Surrogate markers in clinical studies: problems solved or created?
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Biomarkers↗
Biomedical subjects
William F Owen
Publications and source records attributed to William F Owen.
Intradialytic blood volume monitoring in ambulatory hemodialysis patients: a randomized trial.
Complications related to inadequate volume management are common during hemodialysis. This trial tested the hypothesis that availability of an intradialytic blood volume monitoring (IBVM) device improves fluid removal, reducing morbidity. A six-center, randomized trial with 6 mo of intervention comparing IBVM using Crit-Line versus conventional clinical monitoring was conducted. The average rate of non-access-related hospitalizations was compared across treatment groups using Poisson regression. Mortality analysis used the Kaplan Meier method. A total of 227 patients were randomized to Crit-Line, and 216 were randomized to conventional monitoring. Both groups had similar baseline characteristics. During the study, no differences in weight, BP, or number of dialysis-related complications were observed. There were 120 and 81 non-access-related hospitalizations in the Crit-Line and conventional monitoring groups. The adjusted risk ratio for non-access-related and access-related hospitalization was 1.61 (95% confidence interval 1.15 to 2.25; P = 0.01) and 1.52 (95% confidence interval 1.02 to 2.28; P = 0.04) for the Crit-Line monitoring group. Mortality was 8.7% in the Crit-Line monitoring group and 3.3% in the conventional group (P = 0.021). Standardized mortality ratios comparing the Crit-Line and conventional monitoring groups to the prevalent hemodialysis population were 0.77 (NS) and 0.26 (P < 0.001). Hospitalization rates were 1.51 and 1.03 events/yr in the Crit-Line and standard monitoring groups, compared with 2.01 for the prevalent hemodialysis population. IBVM was associated with higher nonvascular and vascular access-related hospitalizations and mortality compared with conventional monitoring. The atypically low hospitalization and mortality rates for the conventional monitoring group suggest that these findings should be generalized to the US hemodialysis population with caution.
Adult↗
Slowing the progression of diabetic nephropathy and its cardiovascular consequences.
This paper incorporates the findings from a multidisciplinary meeting on diabetic nephropathy and its renal and cardiovascular complications into a review article. The epidemic of obesity and the growing elderly population in the United States are primary drivers of a secondary epidemic of incipient type 2 diabetes mellitus and diabetic nephropathy. Current therapies aim to treat blood pressure, particularly with agents that block the renin-angiotensin system, to a target of 130/80 mm Hg. However, even lower blood pressure targets may be optimal. Control of hyperglycemia and dyslipidemia, smoking cessation, exercise, and weight loss all compliment blood pressure control and are achieved most effectively when the patient, provider, and health system are aligned with these goals. Once end-stage renal disease (ESRD) is reached, patients enter the highest cardiovascular risk-state appreciated in human medicine. Because of uniform access to care in the United States, advanced data systems, and circulatory system (intravascular) access in most patients, the ESRD population should be the future sampling frame for newer treatments tested in both prospective cohort and randomized trials. Cardiorenal risk, or the degree of excess cardiovascular risk incurred by patients with chronic kidney disease and ESRD, is a state offering considerable research opportunities for novel cardiovascular risk factors. Future studies should fully consider the possibility that improved outcomes would be achieved at a greater cost; thus, cost-effectiveness studies are essential for understanding the economic aspects of implementation. The goal of an ideal clinical trial would be ESRD prevention; however, pragmatic objectives such as a greater understanding of therapeutic toxicities should also be explored in this population.
Albuminuria↗
Enhanced expression of receptor for advanced glycation end products in chronic kidney disease.
