Phosphate binder use and mortality among hemodialysis patients in the Dialysis Outcomes and Practice Patterns Study (DOPPS): evaluation of possible confounding by nutritional status.

BACKGROUND: Poor nutritional status and both hyper- and hypophosphatemia are associated with increased mortality in maintenance hemodialysis (HD) patients. We assessed associations of phosphate binder prescription with survival and indicators of nutritional status in maintenance HD patients. STUDY DESIGN: Prospective cohort study (DOPPS [Dialysis Outcomes and Practice Patterns Study]), 1996-2008. SETTING & PARTICIPANTS: 23,898 maintenance HD patients at 923 facilities in 12 countries. PREDICTORS: Patient-level phosphate binder prescription and case-mix-adjusted facility percentage of phosphate binder prescription using an instrumental-variable analysis. OUTCOME: All-cause mortality. RESULTS: Overall, 88% of patients were prescribed phosphate binders. Distributions of age, comorbid conditions, and other characteristics showed small differences between facilities with higher and lower percentages of phosphate binder prescription. Patient-level phosphate binder prescription was associated strongly at baseline with indicators of better nutrition, ie, higher values for serum creatinine, albumin, normalized protein catabolic rate, and body mass index and absence of cachectic appearance. Overall, patients prescribed phosphate binders had 25% lower mortality (HR, 0.75; 95% CI, 0.68-0.83) when adjusted for serum phosphorus level and other covariates; further adjustment for nutritional indicators attenuated this association (HR, 0.88; 95% CI, 0.80-0.97). However, this inverse association was observed for only patients with serum phosphorus levels ≥3.5 mg/dL. In the instrumental-variable analysis, case-mix-adjusted facility percentage of phosphate binder prescription (range, 23%-100%) was associated positively with better nutritional status and inversely with mortality (HR for 10% more phosphate binders, 0.93; 95% CI, 0.89-0.96). Further adjustment for nutritional indicators reduced this association to an HR of 0.95 (95% CI, 0.92-0.99). LIMITATIONS: Results were based on phosphate binder prescription; phosphate binder and nutritional data were cross-sectional; dietary restriction was not assessed; observational design limits causal inference due to possible residual confounding. CONCLUSIONS: Longer survival and better nutritional status were observed for maintenance HD patients prescribed phosphate binders and in facilities with a greater percentage of phosphate binder prescription. Understanding the mechanisms for explaining this effect and ruling out possible residual confounding require additional research.

Depression as a potential explanation for gender differences in health-related quality of life among patients on maintenance hemodialysis.

BACKGROUND/AIMS: The reasons for lower health-related quality of life (HRQOL) scores in women compared to men on maintenance hemodialysis (MHD) are unknown. We investigated whether depression accounts for gender differences in HRQOL. METHODS: Cross-sectional study of 868 (40.9% women) Brazilian MHD patients (PROHEMO Study). We used the Kidney Disease Quality of Life Short Form to assess HRQOL and the Center for Epidemiological Studies Depression (CES-D) scale (scores from 0-60) to assess depression with scores >or=18 indicating high depression probability. RESULTS: Higher depression scores were associated with lower HRQOL in both sexes. Women had higher depression scores; 51.8% of women versus 38.2% of men (p < 0.001) had CES-D scores >or=18. Women scored lower on all 9 assessed HRQOL scales. The female-to-male differences in HRQOL were slightly reduced with inclusion of Kt/V and comorbidities in regression models. Substantial additional reductions in female-to-male differences in all HRQOL scales were observed after including depression scores in the models, by 50.9% for symptoms/problems related to renal failure, by 71.6% for mental health and by 87.1% for energy/vitality. CONCLUSIONS: Lower HRQOL among women was largely explained by depression symptoms. Results support greater emphasis on treating depression to improve HRQOL in MHD patients, particularly women.

Independent and joint associations of nutritional status indicators with mortality risk among chronic hemodialysis patients in the Dialysis Outcomes and Practice Patterns Study (DOPPS).

