Urinary Angiotensinogen as a Marker of Intrarenal Angiotensin II Activity Associated with Deterioration of Renal Function in Patients with Chronic Kidney Disease
* First Department of Medicine and Division of Blood Purification, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka; and Faculty of Applied Biological Sciences, Gifu University, Gifu, Japan
Address correspondence to: Dr. Tatsuo Yamamoto, First Department of Medicine, Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu 431-3192, Japan. Phone: +81-53-435-2261; Fax: +81-53-434-9447; ytatsuo{at}hama-med.ac.jp
Received for publication June 3, 2006.
Accepted for publication February 12, 2007.
In chronic kidney disease (CKD), enhanced intrarenal angiotensinII (AngII) is involved in deterioration of renal function, butit is difficult to measure it. For assessment of the potentialof urinary angiotensinogen as a marker of intrarenal AngII activity,the correlation of plasma and urinary renin-angiotensin systemcomponents, including angiotensinogen, with deterioration ofrenal function was investigated in 80 patients who had CKD andwere not treated with AngII blocking agents. Changes that wereinduced by 14 d of losartan treatment (25 mg/d) were also measuredin 28 patients. Angiotensinogen was measured by RIA of AngIafter incubation with renin. Urinary angiotensinogen levelswere greater in patients with low estimated GFR and elevatedurinary protein and type IV collagen and correlated with renalAngII and type I collagen immunostaining intensities. The riskfor deterioration of renal function (i.e., estimated GFR declineof >2.5 ml/min per yr) during a mean follow-up period of23 mo (maximum 43 mo) was associated with urinary angiotensinogenof >3.0 nmol AngI equivalent per 1 g of urinary creatinine(AngI Eq/g Cre) at enrollment (hazard ratio 3.52). The event-freesurvival for deterioration of renal function was better in patientswith urinary angiotensinogen <3.0 nmol AngI Eq/g Cre thanthose >3.0 nmol AngI Eq/g Cre. Losartan reduced urinary andplasma angiotensinogen, urinary protein and type IV collagen,and systolic BP, despite concomitant increases in plasma reninand AngII. These data suggest that urinary angiotensinogen isa potentially suitable marker of intrarenal AngII activity associatedwith increased risk for deterioration of renal function in patientswith CKD.
Chronic kidney disease (CKD) that results in ESRD is a majorinternational health problem. It was also reported that CKDis an independent risk state for cardiovascular disease (1).The crucial role of angiotensin II (AngII), the major effectorof the renin-angiotensin system (RAS), in the development ofrenal fibrosis that results in ESRD is widely recognized. AngII-blockingagents, such as angiotensin-converting enzyme inhibitors (ACEI)and AngII receptor blockers (ARB), provide additional renoprotectionbeyond that of BP control (2). AngII is usually produced inthe bloodstream by the action of renin on angiotensinogen toform AngI, which is further cleaved by ACE to form AngII. However,organ-specific production of AngII has also been recognizedin various organs, such as kidney and heart (3,4), and suchlocal production seems to be unrelated to the systemic releaseof AngII (4,5). There is evidence that local tissue contentsand interstitial fluid concentrations of AngII in the kidneyare far greater than can be explained solely on the basis ofequilibration with circulating concentrations (6–8). Infact, several studies have demonstrated that much of the intrarenalAngII is derived from locally formed angiotensinogen in thekidney (8–13).
Increases in intrarenal RAS components, particularly AngII,in parallel with the severity of fibrotic renal damage, havebeen demonstrated in chronic progressive nephropathy in rat(14) and human (15). Although urinary AngII was proposed previouslyas a marker of intrarenal AngII activity (16), it has not beenconsistently shown to reflect intrarenal AngII activity. Atpresent, no clinical marker is available to evaluate intrarenalAngII activity because it is difficult to measure it directlyin patients.
Angiotensinogen is the only known substrate for renin, and thelevels of angiotensinogen in human and rat are close to theKm value for renin (17). Therefore, changes in either angiotensinogen(substrate) or renin (enzyme) could influence RAS activity.Several in vitro studies demonstrated the positive feedbackof AngII on angiotensinogen expression in hepatocytes, cardiacmyocytes, and proximal tubular cells (18–21). Kobori etal. reported that urinary angiotensinogen level correlates withintrarenal angiotensinogen and AngII levels in AngII-induced(10,11) and spontaneous (22) hypertensive rats. However, itis unknown whether urinary angiotensinogen can be used as amarker of intrarenal AngII activity in patients with CKD.
