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Abstract
Increases in serum creatinine (sCr) and oliguria are the current functional criteria for recognising acute kidney injury (AKI) including AKI causing delayed graft function (DGF) and slow graft function (SGF) following kidney transplantation. However, there are limitations to GFR reduction as a marker of AKI or its successful treatment. Moreover, increases in sCr or oliguria have limitations as surrogates of GFR. Alternatives for evaluation of AKI and DGF include other functional biomarkers and urinary biomarkers of kidney damage.
We developed a time-dependent biomarker profile of moderate-to-severe cisplatin-induced AKI in rats, and evaluated histological injury, functional biomarkers, and kidney-damage biomarkers. Several potential interventions to ameliorate cisplatin-induced AKI were then assessed. Subsequently, kidney damage biomarkers were monitored during the functional amelioration of alpha-lipoic acid (A-LA) for treatment of cisplatin-induced-AKI, with the general aim of evaluating whether damage biomarkers could improve monitoring of intervention in AKI. The clinical use of novel functional and damage biomarkers in the diagnosis of cisplatin-induced AKI was also evaluated in an observational study. Finally, observational studies were conducted to evaluate functional biomarkers including kinetic eGFR, and kidney damage biomarkers for diagnosis of DGF or SGF.
A-LA treatment ameliorated cisplatin-induced AKI in rats with protection demonstrated by reductions in structural damage, markers of loss of function, and in biomarkers of tubular damage. In the first clinical study, plasma cystatin C increased independently of other functional or damage AKI biomarkers after cisplatin-based chemotherapy, suggesting limitations to cystatin C use in this context. In a second clinical study, VEGF-A, urinary clusterin and the cell cycle arrest biomarkers TIMP-2 and IGFBP7 predicted with DGF within 4 hours of transplantation. Despite the usual limitations of sCr, early and frequent assessment of rate of change of sCr also predicted DGF: the creatinine reduction ratio predicted DGF within 12 hours, while estimates of kinetic GFR were predictive within 4 hours of renal transplantation.
Despite a clear need for novel AKI biomarkers, their use and interpretation remains context-specific. These novel AKI biomarkers require robust pre-clinical data, evaluation in specific contexts, and comparison with currently available parameters before clinical use.