Urinary Angiotensinogen Levels Research Articles

Correlation between Urinary Angiotensinogen (AGT) and Albuminuria in Chronic Kidney Disease (CKD)

Chronic kidney disease (CKD) is a global health concern associated with significant morbidity and mortality. Albuminuria, a hallmark of kidney damage, is a strong predictor of CKD progression and adverse outcomes. Recent research has focused on understanding the correlation between urinary angiotensinogen (AGT) levels, a component of the renin-angiotensin system (RAS), and albuminuria in CKD patients. This review article synthesizes evidence from various studies exploring this correlation and elucidates its mechanistic insights and clinical implications. Clinical studies consistently demonstrate a positive correlation between urinary AGT levels and albuminuria in CKD patients. Elevated urinary AGT levels are associated with increased albuminuria, independent of traditional risk factors, suggesting a potential role for AGT in the pathogenesis of kidney damage and proteinuria in CKD. Mechanistic insights suggest that increased intrarenal RAS activity may lead to enhanced AGT production and secretion, contributing to glomerular hypertension, inflammation, and fibrosis, ultimately promoting albuminuria and CKD progression. The clinical implications of this correlation are profound. Elevated urinary AGT levels may serve as a non-invasive biomarker for assessing intrarenal RAS activity and predicting CKD progression and adverse outcomes. Furthermore, interventions targeting the RAS pathway, such as angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs), may help reduce urinary AGT levels and mitigate albuminuria, offering promising therapeutic opportunities for improving patient outcomes in CKD. In conclusion, the correlation between urinary AGT and albuminuria in CKD represents a complex interplay between renal physiology, RAS activation, and kidney damage. By elucidating this correlation, we gain valuable insights into the pathogenesis of CKD and identify urinary AGT as a potential biomarker and therapeutic target for personalized CKD management. Further research is warranted to validate these findings, explore the clinical utility of urinary AGT measurement, and develop targeted interventions aimed at mitigating albuminuria and slowing CKD progression. Through continued investigation, we can strive to improve outcomes and quality of life for patients living with CKD.

Elevated urinary angiotensinogen excretion links central and renal hemodynamic alterations

Inappropriate activation of intrarenal renin–angiotensin system (RAS) may contribute to the pathogenesis of cardio-renal syndrome (CRS). We aimed to examine the cross-sectional associations of urinary angiotensinogen (AGT) excretion, a biomarker of intrarenal RAS activity, with central (aortic) and renal hemodynamic parameters in middle-aged and older adults, including patients with chronic kidney disease. Aortic and renal hemodynamic parameters were measured using applanation tonometry and duplex ultrasonography in 282 participants. Urinary AGT, liver-type fatty acid-binding protein (L-FABP), and plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels were measured for each participant. Multiple linear regression analyses demonstrated that urinary AGT levels were associated with aortic blood pressures, pulsatile measures of renal blood flow, plasma NT-proBNP and urinary L-FABP levels after adjusting for potential covariates, including age, sex, body mass index, estimated glomerular filtration rate (GFR), and medication use. Additionally, when classified based on GFR stages and urinary AGT levels, plasma NT-proBNP and urinary L-FABP levels increased in participants with lower GFR and higher AGT groups. Our findings suggest that urinary AGT excretion is a shared determinant of central (aortic) and renal hemodynamics in middle-aged and older adults, providing clinical evidence for the potential role of intrarenal RAS activity in the development of CRS.

Intrarenal renin–angiotensin system activation and macrophage infiltrations in pediatric chronic glomerulonephritis

