Association of biomarkers of endothelial function, coagulation activation and kidney injury with persistent albuminuria in sickle cell anaemia.

Persistent albuminuria (PA) is common in sickle cell anaemia (SCA). With the association of chronic kidney disease (CKD) with increased mortality, biomarkers that predict its development or progression are needed. We evaluated the association of select biomarkers with PA in adults with SCA using Kruskal-Wallis rank-sum test and logistic regression models, with adjustment for multiple testing. Of 280 subjects, 100 (35.7%) had PA. Median plasma levels of soluble vascular cell adhesion molecule-1 (VCAM-1) (1176.3 vs. 953.4 ng/mL, false discovery rate [FDR] q-value <0.003), thrombin-antithrombin complex (5.5 vs. 4.7 ng/mL, FDR q-value = 0.04), and urinary angiotensinogen (AGT) (12.2 vs. 5.3 ng/mg, FDR q-value <0.003), urinary nephrin (30.6 vs. 27.2 ng/mg, FDR q-value = 0.04), and urinary kidney injury molecule-1 (KIM-1) (0.8 vs. 0.5 ng/mg, FDR q-value <0.003), normalized to urine creatinine, were significantly higher in subjects with PA. In multivariable analysis, only urinary AGT (odds ratio = 1.058, FDR q-value <0.0001) remained a significant predictor of PA. In addition, soluble VCAM-1 (FDR q-value <0.0001), D-dimer (FDR q-value <0.0001), urinary AGT (FDR q-value <0.0001), KIM-1 (FDR q-value <0.0001), and nephrin (FDR q-value <0.0001) were significantly associated with urine albumin-creatinine ratio in multivariable analyses. Longitudinal studies to evaluate the predictive capacity of biomarkers for the development and progression of CKD in SCA are warranted.

Comparative diagnostic utility of different urinary biomarkers during pre-albuminuric stages of non-hypertensive type 2 diabetic nephropathy.

Background & objectives: Activation of renin-angiotensin system and tubulointerstitial damage might be seen in pre-albuminuria stage of diabetic nephropathy (DN). Here, diagnostic utility of four urinary biomarkers [Angiotensinogen (Angio), Interleukin (IL)-18, Neutrophil Gelatinase-Associated Lipocalin (NGAL) and Cystatin] during pre-albuminuria stages of non-hypertensive type 2 diabetes patients was studied. Methods: A total of 952 type 2 diabetes mellitus (T2DM) patients were screened for nephropathy [estimated glomerular filtration rate (eGFR) ≥120 ml/min and albumin-creatinine ratio (ACR) ≥30], and 120 patients were followed up for one year. At one year, they were classified into hyperfiltration (43), normoalbuminuria (29) and microalbuminuria (48) groups. Another 63 T2DM patients without nephropathy were included as controls. Hypertension, patients on angiotensin-converting enzyme inhibitor/angiotensin receptor blocker, eGFR <60 ml/min/1.73 m2 and all proteinuric conditions were excluded. All were subjected to testing for urine protein, ACR, HbA1C, eGFR, along with urinary biomarkers (IL-18, cystatin-C, NGAL and AGT). Comparative analysis of all the diagnostic tests among different subgroups, correlation and logistic regression was done. Results: Urinary IL-18/Cr, cystatin/creatinine (Cr) and AGT/Cr levels were higher in groups of hyperfiltration (13.47, 12.11 and 8.43 mg/g), normoalbuminuria (9.24, 11.74 and 9.15 mg/g) and microalbuminuria (11.59, 14.48 and 10.24 mg/g) than controls (7.38, 8.39 and 1.26 mg/g), but NGAL/Cr was comparable. The area under receiver operating characteristic curve (AUC) and sensitivity of AGT to detect early CKD were higher than ACR and eGFR (0.91 and 90.4%, 0.6 and 40% and 0.6 and 37%, respectively). AUC values of other biomarkers, namely IL-18/Cr, cystatin/Cr and NGAL/Cr, were 0.65, 0.64 and 0.51, respectively. Angio/Cr and IL-18/Cr showed correlation with log albuminuria (r=0.3, P=0.00, and r=0.28, P=0.00, respectively). NGAL showed correlation with log eGFR (r=0.28 P=0.00). Multivariate logistic analysis showed that odds ratio of developing nephropathy was 7.5 times with higher values of log Angio/Cr. Interpretation & conclusions: Urinary AGT showed a higher diagnostic value than ACR and eGFR followed by IL-18 and cystatin to diagnose DN during pre-albuminuric stages.