OBJECTIVE: To consider the Kidney Disease Outcomes Quality Initiative recommendation of using multiple nutritional measurements for patients on maintenance dialysis, we explored data for independent and joint associations of nutritional indicators with mortality risk among maintenance hemodialysis patients treated in 12 countries. SETTING: Dialysis units in seven European countries, the United States, Canada, Australia, New Zealand, and Japan. MAIN OUTCOME: Mortality risk. METHODS: We conducted a prospective cohort study of 40,950 patients from phases I to III of the Dialysis Outcomes and Practice Patterns Study (1996-2008). Independent and joint effects (interactions) of nutritional indicators (serum creatinine, serum albumin, normalized protein catabolic rate, body mass index [BMI]) on mortality risk were assessed by Cox regression with adjustments for demographics, years on dialysis, and comorbidities. RESULTS: Important variations in nutritional indicators were seen by country and patient characteristics. Poorer nutritional status assessed by each indicator was independently associated with higher mortality risk across regions. Significant multiplicative interactions (each p < or = 0.01) between indicators were also observed. For example, by using patients with serum creatinine 7.5-10.5 mg/dL and BMI 21-25 kg/m(2) as referent, BMI <21 kg/m(2) was associated with lower mortality risk among patients with creatinine >10.5 mg/dL (relative risk = 0.68) but with higher mortality risk among those with creatinine <7.5 mg/dL (relative risk = 1.38). The association of lower albumin concentration with higher mortality risk was stronger for patients with lower BMI or lower creatinine. CONCLUSION: The joint effects of nutritional indicators on mortality indicate the need to use multiple measurements when assessing the nutritional status of hemodialysis patients.

Comparative efficacies of two antimony regimens to treat Leishmania braziliensis-induced cutaneous Leishmaniasis in rhesus macaques (Macaca mulatta).

This study compared the efficacies of two N-methylglucomine antimoniate (MA) dose regimens for treating macaques with Leishmania braziliensis-induced chronic skin disease. Whereas all animals treated with the full dose (20 mg MA/kg/day) were cured, 50% of the monkeys receiving a low-dose regimen (5 mg MA/kg/day) relapsed. The antimony concentrations in macaque plasma and tissue samples were greater in the full-dose group than in that receiving a subtherapeutic MA regimen. Our data also suggest the presence of drug-induced hepatic pathology.

Prescription of antihypertensive agents to haemodialysis patients: time trends and associations with patient characteristics, country and survival in the DOPPS.

BACKGROUND: Haemodialysis patients were studied in 12 countries to identify practice patterns of prescription of antihypertensive agents (AHA) associated with survival. METHODS: The sample included 28 513 patients enrolled in DOPPS I and II. The classes of AHA studied were beta blocker (BB), angiotensin-converting enzyme inhibitor (ACEI), angiotensin receptor blocker (ARB), peripheral blocker, central antagonist, vasodilator, long-acting dihydropyridine calcium channel blocker (CCB), short-acting dihydropyridine CCB and non-dihydropyridine CCB. To reduce bias due to unmeasured confounders, the associations with mortality were assessed by separate Cox models based on patient-level prescription and facility prescription practice. RESULTS: An increase in prescription of ARBs (9.5%) and BBs (9.1%) was observed from DOPPS I to II. Prescription of AHA classes varied significantly by country, ranging for BBs from 9.7% in Japan to 52.7% in Sweden and for ARBs from 5.5% in Italy to 21.3% in Japan in DOPPS II. Facilities that treated 10% more patients with ARBs had, on average, 7% lower all-cause mortality, independent of patient characteristics and the prescription patterns of other antihypertensive medications (P = 0.05). Significant and independent associations with reduction in cardiovascular mortality were observed for ARBs (RR = 0.79; P = 0.005) and BBs (RR = 0.87, P = 0.004) in analyses of patient-level prescriptions. These associations in the facility-level model followed the same direction. CONCLUSIONS: DOPPS data show large variations across countries in AHA prescription for haemodialysis patients. The data suggest an association between ARB use and reduction in all-cause mortality, as well as with the use of BBs and reduction in cardiovascular mortality among haemodialysis patients.

