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.

High alkaline phosphatase levels in hemodialysis patients are associated with higher risk of hospitalization and death.

We evaluated risks associated with elevated alkaline phosphatase in hemodialysis patients using longitudinal data from the Dialysis Outcomes and Practice Patterns Study, a prospective observational study of hemodialysis patients in 12 countries. Alkaline phosphatase levels were normalized by the upper limit of the laboratory-reported reference range. Cause-specific hospitalization and mortality risks were evaluated using Cox proportional hazards models, stratified by region and adjusted for phosphorus, calcium, albumin, parathyroid hormone, case mix, and numerous comorbidities. The odds of high normalized alkaline phosphatase were increased twofold in the United States in comparison to Japan. Elevations of normalized alkaline phosphatase were significantly associated with several comorbid conditions, increased fractures, parathyroidectomy, risk of hospitalization due to major adverse cardiac events, higher all-cause cardiovascular, and infection-related mortality risk. Our results also show that elevated serum normalized alkaline phosphatase was associated with higher risks of hospitalization and death in hemodialysis patients, independent of calcium, phosphorus, and parathyroid hormone levels.

Aspirin prescription and outcomes in hemodialysis patients: the Dialysis Outcomes and Practice Patterns Study (DOPPS).

BACKGROUND: We investigated aspirin-prescribing patterns and potential benefits on cardiovascular morbidity and mortality in hemodialysis patients. STUDY DESIGN: Cohort study. SETTING & PARTICIPANTS: Data included 28,320 randomly selected hemodialysis patients from the Dialysis Outcomes and Practice Patterns Study I and II. PREDICTOR: Aspirin prescription at study baseline. OUTCOMES & MEASUREMENTS: Prescription was investigated by means of logistic regression. All-cause mortality, all-cause hospitalization, cardiac event, myocardial infarction, cerebrovascular (CVA), gastrointestinal bleed, transient ischemic attack, and subdural hematoma were examined. Cox regression examined the risk of mortality and hospitalization. All models accounted for facility clustering and demographics and comorbid conditions. RESULTS: Wide variation was found in aspirin prescription, from 8% in Japan to 41% in Australia and New Zealand. Characteristics significantly associated with increased odds of prescription included coronary artery disease, cerebrovascular disease, diabetes, male sex, nonblack race, peripheral vascular disease, age, hypertension, and absence of gastrointestinal bleeding. Aspirin was associated with decreased risk of stroke in all patients (relative risk [RR], 0.82; P < 0.01) and increased risk of myocardial infarction (RR, 1.21; P = 0.01) and cardiac event (RR, 1.08; P < 0.01) in all patients, with similar results for patients with coronary artery disease. There was no increase in gastrointestinal bleeding. LIMITATIONS: Observational studies are not protected from biases, despite adjustments. There is potential for aspirin use to be underreported because of its availability without prescription. CONCLUSIONS: The hypothesis that prescribing aspirin to hemodialysis patients decreases cardiovascular disease risk is not supported. Aspirin might decrease CVA and appears not to increase hemorrhagic risk. This should be an incentive for randomized controlled trials.

Efficacy and safety of 'rescue therapy' with mycophenolate mofetil in resistant primary glomerulonephritis--a multicenter study.