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

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/1.73m2. 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). 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.

Urinary angiotensinogen: an indicator of active antineutrophil cytoplasmic antibody-associated glomerulonephritis.

BACKGROUND: One of the major challenges in improving the management of antineutrophil cytoplasmic antibody-associated glomerulonephritis (ANCA-GN) is the lack of a disease-specific indicator for histological lesions and disease activity. Here we tested the utility of urinary angiotensinogen (UAGT) as a biomarker of renal disease activity in ANCA-GN. METHODS: A prospective, two-stage cohort study was performed in ANCA-GN patients. In Stage I, UAGT was measured at the time of renal biopsy in 69 patients from two centers (test set) and 25 patients from two other centers (validation set). In Stage II, UAGT was monitored in 50 subjects in the test set for 24 months. RESULTS: In Stage I, UAGT significantly increased in ANCA-GN patients, correlating well with cellular crescents formation and active interstitial inflammation. Patients with crescentic ANCA-GN exhibited the highest UAGT compared with other histopathological classes of ANCA-GN. After multivariable adjustment, the highest quartile of UAGT, compared with the lowest quartile, associated with a 6-fold increased risk of crescentic ANCA-GN. For predicting crescentic ANCA-GN, UAGT [area under the receiver operating characteristics curve (AUC) = 0.88] outperformed albuminuria (AUC = 0.73) and estimated glomerular filtration rate (AUC = 0.69). UAGT improved the performance of those clinical markers in diagnosing crescentic ANCA-GN (P < 0.034), suggesting a role of UAGT in identifying active crescentic ANCA-GN. In Stage II, UAGT decreased after immunotherapy and increased at the time of renal relapse during the 2-year follow-up, suggesting the usefulness of UAGT to monitor disease activity over time. CONCLUSIONS: These results suggest the potential use of UAGT for assessing disease activity and renal relapse in ANCA-GN.

Increased heart rate is associated with intrarenal renin-angiotensin system activation in chronic kidney disease patients.

BACKGROUND: A higher heart rate is one of the risk factors for heart failure and cardiovascular disease. Activation of the intrarenal renin-angiotensin system (RAS) plays an important role in the development of hypertension and renal damage. However, the association between heart rate and intrarenal RAS activation is unclear. METHODS: We investigated the relationship between heart rate and urinary angiotensinogen (U-AGT) excretion, a surrogate marker for intrarenal RAS activity, in ten subjects without chronic kidney disease (CKD) and 72 CKD patients who were not taking medications that influence heart rate and RAS blockers (age 50.0 ± 17.4 years, 27 men and 45 women, serum creatinine (sCr) 1.85 ± 2.71 mg/dL, blood pressure 120.5 ± 15.8/72.9 ± 10.1 mmHg, heart rate 67.3 ± 8.9 /min, urinary protein excretion 1.27 ± 2.63 g/day, and U-AGT excretion 747.4 ± 2714.6 µg/day). RESULTS: As heart rate is influenced by behavior and emotion, we divided it into daytime and nighttime. Heart rate had a significant positive association with sCr levels during daytime and nighttime in CKD patients but not in non-CKD subjects. Moreover, although heart rate was not associated with U-AGT excretion levels in non-CKD subjects, it was associated with U-AGT excretion levels during daytime (r = 0.23 and p = 0.047) and nighttime (r = 0.45 and p < 0.01) in CKD patients. Multiple linear regression analysis revealed that heart rate had a significant positive association with the U-AGT excretion levels during nighttime, but not daytime, after adjustments for age, sex, body mass index, and sCr (ß = 0.31 and p = 0.034). CONCLUSION: Heart rate is associated with U-AGT excretion levels, especially during the nighttime, in CKD patients.

