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Purpose of Review: While high levels of lead exposure, as occurs accidentally or occupationally, can cause toxicity across multiple organ systems, the hazard of commonly encountered levels of lead in the environment remains unresolved. Challenges to researching the health effects of lead include its complex interplay with renal function, rendering analyses at risk of unaccounted confounding, and the likely small effect size of environmental levels of exposure. While children are known to be disproportionately susceptible to lead toxicity, resulting in appropriately more stringent regulatory surveillance for those under 5 years old, emerging evidence suggests that those with chronic kidney disease (CKD) similarly are at a greater risk. This review summarizes the role of environmental lead toxicity as a potential cause and consequence of CKD., Recent Findings: Whether environmental lead exposure causes CKD remains debatable, with little recent research advancing the conflicting, mostly cross-sectional, analyses from years ago. However, an emerging body of evidence suggests that CKD increases the susceptibility to lead toxicity. Higher circulating lead levels and lower urinary excretion result in greater lead accumulation in CKD, with simultaneous greater risk of clinically meaningful disease. Recent studies suggest that levels of lead found commonly in the United States drinking water supply, and currently permissible by the Environmental Protection Agency, associate with hematologic toxicity in those with advanced CKD. Whether environmental lead contamination may have additional negative health impact among this at-risk population, including cardiovascular and neurocognitive disease, warrants further study., Summary: The underlying pathophysiology of kidney disease synergizes the susceptibility to environmental lead toxicity for those with CKD. Low levels of exposure, as found commonly in the United States water supply, may have adverse health impact in CKD. Further research will be needed to determine if more stringent environmental regulations are warranted to protect the health of all., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Importance: The consequences of low levels of environmental lead exposure, as found commonly in US household water, have not been established., Objective: To examine whether commonly encountered levels of lead in household water are associated with hematologic toxicity among individuals with advanced kidney disease, a group known to have disproportionate susceptibility to environmental toxicants., Design, Setting, and Participants: Cross-sectional analysis of household water lead concentrations and hematologic outcomes was performed among patients beginning dialysis at a Fresenius Medical Care outpatient facility between January 1, 2017, and December 20, 2021. Data analysis was performed from April 1 to August 15, 2023., Exposure: Concentrations of lead in household water were examined in categorical proportions of the Environmental Protection Agency's allowable threshold (15 μg/L) and continuously., Main Outcomes and Measures: Hematologic toxic effects were defined by monthly erythropoiesis-stimulating agent (ESA) dosing during the first 90 days of incident kidney failure care and examined as 3 primary outcomes: a proportion receiving maximum or higher dosing, continuously, and by a resistance index that normalized to body weight and hemoglobin concentrations. Secondarily, hemoglobin concentrations for patients with data prior to kidney failure onset were examined, overall and among those with concurrent iron deficiency, thought to increase gastrointestinal absorption of ingested lead., Results: Among 6404 patients with incident kidney failure (male, 4182 [65%]; mean [SD] age, 57 [14] years) followed up for the first 90 days of dialysis therapy, 12% (n = 742) had measurable lead in household drinking water. A higher category of household lead contamination was associated with 15% (odds ratio [OR], 1.15 [95% CI, 1.04-1.27]) higher risk of maximum monthly ESA dosing, 4.5 (95% CI, 0.8-8.2) μg higher monthly ESA dose, and a 0.48% (95% CI, 0.002%-0.96%) higher monthly resistance index. Among patients with pre-kidney failure hemoglobin measures (n = 2648), a higher household lead categorization was associated with a 0.12 (95% CI, -0.23 to -0.002) g/dL lower hemoglobin concentration, particularly among those with concurrent iron deficiency (multiplicative interaction, P = .07), among whom hemoglobin concentrations were 0.25 (95% CI, -0.47 to -0.04) g/dL lower., Conclusion: The findings of this study suggest that levels of lead found commonly in US drinking water may be associated with lead poisoning among susceptible individuals.

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., (Copyright © 2022 Elsevier Inc. All rights reserved.)

