Urinary Angiotensinogen and Renin Excretion are Associated with Chronic Kidney Disease

Juretzko, Annett; Steinbach, Antje; Hannemann, Anke; Endlich, Karlhans; Endlich, Nicole; Friedrich, Nele; Lendeckel, Uwe; Stracke, Sylvia; Rettig, Rainer

doi:10.1159/000474932

Cited by 19 publications

(13 citation statements)

References 32 publications

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“…Yet, there is a gap, and limited research focus was on the risk predictors for kidney disease. Some of the proposed candidates are neutrophil gelatinase-associated lipocalin, angiotensinogen, renin, and NEP (20,29,33,42,49,56). In addition, other RAS enzymes, such as urinary ACE and ACE2, have also been investigated as potential new markers for hypertension (6) and diabetes (28).…”

Section: Discussionmentioning

confidence: 99%

Increased urinary angiotensin converting enzyme 2 and neprilysin in patients with type 2 diabetes

Gutta

Grobe

Kumbaji

et al. 2018

American Journal of Physiology-Renal Physiology

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Angiotensin converting enzyme 2 (ACE2) and neprilysin (NEP) are metalloproteases that are highly expressed in the renal proximal tubules. ACE2 and NEP generate renoprotective angiotensin (1-7) from angiotensin II and angiotensin I, respectively, and therefore could have a major role in chronic kidney disease (CKD). Recent data demonstrated increased urinary ACE2 in patients with diabetes with CKD and kidney transplants. We tested the hypothesis that urinary ACE2, NEP, and a disintegrin and metalloproteinase 17 (ADAM17) are increased and could be risk predictors of CKD in patients with diabetes. ACE2, NEP, and ADAM17 were investigated in 20 nondiabetics (ND) and 40 patients with diabetes with normoalbuminuria (Dnormo), microalbuminuria (Dmicro), and macroalbuminuria (Dmacro) using ELISA, Western blot, and fluorogenic and mass spectrometric-based enzyme assays. Logistic regression model was applied to predict the risk prediction. Receiver operating characteristic curves were drawn, and prediction accuracies were calculated to explore the effectiveness of ACE2 and NEP in predicting diabetes and CKD. Results demonstrated that there is no evidence of urinary ACE2 and ADAM17 in ND subjects, but both enzymes were increased in patients with diabetes, including Dnormo. Although there was no detectable plasma ACE2 activity, there was evidence of urinary and plasma NEP in all the subjects, and urinary NEP was significantly increased in Dmicro patients. NEP and ACE2 showed significant correlations with metabolic and renal characteristics. In summary, urinary ACE2, NEP, and ADAM17 are increased in patients with diabetes and could be used as early biomarkers to predict the incidence or progression of CKD at early stages among individuals with type 2 diabetes.

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Section: Discussionmentioning

confidence: 99%

Increased urinary angiotensin converting enzyme 2 and neprilysin in patients with type 2 diabetes

Gutta

Grobe

Kumbaji

et al. 2018

American Journal of Physiology-Renal Physiology

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“…There was no correlation between urinary AGT or renin excretion and the change in eGFR at 24 weeks as well as at 5 years, although baseline urinary AGT and renin excretion were negatively correlated with baseline eGFR. Urinary AGT and renin excretion are negatively correlated with eGFR [21,27,29], but the relationship between urinary AGT or renin excretion and changes in renal function has not been well studied. Previous studies have suggested that baseline AGT excretion may have limited value as a prognostic factor in predicting changes in renal function during RAS-inhibitor treatment, although it has a negative correlation with changes in renal function without RAS inhibitors [8,27,30,31].…”

Section: Discussionmentioning

confidence: 99%

Urinary angiotensinogen as a surrogate marker predicting the antiproteinuric effects of angiotensin receptor blockers in patients with overt proteinuria: a multicenter prospective study

