Associations between long-term exposure to air pollution and kidney function utilizing electronic healthcare records: a cross-sectional study.

BACKGROUND: Chronic kidney disease (CKD) affects more than 38 million people in the United States, predominantly those over 65 years of age. While CKD etiology is complex, recent research suggests associations with environmental exposures. METHODS: Our primary objective is to examine creatinine-based estimated glomerular filtration rate (eGFRcr) and diagnosis of CKD and potential associations with fine particulate matter (PM2.5), ozone (O3), and nitrogen dioxide (NO2) using a random sample of North Carolina electronic healthcare records (EHRs) from 2004 to 2016. We estimated eGFRcr using the serum creatinine-based 2021 CKD-EPI equation. PM2.5 and NO2 data come from a hybrid model using 1 km2 grids and O3 data from 12 km2 CMAQ grids. Exposure concentrations were 1-year averages. We used linear mixed models to estimate eGFRcr per IQR increase of pollutants. We used multiple logistic regression to estimate associations between pollutants and first appearance of CKD. We adjusted for patient sex, race, age, comorbidities, temporality, and 2010 census block group variables. RESULTS: We found 44,872 serum creatinine measurements among 7,722 patients. An IQR increase in PM2.5 was associated with a 1.63 mL/min/1.73m2 (95% CI: -1.96, -1.31) reduction in eGFRcr, with O3 and NO2 showing positive associations. There were 1,015 patients identified with CKD through e-phenotyping and ICD codes. None of the environmental exposures were positively associated with a first-time measure of eGFRcr < 60 mL/min/1.73m2. NO2 was inversely associated with a first-time diagnosis of CKD with aOR of 0.77 (95% CI: 0.66, 0.90). CONCLUSIONS: One-year average PM2.5 was associated with reduced eGFRcr, while O3 and NO2 were inversely associated. Neither PM2.5 or O3 were associated with a first-time identification of CKD, NO2 was inversely associated. We recommend future research examining the relationship between air pollution and impaired renal function.

Controversies in optimal anemia management: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Conference.

In chronic kidney disease, anemia and disordered iron homeostasis are prevalent and associated with significant adverse consequences. In 2012, Kidney Disease: Improving Global Outcomes (KDIGO) issued an anemia guideline for managing the diagnosis, evaluation, and treatment of anemia in chronic kidney disease. Since then, new data have accrued from basic research, epidemiological studies, and randomized trials that warrant a re-examination of previous recommendations. Therefore, in 2019, KDIGO decided to convene 2 Controversies Conferences to review the latest evidence, explore new and ongoing controversies, assess change implications for the current KDIGO anemia guideline, and propose a research agenda. The first conference, described here, focused mainly on iron-related issues, including the contribution of disordered iron homeostasis to the anemia of chronic kidney disease, diagnostic challenges, available and emerging iron therapies, treatment targets, and patient outcomes. The second conference will discuss issues more specifically related to erythropoiesis-stimulating agents, including epoetins, and hypoxia-inducible factor-prolyl hydroxylase inhibitors. Here we provide a concise overview of the consensus points and controversies resulting from the first conference and prioritize key questions that need to be answered by future research.

Long-Term Risks of Intravenous Iron in End-Stage Renal Disease Patients.

Patients with end-stage renal disease on dialysis commonly receive intravenous iron to treat anemia along with erythropoiesis-stimulating agents. While studies of intravenous iron have demonstrated efficacy in raising hemoglobin, the quantity of administered intravenous iron has raised concerns about iron overload leading to long-term toxicities. The goal of this review is to understand recent trends in intravenous iron use, potential mechanisms of iron toxicity, and to evaluate the available evidence in the literature for potential long-term cardiovascular and infectious complications. We include findings from the recently published landmark clinical trial of intravenous iron for patients receiving hemodialysis to contextualize treatment recommendations.

Thirty-year risk of ischemic stroke in individuals with sickle cell trait and modification by chronic kidney disease: The atherosclerosis risk in communities (ARIC) study.

