Spectrum and Burden of Erythropoiesis-Stimulating Agent Hyporesponsiveness Among Contemporary Hemodialysis Patients.

BACKGROUND: Hemodialysis patients with erythropoiesis-stimulating agent (ESA) hyporesponsiveness have been a topic of active research. However, there have been no studies of ESA hyporesponsiveness among US patients following the dramatic change in anemia management that resulted from the 2011 changes in ESA product labeling and bundling of dialysis remuneration. STUDY DESIGN: Retrospective observational study. SETTING & PARTICIPANTS: We studied prevalent hemodialysis patients treated at a large dialysis organization in calendar years 2012 to 2013 (N=98,972). PREDICTOR: ESA hyporesponsiveness, defined as 2 consecutive hemoglobin measurements < 10g/dL (every other week) with contemporaneous ESA dose > 7,700U/treatment. Patients with ESA hyporesponsiveness were identified during the first quarter of 2012 and followed up through 2013 using intention-to-treat principles. OUTCOMES: Associations between the study exposure (ESA hyporesponsiveness) and mortality, missed hemodialysis treatments, ESA and iron use, and hemoglobin levels were determined using generalized estimating equations adjusting for imbalanced baseline covariates. RESULTS: At baseline, 12,361 (12.5%) patients were identified as having ESA hyporesponsiveness. The mean hemoglobin level among patients with ESA hyporesponsiveness was ∼1g/dL lower than in patients without ESA hyporesponsiveness at baseline, narrowing over follow-up to 0.4g/dL. Initially, mean ESA use was approximately 3-fold greater for patients with ESA hyporesponsiveness than for those without ESA hyporesponsiveness, decreasing to 2-fold greater at study end; iron use and missed hemodialysis treatment rates were also greater among patients with ESA hyporesponsiveness throughout. ESA hyporesponsiveness was associated with enhanced mortality risk versus non-ESA hyporesponsiveness: adjusted incidence rate ratios were estimated at 2.24 (95% CI, 1.93-2.60) in the second quarter, gradually decreasing to 1.48 (95% CI, 1.18-1.84) by study end. LIMITATIONS: It is possible that an alternative ESA hyporesponsiveness definition may be optimal. As such, the associations we observed may be conservative estimates of true relationships. CONCLUSIONS: When using a contemporary definition at one point in time, ESA hyporesponsiveness was potently and persistently associated with greater mortality, greater iron and ESA use, and lower hemoglobin levels compared to non-ESA hyporesponsiveness.

Association between Serum Potassium and Outcomes in Patients with Reduced Kidney Function.

BACKGROUND AND OBJECTIVES: Patients with CKD are more likely than others to have abnormalities in serum potassium (K(+)). Aside from severe hyperkalemia, the clinical significance of K(+) abnormalities is not known. We sought to examine the association of serum K(+) with mortality and hospitalization rates within narrow eGFR strata to understand how the burden of hyperkalemia varies by CKD severity. Associations were examined between serum K(+) and discontinuation of medications that block the renin-angiotensin-aldosterone system (RAAS), which are known to increase serum K(+). DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A cohort of patients with CKD (eGFR<60 ml/min per 1.73 m(2)) with serum K(+) data were studied (n=55,266) between January 1, 2009, and June 30, 2013 (study end). Serum K(+), eGFR, and covariates were considered on a time-updated basis. Mortality, major adverse cardiovascular events (MACE), hospitalization, and discontinuation of RAAS blockers were considered per time at risk. RESULTS: During the study, serum K(+) levels of 5.5-5.9 and ≥6.0 mEq/L were most prevalent at lower eGFR: they were present, respectively, in 1.7% and 0.2% of patient-time for eGFR of 50-59 ml/min per 1.73 m(2) versus 7.6% and 1.8% of patient-time for eGFR<30 ml/min per 1.73 m(2). Serum K(+) level <3.5 mEq/L was present in 1.2%-1.4% of patient-time across eGFR strata. The median follow-up time was 2.76 years. There was a U-shaped association between serum K(+) and mortality; pooled adjusted incidence rate ratios were 3.05 (95% confidence interval, 2.53 to 3.68) and 3.31 (95% confidence interval, 2.52 to 4.34) for K(+) levels <3.5 mEq/L and ≥6.0 mEq/L, respectively. Within eGFR strata, there were U-shaped associations of serum K(+) with rates of MACE, hospitalization, and discontinuation of RAAS blockers. CONCLUSIONS: Both hyperkalemia and hypokalemia were independently associated with higher rates of death, MACE, hospitalization, and discontinuation of RAAS blockers in patients with CKD who were not undergoing dialysis. Future studies are needed to determine whether interventions targeted at maintaining normal serum K(+) improve outcomes in this population.