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 m 2 ., Results: In weighted and adjusted analyses of 5638 participants, lead levels were 0.23 (95% CI, 0.03 to 0.42) μ g/dl higher among participants with CKD, and 0.05 (95% CI, 0.01 to 0.09) μ g/dL higher per 10 ml/min per 1.73 m 2 lower eGFR. Cadmium levels were 0.02 (95% CI, 0.01 to 0.03) μ g/L higher per 10 ml/min per 1.73 m 2 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 m 2 lower eGFR was associated with a 0.13 (95% CI, 0.06 to 0.21) μ g/dl higher lead level among Black participants compared with 0.03 (95% CI, -0.04 to 0.11) μ g/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., Competing Interests: J. Danziger reports consultancy for Healthmap Solutions; ownership interest in Healthmap Solutions; and is the regional medical director for Healthmap Solutions. H. Hu reports ownership interest in Advanced Micro Devices, Alphabet, Amazon, Appian Corp., Apple, Costco, Disney, Enphase Energy, Innovative INDL, Kinsale CAP Group, Micron Technology, Netflix, NVIDIA, NOVONIX, Pershing Square, Qualcomm, Taiwan Semiconductor, Wells Fargo, and Zoom; and is Chair of the Scientific Advisory Board for the Marilyn Brachman Hoffman Foundation. K.J. Mukamal reports other interests or relationships with the US Highbush Blueberry Council and Wolters Kluwer. The remaining author has nothing to disclose., (Copyright © 2022 by the American Society of Nephrology.)

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 μ g/L level of detection, and at the 25th, 50th, and 100th percentile of the EPA's actionable level (15 μ g/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., Competing Interests: J. Danziger reports consultancy for Healthmap Solutions; ownership interest in Healthmap Solutions; and is the regional medical director at Healthmap Solutions. K.J. Mukamal reports other interests or relationships with US Highbush Blueberry Council and Wolters Kluwer., (Copyright © 2022 by the American Society of Nephrology.)

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 90 th 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 90 th 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., (Copyright © 2021 by the American Society of Nephrology.)

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., (Copyright © 2020 by the American Society of Nephrology.)

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., (Copyright © 2020 by the American Society of Nephrology.)

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.

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.

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., Competing Interests: The authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2020 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine.)

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., (Copyright © 2019 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

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., (Copyright © 2018 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

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., (Copyright © 2018 Elsevier Inc. All rights reserved.)

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.

Recent epidemiologic data linking proton pump inhibitor (PPI) use to acute and chronic kidney dysfunction is yet to be validated in other populations, and mechanisms have not been explored. Using a large, well phenotyped inception cohort of 15 063 critically ill patients, we examined the risk of acute kidney injury (AKI), as defined by the Kidney Disease Improving Global Outcomes criteria guidelines, according to prior use of a PPI, histamine-2 receptor antagonist (H 2 RA), or neither. A total of 3725 (24.7%) patients reported PPI use prior to admission, while 905 (6.0%) patients reported H 2 RA use. AKI occurred in 747 (20.0%) and 163 (18.0%) of PPI and H 2 RA users respectively, compared to 1712 (16.2%) of those not taking acid suppressive medications. In unadjusted analysis, PPI and H 2 RA users had a 28% (95%CI 1.17-1.41, P < .001) and 10% (95%CI 0.91-1.30, P = .31) higher risk of AKI compared to those taking neither class of medication. However, in sequential models that included adjustment for demographics, cardiovascular comorbidities, indications for PPI use, and severity of illness, the effect of PPI on the risk of AKI was attenuated, and in the adjusted analysis, PPI was not associated with AKI (OR 1.02; 95%CI 0.91-1.13, P = .73). The presence of sterile pyuria and hypomagnesemia did not modify the association between PPI use and AKI. In summary, after adjustment for demographics, illness severity, and the indication for PPI use, PPI use prior to admission is not associated with critical illness AKI., Competing Interests: The contributing authors declare that there was no conflict of interest., (© 2016, The American College of Clinical Pharmacology.)

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., (Copyright © 2016. Published by Elsevier Ireland Ltd.)

The association of proton-pump inhibitor (PPI) use and hypomagnesemia has garnered much attention over the last 5 years. A large body of observational data has linked chronic PPI use with hypomagnesemia, presumably due to decreased intestinal absorption and consequent magnesium deficiency. However, despite the increasing prevalence of this highly popular class of medicine, and despite potential significant risks associated with magnesium depletion, including cardiac arrhythmias and seizures, there are no well-designed studies to delineate the nature of this observed association. Consequently, providers must use best judgment to inform clinical decision making. This review summarizes the current body of evidence linking PPI use with hypomagnesemia, acknowledges the possibility of significant residual confounding in the observational data, explains potential physiologic mechanisms, and offers clinical recommendations., (© 2015, The American College of Clinical Pharmacology.)