Efficacy of sapropterin dihydrochloride in increasing phenylalanine tolerance in children with phenylketonuria: a phase III, randomized, double-blind, placebo-controlled study.

OBJECTIVE: To evaluate the ability of sapropterin dihydrochloride (pharmaceutical preparation of tetrahydrobiopterin) to increase phenylalanine (Phe) tolerance while maintaining adequate blood Phe control in 4- to 12-year-old children with phenylketonuria (PKU). STUDY DESIGN: This international, double-blind, randomized, placebo-controlled study screened for sapropterin response among 90 enrolled subjects in Part 1. In Part 2, 46 responsive subjects with PKU were randomized (3:1) to sapropterin, 20 mg/kg/d, or placebo for 10 weeks while continuing on a Phe-restricted diet. After 3 weeks, a dietary Phe supplement was added every 2 weeks if Phe control was adequate. RESULTS: The mean (+/-SD) Phe supplement tolerated by the sapropterin group had increased significantly from the pretreatment amount (0 mg/kg/d) to 20.9 (+/-15.4) mg/kg/d (P < .001) at the last visit at which subjects had adequate blood Phe control (<360 micromol/L), up to week 10. Over the 10-week period, the placebo group tolerated only an additional 2.9 (+/-4.0) mg/kg/d Phe supplement; the mean difference from the sapropterin group (+/-SE) was 17.7 +/- 4.5 mg/kg/d (P < .001). No severe or serious related adverse events were observed. CONCLUSIONS: Sapropterin is effective in increasing Phe tolerance while maintaining blood Phe control and has an acceptable safety profile in this population of children with PKU.

Lack of appetite in haemodialysis patients--associations with patient characteristics, indicators of nutritional status and outcomes in the international DOPPS.

BACKGROUND: Identification of haemodialysis patients with problems related to lack of appetite should help prevent adverse outcomes. We studied whether a single question about being bothered by lack of appetite within the prior 4 weeks is related to nutritional status, inflammation and risks of death and hospitalization. Additionally, we assessed associations of lack of appetite with depression, dialysis dose and length of haemodialysis. METHODS: This study is an analysis of baseline and longitudinal data from 14 406 patients enrolled in the Dialysis Outcomes and Practice Pattern Study. Cox regression was used to assess whether the degree (not, somewhat, moderately, very much, extremely) that patients were bothered by lack of appetite is an independent predictor of death and hospitalization. Logistic regression was used to identify baseline characteristics associated with being bothered by lack of appetite. RESULTS: The risk of death was more than 2-fold higher [relative risk (RR) = 2.23; 95% confidence interval (CI) = 1.90-2.62] and the risk of hospitalization 33% higher (RR = 1.33; 95% CI = 1.19-1.48) among patients extremely bothered, compared with not bothered, by lack of appetite. These associations followed a dose-response fashion and remained statistically significant after adjustments for 14 comorbidities. Depression, shorter haemodialysis session, hypoalbuminaemia, lower concentration of serum creatinine and normalized protein catabolic rate, lower body mass index and higher leucocyte and neutrophil counts were independently associated with higher odds of being bothered by lack of appetite. CONCLUSIONS: The data suggest that a single question about lack of appetite helps identify haemodialysis patients with poorer nutritional status, inflammation, depression and higher risks of hospitalization and death. The study calls attention to a possible beneficial effect of longer haemodialysis on appetite.

Factors associated with health-related quality of life among hemodialysis patients in the DOPPS.

