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Michael V Rocco,
Robert S Lockridge,
Gerald J Beck,
Paul W Eggers, Jennifer J Gassman,
Tom Greene,
Brett Larive,
Christopher T Chan,
Glenn M Chertow,
Michael Copland, [......],
A Mazzorato,
E Spanner,
J Burkart,
S Moossavi,
V Mauck,
T Kaufman,
A Pierratos,
W Chan,
K Regozo,
S Kwok
[show abstract]
[hide abstract]
ABSTRACT: Prior small studies have shown multiple benefits of frequent nocturnal hemodialysis compared to conventional three times per week treatments. To study this further, we randomized 87 patients to three times per week conventional hemodialysis or to nocturnal hemodialysis six times per week, all with single-use high-flux dialyzers. The 45 patients in the frequent nocturnal arm had a 1.82-fold higher mean weekly stdKt/V(urea), a 1.74-fold higher average number of treatments per week, and a 2.45-fold higher average weekly treatment time than the 42 patients in the conventional arm. We did not find a significant effect of nocturnal hemodialysis for either of the two coprimary outcomes (death or left ventricular mass (measured by MRI) with a hazard ratio of 0.68, or of death or RAND Physical Health Composite with a hazard ratio of 0.91). Possible explanations for the left ventricular mass result include limited sample size and patient characteristics. Secondary outcomes included cognitive performance, self-reported depression, laboratory markers of nutrition, mineral metabolism and anemia, blood pressure and rates of hospitalization, and vascular access interventions. Patients in the nocturnal arm had improved control of hyperphosphatemia and hypertension, but no significant benefit among the other main secondary outcomes. There was a trend for increased vascular access events in the nocturnal arm. Thus, we were unable to demonstrate a definitive benefit of more frequent nocturnal hemodialysis for either coprimary outcome.
Kidney International 07/2011; 80(10):1080-91. · 6.61 Impact Factor
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Michael J Fischer,
Paul L Kimmel,
Tom Greene, Jennifer J Gassman,
Xuelei Wang,
Deborah H Brooks,
Jeanne Charleston,
Donna Dowie,
Denyse Thornley-Brown,
Lisa A Cooper,
Marino A Bruce,
John W Kusek,
Keith C Norris,
James P Lash
[show abstract]
[hide abstract]
ABSTRACT: This study was designed to examine the impact of elevated depressive affect on health outcomes among participants with hypertensive chronic kidney disease in the African-American Study of Kidney Disease and Hypertension (AASK) Cohort Study. Elevated depressive affect was defined by Beck Depression Inventory II (BDI-II) thresholds of 11 or more, above 14, and by 5-Unit increments in the score. Cox regression analyses were used to relate cardiovascular death/hospitalization, doubling of serum creatinine/end-stage renal disease, overall hospitalization, and all-cause death to depressive affect evaluated at baseline, the most recent annual visit (time-varying), or average from baseline to the most recent visit (cumulative). Among 628 participants at baseline, 42% had BDI-II scores of 11 or more and 26% had a score above 14. During a 5-year follow-up, the cumulative incidence of cardiovascular death/hospitalization was significantly greater for participants with baseline BDI-II scores of 11 or more compared with those with scores <11. The baseline, time-varying, and cumulative elevated depressive affect were each associated with a significant higher risk of cardiovascular death/hospitalization, especially with a time-varying BDI-II score over 14 (adjusted HR 1.63) but not with the other outcomes. Thus, elevated depressive affect is associated with unfavorable cardiovascular outcomes in African Americans with hypertensive chronic kidney disease.
Kidney International 06/2011; 80(6):670-8. · 6.61 Impact Factor
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Glenn M Chertow,
Nathan W Levin,
Gerald J Beck,
Thomas A Depner,
Paul W Eggers, Jennifer J Gassman,
Irina Gorodetskaya,
Tom Greene,
Sam James,
Brett Larive, [......],
Sanjay Rajagopalan,
Anjay Rastogi,
Michael V Rocco,
Brigitte Schiller,
Olga Sergeyeva,
Gerald Schulman,
George O Ting,
Mark L Unruh,
Robert A Star,
Alan S Kliger
[show abstract]
[hide abstract]
ABSTRACT: In this randomized clinical trial, we aimed to determine whether increasing the frequency of in-center hemodialysis would result in beneficial changes in left ventricular mass, self-reported physical health, and other intermediate outcomes among patients undergoing maintenance hemodialysis.
Patients were randomly assigned to undergo hemodialysis six times per week (frequent hemodialysis, 125 patients) or three times per week (conventional hemodialysis, 120 patients) for 12 months. The two coprimary composite outcomes were death or change (from baseline to 12 months) in left ventricular mass, as assessed by cardiac magnetic resonance imaging, and death or change in the physical-health composite score of the RAND 36-item health survey. Secondary outcomes included cognitive performance; self-reported depression; laboratory markers of nutrition, mineral metabolism, and anemia; blood pressure; and rates of hospitalization and of interventions related to vascular access.
