Baseline Predictors of Renal Disease Progression in the African American Study of Hypertension and Kidney Disease
Keith C. Norris*,
Tom Greene,
Joel Kopple,
Janice Lea,
Julia Lewis||,
Mike Lipkowitz¶,
Pete Miller**,
Annie Richardson,
Stephen Rostand,
Xuelei Wang,
Lawrence J. Appel** for the AASK Study Group
* Charles R. Drew University, Los Angeles, California; Cleveland Clinic Foundation, Cleveland, Ohio; Harbor-UCLA Medical Center, Torrance, California; Emory University, Atlanta, Georgia; || Vanderbilt University, Nashville, Tennessee; ¶ Mount Sinai School of Medicine, New York, New York; ** Johns Hopkins University, Baltimore, Maryland; University of Southern California, Los Angeles, California; University of Alabama, Birmingham, Alabama
Address correspondence to: Dr. Keith Norris, Associate Dean for Research, Charles R. Drew University, 1731 E. 120th Street, Los Angeles, CA 90059. Phone: 323-249-5702; Fax: 323-357-0747; E-mail: knorris{at}ucla.edu
Received for publication October 24, 2005.
Accepted for publication August 1, 2006.
Patients with chronic kidney disease have an increased riskfor progression to ESRD. The purpose of this study was to examinefactors that predict increased risk for adverse renal outcomes.Cox regression was performed to assess the potential of 38 baselinerisk factors to predict the clinical renal composite outcomeof 50% or 25-ml/min per 1.73 m2 GFR decline or ESRD among 1094black patients with hypertensive nephrosclerosis (GFR 20 to65 ml/min per 1.73 m2). Patients were trial participants whohad been randomly assigned to one of two BP goals and to oneof three antihypertensive regimens and followed for a rangeof 3 to 6.4 yr. In unadjusted and adjusted analyses, baselineproteinuria was consistently associated with an increased riskfor adverse renal outcomes, even at low levels of proteinuria.The relationship of proteinuria with adverse renal outcomesalso was evident in analyses that were stratified by level ofGFR, which itself was associated with adverse renal outcomesbut only at levels <40 ml/min. Other factors that were significantlyassociated with increased renal events after adjustment forbaseline GFR, age, and gender, both with and without adjustmentfor baseline proteinuria, included serum creatinine, urea nitrogen,and phosphorus. In black patients with hypertensive nephrosclerosis,increased proteinuria, reduced GFR, and elevated levels of serumcreatinine, urea nitrogen and phosphorus were directly associatedwith adverse clinical renal events. These findings identifya subset of this high-risk population that might benefit fromeven more aggressive treatment.
Patients with chronic kidney disease (CKD) are at increasedrisk for progression to ESRD and for premature cardiovasculardisease (CVD) (1–4). The number of individuals who receiverenal replacement therapy for ESRD continues to increase andnow has reached epidemic proportions (5). Whereas the estimatedprevalence of CKD is similar for black and white individuals(6), the adjusted incidence of ESRD among black individualsis the highest among racial/ethnic subgroups of the US populationand at 988 per million is nearly four times more common thantheir white counterparts at 254 per million (3). The magnitudeof hypertension-related ESRD among black individuals is highlightedby a nearly six-fold higher incidence than in white individuals;among 20- to 44-yr-olds, the incidence of hypertension-relatedESRD in black individuals is >15 times that of white individuals(3). Indeed, black race, male gender, hypertension, and hypercreatinemiahave been noted as powerful predictors of development of hypertension-relatedESRD (7). The level of proteinuria also has been found to bean especially strong predictor of the rate of progression ina wide range of CKD populations, including black individualswith hypertensive nephrosclerosis (8). Additional factors thatcontribute to the more rapid progression from CKD to ESRD amongblack individuals have not been defined clearly, although higherprevalence of traditional CKD risk factors, worse clinical controlof comorbid conditions, socioeconomic factors, and limited accessto care may play a role (9–12).