This study was designed to determine the potential of urinaryangiotensinogen as a marker of intrarenal AngII activity associatedwith increased risk for deterioration of renal function in patientswith CKD. For this purpose, we investigated the correlationof plasma and urinary RAS components, including angiotensinogen,with deterioration of renal function in 80 patients who hadCKD and were not treated with ACEI or ARB. The levels of urinaryangiotensinogen were compared with renal AngII and type I collagenimmunostaining intensities in consecutive kidney sections. Weprospectively analyzed the risk for decline of estimated GFR(eGFR) of >2.5 ml/min per yr during a mean follow-up periodof 23 mo (maximum 43) in 49 patients who had not dropped outor had not been introduced to hemodialysis within 3 mo of enrollment.We also investigated the effects of losartan, an ARB, on circulatingand urinary RAS components, including angiotensinogen.
Patients and Sampling
Eighty patients who had CKD, were hospitalized in HamamatsuUniversity Hospital between February 2003 and May 2005, hadnot received ACEI or ARB, and gave informed consent were includedin the study. The study protocol was approved by the ethicscommittee of Hamamatsu University School of Medicine. The patientsincluded 37 women and 43 men with a mean age of 52 yr (range18 to 94 yr). The eGFR ranged from 5 to 111 ml/min (mean 54ml/min). The eGFR was calculated using the Cockcroft-Gault formula(23), which was found to correlate well with GFR corrected forbody surface area in adults (24). The background renal diseaseswere IgA nephropathy (n = 17), diabetic nephropathy (n = 14),lupus nephritis (n = 8), membranous nephropathy (n = 4), minimal-changedisease (n = 3), nephrosclerosis (n = 3), purpura nephritis(n = 3), non-IgA nephropathy (n = 3), chronic interstitial nephritis(n = 3), membranoproliferative glomerulonephritis (n = 2), FSGS(n = 1), and chronic renal failure without renal biopsy data(n = 19).
Our preliminary study indicated that the levels of urinary angiotensinogendecreased to almost half in urine samples that were stored overnightat room temperature. Because the levels of circulating RAS componentsare affected by postural changes (25), we measured the levelsof plasma and urinary RAS components in blood samples that werecollected at bed rest early in the morning and fresh urine samplesthat were collected after waking up in hospitalized patientswith CKD. For measurement of plasma renin activity, plasma andurinary angiotensinogen, AngII, and aldosterone, blood and freshurine samples were collected in tubes that contained 4 mM EDTA,ice-cooled immediately, centrifuged, and stored at –70°Cuntil use. Urinary angiotensinogen, AngII, aldosterone, andtype IV collagen levels were expressed per 1 g of urinary creatinine(g Cre).
Measurement of Angiotensinogen
Plasma samples that were diluted 1:200 with 0.2 M PBS that contained125 mM EDTA, 1 mM captopril, and 50 mM PMSF and urine samplesthat were diluted 1:10 were incubated with 150 pM recombinanthuman renin at 37°C for 18 h. Recombinant human renin wasprepared as described previously (26). The reaction mixtureswere mixed with 30 mg of Florisil (Sigma-Aldrich Japan, Tokyo,Japan), incubated for 10 min, centrifuged, washed twice withultra pure water, and eluted with acetone that contained 0.5N HCl. The levels of AngI were then measured by RIA (SRL, Tokyo,Japan). The angiotensinogen levels were finally expressed asthe equivalent amounts of AngI (AngI Eq) by subtracting AngIlevels in untreated samples from those in the renin-treatedsamples. Our preliminary study showed that the generated AngIlevel reached a plateau after >18 h of incubation with 150pM human renin at 37°C in these samples. The sensitivityof the standard curve, defined as the smallest value that canbe distinguished from zero, was 23 fmol AngI Eq/ml. Coefficientsof variation of intra- and interexperimental measurements ofangiotensinogen were 9.5 and 13.2% in plasma samples and 11.6and 13.7% in urine samples, respectively.
Analyses of Correlation between Plasma and Urinary RAS Components and Deterioration of Renal Function
The relationships among circulating and urinary RAS componentsand renal function at enrollment were analyzed in 80 patientswho had CKD and were not treated with ACEI or ARB. For examinationof the effects of losartan treatment, plasma and urine sampleswere also collected after a 14-d administration of losartan25 mg/d in 28 patients. Four (14%) patients also received loopdiuretics, and the dosages were not changed during the 14-dstudy period. Patients who were treated with losartan were selectedby a clinical decision of the attending physicians, who werenot involved in the study. Therefore, patients with hyperkalemia,severe renal failure, or hypotension were not included in thispart of the study. We investigated the effects of low-dosagelosartan because eGFR at enrollment was low in some patients.