Urinary angiotensinogen in pediatric urinary tract infection.

BACKGROUND: Urinary tract infection (UTI) is one of the most common diseases in children, and urinary angiotensinogen (U-AGT) is a new biomarker gathering attention in many renal diseases. U-AGT reflects intrarenal renin-angiotensin system (RAS) activity. We conducted a study to measure U-AGT in children <4 months old with UTI. METHODS: All children <4 months old who came to Toshima Hospital with fever between January 2015 and December 2015 were included. Patients were divided into a UTI group and a non-UTI group, and U-AGT was measured. RESULTS: Median U-AGT was higher in patients with UTI compared with patients without UTI: (0.56 ng/dL, range, 0.025-2.753 ng/dL vs 0.13 ng/dL, range, 0.008-1.697 ng/dL, respectively; P < 0.05). CONCLUSIONS: U-AGT is elevated in UTI patients, and RAS activation may contribute to renal injury caused by UTI.

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

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.

Urinary angiotensinogen level is increased in renal transplant recipients with masked hypertension and is correlated with left ventricular mass index and albuminuria in these patients.

Activation of the local renin-angiotensin system (RAS) is an independent risk factor for the development of proteinuria and left ventricular hypertrophy (LVH) more commonly seen in masked hypertensives. It has been reported that urinary angiotensinogen (UAGT) level provides a specific index of the intrarenal RAS status. The aim of this study was to evaluate the association between UAGT and left ventricular mass index (LVMI) and urinary albumin-creatinine ratio (UACR) in renal transplant recipients (RTRs) with masked hypertension (HT). A total of 116 non-diabetic-treated hypertensive RTRs were included in this study. The patients were divided into two groups: masked hypertensives and controlled hypertensives. Forty-two (36.2%) of RTRs had masked HT. Mean UACR and LVMI levels were higher in RTRs with masked HT than in RTRs with controlled HT (P < 0.001). UAGT level was also higher in masked hypertensives compared to controlled hypertensives (P < 0.001). Multivariable regression analysis showed that UAGT was positively correlated with UACR (ß = 0.024, P = 0.001) and LVMI (ß = 0.082, P = 0.001) in masked hypertensives. Consequently, masked HT was considerably frequent (36.2%) in treated hypertensive RTRs and high UAGT levels accompanied by high albuminuria and LVMI levels were seen in these patients. Overproduction of the UAGT may play a pivotal role in the development of LVH and proteinuria in masked hypertensives.

The elevated levels of urinary angiotensinogen are correlated with the severity of idiopathic membranous nephropathy.

BACKGROUND: Immunosuppressive treatment will predispose an idiopathic membranous nephropathy (iMN) patient to opportunistic infections. Disease severity is one of the main concerns for making the treatment decision. Urinary angiotensinogen (UAGT) level has been shown highly correlated with intrarenal renin-angiotensin system (RAS) activity and severity of chronic kidney diseases (CKD). We aimed to test the relationship between the UAGT level and the severity of iMN. METHODS: This cross-sectional study included a total of 48 biopsy-proven iMN patients, 46 minimal change disease (MCD) patients, and 44 healthy volunteers. The clinical and laboratory data and urine samples were collected from all subjects before the use of RAS inhibitors. We determined the UAGT levels with a method of enzyme-linked immunosorbent assay. RESULTS: The UAGT levels were not different between the iMN (277.05 ± 61.25, µg/g.Cr) and MCD patients (244.19 ± 40.24, µg/g.Cr), but both of them were significantly higher than those of healthy controls (6.85 ± 1.10, µg/g.Cr). UAGT levels were correlated negatively with serum albumin (r = - 0.393, p = 0.006) and estimated glomerular filtration rate (eGFR) (r = - 0.352, p = 0.014) and positively with 24-h proteinuria (r = 0.614, p < 0.001) in iMN patients but not in MCD patients. Multivariate linear regression analysis revealed that only proteinuria independently determinate the levels of UAGT (ß = 0.649, p < 0.001) in iMN patients. CONCLUSIONS: UAGT levels were correlated negatively with serum albumin and glomerular filtration rate and positively with proteinuria in iMN patients at the onset. This suggests that elevated levels of UAGT are associated with the severity of iMN. The UAGT level may be used as a cofactor for deciding immunosuppressive therapy in iMN patient.

