Association of Elevated Urinary Concentration of Renin-Angiotensin System Components and Severe AKI

Abstract

SummaryBackground Prognostic biomarkers that predict the severity of AKI at an early time point are needed. Urinary angiotensinogen was recently identified as a prognostic AKI biomarker. The study hypothesis is that urinary renin could also predict AKI severity and that in combination angiotensinogen and renin would be a strong predictor of prognosis at the time of AKI diagnosis.Design, setting, participants, & measurements In this multicenter, retrospective cohort study, urine was obtained from 204 patients who developed AKI after cardiac surgery from August 2008 to June 1, 2012. All patients were classified as having Acute Kidney Injury Network (AKIN) stage 1 disease by serum creatinine criteria at the time of sample collection. Urine output was not used for staging. Urinary angiotensinogen and renin were measured, and the area under the receiver-operating characteristic curve (AUC) was used to test for prediction of progression to AKIN stage 3 or in-hospital 30-day mortality. These biomarkers were added stepwise to a clinical model, and improvement in prognostic predictive performance was evaluated by category free net reclassification improvement (cfNRI) and chi-squared automatic interaction detection (CHAID).Results Both the urinary angiotensinogen-to-creatinine ratio (uAnCR; AUC, 0.75; 95% confidence interval [CI], 0.65 to 0.85) and the urinary renin-to-creatinine ratio (uRenCR; AUC, 0.70; 95% CI, 0.57 to 0.83) predicted AKIN stage 3 or death. Addition of uAnCR to a clinical model substantially improved prediction of the outcome (AUC, 0.85; cfNRI, 0.673), augmenting sensitivity and specificity. Further addition of uRenCR increased the sensitivity of the model (cfNRI events , 0.44). CHAID produced a highly accurate model (AUC, 0.91) and identified the combination of uAnCR .337.89 ng/mg and uRenCR .893.41 pg/mg as the strongest predictors (positive predictive value, 80.4%; negative predictive value, 90.7%; accuracy, 90.2%). ConclusionThe combination of urinary angiotensinogen and renin predicts progression to very severe disease in patients with early AKI after cardiac surgery.

Urinary Angiotensinogen: A Promising Biomarker of AKI Progression in Acute Decompensated Heart Failure: What Does It Mean?

“…Of note, uAGT outperformed the other three biomarkers. This study is also important, because it confirms previous observations that uAGT is increased in the setting of AKI and can predict its progression to higher stages or death after cardiac surgery (8,9) or in acute decompensated heart failure (10).…”

Methodologic Issues in the Measurement of Urinary Renin

“…Thus, to what degree urinary renin yields information independent from the circulating RAS remains to be determined. Alge et al (4) recently reported that urinary renin, together with urinary angiotensinogen, associates with AKI after cardiac surgery. Their urinary renin levels were measured with the Quantikine Renin ELISA Kit and exceeded published plasma renin levels (11,12).…”

“…Given the noncalibrated standard of this ELISA, it is not surprising that Alge et al (4), when using this kit, obtained urinary renin levels that are far above the normal range in plasma (11) and, most likely, even above the plasma levels in patients who developed AKI after cardiac surgery. It should be noted that plasma renin values were not reported in their study but that their highest urinary total renin levels (2894 pg/ml) exceed the plasma levels of total renin measured in heart failure patients treated with RAS blockers (10).…”

“…Such levels are several orders of magnitude higher than the urinary renin levels reported by others (approximately 1-2 pg/ml; range=0.03-157 pg/ml) (7-9) and even substantially higher than the plasma renin levels in cardiac patients (10). This finding raises questions about the specificity of the ELISA used in the works by Alge et al (4) to measure renin (Quantikine ELISA; R&D Systems, Abingdon, UK). One reason for this discrepancy might be that the ELISA simultaneously detects prorenin, the inactive precursor of renin (i.e., it actually measures total renin [renin and prorenin]), and not renin.…”

“…For instance, Alge et al (3) recently suggested that urinary angiotensinogen is a prognostic biomarker for the progression of AKI after cardiac surgery. In a subsequent study, Alge et al (4) additionally studied urinary renin to improve prognostic power. Remarkably, the urinary renin-to-creatinine ratios in that study, involving patients between 58 and 79 years old, ranged from 114 to 2894 pg/mg.…”