Until recently, no prospective trials were designed to reducethe risk for development of ESRD among black individuals withhypertension-related CKD. Results from the African AmericanStudy of Hypertension and Kidney Disease (AASK) revealed a significantbenefit of initial antihypertensive therapy with an angiotensin-convertingenzyme inhibitor, ramipril, in comparison with a dihydropyridinecalcium channel blocker, amlodipine, or a blocker, metoprolol,for reducing clinical composite outcome (50% or 25-ml/min per1.73 m2 decline in GFR, ESRD, or death) (13,14). The extensivebaseline data that were collected in the AASK provide a uniqueopportunity to identify factors that predict adverse renal outcomesin this understudied high-risk population.
In this setting, we performed a systematic investigation ofthe relationships between baseline risk factors and subsequentrenal events. Because initial proteinuria has been reportedconsistently to be the single strongest risk factor for subsequentdisease progression in CKD cohorts, we also addressed the questionof whether relationships that are observed between other potentialrisk factors and renal events can be accounted for by associationsbetween those risk factors and proteinuria and examined theextent to which these relationships persist after taking intoaccount the level of baseline proteinuria. These analyses shouldprovide useful information that can inform prevention and earlytreatment strategies that are designed to prevent the progressionof CKD.
Participants and Study Design
The study design was described previously (13–15). Briefly,participants were randomly assigned to a usual mean arterialpressure (MAP) goal of 102 to 107 mmHg or to a lower MAP goalof <92 mmHg and to treatment with one of three antihypertensivedrugs (metoprolol, ramipril, or amlodipine). Participants wereself-identified black individuals with hypertension (n = 1094),were aged 18 to 70 yr, had GFR between 20 and 65 ml/min per1.73 m2, and had no other identified causes of renal insufficiency.Exclusion criteria were (1) diastolic BP <95 mmHg, (2) knownhistory of diabetes (fasting glucose >140 mg/dl or randomglucose >200 mg/dl), (3) urinary protein-to-creatinine ratio(UP/Cr) >2.5, (4) accelerated or malignant hypertension within6 mo, (5) secondary hypertension, (6) evidence of non–BP-relatedcauses of renal disease, (7) serious systemic disease, (8) clinicalcongestive heart failure, or (9) specific indication for orcontraindication to a study drug or study procedure. The institutionalreview board at each center approved the protocol and procedures.An independent data, safety, and monitoring board also approvedand monitored the study. All participants gave written informedconsent. Participant enrollment began in February 1995 and endedin September 1998. Follow-up to the end of the study rangedfrom 3 to 6.4 yr.
Measurement of Baseline and Follow-Up Demographic, Laboratory, and Clinical Data
Baseline information was collected for family history, reviewof systems, lifestyle habits, education, and family income.A central laboratory measured baseline serum and urinary chemistrylevels, and GFR was assessed by 125-iothalamate clearance. Urinaryprotein excretion was expressed as the UP/Cr from a 24-h urinecollection. Three consecutive seated BP were measured usinga Hawksley random zero sphygmomanometer after at least 5 minof rest, with the mean of the last two readings recorded (13,16).The baseline BP were those that were obtained at the screeningvisits before randomization. Throughout this report, GFR isexpressed after standardization for body surface area in unitsof ml/min per 1.73 m2. Baseline electrocardiograms (ECG) wereobtained and read locally (14). Abnormal ECG findings were definedin response to the following question: Is the ECG completelynormal, yes or no? Left ventricular hypertrophy (LVH) was definedby voltage criteria, V1+V5 or V6 >35 mm, or V5 or V6 >25mm.
Outcome Variables
The main outcome variable in this report is a clinical renalcomposite given by the time from randomization to either (1)a GFR event, defined by a confirmed decline in GFR by either50% or 25 ml/min per 1.73 m2 from the mean of two baseline GFRmeasurements, or (2) occurrence of ESRD. Because censoring ofpatients who died before reaching ESRD may bias relationshipsof the renal composite outcome with baseline factors, we conductedparallel analyses using an extended clinical composite outcomedefined by the occurrence of either death or the renal end pointslisted in (1) or (2).
