Ronald L. Pisoni

Mortality Risk for Dialysis Patients With Different Levels of Serum Calcium, Phosphorus, and PTH: The Dialysis Outcomes and Practice Patterns Study (DOPPS)

BACKGROUND Abnormalities in serum calcium, phosphorus, and parathyroid hormone (PTH) concentrations are common in patients with chronic kidney disease and have been associated with increased morbidity and mortality. No clinical trials have been conducted to clearly identify categories of calcium, phosphorus, and PTH levels associated with the lowest mortality risk. Current clinical practice guidelines are based largely on expert opinions, and clinically relevant differences exist among guidelines across countries. We sought to describe international trends in calcium, phosphorus, and PTH levels during 10 years and identify mortality risk categories in the Dialysis Outcomes and Practice Patterns Study (DOPPS), an international study of hemodialysis practices and associated outcomes. STUDY DESIGN Prospective cohort study. PARTICIPANTS 25,588 patients with end-stage renal disease on hemodialysis therapy for longer than 180 days at 925 facilities in DOPPS I (1996-2001), DOPPS II (2002-2004), or DOPPS III (2005-2007). PREDICTORS Serum calcium, albumin-corrected calcium (Ca(Alb)), phosphorus, and PTH levels. OUTCOMES Adjusted hazard ratios for all-cause and cardiovascular mortality calculated using Cox models. RESULTS Distributions of mineral metabolism markers differed across DOPPS countries and phases, with lower calcium and phosphorus levels observed in the most recent phase of DOPPS. Survival models identified categories with the lowest mortality risk for calcium (8.6 to 10.0 mg/dL), Ca(Alb) (7.6 to 9.5 mg/dL), phosphorus (3.6 to 5.0 mg/dL), and PTH (101 to 300 pg/mL). The greatest risk of mortality was found for calcium or Ca(Alb) levels greater than 10.0 mg/dL, phosphorus levels greater than 7.0 mg/dL, and PTH levels greater than 600 pg/mL and in patients with combinations of high-risk categories of calcium, phosphorus, and PTH. LIMITATIONS Because of the observational nature of DOPPS, this study can only indicate an association between mineral metabolism categories and mortality. CONCLUSIONS Our results provide important information about mineral metabolism trends in hemodialysis patients in 12 countries during a decade. The risk categories identified in the DOPPS cohort may be relevant to efforts at international harmonization of existing clinical guidelines for mineral metabolism.

Vascular access use and outcomes: an international perspective from the dialysis outcomes and practice patterns study

Background. A well-functioning vascular access (VA) is essential to efficient dialysis therapy. Guidelines have been implemented improving care, yet access use varies widely across countries and VA complications remain a problem. This study took advantage of the unique opportunity to utilize data from the Dialysis Outcomes and Practice Patterns Study (DOPPS) to examine international trends in VA use and trends in patient characteristics and practices associated with VA use from 1996 to 2007. DOPPS is a prospective, observational study of haemodialysis (HD) practices and patient outcomes at >300 HD units from 12 countries and has collected data thus far from >35 000 randomly selected patients. Methods. VA data were collected for each patient at study entry (1996–2007). Practice pattern data from the facility medical director, nurse manager and VA surgeon were also analysed. Results. Since 2005, a native arteriovenous fistula (AVF) was used by 67–91% of prevalent patients in Japan, Italy, Germany, France, Spain, the UK, Australia and New Zealand, and 50–59% in Belgium, Sweden and Canada. From 1996 to 2007, AVF use rose from 24% to 47% in the USA but declined in Italy, Germany and Spain. Moreover, graft use fell by 50% in the USA from 58% use in 1996 to 28% by 2007. Across three phases of data collection, patients consistently were less likely to use an AVF versus other VA types if female, of older age, having greater body mass index, diabetes, peripheral vascular disease or recurrent cellulitis/gangrene. In addition, countries with a greater prevalence of diabetes in HD patients had a significantly lower percentage of patients using an AVF. Despite poorer outcomes for central vein catheters, catheter use rose 1.5- to 3-fold among prevalent patients in many countries from 1996 to 2007, even among non-diabetic patients 18–70 years old. Furthermore, 58–73% of patients new to end-stage renal disease (ESRD) used a catheter for the initiation of HD in five countries despite 60–79% of patients having been seen by a nephrologist >4 months prior to ESRD. Patients were significantly (P < 0.05) less likely to start dialysis with a permanent VA if treated in a faciity that (1) had a longer time from referral to access surgery evaluation or from evaluation to access creation and (2) had longer time from access creation until first AVF cannulation. The median time from referral until access creation varied from 5–6 days in Italy, Japan and Germany to 40–43 days in the UK and Canada. Compared to patients using an AVF, patients with a catheter displayed significantly lower mean Kt/V levels. Conclusions. Most countries meet the contemporary National Kidney Foundations Kidney Disease Outcomes Quality Initiative goal for AVF use; however, there is still a wide variation in VA preference. Delays between the creation and cannulation must be improved to enhance the chances of a future permanent VA. Native arteriovenous fistula is the VA of choice ensuring dialysis adequacy and better patient outcomes. Graft is, however, a better alternative than catheter for patients where the creation of an attempted AVF failed or could not be created for different reasons.

