angiotensinogen and Acute-Kidney-Injury

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.

Topics: Acute Kidney Injury; Angiotensinogen; Biomarkers; Creatinine; Humans; Kidney; Prognosis; Prospective Studies

To investigate the value of renal artery resistance index (RRI) and urinary angiotensinogen (UAGT) in the early diagnosis of acute kidney injury (AKI) in patients with sepsis.. A prospective study was conducted. Seventy-eight patients with sepsis admitted to the department of critical care medicine of General Hospital of Ningxia Medical University from January to September 2021 were enrolled. Patients were observed for the development of AKI within 1 week. General data [gender, age, body mass index (BMI), major infection sites and critical illness related scores], laboratory indicators [mean arterial pressure (MAP), central venous pressure (CVP), procalcitonin (PCT), arterial blood lactic acid (Lac), etc.], duration of mechanical ventilation and length of intensive care unit (ICU) stay were recorded. After hemodynamic stabilization of the patients, renal ultrasound was performed to measure the RRI within 24 hours after ICU admission. Urine samples were taken immediately after diagnosis, and the level of UAGT was detected by enzyme-linked immunosorbent assay (ELISA). The above parameters were compared between the two groups. Multivariate Logistic regression was used to analyze the risk factors of AKI in patients with sepsis. Receiver operator characteristic curve (ROC curve) was drawn to analyze the predictive value of related indicators for AKI in sepsis.. A total of 78 patients were finally enrolled, of which 45 developed AKI and 33 did not. Compared with the non-AKI group, the rates of vasoactive drugs use, 28-day mortality, sequential organ failure assessment (SOFA) score, acute physiology and chronic health evaluation II (APACHE II) score, PCT, Lac, RRI and UAGT were significantly higher in the AKI group [rates of vasoactive drugs use: 68.9% vs. 39.4%, 28-day mortality: 48.9% vs. 24.2%, SOFA score: 12.0 (10.5, 14.0) vs. 8.0 (7.0, 10.0), APACHE II score: 22.0 (18.0, 27.5) vs. 16.0 (15.0, 18.5), PCT (μg/L): 12.5±2.6 vs. 10.9±2.8, Lac (mmol/L): 2.6 (1.9, 3.4) vs. 1.9 (1.3, 2.6), RRI: 0.74±0.03 vs. 0.72±0.02, UAGT (μg/L): 75.16±19.99 vs. 46.28±20.75, all P < 0.05], the duration of mechanical ventilation and the length of ICU stay were significantly prolonged [duration of mechanical ventilation (days): 8.0 (7.0, 12.0) vs. 5.0 (4.0, 6.0), length of ICU stay (days): 14.0 (10.0, 16.0) vs. 9.0 (8.0, 11.5), both P < 0.01], and MAP was significantly lowered [mmHg (1 mmHg ≈ 0.133 kPa): 68.5±11.2 vs. 74.2±12.8, P < 0.05]. There was no significant difference in other parameters between the two groups. Multivariate Logistic regression analysis showed that SOFA score [odds ratio (OR) = 2.088, 95% confidence interval (95%CI) was 1.322-3.299], APACHE II score (OR = 1.447, 95%CI was 1.134-1.845), RRI (OR = 1.432, 95%CI was 1.103-1.859), and UAGT (OR = 1.077, 95%CI was 1.035-1.121) were independent risk factors for sepsis complicated with AKI (all P < 0.01). ROC curve analysis showed that SOFA score, APACHE II score, RRI and UAGT had certain predictive value for AKI in septic patients, the area under the ROC curve (AUC) were 0.814 (95%CI was 0.716-0.912), 0.804 (95%CI was 0.708-0.901), 0.789 (95%CI was 0.690-0.888), and 0.840 (95%CI was 0.747-0.934), respectively, and the AUC of RRI combined with UAGT was 0.912 (95%CI was 0.849-0.974), which was better than the above single index (all P < 0.05).. RRI combined with UAGT has a high early predictive value for septic AKI.

