Trends in haemoglobin, erythropoietin-stimulating agents and iron use in Swedish chronic kidney disease patients between 2008 and 2013.

BACKGROUND: The guidelines for anaemia management in chronic kidney disease (CKD) patients have changed substantially during the past 10 years. We here evaluate whether these changes are followed by subsequent modifications in physicians' anaemia management in Sweden. METHODS: We included patients incident to the Swedish Renal Registry for CKD non-dialysis (CKD-ND, referred patients with an estimated glomerular filtration rate <45 mL/min/1.73 m(2)) and haemodialysis (HD) between 2008 and 2013. Time trends in anaemia management were investigated in relation to prescribed medication, laboratory measures and other relevant clinical characteristics. Linear and binominal regression models were used to describe trends across three predefined time periods (2008-09, 2010-11 and 2012-13). RESULTS: Erythropoiesis-stimulating agents (ESAs) use decreased over time among both CKD-ND and HD patients [risk ratio (RR) 2012-13 compared with 2008-09 for CKD-ND 0.88, 95% confidence interval (CI) 0.81-0.96; RR for HD 0.95, 95% CI 0.93-0.97]. Mean ESA dose decreased significantly among HD patients (7% in 2010-11 compared with 2008-09 and another 3% during 2012-13). Over the time periods studied, ESA doses increased slightly in the CKD-ND population. Mean haemoglobin (Hb) levels decreased in CKD-ND patients, among both ESA users and non-users, whereas it decreased to a lesser degree, albeit significantly, among HD ESA users. The risk of having an Hb >120 g/L decreased, especially between 2008-09 and 2010-11. Iron use increased over time, mainly in the HD population, but also among CKD-ND ESA non-users. CONCLUSIONS: Changes in guidelines have influenced the clinical anaemia practice of Swedish nephrology care, resulting in lower ESA use and lower Hb levels.

Graphical presentation of confounding in directed acyclic graphs.

Since confounding obscures the real effect of the exposure, it is important to adequately address confounding for making valid causal inferences from observational data. Directed acyclic graphs (DAGs) are visual representations of causal assumptions that are increasingly used in modern epidemiology. They can help to identify the presence of confounding for the causal question at hand. This structured approach serves as a visual aid in the scientific discussion by making underlying relations explicit. This article explains the basic concepts of DAGs and provides examples in the field of nephrology with and without presence of confounding. Ultimately, these examples will show that DAGs can be preferable to the traditional methods to identify sources of confounding, especially in complex research questions.

Treatment with high dose of erythropoiesis-stimulating agents and mortality: analysis with a sequential Cox approach and a marginal structural model.

BACKGROUND: Anemia-correction trials indicated higher mortality rates in chronic kidney disease patients assigned to higher hemoglobin targets. The safety of the high erythropoiesis-stimulating agent (ESA) doses that these patients received has therefore been questioned. However, no trial that directly compares treatment with different ESA doses has been published. We thus aimed to estimate the effect of high ESA dose on mortality in an observational cohort of dialysis patients. METHODS: The Netherlands Cooperative Study on the Adequacy of Dialysis is a Dutch cohort study of incident dialysis patients in which ESA dose, comorbidities, and laboratory parameters were collected every 6 months. Mortality in patients with a high ESA dose (above median 6000 units/week) was compared with that in patients with no or low ESA dose with Cox regression analyses. To handle time-dependent confounding, a sequential Cox approach was used conditional on baseline covariates, with inverse probability of censoring weights (IPCW) for dependent censoring. Analyses were repeated with a marginal structural model (MSM) with inverse probability of treatment weights and IPCW. RESULTS: Hazard ratio (HR) for high ESA dose was 1.20 (95%CI 0.83-1.73) with a sequential Cox and 1.54 (95%CI 1.08-2.18) with an MSM. Truncation of weights in the MSM did not affect estimates. To compare, conventional Cox analyses indicated a baseline adjusted HR of 1.66 (95%CI 1.20-2.31). CONCLUSION: Patients treated with high ESA dose have a 1.2-1.5 increased risk of mortality. Our analyses support guidelines advising a conservative ESA dosing regimen, which carefully weighs the patients' benefits and risks.