Thirty-one of 80 patients who had dropped out by moving to otherhospitals or had been introduced to hemodialysis within 3 moof enrollment were excluded from the follow-up study. The creatinineclearance is reported to diminish with age by approximately0.75 ml/min per yr (27), and falls in GFR were <2.5 ml/minper yr in four clinical trials in patients with CKD, in whichthe mean BP was controlled at 100 mmHg or less (28). Therefore,we defined deterioration of renal function in this study asfalls in eGFR of >2.5 ml/min per yr, and the risk for deteriorationof renal function was analyzed prospectively in 49 patientswith CKD during a mean follow-up period of 23 mo (maximum 43mo). eGFR was measured monthly, and any change was evaluatedrelative to more than 3-mo data in each patient.
Renal AngII and Type I Collagen Immunostaining
The kidney biopsy specimens were available in 45 of 80 enrolledpatients with CKD. To examine whether the levels of urinaryangiotensinogen correlated with those of intrarenal AngII andrenal fibrosis, we performed immunostaining for AngII and typeI collagen using a biotin-streptavidin-peroxidase method asdescribed previously (29) in consecutive kidney sections thatwere obtained from 35 patients who had CKD and in whom renalbiopsy was performed within 3 mo of measurement of urinary angiotensinogen.Microwave irradiation was performed to enhance antigen retrieval.The primary antibodies were rabbit anti-human AngII (PeninsulaLaboratories, San Carlos, CA) and mouse anti-human type I collagen(Daiichi Fine Chemical, Takaoka, Japan). The secondary antibodieswere biotinylated donkey anti-rabbit IgG and donkey anti-mouseIgG (Chemicon, Temecula, CA). Sections that were incubated withnonimmune rabbit or mouse sera, as appropriate, instead of theprimary antibodies served as negative controls. All sectionswere stained under identical conditions together with controlincubation. Nuclei were counterstained lightly with hematoxylin.The immunoreactivities for AngII and type I collagen were scoredin a blind manner as follows and were compared with the urinaryangiotensinogen levels: 0, nil; 1, mild; 2, moderate; 3, strongimmunostaining.
Statistical Analyses
We first conducted Pearson and Spearman single regression analysesfor parametric and nonparametric data, respectively, among allparameters studied. Then, factors with significant single correlationwith urinary angiotensinogen were adopted as explanatory variablesin multiple regression analysis. To reduce the impact of multicollinearity,we selected explanatory variables so that the mean sum of squaresfor the residual would be minimal in multiple regression analysis.As a result, diastolic BP was excluded. Because urinary angiotensinogen,AngII, aldosterone, type IV collagen, and protein levels deviatedfrom the normal distribution, the extent of the deviation wassubstantially reduced by common logarithmic transformation.The Kaplan-Meier method with the log-rank test was used forsurvival analysis on the end point of increased risk for deteriorationof renal function (i.e., eGFR decline of >2.5 ml/min peryr) during the follow-up period, and predictive variables weredetected by the Cox proportional hazards regression analysis,in which we set the following cutoff levels: eGFR of 60 ml/minbased on the definition of CKD; urinary angiotensinogen of 3.0nmol AngI Eq/g Cre based on the sensitivity and the specificity,which were shown in the results to detect renal dysfunction;urinary type IV collagen of 5.0 µg/g Cre based on thenormal range; urinary protein of 3.0 g/d; age of 60 yr, andbody mass index (BMI) of 25 kg/m2. The Wald test for globalnull hypothesis was performed to evaluate whether the proportionalassumption was met in the study cohort. Changes in parametersbefore and after losartan administration were compared by pairedt test or Wilcoxon signed rank test according to the distributionsof their measurements. P < 0.05 was considered as statisticallysignificant. Statistical analysis was performed with StatViewsoftware, version 5.0, for Macintosh.