Topics: Acute Kidney Injury; Angiotensinogen; Early Diagnosis; Humans; Intensive Care Units; Procalcitonin; Prognosis; Prospective Studies; Renal Artery; Retrospective Studies; ROC Curve; Sepsis; Vascular Resistance

BACKGROUND Sepsis is a devastating medical condition. In the USA, about 745 000 people are diagnosed with sepsis annually. Although many anti-inflammatory drugs have been used to manage sepsis, the treatment success rate is very low. This study was undertaken to examine the protective effects of naringenin on sepsis-induced kidney injury in rats. MATERIAL AND METHODS Sepsis was induced in Wistar albino rats by cecal ligation and puncture methods. Histological analysis was performed with hematoxylin and eosin (HE) staining. Reactive oxygen species (ROS) levels were determined by flow cytometery. TUNEL assay was used to demonstrate apoptosis. Sandwich ELISA method was used for the determination of urinary angiotensinogen, and protein expression was determined by Western blot analysis. RESULTS We found that naringenin decreased atrophy in the glomerulus and enabled maintenance of the capsule area and normal tubular cavity of the septic rats. Admistration of naringenin at the dosage of 10 and 20 mg/kg to sepsis rats caused significant reduction in the sepsis-induced apoptosis of kidney cells, accompanied by decrease in Bax and increase in Bcl-2 expression. Moreover, naringenin also decreased the ROS levels in septic rats and downregulated the expression of SOD, CAT, and APX. The effects of naringenin were also examined on the levels of urinary angiotensinogen in sepsis rats. We found that naringenin caused a significant decrease in urinary angiotensinogen levels of septic rats. CONCLUSIONS Naringenin appears to have potential in the treatment of sepsis.

Topics: Acute Kidney Injury; Angiotensinogen; Animals; Anti-Inflammatory Agents; Antioxidants; Apoptosis; Cecum; Disease Models, Animal; Flavanones; Kidney; Kidney Glomerulus; Rats; Rats, Wistar; Reactive Oxygen Species; Sepsis; Urinary Tract

Urinary angiotensinogen (uAGT) has been described as a novel biomarker of acute kidney injury (AKI) and chronic kidney disease (CKD). Renal interstitial inflammatory cell infiltration is a common renal pathological feature of AKI and CKD. However, the correlation between uAGT and renal interstitial inflammatory cell infiltration is unknown. The aim of this study was to analyze the expression of uAGT, its relationship with interstitial inflammatory cell infiltration, and prognosis in patients with renal insufficiency.. The expression of uAGT, urinary kidney injury molecule 1 (uKIM-1), and urinary neutrophil gelatinase-associated lipocalin (uNGAL) were examined by enzyme-linked immunosorbent assay (ELISA) at baseline and kidney pathology was evaluated at the same time.. Sixty-five patients with renal insufficiency and 12 healthy controls were enrolled. uAGT, uKIM-1, and uNGAL levels were significantly higher compared with healthy participants. uAGT showed the strongest correlation with interstitial inflammatory cell infiltration (r = 0.366, P < .05). uAGT level was able to identify interstitial inflammatory cell infiltration with greater accuracy (AUC = 0.664, P < .05) than other urinary biomarkers. After a median follow-up of 22 months, 15 patients reached the composite renal endpoint. Kaplan meier survival curves followed by multivariate cox proportional hazards regression analysis showed that uAGT (> 166.8 ng/mg creatinine) independently predicted higher risk of the endpoint.. uAGT may be used as a non-invasive biomarker of interstitial inflammatory cell infiltration and a strong predictor of renal prognosis in patients with renal insufficiency.

Topics: Acute Kidney Injury; Adult; Angiotensinogen; Biomarkers; Case-Control Studies; Disease Progression; Female; Glomerular Filtration Rate; Humans; Kaplan-Meier Estimate; Kidney; Linear Models; Male; Middle Aged; Predictive Value of Tests; Prognosis; Renal Insufficiency, Chronic; ROC Curve

The use of renin-angiotensin-aldosterone system inhibitors has increased over the past few years. There are conflicting data as to their relationship with acute kidney injury following surgery.. The objective of the article was to evaluate the risk of acute kidney injury in diabetic older patients treated with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers and their medical outcomes following fragility hip fracture surgery.. Consecutive diabetic patients presenting with fragility hip fractures to our primary trauma center between January 2012 and June 2016 were included. Demographic and clinical data, including co-morbidities, medication use, and laboratory results, were collected from the electronic medical records. The primary outcome was the incidence of acute kidney injury; the secondary outcome was 1-year mortality.. Two hundred and seventeen patients were included; 125 were receiving treatment with medications targeting the renin-angiotensin-aldosterone system. Demographic and clinical characteristics were similar between groups. No association was found between the use of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers and the risk of acute kidney injury, which occurred in 25% of the cohort. Univariate analysis revealed that diuretic use, particularly furosemide, increased the risk of acute kidney injury during hospitalization (p = 0.003). However, in a multivariate analysis, only age and estimated glomerular filtration rates were associated with an increased risk of acute kidney injury. Patients with acute kidney injury were found to have increased mortality during the first post-operative year (p < 0.001).. Acute kidney injury is a frequent complication after hip fracture surgery in elderly diabetic patients and is associated with increased 1-year mortality; however, it was not found to be associated with angiotensin-converting enzyme inhibitor/angiotensin receptor blocker pre-fracture treatment.