Statistical Analyses
Before the statistical analyses, the investigators selectedthe 38 factors that are listed in Table 1 as potential riskfactors for investigation. The factors were selected to incorporatea wide range of domains, including initial renal function, BPand CVD, traditional risk factors for CVD, biochemical markersof nutritional status, socioeconomic status, and other biochemistryand behavior factors that have been hypothesized to be associatedwith renal disease progression. Cox regression analyses wereused to relate the two composite outcomes individually withfour of these factors: Age, gender, baseline GFR, and baselineproteinuria. Further Cox regressions then were used to relatethe composite outcomes individually to each of the remaining34 baseline factors using two different levels of covariateadjustment: First controlling for baseline GFR, age, and genderand second controlling for proteinuria (expressed as the logUP/Cr) in addition to the first three factors. Subsequently,interaction terms with the randomized treatment groups wereadded to the Cox models to determine whether the treatment assignmentsmodified the associations of the composite outcomes with thebaseline factors. The adjustment for baseline GFR reflects ourobjective to evaluate the association of the baseline factorswith subsequent progression of disease rather than the initiallevel of GFR. Age and gender also were included as covariatesbecause they are nonmodifiable risk factors and because theinterpretation of relationships that involve other factors wasbelieved to be clearer after controlling for these basic demographiccharacteristics. Separate analyses were performed with and withoutadjustment for proteinuria to assess whether relationships betweenspecific factors and the composite outcomes persist independentof the level of proteinuria.
Table 1. Baseline characteristics, overall and by level of baseline proteinuria and baseline GFRa
Analyses of the renal composite, including GFR events and ESRD,were censored at death, permanent loss to follow-up before theend of the trial (nine patients), or the end of the study (September2001 for patients in the ramipril and metoprolol groups and1 yr earlier for patients in the amlodipine group, which wasdiscontinued before the end of the trial on the recommendationof the Data Safety and Monitoring Board [14]). Analyses of theextended clinical composite including death were censored atpermanent loss to follow-up or the end of the study. Becauseof the presence of nonlinear relationships, segmented linearspline terms were used to provide separate estimates of thehazard ratios (HR) of baseline GFR and serum urea nitrogen belowand above their median values. Finally, in addition to the designatedbaseline factors, each of the Cox regression models controlledfor the randomized treatment assignments, and analyses thatadjusted for baseline proteinuria also included interactionterms between log UP/Cr and the treatment assignments.
The assumption of proportional hazards in the Cox regressionmodels was checked by consideration of linear interactions betweenthe 38 baseline factors and follow-up time. The P values forthe interaction tests exceeded 0.05 (indicating no violationof proportional hazards) for all factors except years with hypertension(P = 0.03) and serum urea nitrogen (P = 0.04). These two marginallysignificant P values provide only weak evidence for nonproportionalhazards given the large number of interactions considered, andestimation of separate HR for the first 2 yr versus later infollow-up did not reveal clinically important differences. Hence,overall HR are presented, assuming proportional hazards throughoutthe follow-up period. Unless indicated otherwise, two-sidedP < 0.05 is designated as statistically significant, withoutadjustment for multiple comparisons.
Baseline Clinical Characteristics
The mean age of the participants was 54.6 ± 10.7 yr,and 670 (61%) were male. Average prestudy duration of hypertensionwas 14.2 ± 10.1 yr. The average number of antihypertensivemedications classes was 2.5 ± 1.1 per participant. Themean body mass index was 30.6 ± 6.6 kg/m2, and baselinesystolic and diastolic BP were 150 ± 24 and 96 ±14 mmHg, respectively. The serum creatinine level was 2.0 ±0.7 mg/dl with a mean GFR of 46 ± 14 ml/min per 1.73m2. Characteristics that included mean values and/or frequenciesfor the 38 potential baseline risk factors are shown for theentire cohort as well as stratified by the level of baselineproteinuria and GFR (Table 1). Baseline proteinuria is stratifiedat an UP/Cr of 0.22, which corresponds approximately to a 24-hprotein excretion of 300 mg/d and divides the two thirds withthe lowest proteinuria from the one third with the highest proteinuria,in accordance with the positive skewness of this variable (15).
