Altered consciousness mediates the effect of hypernatremia, but not hyponatremia, on mortality among patients observed in the ICU.

Purpose: Dysnatremias - hypernatremia and hyponatremia - may be associated with mortality through their impact on altered consciousness. We examined the mediating effect of decreased consciousness on the relationship between dysnatremia and mortality. Methods: Among 195,568 critically ill patients in the United States contained in the eICU database, we categorized serum sodium into bands of 5mEq/L. Using causal mediation analysis, we compared bands in the hypernatremia and hyponatremia ranges to a reference band of 135-139mEq/L to determine the proportion of mortality mediated by decreased consciousness as determined by the Glasgow Coma Score (GCS). Results: Both hyponatremia (OR [95%CI] for bands: <120mEq/L: 1.58 [1.26-1.97]; 120-<125mEq/L: 1.92 [1.64-2.25]; 125-<130mEq/L: 1.76 [1.60-1.93]; 130-<135mEq/L: 1.32 [1.24-1.41]) and hypernatremia (OR [95%CI] for bands: 140-<145mEq/L: 1.12 [1.05-1.19]; 145-<150mEq/L: 1.89 [1.70-2.11]; ≥150mEq/L: 1.86 [1.57-2.19]) were significantly associated with increased mortality. GCS mediated the effect of hypernatremia on mortality risk (Proportion mediated [95%CI]: 140-144mEq/L: 0.38 [0.23 to 0.89]; 145-149mEq/L: 0.27 [0.22 to 0.34]; ≥150mEq/L: 0.53 [0.41 to 0.81]) but not hyponatremia (proportion mediated 95%CI upper bound <0.05 for all bands). Conclusion: Decreased consciousness mediates the association between increased mortality and hypernatremia, but not hyponatremia. Further studies are needed to explore neurologic mechanisms and directionality in this relationship.

Susceptibility to Environmental Heavy Metal Toxicity among Americans with Kidney Disease.

Background: The consequences of low levels of environmental heavy metal exposure, as found widely in the United States, in those with impaired renal function remain underexplored. Methods: We examined the cross-sectional association of indices of renal function with lead and cadmium levels in blood and urine among National Health and Nutrition Examination Survey (NHANES) participants. We used the 1999-2002 cycle, which included measures of cystatin C, in order to quantify renal function most precisely and defined chronic kidney disease (CKD) as an estimated glomerular filtration rate (eGFR) <60 ml/min per 1.73 m2. Results: In weighted and adjusted analyses of 5638 participants, lead levels were 0.23 (95% CI, 0.03 to 0.42) µg/dl higher among participants with CKD, and 0.05 (95% CI, 0.01 to 0.09) µg/dL higher per 10 ml/min per 1.73 m2 lower eGFR. Cadmium levels were 0.02 (95% CI, 0.01 to 0.03) µg/L higher per 10 ml/min per 1.73 m2 lower eGFR. Black race significantly modified the association of lower eGFR with higher circulating lead levels (P interaction <0.001). A 10 ml/min per 1.73 m2 lower eGFR was associated with a 0.13 (95% CI, 0.06 to 0.21) µg/dl higher lead level among Black participants compared with 0.03 (95% CI, -0.04 to 0.11) µg/dl higher level among White participants. Among the 1852 participants with urinary metal measurements, despite higher circulating levels, those with CKD had significantly lower urinary lead levels (-0.16 [95% CI, -0.30 to -0.01] ng/ml) and urinary lead/creatinine ratios (-0.003 [95% CI, -0.004 to -0.001]). Conclusions: CKD is associated with higher blood lead levels, particularly among Blacks, and simultaneously, lower urinary lead levels, consistent with the hypothesis that CKD confers a state of heighted susceptibility to heavy metal environmental exposure by reducing its elimination. Given that low levels of exposure remain highly prevalent in the United States, further efforts to protect patients with CKD from heavy metal toxicity may be warranted.

Levels of Lead in Residential Drinking Water and Iron Deficiency among Patients with End Stage Kidney Disease.