Predictors of Early Mortality among Incident US Hemodialysis Patients in the Dialysis Outcomes and Practice Patterns Study (DOPPS)

Mortality risk among hemodialysis (HD) patients may be highest soon after initiation of HD. A period of elevated mortality risk was identified among US incident HD patients, and which patient characteristics predict death during this period and throughout the first year was examined using data from the Dialysis Outcomes and Practice Patterns Study (DOPPS; 1996 through 2004). A retrospective cohort study design was used to identify mortality risk factors. All patient information was collected at enrollment. Life-table analyses and discrete logistic regression were used to identify a period of elevated mortality risk. Cox regression was used to estimate adjusted hazard ratios (HR) measuring associations between patient characteristics and mortality and to examine whether these associations changed during the first year of HD. Among 4802 incident patients, risk for death was elevated during the first 120 d compared with 121 to 365 d (27.5 versus 21.9 deaths per 100 person-years; P = 0.002). Cause-specific mortality rates were higher in the first 120 d than in the subsequent 121 to 365 d for nearly all causes, with the greatest difference being for cardiovascular-related deaths. In addition, 20% of all deaths in the first 120 d occurred subsequent to withdrawal from dialysis. Most covariates were found to have consistent effects during the first year of HD: Older age, catheter vascular access, albumin <3.5, phosphorus <3.5, cancer, and congestive heart failure all were associated with elevated mortality. Pre-ESRD nephrology care was associated with a significantly lower risk for death before 120 d (HR 0.65; 95% confidence interval 0.51 to 0.83) but not in the subsequent 121- to 365-d period (HR 1.03; 95% confidence interval 0.83 to 1.27). This care was related to approximately 50% lower rates of both cardiac deaths and withdrawal from dialysis during the first 120 d. Mortality risk was highest in the first 120 d after HD initiation. Inadequate predialysis nephrology care was strongly associated with mortality during this period, highlighting the potential benefits of contact with a nephrologist at least 1 mo before HD initiation.

Facility Hemodialysis Vascular Access Use and Mortality in Countries Participating in DOPPS: An Instrumental Variable Analysis

BACKGROUND Previously, the Dialysis Outcomes and Practice Patterns Study (DOPPS) has shown large international variations in vascular access practice. Greater mortality risks have been seen for hemodialysis (HD) patients dialyzing with a catheter or graft versus a native arteriovenous fistula (AVF). To further understand the relationship between vascular access practice and outcomes, we have applied practice-based analyses (using an instrumental variable approach) to decrease the treatment-by-indication bias of prior patient-level analyses. STUDY DESIGN A prospective observational study of HD practices. SETTING & PARTICIPANTS Data collected from 1996 to 2004 from 28,196 HD patients from more than 300 dialysis units participating in the DOPPS in 12 countries. PREDICTOR OR FACTOR Patient-level or case-mix-adjusted facility-level vascular access use. OUTCOMES/MEASUREMENTS: Mortality and hospitalization risks. RESULTS After adjusting for demographics, comorbid conditions, and laboratory values, greater mortality risk was seen for patients using a catheter (relative risk, 1.32; 95% confidence interval, 1.22 to 1.42; P < 0.001) or graft (relative risk, 1.15; 95% confidence interval, 1.06 to 1.25; P < 0.001) versus an AVF. Every 20% greater case-mix-adjusted catheter use within a facility was associated with 20% greater mortality risk (versus facility AVF use, P < 0.001); and every 20% greater facility graft use was associated with 9% greater mortality risk (P < 0.001). Greater facility catheter and graft use were both associated with greater all-cause and infection-related hospitalization. Catheter and graft use were greater in the United States than in Japan and many European countries. More than half the 36% to 43% greater case-mix-adjusted mortality risk for HD patients in the United States versus the 5 European countries from the DOPPS I and II was attributable to differences in vascular access practice, even after adjusting for other HD practices. Vascular access practice differences accounted for nearly 30% of the greater US mortality compared with Japan. LIMITATIONS Possible existence of unmeasured facility- and patient-level confounders that could impact the relationship of vascular access use with outcomes. CONCLUSIONS Facility-based analyses diminish treatment-by-indication bias and suggest that less catheter and graft use improves patient survival.