Inappropriate chronic inflammation associated with progressive, chronic kidney disease (CKD) reflects sustained activation of immunocompetent cells, like monocytes/macrophages. Advanced glycation end products (AGE) accumulate in CKD, but it is unclear if they stimulate monocytes by binding with the receptor for AGE (RAGE). Posited was the notion that RAGE plays a contributory role to monocyte-mediated systemic inflammation of progressive CKD. Peripheral blood monocytes were isolated from 102 patients without diabetes with varying severity of CKD. RAGE expression on peripheral blood monocytes increased with worsening CKD (r2 = 0.73) and was strongly correlated with plasma levels of pentosidine, a marker for AGE (r = 0.71). Strongly positive statistical correlations were observed in patients with CKD between monocyte RAGE and plasma levels of tumor necrosis factor alpha (TNF-alpha) (r = 0.61), the monocyte activation marker, neopterin (r = 0.65), and the systemic acute phase reactant, C-reactive protein (r = 0.44). Monocytes obtained from patients with CKD showed a monotonic increase in the number and affinity of specific AGE binding sites and increased production of TNF-alpha under stimulation of AGE. All these upregulatory responses in uremic monocytes could be largely blocked by an anti-RAGE antibody. It was concluded that RAGE expression was upregulated on monocytes from patients with CKD. Enhanced RAGE may amplify AGE-induced monocytes perturbation and contribute to monocyte-mediated systemic inflammation in progressive CKD.
Adult↗
Inequality in quality: are patient health activation and CQI corrective approaches?
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Black People↗
A systematic review of sevelamer in ESRD and an analysis of its potential economic impact in Canada and the United States.
BACKGROUND: The Kidney Disease Outcomes Quality Initiatives (K/DOQI) guidelines on bone metabolism and disease in chronic kidney disease were recently published. Despite limited evidence of clinical effectiveness and without detailed consideration of cost, these guidelines recommend the use of a nonmineral-containing phosphate binder (i.e., sevelamer) in several common clinical situations. The objective of this study is to use the example of sevelamer to outline the information that is needed to assist health care payers with the decision to fund a new and expensive therapy. METHODS: We assessed the clinical benefit of sevelamer by performing a systematic review of all randomized trials evaluating its use. To estimate the direct budget impact associated with implementation of the K/DOQI bone disease guidelines, we used laboratory and medication data available from two cohorts of dialysis patients (one treated in Canada and one in the United States) to determine the proportion of patients who meet the criteria for the use of sevelamer as described in the K/DOQI bone disease guidelines. RESULTS: No randomized trials document the impact of sevelamer on survival, hospitalization, or quality of life. However, at least 51% and 64% of dialysis patients in the Canadian and American cohorts, respectively, would meet K/DOQI criteria for use of sevelamer. Extrapolating to the United States dialysis population, adoption of the K/DOQI bone guidelines would result in expenditures of approximately 781 million dollars annually on sevelamer alone. CONCLUSION: Given their potential budgetary impact, future nephrology clinical practice guidelines should consider resource use, in addition to clinical data.
Canada↗
Regarding impact of epoetin alfa on clinical end points in patients with chronic renal failure: a meta-analysis.
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Anemia↗
Treatment effects of eptifibatide in planned coronary stent implantation in patients with chronic kidney disease (ESPRIT Trial).
The role of platelet glycoprotein IIb/IIIa inhibitor therapy in patients with mild renal impairment is not well characterized. Our objective was to explore the associations of creatinine clearance (CrCl) with outcomes in a trial of eptifibatide therapy in patients who underwent percutaneous coronary intervention (PCI). We analyzed 48-hour and 30-day outcomes of patients enrolled in the Enhanced Suppression of the Platelet IIb/IIIa Receptor with Integrilin Therapy (ESPRIT) trial. Patients were randomly assigned to placebo or eptifibatide as an adjunct to stent implantation (1,755 with CrCl > or =60 ml/min and 289 with CrCl <60 ml/min). CrCl was calculated using the Cockcroft and Gault formula, and the associations of CrCl with outcomes were evaluated using logistic regression models. Patients with CrCl <60 ml/min were more likely to be older, women, hypertensive, and have a history of coronary artery bypass surgery, stroke, or peripheral vascular disease. The interaction of eptifibatide with CrCl had borderline significance for the 30-day outcome (p = 0.109). Treatment effect trended toward a greater magnitude in patients with lower CrCl (60 ml/min) (odds ratio 0.53, confidence interval 0.34 to 0.83) compared with those with higher CrCl (90 ml/min) (odds ratio 0.68, confidence interval 0.49 to 0.94). An accompanying increase in bleeding risk also was not apparent with lower CrCl. The treatment effect of eptifibatide is realized regardless of renal function and trends toward being greater in patients with mild renal impairment.
Aged↗
Developing clinical performance measures based on the Dialysis Outcomes Quality Initiative Clinical Practice Guidelines: process, outcomes, and implications.