Analysis of Risk Predictors for the Renal Composite Outcome (Time to GFR Event or ESRD)
The mean duration of follow-up until GFR event, ESRD, death,or censoring at the end of the study was 3.9 yr (median 4.0yr). As shown in Table 2, in univariate analyses, the renalcomposite outcome was strongly associated with higher baselineurinary protein excretion throughout the full range of proteinuriavalues (HR 1.59 per two-fold increase; 95% confidence interval[CI] 1.50 to 1.69; P < 0.001). The renal composite was inverselyassociated with baseline GFR at lower levels of GFR (HR 1.71per 5-ml/min per 1.73 m2 decrease in GFR when GFR was 40 ml/minper 1.73 m2; 95% CI 1.53 to 1.90; P < 0.001). For GFR forvalues >40 ml/min, there was a similar trend that did notreach statistical difference (HR 1.07; 95% CI 0.97 to 1.17;P = 0.16). Each 10 yr of age was associated with a 26% reducedrisk for adverse renal event (HR 0.74; 95% CI 0.67 to 0.83;P < 0.001), whereas no significant relationship was observedfor gender.
Table 2. Univariate relationships between four baseline factors and risk for GFR event or ESRDa
Because the baseline UP/Cr and GFR were strongly predictiveof the renal composite outcome, their joint relationship isshown in Figure 1. Figure 1 shows that the strong overall associationof the renal composite with baseline proteinuria persisted aftercontrolling for the level of baseline GFR. At each stratum ofGFR, as the UP/Cr ratio increased, so did the risk for the compositerenal outcome. The association between the proteinuria categoryand the log hazard ratio for the renal composite tended to bestronger in the lower GFR strata (interaction P = 0.04). Conversely,in strata that were defined by baseline UP/Cr, as baseline GFRdecreased, the risk for the composite renal outcome tended toincrease, although the relationship was less consistent in thelowest stratum of UP/Cr (0.08).
Figure 1. Joint association of the renal composite (GFR event or ESRD) with baseline proteinuria and baseline GFR. Shown are hazard ratios of the renal composite (GFR event or ESRD) for the designated combinations of levels of baseline proteinuria (expressed as baseline urine protein/creatinine ratio) and baseline GFR, adjusting for age, gender, and randomized treatment groups. Both baseline factors are strongly predictive of the occurrence of a GFR event or ESRD after controlling for the other.
Table 3 describes the association of the remaining 34 baselinefactors with the renal composite while controlling for randomizedgroup, baseline GFR, age, and gender, both with and withoutadjustment for baseline proteinuria. A total of 15 factors,listed first in Table 3, reached statistical significance withan unadjusted P <0.05 for one or both of these analyses.Factors that were significantly associated with an increasedrisk for the renal composite after adjustment for baseline GFR,age, and gender, both with and without adjustment for baselineproteinuria, included higher serum creatinine, urine urea nitrogen,and serum phosphorus. Paradoxically, a self-reported historyof heart disease, evidence of LVH on ECG, or an abnormal ECGwere each associated with a reduced risk for the renal compositeoutcome. Six additional baseline factors were significantlyassociated with the renal composite without adjustment but notwith adjustment for baseline proteinuria. These included greaterbody weight, higher serum glucose, higher triglyceride concentration,lower serum albumin, and higher levels of both urine urea nitrogenwhen >7.8 and urine sodium. In most cases, the HR of thesesix factors attenuated substantially toward 1.00 after adjustmentfor proteinuria. Finally, the risk that was associated withthree factors—hematocrit, MAP, and systolic BP—becamestatistically significant only after adjustment for proteinuria.