Urinary angiotensinogen level is correlated with blood pressure level and proteinuria in patients with masked hypertension.

Urinary angiotensinogen (UAGT) level is an index of the intrarenal-renin angiotensin system status and is significantly correlated with blood pressure (BP) and proteinuria in patients with hypertension (HT). We aimed to investigate the possible relationship between UAGT levels and albuminuria in masked hypertensives. A total of 96 nondiabetic treated hypertensive patients were included in this study. The patients were divided into two groups: masked hypertensives (office BP <140/90 mmHg and ambulatory BP ≥130/80 mmHg) and controlled hypertensives (office BP <140/90 mmHg and ambulatory BP <130/80). The mean UAGT/UCre level and urinary albumin-creatinine ratio (UACR) of masked hypertensives were higher than those of controlled hypertensives (7.76 µg/g vs 4.02 µg/g, p < 0.001 and 174.21 mg/g vs 77.74 mg/g, p < 0.001, respectively). A significant positive correlation was found between UAGT/UCre levels and ambulatory systolic BP and diastolic BP levels in patients with masked HT, but this was not found with office SBP or DBP levels. Importantly, UAGT/UCre levels showed a significant positive correlation with UACR in both groups, but correlation of the UAGT levels with UACR was more pronounced in masked hypertensives (r = 0.854, p < 0.001 vsr = 0.512, p < 0.01). As a result, UAGT level was increased in patients with masked HT, which was associated with an elevation in albuminuria. Overproduction of the UAGT may play a pivotal role in development of proteinuria.

Impaired endogenous nighttime melatonin secretion relates to intrarenal renin-angiotensin system activation and renal damage in patients with chronic kidney disease.

BACKGROUND: Activation of the intrarenal renin-angiotensin system (RAS) plays a critical role in the pathophysiology of chronic kidney disease (CKD) and hypertension. The circadian rhythm of intrarenal RAS activation leads to renal damage and hypertension, which are associated with diurnal blood pressure (BP) variation. The activation of intrarenal RAS following reactive oxygen species (ROS) activation, sympathetic hyperactivity and nitric oxide (NO) inhibition leads to the development of renal damage. Melatonin is a hormone regulating the circadian rhythm, and has multiple functions such as anti-oxidant and anti-adrenergic effects and enhancement of NO bioavailability. Nocturnal melatonin concentrations are lower in CKD patients. However, it is not known if impaired endogenous melatonin secretion is related to BP, intrarenal RAS, or renal damage in CKD patients. METHODS: We recruited 53 CKD patients and conducted 24-h ambulatory BP monitoring. urine was collected during the daytime and nighttime. We investigated the relationship among the melatonin metabolite urinary 6-sulphatoxymelatonin (U-aMT6s), BP, renal function, urinary angiotensinogen (U-AGT), and urinary albumin (U-Alb). RESULTS: Patients' U-aMT6s levels were significantly and negatively correlated with clinical parameters such as renal function, systolic BP, U-AGT, and U-Alb, during both day and night. Multiple regression analyses for U-aMT6s levels were performed using age, gender, renal function, and each parameter (BPs, U-AGT or U-Alb), at daytime and nighttime. U-aMT6s levels were significantly associated with U-AGT (ß = -0.31, p = 0.044) and U-Alb (ß = -0.25, p = 0.025) only at night. CONCLUSION: Impaired nighttime melatonin secretion may be associated with nighttime intrarenal RAS activation and renal damage in CKD patients.

Urinary Angiotensinogen Level Predicts AKI in Acute Decompensated Heart Failure: A Prospective, Two-Stage Study.

