Urinary angiotensinogen predicts progressive chronic kidney disease after an episode of experimental acute kidney injury

Abstract

One of the major obstacles to prevent AKI-CKD transition is the lack of effective methods to follow and predict the ongoing kidney injury after an AKI episode. In the present study, we test the utility of urinary angiotensinogen (UAGT) for dynamically evaluating renal structural changes and predicting AKI-CKD progression by using both mild and severe bilateral renal ischemia/reperfusion injury mice. UAGT returns to pre-ischemic levels 14 days after mild AKI followed by kidney architecture restoration, whereas sustained increase in UAGT accompanies by ongoing renal fibrosis after severe AKI. UAGT at day 14-42 correlates with renal fibrosis 84 days after AKI. For predicting fibrosis at day 84, the area under receiver operating characteristics curve of UAGT at day 14 is 0.81. Persistent elevation in UAGT correlates with sustained activation of intrarenal renin-angiotensin system (RAS) during AKI-CKD transition. Abrogating RAS activation post AKI markedly reduced renal fibrosis, with early RAS intervention (from 14 days after IRI) more beneficial than late intervention (from 42 days after IRI) in alleviating fibrosis. Importantly, UAGT decreases after RAS intervention, and its level at day 14-28 correlates with the extent of renal fibrosis at day 42 post RAS blockade. A pilot study conducted in patients with acute tubular necrosis finds that compared with those recovered, patients with AKI-CKD progression exhibits elevated UAGT during the 3-month follow-up after biopsy. Our study suggests that UAGT enables the dynamical monitoring of renal structural recovery after an AKI episode and may serve as an early predictor for AKI-CKD progression and treatment response.

Meta-analysis of AKI to CKD transition in perioperative patients

“…A critical translational step in monitoring patients after AKI would be development of specific biomarkers of AKI-CKD transition. Indeed, several have been proposed and recently reviewed (Wen and Parikh 2021 ); particularly hopeful may be urinary angiotensinogen, as this marker could also potentially be used to guide renin-angiotensin system based therapy (Cui et al 2018 ). Thus, it is reasonable to speculate that with the right data, perioperative providers may be able to influence the course of AKI-CKD transition in the future.…”

Pediatric Acute Kidney Injury to the Subsequent CKD Transition

“…Emerging evidence suggests that urinary AGT is an encouraging biomarker to predict AKI or CKD progression [28]. Using a murine bilateral renal ischemia/reperfusion injury model and a prospective cohort study of 20 pa-tients with acute tubular necrosis, Cui and colleagues found that urinary AGT can dynamically detect renal structural recovery following AKI [29]. However, additional studies are required to determine urinary AGT ability to predict early pediatric AKI-CKD transition.…”

Biomarkers of acute kidney injury and their role in clinical patient management

“…Angiotensinogen (AGT) is an amino acid that plays an important role in the renin -angiotensin system (RAS) and leads to the formation of angiotensin I. It is produced in the kidney by proximal tubule cells and thick ascending limb of Henle (61). Due to its high molecular weight (65 kD), it is not filtered (62).…”

“…Detection in urine is due to intra-renal RAS origination rather than systemic RAS activation and it occurs by being released to the tubular lumen (62,63). uAGT is upregulated in tubular cells after AKI and correlated with intra-renal RAS activation and severity of kidney damage (61,64). uAGT is a biomarker indicating kidney damage that can be used for early detection of AKI and prediction of chronic kidney disease earlier than SCr and proteinuria (65)(66)(67), as well as to estimate the probability of recovery from AKI (61).…”