BACKGROUND: Studies of mycophenolate mofetil (MMF) in primary glomerulonephritis have varied in their inclusion criteria, regimen and follow-up compromising assessments of efficacy and optimal dose. METHOD: This multicentre study analysed the safety and efficacy of MMF monotherapy in a large cohort with primary glomerulonephritis that was resistant to other conventional therapies. A total of 98 patients with biopsy-proven primary glomerulonephritis resistant to other drugs received MMF monotherapy for 1 year. Primary outcome measures were urinary protein excretion and the number of patients with complete or partial remission of proteinuria. Secondary analyses were time to remission and changes in the slope of creatinine clearance. RESULTS: Fifty-four percent of the patients achieved either complete or partial remission of proteinuria with no significant differences between glomerulonephritis types. Median (range) dose of MMF was 2 g/day (1.5-2 g/day) Mean (SD) treatment time to remission was 141.5 (+/-61.1) days with no significant differences between glomerulonephritis types. Serum albumin increased (P<0.01), whereas proteinuria (P<0.01) serum LDL-cholesterol (P<0.01) and mean blood pressure (P<0.05) decreased post-treatment. No significant changes were observed in glomerular filtration rate (GFR), serum creatinine or slopes of GFR. The reduction of urinary protein excretion was significantly higher in patients with basal nephrotic proteinuria and preserved renal function; it did not arise from an increased dose of angiotensin-converting enzyme inhibitors or angiotensin II receptor antagonists, since, among responders, mean blood pressure significantly decreased and the number of anti-hypertensive drugs could be reduced. CONCLUSIONS: MMF monotherapy causes a moderate decrease in proteinuria in >50% of the patients who do not have other treatment options. The response to therapy is largely influenced by a preserved renal function and requires sustained MMF treatment.

Kidney transplantation and wait-listing rates from the international Dialysis Outcomes and Practice Patterns Study (DOPPS).

BACKGROUND: The international Dialysis Outcomes and Practice Patterns Study (DOPPS I and II) allows description of variations in kidney transplantation and wait-listing from nationally representative samples of 18- to 65-year-old hemodialysis patients. The present study examines the health status and socioeconomic characteristics of United States patients, the role of for-profit versus not-for-profit status of dialysis facilities, and the likelihood of transplant wait-listing and transplantation rates. METHODS: Analyses of transplantation rates were based on 5267 randomly selected DOPPS I patients in dialysis units in the United States, Europe, and Japan who received chronic hemodialysis therapy for at least 90 days in 2000. Left-truncated Cox regression was used to assess time to kidney transplantation. Logistic regression determined the odds of being transplant wait-listed for a cross-section of 1323 hemodialysis patients in the United States in 2000. Furthermore, kidney transplant wait-listing was determined in 12 countries from cross-sectional samples of DOPPS II hemodialysis patients in 2002 to 2003 (N= 4274). RESULTS: Transplantation rates varied widely, from very low in Japan to 25-fold higher in the United States and 75-fold higher in Spain (both P values <0.0001). Factors associated with higher rates of transplantation included younger age, nonblack race, less comorbidity, fewer years on dialysis, higher income, and higher education levels. The likelihood of being wait-listed showed wide variation internationally and by United States region but not by for-profit dialysis unit status within the United States. CONCLUSION: DOPPS I and II confirmed large variations in kidney transplantation rates by country, even after adjusting for differences in case mix. Facility size and, in the United States, profit status, were not associated with varying transplantation rates. International results consistently showed higher transplantation rates for younger, healthier, better-educated, and higher income patients.

Predictors and consequences of altered mineral metabolism: the Dialysis Outcomes and Practice Patterns Study.