Objective: Vitamin K-dependent proteins (VKDPs), which require post-translational modification to achieve biological activity, seem to contribute to thrombus formation, vascular calcification, and vessel stiffness. Whether VKDP activity is prospectively associated with incident cardiovascular disease has not been studied., Approach and Results: VKDP activity was determined by measuring circulating des-γ-carboxy prothrombin concentrations in a random sample of 709 multiethnic adults free of cardiovascular disease drawn from the Multi-Ethnic Study of Atherosclerosis (MESA). Lower des-γ-carboxy prothrombin concentrations reflect greater VKDP activity. Subjects were followed up for the risk of ischemic cardiovascular disease (coronary heart disease, stroke, and fatal cardiovascular disease) for 11.0 years of follow-up. A total of 75 first ischemic CVD events occurred during follow-up. The incidence of ischemic cardiovascular disease increased progressively across des-γ-carboxy prothrombin quartiles, with event rates of 5.9 and 11.7 per 1000 person-years in the lowest and highest quartiles. In analyses adjusted for traditional cardiovascular risk factors and measures of vitamin K intake, a doubling of des-γ-carboxy prothrombin concentration was associated with a 1.53 (95% confidence interval, 1.09-2.13; P=0.008) higher risk of incident ischemic cardiovascular disease. The association was consistent across strata of participants with diabetes mellitus, hypertension, renal impairment, and low vitamin K nutritional intake., Conclusions: In this sample of middle-aged and older adults, VKDP activity was associated with incident ischemic cardiovascular events. Further studies to understand the role of this large class of proteins in cardiovascular disease are warranted., (© 2016 American Heart Association, Inc.)

Rationale: The clinical significance of peripheral edema has not been well described in critical illness., Objectives: To assess the clinical significance of peripheral edema detected on physical examination at the time of hospital admission for patients who were treated in an intensive care unit (ICU)., Methods: Using a large inception cohort of critically ill patients, we examined the association of peripheral edema, as documented on hospital admission physical examination, with hospital and 1-year survival., Measurements and Main Results: Of 12,778 patients admitted to an ICU at a teaching hospital in Boston, Massachusetts, 2,338 (18%) had peripheral edema. Adjusting for severity of illness and comorbidities, including pulmonary edema, admission peripheral edema was associated with a 26% (95% confidence interval [CI] = 1.11-1.44, P < 0.001) higher risk of hospital mortality. In those patients whose peripheral edema could be graded, trace, 1+, 2+, and 3+ admission peripheral edema was associated with a 2% (95% CI = 0.80-1.31, P = 0.89), 17% (95% CI = 1.00-1.56, P = 0.05), 60% (95% CI = 1.26-2.04, P < 0.001), and 54% (95% CI = 1.04-2.29, P = 0.03) higher adjusted risk of hospital mortality, respectively, compared with patients without edema. The association was consistent across strata of patients with diabetes, congestive heart failure, sepsis, and premorbid diuretic or calcium channel blocker use. In a subset of patients with central venous pressures measurements obtained within 6 hours of ICU admission, the highest central venous pressure quartile (>13 cm H2O) was similarly associated with a 35% (95% CI = 1.05-1.75, P = 0.02) higher adjusted risk of hospital mortality compared with the lowest quartile (≤7 cm H2O)., Conclusions: Peripheral edema, as detected on physical examination at the time of hospital admission, is a poor prognostic indicator in critical illness. Whether peripheral edema simply reflects underlying pathophysiology, or has an independent pathogenic role, will require further interventional studies.