Background: Although those with kidney disease may have heightened susceptibility to heavy metal toxicity, whether low levels of drinking water lead contamination have clinical consequence is unknown. Methods: Given that lead toxicity is known to associate with iron deficiency, we merged data from the Environmental Protection Agency (EPA) Safe Drinking Water Information and United States Renal Data Systems to examine whether municipal 90th percentile drinking water lead levels associate with iron deficiency among incident dialysis patients. Iron deficiency was defined across thresholds of transferrin saturation (<10% and 20%) and ferritin (<100 and <200 ng/ml), and simultaneous transferrin saturation <20% and ferritin <200 ng/ml, all obtained within 30 days of dialysis initiation. The average 90th percentile of drinking water lead samples per patient city of residence over a 5-year period before dialysis initiation was examined at the <1 µg/L level of detection, and at the 25th, 50th, and 100th percentile of the EPA's actionable level (15 µg/L). Results: Among 143,754 incident ESKD patients, those in cities with drinking water lead contamination had 1.06 (95% CI, 1.03 to 1.09), 1.06 (95% CI, 1.02 to 1.10), and 1.07 (95% CI, 1.03 to 1.11) higher adjusted odds of a transferrin saturation <20%, ferritin <200 ng/ml, and simultaneous transferrin saturation <20% and ferritin <200 ng/ml, respectively. These associations were apparent across the range of lead levels found commonly in the United States and were significantly greater among Black patients (multiplicative interaction P values between lead and race <0.05). Conclusions: Even exposure to low levels of lead contamination, as commonly found in US drinking water, may have adverse hematologic consequence in patients with advanced kidney disease. These associations are particularly evident among Black people and, although consistent with other environmental injustices facing minorities in the United States, might reflect a greater susceptibility to lead intoxication.

Role of renal function in the association of drinking water fluoride and plasma fluoride among adolescents in the United States: NHANES, 2013-2016.

CONTEXT: While fluoride has been added to drinking water and dental products for decades in order to prevent tooth decay, there are growing concerns about its potential toxicity. Given that fluoride is primarily excreted in urine, an important question that has not been examined is whether among those whose drinking water is fluoridated, impaired renal function is associated with higher levels of circulating fluoride. OBJECTIVE: To examine the association between drinking water and plasma fluoride and its modification by renal function. DESIGN, SETTING, AND PARTICIPANTS: Participants in the National Health and Nutrition Examination Survey (NHANES) between 2013 and 2016 with measures of fluoride in plasma and drinking water and renal function. These measures were only available in adolescent age 12-19 years. OUTCOMES: Plasma fluoride levels and their modification by strata of renal function, measured by the estimated glomerular filtration rate (eGFR). RESULTS: Among 1841 healthy adolescents, a 10 ml/min/1.73 m (Penman et al., 1997) lower eGFR and a 1 mg/L higher drinking water fluoride concentration were associated with a 0.02 (95%CI -0.02, -0.03) umol/L and 0.23 (95%CI 0.15,0.30) umol/L higher adjusted plasma fluoride level, respectively. The association of water and plasma fluoride levels was most robust among those with lower renal function (multiplicative interaction p value < 0.001). For adolescents in the lowest eGFR quartile, a 1 mg/L higher drinking water fluoride concentration was associated with a 0.35 (95%CI 0.21,0.48) umol/L higher plasma fluoride level, compared to 0.20 (95%CI 0.14,0.26) umol/L in the highest eGFR quartile. Restriction to those with measurable plasma fluoride levels yielded similar results. CONCLUSIONS: Water fluoridation results in higher plasma fluoride levels in those with lower renal function. How routine water fluoridation may affect the many millions of Americans with Chronic Kidney Disease, who are particularly susceptible to heavy metal and mineral accumulation, needs to be further investigated.

Associations of Community Water Lead Concentrations with Hemoglobin Concentrations and Erythropoietin-Stimulating Agent Use among Patients with Advanced CKD.