BackgroundThe current study tested the hypothesis that urinary angiotensinogen (UAGT) and urinary monocyte chemoattractant protein-1 (UMCP-1) levels provide a specific index of intrarenal renin–angiotensin system (RAS) status and the degree of infiltration of macrophages associated with RAS blockade and immunosuppressant treatment in pediatric patients with chronic glomerulonephritis.MethodsWe measured baseline UAGT and UMCP-1 levels to examine the correlation between glomerular injury in 48 pediatric chronic glomerulonephritis patients before treatment. Furthermore, we performed immunohistochemical analysis of angiotensinogen (AGT) and CD68 in 27 pediatric chronic glomerulonephritis patients treated with RAS blockades and immunosuppressants for 2 years. Finally, we examined the effects of angiotensin II (Ang II) on monocyte chemoattractant protein-1 (MCP-1) expression in cultured human mesangial cells (MCs).ResultsBaseline UAGT and UMCP-1 levels positively correlated with urinary protein levels, scores for mesangial hypercellularity, rate of crescentic formation, and expression levels of AGT and CD68 in renal tissues (p < 0.05). UAGT and UMCP-1 levels were significantly decreased after RAS blockade and immunosuppressant treatment (p < 0.01), which was accompanied by AGT and CD68 (p < 0.01), as well as the magnitude of glomerular injury. Cultured human MCs showed increased MCP-1 messenger ribonucleic acid and protein levels after Ang II treatment (p < 0.01).ConclusionsThe data indicates that UAGT and UMCP-1 are useful biomarkers of the degree of glomerular injury during RAS blockade and immunosuppressant treatment in pediatric patients with chronic glomerulonephritis.

Intrarenal Renin-Angiotensin System Activation Alters Relationship Between Systolic Blood Pressure and Progression of Chronic Kidney Disease.

Elevated blood pressure and intrarenal renin-angiotensin system activity are closely related to chronic kidney disease (CKD) progression. However, interrelationship between blood pressure and intrarenal renin-angiotensin system activity on the risk of CKD progression is unknown. We analyzed 2076 participants from the Korean Cohort Study for Outcomes in Patients With CKD. The main exposure was systolic blood pressure (SBP). The urinary angiotensinogen-to-creatinine ratio was stratified according to the median value (3.65 μg/gCr). The primary outcome was a composite kidney outcome of a ≥50% decline in estimated glomerular filtration rate from baseline measurement or initiation of kidney replacement therapy. During 10 550 person-years of follow-up (median, 5.2 years), the composite outcome occurred in 800 (38.5%) participants. In the multivariable cause-specific hazard model, higher SBP was associated with an increased risk of CKD progression. There was a significant interaction between SBP and urinary angiotensinogen-to-creatinine ratio on the risk of the primary outcome (P value for interaction=0.019). In patients with urinary angiotensinogen-to-creatinine <3.65 μg/gCr, the hazard ratios (95% CIs) for SBP 120 to 129, 130 to 139, and ≥140 mmHg were 1.46 (1.07-1.99), 1.71 (1.25-2.35), and 2.40 (1.73-3.32), respectively, compared with SBP <120 mmHg. However, these associations were not observed in patients with urinary angiotensinogen-to-creatinine ≥3.65 μg/gCr. In this prospective CKD cohort, higher SBP was associated with CKD progression when urinary angiotensinogen levels were low, while this association was not seen when urinary angiotensinogen levels were high. This finding suggests that intrarenal renin-angiotensin system activity may modify the relationship between SBP and adverse kidney outcome.

PS-C30-1: URINARY ANGIOTENSINOGEN-MELATONIN RATIO IN GESTATIONAL DIABETES AND PREECLAMPSIA

Objective: A large research portfolio indicates that an activated renal renin-angiotensin system or a deficit on melatonin is associated with several cardiovascular pathologies. In this observational clinical study, we hypothesized that alterations in urinary melatonin or angiotensinogen levels may be altered in two common conditions, preeclampsia and gestational diabetes. Our primary objective was to assess melatonin and angiotensinogen as novel disease biomarkers detectable and quantifiable in the urine of pregnant women with or without pregnancy complications. Design and Methods: This was a concurrent cohort study of pregnant women with selected obstetric pathologies (gestational diabetes, preeclampsia, hypertension and obesity with hypertension). A group of healthy controls was also included. Urinary 6-sulfatoxymelatonin and angiotensinogen were measured by sensitive and specific ELISAs in first morning void urine samples. The patients were included in the cohort consecutively, and the diagnosis was blinded at the level of urine collection. Urinary 6-sulfatoxymelatonin and angiotensinogen levels were investigated in the patients included in the cohort. Results: Urinary levels of angiotensinogen were significantly higher in the gestational diabetes [angiotensinogen/creatinine ratio median (25th, 75th): 0.11 (0.07, 0.18)] and preeclampsia [0.08 (0.06, 0.18)] groups than in those with healthy pregnancy [0.05(0.04, 0.06]; 6-sulfatoxymelatonin levels were significantly lower in the gestational diabetes [ug/h: median (25th, 75th): 0.12(0.08, 0.17)] and preeclampsia [0.12 (0.09, 0.15)] groups than in those with healthy pregnancy [0.20 (0.15, 0.27]. Neither morning void protein/creatinine ratio nor 24-h urine protein estimate were significantly different between the study groups. Conclusion: These results suggest that urinary angiotensinogen levels may indicate an intrarenal RAS activation while melatonin production appears to be defective in gestational diabetes or hypertension. An angiotensinogen/melatonin ratio is suggested as an early biomarker for identification of gestational diabetes or hypertension. This report provides a basis for the potential use of melatonin for the treatment of preeclampsia. A prospective study in a larger number of patients to determine the operative characteristics of these markers as potential diagnostic tests is justified.