Patients in the frequent-hemodialysis group averaged 5.2 sessions per week; the weekly standard Kt/V(urea) (the product of the urea clearance and the duration of the dialysis session normalized to the volume of distribution of urea) was significantly higher in the frequent-hemodialysis group than in the conventional-hemodialysis group (3.54±0.56 vs. 2.49±0.27). Frequent hemodialysis was associated with significant benefits with respect to both coprimary composite outcomes (hazard ratio for death or increase in left ventricular mass, 0.61; 95% confidence interval [CI], 0.46 to 0.82; hazard ratio for death or a decrease in the physical-health composite score, 0.70; 95% CI, 0.53 to 0.92). Patients randomly assigned to frequent hemodialysis were more likely to undergo interventions related to vascular access than were patients assigned to conventional hemodialysis (hazard ratio, 1.71; 95% CI, 1.08 to 2.73). Frequent hemodialysis was associated with improved control of hypertension and hyperphosphatemia. There were no significant effects of frequent hemodialysis on cognitive performance, self-reported depression, serum albumin concentration, or use of erythropoiesis-stimulating agents.
Frequent hemodialysis, as compared with conventional hemodialysis, was associated with favorable results with respect to the composite outcomes of death or change in left ventricular mass and death or change in a physical-health composite score but prompted more frequent interventions related to vascular access. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; ClinicalTrials.gov number, NCT00264758.).
New England Journal of Medicine 12/2010; 363(24):2287-300. · 53.30 Impact Factor
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Lawrence J Appel,
Jackson T Wright,
Tom Greene,
Lawrence Y Agodoa,
Brad C Astor,
George L Bakris,
William H Cleveland,
Jeanne Charleston,
Gabriel Contreras,
Marquetta L Faulkner, [......],
Shaul G Massry,
Edgar R Miller,
Keith Norris,
Robert A Phillips,
Velvie A Pogue,
Otelio S Randall,
Stephen G Rostand,
Miroslaw J Smogorzewski,
Robert D Toto,
Xuelei Wang
[show abstract]
[hide abstract]
ABSTRACT: In observational studies, the relationship between blood pressure and end-stage renal disease (ESRD) is direct and progressive. The burden of hypertension-related chronic kidney disease and ESRD is especially high among black patients. Yet few trials have tested whether intensive blood-pressure control retards the progression of chronic kidney disease among black patients.
We randomly assigned 1094 black patients with hypertensive chronic kidney disease to receive either intensive or standard blood-pressure control. After completing the trial phase, patients were invited to enroll in a cohort phase in which the blood-pressure target was less than 130/80 mm Hg. The primary clinical outcome in the cohort phase was the progression of chronic kidney disease, which was defined as a doubling of the serum creatinine level, a diagnosis of ESRD, or death. Follow-up ranged from 8.8 to 12.2 years.
During the trial phase, the mean blood pressure was 130/78 mm Hg in the intensive-control group and 141/86 mm Hg in the standard-control group. During the cohort phase, corresponding mean blood pressures were 131/78 mm Hg and 134/78 mm Hg. In both phases, there was no significant between-group difference in the risk of the primary outcome (hazard ratio in the intensive-control group, 0.91; P=0.27). However, the effects differed according to the baseline level of proteinuria (P=0.02 for interaction), with a potential benefit in patients with a protein-to-creatinine ratio of more than 0.22 (hazard ratio, 0.73; P=0.01).
In overall analyses, intensive blood-pressure control had no effect on kidney disease progression. However, there may be differential effects of intensive blood-pressure control in patients with and those without baseline proteinuria. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases, the National Center on Minority Health and Health Disparities, and others.)
New England Journal of Medicine 09/2010; 363(10):918-29. · 53.30 Impact Factor
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Michael J Fischer,
Paul L Kimmel,
Tom Greene, Jennifer J Gassman,
Xuelei Wang,
Deborah H Brooks,
Jeanne Charleston,
Donna Dowie,
Denyse Thornley-Brown,
Lisa A Cooper,
Marino A Bruce,
John W Kusek,
Keith C Norris,
James P Lash
[show abstract]
[hide abstract]
ABSTRACT: Depression is common in end-stage renal disease and is associated with poor quality of life and higher mortality; however, little is known about depressive affect in earlier stages of chronic kidney disease. To measure this in a risk group burdened with hypertension and kidney disease, we conducted a cross-sectional analysis of individuals at enrollment in the African American Study of Kidney Disease and Hypertension Cohort Study. Depressive affect was assessed by the Beck Depression Inventory II and quality of life by the Medical Outcomes Study-Short Form and the Satisfaction with Life Scale. Beck Depression scores over 14 were deemed consistent with an increased depressive affect and linear regression analysis was used to identify factors associated with these scores. Among 628 subjects, 166 had scores over 14 but only 34 were prescribed antidepressants. The mean Beck Depression score of 11.0 varied with the estimated glomerular filtration rate (eGFR) from 10.7 (eGFR 50-60) to 16.0 (eGFR stage 5); however, there was no significant independent association between these. Unemployment, low income, and lower quality and satisfaction with life scale scores were independently and significantly associated with a higher Beck Depression score. Thus, our study shows that an increased depressive affect is highly prevalent in African Americans with chronic kidney disease, is infrequently treated with antidepressants, and is associated with poorer quality of life. Sociodemographic factors have especially strong associations with this increased depressive affect. Because this study was conducted in an African-American cohort, its findings may not be generalized to other ethnic groups.
