Control of hyperphosphatemia among patients with ESRD.

Derangements of mineral metabolism occur during the early stages of chronic kidney disease (CKD). Hyperphosphatemia develops in the majority of patients with ESRD and has long been associated with progression of secondary hyperparathyroidism and renal osteodystrophy. More recent observational data have associated hyperphosphatemia with increased cardiovascular mortality among dialysis patients. Adequate control of serum phosphorus remains a cornerstone in the clinical management of patients with CKD not only to attenuate the progression of secondary hyperparathyroidism but also possibly to reduce the risk for vascular calcification and cardiovascular mortality. These measures include dietary phosphorus restriction, dialysis, and oral phosphate binders. Dietary restriction is limited in advanced stages of CKD. Phosphate binders are necessary to limit dietary absorption of phosphorus. Aluminum hydroxide is an efficient binder; however, its use has been nearly eliminated because of concerns of toxicity. Calcium salts are inexpensive and have been used effectively worldwide as an alternative to aluminum. Concerns of calcium overload have led to the investigation of alternatives. Currently, only two Food and Drug Administration-approved noncalcium, nonaluminum binders are available. Sevelamer hydrochloride is an exchange resin and was not as effective as calcium acetate in meeting new guideline recommendations in one double-blind clinical trial. Lanthanum carbonate is a rare earth element and has been studied less extensively. Concerns of long-term administration and toxicity exist. Furthermore, these agents are significantly more expensive than calcium salts, which may contribute to patient noncompliance.

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.

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.

Key concepts in biostatistics: using statistics to answer the question "is there a difference?".

Biostatistics seeks to answer the question "Is there a difference?" in the rate of a disease or characteristic among subgroups of patients. The goal of this article is to introduce and define measures used in epidemiology and discuss different types of analyses in clinical research with an emphasis on the concepts and implications of the analyses rather than the mathematics. The implications of the use of measures such as incidence and prevalence, as well as odds, risk, and hazards ratios may affect study conclusions. An understanding of the distinction between these summary measures is essential. The concepts of univariate and multivariate analyses, a discussion of what it means to control for potential confounders, and a description of statistical power and significance are also presented. These concepts are integral to the design and analysis of clinical studies. An understanding of their advantages and applications will enhance the reader's ability to understand and evaluate the literature.

Secondary hyperparathyroidism and its therapy as a cardiovascular risk factor among end-stage renal disease patients.

Secondary hyperparathyroidism (HPTH) was initially viewed as a disorder of the skeletal system; however, recent population-based data have associated markers of HPTH with an increased cardiovascular mortality among patients with end-stage renal disease (ESRD). This has stimulated much interest in further evaluating secondary HPTH as a cardiovascular disease risk factor, as well as the putative role of its therapy. This article explores the current state of scientific evidence concerning the pathophysiology of cardiovascular disease among the ESRD population and potential risk factors for its development, including markers of HPTH, and its therapies.

Study designs and their potential influence on conclusions.

Epidemiology is the basic medical science that focuses on the distribution and determinants of disease frequency in human populations. An understanding of the tools of epidemiology is helpful in defining the limitations of medical research and evaluating the conclusions of studies. This is the second in a series of three articles whose objective is to present the basic concepts of epidemiology and biostatistics, highlighted by examples of these concepts applied in the medical literature studying patients receiving dialysis. This article describes the study designs of case-control, cohort, and randomized trials and issues in the conduct and analysis of each. Several studies examining the association between hematocrit and survival of dialysis patients are discussed. Their differences in design and methods are discussed in the context of their effect on study conclusions. The goal of this article is to present the reader with the issues of study design and the limitations they impose on study conclusions. Through the examination of these methods, the reader will be able to rigorously examine study methods and understand how design affects study conclusions and their application to patient care.

Trends in anemia management among US hemodialysis patients.