Serum and urinary angiotensinogen levels as prognostic indicators in acute kidney injury: a prospective study.

The delayed increase in serum creatinine levels poses challenges in the timely diagnosis of acute kidney injury. This study aimed to investigate the relationship between serum angiotensinogen and urinary angiotensinogen levels and the prognosis of renal function in patients diagnosed with acute kidney injury. A total of 79 newly diagnosed acute kidney injury patients aged 18 years and older were enrolled. Serum angiotensinogen and urinary angiotensinogen levels were measured at the onset of the disease, as well as on the 15th and 30th days of follow-up. After 3 months, renal function was evaluated by measuring serum creatinine levels. Among the acute kidney injury patients, those in Kidney Disease: Improving Global Outcomes stage 3 exhibited significantly higher urinary angiotensinogen/urine creatinine levels compared with stages 1 and 2 patients at the time of diagnosis (p<0.05). Furthermore, a positive correlation was observed between the urinary angiotensinogen/urine creatinine level at the time of diagnosis and the serum creatinine level at the third month (r=0.408, p=0.048). The findings suggest that urinary angiotensinogen levels can serve as an indicator of the severity of acute kidney injury. Monitoring urinary angiotensinogen levels could potentially contribute to the prognosis assessment and management of acute kidney injury patients.

Relationship Between Urinary Angiotensinogen and Mortality in Patients with Heart Failure with Reduced Ejection Fraction.

Activation of the reninangi otens in-aldosterone system has an important role in the pathophysiology of heart failure with reduced ejection fraction. While the effects of systemic reninangi otens in-aldosterone system activation on heart failure with reduced ejection fraction are well known, the impact of the local reninangi otens in-aldosterone system on heart failure with reduced ejection fraction is not fully understood because of limited clinical research. This study aimed to investigate the effect of urinary angiotensinogen level, an accepted indicator of local reninangi otens in-aldosterone system activation, on all-cause mortality in patients with heart failure with reduced ejection fraction. This retrospective, single-center study included 60 patients with baseline urinary angiotensinogen data and survival/mortality data at 4 years. Urinary angiotensinogen values were standardized to the urinary creatinine value measured from the same urine sample. The median urinary angio tensi nogen /urin ary creatinine value among all patients (114 μg/g) was used as a cutoff to divide the patients into 2 groups. Mortality data were obtained from the national registry systems or by telephone. Comparison of all-cause mortality in the 2 groups showed that 22 deaths (71%) occurred in the group with a urinary angio tensinogen/urinary creatinine ratio above the median and 10 deaths (35.5%) occurred in the group of patients with urinary angio tensinogen/urinary creatinine equal to or below the median value (P =.005). Our study suggests that urinary angiotensinogen can be used as a new biomarker in the prognosis and follow-up of heart failure patients.

Urinary Angiotensinogen and Progression of Chronic Kidney Disease: Results from KNOW-CKD Study

The prognostic value of urinary angiotensinogen (UAGT) in patients with chronic kidney disease (CKD) has not been completely evaluated, although the association of UAGT with renal outcomes has been suggested in specific subsets of CKD. In the present study, to investigate the association of UAGT with renal outcomes in patients with non-dialysis CKD irrespective of the primary cause, a total of 1688 subjects from the Korean Cohort Study for Outcomes in Patients With Chronic Kidney Disease (KNOW-CKD) were prospectively analyzed. The subjects were divided into the quintile by UAGT to urine creatinine ratio (UAGT/Cr) level. The primary outcomes of interest were composite renal event, which included decline in kidney function and onset of end-stage renal disease during follow-up periods. The median follow-up duration was 6.257 years. Cox regression model analysis unveiled that the risk of composite renal event was significantly higher in the fifth quintile (adjusted hazard ratio 1.528, 95% confidence interval 1.156 to 2.021) compared to that of the first quartile. The association between high UAGT/Cr level and adverse renal outcome remained consistent in sensitivity analyses, including the analysis of the cause-specific hazard model. Subgroup analyses revealed that the association of UAGT level with renal outcomes is modified by certain clinical contexts, such as BMI and albuminuria. In conclusion, high UAGT level is associated with adverse renal outcomes in patients with non-dialysis CKD. Further studies are warranted to elaborate and expand the predictive role of UAGT as a biomarker for renal outcomes in CKD.