The association between dialysis modality and the risk for dialysis technique and non-dialysis technique-related infections.

BACKGROUND: Infections are a major cause of morbidity and mortality among dialysis patients. Dialysis modality has been hypothesized to be a potential immunomodulatory factor. The objective of this study was to determine the influence of the first dialysis modality on the risk for infections on dialysis. METHODS: Our study was conducted utilizing the Netherlands Cooperative Study on the Adequacy of Dialysis (NECOSAD) cohort of incident dialysis patients. Medical records of all patients from two tertiary care university hospitals and three regional hospitals were reviewed using pre-specified criteria. Information about infections was collected from the start of dialysis until death, modality switch, study withdrawal, kidney transplantation or at the end of the study. Age-standardized incidence rates for infections were calculated. Poisson regression analysis was used to calculate adjusted incidence rate ratios (IRRs). RESULTS: In total, 452 patients, of whom 285 started with haemodialysis (HD) and 167 with peritoneal dialysis (PD), were included. The median follow-up time on the first dialysis modality was similar for HD and PD, 1.8 and 2.0 dialysis years, respectively. During the first 6 months, the age-standardized infection incidence rate was higher on HD compared with PD patients (P = 0.02). Overall, PD patients had a higher infection risk [adjusted IRR: 1.65, 95% confidence interval (CI): 1.34-2.03], which could be attributed to a 4-fold increased risk for dialysis technique-related infections. The risk for non-dialysis technique-related infections was lower in PD patients (adjusted IRR: 0.56, 95% CI: 0.40-0.79). CONCLUSIONS: Overall, PD patients carry a higher risk for infections. Interestingly, the risk for non-dialysis technique-related infections was higher in HD patients. The links between dialysis modality and the immune system are expected to explain this difference, but future studies are needed to test these assumptions.

The influence of Erythropoietin on platelet activation, thrombin generation and FVII/active FVII in patients with AMI.

BACKGROUND: Erythropoietin (Epo) has been shown to improve myocardial function in models of experimental myocardial infarction, but has also been associated with a rise in thromboembolic events. Thus, the aim of this study was to investigate the influence of Epo on platelet activation and coagulation in patients with acute myocardial infarction (AMI). METHODS: The study was designed as a substudy of the randomised, double-blind, placebo controlled REVIVAL-3 (REgeneration of VItal Myocardium in ST-Segment EleVation MyocardiAL Infarction by Erythropoietin) study that investigated the effects of recombinant human Epo in AMI. Serial venous blood samples were collected before and after study medication. Circulating prothrombin fragment F1 + 2, FVII, active FVII, beta thromboglobulin (TG) and P-Selectin were measured before and 60 hours after randomization by immunoassay (n = 94). In a randomly selected subgroup platelet aggregation was measured using whole blood aggregometry (Multiplate Analyzer, n = 45). RESULTS: After 5 days an increase in FVII was observed after Epo as compared to placebo (P = 0.02), yet active FVII and prothrombin fragment F1 + 2 remained unchanged. Moreover, no statistically significant differences in circulating TG or P-selectin were observed between the groups. As an expected response to peri-interventional therapy with clopidogrel and aspirin, platelet aggregation after stimulation with ADP, TRAP, ASPI or collagen decreased 12 hours and 2 days after PCI. However, no difference between the Epo and the placebo group was observed. CONCLUSION: After treatment with Epo in patients with AMI a slight increase in circulating FVII after Epo was not associated with an increase in active FVII, prothrombin fragment F1 + 2, TG or P-selectin. Moreover, platelet aggregation was not altered after treatment with Epo as compared to placebo. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01761435.

Erythropoiesis-stimulating agent resistance and mortality in hemodialysis and peritoneal dialysis patients.