Background and Objectives: Although venous congestion has been linked to renal dysfunction in heart failure, its significance in a broader context has not been investigated., Design, Setting, Participants, & Measurements: Using an inception cohort of 12,778 critically ill adult patients admitted to an urban tertiary medical center between 2001 and 2008, we examined whether the presence of peripheral edema on admission physical examination was associated with an increased risk of AKI within the first 7 days of critical illness. In addition, in those with admission central venous pressure (CVP) measurements, we examined the association of CVPs with subsequent AKI. AKI was defined using the Kidney Disease Improving Global Outcomes criteria., Results: Of the 18% (n=2338) of patients with peripheral edema on admission, 27% (n=631) developed AKI, compared with 16% (n=1713) of those without peripheral edema. In a model that included adjustment for comorbidities, severity of illness, and the presence of pulmonary edema, peripheral edema was associated with a 30% higher risk of AKI (95% confidence interval [95% CI], 1.15 to 1.46; P<0.001), whereas pulmonary edema was not significantly related to risk. Peripheral edema was also associated with a 13% higher adjusted risk of a higher AKI stage (95% CI, 1.07 to 1.20; P<0.001). Furthermore, levels of trace, 1+, 2+, and 3+ edema were associated with 34% (95% CI, 1.10 to 1.65), 17% (95% CI, 0.96 to 1.14), 47% (95% CI, 1.18 to 1.83), and 57% (95% CI, 1.07 to 2.31) higher adjusted risk of AKI, respectively, compared with edema-free patients. In the 4761 patients with admission CVP measurements, each 1 cm H2O higher CVP was associated with a 2% higher adjusted risk of AKI (95% CI, 1.00 to 1.03; P=0.02)., Conclusions: Venous congestion, as manifested as either peripheral edema or increased CVP, is directly associated with AKI in critically ill patients. Whether treatment of venous congestion with diuretics can modify this risk will require further study., (Copyright © 2016 by the American Society of Nephrology.)

Since the early reports nearly a decade ago, proton-pump inhibitor-induced hypomagnesemia (PPIH) has become a well-recognized phenomenon. While many observational studies in the inpatient and outpatient populations have confirmed the association of PPI exposure and serum magnesium concentrations, there are no prospective, controlled studies to support causation. Molecular mechanisms of magnesium transporters, including the pH-dependent regulation of transient receptor potential melastatin-6 transporters in the colonic enterocyte, have been proposed to explain the effect of PPIs on magnesium reabsorption, but may be a small part of a more complicated interplay of molecular biology, pharmacology, and genetic predisposition. This review explores the current state of research in the field of PPIH and the proposed mechanisms of this effect.

Introduction: Although magnesium plays an important role in aerobic metabolism and magnesium deficiency is a common phenomenon in critical illness, the association between magnesium deficiency and lactic acidosis in the intensive care unit (ICU) has not been defined., Methods: This was a retrospective, cross-sectional study conducted at a 77 ICU bed tertiary medical center. Data pertaining to the first unique admission of any ICU patient between 2001 and 2008 were extracted from the Multiparameter Intelligent Monitoring in Intensive Care database. Hypomagnesemia was defined as serum magnesium <1.6 mg/dL. Mild and severe lactic acidosis were defined as lactate concentrations of >2 and > 4 mmol/L, respectively. Multivariate modeling was used to explore the association between magnesium and lactate concentrations., Results: Of 8922 critically ill patients, 22.6% were hypomagnesemic. Hypomagnesemia was associated with an increased adjusted risk of mild lactic acidosis (odds ratio [OR] 1.71, 95% confidence interval [95%CI] 1.51-1.94, P < .001) and severe lactic acidosis (OR 1.56, 95%CI 1.32-1.84, P < .001) than the reference quartile. The association between hypomagnesemia and mild lactic acidosis was stronger in those at risk of magnesium deficiency, including diabetics (OR 2.02, 95%CI 1.51-2.72, P < .001) and alcoholics (OR 1.92, 95%CI 1.16-3.19, P = .01). As an internal model control, hypokalemia was not associated with an increased risk of lactic acidosis., Conclusions: Magnesium deficiency is a common finding in patients admitted to the ICU and is associated with lactic acidosis. Our findings support the biologic role of magnesium in metabolism and raise the possibility that hypomagnesemia is a correctable risk factor for lactic acidosis in critical illness., (© The Author(s) 2014.)

Objectives: Although obesity is associated with risk for chronic kidney disease and improved survival, less is known about the associations of obesity with risk of acute kidney injury and post acute kidney injury mortality., Design: In a single-center inception cohort of almost 15,000 critically ill patients, we evaluated the association of obesity with acute kidney injury and acute kidney injury severity, as well as in-hospital and 1-year survival. Acute kidney injury was defined using the Kidney Disease Outcome Quality Initiative criteria., Measurements and Main Results: The acute kidney injury prevalence rates for normal, overweight, class I, II, and III obesity were 18.6%, 20.6%, 22.5%, 24.3%, and 24.0%, respectively, and the adjusted odds ratios of acute kidney injury were 1.18 (95% CI, 1.06-1.31), 1.35 (1.19-1.53), 1.47 (1.25-1.73), and 1.59 (1.31-1.87) when compared with normal weight, respectively. Each 5-kg/m² increase in body mass index was associated with a 10% risk (95% CI, 1.06-1.24; p < 0.001) of more severe acute kidney injury. Within-hospital and 1-year survival rates associated with the acute kidney injury episodes were similar across body mass index categories., Conclusion: Obesity is a risk factor for acute kidney injury, which is associated with increased short- and long-term mortality.