BACKGROUND: The National Kidney Foundation-Dialysis Outcomes Quality Initiative (NKF-DOQI) Clinical Practice Guidelines established a widely accepted set of recommendations for high-quality dialysis care. To enhance the End-Stage Renal Disease Core Indicators Project, an ongoing effort to assess and improve dialysis care in the United States, the Centers for Medicare and Medicaid Services (CMS) commissioned a project to develop clinical performance measures (CPMs) based on the NKF-DOQI guidelines. METHODS: The CMS contracted with Qualis Health, a private nonprofit organization serving as a Medicare Quality Improvement Organization, to facilitate a 9-month project to develop dialysis CPMs with the participation of a broad range of stakeholders from the renal community. Work groups were established to develop CPMs addressing 4 areas: hemodialysis adequacy, peritoneal dialysis adequacy, vascular access management, and anemia management. The NKF-DOQI guidelines were prioritized based on the strength of the evidence supporting the guidelines, the feasibility of developing performance measures, and the significance of the areas addressed to the quality of care delivered to dialysis patients. Expert panels developed data specifications, sampling approaches, data-collection tools, and analytic strategies. RESULTS: Sixteen CPMs were developed based on 22 of 114 NKF-DOQI guidelines. After establishing reliability through field-testing of data-collection instruments, the CPMs were applied to a sample of 8,838 randomly selected hemodialysis patients and 1,650 randomly selected adult peritoneal dialysis patients in summer 1999. CONCLUSION: The development of CPMs based on the NKF-DOQI Clinical Practice Guidelines for dialysis care was accomplished in a timely and effective manner by engaging a broad range of stakeholders and technical experts. The CPMs are important tools to assess and improve the quality of dialysis care in the United States. Few comparable efforts exist in other fields of medicine.
Allied Health Occupations↗
The cost-effectiveness of maintaining higher hemoglobin targets with erythropoietin in hemodialysis patients.
BACKGROUND: There is uncertainty regarding the appropriate target hemoglobin level in hemodialysis patients treated with erythropoietin (EPO). METHODS: We sought to determine the incremental cost-effectiveness of prescribing EPO to maintain different target hemoglobin levels, by incorporating the impact of EPO on health-related quality-of-life (HRQOL) issues and adopting the perspective of the health care purchaser. We evaluated the prescription of EPO to maintain target hemoglobin levels of 11.0 to 12.0, 12.0 to 12.5, and 14.0 g/dL, compared with 9.5 to 10.5 g/dL. Model outputs were quality-adjusted life expectancy and costs. RESULTS: The base case analysis estimated intravenous EPO requirements to be 3523, 5078, 6097, and 9341 units three times per week to maintain targets of 9.5 to 10.5, 11.0 to 12.0, 12.0 to 12.5, and 14.0 g/dL, respectively. The cost per quality-adjusted life year (QALY) gained for the 11.0 to 12.0 g/dL target vs. 9.5 to 10.5 g/dL was $55,295 US. For the 12.0 to 12.5 g/dL target compared to 11.0 to 12.0 g/dL, and 14.0 g/dL target compared to 12.0 to 12.5 g/dL, the costs per QALY gained were $613,015 US and $828,215 US, respectively. In sensitivity analysis, clinically implausible reductions in hospitalization or EPO requirements associated with the two higher hemoglobin targets were required to make their incremental cost per QALY gained <$100,000 US. CONCLUSION: Dosing intravenous EPO to achieve hemoglobin targets of 11.0 to 12.0 g/dL appears to be associated with incremental cost per QALY gained of $50,000 to $60,000, compared with a hemoglobin target of 9.5 to 10.5 g/dL. Aiming for hemoglobin targets in excess of 12.0 g/dL is associated with unfavorable cost-effectiveness ratios and should not be undertaken based on current data.
Cost-Benefit Analysis↗
Regional variability in anaemia management and haemoglobin in the US.