Kidney International 03/2010; 77(11):1010-9. · 6.61 Impact Factor
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Joy M Weinberg,
Lawrence J Appel,
George Bakris, Jennifer J Gassman,
Tom Greene,
Cynthia A Kendrick,
Xuelei Wang,
James Lash,
Julia A Lewis,
Velvie Pogue,
Denyse Thornley-Brown,
Robert A Phillips
[show abstract]
[hide abstract]
ABSTRACT: The incidence and factors associated with hyperkalemia in patients with chronic kidney disease (CKD) treated with angiotensin converting enzyme inhibitors (ACEIs) and other antihypertensive drugs was investigated using the African American Study of Kidney Disease and Hypertension (AASK) database.
A total of 1094 nondiabetic adults with hypertensive CKD (glomerular filtration rate [GFR], 20-65 mL/min/1.73 m(2)) were followed for 3.0 to 6.4 years in the AASK trial. Participants were randomly assigned to ACEI, beta-blocker (BB), or dihydropyridine calcium channel blocker (CCB). The outcome variables for this analysis were a serum potassium level higher than 5.5 mEq/L (to convert to millimoles per liter, multiply by 1.0), or a clinical center initiated hyperkalemia stop point.
A total of 6497 potassium measurements were obtained, and 80 events in 51 subjects were identified (76 events driven by a central laboratory result and 4 driven by a clinical center-initiated hyperkalemia stop point). Compared with a GFR higher than 50 mL/min/1.73 m(2), after multivariable adjustment, the hazard ratio (HR) for hyperkalemia in patients with a GFR between 31 and 40 mL/min/1.73 m(2) and a GFR lower than 30 mL/min/1.73 m(2) was 3.61 (95% confidence interval [CI], 1.42-9.18 [P = .007]) and 6.81 (95% CI, 2.67-17.35 [P < .001]), respectively; there was no increased risk of hyperkalemia if GFR was 41 to 50 mL/min/1.73 m(2). Use of ACEIs was associated with more episodes of hyperkalemia compared with CCB use (HR, 7.00; 95% CI, 2.29-21.39 [P < .001]) and BB group (HR, 2.85; 95% CI, 1.50-5.42 [P = .001]). Diuretic use was associated with a 59% decreased risk of hyperkalemia.
In nondiabetic patients with hypertensive CKD treated with ACEIs, the risk of hyperkalemia is small, particularly if baseline and follow-up GFR is higher than 40 mL/min/1.73 m(2). Including a diuretic in the regimen may markedly reduce risk of hyperkalemia.
Archives of internal medicine 09/2009; 169(17):1587-94. · 11.46 Impact Factor
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Bradley S Dixon,
Gerald J Beck,
Miguel A Vazquez,
Arthur Greenberg,
James A Delmez,
Michael Allon,
Laura M Dember,
Jonathan Himmelfarb, Jennifer J Gassman,
Tom Greene, [......],
James R Cotton,
Kevin J Martin,
James W McNeil,
Asif Rahman,
Jeffery H Lawson,
James F Whiting,
Bo Hu,
Catherine M Meyers,
John W Kusek,
Harold I Feldman
[show abstract]
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ABSTRACT: Arteriovenous graft stenosis leading to thrombosis is a major cause of complications in patients undergoing hemodialysis. Procedural interventions may restore patency but are costly. Although there is no proven pharmacologic therapy, dipyridamole may be promising because of its known vascular antiproliferative activity.
We conducted a randomized, double-blind, placebo-controlled trial of extended-release dipyridamole, at a dose of 200 mg, and aspirin, at a dose of 25 mg, given twice daily after the placement of a new arteriovenous graft until the primary outcome, loss of primary unassisted patency (i.e., patency without thrombosis or requirement for intervention), was reached. Secondary outcomes were cumulative graft failure and death. Primary and secondary outcomes were analyzed with the use of a Cox proportional-hazards regression with adjustment for prespecified covariates.