OBJECTIVE: To identify modifiable factors associated with health-related quality of life (HRQOL) among chronic hemodialysis patients. METHODS: Analysis of baseline data of 9,526 hemodialysis patients from seven countries enrolled in phase I of the Dialysis Outcomes and Practice Patterns Study (DOPPS). Using the Kidney Disease Quality of Life Short Form (KDQOL-SF(TM)), we determined scores for 8 generic scale summaries derived from these scales, i.e., the physical component summary [PCS] and mental component summary [MCS], and 11 kidney disease- targeted scales. Regression models were used to adjust for differences in comorbidities and sociodemographic and treatment factors. The Benjamini-Hochberg procedure was used to correct P-values for multiple comparisons. RESULTS: Unemployment and psychiatric disease were independently and significantly associated with lower scores for all generic and several kidney disease-targeted HRQOL measures. Several other comorbidities, lower educational level, lower income, and hypoalbuminemia were also independently and significantly associated with lower scores of PCS and/or MCS and several generic and kidney disease-targeted scales. Hemodialysis by catheter was associated with significantly lower PCS scores, partially explained by the correlation with covariates. CONCLUSION: Associations of poorer HRQOL with preventable or controllable factors support a greater focus on psychosocial and medical interventions to improve the well-being of hemodialysis patients.

Screening for depression in hemodialysis patients: associations with diagnosis, treatment, and outcomes in the DOPPS.

BACKGROUND: Depressive symptoms and depression are the most frequent psychologic problems reported by hemodialysis patients. We assessed the prevalence of depressive symptoms and physician-diagnosed depression, their variations by country, and associations with treatment by antidepressants among hemodialysis patients. We also assessed whether depressive symptoms were independently associated with mortality, hospitalization, and dialysis withdrawal. METHODS: The sample was represented by 9382 hemodialysis patients randomly selected from dialysis centers of 12 countries enrolled in the Dialysis Outcomes and Practice Patterns Study (DOPPS II). Depressive symptoms were assessed by the short version of the Center for Epidemiological Studies Depression Screening Index (CES-D), using > or =10 CES-D score as the cut-off value. RESULTS: Overall prevalence of physician-diagnosed depression was 13.9%, and percentage of CES-D score > or =10 43.0%. While the smallest prevalence of physician-diagnosed depression was observed in Japan (2.0%) and France (10.6%), the percentage of CES-D score > or =10 in these counties was similar to the whole sample. Patients on antidepressants also varied by country, 34.9% and 17.3% among those with physician-diagnosed depression and CES-D scores > or =10, respectively. In Cox models adjusted for several comorbidities, CES-D scores > or =10 were associated with significantly higher relative risks (RR) of death (RR = 1.42; 95% CI = 1.29 to 1.57), hospitalization (RR = 1.12; 95% CI = 1.03 to 1.22), and dialysis withdrawal (RR = 1.55; 95% CI = 1.29 to 1.85). CONCLUSION: The data suggest that depression is underdiagnosed and undertreated among hemodialysis patients. CES-D can help identify hemodialysis patients who are at higher risk of death and hospitalization. Interventions should target these patients with the goal to improve survival and reduce hospitalizations.

Meeting the challenge to improve the treatment of hypertension in blacks.

Hypertension is more prevalent and severe in African descendent populations living outside Africa than in any other population. Given this greater burden of hypertension in blacks, it is increasingly necessary to refine strategies to prevent the disorder as well as improve its treatment and control. This review assesses results from clinical trials on lifestyle and pharmacologic interventions to identify which approaches most effectively prevent adverse hypertension-related outcomes in African descendent populations. The Dietary Approaches to Stop Hypertension (DASH) study provided evidence that a carefully controlled diet rich in fruits, vegetables, low-fat dairy foods, and reduced in saturated fat, total fat, and cholesterol (i.e., the DASH diet) reduces blood pressure in blacks and is well accepted. The combination of the DASH diet with reduction in dietary sodium below 100 mmol/d may provide a reduction in blood pressure beyond that reached by the DASH diet alone. Physical exercise and interventions to reduce psychological stress may also reduce blood pressure in blacks. Strong evidence from numerous studies is a compelling argument for continuing to recommend diuretics and beta blockers as first-line antihypertensive therapy for persons of all races. Some new studies also favor angiotensin-converting enzyme inhibitors as first-line antihypertensive drugs. The African American Study of Kidney Disease and Hypertension provided evidence that an angiotensin-converting enzyme inhibitor-based treatment program is more beneficial than calcium channel blockers and beta blockers in reducing the progression of renal failure in blacks with hypertensive nephropathy. Studies in patients with diabetes have also shown evidence that both angiotensin-converting enzyme inhibitors and angiotensin receptor antagonists are more effective than other classes of antihypertensives in reducing adverse renal events. Studies to evaluate the effects of the new antihypertensives in improving outcomes in blacks living outside the United States are needed.