Transjugular intrahepatic portosystemic shunts (TIPS) have been used for almost 40 years as a safe and effective alternative to surgical shunts, mostly in the setting of portal hypertension. Well described procedural complications include hepatic encephalopathy, hemorrhage, liver infarction and failure. The risk of post procedural acute kidney injury (AKI) associated with intraprocedural intravenous contrast administration has not been evaluated. Using a retrospective chart review of all consecutive patients undergoing a TIPS procedure as part of routine clinical care between 2001 and 2011, we examined whether the volume of administered intravenous contrast was associated with AKI. Of 163 patients who had a TIPS procedure, 16% developed AKI as defined by a 0.3 mg/dl increase in serum creatinine within 48 h of the procedure. In adjusted analysis, a 50 ml increase of intravenous contrast was associated with a 1.27 (95% CI 1.01-1.60), p = 0.04 increased risk of AKI. Baseline serum creatinine was also associated with post procedural AKI; a 0.1 mg/dl increase in creatinine was associated with a 1.17 (1.04-1.31), p = 0.008 risk. In patients with underlying kidney dysfunction, a 50 ml increase of intravenous contrast was associated with a 1.63 (1.20-2.31), p = 0.003 adjusted risk of AKI. In conclusion, intravenous contrast administered during a TIPS procedure is associated with an increased risk of AKI, particularly in patients with impaired renal function at baseline.

Hypomagnesemia can lead to cardiac arrythmias. Recently, observational data have linked chronic proton pump inhibitor (PPI) exposure to hypomagnesemia. Whether PPI exposure increases the risk for arrhythmias has not been well studied. Using a large, single-center inception cohort of critically ill patients, we examined whether PPI exposure was associated with admission electrocardiogram readings of a cardiac arrhythmia in more than 8000 patients. There were 25.4% PPI users, whereas 6% were taking a histamine 2 antagonist. In all, 14.0% had a cardiac arrhythmia. PPI use was associated with an unadjusted risk of arrhythmia of 1.15 (95% CI,1.00-1.32; P =.04) and an adjusted risk of arrhythmia of 0.91 (95% CI, 0.77-1.06; P =.22). Among diuretic users (n = 2476), PPI use was similarly not associated with an increased risk of cardiac arrhythmia. In summary, in a large cohort of critically ill patients, PPI exposure is not associated with an increased risk of cardiac arrhythmia., (© 2015, The American College of Clinical Pharmacology.)

Self-treatment of cancer with cesium chloride, despite proven lack of efficacy, continues to produce serious adverse effects. Among these is hypokalemia predisposing to life-threatening arrhythmia. The mechanism of cesium-associated hypokalemia (CAH) has not been described. We report urinary potassium wasting responsive to amiloride therapy in a cancer patient with CAH, and discuss possible mechanisms.

Objective: Sodium retention occurs commonly in cardiac and liver disease, requiring the administration of diuretics to restore fluid balance. Whether obesity is associated with sodium retention has not been fully evaluated., Methods: In a large single-center cohort of critically ill patients, we evaluated whether admission body mass index was associated with the administration of either oral or intravenous diuretics during the intensive care unit (ICU) stay., Main Results: Of 7724 critically ill patients, 3946 (51.1%) were prescribed diuretics during the ICU stay. Overweight, class I obesity, and class II/III obesity were associated with a 1.35 (95% confidence interval [CI], 1.20-1.53; P < .001), 1.56 (95% CI, 1.35-1.80; P < .001), and 1.91 (95% CI, 1.61-2.26; P < .001) adjusted risk of receiving diuretics within the ICU, respectively. In adjusted analysis, a 5-kg/m(2) increment of body mass index was associated with a 1.19 (95% CI, 1.14-1.23; P < .001) increased adjusted risk of within-ICU diuretics. Among those patients receiving loop diuretics, obese patients received significantly larger daily diuretic doses., Conclusion: Critically ill obese patients are more likely to receive diuretics during their stay in the ICU and to receive higher dosages of diuretics. Our data suggest that obesity is an independent risk factor for sodium retention., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Alterations in water homeostasis can disturb cell size and function. Although most cells can internally regulate cell volume in response to osmolar stress, neurons are particularly at risk given a combination of complex cell function and space restriction within the calvarium. Thus, regulating water balance is fundamental to survival. Through specialized neuronal "osmoreceptors" that sense changes in plasma osmolality, vasopressin release and thirst are titrated in order to achieve water balance. Fine-tuning of water absorption occurs along the collecting duct, and depends on unique structural modifications of renal tubular epithelium that confer a wide range of water permeability. In this article, we review the mechanisms that ensure water homeostasis as well as the fundamentals of disorders of water balance., (Copyright © 2015 by the American Society of Nephrology.)