At 13 centers in the United States, 649 patients were randomly assigned to receive dipyridamole plus aspirin (321 patients) or placebo (328 patients) over a period of 4.5 years, with 6 additional months of follow-up. The incidence of primary unassisted patency at 1 year was 23% (95% confidence interval [CI], 18 to 28) in the placebo group and 28% (95% CI, 23 to 34) in the dipyridamole-aspirin group, an absolute difference of 5 percentage points. Treatment with dipyridamole plus aspirin significantly prolonged the duration of primary unassisted patency (hazard ratio, 0.82; 95% CI, 0.68 to 0.98; P=0.03) and inhibited stenosis. The incidences of cumulative graft failure, death, the composite of graft failure or death, and serious adverse events (including bleeding) did not differ significantly between study groups.
Treatment with dipyridamole plus aspirin had a significant but modest effect in reducing the risk of stenosis and improving the duration of primary unassisted patency of newly created grafts. (ClinicalTrials.gov number, NCT00067119.)
New England Journal of Medicine 06/2009; 360(21):2191-201. · 53.30 Impact Factor
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Laura M Dember,
Gerald J Beck,
Michael Allon,
James A Delmez,
Bradley S Dixon,
Arthur Greenberg,
Jonathan Himmelfarb,
Miguel A Vazquez, Jennifer J Gassman,
Tom Greene,
Milena K Radeva,
Gregory L Braden,
T Alp Ikizler,
Michael V Rocco,
Ingemar J Davidson,
James S Kaufman,
Catherine M Meyers,
John W Kusek,
Harold I Feldman
[show abstract]
[hide abstract]
ABSTRACT: The arteriovenous fistula is the preferred type of vascular access for hemodialysis because of lower thrombosis and infection rates and lower health care expenditures compared with synthetic grafts or central venous catheters. Early failure of fistulas due to thrombosis or inadequate maturation is a barrier to increasing the prevalence of fistulas among patients treated with hemodialysis. Small, inconclusive trials have suggested that antiplatelet agents may reduce thrombosis of new fistulas.
To determine whether clopidogrel reduces early failure of hemodialysis fistulas.
Randomized, double-blind, placebo-controlled trial conducted at 9 US centers composed of academic and community nephrology practices in 2003-2007. Eight hundred seventy-seven participants with end-stage renal disease or advanced chronic kidney disease were followed up until 150 to 180 days after fistula creation or 30 days after initiation of dialysis, whichever occurred later.
Participants were randomly assigned to receive clopidogrel (300-mg loading dose followed by daily dose of 75 mg; n = 441) or placebo (n = 436) for 6 weeks starting within 1 day after fistula creation.
The primary outcome was fistula thrombosis, determined by physical examination at 6 weeks. The secondary outcome was failure of the fistula to become suitable for dialysis. Suitability was defined as use of the fistula at a dialysis machine blood pump rate of 300 mL/min or more during 8 of 12 dialysis sessions.
Enrollment was stopped after 877 participants were randomized based on a stopping rule for intervention efficacy. Fistula thrombosis occurred in 53 (12.2%) participants assigned to clopidogrel compared with 84 (19.5%) participants assigned to placebo (relative risk, 0.63; 95% confidence interval, 0.46-0.97; P = .018). Failure to attain suitability for dialysis did not differ between the clopidogrel and placebo groups (61.8% vs 59.5%, respectively; relative risk, 1.05; 95% confidence interval, 0.94-1.17; P = .40).
Clopidogrel reduces the frequency of early thrombosis of new arteriovenous fistulas but does not increase the proportion of fistulas that become suitable for dialysis. Trial Registration clinicaltrials.gov Identifier: NCT00067119.
JAMA The Journal of the American Medical Association 06/2008; 299(18):2164-71. · 30.03 Impact Factor
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Lawrence J Appel,
Jackson T Wright,
Tom Greene,
John W Kusek,
Julia B Lewis,
Xuelei Wang,
Michael S Lipkowitz,
Keith C Norris,
George L Bakris,
Mahboob Rahman,
Gabriel Contreras,
Stephen G Rostand,
Joel D Kopple,
Francis B Gabbai,
Gerald I Schulman, Jennifer J Gassman,
Jeanne Charleston,
Lawrence Y Agodoa
[show abstract]
[hide abstract]
ABSTRACT: Antihypertensive drugs that block the renin-angiotensin system (angiotensin-converting enzyme inhibitors [ACEIs] or angiotensin receptor blockers) are recommended for patients with chronic kidney disease (CKD). A low blood pressure (BP) goal (BP, <130/80 mm Hg) is also recommended. The objective of this study was to determine the long-term effects of currently recommended BP therapy in 1094 African Americans with hypertensive CKD.
Multicenter cohort study following a randomized trial. Participants were 1094 African Americans with hypertensive renal disease (glomerular filtration rate, 20-65 mL/min/1.73 m2). Following a 3x2-factorial trial (1995-2001) that tested 3 drugs used as initial antihypertensive therapy (ACEIs, calcium channel blockers, and beta-blockers) and 2 levels of BP control (usual and low), we conducted a cohort study (2002-2007) in which participants were treated with ACEIs to a BP lower than 130/80 mm Hg. The outcome measures were a composite of doubling of the serum creatinine level, end-stage renal disease, or death.
