Transdermal GFR Enables Early Detection of Functional Acute Kidney Injury in a Cirrhotic Mouse Model Without Tubular Injury.

Abstract

Background: AKI is a common complication associated with significant mortality in patients with end-stage liver disease. Current diagnostic criteria primarily rely on serum creatinine levels, which may be influenced by reduced muscle mass commonly observed in cirrhotic patients, thereby delaying the recognition of renal impairment. This study aims to evaluate the efficacy of transdermal glomerular filtration rate (tGFR) measurement for the early diagnosis of renal dysfunction in a AKI murine model of cirrhosis.

Methods: A murine model of cirrhosis-associated AKI (cAKI) was established through a 12-week regimen of intragastric administration of 50% carbon tetrachloride (CCl4, 1 mL/kg), followed by a single intraperitoneal injection of lipopolysaccharide (LPS). Renal function was evaluated using transdermal glomerular filtration rate (tGFR) measurement and compared with conventional markers, including serum creatinine and blood urea nitrogen (BUN) levels.

Results: Following the induction of the murine model of cAKI, mice received a single intravenous dose of fluorescein-isothiocyanate (FITC)-conjugated sinistrin (75 mg/kg). FITC-sinistrin fluorescence intensity was continuously monitored every 2 seconds for 1.5 to 2 hours using a skin-attached miniaturized sensor. The transdermal glomerular filtration rate (tGFR) was calculated based on a relative fluorescence intensity (RFI) curve using a two-compartment pharmacokinetic model. Serum blood urea nitrogen (BUN) and creatinine (CREA) levels were measured at 2, 4, 8, 12, and 24 hours after LPS administration. Histological analysis revealed that cAKI did not induce significant tubular injury. Notably, tGFR detected a significant reduction in glomerular filtration as early as 2 hours post-LPS ( 0.54± 0.207 vs. 1.06 ± 0.273 μL/min/100 g), whereas BUN levels did not rise significantly until 4 hours (33.94 ± 3.683 vs. 18.7 ± 2.414mmol/L). Serum creatinine and the BUN/CREA ratio showed no significant changes throughout the observation period.

Conclusions: Transdermal glomerular filtration rate demonstrates superior sensitivity compared to creatinine- and BUN-based criteria for the early detection of renal impairment in cirrhosis-associated AKI, highlighting its potential clinical utility and warranting further investigation.