Table 3. Association of risk for GFR event or ESRD with baseline factorsa
Figure 2 presents the HR of the renal composite outcomes, withand without death, for the 16 factors with P < 0.05 for atleast one of the analyses in Table 3 plus current smoking, whichwas positively associated with the renal composite outcome thatincluded death. The hazard ratios are expressed per 1-SD increasein the respective baseline factors, so the sizes of the effectscan be compared between factors that are measured in differentunits. Baseline proteinuria was the strongest predictor of progressionfor both of the composite outcomes among the factors considered.The paradoxic trends that suggested a reduced rate of renalevents among patients with cardiovascular risk factors attenuatedand no longer reached statistical significance when death wasincluded in the composite outcome, although the direction ofthe relationships remained unchanged.
Figure 2. Association of composite outcomes with baseline factors, with and without adjustment for baseline proteinuria. Shown are the hazard ratios (with 95% confidence intervals [CI]) of two composite outcomes that are associated with 1-SD increases in the indicated baseline factors: (1) GFR event or ESRD and (2) GFR event, ESRD, or death. Results are provided both without adjustment for baseline proteinuria (CI indicated with solid lines) and then with adjustment for baseline proteinuria (CI indicated with dashed lines). All analyses are adjusted for age, gender, mean baseline GFR, and randomized treatment groups. S., serum; ECG, electrocardiogram; LVH, left ventricular hypertrophy; U., urine.
Interactions with Treatment Group
When considered without adjustment for other baseline factors,the association of baseline proteinuria with the renal compositeoutcome was slightly stronger for patients who were assignedto the usual BP group than the low BP group (HR 1.72 per two-foldincrease in UP/Cr in the usual BP group versus 1.41 per two-foldincrease in the low BP group; P = 0.001 for interaction). Relationshipsbetween the renal composite outcome and drug groups and severalother baseline factors also exhibited nominally significantdifferences between the treatment groups (P < 0.05), butno consistent pattern that would alter the conclusions of thisarticle emerged (data not shown).
This systematic investigation of the baseline variables thatwere collected in the AASK identified several factors that werepredictive of subsequent renal outcomes among black individualswith hypertensive nephrosclerosis. In particular, higher levelsof urine protein excretion, elevated serum creatinine, and alower initial GFR were highly predictive of an increased riskfor the composite clinical renal outcome. Importantly, the relationshipbetween proteinuria and renal outcomes was evident in each stratumof baseline GFR. Of note, the strong, graded association betweenproteinuria and renal outcomes was noted even at very low levelsof proteinuria. Previous reports of this association have beenin patient populations with higher levels of proteinuria.
The finding of a strong direct association of urinary proteinexcretion with clinical renal outcomes in our study confirmsand expands on previous findings from randomized prospectiveCKD trials (17,18). We also found that the association betweenrate of renal events and baseline GFR was greater at valuesbelow compared with those above 40 ml/min (as did GFR slope;data not shown), suggesting a nonlinear relationship betweenhypertensive CKD and decline in renal function. This is in contrastto the Modification of Diet in Renal Disease (MDRD) trial, whichreported a linear mean GFR decline as renal disease progressed(19). These contrasting results support heterogeneity in theprogression of CKD and/or potential response to therapy by etiologyand population examined. Heterogeneity within hypertensive nephrosclerosiswas described by Bohle et al. (20), who identified and characterizedthree distinct histologic classes: (1) compensated benign, (2)decompensated benign, and (3) malignant. The clinical profileof these histologic classes also differs, with the more severeforms of hypertensive nephrosclerosis occurring at an earlierage. This may help explain, in part, the inverse relationshipbetween age and rate of adverse renal outcomes. Alternatively,for any given level of baseline GFR, increased age may serveas a surrogate for a slower rate of disease progression; asfor the older patients, renal disease may have progressed overa longer period to reach the same GFR.