During each year of the cohort study, the annual use of an ACEI or an angiotensin receptor blocker ranged from 83.7% to 89.0% (vs 38.5% to 49.8% during the trial). The mean BP in the cohort study was 133/78 mm Hg (vs 136/82 mm Hg in the trial). Overall, 567 participants experienced the primary outcome; the 10-year cumulative incidence rate was 53.9%. Of 576 participants with at least 7 years of follow-up, 33.5% experienced a slow decline in kidney function (mean annual decline in the estimated glomerular filtration rate, <1 mL/min/1.73 m2).
Despite the benefits of renin-angiotensin system-blocking therapy on CKD progression, most African Americans with hypertensive CKD who are treated with currently recommended BP therapy continue to progress during the long term.
Archives of internal medicine 05/2008; 168(8):832-9. · 11.46 Impact Factor
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Michael Allon,
Milena Radeva,
James Bailey,
Srinivasan Beddhu,
David Butterly,
Daniel W Coyne,
Thomas A Depner, Jennifer J Gassman,
Allen M Kaufman,
George A Kaysen,
Julia A Lewis,
Steve J Schwab
[show abstract]
[hide abstract]
ABSTRACT: Infection is a common cause of mortality and morbidity in haemodialysis patients. Few prospective studies have examined the clinical consequences of infection-related hospitalizations in haemodialysis patients or the risk factors predictive of clinical outcomes.
The outcomes of all first infection-related hospitalizations of patients enrolled in the HEMO Study were categorized in terms of mortality, requirement for intensive care unit (ICU) stay and length of hospitalization. In addition, the association of hospitalization outcomes with clinical and laboratory parameters was evaluated.
Among the 783 first infection-related hospitalizations, 57.7% had a severe outcome (death, ICU stay or hospitalization >/=7 days). The likelihood of a severe outcome increased with patient age (P<0.0001) and with decreased serum albumin (P<0.001). The frequency of a severe outcome varied greatly by infectious disease category (P<0.001), being highest for cardiac infections (95.6%) and infection of unknown source (68.4%), and lowest for urinary tract infections (35.5%) and access-related infections (43.8%). On multivariate analysis, hospitalization outcome was independently associated with patient age, serum albumin and disease category, but not with the randomized Kt/V or flux, gender, race or diabetic status.
In summary, infection-related hospitalizations are associated with substantial morbidity. Patient age, serum albumin and infectious disease category are independently correlated with the hospitalization outcome, and can be used to estimate the likelihood of serious outcomes at the time of hospital admission.
Nephrology Dialysis Transplantation 07/2005; 20(6):1180-6. · 3.40 Impact Factor
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Laura M Dember,
James S Kaufman,
Gerald J Beck,
Bradley S Dixon, Jennifer J Gassman,
Tom Greene,
Jonathan Himmelfarb,
Lawrence G Hunsicker,
John W Kusek,
Jeffrey H Lawson,
John P Middleton,
Milena Radeva,
Steve J Schwab,
James F Whiting,
Harold I Feldman
[show abstract]
[hide abstract]
ABSTRACT: The Dialysis Access Consortium (DAC) was developed to investigate interventions to improve hemodialysis vascular access outcomes. The autogenous arteriovenous fistula created by direct connection of native artery to vein is the recommended vascular access for hemodialysis. However, it fails frequently due to clotting after surgery.
The DAC Early AV Fistula Thrombosis Trial tests the hypothesis that clopidogrel can prevent early fistula failure and increase the number of fistulas that ultimately become usable for hemodialysis access. This is one of two initial and concurrent trials being performed by the DAC. The companion trial investigates pharmacologic approaches to prevent venous stenosis leading to AV graft failure.
This is a multicenter, randomized, double-blind, placebo-controlled trial that will enroll 1,284 patients over four years. Patients undergoing creation of a new native arteriovenous (AV) fistula are randomized to treatment with clopidogrel or placebo for six weeks following fistula creation surgery. The primary outcome is fistula patency at six weeks. The major secondary outcome is fistula suitability for dialysis.
This paper examines key aspects of this study that have broad relevance to trial design including: 1) the selection of an intermediate event as the primary outcome, 2) timing of the intervention to balance efficacy and safety concerns, 3) ethical considerations arising from required modifications of concomitant drug therapy, and 4) choosing an efficacy or effectiveness evaluation of the intervention.
This is the first, large, multicenter trial evaluating a pharmacologic approach to prevent early AV fistula failure and promote more usable fistulas for hemodialysis. The methodologic challenges identified and addressed during the development of this trial should help to inform the design of future vascular access trials, and are relevant to clinical trials addressing a wide range of questions.