A major challenge in prevention and early treatment of acute cardiorenal syndrome (CRS) is the lack of high-performance predictors. To test the hypothesis that urinary angiotensinogen (uAGT) is an early predictor for acute CRS and 1-year prognosis in patients with acute decompensated heart failure (ADHF), we performed a prospective, two-stage, multicenter cohort study in patients with ADHF. In stage I (test set), 317 patients were recruited from four centers. In stage II (validation set), 119 patients were enrolled from two other centers. Daily uAGT levels were analyzed consecutively. AKI was defined according to Kidney Disease Improving Global Outcomes (KDIGO) Clinical Practice Guidelines. In stage I, 104 (32.8%) patients developed AKI during hospitalization. Daily uAGT peaked on the first hospital day in patients who subsequently developed AKI. After multivariable adjustment, the highest quartile of uAGT on admission was associated with a 50-fold increased risk of AKI compared with the lowest quartile. For predicting AKI, uAGT (area under the receiver-operating characteristic curve [AUC]=0.84) outperformed urinary neutrophil gelatinase-associated lipocalin (AUC=0.78), the urinary albumin/creatinine ratio (AUC=0.71), and the clinical model (AUC=0.77). Survivors in stage I were followed prospectively for 1 year after hospital discharge. The uAGT level independently predicted the risk of 1-year mortality (adjusted odds ratio, 4.5; 95% confidence interval, 2.1 to 9.5) and rehospitalization (adjusted odds ratio, 3.6; 95% confidence interval, 1.6 to 5.7). The ability of uAGT in predicting AKI was validated in stage II (AUC=0.79). In conclusion, uAGT is a strong predictor for acute CRS and 1-year prognosis in ADHF.

Vitamin D receptor activation with calcitriol for reducing urinary angiotensinogen in patients with type 2 diabetic chronic kidney disease.

BACKGROUND: Recently, it has been reported that urinary angiotensinogen levels is a specific index of the intrarenal renin-angiotensin-aldosterone system (RAAS) status and it is significantly correlated with urinary albumin:creatinine (Cr) ratio in hypertensive patients. The aim of the present study was to assess the effect of activation of the Vitamin D receptor with calcitriol on albuminuria and urinary angiotensinogen as a novel biomarker of the intra-renal RAAS status in patients with diabetic nephropathy (DN). METHODS: Ninety-eight patients with type 2 diabetes and albuminuria who were treated with RAAS inhibitors (angiotensin-converting enzyme inhibitor (ACE-i) or angiotensin receptor blocker (ARB)) have participated in this study. Patients were randomized to receive either placebo (n = 50) or 0.25 µg/day calcitriol (n = 48). We have examined urinary albumin:Cr ratio and urinary angiotensinogen:Cr ratio before and 24 weeks later after treatment in both group. RESULTS: The mean urinary albumin:Cr ratio and urinary angiotensinogen:Cr ratio were significantly higher in patients with DN than in normal controls (p < 0.001). Urinary angiotensinogen:Cr ratio was significantly, positively correlated with urinary albumin:Cr ratio in both groups (in the placebo group; p = 0.01, r = 0.4236, in calcitriol group; p = 0.01, r = 0.4564). CONCLUSION: These data indicated that administration of Vitamin D receptor activator in combination with RAAS inhibitors had an additional benefit in lowering albuminuria in patients with DN. More pronounced reduction of urinary albumin:Cr ratio that was positively correlated with angiotensinogen:Cr ratio in calcitriol group suggested that Vitamin D receptor activation might blunt albuminuria by reducing urinary angiotensinogen levels reflecting intra-renal RAAS status.

Urinary Angiotensinogen Could Be a Prognostic Marker of the Renoprotection of Olmesartan in Metabolic Syndrome Patients.