Topics: Acute Kidney Injury; Age Factors; Aged, 80 and over; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Cohort Studies; Diabetes Mellitus; Female; Glomerular Filtration Rate; Hip Fractures; Humans; Incidence; Male; Renin-Angiotensin System; Retrospective Studies

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.

Topics: Acute Kidney Injury; Angiotensinogen; Animals; Biomarkers; Disease Progression; Fibrosis; Humans; Kidney; Male; Mice, Inbred C57BL; Predictive Value of Tests; Renal Insufficiency, Chronic; Renin-Angiotensin System; Reperfusion Injury; ROC Curve; Time Factors

Accurate biomarkers that both predict the progression to, and detect the early stages of chronic kidney disease (CKD) are lacking, resulting in difficulty in identifying individuals who could potentially benefit from targeted intervention. In a recent issue [

Topics: Acute Kidney Injury; Angiotensinogen; Animals; Biomarkers; Humans; Kidney; Mice; Prognosis; Prospective Studies; Renal Insufficiency, Chronic

Uncontrolled hypertension is an important contributor to cardiovascular disease. Despite the armamentarium of antihypertensive treatments, there remains a need for novel agents effective in individuals who cannot reach acceptable blood pressure levels. Inhibitors targeting the renin-angiotensin-aldosterone system (RAAS) are widely used but may not optimally inhibit RAAS and demonstrate an acceptable safety profile. Experiments were conducted to characterize a series of AGT (angiotensinogen) antisense oligonucleotides (ASOs) and compare their efficacy and tolerability to traditional RAAS blockade. AGT ASOs which target multiple systemic sites of AGT versus an N-acetylgalactosamine-conjugated AGT ASO that targets the liver were compared with captopril and losartan. Spontaneously hypertensive rats fed an 8% NaCl diet, a model of malignant hypertension resistant to standard RAAS inhibitors, demonstrated robust and durable blood pressure reductions with AGT ASO treatments, which was not observed with standard RAAS blockade. Studies in rat models of acute kidney injury produced by salt deprivation revealed kidney injury with ASO treatment that reduced kidney-expressed AGT, but not in animals treated with the N-acetylgalactosamine AGT ASO despite comparable plasma AGT reductions. Administration of either captopril or losartan also produced acute kidney injury during salt deprivation. Thus, intrarenal RAAS derived from kidney AGT, and inhibited by the standard of care, contributes to the maintenance of renal function during severe RAAS challenge. Such improvements in efficacy and tolerability by a liver-selective AGT inhibitor could be desirable in individuals not at their blood pressure goal with existing RAAS blockade.

Topics: Acute Kidney Injury; Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Animals; Antihypertensive Agents; Blood Pressure; Disease Models, Animal; Drug Resistance; Hypertension; Kidney; Oligonucleotides, Antisense; Rats; Rats, Inbred SHR; Renin-Angiotensin System; Treatment Outcome

Ischemia-reperfusion (I/R) injury is one of the most important pathologic processes causing acute kidney injury. Human atrial natriuretic peptide (hANP) has various effects, including renal protection. The purpose of the present work was to study the effects of intrarenal angiotensin II (Ang II) and investigate the potential of hANP to prevent kidney injury.. Male Sprague-Dawley rats were divided into three groups as follows: (1) sham; (2) I/R (30 min of bilateral renal ischemia followed by 6 h reperfusion); and (3) I/R + hANP (I/R injury + continuous intravenous infusion of hANP at 0.025 μg/kg/min). After 6 h of reperfusion, both renal and plasma Ang II concentrations were measured. Urinary angiotensinogen and neutrophil gelatinase-associated lipocalin were measured before ischemia and 2, 4, and 6 h after reperfusion. To evaluate the renal-protective effects of hANP, serum creatinine was determined 6 and 24 h after reperfusion. In addition, mitochondrial oxygen consumption in kidney cortex was measured in the presence of Ang II and hANP.. Renal Ang II concentrations were 24.5 ± 3.9 and 14.2 ± 3.4 pg/mg renal weight in the I/R and I/R + hANP groups, respectively. Urinary angiotensinogen and neutrophil gelatinase-associated lipocalin excretions were elevated after I/R injury. Treatment with hANP significantly attenuated this effect after 4 and 6 h. Oxygen consumption in renal mitochondria increased with the addition of Ang II, which was also attenuated by hANP.. Production of intrarenal Ang II was attenuated by hANP, indicating a potential to diminish renal I/R injury.