Abstract 044: Stimulation Of Intrarenal Angiotensinogen Expression And The Development Of Hypertension And Kidney Injury In Angiotensin II-infused Hepatic Angiotensinogen Knockout Mice

Regulation of systemic and local angiotensinogen (AGT) levels is a key determinant of tissue angiotensin II (Ang II) levels and inappropriate AGT augmentation promotes the development of hypertension and tissue injury. Kidney and urinary AGT levels are increased in Ang II-mediated hypertension. Recent studies have demonstrated that circulating hepatocyte-derived AGT (hAGT) enters kidneys sustaining kidney and urinary AGT levels. However, roles of hAGT in blood pressure elevation and kidney injury in Ang II-mediated hypertension have not been delineated. This study tested if hAGT contributes to the development of the pathophysiological events in Ang II-infused mice. A low dose of Ang II (400 ng/kg/min) was infused to male wild type (WT) and hAGT gene knockout (KO) mice (N=9 and 13) for 4 weeks. The control group in each genotype received vehicle (Veh) infusion (N=5 and 6). Western blot confirmed non-detectable levels of hAGT in KO mice. hAGT KO markedly decreased plasma AGT levels (WT+Veh:12.2±0.6 vs. hAGT KO+Veh: 0.8±0.1 μg/ml). Ang II infusion did not elevate plasma AGT levels in either WT and hAGT KO mice. Although hAGT KO mice exhibited a lower baseline of systolic blood pressure (SBP) than WT mice, Ang II-mediated increases in SBP was not attenuated in hAGT KO mice (ΔSBP in WT+Ang II: 30.1±4.4 vs. hAGT KO+Ang II: 26.0±4.2 mmHg). Kidney AGT mRNA levels were increased by Ang II infusion to the same extent in both WT and hAGT mice (WT+Ang II: 1.30±0.04 vs. hAGT KO+Ang II: 1.34±0.06, ratio to control). Likewise, Ang II infusion increased IL-6 mRNA to the same magnitude in both WT and hAGT KO mice. Urinary AGT was sustained in hAGT KO+Veh mice (66±9%) compared to WT+Veh mice. Ang II infusion did not alter urinary AGT levels in both groups. Glomerular mesangial expansion and fibrosis by Ang II infusion were not observed. Ang II infusion developed tubulointerstitial fibrosis in renal cortex and medulla. hAGT KO prevented the fibrosis only in the medulla. These outcomes demonstrate that elevation of SBP, augmentation of intrarenal AGT and IL-6 expression, and the development of renal cortical fibrosis in Ang II-mediated hypertension do not require hAGT. In contrast, hAGT contributes to renal medullary fibrosis which may be due to the lower absolute levels of blood pressure.

Urinary Angiotensinogen-Melatonin Ratio in Gestational Diabetes and Preeclampsia.