This study was performed to demonstrate urinary angiotensinogen as a potential prognostic marker of the albuminuria reduction effects of olmesartan in patients with metabolic syndrome. In 24 patients (eight women, 57.88 ± 2.00 years), 5-40 mg/day of olmesartan were given. Urinary concentrations of albumin and angiotensinogen (normalized by urinary concentrations of creatinine) and plasma renin activity were measured before and after the 12- and 24-week marks of olmesartan treatment. Olmesartan treatment increased plasma renin activity and decreased urinary albumin and urinary angiotensinogen significantly (p < 0.05). Based on the % change in urinary albumin, patients were divided into two groups, responders (<-50%) and non-responders (≥-50%), and a logistic analysis of urinary angiotensinogen before treatment showed the area under the curve as 0.694. When the cutoff value of urinary angiotensinogen before the treatment of 13.9 µg/g Cr was used, the maximum Youden index (0.500, specificity: 11/12 = 91.7% and sensitivity: 7/12 = 58.3%) was obtained. When all patients were re-divided into two groups, those with higher values of urinary angiotensinogen before the treatment (Group H, n = 16) and those with lower values, Group H showed significantly decreased urinary albumin (p < 0.05). Therefore, urinary angiotensinogen could be a prognostic marker of the albuminuria reduction effects of olmesartan in patients with metabolic syndrome.

Association between urinary angiotensinogen excretion rates and left ventricular mass index and carotid intima-media thickness in hypertensive kidney transplant recipients.

OBJECTIVES: The renin-angiotensin system (RAS) is thought to regulate blood pressure and to be an independent risk factor for the development of left ventricular hypertrophy (LVH) and carotid intima-media thickness (CIMT). Locally produced RAS in most tissues has been recently described. It has been reported that urinary angiotensinogen levels provide a specific index of the intrarenal RAS status and is significantly correlated with blood pressure and proteinuria. The aim of this study was to evaluate the relationship of local intrarenal RAS with LVH and CIMT in hypertensive renal transplant recipients (RTRs). RESULTS: A total of 96 non-diabetic RTRs (50 hypertensive patients, 46 normotensive patients) were included in this study. Urinary angiotensinogen (UAGT)/urinary creatinine (Ucre) was significantly higher in hypertensive patients compared with normotensive patients (p < 0.01). Left ventricular mass (LVM)I and CIMT were significantly higher in hypertensive patients compared with the normotensive patients (p < 0.01). Importantly, a significant positive correlation was found between UAGT/Ucre levels and LVMI (r = 0.724, p = 0.012) and also CIMT (r = 0.452, p = 0.02) in hypertensive RTRs. CONCLUSIONS: These data indicate that UAGT is increased in hypertensive RTRs, and local RAS may play an important role in the development of cardiovascular abnormalities in hypertensive renal transplant recipients.

Urinary angiotensinogen, related factors and clinical implications in normotensive autosomal dominant polycystic kidney disease patients.

BACKGROUND: Although several lines of evidence suggest that renin angiotensin system (RAS) proteins are synthesized by cyst epithelium and dilated tubules, role of intrarenal RAS in the progression of otozomal dominant polycystic kidney disease (ADPKD) is not well known. We aimed to study the levels and clinical correlations of urinary angiotensinogen (UAGT) in normotensive ADPKD patients compared with age- and sex-matched healthy subjects. METHODS: The study included 20 normotensive ADPKD patients (F/M: 11/9) and 20 age and sex matched healthy controls (F/M: 9/11). Diagnosis of ADPKD was made based on Ravine criteria. Twenty-four hours ambulatory blood pressure monitoring (ABPM) was performed. Serum concentrations of creatinine, Na, K, uric acid, and urinary concentrations of Na, K, uric acid, creatinine, protein and albumin were measured. UAGT were measured via commercially available ELISA kit. RESULTS: ADPKD patients had higher urinary albumin:creatinine ratio (UAIb/UCrea) than healthy controls (p < 0.01). UAGT/UCrea levels significantly positively correlated with urinary protein: creatinine ratio (UPro/UCrea) (r = 0.785, p = 0.01), and UAIb/UCrea (r = 0.681, p = 0.01) in normotensive ADPKD patients. CONCLUSION: This pilot study demonstrates that UAGT levels tend to be elevated and are correlated with proteinuria and albuminuria in normotensive ADPKD patients during relatively early stages of the disease.

Urinary angiotensinogen as a novel marker of obstructive nephropathy in children.