Although CKD generally is associated with an increase in CVDevents, in the AASK cohort, baseline LVH, abnormal ECG, andhistory of heart disease each were unexpectedly associated witha reduced risk for clinical renal outcomes. By contrast, previouscross-sectional studies had reported that the presence of CVDpredicted a faster decline of kidney function and earlier needfor dialysis (21), and several studies have noted a direct associationbetween increased prevalence of LVH and advanced stages of CKD(22,23). One potential explanation for this pattern is the occurrenceof informative censoring of renal outcomes from the competingrisk for death. That is, patients with cardiovascular risk factorsmay have been more likely to die before the occurrence of renalevents, thus distorting the relationship between cardiovascularrisk factors and clinical renal outcomes when follow-up timeis censored at death. The possibility of informative censoringis suggested by the analyses of the composite renal outcomeincluding death, in which apparent protective effects of thenoted cardiovascular risk factors were diminished and no longerstatistically significant.
Alternative explanations for our findings include an early expressionof reverse epidemiology for CVD that more commonly is seen inpatients with ESRD (24) and selection bias (individuals withsevere CVD were excluded or did not enroll in the trial). Italso is possible that the lower risk for renal events in thepatients with higher baseline BP and other cardiovascular riskfactors is related to the large reduction in BP levels thatwas experienced by the large majority of AASK participants,irrespective of their randomized treatment group assignment(25). Because the reduction in BP during the trial was largerin patients with higher initial BP, it is possible that higherBP levels and associated cardiovascular risk factors at entryidentified patients who benefited the most from their participationin the trial, thus reducing their risk for adverse events. Finally,because several analyses were considered for each of a largenumber of risk factors, it is not unlikely that some associationswith P < 0.05 are spurious positive results from multipleanalyses.
It is interesting that cigarette smokers compared with nonsmokersdid not predict clinical renal outcomes, in contrast to twocross-sectional studies that linked smoking to CKD progression(26,27). A prospective evaluation of 84 patients who had type2 diabetes and underwent BP control with angiotensin-convertingenzyme inhibition noted that both cigarette smoking and increasedproteinuria were interrelated predictors of nephropathy progression(28). Similarly, a multivariate analysis of 53 patients whohad essential hypertension and were followed prospectively for36 mo found that cigarette smoking, the baseline creatininelevel, and black ethnicity were the only variables that wereassociated with faster progression of kidney disease (29). However,we did note a strong association between smoking and the renalcomposite outcome when death was included; this finding suggeststhe possibility of informative censoring.
Anemia is more likely to occur as GFR declines (30). A lowerbaseline serum hematocrit was found to be an independent riskfor adverse renal events after adjustment for age, gender, andboth baseline GFR and proteinuria (P = 0.01), consistent withprevious observations (19), as well as analyses of clinicalpredictors for morbidity and mortality at initiation of dialysis(31–34). Although the precise mechanism(s) whereby anemiamight influence progression of kidney disease remains unclear,altered oxygen delivery to the kidney and the heart has beenposited as an important contributor (34,35).
Although the association of increased serum creatinine and increasedrenal and other vascular outcomes is well established (1–4,36,37),the finding of elevated baseline creatinine level to predictindependently an increase in renal outcome events even aftercontrolling for GFR was somewhat unexpected but may be relatedto the BP goal intervention. In the MDRD study, serum creatinineconcentration was noted to vary independent of GFR as a resultof differences in dietary protein intake (affecting creatininesecretion and excretion) and lower BP goal (affecting creatininesecretion) but not class of antihypertensive agents (38). Theassociation of increased serum phosphorus levels with both clinicalrenal events and the composite of clinical renal events anddeath builds on similar recent findings in both ESRD and CKDpopulations (39,40).