BACKGROUND: Although patients with kidney disease may be particularly susceptible to the adverse health effects associated with lead exposure, whether levels of lead found commonly in drinking water are associated with adverse outcomes in patients with ESKD is not known. METHODS: To investigate associations of lead in community water systems with hemoglobin concentrations and erythropoietin stimulating agent (ESA) use among incident patients with ESKD, we merged data from the Environmental Protection Agency (EPA) Safe Drinking Water Information System (documenting average 90th percentile lead concentrations in community water systems during 5 years before dialysis initiation, according to city of residence) with patient-level data from the United States Renal Data System. RESULTS: Among 597,968 patients initiating dialysis in the United States in 2005 through 2017, those in cities with detectable lead levels in community water had significantly lower pre-ESKD hemoglobin concentrations and more ESA use per 0.01 mg/L increase in 90th percentile water lead. Findings were similar for the 208,912 patients with data from the first month of ESKD therapy, with lower hemoglobin and higher ESA use per 0.01 mg/L higher lead concentration. These associations were observed at lead levels below the EPA threshold (0.015 mg/L) that mandates regulatory action. We also observed environmental inequities, finding significantly higher water lead levels and slower declines over time among Black versus White patients. CONCLUSIONS: This first nationwide analysis linking EPA water supply records to patient data shows that even low levels of lead that are commonly encountered in community water systems throughout the United States are associated with lower hemoglobin levels and higher ESA use among patients with advanced kidney disease.

Use of Do-Not-Resuscitate Orders for Critically Ill Patients with ESKD.

BACKGROUND: Despite having high comorbidity rates and shortened life expectancy, patients with ESKD may harbor unrealistically optimistic expectations about their prognoses. Whether this affects resuscitation orders is unknown. METHODS: To determine whether do-not-resuscitate (DNR) orders differ among patients with ESKD compared with other critically ill patients, including those with diseases of other major organs, we investigated DNR orders on admission to intensive care units (ICUs) among 106,873 patients in the United States. RESULTS: Major organ disease uniformly associated with increased risk of hospital mortality, particularly for cirrhosis (adjusted odds ratio [aOR], 2.67; 95% confidence interval [95% CI], 2.30 to 3.08), and ESKD (aOR, 1.47; 95% CI, 1.31 to 1.65). Compared with critically ill patients without major organ disease, patients with stroke, cancer, heart failure, dementia, chronic obstructive pulmonary disease, and cirrhosis were statistically more likely to have a DNR order on ICU admission; those with ESKD were not. Findings were similar when comparing patients with a single organ disease with those without organ disease. The disconnect between prognosis and DNR use was most notable among Black patients, for whom ESKD (compared with no major organ disease) was associated with a 62% (aOR, 1.62; 95% CI, 1.27 to 2.04) higher odds of hospital mortality, but no appreciable difference in DNR utilization (aOR, 1.06; 95% CI, 0.66 to 1.62). CONCLUSIONS: Unlike patients with diseases of other major organs, critically ill patients with ESKD were not more likely to have a DNR order than patients without ESKD. Whether this reflects a greater lack of advance care planning in the nephrology community, as well as a missed opportunity to minimize potentially needless patient suffering, requires further study.

Racial and Ethnic Disparities in Seasonal Influenza Vaccination among Dialysis Facilities in the United States.

BACKGROUND: Racial and ethnic disparities in vaccination rates for seasonal influenza exist. Whether such disparities extend to patients with ESKD, who simultaneously are at risk for complications of infection and have extensive contact with health care providers, has not been investigated. METHODS: To determine whether the proportion of patients vaccinated at a dialysis facility differs according to the facility's racial and ethnic composition, we examined dialysis facility data reported to the Centers for Medicare and Medicaid Services. The main outcome was the proportion of facility patients vaccinated for influenza among 6735 Medicare-certified facilities operating between 2014 and 2017. RESULTS: Among dialysis facilities, the mean percentage of patients vaccinated during the influenza season was 72.1%. Facilities with higher proportions of Black and Hispanic patients had significantly lower vaccination percentages than less diverse facilities. The average proportion of patients vaccinated at each facility decreased significantly from 2014 to 2017 (a decrease of 1.05% vaccinated per year) and decreased significantly more so among facilities with higher minority proportions. The share of vaccinated patients in facilities in the quartile with the highest proportion of Black patients decreased 1.21% per year compared with a decrease of 0.88% per year in facilities in the quartile with the lowest proportion of Black patients. We found similar trends for Hispanic patients. CONCLUSIONS: Rates of seasonal influenza vaccination are modestly but significantly lower among dialysis facilities with larger proportions of minority patients, and the gap seems to be widening over time. As wide-scale vaccination efforts grow more urgent amid the current COVID-19 pandemic, these disparities must be addressed to protect patients and communities equitably.