Sickle cell trait (SCT) has been associated with hypercoagulability, chronic kidney disease (CKD), and ischemic stroke. Whether concomitant CKD modifies long-term ischemic stroke risk in individuals with SCT is uncertain. We analyzed data from 3602 genotyped black adults (female = 62%, mean baseline age = 54 years) who were followed for a median 26 years by the Atherosclerosis Risk in Communities Study. Ischemic stroke was verified by physician review. Associations between SCT and ischemic stroke were analyzed using repeat-events Cox regression, adjusted for potential confounders. SCT was identified in 236 (7%) participants, who more often had CKD at baseline than noncarriers (18% vs 13%, P = .02). Among those with CKD, elevated factor VII activity was more prevalent with SCT genotype (36% vs 22%; P = .05). From 1987-2017, 555 ischemic strokes occurred in 436 individuals. The overall hazard ratio of ischemic stroke associated with SCT was 1.31 (95% CI: 0.95-1.80) and was stronger in participants with concomitant CKD (HR = 2.18; 95% CI: 1.16-4.12) than those without CKD (HR = 1.09; 95% CI: 0.74-1.61); P for interaction = .04. The hazard ratio of composite ischemic stroke and/or death associated with SCT was 1.20 (95% CI: 1.01-1.42) overall, 1.44 (95% CI: 1.002-2.07) among those with CKD, and 1.15 (95% CI: 0.94-1.39) among those without CKD; P for interaction = .18. The long-term risk of ischemic stroke associated with SCT relative to noncarrier genotype appears to be modified by concomitant CKD.

Safety of Dynamic Intravenous Iron Administration Strategies in Hemodialysis Patients.

BACKGROUND AND OBJECTIVES: Intravenous iron therapy for chronic anemia management is largely driven by dosing protocols that differ in intensity with respect to dosing approach (i.e., dose, frequency, and duration). Little is known about the safety of these protocols. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Using clinical data from a large United States dialysis provider linked to health care utilization data from Medicare, we constructed a cohort of patients with ESKD aged ≥65 years who initiated and continued center-based hemodialysis for ≥90 days between 2009 and 2012, and initiated at least one of the five common intravenous iron administration strategies; ranked by intensity (the amount of iron given at moderate-to-high iron indices), the order of strategies was 3 (least intensive), 2 (less intensive), 1 (reference), 4 (more intensive), and 5 (most intensive). We estimated the effect of continuous exposure to these strategies on cumulative risks of mortality and infection-related events with dynamic Cox marginal structural models. RESULTS: Of 13,249 eligible patients, 1320 (10%) died and 1627 (12%) had one or more infection-related events during the 4-month follow-up. The most and least commonly initiated strategy was strategy 2 and 5, respectively. Compared with the reference strategy 1, more intensive strategies (4 and 5) demonstrated a higher risk of all-cause mortality (e.g., most intensive strategy 5: 60-day risk difference: 1.3%; 95% confidence interval [95% CI], 0.8% to 2.1%; 120-day risk difference: 3.1%; 95% CI, 1.0% to 5.6%). Similarly, higher risks were observed for infection-related morbidity and mortality among more intensive strategies (e.g., strategy 5: 60-day risk difference: 1.8%; 95% CI, 1.2% to 2.6%; 120-day risk difference: 4.3%; 95% CI, 2.2% to 6.8%). Less intensive strategies (2 and 3) demonstrated lower risks of all-cause mortality and infection-related events. CONCLUSIONS: Among dialysis patients surviving 90 days, subsequent intravenous iron administration strategies promoting more intensive iron treatment at moderate-to-high iron indices levels are associated with higher risks of mortality and infection-related events.

Data concordance between ESRD Medical Evidence Report and Medicare claims: is there any improvement?

