Time course profiling of the kynurenine pathway activity in a pig model of crescentic glomerulonephritis

The kynurenine (KYN) pathway is activated in acute kidney disease, including crescentic glomerulonephritis (CGN), an immune-mediated life-threatening syndrome characterized by rapid loss of renal function. The non-invasive measurement of KP metabolites may have clinical diagnostic or prognostic value, but has never been systematically studied using sensitive analytical tools. We have recently developed and validated a sensitive and rapid liquid chromatography-tandem mass spectrometry (LC-MS/MS) method to measure a comprehensive panel of tryptophan (TRP) catabolic intermediates in blood and urine. We used a novel model of CGN to approximate human biochemical and physiological parameters. We show that for a period of 28 days after the onset of the disease, monitoring plasma KP is not informative as it is likely to reflect an accumulation of uremic retention solutes and does not allow to follow the activity of the disease over time. In contrast, the urinary metabolic profile is noteworthy, with an early and significant yet transient increase in urinary KYN/TRP ratio levels. Urinary KYN/TRP ratio is independent of proteinuria. These findings suggest that increased urinary KYN/TRP ratio levels by LC/MSMS in patients with CGN reflect early disease activity.