BACKGROUND: Altered mineral metabolism contributes to bone disease, cardiovascular disease, and other clinical problems in patients with end-stage renal disease. METHODS: This study describes the recent status, significant predictors, and potential consequences of abnormal mineral metabolism in representative groups of hemodialysis facilities (N= 307) and patients (N= 17,236) participating in the Dialysis Outcomes and Practice Patterns Study (DOPPS) in the United States, Europe, and Japan from 1996 to 2001. RESULTS: Many patients fell out of the recommended guideline range for serum concentrations of phosphorus (8% of patients below lower target range, 52% of patients above upper target range), albumin-corrected calcium (9% below, 50% above), calcium-phosphorus product (44% above), and intact PTH (51% below, 27% above). All-cause mortality was significantly and independently associated with serum concentrations of phosphorus (RR 1.04 per 1 mg/dL, P= 0.0003), calcium (RR 1.10 per 1 mg/dL, P < 0.0001), calcium-phosphorus product (RR 1.02 per 5 mg(2)/dL(2), P= 0.0001), PTH (1.01 per 100 pg/dL, P= 0.04), and dialysate calcium (RR 1.13 per 1 mEq/L, P= 0.01). Cardiovascular mortality was significantly associated with the serum concentrations of phosphorus (RR 1.09, P < 0.0001), calcium (RR 1.14, P < 0.0001), calcium-phosphorus product (RR 1.05, P < 0.0001), and PTH (RR 1.02, P= 0.03). The adjusted rate of parathyroidectomy varied 4-fold across the DOPPS countries, and was significantly associated with baseline concentrations of phosphorus (RR 1.17, P < 0.0001), calcium (RR 1.58, P < 0.0001), calcium-phosphorus product (RR 1.11, P < 0.0001), PTH (RR 1.07, P < 0.0001), and dialysate calcium concentration (RR 0.57, P= 0.03). Overall, 52% of patients received some form of vitamin D therapy, with parenteral forms almost exclusively restricted to the United States. Vitamin D was potentially underused in up to 34% of patients with high PTH, and overused in up to 46% of patients with low PTH. Phosphorus binders (mostly calcium salts during the study period) were used by 81% of patients, with potential overuse in up to 77% patients with low serum phosphorus concentration, and potential underuse in up to 18% of patients with a high serum phosphorus concentration. CONCLUSION: This study expands our understanding of the relationship between altered mineral metabolism and outcomes and identifies several potential opportunities for improved practice in this area.

Angiotensin-converting enzyme i/d polymorphism in patients with malignant hypertension.

The angiotensin-converting enzyme (ACE) gene has been implicated in the manifestation of the phenotype of malignant hypertension (MH). In 1990 the ACE gene polymorphism characterized by the insertion or deletion of a 287-base pair fragment in the 17q23 chromosome was identified. The DD genotype is associated with increased tissue and circulating ACE levels and elevated angiotensin II. ACE polymorphism was studied in 48 patients with MH, 25 patients with non-MH, and a control group of 78 normotensive individuals by real-time polymerase chain reaction using the LightCycler system (Roche Diagnostics Corporation, Indianapolis, IN). The DD genotype was found statistically more frequently in MH patients than controls (p=0.028; odds ratio, 2.5; confidence interval, 1.1-5.5). Presence of the DD genotype of the ACE gene is more frequent in MH patients than in controls, indicating that this genotype could be a significant risk factor and a predictor for the development of MH.

Timing of first cannulation and vascular access failure in haemodialysis: an analysis of practice patterns at dialysis facilities in the DOPPS.

BACKGROUND: Optimal waiting time before first use of vascular access is not known. METHODS: Two practices-first cannulation time for fistulae and grafts, and blood flow rate-were examined as potential predictors of vascular access failure in the Dialysis Outcomes and Practice Patterns Study (DOPPS). Access failure (defined as time to first failure or first salvage intervention) was modelled using Cox regression. RESULTS: Among 309 haemodialysis facilities, 2730 grafts and 2154 fistulae were studied. For grafts, first cannulation typically occurred within 2-4 weeks at 62% of US, 61% of European and 42% of Japanese facilities. For fistulae, first cannulation occurred <2 months after placement in 36% of US, 79% of European and 98% of Japanese facilities. Overall, the relative risk (RR) of graft failure in Europe was lower compared with the USA (RR = 0.69, P = 0.04). The RR of graft failure (reference group = first cannulation at 2-3 weeks) was 0.84 with first cannulation at <2 weeks (P = 0.11), 0.94 with first cannulation at 3-4 weeks (P = 0.48) and 0.93 with first cannulation at >4 weeks (P = 0.48). The RR of fistula failure was 0.72 with first cannulation at <4 weeks (P = 0.08), 0.91 at 2-3 months (P = 0.43) and 0.87 at >3 months (P = 0.31) (reference group = first cannulation at 1-2 months). Facility median blood flow rate was not a significant predictor of access failure. CONCLUSIONS: Earlier cannulation of a newly placed vascular access at the haemodialysis facility level was not associated with increased risk of vascular access failure. Potential for confounding due to selection bias cannot be excluded, implying the importance of clinical judgement in determining time to first use of vascular access.

Mortality and hospitalization in haemodialysis patients in five European countries: results from the Dialysis Outcomes and Practice Patterns Study (DOPPS).