The survival advantage for haemodialysis patients taking vitamin D is questioned: findings from the Dialysis Outcomes and Practice Patterns Study

BACKGROUND Retrospective studies of haemodialysis patients from large dialysis organizations in the United States have indicated that intravenous vitamin D may be associated with a survival benefit. However, patients prescribed vitamin D are generally healthier than those who are not, suggesting that treatment by indication may have biased previous findings. Additionally, no survival benefit associated with vitamin D has been shown in a recent meta-analysis in CKD patients. Because treatment-by-indication bias due to both measured and unmeasured confounders cannot be completely accounted for in standard regression or marginal structural models (MSMs), this study evaluates the association between vitamin D and mortality among participants in the Dialysis Outcomes and Practice Patterns Study (DOPPS) using standard regression and MSMs with an expanded set of covariates, as well as by instrumental variable models to minimize potential bias due to unmeasured confounders. METHODS Data from 38 066 DOPPS participants from 12 countries between 1996 and 2007 were analysed. Mortality risk was assessed using standard baseline and time-varying Cox regression models, adjusted for demographics and detailed comorbidities, and MSMs. In models similar to instrumental variable analysis, the facility percentage of patients prescribed vitamin D, adjusted for the patient case mix, was used to predict patient-level mortality. RESULTS Vitamin D prescription was significantly higher in the USA compared to other countries. On average, patients prescribed vitamin D had fewer comorbidities compared to those who were not. Vitamin D therapy was associated with lower mortality in adjusted time-varying standard regression models [relative ratio (RR) = 0.92 (95% confidence interval: 0.87-0.96)] and baseline MSMs [RR = 0.84 (0.78-0.98)] and time-varying MSMs [RR = 0.78 (0.73-0.84)]. No significant differences in mortality were observed in adjusted baseline standard regression models for patients with or without vitamin D prescription [RR = 0.98 (0.93-1.02)] or for patients in facility practices where vitamin D prescription was more frequent [RR for facilities in 75th versus 25th percentile of vitamin D prescription = 0.99 (0.94-1.04)]. CONCLUSIONS Vitamin D was associated with a survival benefit in models prone to bias due to unmeasured confounding. In agreement with a meta-analysis of randomized controlled studies, no difference in mortality was observed in instrumental variable models that tend to be more independent of unmeasured confounding. These findings indicate that a randomized controlled trial of vitamin D and clinical outcomes in haemodialysis patients are needed and can be ethically conducted.

Clinical Practices and Outcomes in Elderly Hemodialysis Patients: Results from the Dialysis Outcomes and Practice Patterns Study (DOPPS)

BACKGROUND AND OBJECTIVES Demand for hemodialysis among elderly patients is increasing worldwide. Although clinical care of this high-risk group is complex and challenging, no guidelines exist to inform hemodialysis practices. The Dialysis Outcomes and Practice Patterns Study (DOPPS) provides a unique opportunity to assess dialysis practices and associated outcomes among elderly versus younger patients on chronic in-center hemodialysis in 12 countries. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Clinical characteristics, dialysis practices, and outcomes of elderly versus younger patients were compared among participants in four DOPPS regions in 2005 through 2007. RESULTS Although participant mean age increased over time in all DOPPS countries, the percentage of elderly varied widely. Overall, comorbidities and malnutrition were more common in the elderly. Fistulae were used less frequently among elderly versus younger patients in Europe and North America but not in Australia, New Zealand, and Japan. No difference in treatment time was observed between elderly and younger patients after normalizing for body weight. In all regions, ultrafiltration rates were lower among elderly patients. Elderly patients reported poorer quality of life with respect to the physical but not mental component scores. Mortality risk was three- to sixfold higher in the elderly group, whereas causes of death overall were similar for elderly and younger patients. CONCLUSIONS Elderly patients represent a different proportion of DOPPS participants across countries, possibly reflecting differences in policies and clinical practices. In general, hemodialysis practices in the elderly reflected each regions clinical patterns, with some variation by age group depending upon the practice.