Objective: Although the consequences of chronic fluid retention are well known, those of iatrogenic fluid retention that occurs during critical illness have not been fully determined. Therefore, we investigated the association between fluid balance and survival in a cohort of almost 16,000 individuals who survived an intensive care unit (ICU) stay in a large, urban, tertiary medical centre., Design: Longitudinal analysis of fluid balance at ICU discharge and 90-day post-ICU survival., Measurements: Associations between fluid balance during the ICU stay, determined from the electronic bedside record, and survival were tested using Cox proportional hazard models adjusted for severity of critical illness., Results: There were 1827 deaths in the first 90 days after ICU discharge. Compared with the lowest quartile of discharge fluid balance [median (interquartile range) -1.5 (-3.1, -0.7) L], the highest quartile [7.6 (5.7, 10.8) L] was associated with a 35% [95% confidence interval (CI) 1.13-1.61)] higher adjusted risk of death. Fluid balance was not associated with outcome amongst individuals without congestive heart failure or renal dysfunction. Amongst patients with either comorbidity, however, fluid balance was strongly associated with outcome, with the highest quartile having a 55% (95% CI 1.24-1.95) higher adjusted risk of death than the lowest quartile. Isotonic fluid balance, defined as the difference between intravenous isotonic fluid administration and urine output, was similarly associated with 90-day outcomes., Conclusion: Positive fluid balance at the time of ICU discharge is associated with increased risk of death, after adjusting for markers of illness severity and chronic medical conditions, particularly in patients with underlying heart or kidney disease. Restoration of euvolaemia prior to discharge may improve survival after acute illness., (© 2014 The Association for the Publication of the Journal of Internal Medicine.)

Aims: Although multiple recent studies have confirmed an association between chronic proton-pump inhibitor (PPI) use and hypomagnesaemia, the physiologic explanation for this association remains uncertain. To address this, we investigated the association of PPI use with urinary magnesium excretion., Methods: We measured 24-hour urine magnesium excretion in collections performed for nephrolithiasis evaluation in 278 consecutive ambulatory patients and determined PPI use from contemporaneous medical records., Results: There were 50 (18%) PPI users at the time of urine collection. The mean daily urinary magnesium was 84.6 ± 42.8 mg in PPI users, compared with 101.2 ± 41.1 mg in non-PPI users (P = 0.01). In adjusted analyses, PPI use was associated with 10.54 ± 5.30 mg/day lower daily urinary magnesium excretion (P = 0.05). Diuretic use did not significantly modify the effect of PPI on urinary magnesium. As a control, PPI use was not associated with other urinary indicators of nutritional intake., Conclusions: Our findings suggest that PPI use is associated with lower 24-hour urine magnesium excretion. Whether this reflects decreased intestinal uptake due to PPI exposure, or residual confounding due to decreased magnesium intake, requires further study., (© 2014 Asian Pacific Society of Nephrology.)

Purpose: To demonstrate a novel method that utilizes retrospective data to develop statistically optimal dosing strategies for medications with sensitive therapeutic windows. We illustrate our approach on intravenous unfractionated heparin, a medication which typically considers only patient weight and is frequently misdosed., Methods: We identified available clinical features which impact patient response to heparin and extracted 1,511 patients from the multi-parameter intelligent monitoring in intensive care II database which met our inclusion criteria. These were used to develop two multivariate logistic regressions, modeling sub- and supra-therapeutic activated partial thromboplastin time (aPTT) as a function of clinical features. We combined information from these models to estimate an initial heparin dose that would, on a per-patient basis, maximize the probability of a therapeutic aPTT within 4-8 h of the initial infusion. We tested our model's ability to classifying therapeutic outcomes on a withheld dataset and compared performance to a weight-alone alternative using volume under surface (VUS) (a multiclass version of AUC)., Results: We observed statistically significant associations between sub- and supra-therapeutic aPTT, race, ICU type, gender, heparin dose, age and Sequential Organ Failure Assessment scores with mean validation AUC of 0.78 and 0.79 respectively. Our final model improved outcome classification over the weight-alone alternative, with VUS values of 0.48 vs. 0.42., Conclusions: This work represents an important step in the secondary use of health data in developing models to optimize drug dosing. The next step would be evaluating whether this approach indeed achieves target aPTT more reliably than the current weight-based heparin dosing in a randomized controlled trial.