Factors Related to Urinary Angiotensinogen Levels at Enrollment
The correlation matrix among eGFR, urinary and plasma RAS components,urinary protein and type IV collagen, BP, age, BMI, gender,and diabetic status at the time of enrollment is shown in Table 1.Urinary angiotensinogen correlated negatively with eGFR (r =–0.74, P < 0.0001; Figure 1A) and positively with urinarytype IV collagen (r = 0.78, P < 0.0001), urinary protein(r = 0.60, P < 0.0001), systolic BP (r = 0.54, P < 0.0001),urinary AngII (r = 0.44, P < 0.0001), diastolic BP (r = 0.34,P = 0.002), age (r = 0.46, P < 0.0001), and diabetic status( = 0.54, P < 0.0001). Urinary angiotensinogen did not correlatesignificantly with plasma renin activity, plasma angiotensinogen(Figure 1B), plasma AngII, plasma and urinary aldosterone, BMI,or gender. Multiple regression analysis indicated that low eGFR(P = 0.002), high proteinuria (P < 0.0001), and high urinarytype IV collagen (P = 0.003) correlated significantly with highurinary angiotensinogen (Table 2). The sensitivity of >3.0nmol AngI Eq/g Cre of urinary angiotensinogen for predictionof moderate (eGFR <60 ml/min) and severe (eGFR <30 ml/min)renal dysfunction was 81 and 91%, and the specificity was 77and 73%, respectively.
Figure 1. Scatter diagrams of bivariate correlations between urinary angiotensinogen and estimated GFR (eGFR; A) and plasma angiotensinogen (B). r, Pearson correlation coefficient; Ao, angiotensinogen; AngI Eq, equivalent amount of angiotensin I; g Cre, 1 g of urinary creatinine.
Table 2. Results of multiple regression analysis for urinary angiotensinogen (nmol AI Eq/g Cre) at enrollment in 80 patients who had CKD and were not treated with ACEI or ARBa
Correlation between Urinary Angiotensinogen Levels and Renal AngII and Type I Collagen Immunostaining Intensities
Representative pictures of AngII and type I collagen immunostainingare shown in Figure 2. In mild mesangial proliferative glomerulonephritis,AngII staining was detected mainly in distal tubules. Mild AngIIstaining was also noted in brush borders, some proximal tubularcells, Bowman's epithelial cells, and some glomerular cells.Mild and focal type I collagen staining was noted in the interstitium.In diffuse global lupus nephritis of class IV-G (A) (30) withfibrotic tubulointerstitial lesions, increased AngII stainingwas noted in the glomerular and tubulointerstitial lesions.Increased interstitial type I collagen staining was also observed.Some interstitial mononuclear cells were also positive for AngIIand type I collagen staining. Urinary angiotensinogen levelscorrelated positively with renal AngII ( = 0.652, P = 0.0001)and type I collagen ( = 0.678, P < 0.0001) immunostainingintensities (Figure 3).
Figure 2. Immunostaining of consecutive kidney sections for angiotensin II (AngII; A and C) and type I collagen (Col I; B and D) in mild mesangial proliferative glomerulonephritis (A and B) and diffuse global lupus nephritis of class IV-G (A) with fibrotic tubulointerstitial lesions (C and D). In mild mesangial proliferative glomerulonephritis, AngII staining is detected mainly in distal tubules. Mild AngII staining is also noted in brush borders, some proximal tubular cells, Bowman's epithelial cells, and some glomerular cells. In lupus nephritis, increased AngII and Col I staining is noted in the glomerular and tubulointerstitial lesions. Some interstitial mononuclear cells are also positive for AngII and Col I staining. Magnification, x120.
Figure 3. Correlations between urinary angiotensinogen levels and renal AngII (A) and Col I (B) immunostaining scores in 35 patients who had chronic kidney disease (CKD) and in whom renal biopsy was performed within 3 mo of measurement of urinary angiotensinogen. The levels of urinary angiotensinogen correlated significantly with renal AngII and Col I staining scores. • and error bars represent means and SD, respectively. , Spearman correlation coefficient.
Factors Associated with Deterioration of Renal Function
Kaplan-Meier test showed significant difference in event-freesurvival for deterioration of renal function between patientswith urinary angiotensinogen levels of > and <3.0 nmolAngI Eq/g Cre at enrollment (Figure 4). The P value of the Waldtest for global null hypothesis was >0.05, indicating thatthe hazard ratio did not change significantly during the follow-upperiod and the Cox proportional model fits in the follow-upstudy cohort. Multivariate analysis indicated that urinary angiotensinogenlevels of >3.0 nmol AngI Eq/g Cre at enrollment correlatedsignificantly with the risk for deterioration of renal function(decline in eGFR exceeding 2.5 ml/min per yr; hazard ratio 3.52;95% confidence interval 1.21 to 10.23; Table 3).