BACKGROUND: Medicare is one of the world's largest health insurance programs. It provides health insurance to nearly 44 million beneficiaries whose entitlements are based on age, disability, or end-stage renal disease (ESRD). Data of these ESRD beneficiaries are collected in the US Renal Data System (USRDS), which includes comorbidity information entered at the time of dialysis initiation (medical evidence data), and are used to shape health care policy. One limitation of USRDS data is the lack of validation of these medical evidence comorbidities against other comorbidity data sources, such as medical claims data. METHODS: We examined the potential for discordance between USRDS Medical Evidence and medical claims data for 11 comorbid conditions amongst Medicare beneficiaries in 2011-2013 via sensitivity, specificity, kappa and hierarchical logistic regression. RESULTS: Among 61,280 patients, most comorbid conditions recorded on the Medical Evidence forms showed high specificity (>0.9), compared to prior medical claims as reference standard. However, both sensitivity and kappa statistics varied greatly and tended to be low (most <0.5). Only diabetes appeared accurate, whereas tobacco use and drug dependence showed the poorest quality (sensitivity and kappa <0.1). Institutionalization and patient region of residency were associated with data discordance for six and five comorbidities out of 11, respectively, after conservative adjustment of multiple testing. Discordance appeared to be non-informative for congestive heart failure but was most varied for drug dependence. CONCLUSIONS: We conclude that there is no improvement in comorbidity data quality in incident ESRD patients over the last two decades. Since these data are used in case-mix adjustment for outcome and quality of care metrics, the findings in this study should press regulators to implement measures to improve the accuracy of comorbidity data collection.

Excess Readmission-Based Penalty: Is Arthroplasty Different From the Other Outcomes?

Whether factors not under a hospital's control affect readmissions remains intensely debated in the context of the Centers for Medicare & Medicaid Services' Hospital Readmission Reduction Program. This study aimed to evaluate the potential effects of poverty, race, and hospital volume on excess readmissions, with >3000 hospitals participating in "Hospital Compare." Correlations between excess readmission ratios for five eligible outcomes (including hip and knee arthroplasty) were assessed with the three area and hospital-level factors: poverty, race (percent of black population), and hospital volume (number of discharges). Correlation coefficients of the ratios with race were approximately r = 0.2, consistently larger than those with poverty (r = 0-0.1), and those with volume were r = 0 to -0.5. Hip and knee arthroplasty had unique findings: null correlation with poverty (r ≈ 0), largest variability, and strong monotonicity with volume (r ≈ -0.5). The percent of Hispanic population showed negligible correlations in secondary analysis. Penalty assessment and hospital profiling should consider areas with high percentages of black population and a small volume of hospitals and providers of hip and knee surgery. (Journal of Surgical Orthopaedic Advances 27(4):286-294, 2018).

Association Between Gestational Diabetes and Incident Maternal CKD: The Coronary Artery Risk Development in Young Adults (CARDIA) Study.

BACKGROUND: Gestational diabetes mellitus (GDM) is associated with increased risk for diabetes mellitus, metabolic syndrome, and cardiovascular disease. We evaluated whether GDM is associated with incident chronic kidney disease (CKD), controlling for prepregnancy risk factors for both conditions. STUDY DESIGN: Prospective cohort. SETTING & PARTICIPANTS: Of 2,747 women (aged 18-30 years) enrolled in the Coronary Artery Risk Development in Young Adults (CARDIA) Study in 1985 to 86, we studied 820 who were nulliparous at enrollment, delivered at least 1 pregnancy longer than 20 weeks' gestation, and had kidney function measurements during 25 years of follow-up. PREDICTOR: GDM was self-reported by women for each pregnancy. OUTCOMES: CKD was defined as the development of estimated glomerular filtration rate (eGFR)<60mL/min/1.73m2 or urine albumin-creatinine ratio ≥ 25mg/g at any one CARDIA examination in years 10, 15, 20, or 25. MEASUREMENTS: HRs for developing CKD were estimated for women who developed GDM versus women without GDM using complementary log-log models, adjusting for prepregnancy age, systolic blood pressure, dyslipidemia, body mass index, smoking, education, eGFR, fasting glucose concentration, physical activity level (all measured at the CARDIA examination before the first pregnancy), race, and family history of diabetes. We explored for an interaction between race and GDM. RESULTS: During a mean follow-up of 20.8 years, 105 of 820 (12.8%) women developed CKD, predominantly increased urine albumin excretion (98 albuminuria only, 4 decreased eGFR only, and 3 both). There was evidence of a GDM-race interaction on CKD risk (P=0.06). Among black women, the adjusted HR for CKD was 1.96 (95% CI, 1.04-3.67) in GDM compared with those without GDM. Among white women, the HR was 0.65 (95% CI, 0.23-1.83). LIMITATIONS: Albuminuria was assessed by single untimed measurements of urine albumin and creatinine. CONCLUSIONS: GDM is associated with the subsequent development of albuminuria among black women in CARDIA.