BACKGROUND: Regional differences in haemoglobin values and process care measures were examined using data from the Centers for Medicare & Medicaid Services' End-Stage Renal Disease (ESRD) Clinical Performance Measures Project. It was posited that regional differences in haemoglobin values are consequent upon differences in components of clinical practice. METHODS: A national random sample of 8336 adult, in-centre haemodialysis patients, stratified by the 18 regional ESRD Networks, was drawn. Information was collected for October-December 1998. Multivariable stepwise linear and logistic regression analyses were performed to identify variables associated with haemoglobin. Linear regression analysis was used to identify variables associated with Epo/Hb index (mean weight-adjusted treatment level erythropoietin (Epo) dose divided by mean haemoglobin). RESULTS: The percentage of patients with haemoglobin concentration < 11 g/dl ranged from 34 to 52% across ESRD Networks. In addition to haemoglobin there was significant, non-random variation among ESRD Networks with regard to prescribed Epo dose and administration route, intravenous (IV) iron prescription and dialyser flux (high flux = KUf > or = 20 ml/mmHg/h) (all P-values < 0.001). Higher haemoglobin was associated with older age, male gender, higher serum albumin, higher transferrin saturation, higher Kt/V, lower serum ferritin and lower prescribed Epo dose (all P-values < 0.01). Diabetes mellitus as cause of ESRD, high-flux dialyser use, IV iron prescription or subcutaneous Epo prescription were not associated with haemoglobin. Male gender, diabetes as cause of ESRD, older age, higher transferrin saturation and higher albumin concentrations were associated with lower Epo/Hb index. Prescription of IV iron and IV Epo were associated with higher Epo/Hb index. CONCLUSIONS: Regional mean haemoglobin levels vary considerably across the US and the variation in haemoglobin is explained by both non-modifiable factors and modifiable clinical practice-derived variables.
Adult↗
White blood cells as a novel mortality predictor in haemodialysis patients.
BACKGROUND: Many conventional cardiovascular risk factors in the general population are not as predictive in end-stage renal disease (ESRD). As absolute neutrophil count and total white blood cell (WBC) count are associated with adverse cardiovascular outcomes and all-cause mortality, this analysis was undertaken to explore the associations of WBC variables with mortality risk in ESRD. METHODS: Of a total study population of 44 114 ESRD patients receiving haemodialysis during 1998 at facilities operated by Fresenius Medical Care, North America, 25 661 patients who underwent differential white cell count and had complete follow-up were included. Information on case mix (age, gender, race), clinical (diabetes, body mass index), and laboratory variables (haematocrit, albumin, creatinine, potassium, calcium, phosphorus, bicarbonate, ferritin, transferrin saturation and differential WBC count) was obtained. Associations between lymphocyte count, neutrophil count and demographic and clinical variables were examined using linear regression. Associations between WBC variables and survival were estimated using Cox proportional hazard regression. RESULTS: A higher lymphocyte count was associated with higher serum albumin and creatinine, lower age and black race. High neutrophil count was associated with lower serum albumin and creatinine, younger age and white race (all Ps <0.0001). Cox proportional hazard regression showed an increased lymphocyte count was associated with reduced mortality risk [HR 0.86 (0.83-0.89) per 500/ml increase in lymphocyte count] and an increased neutrophil count was associated with increased mortality risk [HR 1.08 (1.06-1.09) per 1000/ml increase in neutrophil count]. CONCLUSIONS: An increased neutrophil count is strongly associated with, and reduced lymphocyte count associated less strongly with, many surrogates of both malnutrition and inflammation. An increased neutrophil count and reduced lymphocyte count are independent predictors of increased mortality risk in haemodialysis patients.
Adult↗
Interactions between dialysis-related volume exposures, nutritional surrogates and mortality among ESRD patients.