Figure 4. Kaplan-Meier survival curves for event-free survival of deterioration of renal function (i.e., decline in eGFR of >2.5 ml/min per yr) in the study cohort. Patients were stratified into three groups according to urinary angiotensinogen levels at enrollment (first group, urinary angiotensinogen <1.0 nmol AngI Eq/g Cre; second group, 1.0 urinary angiotensinogen < 3.0 nmol AngI Eq/g Cre; third group, urinary angiotensinogen 3.0 nmol AngI Eq/g Cre).
Our results demonstrated that (1) urinary angiotensinogen levelswere greater in patients with CKD, low eGFR, and high urinaryprotein and type IV collagen excretion; (2) urinary angiotensinogenlevels correlated positively with renal AngII and type I collagenimmunostaining intensities; (3) increased risk for deteriorationof renal function (i.e., eGFR decline of >2.5 ml/min peryr) was associated with increased urinary angiotensinogen levels;and (4) losartan reduced urinary angiotensinogen levels despiteconcomitant increases in plasma renin activity and plasma AngIIlevels. These data suggest the potential of urinary angiotensinogenas a marker of intrarenal AngII activity in patients with CKD,in whom intrarenal AngII activity is increased in parallel withthe severity of fibrotic renal damage. The data also demonstratedthat the levels of urinary angiotensinogen could help identifypatients who have CKD and are at increased risk for progressiverenal failure.
Recently, there has been a paradigm shift from a focus primarilyon the role of the circulating RAS in BP regulation and sodiumhomeostasis to emphasis on the expression of organ-specificRAS involved in organ fibrosis. In the kidney, all componentsthat are needed for AngII generation are present (12,14). Increasedexpression of renin, angiotensinogen, and ACE were demonstratedin kidneys of hypertensive patients and patients with CKD (12,15).AngII-induced augmentation of angiotensinogen and AngII wasalso demonstrated in AngII-infused hypertensive rat kidneys(13). In contrast to renin in the juxtaglomerular apparatus,renin in the collecting ducts is augmented by AngII (31). Thesedata suggest that much of the intrarenal AngII is derived fromlocally formed angiotensinogen and that renal angiotensinogenexpression is stimulated, at least in part, by AngII itself.
In AngII-infused hypertensive rats, urinary angiotensinogenwas proposed as a marker of intrarenal AngII activity becauseits level correlated well with intrarenal angiotensinogen andAngII levels (10,11). The increase in intrarenal AngII activitywas also shown to parallel the severity of fibrotic renal damagein chronic progressive nephropathy in rat (14) and human (15).In this study, urinary angiotensinogen levels were greater inpatients with CKD, low eGFR, and high urinary excretion of proteinand type IV collagen, a marker of renal extracellular matrixproduction (32,33), and correlated positively with renal AngIIand type I collagen immunostaining intensities. It is conceivablethat increased urinary angiotensinogen excretion in patientswith low eGFR and high urinary type IV collagen excretion isdue to enhanced angiotensinogen expression in the kidneys withprogressive fibrosis, which is mediated by increased intrarenalAngII activity and results in progressive deterioration of renalfunction. This notion was further supported by the findingsthat urinary angiotensinogen of >3.0 nmol AngI Eq/g Cre atenrollment was associated with increased risk for deteriorationof renal function with a hazard ratio of 3.52 after adjustmentfor eGFR, urinary type IV collagen and protein, systolic BP,age, BMI, gender, and diabetes status. The event-free survivalfor deterioration of renal function was significantly higherin patients with urinary angiotensinogen of <3.0 nmol AngIEq/g Cre than those who were over the level at enrollment. Ourresults also demonstrated that the levels of urinary angiotensinogenwere reduced by losartan, which is thought to suppress intrarenalAngII activity, despite the concomitant rises in plasma reninactivity and plasma AngII. A decrease in intrarenal AngII inducedby candesartan, another ARB, has been reported in Dahl salt-sensitiverats on a high salt intake, despite the increase in plasma AngII(34). Taken together, these results suggest the potential ofurinary angiotensinogen as a marker of intrarenal AngII activityinvolved in the progression of renal fibrosis with subsequentdeterioration of renal function in patients with CKD.