Safety of intravenous iron in hemodialysis patients.

Among end-stage renal disease patients maintained by hemodialysis, anemia has been managed primarily through erythropoiesis-stimulating agents (ESAs) and intravenous (IV) iron. Following concerns about the cardiovascular (CV) safety of ESAs and changes in the reimbursement policies in Medicare's ESRD program, the use of IV iron has increased. IV iron supplementation promotes hemoglobin production and reduces ESA requirements, yet there exists relatively little evidence on the long-term safety of iron supplementation in hemodialysis patients. Labile iron can induce oxidative stress and is also essential in bacterial growth, leading to concerns about IV iron use and risk of CV events and infections in hemodialysis patients. Existing randomized controlled trials provide little evidence about safety due to insufficient power and short follow-up; recent observational studies have been inconsistent, but some have associated iron exposure with increased risk of infections and CV events. Given the widespread use and potential safety concerns related to IV iron, well-designed large prospective studies are needed to assess to identify optimal strategies for iron administration that maximize its benefits while avoiding potential risks.

Predictors of 30-Day Hospital Readmission among Maintenance Hemodialysis Patients: A Hospital's Perspective.

BACKGROUND AND OBJECTIVES: Over 35% of patients on maintenance dialysis are readmitted to the hospital within 30 days of hospital discharge. Outpatient dialysis facilities often assume responsibility for readmission prevention. Hospital care and discharge practices may increase readmission risk. We undertook this study to elucidate risk factors identifiable from hospital-derived data for 30-day readmission among patients on hemodialysis. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Data were taken from patients on maintenance hemodialysis discharged from University of North Carolina Hospitals between May of 2008 and June of 2013 who received in-patient hemodialysis during their index hospitalizations. Multivariable logistic regression models with 30-day readmission as the dependent outcome were used to identify readmission risk factors. Models considered variables available at hospital admission and discharge separately. RESULTS: Among 349 patients, 112 (32.1%) had a 30-day hospital readmission. The discharge (versus admission) model was more predictive of 30-day readmission. In the discharge model, malignancy comorbid condition (odds ratio [OR], 2.08; 95% confidence interval [95% CI], 1.04 to 3.11), three or more hospitalizations in the prior year (OR, 1.97; 95% CI, 1.06 to 3.64), ≥10 outpatient medications at hospital admission (OR, 1.69; 95% CI, 1.00 to 2.88), catheter vascular access (OR, 1.82; 95% CI, 1.01 to 3.65), outpatient dialysis at a nonuniversity-affiliated dialysis facility (OR, 3.59; 95% CI, 2.03 to 6.36), intradialytic hypotension (OR, 3.10; 95% CI, 1.45 to 6.61), weekend discharge day (OR, 1.82; 95% CI, 1.01 to 3.31), and serum albumin <3.3 g/dl (OR, 4.28; 95% CI, 2.37 to 7.73) were associated with higher readmission odds. A decrease in prescribed medications from admission to discharge (OR, 0.20; 95% CI, 0.08 to 0.51) was associated with lower readmission odds. Findings were robust across different model-building approaches. CONCLUSIONS: Models containing discharge day data had greater predictive capacity of 30-day readmission than admission models. Identified modifiable readmission risk factors suggest that improved medication education and improved transitions from hospital to community may potentially reduce readmissions. Studies evaluating targeted transition programs among patients on dialysis are needed.