Treatment in Disproportionately Minority Hospitals Is Associated With Increased Risk of Mortality in Sepsis: A National Analysis.

OBJECTIVES: Treatment in a disproportionately minority-serving hospital has been associated with worse outcomes in a variety of illnesses. We examined the association of treatment in disproportionately minority hospitals on outcomes in patients with sepsis across the United States. DESIGN: Retrospective cohort analysis. Disproportionately minority hospitals were defined as hospitals having twice the relative minority patient population than the surrounding geographical mean. Minority hospitals for Black and Hispanic patient populations were identified based on U.S. Census demographic information. A multivariate model employing a validated algorithm for mortality in sepsis using administrative data was used. SETTING: The National Inpatient Sample from 2008 to 2014. PATIENTS: Patients over 18 years of age with sepsis. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A total of 4,221,221 patients with sepsis were identified. Of these, 612,217 patients (14.5%) were treated at hospitals disproportionately serving the black community (Black hospitals), whereas 181,141 (4.3%) were treated at hospitals disproportionately serving the Hispanic community (Hispanic hospitals). After multivariate analysis, treatment in a Black hospital was associated with a 4% higher risk of mortality compared to treatment in a nonminority hospital (odds ratio, 1.04; 95% CI, 1.03-1.05; p < 0.01). Treatment in a Hispanic hospital was associated with a 9% higher risk of mortality (odds ratio, 1.09; 95% CI, 1.07-1.11; p < 0.01). Median hospital length of stay was almost 1 day longer at each of the disproportionately minority hospitals (nonminority hospitals: 5.9 d; interquartile range, 3.1-11.0 d vs Hispanic: 6.9 d; interquartile range, 3.6-12.9 d and Black: 6.7 d, interquartile range, 3.4-13.2 d; both p < 0.01). CONCLUSIONS: Patients with sepsis regardless of race who were treated in disproportionately high minority hospitals suffered significantly higher rates of in-hospital mortality.

Do Hyponatremia or Its Underlying Mechanisms Associate With Mortality Risk in Observational Data?

OBJECTIVES: Whether unaccounted determinants of hyponatremia, rather than water excess per se, primarily associate with mortality in observational studies has not been explicitly examined. DESIGN: Retrospective cohort study of the association between hyponatremia and mortality, stratified by outpatient diuretic use in three strata. SETTING: An inception cohort of 13,661 critically ill patients from a tertiary medical center. MEASUREMENTS AND MAIN RESULTS: Admission serum sodium concentrations, obtained within 12 hours of admission to the ICU, were the primary exposure. Hyponatremia was associated with 1.82 (95% CI, 1.56-2.11; p < 0.001) higher odds of mortality, yet differed according to outpatient diuretic use (multiplicative interaction between thiazide and serum sodium < 133 mEq/L; p = 0.002). Although hyponatremia was associated with a three-fold higher (odds ratio, 3.11; 95% CI, 2.32-4.17; p < 0.001) odds of mortality among those prescribed loop diuretics, no increase of risk was observed among thiazide diuretic users (odds ratio, 0.87; 95% CI, 0.47-1.51; p = 0.63). When examined as a continuous variable, each one mEq/L higher serum sodium was associated with 8% (odds ratio, 0.92; 95% CI, 0.90-0.94; p < 0.001) lower odds of mortality in loop diuretic patients and 5% (odds ratio, 0.95; 95% CI, 0.93-0.96, p < 0.001) lower in diuretic naïve patients, but was not associated with mortality risk among thiazide users (odds ratio, 0.99; 95% CI, 0.95-1.02; p = 0.45). CONCLUSIONS: Hyponatremia is not uniformly associated with increased mortality, but differs according to diuretic exposure. Our results suggest that the underlying pathophysiologic factors that lead to water excess, rather water excess itself, account in part for the association between hyponatremia and poor outcomes. More accurate estimations about the association between hyponatremia and outcomes might influence clinical decision-making.

