Reliable markers of early acute injury following renal transplantation would enable timely therapeutic interventions. Standard serum creatinine and blood urea nitrogen measurements increase only after significant renal damage has occurred. We examined serial changes of neutrophil-gelatinase associated lipocalin (NGAL) and nephrin (NPHS2) as markers of tubular and glomerular injury, respectively. A/J (H-2a) kidneys were perfused with UW solution and subjected to a clinically relevant 4 hours of cold-ischemia prior to transplantation to C57BL/6 (H-2b) recipients. Mice were sacrificed at 2, 6, 14 and 28 days. Allografted kidneys were excised for protein and histological analysis. Daily urine samples were collected in the first 6 days and at 14, 21 and 28 days. Urinary NGAL was increased 1 day after transplantation (3037 ng/ml; n=4) and decreased on days 2 and 3 (776 and 612 ng/ml, respectively). These values were similar to isografts and reflect ischemia-reperfusion injury. Subsequently, urinary NGAL increased progressively on days 4 to 6 (923, 1659 and 4011 ng/ml, respectively) in allografts, but not isografts. In the graft tissue, NGAL was increased 10-fold compared with isograft controls at 2 days (90 vs 9 ng/mg), and peaked (26 fold increase; 233 vs 9 ng/mg) at 6 days. The increase in NGAL at day 6 corresponded to positive staining for NGAL in proximal tubules and intense infiltrates of T cells. By day 14, NGAL decrease to 70 ng/mg, followed by a rebound (200 ng/mg) on day 28. In contrast, urinary nephrin concentrations progressively increased from day 2 to day 28, while the levels of nephrin in the allografts progressively decreased from day 2 (73 ng/mg) through day 6 (53 ng/mg) and 14 (52 ng/mg) to day 28 (27 ng/mg). The decrease in nephrin protein in the allograft coincided with progressive deposits C4d in capillaries and glomerular pathology. These data indicate that urinary NGAL and nephrin could serve as markers of T cell-mediated tubular injury and antibody-mediated glomerular injury, respectively.

CITATION INFORMATION: Shim Y., Fan R., Dvorina N., Baldwin W. Acute Tubular and Glomerular Kidney Injury Markers Reflect Ischemia-Reperfusion and Rejection Am J Transplant. 2017;17 (suppl 3).

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