A retrospective, longitudinal study estimating the association between interdialytic weight gain and cardiovascular events and death in hemodialysis patients.

BACKGROUND: Greater interdialytic weight gain (IDWG) is associated with risk of all-cause mortality and hospitalization. Dialysis patients are also at greater risk of cardiovascular (CV) events than patients without kidney disease. This retrospective study examined the potential association between IDWG and specific types of CV events. METHODS: Data were obtained from United States Renal Data System claims and the electronic health records of Medicare patients who initiated hemodialysis between 01 January 2007 and 31 December 2008 at a large dialysis organization. Absolute IDWG was defined as predialysis weight minus postdialysis weight from the prior treatment, and relative IDWG was calculated as percentage of postdialysis weight with mean values for each, calculated over dialysis days 91 to 180. Patient outcomes were considered beginning on day 181, continuing until death, discontinuation of care, censoring, or study end (31 December 2009). Outcomes included all-cause mortality, CV mortality, hospitalization for nonfatal heart failure/volume overload, hospitalization for nonfatal myocardial infarction, MACE (a composite measure of nonfatal myocardial infarction, nonfatal ischemic stroke, or CV death), and MACE+ (events comprising MACE as well as arrhythmia, nonfatal hemorrhagic stroke, or hospitalization for heart failure). Associations between IDWG and outcomes over the exposure period were estimated using proportional hazards regression and adjusted for baseline characteristics. RESULTS: 39,256 patients qualified for analysis. In general, associations of relative IDWG with outcomes were more potent, consistent, and monotonic than those for absolute IDWG. Relative IDWG > 3.5 % body weight was independently associated with all outcomes studied: point estimates ranged from 1.18 (myocardial infarction) to 1.26 (CV mortality) and were consistent among patients with and without diabetes, and with and without baseline heart failure. Absolute IDWG > 3 kg was associated with outcomes other than myocardial infarction: point estimates ranged from 1.11 (MACE) to 1.20 (heart failure). CONCLUSIONS: Greater IDWG is associated with an increased risk of CV morbid events. Strategies that mitigate IDWG may improve CV health and survival among hemodialysis patients.

Intradialytic hypotension and risk of cardiovascular disease.

BACKGROUND AND OBJECTIVES: Patients undergoing hemodialysis have an elevated risk of cardiovascular disease-related morbidity and mortality compared with the general population. Intradialytic hypotension (IDH) is estimated to occur during 20%-30% of hemodialysis sessions. To date, no large studies have examined whether IDH is associated with cardiovascular outcomes. This study determined the prevalence of IDH according to interdialytic weight gain (IDWG) and studied the association between IDH and outcomes for cardiovascular events and mortality to better understand its role. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This study retrospectively examined records of 39,497 hemodialysis patients during 2007 and 2008. US Renal Data System claims and dialysis provider data were used to determine outcomes. IDH was defined by current Kidney Disease Outcomes Quality Initiative guidelines (≥20 mmHg fall in systolic BP from predialysis to nadir intradialytic levels plus ≥2 responsive measures [dialysis stopped, saline administered, etc.]). IDWG was measured absolutely (in kilograms) and relatively (in percentages). RESULTS: IDH occurred in 31.1% of patients during the 90-day exposure assessment period. At baseline, the higher the IDWG (relative or absolute), the greater the frequency of IDH (P<0.001). For all-cause mortality, the median follow-up was 398 days (interquartile range, 231-602 days). Compared with patients without IDH, IDH was associated with all-cause mortality (7646 events; adjusted hazard ratio, 1.07 [95% confidence interval, 1.01 to 1.14]), myocardial infarction (2396 events; 1.20 [1.10 to 1.31]), hospitalization for heart failure/volume overload (8896 events; 1.13 [1.08 to 1.18]), composite hospitalization for heart failure/volume overload or cardiovascular mortality (10,805 events; 1.12 [1.08 to 1.17]), major adverse cardiac events (MACEs; myocardial infarction, stroke, cardiovascular mortality) (4994 events, 1.10 [1.03 to 1.17]), and MACEs+ (MACEs plus arrhythmia or hospitalization for heart failure/volume overload) (12,221 events; 1.14 [1.09 to 1.19]). CONCLUSIONS: IDH was potently associated with cardiovascular morbidity and mortality. Clinical trials to ascertain causality are needed and should consider reduction in IDWG as a potential means to reduce IDH.