Clinical Trials 02/2005; 2(5):413-22. · 1.92 Impact Factor
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Bradley S Dixon,
Gerald J Beck,
Laura M Dember,
Thomas A Depner, Jennifer J Gassman,
Tom Greene,
Jonathan Himmelfarb,
Lawrence G Hunsicker,
James S Kaufman,
Jeffrey H Lawson,
Catherine M Meyers,
John P Middleton,
Milena Radeva,
Steve J Schwab,
James F Whiting,
Harold I Feldman
[show abstract]
[hide abstract]
ABSTRACT: Surgically created arteriovenous (AV) grafts are the most common type of hemodialysis vascular access in the United States, but fail frequently due to the development of venous stenosis. The Dialysis Access Consortium (DAC) Aggrenox Prevention of Access Stenosis Trial tests the hypothesis that Aggrenox (containing dipyridamole and aspirin) can prevent stenosis and prolong survival of arteriovenous grafts.
This is a multicenter, randomized, double-blind, placebo-controlled trial that will enroll 1056 subjects over four years with one-half year follow-up. Subjects undergoing placement of a new AV graft for hemodialysis are randomized to treatment with Aggrenox or placebo immediately following access surgery. The primary outcome is primary unassisted patency defined as the time from access placement until thrombosis or an access procedure carried out to maintain or restore patency. The major secondary outcome is cumulative access patency. Monthly access flow monitoring is incorporated in the study design to enhance detection of a hemodynamically significant access stenosis before it leads to thrombosis.
This paper describes the key issues in trial design, broadly including: 1) ethical issues surrounding the study of a clinical procedure that, although common, is no longer the clinical intervention of choice; 2) acceptable risk (bleeding) from the primary intervention; 3) inclusion of subjects already receiving a portion of the study intervention; 4) inclusion of subjects with incident rather than prevalent qualifying clinical conditions; 5) timing of the study intervention to balance safety and efficacy concerns; and 6) the selection of primary and secondary study endpoints.
This is the first, large, multicenter trial evaluating a pharmacologic approach to prevent AV graft stenosis and failure, an important and costly problem in this patient population. Numerous design issues were addressed in implementing the trial and these will form a roadmap for future trials in this area.
Clinical Trials 02/2005; 2(5):400-12. · 1.92 Impact Factor
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Michael Allon,
Thomas A Depner,
Milena Radeva,
James Bailey,
Srinivasan Beddhu,
David Butterly,
Daniel W Coyne, Jennifer J Gassman,
Allen M Kaufman,
George A Kaysen,
Julia A Lewis,
Steve J Schwab
[show abstract]
[hide abstract]
ABSTRACT: Infection is the second most common cause of death among hemodialysis patients. A predefined secondary aim of the HEMO study was to determine if dialysis dose or flux reduced infection-related deaths or hospitalizations. The effects of dialysis dose, dialysis membrane, and other clinical parameters on infection-related deaths and first infection-related hospitalizations were analyzed using Cox regression analysis. Among the 1846 randomized patients (mean age, 58 yr; 56% female; 63% black; 45% with diabetes), there were 871 deaths, of which 201 (23%) were due to infection. There were 1698 infection-related hospitalizations, yielding a 35% annual rate. The likelihood of infection-related death did not differ between patients randomized to a high or standard dose (relative risk [RR], 0.99 [0.75 to 1.31]) or between patients randomized to high-flux or low-flux membranes (RR, 0.85 [0.64 to 1.13]). The relative risk of infection-related death was associated (P < 0.001 for each variable) with age (RR, 1.47 [1.29 to 1.68] per 10 yr); co-morbidity score (RR, 1.46 [1.21 to 1.76]), and serum albumin (RR, 0.19 [0.09 to 0.41] per g/dl). The first infection-related hospitalization was related to the vascular access in 21% of the cases, and non-access-related in 79%. Catheters were present in 32% of all study patients admitted with access-related infection, even though catheters represented only 7.6% of vascular accesses in the study. In conclusion, infection accounted for almost one fourth of deaths. Infection-related deaths were not reduced by higher dose or by high flux dialyzers. In this prospective study, most infection-related hospitalizations were not attributed to vascular access. However, the frequency of access-related, infection-related hospitalizations was disproportionately higher among patients with catheters compared with grafts or fistulas.
