹⁹ Additionally, with the exception of IGF, it is often impossible to predict recovery. Noninvasive measurement of accurate biomarkers near injury onset could make postoperative course prediction feasible and may ultimately promote advances in kidney transplantation and ischemic AKI.Ongoing studies of kidney IRI mechanisms have identified many potential biomarkers. Multiple translational studies have subsequently evaluated over 21 serum and urine biomarkers.²⁰ Three of the most intensely studied include neutrophil gelatinase-associated lipocalin (NGAL), IL-18, and kidney injury molecule-1 (KIM-1). Transplantation involves organ ischemia with eventual reperfusion. This makes DDKT a reliable model to evaluate the role of biomarkers in detecting IRI leading to DGF of variable severity/duration. We therefore conducted a multicenter, prospective-cohort study of patients receiving DDKTs to evaluate the timing and efficacy of using urinary NGAL, IL-18, and KIM-1 for predicting recovery of graft function and the need for dialysis within 1 wk after transplantation.