Topics: Acute Kidney Injury; Acute-Phase Proteins; Angiotensin II; Angiotensinogen; Animals; Atrial Natriuretic Factor; Kidney; Lipocalin-2; Lipocalins; Male; Mitochondria; Oxygen Consumption; Postoperative Complications; Proto-Oncogene Proteins; Rats, Sprague-Dawley; Reperfusion Injury

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.. 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).. 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.. uAGT, uNGAL, and uIL-18 measured at time of AKI diagnosis improved risk stratification and identified CRS patients at highest risk of adverse outcomes.

Topics: Acute Disease; Acute Kidney Injury; Aged; Aged, 80 and over; Albuminuria; Angiotensinogen; Biomarkers; Cardio-Renal Syndrome; Creatinine; Disease Progression; Female; Hepatitis A Virus Cellular Receptor 1; Humans; Interleukin-18; Lipocalin-2; Male; Middle Aged; Prospective Studies; Risk Assessment; Time Factors

Topics: Acute Kidney Injury; Acute-Phase Proteins; Angiotensinogen; Biomarkers; Creatinine; Disease Progression; Heart Failure; Humans; Lipocalins; Proto-Oncogene Proteins

Although several risk factors for acute kidney injury (AKI) have been identified, early detection of AKI in acute decompensated heart failure patients remains a challenge. The aim of this study was to develop and validate a risk score for early prediction of AKI in acute decompensated heart failure patients.. A total of 676 consecutive acute decompensated heart failure participants were prospectively enrolled from 6 regional central hospitals. Data from 507 participants were analyzed. Participants from 4 of the 6 hospitals (n=321) were used to develop a risk score and conduct internal validation. External validation of the developed risk score was conducted in participants from the other 2 hospitals (n=186). Sequential logistic regression was used to develop and validate the risk score. The c statistic and calibration plot were used to assess the discrimination and calibration of the proposed risk score. The overall occurrence of AKI was 33.1% (168/507). The risk score, ranging from 0 to 55, demonstrated good discriminative power with an optimism-corrected c statistic of 0.859. Similar results were obtained from external validation with c statistic of 0.847 (95% CI 0.819-0.927). The risk score had good calibration with no apparent over- or under-prediction observed from calibration plots.. The novel risk score is a simple and accurate tool that can help clinicians assess the risk of AKI in acute decompensated heart failure patients, which in turn helps them plan and initiate the most appropriate disease management for patients in time.

Topics: Acute Disease; Acute Kidney Injury; Aged; Aged, 80 and over; Angiotensinogen; Cardio-Renal Syndrome; China; Cohort Studies; Female; Heart Failure; Humans; Lipocalin-2; Logistic Models; Male; Middle Aged; Prospective Studies; Renal Insufficiency, Chronic; Reproducibility of Results; Risk Assessment; Risk Factors

(Pro)renin receptor [(P)RR], a trans-membrane receptor for renin and prorenin, is involved in the local activation of renin-angiotensin system (RAS) in the kidney. However, it remains to be determined whether (P)RR plays a role in the development of ischemic acute kidney injury (AKI).. We examined the abundance of (P)RR, renin/prorenin, angiotensinogen (AGT), AT1 receptor (AT1R), phosphorylation of extracellular signal-regulated protein kinase 1/2 (ERK 1/2) and nuclear factor-κB (NF-κB) by Western blots at 6, 24 and 48 h, and at 7 days after 45-min ischemic injury in rats. Intrarenal angiotensin II (Ang II) levels were determined by radioimmunoassay. We then tested whether the beneficial effects of oral loading of saline solution (1.0 % NaCl) for 7 days prior to ischemic injury were associated with changes in RAS components and ERK 1/2 and NF-κB phosphorylation in the kidney. We also examined the effect of AT1R blocker, olmesartan, on ischemia-induced changes of (P)RR downstream such as AGT and phosphorylation of ERK 1/2.. Renal ischemia increased the abundance of (P)RR protein at 24 h, and peaked at 48 h. (P)RR was mainly stained in the connecting tubules and collecting ducts in control rats, while ischemia increased its immunointensity in the damaged proximal tubules. Renal ischemia increased phosphorylation of ERK 1/2 and NF-κB proteins as early as at 6 h. There was a significant increase in AGT and Ang II levels at 24 and 48 h. Prior saline loading prevented the increase in serum creatinine at 48 h (5.36 ± 1.26 vs. 3.38 ± 1.74 mg/dL, p < 0.05), and suppressed the increases in renal (P)RR, AGT and Ang II contents. Saline drinking also significantly blocked the ischemia-induced increases in phosphorylation of ERK 1/2 and NF-κB. In contrast, although treatment with olmesartan (10 mg/kg/day) for 14 days suppressed an increase of intrarenal AGT, olmesartan did not alleviate ischemic AKI, along with no change of (P)RR and phosphorylated ERK 1/2.. These findings suggest that increased (P)RR is associated with activation of RAS-independent downstream such as ERK 1/2 and NF-κB phosphorylation in the ischemic kidney.