Journal of the American Society of Nephrology 07/2003; 14(7):1863-70. · 9.66 Impact Factor
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Jennifer J Gassman,
Tom Greene,
Jackson T Wright,
Lawrence Agodoa,
George Bakris,
Gerald J Beck,
Janice Douglas,
Ken Jamerson,
Julia Lewis,
Michael Kutner,
Otelio S Randall,
Shin-Ru Wang
[show abstract]
[hide abstract]
ABSTRACT: The African American Study of Kidney Disease and Hypertension (AASK) is a multicenter randomized clinical trial designed to test the effectiveness of three anti-hypertensive drug regimens and two levels of BP control on the progression of hypertensive kidney disease. Participants include African-American men and women aged 18 to 70 yr who have hypertensive kidney disease and GFR between 20 and 65 ml/min per 1.73 m(2). The three anti-hypertensive drug regimens include an angiotensin converting enzyme inhibitor (ramipril), a dihydropyridine calcium channel blocker (amlodipine) or a beta-blocker (metoprolol) as initial therapy. The BP control levels are a lower goal (mean arterial pressure, </=92 mmHg) and a usual goal (mean arterial pressure, 102 to 107 mmHg inclusive). The primary outcome is rate of change in renal function as measured by GFR, assessed by (125) I-iothalamate clearance. The main secondary patient outcome is a composite including the following events: (1) reduction in GFR by 50%, (2) end-stage renal disease, or (3) death.
Journal of the American Society of Nephrology 07/2003; 14(7 Suppl 2):S154-65. · 9.66 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: The relationship between volume status and blood pressure (BP) in chronic hemodialysis (HD) patients remains incompletely understood. Specifically, the effect of interdialytic fluid accumulation (or intradialytic fluid removal) on BP is controversial.
We determined the association of the intradialytic decrease in body weight (as an indicator of interdialytic fluid gain) and the intradialytic decrease in plasma volume (as an indicator of postdialysis volume status) with predialysis and postdialysis BP in a cross-sectional analysis of a subset of patients (N=468) from the Hemodialysis (HEMO) Study. Fifty-five percent of patients were female, 62% were black, 43% were diabetic and 72% were prescribed antihypertensive medications. Dry weight was defined as the postdialysis body weight below which the patient developed symptomatic hypotension or muscle cramps in the absence of edema. The intradialytic decrease in plasma volume was calculated from predialysis and postdialysis total plasma protein concentrations and was expressed as a percentage of the plasma volume at the beginning of HD.
Predialysis systolic and diastolic BP values were 153.1 +/- 24.7 (mean +/- SD) and 81.7 +/- 14.8 mm Hg, respectively; postdialysis systolic and diastolic BP values were 136.6 +/- 22.7 and 73.9 +/- 13.6 mm Hg, respectively. As a result of HD, body weight was reduced by 3.1 +/- 1.3 kg and plasma volume was contracted by 10.1 +/- 9.5%. Multiple linear regression analyses showed that each kg reduction in body weight during HD was associated with a 2.95 mm Hg (P=0.004) and a 1.65 mm Hg (P=NS) higher predialysis and postdialysis systolic BP, respectively. In contrast, each 5% greater contraction of plasma volume during HD was associated with a 1.50 mm Hg (P=0.026) and a 2.56 mm Hg (P < 0.001) lower predialysis and postdialysis systolic BP, respectively. The effects of intradialytic decreases in body weight and plasma volume were greater on systolic BP than on diastolic BP.
HD treatment generally reduces BP, and these reductions in BP are associated with intradialytic decreases in both body weight and plasma volume. The absolute predialysis and postdialysis BP levels are influenced differently by acute intradialytic decreases in body weight and acute intradialytic decreases in plasma volume; these parameters provide different information regarding volume status and may be dissociated from each other. Therefore, evaluation of volume status in chronic HD patients requires, at minimum, assessments of both interdialytic fluid accumulation (or the intradialytic decrease in body weight) and postdialysis volume overload.
Kidney International 01/2002; 61(1):266-75. · 6.61 Impact Factor
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ABSTRACT: Relationship between volume status and blood pressure during chronic hemodialysis.Background The relationship between volume status and blood pressure (BP) in chronic hemodialysis (HD) patients remains incompletely understood. Specifically, the effect of interdialytic fluid accumulation (or intradialytic fluid removal) on BP is controversial.