et al. 2020

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Background: Although urinary angiotensinogen (AGT) and renin reflect intrarenal renin-angiotensin system activity and are enhanced in proteinuric chronic kidney disease, the clinical value of urinary AGT and renin levels during antiproteinuric treatment has yet to be determined. We investigated the clinical usefulness of initial urinary AGT or renin to determine the antiproteinuric effects of angiotensin receptor blockers (ARBs). Methods: This multicenter, prospective, single-arm study included 205 patients with overt proteinuria (urinary protein/creatinine ratio [uPCR] ≥ 1 mg/mg) enrolled between April 2009 and December 2011. All patients were treated with valsartan. The urinary AGT/creatinine ratio (uAGT/Cr) was measured at the baseline and 24 weeks, and the renin/creatinine ratio (uR/Cr) was measured at the baseline. Fifty-six patients were followed-up for 5 years. Results: The mean age was 47.6 years and 51.2% were male. The mean uPCR was 2.32 mg/mg and the mean eGFR was 63.2 mL/min/1.73m 2. Natural logarithms (ln) (uAGT/Cr), ln(uR/Cr), and diabetes mellitus were associated with proteinuria decrement (decrease in uPCR ≥1 mg/mg). Ln(uAGT/Cr) was an independent predictor for proteinuria decrement (OR 1.372, 95% CI, 1.068-1.762, P = 0.013). Among the 56 patients followed-up for 5 years, Δln(uAGT/Cr) at 24 weeks was an independent predictor for uPCR < 1 mg/mg at 5 years (OR 0.379, 95% CI, 0.20-0.715, P = 0.003). Conclusions: Our study demonstrates the potential role of both baseline urinary AGT and changes in urinary AGT during the initial 24 weeks as surrogate markers predicting the antiproteinuric effects of ARBs in patients with overt proteinuria.

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“…The two proteins may increase in parallel but for different reasons, that is, an increase in filtration in the case of albumin and both an increase in filtration and in intrarenal formation in the case of AOG. In cross‐sectional studies involving patients with CKD, an association between increased uAOG and reduced eGFR was found independently of AER (Mills et al, ; Juretzko et al, ). This would further support the concept that elevated uAOG is not solely the result of passage of AOG via altered glomerular permeability but also excretion of AOG that originates, in part, from local intra‐renal formation.…”

Section: Discussionmentioning

confidence: 99%

“…There is evidence from cross-sectional studies that uAOG is increased in patients with DKD, (Yamamoto et al, 2007;Kobori et al, 2008;Mills et al, 2012;Afkarian et al, 2014;Wysocki et al, 2017;Juretzko et al, 2017) but longitudinal data from patients with either type 1 or type 2 diabetes, to our knowledge, are lacking. Accordingly, at what point kidney RAS overactivity develops during the evolution of DKD is unknown.…”

Section: Introductionmentioning

confidence: 97%

Urinary angiotensinogen antedates the development of stage 3 CKD in patients with type 1 diabetes mellitus

Aqeel

Wysocki

et al. 2019

Physiol Rep

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We examined if urinary angiotensinogen (uAOG), a marker of intrarenal renin‐angiotensin system activity, antedates stage 3 chronic kidney disease (CKD) using samples from participants in the Diabetes Control and Complications Trial (DCCT) and later in the Epidemiology of Diabetes Intervention and Complications (EDIC) trial. In a nested case–control design, cases were matched at the outcome visit (eGFR less than 60, 21‐59 mL/min per 1.73 m2) on age, gender, and diabetes duration, with controls: eGFR (95, 75‐119, mL/min per 1.73 m2.) Additionally, in an exploratory analysis progressive renal decline (PRD), defined as eGFR loss >3.5 mL/min per 1.73m2/year, was evaluated using only data from EDIC because no progressions were observed during DCCT. At the EDIC visit, which antedated the GFR outcome visit by 2 years (range 1–7years) the median uAOG/creatinine was markedly higher in cases than in controls (13.9 vs. 3.8 ng/mg P = 0.003) whereas at the DCCT visit, which antedated the GFR outcome by 17 to 20 years it was not (2.75 vs. 3.16 ng/mg, respectively). The Odds Ratio for uAOG and CKD stage 3 development was significant after adjusting for eGFR, HbA1c, and systolic blood pressure 1.82 (1.00–3.29) but no longer significant when Albumin Excretion Ratio (AER) was included 1.21 (0.65–2.24).In the PRD analysis, uAOG/creatinine was sixfold higher in participants who experienced PRD than in those who did not (26 vs. 4.0 ng/mg, P = 0.003). The Odds Ratio for uAOG and PRD was significant after adjusting for eGFR, HbA1c, and systolic blood pressure 2.48 (1.46–4.22) but no longer significant when AER was included 1.32 (0.76–2.30). In people with type1 diabetes, a robust increase in uAOG antedates the development of stage 3 CKD but is not superior to AER in predicting this renal outcome. Increased uAOG moreover is associated with PRD, an index of progression to End Stage Kidney Disease (ESKD).

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Urinary Angiotensinogen and Renin Excretion are Associated with Chronic Kidney Disease

Cited by 19 publications

References 32 publications

Increased urinary angiotensin converting enzyme 2 and neprilysin in patients with type 2 diabetes

Increased urinary angiotensin converting enzyme 2 and neprilysin in patients with type 2 diabetes

Urinary angiotensinogen as a surrogate marker predicting the antiproteinuric effects of angiotensin receptor blockers in patients with overt proteinuria: a multicenter prospective study

Urinary angiotensinogen antedates the development of stage 3 CKD in patients with type 1 diabetes mellitus

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