Topics: Acute Kidney Injury; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Angiotensinogen; Animals; Creatinine; Extracellular Signal-Regulated MAP Kinases; Imidazoles; Ischemia; Kidney Tubules; Male; NF-kappa B; Phosphorylation; Prorenin Receptor; Proton-Translocating ATPases; Rats; Rats, Sprague-Dawley; Receptor, Angiotensin, Type 1; Receptors, Cell Surface; Sodium Chloride; Tetrazoles; Vacuolar Proton-Translocating ATPases

Hypertension and persistent activation of the renin-angiotensin system (RAS) are predisposing factors for the development of acute kidney injury (AKI). Although bone-marrow-derived stromal cells (BMSCs) have shown therapeutic promise in treatment of AKI, the impact of pathological RAS on BMSC functionality has remained unresolved. RAS and its local components in the bone marrow are involved in several key steps of cell maturation processes. This may also render the BMSC population vulnerable to alterations even in the early phases of RAS pathology. We isolated transgenic BMSCs (TG-BMSCs) from young end-organ-disease-free rats with increased RAS activation [human angiotensinogen/renin double transgenic rats (dTGRs)] that eventually develop hypertension and die of end-organ damage and kidney failure at 8 weeks of age. Control cells (SD-BMSCs) were isolated from wild-type Sprague-Dawley rats. Cell phenotype, mitochondrial reactive oxygen species (ROS) production and respiration were assessed, and gene expression profiling was carried out using microarrays. Cells' therapeutic efficacy was evaluated in a rat model of acute ischaemia/reperfusion-induced AKI. Serum urea and creatinine were measured at 24 h and 48 h. Acute tubular damage was scored and immunohistochemistry was used for evaluation for markers of inflammation [monocyte chemoattractant protein (MCP-1), ED-1], and kidney injury [kidney injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL)]. TG-BMSCs showed distinct mitochondrial morphology, decreased cell respiration and increased production of ROS. Gene expression profiling revealed a pronounced pro-inflammatory phenotype. In contrast with the therapeutic effect of SD-BMSCs, administration of TG-BMSCs in the AKI model resulted in exacerbation of kidney injury and high mortality. Our results demonstrate that early persistent RAS activation can dramatically compromise therapeutic potential of BMSCs by causing a shift into a pro-inflammatory phenotype with mitochondrial dysfunction.

Topics: Acute Kidney Injury; Acute-Phase Proteins; Angiotensinogen; Animals; Cell Adhesion Molecules; Chemokine CCL2; Gene Expression Profiling; Humans; Hypertension; Immunohistochemistry; Lipocalin-2; Lipocalins; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Mitochondria; Oligonucleotide Array Sequence Analysis; Oxygen Consumption; Proto-Oncogene Proteins; Rats, Sprague-Dawley; Rats, Transgenic; Reactive Oxygen Species; Renal Insufficiency; Renin; Renin-Angiotensin System

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.

Topics: Acute Kidney Injury; Aged; Aged, 80 and over; Angiotensinogen; Biomarkers; China; Female; Heart Failure; Humans; Male; Middle Aged; Predictive Value of Tests; Prospective Studies