Background: A large research portfolio indicates that an activated renal renin-angiotensin system or a deficit on melatonin is associated with several cardiovascular pathologies. In this observational clinical study, we hypothesized that alterations in urinary melatonin or angiotensinogen levels may be altered in two common conditions, preeclampsia and gestational diabetes. Our study’s primary objective was to assess melatonin and angiotensinogen as novel disease biomarkers detectable and quantifiable in the urine of pregnant women with or without pregnancy complications. Methods: This was a concurrent cohort study of pregnant women with selected obstetric pathologies (gestational diabetes, preeclampsia, hypertension and obesity with hypertension). A group of healthy controls was also included. Urinary 6-sulfatoxymelatonin and angiotensinogen were measured by sensitive and specific ELISAs in first morning void urine samples. The patients were included in the cohort consecutively, and the diagnosis was blinded at the level of urine collection. Urinary 6-sulfatoxymelatonin and angiotensinogen levels were investigated in the patients included in the cohort. Results: Urinary levels of angiotensinogen were significantly higher in the gestational diabetes [angiotensinogen/creatinine ratio median (25th, 75th): 0.11 (0.07, 0.18)] and preeclampsia [0.08 (0.06, 0.18)] groups than in those with healthy pregnancy [0.05(0.04, 0.06]; 6-sulfatoxymelatonin levels were significantly lower in the gestational diabetes [ug/h: median (25th, 75th): 0.12(0.08, 0.17)] and preeclampsia [0.12 (0.09, 0.15)] groups than in those with healthy pregnancy [0.20 (0.15, 0.27]. Neither morning void protein/creatinine ratio nor 24-h urine protein estimate were significantly different between the study groups. Conclusion: These results suggest that urinary angiotensinogen levels may indicate an intrarenal RAS activation while melatonin production appears to be defective in gestational diabetes or hypertension. An angiotensinogen/melatonin ratio is suggested as an early biomarker for identification of gestational diabetes or hypertension. This report provides a basis for the potential use of melatonin for the treatment of preeclampsia. A prospective study in a larger number of patients to determine the operative characteristics of these markers as potential diagnostic tests is justified.

Angiotensinogen and Risk of Stroke Events in Patients with Type 2 Diabetes Mellitus.

BackgroundActivation of the renin-angiotensin system (RAS) in diabetic patients is a vital pathophysiological mechanism of cardiovascular complications.AimWe aimed to assess whether serum and urinary angiotensinogen levels could predict the risk of stroke events in patients with type 2 diabetes.MethodsAn analysis of the relationships between serum and urinary angiotensinogen levels at baseline and the risk of stroke events was performed in a study consisting of 467 patients with type 2 diabetes with a follow-up of 5 years. Multivariate Cox regression models were built by controlling for a large range of related risk factors.ResultsKaplan–Meier analysis showed that patients with low estimated glomerular filtration rate (eGFR) <57 mL/min/1.73 m2 had a significantly higher risk of stroke events than those with high eGFRs (≥57 mL/min/1.73 m2, P=0.040). Our results suggested that urinary angiotensinogen levels (HR=2.74, 95% CI 1.50–5.88, P=<0.001), but not serum angiotensinogen levels (HR=1.42, 95% CI 0.95–2.65, P=0.071), were independent predictors of the risk of stroke events in patients with type 2 diabetes after adjusting for confounding factors. Similarly, sensitivity analysis also suggested that higher urinary angiotensinogen levels still contributed to an increased risk of stroke events (HR=2.71, 95% CI 1.48–5.82, P<0.001) but not serum angiotensinogen levels (HR=1.37, 95% CI 0.89–2.21, P=0.104). Importantly, we found that significant associations only existed in patients with eGFRs<60 mL/min/1.73 m2 (HR=2.78, 95% CI 1.59–6.30, P<0.001) but not in patients with eGFRs≥60 mL/min/1.73 m2 (HR=1.39, 95% CI 0.95–3.53, P=0.054).ConclusionThe study suggested that elevated urinary angiotensinogen levels were correlated with a higher risk of stroke events in patients with type 2 diabetes mellitus.

Association of urinary angiotensinogen with renal arteriolar remodeling in chronic kidney disease.

Renin-angiotensin system (RAS) might be associated with arteriolar remodeling. The present study aimed to explore the hitherto unknown relationship between renal RAS and renal arteriolar remodeling and to elucidate whether altered renal RAS subsequently affects renal function in patients with chronic kidney disease (CKD). In this retrospective study, patients with various CKDs not using RAS inhibitors who underwent renal biopsy were included in cross-sectional and longitudinal analyses. Urinary angiotensinogen (UAGT) levels and wall/lumen ratio (WLR) were determined to evaluate renal RAS and renal arteriolar remodeling, respectively. The association between ln(UAGT) and ln(WLR) was cross-sectionally examined using a liner regression model. Furthermore, the association of ln(UAGT) with subsequent changes in estimated glomerular filtration rate (eGFR) per year were longitudinally examined in the largest subgroup of patients who were diagnosed with IgA nephropathy. In the overall cohort (n = 54), the median age, blood pressures, eGFR, and WLR were 37 years, 120/73 mmHg, 85 ml/min per 1.73 m2, and 0.93, respectively. Ln(UAGT) was significantly and positively associated with ln(WLR) even after adjusting for classical and nonclassical clinical renal risk factors. In patients with IgA nephropathy, higher ln(UAGT) was associated with higher ln(WLR). Ln(UAGT) also tended to be associated with a greater decline in eGFR per year over a median period of 8.7 years, even after adjusting for potential confounding factors. In patients with CKD, renal RAS might be associated with renal arteriolar remodeling and future decline in eGFR, independent of potential risk factors.