BACKGROUND: Mortality and hospitalization rates are reported for nationally representative random samples of haemodialysis patients treated at randomly selected dialysis facilities in five European countries participating in the Dialysis Outcomes and Practice Pattern Study (DOPPS) (France, Germany, Italy, Spain and the UK). RESULTS: In the UK, 28.1% of haemodialysis patients received prior peritoneal dialysis treatment compared with 4.2-8.3% in other countries. Kidney transplantation rates ranged from 3.3 (per 100 patient years) in Italy to 11.6 in Spain. The relative risk (RR) of mortality, adjusted for age, sex and diabetes status was significantly higher in the UK (RR = 1.39, P = 0.02) compared with Italy (reference) and increased in association with age (RR = 1.60 for every 10 years older, P <0.001), diabetes as cause of end-stage renal disease (ESRD) (RR = 1.55, P < 0.001), male patients <65 years (RR = 1.29, P = 0.02) and peritoneal dialysis in the 12 months prior to starting haemodialysis (RR = 1.72, P = 0.06). Hospitalization for cardiovascular disease was highest in France and Germany (0.40 and 0.43 hospitalizations per patient year, respectively) and lowest in the UK (0.19), although cardiovascular comorbidity was similar in the UK and France. Hospitalization rates for vascular access-related infection ranged from 0.01 hospitalizations per patient year in Italy to 0.08 in the UK, consistent with the higher dialysis catheter use in the UK (25%) vs Italy (5%). Hospitalization risk was significantly higher in France than in other Euro-DOPPS countries and was significantly (P < 0.05) associated with prior peritoneal dialysis therapy, peripheral vascular disease, gastrointestinal bleeding in the prior 12 months, diabetes, cancer, cardiac disease, psychiatric disease and recent onset of ESRD (within 30 days of study entry). CONCLUSIONS: The large differences in haemodialysis practice and outcomes in the Euro-DOPPS countries suggest opportunities for improvement in patient care.

Anaemia in haemodialysis patients of five European countries: association with morbidity and mortality in the Dialysis Outcomes and Practice Patterns Study (DOPPS).

BACKGROUND: The Dialysis Outcomes and Practice Patterns Study (DOPPS) is a prospective, observational study based on data collected from nationally representative samples of haemodialysis facilities. The burden of anaemia in haemodialysis patients is substantial, leading to considerable morbidity, mortality and reduced quality of life. This study examines anaemia management and outcomes based on data from five European countries participating in the DOPPS: France, Germany, Italy, Spain and the UK. METHODS: Baseline data on demographics, co-morbidities and anaemia management in 4591 haemodialysis patients from 101 nephrology facilities were collected in 1998-2000. Using multivariate Cox survival analyses to adjust for patient characteristics, relationships between haemoglobin concentration at study entry and rates of mortality and hospitalization were evaluated. RESULTS: For a year 2000 sample of prevalent patients on haemodialysis >180 days, mean haemoglobin concentration was 11.0 g/dl; 53% had a haemoglobin concentration > or = 11 g/dl [1998-1999 = 44% (P < 0.05)]. In 2000, 84% of prevalent patients were prescribed recombinant human erythropoietin (rHuEpo). Higher haemoglobin concentrations were associated with decreased relative risk (RR) for mortality (RR = 0.95 for every 1 g/dl higher haemoglobin, P = 0.03) and hospitalization (RR = 0.96, P = 0.02). Patients with haemoglobin <10 g/dl were 29% more likely to be hospitalized than patients with haemoglobin 11-12 g/dl (P < 0.001). CONCLUSION: Even after adjustment, lower haemoglobin concentrations were associated with higher morbidity and mortality in European haemodialysis patients. A trend to increased haemoglobin concentrations was observed following publication of the European Best Practice Guidelines (EBPG) on anaemia management for chronic kidney disease patients, but efforts must continue to achieve EBPG goals.

Nonadherence in hemodialysis: associations with mortality, hospitalization, and practice patterns in the DOPPS.