This study was undertaken to describe the relationship between hematocrit (Hct) and changes in the prescribed dose of erythropoietin (EPO) as well as selected patient and process care measures across annual national samples of hemodialysis patients from 1994 to 1998. This study uses the cohorts identified in the ESRD Core Indicators Project, random samples of 6181, 6241, 6364, 6634, and 7660 patients, stratified by ESRD Networks drawn for each year from 1994 to 1998. Patient demographic and clinical information was collected from October to December for each year. Surrogates of iron stores and patterns of iron and EPO administration were profiled from 1996 to 1998. Multivariable stepwise linear regression analyses were performed to adjust for potential confounding variables and to identify independent variables associated with Hct and EPO dose. Mean Hct and EPO dose increased each year from 31.1 +/- 5.2% to 34.1 +/- 3.7% and from 58.2 +/- 41.8 U/kg to 68.2 +/- 55.0 U/kg, respectively (P = 0.0001). Increasing Hct was positively associated with male gender, more years on dialysis, older age, higher urea reduction ratio and transferrin saturation, prescription of intravenous iron, and lower ferritin and EPO dose in multivariable models (all P = 0.0001). Male gender, older age, diabetes, higher Hct, and increasing weight, urea reduction ration, and transferrin saturation were associated with lower EPO doses (all P < 0.01). Conversely, intravenous EPO and iron were associated with higher prescribed EPO doses (all P = 0.0001). Although increasing Hct is associated with decreasing EPO dose at the patient level, the increase in Hct seen across years among the cohorts of hemodialysis patients in the United States has been associated with increasing doses of EPO at the population level.

Association between pulse pressure and mortality in patients undergoing maintenance hemodialysis.

CONTEXT: Although increased blood pressure is associated with adverse outcomes in the general population, elevated blood pressure is associated with decreased mortality in patients with end-stage renal disease undergoing maintenance hemodialysis. Recent investigations in the general population have demonstrated the predictive utility of pulse pressure (systolic minus diastolic blood pressure), a measure reflecting the pulsatile nature of the cardiac cycle. OBJECTIVES: To estimate the relationship between pulse pressure and mortality in patients undergoing maintenance hemodialysis and to test our hypothesis that an increasing pulse pressure would be associated with increased risk of death up to 1 year despite the inverse relationship between conventional blood pressure measures and mortality in patients with end-stage renal disease. DESIGN, SETTING, AND PATIENTS: Retrospective cohort investigation of patients with end-stage renal disease undergoing maintenance hemodialysis at 782 hemodialysis facilities throughout the United States. Of 44 069 eligible patients as of January 1, 1998, 37 069 with complete demographic data were included in the analyses of clinical and laboratory data collected from October 1 through December 31, 1997. Patients were followed up through December 31, 1998. MAIN OUTCOME MEASURES: The primary study outcome was death at 1 year. A secondary outcome was the magnitude of the pulse pressure. RESULTS: The final patient cohort was similar to national averages with respect to age, sex, race, and diabetic status. Mean (SD) pulse pressures before dialysis were 75.0 (15.0) mm Hg and 66.9 (13.9) mm Hg after dialysis. By the end of the 1-year follow-up, 5731 patients (18.4%) died. After adjusting for level of systolic blood pressure, multivariable Cox proportional hazards modeling showed a direct and consistent relationship between increasing pulse pressure and increasing death risk. Each incremental elevation of 10 mm Hg in postdialysis pulse pressure was associated with a 12% increase in the hazard for death (hazard ratio, 1.12; 95% confidence interval, 1.06-1.18). Postdialysis systolic blood pressure was inversely related to mortality with a 13% decreased hazard for death for each incremental elevation of 10 mm Hg (hazard ratio, 0.87; 95% confidence interval, 0.84-0.90). In a multivariable linear regression model, important variables directly associated with elevated pulse pressure included age, diabetes, white race, female sex, and number of years receiving dialysis (all P<.001). CONCLUSIONS: Pulse pressure is associated with risk of death in a large, nationally representative sample of patients undergoing maintenance hemodialysis. The recognition of pulse pressure as an important correlate of mortality in patients receiving dialysis highlights the need to investigate the relationship between potential therapeutic implications of conduit vessel function and clinical outcomes in patients with end-stage renal disease.

An introduction to epidemiology and biostatistics and issues in interpretation of studies.

Epidemiology is the basic medical science that focuses on the distribution and determinants of disease frequency in human populations. An understanding of the tools of epidemiology is helpful in defining the limitations of medical research and evaluating the conclusions of studies. This is the first in a series of three articles whose objective will be to present the basic concepts of epidemiology and biostatistics. Examples of each of the tools and limitations discussed from studies of patients with end-stage renal disease (ESRD) will be presented to provide the reader with a practical application of the concepts. This series of articles will help the reader to weigh methods and study designs to understand the appropriate conclusions that may be drawn from any data.