Physical exercise among participants in the Dialysis Outcomes and Practice Patterns Study (DOPPS): correlates and associated outcomes

BACKGROUND Levels of physical exercise among haemodialysis patients are low. Increased physical activity in this population has been associated with improved health-related quality of life (HRQoL) and survival. However, results of previous studies may not be applicable to the haemodialysis population as a whole. The present study provides the first description of international patterns of exercise frequency and its association with exercise programmes and clinical outcomes among participants in the Dialysis Outcomes and Practice Patterns Study (DOPPS). METHODS Data from a cross section of 20,920 DOPPS participants in 12 countries between 1996 and 2004 were analysed. Regular exercise was defined as exercise frequency equal to or more than once/week based on patient self-report. Linear mixed models and logistic regression assessed associations of exercise frequency with HRQoL and other psychosocial variables. Mortality risk was calculated in Cox proportional hazard models using patient-level (patient self-reported exercise frequency) and facility-level (the dialysis facility percentage of regular exercisers) predictors. RESULTS Regular exercise frequency varied widely across countries and across dialysis facilities within a country. Overall, 47.4% of participants were categorized as regular exercisers. The odds of regular exercise was 38% higher for patients from facilities offering exercise programmes (adjusted odds ratio = 1.38 [95% confidence interval: 1.03-1.84]; P = 0.03). Regular exercisers had higher HRQoL, physical functioning and sleep quality scores; reported fewer limitations in physical activities; and were less bothered by bodily pain or lack of appetite (P <or= 0.0001 for all). Regular exercise was also correlated with more positive patient affect and fewer depressive symptoms (P <or= 0.0001). In models extensively adjusted for demographics, comorbidities and socio-economic indicators, mortality risk was lower among regular exercisers (hazard ratio = 0.73 [0.69-0.78]; P < 0.0001) and at facilities with more regular exercisers (0.92 [0.89-0.94]; P < 0.0001 per 10% more regular exercisers). CONCLUSIONS Results from an international study of haemodialysis patients indicate that regular exercise is associated with better outcomes in this population and that patients at facilities offering exercise programmes have higher odds of exercising. Dialysis facility efforts to increase patient physical activity may be beneficial.

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.

International Differences in Dialysis Mortality Reflect Background General Population Atherosclerotic Cardiovascular Mortality

Existing national, racial, and ethnic differences in dialysis patient mortality rates largely are unexplained. This study aimed to test the hypothesis that mortality rates related to atherosclerotic cardiovascular disease (ASCVD) in dialysis populations (DP) and in the background general populations (GP) are correlated. In a cross-sectional, multinational study, all-cause and ASCVD mortality rates were compared between GP and DP using the most recent data from the World Health Organization mortality database (67 countries; 1,571,852,000 population) and from national renal registries (26 countries; 623,900 population). Across GP of 67 countries (14,082,146 deaths), all-cause mortality rates (median 8.88 per 1000 population; range 1.93 to 15.40) were strongly related to ASCVD mortality rates (median 3.21; range 0.53 to 8.69), with Eastern European countries clustering in the upper and Southeast and East Asian countries in the lower rate ranges. Across DP (103,432 deaths), mortality rates from all causes (median 166.20; range 54.47 to 268.80) and from ASCVD (median 63.39 per 1000 population; range 21.52 to 162.40) were higher and strongly correlated. ASCVD mortality rates in DP and in the GP were significantly correlated; the relationship became even stronger after adjustment for age (R(2) = 0.56, P < 0.0001). A substantial portion of the variability in mortality rates that were observed across DP worldwide is attributable to the variability in background ASCVD mortality rates in the respective GP. Genetic and environmental factors may underlie these differences.

Worldwide, mortality risk is high soon after initiation of hemodialysis

Mortality rates for maintenance hemodialysis patients are much higher than the general population and are even greater soon after starting dialysis. Here we analyzed mortality patterns in 86,886 patients in 11 countries focusing on the early dialysis period using data from the Dialysis Outcomes and Practice Patterns Study; a prospective cohort study of in-center hemodialysis. The primary outcome was all-cause mortality, using time-dependent Cox regression, stratified by study phase adjusted for age, sex, race, and diabetes. The main predictor was time since dialysis start as divided into early (up to 120 days), intermediate (121–365 days), and late (over 365 days) periods. Mortality rates (deaths/100 patient-years) were 26.7 (95% confidence intervals 25.6, 27.9), 16.9 (16.2, 17.6), and 13.7 (13.5, 14.0) in the early, intermediate, and late periods, respectively. In each country, mortality was higher in the early compared to the intermediate period with an adjusted range from 3.10 (2.22, 4.32) in Japan to 1.15 (0.87, 1.53) in the United Kingdom. Adjusted mortality rates were similar for intermediate and late periods. The ratio of elevated mortality rates in the early to the intermediate period increased with age. Within each period, mortality was higher in the United States than in most other countries. Thus, internationally, the early hemodialysis period is a high-risk time for all countries studied, with substantial differences in mortality between countries. Efforts to improve outcomes should focus on the transition period and first few months of dialysis.