Statin initiation and acute kidney injury following elective cardiovascular surgery: a population cohort study in Denmark†.

OBJECTIVES: Acute kidney injury (AKI) is a serious complication of cardiac surgery. Statins may prevent post-surgical AKI, yet methodological concerns about existing studies raise questions about the magnitude of a protective effect. We sought to determine the effect of initiating a statin prior to elective cardiac surgery on post-surgical AKI in a regional Danish surgical cohort. METHODS: We identified adults who underwent cardiac surgery during 2006-11 using the Western Denmark Heart Registry. Presurgical medication use, pre- and post-surgical serum creatinine (sCr) measures, and other patient characteristics were obtained from Danish population-based registries. Post-surgical AKI was assessed using sCr measures within 5 days of surgery. The adjusted risk ratio (RR) of AKI and 95% confidence interval (CI) were estimated for patients who initiated a statin within 100 days prior to surgery compared with patients without prior statin use; long-term statin users were excluded to reduce healthy-user bias. Subanalyses were stratified by surgery type: coronary artery bypass grafting (CABG) and non-CABG surgeries. RESULTS: We identified 1929 CABG and 1775 non-CABG patients. AKI occurred in 25% of CABG and 28% of non-CABG surgeries, and in 29% of the non-users and 21% of the statin initiators. Half of CABG patients and 9% of non-CABG patients initiated a statin prior to surgery. The adjusted RRs for the effect of statin initiation on AKI were as follows: all surgeries combined, RR = 0.86 (95% CI: 0.74, 0.98); CABG, RR = 0.88 (0.74, 1.05); non-CABG RR = 0.87 (0.68, 1.11). CONCLUSIONS: Presurgical statin initiation is associated with a reduction in AKI risk after cardiac surgery.

Comparative Short-term Safety of Sodium Ferric Gluconate Versus Iron Sucrose in Hemodialysis Patients.

BACKGROUND: Despite different pharmacologic properties, little is known about the comparative safety of sodium ferric gluconate versus iron sucrose in hemodialysis patients. STUDY DESIGN: Retrospective cohort study using the clinical database of a large dialysis provider (2004-2005) merged with administrative data from the US Renal Data System. SETTING & PARTICIPANTS: 66,207 patients with Medicare coverage who received center-based hemodialysis. PREDICTORS: Iron formulation use assessed during repeated 1-month exposure periods (n=278,357). OUTCOMES: All-cause mortality, infection-related hospitalizations and mortality, and cardiovascular-related hospitalizations and mortality occurring during a 3-month follow-up period. MEASUREMENTS: For all outcomes, we estimated 90-day risk differences between the formulations using propensity score weighting of Kaplan-Meier functions, which controlled for a wide range of demographic, clinical, and laboratory variables. Risk differences were also estimated within various clinically important subgroups. RESULTS: Ferric gluconate was administered in 11.4%; iron sucrose, in 48.9%; and no iron in 39.7% of the periods. Risks for most study outcomes did not differ between ferric gluconate and iron sucrose; however, among patients with a hemodialysis catheter, use of ferric gluconate was associated with a slightly decreased risk for both infection-related death (risk difference, -0.3%; 95% CI, -0.5% to 0.0%) and infection-related hospitalization (risk difference, -1.5%; 95% CI, -2.3% to -0.6%). Bolus dosing was associated with an increase in infection-related events among both ferric gluconate and iron sucrose users. LIMITATIONS: Residual confounding and outcome measurement error. CONCLUSIONS: Overall, the 2 iron formulations studied exhibited similar safety profiles; however, ferric gluconate was associated with a slightly decreased risk for infection-related outcomes compared to iron sucrose among patients with a hemodialysis catheter. These associations should be explored further using other data or study designs.

