Kidney Tubule Secretion Can Discriminate the Cause of Acute Kidney Injury in Cirrhosis

Key Points In cirrhotic patients with AKI, tubular secretion differentiates those with acute tubular necrosis versus other causes. Different secretory function by cause of AKI may affect treatment approaches and drug dosing in patients with cirrhosis and AKI. Background AKI is a common and severe complication among hospitalized patients with cirrhosis. The most common causes of AKI in cirrhosis are prerenal azotemia (PRA), hepatorenal syndrome (HRS), and acute tubular necrosis (ATN), and treatment depends on its causes. Kidney proximal tubular secretion is an essential mechanism for elimination of many drugs and toxins and may be affected in AKI. We hypothesized that assessing secretion would help distinguish between structural tubular injury (ATN) and hemodynamic perturbations (PRA and HRS). Methods We collected paired plasma and spot urine specimens from 76 hospitalized patients with cirrhosis and AKI from four tertiary care centers in North America. A panel of endogenous metabolites known to be secreted was measured in blood and urine by tandem mass spectrometry, and a summary secretion score was calculated by averaging the standardized spot urine-to-plasma ratios of the endogenous secretion markers, with higher urine-to-plasma ratios reflecting greater tubular secretion. The summary secretion score was assessed for its ability to discriminate ATN from non-ATN. Results Among the 76 patients with cirrhosis and AKI, 39 (51%) had PRA, 13 (17%) had HRS, and 24 (32%) had ATN. Median secretion scores were significantly lower in ATN (50.3; 95% confidence intervals [CIs], 42.2 to 61.2) compared with PRA (61.7; 95% CI, 55.4 to 75.4) or HRS (62.5; 95% CI, 55.6 to 66.5; P = 0.007). In models adjusted for clinical characteristics, baseline eGFR, and model for end stage liver disease score, higher summary secretion score was associated with lower odds of ATN (odds ratio per SD higher secretion score, 0.34; 95% CI, 0.15 to 0.67). The summary secretion score showed good discriminative ability in diagnosing ATN versus other causes of AKI (area under the receiver operating curve, 0.73; 95% CI, 0.60 to 0.85). Conclusions In patients with cirrhosis and AKI, substantially lower tubular secretion was observed among inpatients with ATN relative to those with PRA and HRS. These results support the use of tubular secretion for the differential diagnosis of AKI in cirrhosis and may have important therapeutic and prognostic implications.