Our findings reinforce the observations that proteinuria andbaseline GFR are powerful predictors of CKD progression forthis high-risk hypertensive nephropathy population (black individuals)that was followed closely for approximately 4 yr. Although proteinuriaand estimated GFR are not measured routinely in many clinicalsettings, they are relatively simple clinical studies to obtain.The finding of significant predictive value for clinical renalevents with serum creatinine, hematocrit, and urea nitrogenprovide further support for these markers both in creating anoverall risk profile and for designing future prospective evaluationsof highly specific interventions.
Acknowledgments
In addition to funding under a cooperative agreement from NationalInstitute of Diabetes and Digestive and Kidney Diseases, thisstudy was supported in part by the following institutional GeneralClinical Research Centers and other National Institutes of Healthgrants: M01 RR-00080, 5M01 RR-00071, M01 00032, P20-RR11145,M01 RR00827, M01 RR00052, 2P20 RR11104, and DK 2818-02.
These data were presented in part at the annual meeting of theAmerican Society of Nephrology, November 12 through 17, 2003,in San Diego, CA.
The AASK Study Group includes the following. Case Western ReserveUniversity: J. Wright (Principal Investigator), Y. Hall (StudyCoordinator), R. Haynie, C. Mbanefo, M. Rahman, M. Smith, B.Crenshaw, R. Dancie, L. Jaen; Emory University: J. Lea (PrincipalInvestigator), A. Chapman, L. Dean, M. Douglas (Study Coordinator),D. Watkins, B. Wilkening, L. Williams, C. Ross; Harbor-UCLAMedical Center: J. Kopple (Principal Investigator), L. Miladinovich(Study Coordinator), P. Oleskie; Harlem Hospital Center: V.Pogue (Principal Investigator), D. Dowie (Study Coordinator),H. Anderson, L. Herbert, R. Locko, H. Nurse, J. Cheng, G. Darkwa,V. Dowdy, B. Nicholas; Howard University: O. Randall (PrincipalInvestigator), G. Ali, T. Retta, S. Xu (Study Coordinator),T. Alexander, M. Ketete, E. Mathew, D. Ordor, C. Tilghman; JohnsHopkins University: L. Appel (Principal Investigator), J. Charleston(Study Coordinator), C. Diggs, C. Harris, P. Miller, T. Shields,M. Sotomayer; Martin Luther King, Sr.–Charles R. DrewMedical Center: K. Norris (Principal Investigator), H. Ward,D. Martins, M. Miller (Study Coordinator), H. Howell; MedicalUniversity of South Carolina: D. Cheek (Principal Investigator),C. Gadegbeku, D. Ploth, D. Brooks (Study Coordinator), N. Monestime,S. Murner, S. Thompson; Meharry Medical College: M. Faulkner(Principal Investigator), O. Adeyele, K. Phillips (Study Coordinator),G. Sanford, C. Weaver; Morehouse School of Medicine: W. Cleveland(Principal Investigator), A. Howard, K. Chapman, S. Plater,W. Smith (Study Coordinator); Mount Sinai School of Medicine:R. Phillips (Principal Investigator), M. Lipkowitz, A. Gabriel(Study Coordinator), A. Travis, J. Williams; Ohio State University:L. Hebert (Principal Investigator), M. Falkenhain, S. Ladson-Wofford,N. Nahman, K. Osei, L. Hiremath (Study Coordinator), A. Dodley,J. Parks, D. Veley; Rush Presbyterian St. Luke’s MedicalCenter: G. Bakris (Principal Investigator), J. Lash, L. Fondren(Study Coordinator), L. Bagnuolo (Study Coordinator), J. Cohen(Study Coordinator), M. Powell (Study Coordinator), A. Smith,D. White, G. Henry, A. Johnson, T. Collins, S. Koshy, E. Afante;University of Alabama, Birmingham: S. Rostand (Principal Investigator),D. Thornley-Brown, R. Gay, C. Johnson (Study Coordinator), B.Key; University of California, San Diego: D. O’Connor(Principal Investigator), F. Gabbai, R. Parmer, F. Rao, J. Little,T. Makrogiannis, J. Mount (Study Coordinator), A. Ogundipe,A. Stephenson; University of Florida: C. Tisher (Principal Investigator),D. Allen, L. Burgin (Study Coordinator), A. Diaz, C. Sarmiento;University of Miami: J. Bourgoignie (Principal Investigator),G. Contreras, D. Florence-Green, A. Doss (Study Coordinator),J. Junco, D. Merrill, J. Vassallo, A. de Velasco; Universityof Michigan: K. Jamerson (Principal Investigator), F. Port,M. Keshishian, A. Ojo, S. Steigerwalt, D. Cornish-Zirker (StudyCoordinator), T. Graham, A. Johnson, J. Layne, S. Nesbitt, K.Manchester, W. Bloembergen; University of Southern California:S. Massry (Principal Investigator), V. Campese, M. Smogorzewski,A. Richardson (Study Coordinator); University of Texas SouthwesternMedical Center, Dallas: J. Middleton (Principal Investigator),E. Kuo, S. Leach, R. Toto, K. Jones, K. Hart, T. Lightfoot (StudyCoordinator), L. Littmon, B. McNeill, C. Ying; Vanderbilt University:J. Lewis (Principal Investigator), G. Schulman, S. McLeroy,N. Rogers (Study Coordinator), M. Sika; National Institute ofDiabetes and Digestive and Kidney Diseases: L.Y. Agodoa, J.P.Briggs, J.W. Kusek; Steering Committee Chair: J. Douglas; DataCoordinating Center (Cleveland Clinic Foundation): J. Gassman,G. Beck, V. Dennis, T. Greene, M. Kutner, K. Brittain (StudyCoordinator), S. Sherer, R. Stewart, L. Tuason, S.-R. Wang,W. Zhang; Central Biochemistry Laboratory: F. Van Lente, J.Waletzky, C. O’Laughlin, C. Peck; Central GFR Laboratory:P. Hall, D. Pexa, H. Rolin; Blood Pressure Consultant: R. Byington;Psychologic Consultant: P. Greene; Data Safety and MonitoringCommittee: R. Luke, V. Chinchilli, C. Cook, B. Falkner, C. Ford,R. Glassock, T. Karrison, T. Kotchen, E. Saunders, M. Secundy,D. Wesson.
We gratefully acknowledge support from the Office of Researchin Minority Health and the donation of drug and some financialsupport to the National Institute of Diabetes and Digestiveand Kidney Disease by Pfizer, Astra-Zeneca Pharmaceuticals,and King Pharmaceuticals. A special acknowledgment is extendedto the AASK participants for their time and commitment to thetrial.
The following authors have received honoraria from one or morepharmaceutical companies that manufacture antihypertensive medications:Lea, Lewis, Norris, Phillips, Rostand. The following authorshave received funding for research from one or more pharmaceuticalcompanies that manufacture antihypertensive medications: Appel,Greene, Norris, Phillips, Rostand. The following authors haveserved on the advisory panel for one or more pharmaceuticalcompanies that manufacture antihypertensive medications: Norris.The following authors have stock in one or more pharmaceuticalcompanies that manufacture antihypertensive medications: Rostand.
Footnotes
Published online ahead of print. Publication date availableat www.jasn.org.
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Top
Abstract
Introduction
blocker, metoprolol, for reducing clinical composite outcome (50% or 25-ml/min per 1.73 m2 decline in GFR, ESRD, or death) (13,14). The extensive baseline data that were collected in the AASK provide a unique opportunity to identify factors that predict adverse renal outcomes in this understudied high-risk population. 
40 ml/min per 1.73 m2; 95% CI 1.53 to 1.90; P < 0.001). For GFR for values >40 ml/min, there was a similar trend that did not reach statistical difference (HR 1.07; 95% CI 0.97 to 1.17; P = 0.16). Each 10 yr of age was associated with a 26% reduced risk for adverse renal event (HR 0.74; 95% CI 0.67 to 0.83; P < 0.001), whereas no significant relationship was observed for gender. 
