Urinary Angiotensinogen and Risk of Severe AKI

Alge, Joseph L.; Karakala, Nithin; Neely, Benjamin A.; Janech, Michael G.; Tumlin, James A.; Chawla, Lakhmir S.; Shaw, Andrew; Arthur, John M.

doi:10.2215/cjn.06280612

Cited by 68 publications

(76 citation statements)

References 35 publications

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“…This cohort involved 74 samples included in our previously described study (19). Informed consent was obtained in accordance with the institutional review boardapproved protocol at each institution.…”

Section: Patients and Urine Samplesmentioning

confidence: 99%

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

Alge

Karakala

Neely

et al. 2013

Clinical Journal of the American Society of Nephrology

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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.

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Section: Patients and Urine Samplesmentioning

confidence: 99%

“…We recently identified urinary angiotensinogen as a novel prognostic biomarker of AKI (19,20). In the current retrospective cohort study, we further evaluated the prognostic predictive power of angiotensinogen and its combination with renin.…”

Section: Introductionmentioning

confidence: 99%

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

Alge

Karakala

Neely

et al. 2013

Clinical Journal of the American Society of Nephrology

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“…We have recently shown that uAGT level on admission predicts subsequent development of AKI in patients with ADHF (30). Elevated uAGT is also associated with severe AKI after cardiac surgery (20).…”

Section: Introductionmentioning

confidence: 99%

“…Diagnostic mainstays such as the fractional excretion of sodium and urea have been shown to be suboptimal in a variety of clinical settings (13)(14)(15)(16)(17). Assessment of biomarkers for renal tubular injury (e.g., neutrophil gelatinase-associated lipocalin [NGAL], kidney injury molecule-1 [KIM-1] and IL-18) at the time of creatinine-based diagnosis of AKI offers prognostic information in multiple clinical settings such as cardiac surgery, ICU, transplantation, and cirrhosis (18)(19)(20)(21)(22)(23). However, their utility has not been tested in ADHF.…”

Section: Introductionmentioning

confidence: 99%

Urinary Biomarkers at the Time of AKI Diagnosis as Predictors of Progression of AKI among Patients with Acute Cardiorenal Syndrome

Chen¹,

Yang

Lei

et al. 2016

CJASN

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Background and objectives A major challenge in early treatment of acute cardiorenal syndrome (CRS) is the lack of predictors for progression of AKI. We aim to investigate the utility of urinary angiotensinogen and other renal injury biomarkers in predicting AKI progression in CRS.Design, settings, participants, & measurements In this prospective, multicenter study, we screened 732 adults who admitted for acute decompensated heart failure from September 2011 to December 2014, and evaluated whether renal injury biomarkers measured at time of AKI diagnosis can predict worsening of AKI. In 213 patients who developed Kidney Disease Improving Global Outcomes stage 1 or 2 AKI, six renal injury biomarkers, including urinary angiotensinogen (uAGT), urinary neutrophil gelatinase-associated lipocalin (uNGAL), plasma neutrophil gelatinase-associated lipocalin, urinary IL-18 (uIL-18), urinary kidney injury molecule-1, and urinary albumin-to-creatinine ratio, were measured at time of AKI diagnosis. The primary outcome was AKI progression defined by worsening of AKI stage (50 patients). The secondary outcome was AKI progression with subsequent death (18 patients).Results After multivariable adjustment, the highest tertile of three urinary biomarkers remained associated with AKI progression compared with the lowest tertile: uAGT (odds ratio [OR], 10.8; 95% confidence interval [95% CI], 3.4 to 34.7), uNGAL (OR, 4.7; 95% CI, 1.7 to 13.4), and uIL-18 (OR, 3.6; 95% CI, 1.4 to 9.5). uAGT was the best predictor for both primary and secondary outcomes with area under the receiver operating curve of 0.78 and 0.85. These three biomarkers improved risk reclassification compared with the clinical model alone, with uAGT performing the best (category-free net reclassification improvement for primary and secondary outcomes of 0.76 [95% CI, 0.46 to 1.06] and 0.93 [95% CI, 0.50 to 1.36]; P,0.001). Excellent performance of uAGT was further confirmed with bootstrap internal validation.Conclusions uAGT, uNGAL, and uIL-18 measured at time of AKI diagnosis improved risk stratification and identified CRS patients at highest risk of adverse outcomes.

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“…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.…”

Section: Introductionmentioning

confidence: 99%

Methodologic Issues in the Measurement of Urinary Renin

Roksnoer

Verdonk

Garrelds

et al. 2014

Clinical Journal of the American Society of Nephrology

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Background and objectives Alge et al. recently reported that urinary renin may be a prognostic biomarker for AKI after cardiac surgery. However, their urinary renin levels far exceeded published plasma renin levels, whereas normally, urinary renin is ,10% of plasma renin. This result raises questions about the specificity of the new Quantikine Renin ELISA Kit used in the work by Alge et al., which is claimed to detect total renin (i.e., renin and prorenin). Therefore, this study tested this assay.Design, setting, participants, & measurements Plasma and urine from 30 patients with hypertension, diabetes, or preeclampsia and 10 healthy pregnant women (randomly selected from sample sets obtained earlier to investigate urinary renin-angiotensin system components) were used to compare the ELISA with a validated renin immunoradiometric assay and an in-house enzyme kinetic assay. Measurements were performed before and after in vitro prorenin activation, representing renin and total renin, respectively.Results Total renin measurements by ELISA, immunoradiometric assay, and enzyme kinetic assay were highly correlated. However, ELISA results were consistently $10-fold higher. The ELISA standard yielded low to undetectable levels in the immunoradiometric assay and enzyme kinetic assay, except after prorenin activation, when the results were $10-fold lower than the ELISA results. In plasma, prorenin activation increased ELISA results by 10%-15%. Urine contained no detectable prorenin. ConclusionsThe ELISA renin kit standard is prorenin, and its immunoreactivity and enzymatic activity after conversion to renin do not match the International Reference Preparation of human renin that has been used to validate previous immunoradiometric assays and enzyme kinetic assays; in fact, they are at least 10-fold lower, and thus, any measurements obtained with this ELISA kit yield levels that are at least 10-fold too high. The ELISA antibodies detect both renin and prorenin, with a preference for the former. Given these inconsistencies, urinary renin levels should be measured by established renin assays.

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Urinary Angiotensinogen and Risk of Severe AKI

Cited by 68 publications

References 35 publications

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

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

Urinary Biomarkers at the Time of AKI Diagnosis as Predictors of Progression of AKI among Patients with Acute Cardiorenal Syndrome

Methodologic Issues in the Measurement of Urinary Renin

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