Objective: To investigate circulating biomarkers of initial graft injury in a porcine kidney autotransplant model.
Background: Injury endured by kidney grafts early posttransplant determines their outcome. However, creatinine (clearance) is a poor surrogate of tissue injury and urinary biomarkers are limited by graft anuria or persistent native kidney diuresis. No validated circulating biomarkers quantifying initial graft injury exist.
Methods: Minimally injured porcine kidney grafts (n = 6) were cold stored (18 hours) and autotransplanted. Moderately (n = 6) and severely injured grafts (n = 7) were exposed to 30 or 60 minutes warm ischemia before storage and autotransplantation. Four biomarkers [aspartate transaminase (AST), heart-type fatty acid–binding protein (H-FABP), neutrophil gelatinase–associated lipocalin (NGAL), and N-acetyl-β-glucosaminidase (NAG)] were measured posttransplant and compared with creatinine (clearance) and histology.
Results: Diuresis was delayed in moderately [2.5 days (2–3)] and severely [4 days (4–5)] versus minimally injured grafts (P < 0.001). Creatinine peaked later than AST, H-FABP, and NGAL [4 days (3–5) vs 3 hours (3–6), 6 hours (6–24), 2 days (1–3), respectively] and only differentiated minimally from severely injured grafts. Peak AST and H-FABP distinguished all injury grades. Neutrophil gelatinase–associated lipocalin discriminated initial graft injury 2 days posttransplant. Peak AST, H-FABP, and NGAL correlated with peak creatinine [Pearson coefficients: 0.70 (P = 0.001), 0.85 (P < 0.0001), 0.80 (P < 0.0001)]. N-acetyl-β-glucosaminidase was not different. Decreased clearance accounted for a small percentage of H-FABP and NGAL increase. Histology was not different among transplanted groups.
Conclusion: Plasma AST, H-FABP, and NGAL reflect the severity of initial kidney graft injury and predict graft dysfunction earlier and more accurately than creatinine (clearance) and histology. They represent promising tools to improve patient care after kidney transplantation.
No validated biomarkers quantifying kidney graft injury exist. This study showed that plasma aspartate transaminase, heart fatty acid–binding protein, and neutrophil gelatinase–associated lipocalin were earlier, more accurate markers of initial graft injury compared with creatinine (clearance), histology, and urinary biomarkers in a clinically relevant kidney transplant model.
*Department of Abdominal Transplant Surgery
†Department of Morphology and Molecular Pathology, University Hospitals Leuven, KULeuven, Belgium;
‡Department of Pathophysiology, Liver Research Facility/Laboratory of Hepatology, Faculty of Medicine, KULeuven, Belgium.
Reprints: Ina Jochmans, MD, University Hospitals Leuven, Department of Abdominal Transplant Surgery, Herestraat 49, B-3000 Leuven, Belgium. E-mail: firstname.lastname@example.org.
Histidine-tryptophan-ketoglutarate preservation solution was provided by Köhler Chemie, Alsbach-Hanhlein, Germany; University of Wisconsin solution was provided by Organ Recovery Systems, Zaventem, Belgium as SPS-1 Static Preservation Solution.
I.J. is a doctoral fellow associated with the Research Foundation-Flanders, Belgium.
J.P. and D.M. are holders of a chair Abdominal Transplant Surgery from the Centrale Afdeling voor Fractionering, Vilvoorde, Belgium.
Disclosure: Supported (in part) by unrestricted grants from Astellas and Roche, Belgium.