Biomarkers for early diagnosis of diabetic kidney disease: still a long way to go.

Biomarkers for early diagnosis of diabetic kidney disease: still a long way to go.

Elevated Urinary VEGF-A, Transferrin, and Angiotensinogen Levels in Normoalbuminuric Children and Adolescents with Type 1 Diabetes: Can They Be Early Markers of Diabetic Kidney Disease?

Objective: We hypothesized that diabetic kidney disease (DKD) begins early, before albuminuria occurs. We therefore aimed to assess potential early urinary biomarkers of DKD in normoalbuminuric and normotensive children and adolescents with type 1 diabetes (T1D) to evaluate the relationship between these markers and clinical and laboratory risk factors for DKD. Methods: This cross-sectional study included 75 children and adolescents with T1D (62% females, mean age 13.9 ± 3.2 years) with normoalbuminuria (an albumin/creatinine ratio [ACR] below 30 mg/g creatinine). Fifty-five age- and sex-matched healthy children and adolescents served as controls. For the assessment of early DKD, urinary levels of angiotensinogen (AGT), transferrin, nephrin, vascular endothelial growth factor-A (VEGF-A), and kidney injury molecule-1 (KIM-1) were measured in adequately collected 24-h urine samples using enzyme-linked immunoassays. Results: The mean disease duration was 7.3 ± 3.2 (range 2.1–15.7) years, and the mean HbA1c level was 8.8 ± 1.4%. The median levels of urine VEGF-A/Cr, AGT/Cr, and transferrin/Cr were significantly higher in normoalbuminuric patients with T1D, compared with those of controls (p < 0.001, p = 0.02, and p = 0.001, respectively), but there was no difference in nephrin/Cr and KIM-1/Cr between the 2 groups. Although none of the patients had albuminuria, the median level of urine ACR was significantly higher in the patient group than the control group (p = 0.003). The ACR was positively correlated with glomerular filtration rate (GFR). Urinary transferrin/Cr, AGT/Cr, and VEGF-A/Cr were significantly correlated with ACR, but not with either GFR or diabetic risk factors including HbA1c or disease duration. Conclusion: Normoalbuminuric and normotensive children and adolescents with T1D have elevated urinary VEGF, AGT, and transferrin levels, which may indicate the development of DKD before albuminuria occurs.

Coregulation Analysis of Mechanistic Biomarkers in Autosomal Dominant Polycystic Kidney Disease.

Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary kidney disorder leading to deterioration of kidney function and end stage kidney disease (ESKD). A number of molecular processes are dysregulated in ADPKD but the exact mechanism of disease progression is not fully understood. We measured protein biomarkers being linked to ADPKD-associated molecular processes via ELISA in urine and serum in a cohort of ADPKD patients as well as age, gender and eGFR matched CKD patients and healthy controls. ANOVA and t-tests were used to determine differences between cohorts. Spearman correlation coefficient analysis was performed to assess coregulation patterns of individual biomarkers and renal function. Urinary epidermal growth factor (EGF) and serum apelin (APLN) levels were significantly downregulated in ADPKD patients. Serum vascular endothelial growth factor alpha (VEGFA) and urinary angiotensinogen (AGT) were significantly upregulated in ADPKD patients as compared with healthy controls. Arginine vasopressin (AVP) was significantly upregulated in ADPKD patients as compared with CKD patients. Serum VEGFA and VIM concentrations were positively correlated and urinary EGF levels were negatively correlated with urinary AGT levels. Urinary EGF and AGT levels were furthermore significantly associated with estimated glomerular filtration rate (eGFR) in ADPKD patients. In summary, altered protein concentrations in body fluids of ADPKD patients were found for the mechanistic markers EGF, APLN, VEGFA, AGT, AVP, and VIM. In particular, the connection between EGF and AGT during progression of ADPKD warrants further investigation.