Temporal Trends in Critical Care Outcomes in U.S. Minority-Serving Hospitals.

Rationale: Whether critical care improvements over the last 10 years extend to all hospitals has not been described.Objectives: To examine the temporal trends of critical care outcomes in minority and non-minority-serving hospitals using an inception cohort of critically ill patients.Measurements and Main Results: Using the Philips Health Care electronic ICU Research Institute Database, we identified minority-serving hospitals as those with an African American or Hispanic ICU census more than twice its regional mean. We examined almost 1.1 million critical illness admissions among 208 ICUs from across the United States admitted between 2006 and 2016. Adjusted hospital mortality (primary) and length of hospitalization (secondary) were the main outcomes. Large pluralities of African American (25%, n = 27,242) and Hispanic individuals (48%, n = 26,743) were cared for in minority-serving hospitals, compared with only 5.2% (n = 42,941) of white individuals. Over the last 10 years, although the risk of critical illness mortality steadily decreased by 2% per year (95% confidence interval [CI], 0.97-0.98) in non-minority-serving hospitals, outcomes within minority-serving hospitals did not improve comparably. This disparity in temporal trends was particularly noticeable among African American individuals, where each additional calendar year was associated with a 3% (95% CI, 0.96-0.97) lower adjusted critical illness mortality within a non-minority-serving hospital, but no change within minority-serving hospitals (hazard ratio, 0.99; 95% CI, 0.97-1.01). Similarly, although ICU and hospital lengths of stay decreased by 0.08 (95% CI, -0.08 to -0.07) and 0.16 (95% CI, -0.16 to -0.15) days per additional calendar year, respectively, in non-minority-serving hospitals, there was little temporal change for African American individuals in minority-serving hospitals.Conclusions: Critically ill African American individuals are disproportionately cared for in minority-serving hospitals, which have shown significantly less improvement than non-minority-serving hospitals over the last 10 years.

Acute Kidney Injury Associated With Human Granulocytic Anaplasmosis: A Case Report.

Tick-borne illnesses are a growing problem in the United States. Human granulocytic anaplasmosis (HGA), carried by the Ixodes scapularis tick, is caused by Anaplasma phagocytophilum. While the clinical manifestations of HGA may be protean, ranging from asymptomatic infection to life-threatening multiorgan failure, renal involvement is uncommon. We report a case of a 64-year-old man presenting with a febrile illness and acute nephritis in the setting of HGA infection. The patient's kidney biopsy was characterized by a membranoproliferative glomerulonephritis pattern and acute interstitial inflammation. After appropriate antibiotic treatment and high-dose steroids, the patient had a marked improvement in kidney function, although a subsequent recrudescence of nephritis required a 6-month course of additional steroids. As the prevalence of tick-borne diseases continues to spread across the United States, raising awareness of the potential for atypical presentations is important, particularly because early diagnosis and treatment can be curative and prevent further complications.

Magnesium and Drugs Commonly Used in Chronic Kidney Disease.

As with other electrolytes, magnesium homeostasis depends on the balance between gastrointestinal absorption and kidney excretion. Certain drugs used commonly in patients with CKD can decrease gastrointestinal ingestion and kidney reclamation, and potentially cause hypomagnesemia. Other magnesium-containing drugs such as laxatives and cathartics can induce hypermagnesemia, particularly in those with impaired glomerular filtration and magnesium excretion. In this review, we will discuss the potential magnesium complications associated with a range of commonly encountered drugs in the care of CKD patients, discuss the potential mechanisms, and provide basic clinical recommendations.

Marijuana Use and Renal Function Among US Adults.