AIM: Obstructive nephropathy due to congenital or acquired urinary tract obstruction is one of the most important causes of chronic renal failure in children. There is a need for identification of new noninvasive urinary biomarkers to provide the clinician with fast, specific and reliable diagnostic and prognostic tool. The aim of the study was to determine whether urinary angiotensinogen (uAGT) may be a useful marker of obstruction in children with hydronephrosis (HN) caused by ureteropelvic junction obstruction (UPJO). METHODS: The study cohort consisted of surgical group (SG): 31 children with severe HN who required surgery; nonsurgical group (NSG): 20 patients with mild HN, and reference group (RG): 19 healthy children. Urinary concentrations of angiotensinogen were measured using immunoenzymatic ELISA commercial kit and were expressed in ng/mg Cre (uAGT/uCre). RESULTS: uAGT/uCre level was higher in SG when compared to NSG (p < 0.01) and healthy participants (SG vs. RG: p < 0.01). The difference between the uAGT/uCre in NSG and RG was not statistically significant (p > 0.05). uAGT/uCre was correlated negatively with differential renal function (r = -0.46; p < 0.01). CONCLUSION: The present pilot study has clearly demonstrated that children with UPJO showed increased uAGT levels, which correlated negatively with differential renal function in radionuclide scan.

Reduced urinary angiotensinogen excretion in preeclampsia.

OBJECTIVE: This study evaluated urinary angiotensinogen in preeclampsia. METHODS: Normal pregnant (n = 57) and preeclamptic patients (n = 31); Normal pregnant (n = 10) and preeclamptic rats (n = 10) were studied. Urinary angiotensinogen and plasma angiotensin II were assayed by enzyme-linked immunosorbent assay (ELISA). RESULTS: Urinary angiotensinogen in preeclampsia patients (2.0 ± 1.1 ng/mg creatinine) was suppressed (*p < 0.05) compared to normal pregnant (2.7 ± 1.5 ng/mg creatinine). Plasma angiotensin II in preeclampsia patients (preeclampsia: 36.2 ± 7; normal pregnant: 48.1 ± 5 fmol/mL) was lower. The similar result was observed in preeclampsia rat model. CONCLUSIONS: The reduced urinary excretion of angiotensinogen was both in human preeclampsia patients and rat model of preeclampsia.

Use of ultra high performance liquid chromatography with high resolution mass spectrometry to analyze urinary metabolome alterations following acute kidney injury in post-cardiac surgery patients.

BACKGROUND: Cardiac surgery-associated acute kidney injury (AKI) can increase the mortality and morbidity, and the incidence of chronic kidney disease, in critically ill survivors. The purpose of this research was to investigate possible links between urinary metabolic changes and cardiac surgery-associated AKI. METHODS: Using ultra-high-performance liquid chromatography coupled with Q-Exactive Orbitrap mass spectrometry, non-targeted metabolomics was performed on urinary samples collected from groups of patients with cardiac surgery-associated AKI at different time points, including Before_AKI (uninjured kidney), AKI_Day1 (injured kidney) and AKI_Day14 (recovered kidney) groups. The data among the three groups were analyzed by combining multivariate and univariate statistical methods, and urine metabolites related to AKI in patients after cardiac surgery were screened. Altered metabolic pathways associated with cardiac surgery-induced AKI were identified by examining the Kyoto Encyclopedia of Genes and Genomes database. RESULTS: The secreted urinary metabolome of the injured kidney can be well separated from the urine metabolomes of uninjured or recovered patients using multivariate and univariate statistical analyses. However, urine samples from the AKI_Day14 and Before_AKI groups cannot be distinguished using either of the two statistical analyses. Nearly 4000 urinary metabolites were identified through bioinformatics methods at Annotation Levels 1-4. Several of these differential metabolites may also perform essential biological functions. Differential analysis of the urinary metabolome among groups was also performed to provide potential prognostic indicators and changes in signalling pathways. Compared with the uninjured kidney group, the patients with cardiac surgery-associated AKI displayed dramatic changes in renal metabolism, including sulphur metabolism and amino acid metabolism. CONCLUSIONS: Urinary metabolite disorder was observed in patients with cardiac surgery-associated AKI due to ischaemia and medical treatment, and the recovered patients' kidneys were able to return to normal. This work provides data on urine metabolite markers and essential resources for further research on AKI.

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.