BACKGROUND: Responsiveness to erythropoiesis-stimulating agents (ESAs) varies widely among dialysis patients. ESA resistance has been associated with mortality in hemodialysis (HD) patients, but in peritoneal dialysis (PD) patients data is limited. Therefore we assessed the relation between ESA resistance in both HD and PD patients. METHODS: NECOSAD is a Dutch multi-center prospective cohort study of incident dialysis patients who started dialysis between January 1997 and January 2007. ESA resistance was defined as hemoglobin level < 11 g/dL with an above median ESA dose (i.e. 8,000 units/week in HD and 4,000 units/week in PD patients). Unadjusted and adjusted Cox regression analysis for all-cause 5-year mortality was performed for HD and PD patients separately. RESULTS: 1013 HD and 461 PD patients were included in the analysis. ESA resistant HD patients had an adjusted hazard ratio of 1.37 (95% CI 1.04-1.80) and ESA resistant PD patients had an adjusted hazard ratio of 2.41 (1.27-4.57) as compared to patients with a good response. CONCLUSIONS: ESA resistance, as defined by categories of ESA and Hb, is associated with increased mortality in both HD and PD patients. The effect of ESA resistance, ESA dose and hemoglobin are closely related and the exact mechanism remains unclear. Our results strengthen the need to investigate and treat causes of ESA resistance not only in HD, but also in PD patients.

Association between busulfan exposure and outcome in children receiving intravenous busulfan before hematologic stem cell transplantation.

Busulfan, combined with therapeutic drug monitoring-guided dosing, is associated with higher event-free survival (EFS) rates due to fewer graft failures/relapses and lower toxicity. The optimal target area under the curve (AUC) and dosing schedule of intravenous busulfan in children undergoing hematopoietic stem cell transplantation (HSCT) remain unclear, however. We conducted a retrospective analysis of the association between busulfan exposure and clinical outcome in 102 children age 0.2 to 21 years who received busulfan 1 or 4 times daily before undergoing HSCT (46 malignant and 56 nonmalignant indications). EFS and overall survival after a median of 2 years of follow-up were 68% and 72%, respectively. EFS was optimal when the exposure of busulfan (AUC) was 78 mg x h/L (95% confidence interval=74 to 82 mg x h/L). Acute graft-versus-host disease (aGVHD) grade II-IV occurred more frequently with greater busulfan exposure. The addition of melphalan was an independent risk factor; melphalan use combined with high busulfan exposure (AUC >74 mg x h/L) was associated with high incidences of aGVHD (58%), veno-occlusive disease (66%), and mucositis grade III-IV (26%). Dosing frequency (1 or 4 times daily) was not related to any outcome. In conclusion, dose targeting of busulfan to a narrow therapeutic range was found to increase EFS in children. Adding melphalan to optimal busulfan exposure is associated with a high incidence of toxicity.

Erythropoiesis-stimulating agents and cardiovascular events in patients with myelodysplastic syndrome and multiple myeloma.

INTRODUCTION: Erythropoiesis-stimulating agent (ESA) treatment has been associated with an increased risk of venous thromboembolism (VTE) in patients with solid tumors and with an increased risk of cardiovascular events in patients with chronic kidney disease. The ESA-related risk in patients with hematological neoplasms remains unclear. We, therefore, aimed to assess the ESA-related risk of VTE, myocardial infarction (MI), and stroke in patients with multiple myeloma (MM) and myelodysplastic syndrome (MDS). MATERIALS AND METHODS: We conducted a population-based cohort study in Denmark, using medical databases to identify 2,114 MDS patients and 3,105 MM patients diagnosed in 2004-2013. Incidence rates per 1,000 person-years and hazard ratios (HRs) with 95% confidence intervals (CIs) for VTE, MI, and stroke associated with ESA treatment were computed. HRs were calculated in time-dependent Cox regression and adjusted for age, sex, MDS prognosis group, comorbidities, and treatments. RESULTS: Incidence rates per 1,000 person-years for VTE, MI, and stroke were 10.8, 8.2, and 16.0 in MDS patients, and 21.9, 10.2 and 9.9 in MM patients without ESA treatment, respectively. MDS patients with ESA treatment had a 1.6-fold increased risk of MI (HR 1.60 [95% CI 0.90-2.86]) and an almost twofold increased risk of stroke (HR 1.94 [95% CI 1.28-2.94]). Adjusted HR for VTE was 1.04 (95% CI 0.57-1.89) compared with MDS patients without ESAs. In MM patients with ESAs compared with patients without ESAs, HRs were 1.41 (95% CI 0.96-2.08) for VTE, 1.23 (95% CI 0.68-2.20) for MI, and 1.63 (95% CI 0.96-2.77) for stroke. CONCLUSION: ESA use was associated with stroke in MDS patients. Among MM patients, ESA treatment was associated with a higher risk of all cardiovascular events, although all CIs included equivalence.