BACKGROUND: Nonadherence among hemodialysis patients compromises dialysis delivery, which could influence patient morbidity and mortality. The Dialysis Outcomes and Practice Patterns Study (DOPPS) provides a unique opportunity to review this problem and its determinants on a global level. METHODS: Nonadherence was studied using data from the DOPPS, an international, observational, prospective hemodialysis study. Patients were considered nonadherent if they skipped one or more sessions per month, shortened one or more sessions by more than 10 minutes per month, had a serum potassium level openface>6.0 mEq/L, a serum phosphate level openface>7.5 mg/dL (>2.4 mmol/L), or interdialytic weight gain (IDWG)>5.7% of body weight. Predictors of nonadherence were identified using logistic regression. Survival analysis used the Cox proportional hazards model adjusting for case-mix. RESULTS: Skipping treatment was associated with increased mortality [relative risk (RR) = 1.30, P = 0.01], as were excessive IDWG (RR = 1.12, P = 0.047) and high phosphate levels (RR = 1.17, P = 0.001). Skipping also was associated with increased hospitalization (RR = 1.13, P = 0.04), as were high phosphate levels (RR = 1.07, P = 0.05). Larger facility size (per 10 patients) was associated with higher odds ratios (OR) of skipping (OR = 1.03, P = 0.06), shortening (OR = 1.03, P = 0.05), and IDWG (OR = 1.02, P = 0.07). An increased percentage of highly trained staff hours was associated with lower OR of skipping (OR = 0.84 per 10%, P = 0.02); presence of a dietitian was associated with lower OR of excessive IDWG (OR = 0.75, P = 0.08). CONCLUSION: Nonadherence was associated with increased mortality risk (skipping treatment, excessive IDWG, and high phosphate) and with hospitalization risk (skipping, high phosphate). Certain patient/facility characteristics also were associated with nonadherence.

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.

Combined therapy of tacrolimus and corticosteroids in cyclosporin-resistant or -dependent idiopathic focal glomerulosclerosis: a preliminary uncontrolled study with prospective follow-up.

BACKGROUND: Cyclosporin has improved the outcome for steroid-resistant patients with focal glomerulosclerosis, but there is a proportion of patients that are either cyclosporin-resistant or suffer relapses, needing long-term therapy to sustain the remission. In these cases, preliminary reports suggest that tacrolimus could be an alternative therapy, but to date the evidence is limited to small series of patients with no long-term follow-up. METHODS: In this study we analysed the efficacy and safety of a combined therapy of tacrolimus and steroids in 25 patients (mean serum creatinine= 1.24+/-0.49 mg/dl; mean proteinuria=10.2+/-9.5 g/day; mean serum albumin=2.4+/-0.58 g/dl) with idiopathic primary focal glomerulosclerosis and proven resistance to or dependence on cyclosporin A. RESULTS: After a 6 months trial of tacrolimus and steroids, proteinuria decreased in 17 patients (68%) (complete remission in 10 patients (40%), partial remission in two patients (8%) and a moderate reduction in proteinuria to levels <3 g/day was seen in five additional patients (20%)). The only predictor of response to tacrolimus was a previous response to cyclosporin and prednisone, either as a complete or partial remission (remission rate 75% vs 15.3; P=0.036). Mean time to remission was 112+/-24 days. After tacrolimus discontinuation, 13/17 patients (76%) relapsed and were treated with a second trial of tacrolimus for 1 year, achieving complete remission in five patients (38.4%), partial remission in four patients (30.7%) and reduction of proteinuria <3 g/day in four patients (30.7%). After 2 years of follow-up, 12 patients (48%) were on sustained remission. The main side effect was acute reversible nephrotoxicity (40%). Predictors of renal toxicity were age (P=0.037), baseline creatinine (P=0.046) and tacrolimus trough level (P=0.001). CONCLUSIONS: We conclude that combined therapy of tacrolimus and steroids induce sustained remission of proteinuria in a significant number of patients with idiopathic focal glomerulosclerosis whose disease was not controlled by the standard therapy of steroids and cyclosporin A.