It is plausible that plasma angiotensinogen cannot easily filteracross the glomerular membrane because of its size (9). It iswidely known that >3.5 g/d proteinuria, mainly albuminuria,causes a marked decrease of serum albumin level to <30 g/Lin nephrotic syndrome. As shown in Figure 1B, the levels ofurinary angiotensinogen ranged between 0.4 and 124 nmol AngIEq/g Cre excretion, and those of plasma angiotensinogen werebetween 63 and 705 nmol AngI Eq/L. Because the daily urinarycreatinine excretion is nearly 1 g in adults, the urinary angiotensinogenlevels that were observed in this study seem high enough tocause significant decreases in plasma angiotensinogen in somepatients, if the urinary angiotensinogen originated from thecirculation and filtered across the glomerular membrane. However,we found no significant correlation between urinary and plasmaangiotensinogen levels. It is therefore unlikely that most ofthe increased urinary angiotensinogen in patients with highproteinuria originated from the circulation, although we cannotcompletely rule out the possible contribution of derangementof glomerular permeability, which could result from progressiverenal fibrosis, to the increased urinary angiotensinogen.
Losartan also decreased plasma angiotensinogen levels. A decreasein plasma angiotensinogen induced by losartan or enalapril,an ACEI, has been demonstrated in spontaneously hypertensiverats, despite concomitant increases in plasma and renal reninand plasma AngII (35). Because the majority of plasma angiotensinogenoriginates from the liver (36), such losartan-induced decreasein plasma angiotensinogen may reflect the effect of ARB on systemicangiotensinogen expression mediated by AngII.
We measured angiotensinogen levels by measuring AngI releasedby excess renin. Recently, an ELISA that used anti-angiotensinogenantibody was reported (37,38). In contrast to our measurementthat detects intact angiotensinogen only, the ELISA detectsintact angiotensinogen as well as its inactive residue, thedes-angiotensin I-angiotensinogen (des-AngI-Ao), cleaved byrenin (39). Clauser et al. (39) reported that no significantchanges in the circulating levels of total angiotensinogen,composed of intact angiotensinogen and des-AngI-Ao, were observedby the RIA using anti-angiotensinogen antibody in sodium-depleted,captopril-treated, or adrenalectomized rats, although intactangiotensinogen levels, measured using renin, were decreasedin proportion to the elevation of renin levels in these conditions.Because plasma des-AngI-Ao levels correlate with plasma reninlevels (40), we consider that the ELISA is not superior to themethod that uses renin to detect angiotensinogen that is inducedby increased intrarenal AngII activity in patients with CKD.
We have demonstrated in this study the presence of high urinaryangiotensinogen levels in patients with low eGFR, high urinaryprotein and type IV collagen excretion, and increased renalAngII and type I collagen expression and that treatment withlosartan reduced urinary angiotensinogen levels. Increased riskfor deterioration of renal function was associated with increasedurinary angiotensinogen levels. Our data suggest the potentialof urinary angiotensinogen as a novel tool for evaluation ofintrarenal AngII activity and for identification of patientswho have CKD and are at increased risk for progressive deteriorationof renal function. However, our study has certain limitations,including the small sample size, concomitant wide confidenceintervals of the hazard ratios, and the dichotomizing approachin the Cox proportional hazards regression analysis. Furtherstudies with a larger patient population are clearly needed.
This study was supported by a clinical research grant from HamamatsuUniversity School of Medicine and in part by a Grant-in-Aidfor Scientific Research (17590824 to T.Y.) from the Ministryof Education, Culture, Sports, Science and Technology, Japan.
Portions of this study were presented in abstract forms at the38th (November 8 to 13, 2005; Philadelphia, PA) and 39th AnnualRenal Week Meetings (November 14 to 19, 2006; San Diego, CA)of the American Society of Nephrology.
The authors thank Takahito Kaji from Banyu Pharmaceutical Co.(Tokyo, Japan) for the advice on statistical analysis.
Footnotes
Published online ahead of print. Publication date availableat www.jasn.org.
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[Abstract][Full Text][PDF]
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Abstract
Introduction
= 0.54, P < 0.0001). Urinary angiotensinogen did not correlate significantly with plasma renin activity, plasma angiotensinogen (Figure 1B), plasma AngII, plasma and urinary aldosterone, BMI, or gender. Multiple regression analysis indicated that low eGFR (P = 0.002), high proteinuria (P < 0.0001), and high urinary type IV collagen (P = 0.003) correlated significantly with high urinary angiotensinogen (Table 2). The sensitivity of >3.0 nmol AngI Eq/g Cre of urinary angiotensinogen for prediction of moderate (eGFR <60 ml/min) and severe (eGFR <30 ml/min) renal dysfunction was 81 and 91%, and the specificity was 77 and 73%, respectively. 
urinary angiotensinogen < 3.0 nmol AngI Eq/g Cre; third group, urinary angiotensinogen 
3.0 nmol AngI Eq/g Cre).