Health-related quality of life and associated outcomes among hemodialysis patients of different ethnicities in the United States: the Dialysis Outcomes and Practice Patterns Study (DOPPS).

BACKGROUND: In the United States, an association between mortality risk and ethnicity has been observed among hemodialysis patients. This study was developed to assess whether health-related quality of life (HRQOL) scores also vary among patients of different ethnic backgrounds. Associations between HRQOL and adverse dialysis outcomes (ie, death and hospitalization) also were assessed for all patients and by ethnicity. METHODS: Data are from the Dialysis Outcomes and Practice Patterns Study for 6,151 hemodialysis patients treated in 148 US dialysis facilities who filled out the Kidney Disease Quality of Life Short Form. We determined scores for three components of HRQOL: Physical Component Summary (PCS), Mental Component Summary (MCS), and Kidney Disease Component Summary (KDCS). Patients were classified by ethnicity as Hispanic and five non-Hispanic categories: white, African American, Asian, Native American, and other. Multiple linear regression models were used to estimate differences in HRQOL scores among ethnic groups, using whites as the referent category. Cox regression models were used for associations between HRQOL and outcomes. Regression models were adjusted for sociodemographic variables, delivered dialysis dose (equilibrated Kt/V), body mass index, years on dialysis therapy, and several laboratory/comorbidity variables. RESULTS: Compared with whites, African Americans showed higher HRQOL scores for all three components (MCS, PCS, and KDCS). Asians had higher adjusted PCS scores than whites, but did not differ for MCS or KDCS scores. Compared with whites, Hispanic patients had significantly higher PCS scores and lower MCS and KDCS scores. Native Americans showed significantly lower adjusted MCS scores than whites. The three major components of HRQOL were significantly associated with death and hospitalization for the entire pooled population, independent of ethnicity. CONCLUSION: The data indicate important differences in HRQOL among patients of different ethnic groups in the United States. Furthermore, HRQOL scores predict death and hospitalization among these patients.

Depression as a predictor of mortality and hospitalization among hemodialysis patients in the United States and Europe.

BACKGROUND: Depression is not uncommon among patients with end-stage renal disease (ESRD) being treated by hemodialysis. We investigated whether risk of mortality and rate of hospitalization may be predicted from physician-diagnosed depression and patients' self-reports of depressive symptoms. METHODS: Data were analyzed from the Dialysis Outcomes and Practice Patterns Study (DOPPS) for randomly selected ESRD patients being treated by hemodialysis in the United States (142 facilities, 2855 patients) and five European countries (101 facilities, 2401 patients). The diagnosis of depression during the past year was abstracted from the medical records. In addition, the patients were asked to indicate how much of their time over the previous four weeks they had felt (1) "so down in the dumps that nothing could cheer you up" and (2) "downhearted and blue." A response of "a good bit,""most," or "all" of the time were classified as depressed. RESULTS: The prevalence of depression was nearly 20%. The relative risks of mortality and hospitalization among depressed (vs. non-depressed), adjusted for time on dialysis, age, race, socioeconomic status, comorbid indicators and country were, respectively: 1.23 and 1.11 for physician-diagnosed depression, 1.48 and 1.15 for the "so down in the dumps" question, and 1.35 and 1.11 for the "downhearted and blue" question (P < 0.05 for all six relative risks). These associations were not significantly different between US and European patients. CONCLUSIONS: Self-reported depression by two simple questions was associated with increased risks of mortality and hospitalization for hemodialysis patients. Future research needs to assess whether early identification and treatment of depression may help to improve quality of life and survival in hemodialysis patients.