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 question

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 -22.7;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

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

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. 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. 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). 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 risk

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

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. 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. 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. 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 patient

Difference in antihypertensive drugs and BP in patients with and without ESA.

<p>Values are presented as mean difference in number of antihypertensive drugs or difference in blood pressure (with 95% Confidence Interval).</p><p>¹ Adjusted for age and sex.</p><p>² Adjusted for age, sex, BMI, Diabetes Mellitus, Cardiovascular disease, eGFR.</p><p>Abbreviations: ESA = Erythropoiesis-Stimulating Agent, SBP = Systolic Blood Pressure, DBP = Diastolic Blood pressure, ref = Reference, BMI = Body Mass Index, eGFR = estimated Glomerular Filtration Rate.</p

Distribution of systolic and diastolic blood pressure at baseline.

<p>The distribution of SBP and DBP are presented for the total population and stratified by ESA use. The total percentage of patients within the blood pressure target (DBP: 80 mmHg and SBP: 130 mmHg) are depicted in the histogram. Abbreviations: ESA = Erythropoiesis-Stimulating Agent, SBP = Systolic Blood Pressure, DBP = Diastolic Blood Pressure.</p

Characteristics of patients with and without ESA at the start of pre-dialysis care.

<p>Values are presented as mean (standard deviation) or percentage.</p><p>Abbreviations: ESA = Erythropoiesis-Stimulating Agent, BMI = Body Mass Index, eGFR = estimated Glomerular Filtration Rate.</p

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*h/L (95% confidence interval = 74 to 82 mg*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*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