Erythropoiesis-stimulating agents and thrombotic events in dialysis patients.

BACKGROUND: Erythropoiesis-stimulating agents (ESA) have been associated with a higher cardiovascular event and mortality rate in dialysis patients. The ESA-associated risk of arterial thrombotic events is mainly based on composite endpoints of anemia-correction trials targeting high hemoglobin levels. The ESA-associated risk of venous thromboembolism (VTE) has not been studied in dialysis patients yet. We therefore aimed to determine the association between ESA use and dose with ischemic stroke, myocardial infarction (MI) and VTE. MATERIALS AND METHODS: In NECOSAD, a Dutch cohort study of incident dialysis patients, data on ESA use and dose, comorbidities and laboratory parameters were routinely collected every 6 months. Thrombotic events were collected by chart review of all dialysis patients from 6 participating centers. Time-dependent Cox regression analysis was performed to calculate hazard ratios (HR) with 95% confidence interval (CI) for ischemic stroke, MI and VTE with updated information on ESA use and dose. RESULTS: Patients with ESA had a 2 times lower ischemic stroke rate than patients without ESA: adjusted HR 0.45 (95% CI 0.23-0.90), and an adjusted HR of 1.12 (95% CI 0.58-2.14) for MI. No evident ESA dose response effect was present. Unadjusted HR for VTE was 0.41 (95% CI 0.11-1.50) for patients with ESA compared to patients without, but the low event rate made further adjustments impossible. CONCLUSIONS: In our observational cohort of dialysis patients, reflecting everyday clinical practice, ESA was not associated with an excess of thrombotic events. Further investigation is needed to enlighten the true cause of ESA-associated cardiovascular events and mortality.

Effect of erythropoiesis-stimulating agents on blood pressure in pre-dialysis patients.

INTRODUCTION: Erythropoiesis-Stimulating Agents (ESA) are hypothesized to increase cardiovascular mortality in patients with chronic kidney disease. One of the proposed mechanisms is the elevation of blood pressure (BP) by ESA. Therefore, we aimed to determine whether the use of ESA was associated with antihypertensive treatment and higher BP. MATERIALS AND METHODS: In this cohort 502 incident pre-dialysis patients were included who started specialized pre-dialysis care in 25 clinics in the Netherlands. Data on medication including ESA use and dose, co-morbidities and BP were routinely collected every 6 months. Antihypertensive treatment and BP were compared for patients with and without ESA at baseline. Differences in antihypertensive medication and BP during pre-dialysis care were estimated with linear mixed models adjusted for age, sex, body mass index, cardiovascular disease, diabetes mellitus and estimated glomerular filtration rate. RESULTS: At baseline, 95.6% of patients with ESA were treated with antihypertensive medication and 73.1% of patients without ESA. No relevant difference in BP was found. During pre-dialysis care patients with ESA used 0.77 (95% CI 0.63;0.91) more classes of antihypertensive drugs. The adjusted difference in systolic blood pressure (SBP) was -0.3 (95% CI -2.7;2.0) mmHg and in diastolic blood pressure (DBP) was -1.0 (95% CI -2.1;0.3) mmHg for patients with ESA compared to patients without ESA. Adjusted SBP was 3.7 (95% CI -1.6;9.0) mmHg higher in patients with a high ESA dose compared to patients with a low ESA dose. CONCLUSIONS: Our study confirms the hypertensive effect of ESA, since ESA treated patients received more antihypertensive agents. However, no relevant difference in BP was found between patients with and without ESA, thus the increase in BP seems to be controlled for by antihypertensive medication.