Comparative Effectiveness of Iron and Erythropoiesis-Stimulating Agent Dosing on Health-Related Quality of Life in Patients Receiving Hemodialysis.

BACKGROUND: The potential effects of iron-dosing strategies and erythropoiesis-stimulating agents (ESAs) on health-related quality of life (HRQoL) in the dialysis population are unclear. We examined the independent associations of bolus versus maintenance iron dosing and high versus low ESA dosing on HRQoL. STUDY DESIGN: Retrospective cohort design. SETTING & PARTICIPANTS: Clinical data (2008-2010) from a large dialysis organization merged with data from the US Renal Data System. 13,039 patients receiving center-based hemodialysis were included. PREDICTOR: Iron and ESA dosing were assessed during 1-month (n=14,901) and 2-week (n=15,296) exposure periods. OUTCOMES: HRQoL was measured by the Kidney Disease Quality of Life (KDQOL) instrument (0-100 scale) during a 3-month follow-up period. MEASUREMENTS: Generalized linear mixed models, adjusting for several covariates, were used to estimate associations between iron and ESA dosing and HRQoL overall and for clinically relevant subgroups. RESULTS: For the 1-month exposure period, patients with lower baseline hemoglobin levels who received higher ESA dosing had higher physical health and kidney disease symptom scores (by 2.4 [95% CI, 0.6-4.2] and 5.6 [95% CI, 2.8-8.4] points, respectively) in follow-up than patients who received lower ESA dosing. For the 2-week exposure period, patients with low baseline hemoglobin levels who received bolus dosing had higher mental health scores (by 1.9 [95% CI, 0.0-3.8] points) in follow-up. Within the low-baseline-hemoglobin subgroup, individuals with a catheter or dialysis vintage less than 1 year who received higher ESA dosing had higher HRQoL scores in follow-up (by 5.0-9.9 points) and individuals with low baseline transferrin saturations who received bolus dosing had higher HRQoL scores in follow-up (by 2.6-5.8 points). LIMITATIONS: Observational design; short duration of observation. CONCLUSIONS: For individuals with low baseline hemoglobin levels, higher ESA dosing and bolus iron dosing were associated with slightly higher HRQoL scores in follow-up. These differences became more pronounced and clinically relevant for specific subgroups.

Trends in Anemia Management in Hemodialysis Patients with Cancer.

BACKGROUND: Erythropoiesis-stimulating agents (ESAs), intravenous iron, and blood transfusion are used to treat anemia in both end-stage renal disease (ESRD) and cancer. However, anemia treatment patterns have not been described among ESRD patients undergoing hemodialysis with concurrent cancer, especially in the recent era of ESA-related safety concerns. METHODS: We analyzed Medicare data from a cohort of hemodialysis patients diagnosed with incident cancer. We used multivariable generalized linear models to estimate trends and patterns in ESA use, iron use, transfusion use, epoetin alfa (EPO) dose, iron dose, and resulting hemoglobin levels (2000-2011). RESULTS: Of 43,760 eligible patients, quarterly ESA use declined slightly from a peak of 94.1 to 90.0%. Quarterly EPO dose increased from 2000 to 2004, then declined; quarterly hemoglobin levels followed a similar pattern. Iron use increased rapidly from 46.9 to 79.3%. Iron dose increased until 2010 and then declined. There was an increase in the quarterly transfusion use (6.3-11.7%) and in the mean number of transfusion days per year (1.4-1.8). Anemia treatment patterns varied by demographic/clinical subgroups, especially among patients receiving chemotherapy, who required higher ESA use, EPO dose, and frequency of transfusions. CONCLUSIONS: Despite safety concerns about ESAs in both the ESRD and cancer populations, the proportion of hemodialysis patients with cancer who used ESAs between 2000 and 2011 remained extremely high. EPO dose and hemoglobin levels increased and then decreased. Iron use, iron dose, and transfusions increased substantially. Future research examining the risk-benefit profile of different anemia management strategies in the dialysis population with cancer is needed.