This study investigated the impact of catalase (Cat) overexpression in renal proximal tubule cells (RPTCs) on nuclear factor erythroid 2-related factor 2 (Nrf2) stimulation of angiotensinogen (Agt) gene expression and the development of hypertension and renal injury in diabetic Akita transgenic mice. Additionally, adult male mice were treated with the Nrf2 activator oltipraz with or without the inhibitor trigonelline. Rat RPTCs, stably transfected with plasmid containing either rat Agt or Nrf2 gene promoter, were also studied. Cat overexpression normalized systolic BP, attenuated renal injury, and inhibited RPTC Nrf2, Agt, and heme oxygenase-1 (HO-1) gene expression in Akita Cat transgenic mice compared with Akita mice. In vitro, high glucose level, hydrogen peroxide, and oltipraz stimulated Nrf2 and Agt gene expression; these changes were blocked by trigonelline, small interfering RNAs of Nrf2, antioxidants, or pharmacological inhibitors of nuclear factor-κB and p38 mitogen-activated protein kinase. The deletion of Nrf2-responsive elements in the rat Agt gene promoter abolished the stimulatory effect of oltipraz. Oltipraz administration also augmented Agt, HO-1, and Nrf2 gene expression in mouse RPTCs and was reversed by trigonelline. These data identify a novel mechanism, Nrf2-mediated stimulation of intrarenal Agt gene expression and activation of the renin-angiotensin system, by which hyperglycemia induces hypertension and renal injury in diabetic mice.

Topics: Acute Kidney Injury; Angiotensinogen; Animals; Blood Glucose; Catalase; Diabetes Mellitus, Experimental; Gene Expression; Hypertension; Kidney Tubules, Proximal; Mice; Mice, Transgenic; NF-E2-Related Factor 2; NF-kappa B; Pyrazines; Reverse Transcriptase Inhibitors; Signal Transduction; Thiones; Thiophenes

Despite a significant improvement in the management of chronic kidney disease (CKD), its incidence and prevalence has been increasing over the years. Progressive renal fibrosis is present in CKD and involves the participation of several cytokines, including Transforming growth factor-β1 (TGF-β1). Besides cardiovascular diseases and infections, several studies show that Vitamin D status has been considered as a non-traditional risk factor for the progression of CKD. Given the importance of vitamin D in the maintenance of essential physiological functions, we studied the events involved in the chronic kidney disease progression in rats submitted to ischemia/reperfusion injury under vitamin D deficiency (VDD).. Rats were randomized into four groups: Control; VDD; ischemia/reperfusion injury (IRI); and VDD+IRI. At the 62 day after sham or IRI surgery, we measured inulin clearance, biochemical variables and hemodynamic parameters. In kidney tissue, we performed immunoblotting to quantify expression of Klotho, TGF-β, and vitamin D receptor (VDR); gene expression to evaluate renin, angiotensinogen, and angiotensin-converting enzyme; and immunohistochemical staining for ED1 (macrophages), type IV collagen, fibronectin, vimentin, and α-smooth mucle actin. Histomorphometric studies were performed to evaluate fractional interstitial area.. IRI animals presented renal hypertrophy, increased levels of mean blood pressure and plasma PTH. Furthermore, expansion of the interstitial area, increased infiltration of ED1 cells, increased expression of collagen IV, fibronectin, vimentin and α-actin, and reduced expression of Klotho protein were observed. VDD deficiency contributed to increased levels of plasma PTH as well as for important chronic tubulointerstitial changes (fibrosis, inflammatory infiltration, tubular dilation and atrophy), increased expression of TGF-β1 and decreased expression of VDR and Klotho protein observed in VDD+IRI animals.. Through inflammatory pathways and involvement of TGF-β1 growth factor, VDD could be considered as an aggravating factor for tubulointerstitial damage and fibrosis progression following acute kidney injury induced by ischemia/reperfusion.

Topics: Actins; Acute Kidney Injury; Angiotensinogen; Animals; Disease Progression; Fibronectins; Kidney; Male; Rats; Rats, Wistar; Receptors, Calcitriol; Renal Insufficiency, Chronic; Renin; Reperfusion Injury; Transforming Growth Factor beta; Transforming Growth Factor beta1; Vitamin D Deficiency

Acute kidney injury (AKI) is commonly observed in the intensive care unit (ICU), where it can be caused by a variety of factors. The objective of this study was to evaluate the prognostic value of urinary angiotensinogen, a candidate prognostic AKI biomarker identified in post-cardiac surgery patients, in this heterogeneous population.. Urinary angiotensinogen was measured by ELISA and corrected for urine creatinine in 45 patients who developed AKI in the ICU. Patients were grouped by AKI etiology, and the angiotensinogen-to-creatinine ratio (uAnCR) was compared among the groups using the Kruskal-Wallis test. The ability of uAnCR to predict the following endpoints was tested using the area under the ROC curve (AUC): the need for renal replacement therapy (RRT) or death, increased length of stay (defined as hospital discharge>7 days or death≤7 days from sample collection), and worsening AKI (defined as an increase in serum creatinine>0.3 mg/dL after sample collection or RRT).. uAnCR was significantly elevated in patients who met the composite outcome RRT or death (89.4 vs 25.4 ng/mg; P=0.01), and it was a strong predictor of this outcome (AUC=0.73). Patients with uAnCR values above the median for the cohort (55.21 ng/mg) had increased length of stay compared to patients with uAnCR≤55.21 ng/mg (22 days vs 7 days after sample collection; P=0.01). uAnCR was predictive of the outcome increased length of stay (AUC=0.77). uAnCR was also a strong predictor of worsening of AKI (AUC=0.77). The uAnCR of patients with pre-renal AKI was lower compared to patients with AKI of other causes (median uAnCR 11.3 vs 80.2 ng/mg; P=0.02).. Elevated urinary angiotensinogen is associated with adverse events in AKI patients in the ICU. It could be used to identify high risk patients who would benefit from timely intervention that could improve their outcomes.