BACKGROUND: Interdialytic weight gain is used as a surrogate for volume expansion in haemodialysis patients and as an indicator of non-compliance. Increased weight gain is associated with both a greater mortality risk and better nutrition indices. This analysis characterizes the association between dialysis-related volume expansion and mortality in the context of its interaction with nutritional surrogates. METHODS: All patients receiving haemodialysis through Fresenius Medical Care-North America during 1998 were included. The percentage reduction in weight or intradialytic weight loss (IDWL%) was defined as the difference between the average of pre- and post-dialysis weights from the last 3 months of 1997 expressed as a percentage of post-dialysis weight. Associations between IDWL% and clinical and demographic variables were estimated using linear regression. The association between mortality risk and IDWL% was estimated using Cox proportional hazards regression. RESULTS: Younger age, male gender, the presence of diabetes mellitus, decreasing cholesterol, post-dialysis weight and pre-dialysis blood pressure (systolic and pulse pressure) were associated with increased IDWL%. Increasing IDWL% was associated with increasing phosphorus, creatinine, albumin, potassium and urea reduction ratio. Increasing IDWL% was significantly associated with mortality at 1 year [hazard ratio (HR) = 1.07, P = 0.003]. Among patients with diabetes mellitus, increasing IDWL% was associated with a mortality HR of 1.03 (P = 0.02). Among patients without diabetes mellitus, increasing IDWL% was not associated with an increased mortality risk. Increasing IDWL% is associated with a greater mortality risk among patients with creatinine <7.26, which failed to remain significant for patients whose creatinine was >or=7.26 mg/dl. Increasing IDWL% is associated with a greater mortality risk among patients with greater post-dialysis weight, greater body mass index and lower serum sodium measurements. CONCLUSIONS: This study confirms and extends the findings of the deleterious association between increasing IDWL% and mortality among patients with diabetes mellitus and among subgroups based on serum creatinine and body weight. The putative deleterious effect of dialysis-related volume expansion on mortality must be interpreted in the context of the patient's diabetic and nutritional status.
Adolescent↗
Left ventricular hypertrophy: a surrogate end point or correlate of cardiovascular events in kidney disease?
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Anemia↗
A propensity analysis of late versus early nephrologist referral and mortality on dialysis.
Previous studies have analyzed the association between late versus early nephrologist referral (LR, ER) and poor clinical outcomes in patients with end-stage renal disease. We sought to determine whether these poor outcomes were causally related to LR, or whether LR was a proxy for poorer access to health care in general. An inception cohort of incident dialysis patients enrolled in the New Jersey Medicare or Medicaid programs was identified. Using a large number of demographic, clinical, and health care utilization covariates, propensity scores (PS) were then calculated to predict whether a given patient had been seen by a nephrologist at 90 d before first dialysis. Cox proportional hazards models were then built to test the association between timing of nephrologist referral and mortality during the first year of dialysis, using PS adjustment and matching to determine whether this association was confounded by other measures of reduced healthcare utilization. Neither adjustment for PS (HR = 1.31; 95% CI, 1.17 to 1.47) nor matching (HR = 1.40; 95% CI, 1.23 to 1.59) materially changed the initial 36% excess mortality in LR compared with ER patients (HR = 1.36; 95% CI, 1.22 to 1.51). Excess mortality among LR was limited to the first 3 mo of dialysis (HR = 1.75; 95% CI, 1.48 to 2.08) but not present thereafter (HR = 1.03; 95% CI, 0.84 to 1.25). Late nephrologist referral is an independent risk factor for early death on dialysis, even after controlling for other indicators of healthcare utilization. Further research is needed to identify patients at particular risk so that interventions to prevent early deaths on dialysis in LR patients can be developed and tested.
Aged↗
Patterns of care for patients with chronic kidney disease in the United States: dying for improvement.