BACKGROUND: In recent years, the number of states that have legalized medical marijuana or retail sales has increased, bringing potential changes of marijuana use pattern among the general population. However, health effects of acute and chronic marijuana use on many relevant health outcomes, including renal function, remain largely unexamined. In this study, we aimed to assess the association between recent and past marijuana use and renal function. METHODS: We conducted a cross-sectional study among 13,995 US adults aged 18 to 59 years in the National Health and Nutrition Examination Survey from 2007 to 2014. We examined associations between marijuana use and serum creatinine concentration, estimated glomerular filtration rate (eGFR), and odds of having stage 2 or greater chronic kidney disease using weighted multivariable linear regression. RESULTS: In the study population, 6483 were never users, 5499 were past users, and 2013 were current users. Marijuana use did not have a significant association with serum creatinine, eGFR, or odds of having stage 2 or greater chronic kidney disease. Serum creatinine and eGFR had an increasing trend comparing past and current users with never users that did not reach statistical significance. All associations remained unchanged in the sensitivity analysis restricted to people without cardiovascular disease. CONCLUSIONS: We did not observe any clinically significant association between current or past self-reported marijuana use and measures of kidney function.

Right Ventricular Function, Peripheral Edema, and Acute Kidney Injury in Critical Illness.

INTRODUCTION: The cardiorenal syndrome generally focuses on left ventricular function, and the importance of the right ventricle as a determinant of renal function is described less frequently. In a cohort of critically ill patients with echocardiographic measurements obtained within 24 hours of admission to the intensive care unit, we examined the association of right ventricular function with acute kidney injury (AKI) and AKI-associated mortality. We also examined whether clinical measurement of volume overload modified the association between ventricular function and AKI in a subpopulation with documented admission physical examinations. METHODS: Among 1879 critically ill patients with echocardiographic ventricular measurements, 43% (n = 807) had ventricular dysfunction-21% (n = 388), 9% (n = 167), and 13% (n = 252) with isolated left ventricular dysfunction, isolated right ventricular dysfunction, and biventricular dysfunction, respectively. Overall, ventricular dysfunction was associated with a 43% higher adjusted risk of AKI (95% confidence interval [CI] 1.14-1.80; P = 0.002) compared with those with normal biventricular function, whereas isolated left ventricular dysfunction, isolated right ventricular dysfunction, and biventricular dysfunction were associated with a 1.34 (95% CI 1.00-1.77, P = 0.05), 1.35 (95% CI 0.90-2.10, P = 0.14) and 1.67 (95% CI 1.23-2.31, P = 0.002) higher adjusted risk. Although an episode of AKI was associated with an approximately 2-fold greater risk of hospital mortality in those with isolated left ventricular dysfunction and biventricular dysfunction, in those with isolated right ventricular dysfunction, AKI was associated with a 7.85-fold greater risk of death (95% CI 2.89-21.3, P < 0.001). Independent of ventricular function, peripheral edema was an important determinant of AKI. DISCUSSION: Like left ventricular function, right ventricular function is an important determinant of AKI and AKI-associated mortality. Volume overload, independently of ventricular function, is a risk factor for AKI. Whether establishment of euvolemia might mitigate AKI risk will require further study.

Circulating Des-gamma-carboxy prothrombin is not associated with cardiovascular calcification or stiffness: The Multi-Ethnic Study of Atherosclerosis (MESA).

BACKGROUND AND AIMS: Vitamin K-dependent protein (VKDP) activity may have a role in preventing cardiovascular calcification, but has not previously been studied in large, generally healthy populations. METHODS: Using an elevated ankle-brachial index (ABI) as a measure of medial vascular calcification, we performed a case-cohort analysis within the Multi-Ethnic Study of Atherosclerosis, measuring Des-gamma-carboxy prothrombin (DCP) to estimate VKDP activity. In secondary analyses of the weighted subcohort, we examined the cross-sectional associations between DCP and prevalent vascular calcification of the coronary vessels, aortic and mitral valves, and aortic wall, and with vascular stiffness. RESULTS: In adjusted analysis, cases (n = 104) had 0.21 ng/ml (-0.94-0.52) lower DCP concentrations than the subcohort (n = 613). Furthermore, amongst the 717 participants in the weighted cohort, VKDP activity was not associated with coronary artery, mitral valve, aortic valve or aortic wall calcification, nor was it associated with vascular stiffness. CONCLUSIONS: Our negative results do not support a role of circulating VKDP activity in cardiovascular calcification in community-dwelling adults.