Topics: Acute Kidney Injury; Adult; Aged; Aged, 80 and over; Angiotensinogen; Biomarkers; Female; Humans; Intensive Care Units; Male; Middle Aged; Predictive Value of Tests

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.. 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).. 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%).. The combination of urinary angiotensinogen and renin predicts progression to very severe disease in patients with early AKI after cardiac surgery.

Topics: Acute Kidney Injury; Aged; Angiotensinogen; Area Under Curve; Biomarkers; Cardiac Surgical Procedures; Chi-Square Distribution; Creatinine; Disease Progression; Female; Hospital Mortality; Humans; Logistic Models; Male; Middle Aged; Multivariate Analysis; Predictive Value of Tests; Prognosis; Renin; Renin-Angiotensin System; Retrospective Studies; Risk Factors; ROC Curve; Severity of Illness Index; United States; Up-Regulation

Biomarkers of AKI that can predict which patients will develop severe renal disease at the time of diagnosis will facilitate timely intervention in populations at risk of adverse outcomes.. Liquid chromatography/tandem mass spectrometry was used to identify 30 potential prognostic urinary biomarkers of severe AKI in a group of patients that developed AKI after cardiac surgery. Angiotensinogen had the best discriminative characteristics. Urinary angiotensinogen was subsequently measured by ELISA and its prognostic predictive power was verified in 97 patients who underwent cardiac surgery between August 1, 2008 and October 6, 2011.. The urine angiotensinogen/creatinine ratio (uAnCR) predicted worsening of AKI, Acute Kidney Injury Network (AKIN) stage 3, need for renal replacement therapy, discharge >7 days from sample collection, and composite outcomes of AKIN stage 2 or 3, AKIN stage 3 or death, and renal replacement therapy or death. The prognostic predictive power of uAnCR was improved when only patients classified as AKIN stage 1 at the time of urine sample collection (n=79) were used in the analysis, among whom it predicted development of stage 3 AKI or death with an area under the curve of 0.81. Finally, category free net reclassification improvement showed that the addition of uAnCR to a clinical model to predict worsening of AKI improved the predictive power.. Elevated uAnCR is associated with adverse outcomes in patients with AKI. These data are the first to demonstrate the utility of angiotensinogen as a prognostic biomarker of AKI after cardiac surgery.

Topics: Acute Kidney Injury; Aged; Angiotensinogen; Biomarkers; Female; Humans; Male; Middle Aged; Prognosis; Risk; Severity of Illness Index

As a noninvasive examination, urinary proteomics is a very useful tool to identify renal disease. The purpose of the present study was to find differential proteins among women with preeclampsia, gestational hypertension and normal pregnancy, and to screen potential biomarkers for the early diagnosis of preeclampsia.. Urinary proteins were identified by iTRAQ labeling coupled with 2-D LC-MS/MS. The bioinformatics analysis was performed with the Metacore software and the International Protein Index (IPI) and the Gene Ontology (GO) Database. The differentially expressed proteins were verified by ELISA.. 362 nonredundant proteins were identified, 113 of which were expressed differentially between preeclampsia and normal pregnant group and 31 differential proteins among three groups. These differential proteins were associated with biological processes of blood coagulation, cell adhesion and differentiation, immune response and cytoskeleton development, etc. They interacted with each other in the network. The urinary angiotensinogen (AGT) was downregulated, which was consistent with the ELISA validation results.. The present study found a multitude of differential proteins that might provide a clue for investigating the mechanism of proteinuria development in preeclampsia. Low urinary angiotensinogen levels were useful for identifying preeclampsia.