Kidney International 12/2001; 61(1):266-275. · 6.61 Impact Factor
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Joy M. Weinberg,
Lawrence J. Appel,
George Bakris, Jennifer J. Gassman,
Tom Greene,
Cynthia A. Kendrick,
Xuelei Wang,
James Lash,
Julia A. Lewis,
Velvie Pogue,
Denyse Thornley-Brown,
Robert A. Phillips
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ABSTRACT: Background
The incidence and factors associated with hyperkalemia in patients with chronic kidney disease (CKD) treated with angiotensin converting enzyme inhibitors (ACEIs) and other antihypertensive drugs was investigated using the African American Study of Kidney Disease and Hypertension (AASK) database.Methods
A total of 1094 nondiabetic adults with hypertensive CKD (glomerular filtration rate [GFR], 20-65 mL/min/1.73 m2) were followed for 3.0 to 6.4 years in the AASK trial. Participants were randomly assigned to ACEI, β-blocker (BB), or dihydropyridine calcium channel blocker (CCB). The outcome variables for this analysis were a serum potassium level higher than 5.5 mEq/L (to convert to millimoles per liter, multiply by 1.0), or a clinical center initiated hyperkalemia stop point.Results
A total of 6497 potassium measurements were obtained, and 80 events in 51 subjects were identified (76 events driven by a central laboratory result and 4 driven by a clinical center–initiated hyperkalemia stop point). Compared with a GFR higher than 50 mL/min/1.73 m2, after multivariable adjustment, the hazard ratio (HR) for hyperkalemia in patients with a GFR between 31 and 40 mL/min/1.73 m2 and a GFR lower than 30 mL/min/1.73 m2 was 3.61 (95% confidence interval [CI], 1.42-9.18 [P = .007]) and 6.81 (95% CI, 2.67-17.35 [P < .001]), respectively; there was no increased risk of hyperkalemia if GFR was 41 to 50 mL/min/1.73 m2. Use of ACEIs was associated with more episodes of hyperkalemia compared with CCB use (HR, 7.00; 95% CI, 2.29-21.39 [P < .001]) and BB group (HR, 2.85; 95% CI, 1.50-5.42 [P = .001]). Diuretic use was associated with a 59% decreased risk of hyperkalemia.Conclusions
In nondiabetic patients with hypertensive CKD treated with ACEIs, the risk of hyperkalemia is small, particularly if baseline and follow-up GFR is higher than 40 mL/min/1.73 m2. Including a diuretic in the regimen may markedly reduce risk of hyperkalemia.
Figures in this Article
Several studies have demonstrated that angiotensin-converting enzyme inhibitors (ACEIs) blunt progression of renal disease in nondiabetic patients with chronic kidney disease (CKD).1- 4 However, ACEIs can cause hyperkalemia by impairing renal potassium excretion through interference with production and/or secretion of aldosterone.5 Hyperkalemia from ACEI use has been frequently described,6- 8 and ACEIs are often underprescribed in patients with CKD because of concerns of hyperkalemia.9 β-Blocker (BB) use has also been associated with hyperkalemia, most likely through redistribution of potassium from intracellular to extracellular compartments as a result of blockade of β2-adrenoreceptor–mediated cellular potassium uptake.10- 11
The African American Study of Kidney Disease and Hypertension (AASK) was a randomized clinical trial in nondiabetic African Americans with hypertensive CKD. One primary goal was to determine the effects of 3 different classes of antihypertensive agents on progression of renal disease: a dihydropyridine calcium channel blocker (CCB), a BB, and an ACEI. The most beneficial drug therapy was with ACEIs.12 The other primary goal was to determine the effects of 2 different BP goals on progression of renal disease; the trial demonstrated that a target mean arterial BP (MAP) of 102 to 107 mm Hg was as effective as stricter BP goal of a MAP lower than 92 mm Hg.12 Participants had a glomerular filtration rate (GFR) between 20 and 65 mL/min/1.73 m2 and no identified causes of renal insufficiency other than hypertension. After the close of the trial phase of the AASK, the investigators were directed by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) appointed Data Safety Monitoring Board to use the AASK database to explore factors associated with development of hyperkalemia. In this report, we describe the incidence of hyperkalemia by class of antihypertensive drug in the AASK and report the independent associations of other clinically measured factors
Archives of Internal Medicine 169(17):1587-1594. · 11.46 Impact Factor
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ABSTRACT: The Hemodialysis Study is a multicenter clinical trial of hemodialysis prescriptions for patients with end stage renal disease. Participants from over 65 dialysis facilities associated with 15 clinical centers in the United States are randomized in a 2 × 2 factorial design to dialysis prescriptions targeted to a standard dose or a high dose , and to either low or high flux membranes. The primary outcome variable is mortality; major secondary outcomes are defined based on hospitalizations due to cardiovascular or infectious complications, and on the decline of serum albumin. The Outcome Committee, consisting of study investigators, uses a blinded review system to classify causes of death and hospitalizations related to the major secondary outcomes. The dialysis dose intervention is directed by the Data Coordinating Center using urea kinetic modeling programs that analyze results from dialysis treatments to monitor adherence to the study targets, adjust suggested dialysis prescriptions, and assist in trouble-shooting problems with the delivery of dialysis. The study design has adequate power to detect reductions in mortality rate equal to 25% of the projected baseline mortality rate for both of the interventions. Control Clin Trials 2000;21:502–525
Controlled Clinical Trials.
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ABSTRACT: The Modification of Diet in Renal Disease Trial is a multicenter randomized clinical trial for men and women aged 18–70 years with chronic renal disease who are not on dialysis and who have not had a kidney transplant. Study participants are randomized in a 2 × 2 factorial design to diets containing different amounts of protein and phosphorus and to two levels of blood pressure control. The prescribed modifications differ depending on the level of a patient's kidney function. The primary outcome variable to compare diet or blood pressure groups is each patient's slope (or the change) in glomerular filtration rate with time. This paper describes the study design with particular emphasis on sample size determination. Special statistical analysis issues that arise with slope as the outcome are also discussed.
Controlled Clinical Trials.