ENHANCED PRODUCTIONS OF INTRARENAL NLRP-3 INFLAMMASOME AND ANGIOTENSINOGEN IN ANGIOTENSIN II-DEPENDENT HYPERTENSION ARE PREVENTED BY IMMUNOSUPPRESSANT TREATMENT

Objective: Activated inflammasomes enhance maturation of pro-inflammatory cytokines, which facilitates the development of kidney injury. NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3), one of major subunits in the inflammasome complex, plays a crucial role in innate immunity and inflammation. NLRP3 inflammasome is activated by ATP-P2X7 axis and reactive oxygen species. Expression of pro-NLRP3 is promoted by activated NF-κB by cytokines or PAMPs/DAMPs. In angiotensin II (Ang II)-dependent hypertension, there is augmentation of renal immune cells leading to enhanced production of cytokines and consequent activation of NF-κB. Therefore, we hypothesized that intrarenal NLRP3 levels are increased in Ang II-dependent hypertension in association with the kidney injury, and treatment with mycophenolate mofetil (MMF), an immunosuppressant, prevents the augmentation of NLRP3 and attenuates the consequent progression of kidney injury. Design and method: Ang II (80 ng/min) was infused with/without daily MMF administration (50 ng/kg) to male rats for 2 weeks. mRNA levels of intrarenal NLRP3 and AIM2, which forms another type of inflammasome complex by viral or bacterial infections, were measured by droplet digital PCR. Furthermore, levels of intrarenal angiotensinogen (AGT), a critical contributor to activation of intrarenal renin-angiotensin system leading to the development of hypertension and associated kidney injury, were evaluated. Histological analyses of kidney injury were also performed. Results: MMF prevented increases in intrarenal macrophage/monocyte and IL-6 levels induced by Ang II infusion, confirming immunosuppression by the drug. Ang II infusion significantly increased intrarenal NLRP3 levels (control group: 4.12 ± 1.1 copies/ng RNA vs. Ang II-infused group: 9.96 ± 1.8 copies). The elevated NLRP3 expression was attenuated by MMF (6.24 ± 1.4 copies). In contrast, intrarenal AIM2 levels were not altered by Ang II infusion or MMF. Urinary protein and AGT levels were elevated in Ang II-infused rats, which were prevented by MMF. Histological analyses showed mesangial expansion and tubulointerstitial fibrosis observed in Ang II-infused group, but these injury markers were in normal ranges in the group receiving Ang II + MMF. Conclusions: These results demonstrate activation of the NLRP3 inflammasome in Ang II dependent hypertension and indicate that immunosuppression by MMF mitigates the inflammasome activation, which contributes to attenuation of the kidney injury.

Baseline Urinary Angiotensinogen Excretion Predicts Deterioration of the Kidney Function in Patients with Chronic Kidney Disease.

Objective The intrarenal renin-angiotensin system (RAS) is activated in patients with chronic kidney disease (CKD), and urinary angiotensinogen (AGT) levels, a surrogate marker of the intrarenal RAS activation, are associated with blood pressure (BP) and urinary albumin excretion. In addition, it has been shown that changes in urinary AGT levels correlate with annual changes in the estimated glomerular filtration rate (eGFR) in patients with type 2 diabetes and that elevated levels of urinary AGT in type 2 diabetic patients with albuminuria are a high-risk factor for worsening renal and cardiovascular complications. However, whether or not baseline urinary AGT levels predict deterioration of the kidney function in all patients with CKD is unclear. Methods We recruited 62 patients with CKD whose eGFR was ＞15 mL/min/1.73 m2. We performed 24-hour ambulatory BP monitoring at 30-min intervals and daily urinary collection to examine the urinary AGT levels and albumin excretion and measured the levels of plasma angiotensin II (Ang II), a surrogate marker of circulating RAS. In addition, annual changes in the eGFR were followed up for 3.4±1.5 years. Results Annual changes in the eGFR were significantly and negatively associated with urinary AGT levels (r=-0.31, p=0.015) as well as the age, systolic BP, and urinary albumin levels. In contrast, annual changes in the eGFR were not correlated with plasma Ang II levels. Furthermore, when dividing patients into quartiles according to urinary AGT levels, patients with the highest urinary AGT levels showed a progressive decline in the eGFR. Conclusion These results suggest that elevated baseline urinary AGT levels can predict renal dysfunction in patients with CKD.