Topics: Acute Kidney Injury; Adult; Angiotensinogen; Case-Control Studies; Chromatography, Liquid; Computational Biology; Enzyme-Linked Immunosorbent Assay; Female; Gene Expression Regulation; Humans; Hypertension, Pregnancy-Induced; Pre-Eclampsia; Pregnancy; Proteinuria; Proteomics; Reproducibility of Results; Staining and Labeling; Tandem Mass Spectrometry

Topics: Acute Kidney Injury; Angiotensin II; Angiotensinogen; Animals; Male; NF-kappa B; Rats; Rats, Sprague-Dawley; rho-Associated Kinases

1. Plasma renin activity (PRA), plasma angiotensin I concentration (ANG I), plasma angiotensinogen concentration (PAC) and the plasma levels of active, total and inactive renin (prorenin) were measured in rats with carbon tetrachloride (CCl4)-induced acute renal failure. Rats were treated with a single oral dose of CCl4 (2.5 mL/kg) and killed 1, 2, 3 and 7 days later. 2. On days 1-3 PRA, ANG I and PAC decreased and increased on day 7. Active renin fell on days 2 and 3, total renin (trypsin treatment) augmented on day 1 and diminished on day 3, prorenin and per cent prorenin increased on days 1 and 2. Angiotensin I concentration paralleled PRA and PAC. The CCl4-induced decrease in PRA was secondary to the fall in active renin and in PAC. Total renin augmented as a consequence of the elevation of prorenin. Renal function, evaluated by serum urea, serum creatinine and creatinine clearance, decreased on days 1 and 2 when PRA was low and plasma prorenin was high. 3. These data do not support the involvement of the circulating active renin-angiotensin system (RAS) in the pathophysiology of acute renal failure induced by CCl4, however, increased prorenin levels were associated with the decrease in renal function.

Topics: Acute Kidney Injury; Angiotensin I; Angiotensinogen; Animals; Carbon Tetrachloride; Enzyme Precursors; Male; Rats; Rats, Wistar; Renin

Topics: Acute Kidney Injury; Angiotensinogen; Animals; Blood; Blood Pressure; Diabetes Insipidus; Female; Glomerular Filtration Rate; Glycerol; Hypothalamus; Osmolar Concentration; Rats; Renin; Urea

Topics: Acute Kidney Injury; Angiotensinogen; Animals; Arginine Vasopressin; Blood Pressure; Glycerol; Hematocrit; Immune Sera; Male; Osmolar Concentration; Rats; Renin; Saralasin; Urea; Vasopressins

Topics: Acute Kidney Injury; Aldosterone; Angiotensin II; Angiotensinogen; Ascites; Blood Pressure; Endopeptidases; Humans; Liver Diseases; Renin

Ten patients with severe liver disease and the hepatorenal syndrome underwent exchange transfusions with 9 to 16 units of fresh heparinized blood to improve renal function by either removing a vasoconstrictive substance or adding a vasodilatory substance. One patient recovered from renal failure within ten days without showing natriuresis. The renal function of one patient improved somewhat, but he died 35 days after the transfusion. The other eight aptients died from 1 to 35 days after exchange transfusion, without any appreciable improvement in renal function. In six patients, renin substrate levels increased after the transfusion, but renal function remained unchanged. The results of this study failed to support a humoral concept of pathogenesis of the hepatorenal syndrome.

Topics: Acute Kidney Injury; Adult; Alcoholism; Angiotensinogen; Chemical and Drug Induced Liver Injury; Creatinine; Exchange Transfusion, Whole Blood; Female; Hepatic Encephalopathy; Humans; Male; Middle Aged

Plasma concentrations of angiotensin II, renin, renin-substrate and aldosterone were measured in cases of acute renal failure. Angiotensin II, and renin levels were abnormally high on at least one occasion in nearly all patients. Mean angiotensin II and renin levels were highest in the first ten days of the disease. There was a highly significant positive correlation between concurrent estimations of renin and angiotensin II. Renin-substrate was also frequently elevated, but the correlations with renin and angiotensin II were not statistically significant. Despite the frequently marked elevation of plasma angiotensin II, only 2 of 17 measurements of plasma aldosterone were abnormally high. There was no significant relationship between aldosterone and plasma concentrations of angiotensin II, renin, sodium or potassium. The data are discussed in relation to current hypotheses implicating renin and angiotensin in the pathogenesis of acute circulatory renal failure.

Topics: Acute Kidney Injury; Adolescent; Adult; Aged; Aldosterone; Angiotensin II; Angiotensinogen; Female; Humans; Male; Middle Aged; Peritoneal Dialysis; Potassium; Renal Dialysis; Renin; Sodium

Topics: Acute Kidney Injury; Angiotensin II; Angiotensinogen; Humans; Liver Diseases; Renin