The burden of chronic kidney disease can be assessed by multiple criteria that underscore the need for improved detection, treatment, and outcome monitoring. Several process measures for the care of advanced CKD patients are examined herein. Twenty seven and 11% of patients with CKD in National Health and Nutrition Examination Surveys (NHANES) III had BP <140/90 and 130/85, respectively. In addition to inadequate prescription of antihypertensive drugs, another confounder is poor diagnostic recognition of CKD. Recent surveys of incident Medicare-eligible ESRD patients observed severe anemia in a preponderance of patients; mean and median hematocrit values were 27.7% +/- 5.9 and 27.8%, respectively. Only 23 to 28% of these patients were prescribed epoetin alfa. Clinical practice guidelines recommend that <10% of maintenance hemodialysis patients should be chronically dialyzed using percutaneous catheters. A recent national survey of vascular access types among incident American hemodialysis patients found that 30%, 41%, and 29% were dialyzing through a catheter, prosthetic graft, and autologous fistula, respectively. Tunneled catheters are associated with a 39% annual increased risk of death. Based on pharmacokinetic assumptions about the minimum amount of solute clearance by hemodialysis needed for patient survival in ESRD, a GFR of 10.5 ml/min per 1.73 m(2) is needed. The mean GFR of incident ESRD patients in the United States was 9.5 ml/min per 1.73 m(2) in 2000. In addition to the wide international variability in modality treatment selection, geographic variability exists within the United States; <7 to >15% of the prevalent patients are treated by peritoneal dialysis across the country. Despite survival and quality-of-life benefits with transplantation, most eligible recipients in the United States have not been placed on a transplant waiting list 6 mo after beginning dialysis. Last, <40% of incident ESRD patients in the United States have received the recommended frequency of mammography, PAP examinations, or prostate-specific antigen (PSA) or HbA1c measurements. These deficiencies in care for patients with advanced CKD likely adversely influence the survival of US ESRD patients. Contemporary outcome information supports this contention. CKD patients referred to a nephrologist for the first time within 90 d of the start of dialysis have an approximately 40% to 60% increased risk of death during their first year of renal replacement therapy (RRT). Thirty-five percent of CKD patients are seen within 90 d of receiving RRT. In addition, if fewer than five nephrology visits occur, death risks are increased by 15%. These findings confirm the urgent need for improvement in healthcare delivery for CKD patient in the United States.
Adolescent↗
Chronic kidney disease, mortality, and treatment strategies among patients with clinically significant coronary artery disease.
Cardiovascular disease is an important cause of mortality among patients with chronic kidney disease (CKD). This study describes associations between CKD, cardiac revascularization strategies, and mortality among patients with CKD and cardiovascular disease. All patients undergoing cardiac catheterization at Duke University Medical Center (1995 to 2000) with documented stenosis > or =75% of at least one coronary artery and available creatinine data were included. CKD was staged using creatinine clearance (CrCl) derived from the Cockcroft-Gault formula (normal, > or = 90 ml/min; mild, 60 to 89 ml/min; moderate, 30 to 59 ml/min; severe, 15 to 29 ml/min). Cox proportional-hazard regression estimated the relationship between clinical variables, including CrCl and percutaneous coronary artery intervention (PCI), coronary artery bypass grafting (CABG), medical management, and patient survival. There were 4584 patients included, and 24% had CrCl <60 ml/min. Each 10-ml/min decrement in CrCl was associated with an increase in mortality (hazard ratio, 1.14; P < 0.0001). CABG was associated with a survival benefit among patients with both normal renal function and patients with CKD compared with medical management. In patients with normal renal function, CABG was not associated with survival benefit over PCI. However, in patients with CKD, CABG was associated with improved survival. PCI was associated with a survival benefit compared with medical management among patients with normal, mildly, and moderately impaired renal function. Among patients with severe CKD, PCI was not associated with improved survival. CABG is associated with greater mortality reduction than PCI in severe CKD.
Aged↗
Nephrologist care and mortality in patients with chronic renal insufficiency.
BACKGROUND: For patients with chronic renal insufficiency, rates of referral to nephrologists are highly variable, and little is known about the effect of such consultation on clinical outcomes. We sought to determine whether early or frequent access to nephrologist care prior to the initiation of dialysis was associated with a difference in mortality rates in the first year after dialysis began. METHODS: We identified all patients in the New Jersey Medicaid and Medicare programs who began maintenance dialysis during a 6-year period and who had been diagnosed with renal disease more than 12 months prior to dialysis. Use of nephrologist services was documented during this 1-year period, along with other clinical and sociodemographic variables. The outcome measure of our analysis was mortality in the first year after initiation of dialysis. RESULTS: From multivariate analyses, we found that patients who did not see a nephrologist until 90 days or less before initiation of dialysis had a 37% higher likelihood of death in the first year of dialysis compared with patients with earlier referral (95% confidence interval, 1.22-1.52; P<.001). Similarly, those who saw a nephrologist on fewer than 5 occasions in the year prior to dialysis had a 15% higher mortality rate in the first year of dialysis compared with those who had had 5 or more nephrologist visits (95% confidence interval, 1.03-1.28; P =.01). CONCLUSIONS: For patients with long-standing renal disease, earlier consultation with a nephrologist and more frequent specialist encounters is associated with lower mortality in the first year of dialysis. These findings need to be confirmed in younger and less indigent patients as well.
Adult↗