Effect of Vitamin D on Urinary Angiotensinogen Level in Early Diabetic Nephropathy.

Background:Urinary angiotensinogen (UAGT) is supposed to be a marker of activation of the intrarenal renin– angiotensin system (RAS) system in early diabetic nnephropathy (EDN). Vitamin D has been studied as a negative regulator of the circulating and tissue RAS activity, so its supplementation may prevent the progression of diabetic nephropathy (DN). This study was planned to assess the RAS activation and effect of vitamin D supplementation in EDN progression by estimating the UAGT level.Methods:A total of 103 EDN subjects were randomized in two groups to receive either cholecalciferol (54) or matching placebo (49) in a double-blind manner. All were subjected to routine investigations, urinary albumin-to-creatinine ratio (UACR), UAGT, vitamin D, and intact parathyroid hormone (iPTH) at the 0 and 6 months. A total 40 healthy controls were also included for assessment of the same investigations at 0 month.Results:Significant reduction of UACR, UAGT, and iPTH level were corroborated with an increase in 25(OH) vitamin D level from 0 to 6 months (all four P < 0.001). After 6 months, the median [interquartile range (IQR)] of UAGT and UACR levels was significantly lower in the cholecalciferol group as compared to placebo group (p < 0.001 and P = 0.04, respectively). The median UAGT level was significantly higher in patients with EDN (cholecalciferol & placebo Group) than control group at 0 month (p = 0.001).Conclusion:Significantly higher UAGT levels in EDN supports the role of intrarenal RAS activation. A significant decrease in UAGT level in the cholecalciferol group supports the beneficial role of vitamin D supplementation in the progression of EDN.

Abstract P141: Immunosuppressant Treatment Attenuates Augmentation Of Intrarenal NLRP-3 Inflammasome In Angiotensin II-dependent Hypertension

Activated inflammasomes enhance maturation of pro-inflammatory cytokines, which facilitates the development of kidney injury. NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3), one of major subunits in the inflammasome complex, plays a crucial role in innate immunity and inflammation. Although NLRP3 inflammasome is activated by ATP-P2Y7 axis and reactive oxygen species, the expression of pro-NLRP3 is promoted by NF-κB activated by cytokines or PAMPs/DAMPs. Thus, we hypothesized that mycophenolate mofetil (MMF), an immunosuppressant, attenuates augmentation of intrarenal NLRP3 and consequent progression of kidney injury in angiotensin II (Ang II)-dependent hypertension. Ang II (80 ng/min) was infused with/without daily MMF administration (50 ng/kg) to Sprague-Dawley rats for 2 weeks. mRNA levels of intrarenal NLRP3 and AIM2, which forms another type of inflammasome complex by viral or bacterial infections, were measured by droplet digital PCR. Furthermore, kidney injury was evaluated. MMF treatment mitigated Ang II-induced macrophage infiltration into kidneys, suggesting immunosuppression by the drug. Ang II infusion significantly increased intrarenal NLRP3 mRNA levels (normotensive control group: 4.12±1.1 copies/ng RNA vs. Ang II-infused group: 9.96±1.8 copies, N=5). The elevated NLRP3 expression in kidneys of Ang II-infused rats was attenuated by MMF treatment (6.24±1.4 copies). In contrast, intrarenal AIM2 levels were lower than NLRP3 in the control group and the levels were not altered by Ang II infusion or MMF treatment (normotensive control group: 0.42±0.1 copies, Ang II-infused group: 0.35±0.06 copies and Ang II+MMF group: 0.35±0.08 copies). Urinary protein and angiotensinogen levels were elevated in Ang II-infused rats and MMF treatment suppressed the augmentations. Histological analyses also showed the development of kidney injury including mesangial expansion and tubulointerstitial fibrosis observed in the hypertensive rats, but these injury markers were mitigated by MMF. These results demonstrate activation of the NLRP3 inflammasome in Ang II dependent hypertension and indicate that immunosuppression by MMF mitigates the inflammasome activation, which contributes to attenuation of the kidney injury.

Urinary angiotensinogen as a surrogate marker predicting the antiproteinuric effects of angiotensin receptor blockers in patients with overt proteinuria: a\xa0multicenter prospective study

BackgroundAlthough 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).MethodsThis 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.ResultsThe 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/1.73m2. 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).ConclusionsOur 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.