Background: Despite extensive study, the role of vitamin D in insulin resistance and secretion remains unclear., Objective: To examine the cross-sectional and longitudinal relationships between 25-hydroxyvitamin D (25(OH)D) concentrations and indices of insulin resistance and secretion in older adults., Methods and Results: Among 2134 participants of the Cardiovascular Health Study who were free from cardiovascular disease, we measured serum 25(OH)D concentrations in samples collected in 1992-1993. We examined insulin resistance and secretion using Homeostasis Model Assessment (HOMA) estimates cross-sectionally and among 1469 participants who had repeated HOMA measures four years later (1996-1997). In cross-sectional analysis, each 10 ng/mL increment in 25(OH)D concentration was associated with a 0.09 lower adjusted HOMA-IR [95% CI (-0.17, -0.02), p=0.01]. However, baseline 25(OH)D concentrations were not associated with change in HOMA-IR over 4 years of follow up (p=0.48). 25(OH)D concentrations were not associated with insulin secretion, as determined by HOMA-β, in either cross-sectional or longitudinal analysis., Conclusions: Circulating 25(OH)D concentrations are associated with lower insulin resistance in cross-sectional but not longitudinal analyses. Whether this reflects residual confounding in cross-sectional analyses or the short-term nature of the relationship between vitamin D and insulin sensitivity will require trials with repeated measures of these factors., (© 2013.)

Background: Although magnesium is important in the biology of blood pressure regulation, little clinical data exist on the association of hypermagnesemia and blood pressure., Method: We examined the association of hypermagnesemia and SBP in a cross-sectional study of 10 521 ICU patients from a single tertiary care medical center, 6% of whom had a serum magnesium above 2.6 mg/dl at time of admission., Results: In a multivariable analysis, hypermagnesemia was associated with SBP 6.2 mmHg lower [95% confidence interval (CI) -8.2, -4.2, P < 0.001] than in patients with admission values of serum magnesium 2.6 mg/dl or less. Each mg/dl increase in serum magnesium was associated with a decrease in SBP of 4.3 mmHg (95% CI -5.5, -3.1, P < 0.001). In addition, hypermagnesemic patients had a 2.48-fold greater likelihood (95% CI 2.06, 3.00, P < 0.001) of receiving intravenous vasopressors during the first 24 h of ICU care, independent of admission SBP., Conclusion: Our findings add support to the biologic importance of magnesium regulation in blood pressure control.

Rates of morbidity and mortality are significantly higher in homeless populations. Homeless people experience many barriers to receive adequate palliative care. This qualitative study examines how a major urban city's palliative care resources can be improved to increase access and better serve the homeless. Audiotaped interviews were preformed with 7 homeless care providers in Toronto, Canada, and their transcripts were analyzed using thematic analysis. The findings of the study suggest that in order to increase access and to serve the city's terminally ill homeless better, the following 4 areas must be addressed: (1) increasing positive interaction between the health care system and the homeless, (2) training staff to deal with the unique issues confronting the homeless, (3) providing patient-centered care, and (4) diversifying the methods of delivery.

Although case reports link proton-pump inhibitor (PPI) use and hypomagnesemia, no large-scale studies have been conducted. Here we examined the serum magnesium concentration and the likelihood of hypomagnesemia (<1.6 mg/dl) with a history of PPI or histamine-2 receptor antagonist used to reduce gastric acid, or use of neither among 11,490 consecutive adult admissions to an intensive care unit of a tertiary medical center. Of these, 2632 patients reported PPI use prior to admission, while 657 patients were using a histamine-2 receptor antagonist. PPI use was associated with 0.012 mg/dl lower adjusted serum magnesium concentration compared to users of no acid-suppressive medications, but this effect was restricted to those patients taking diuretics. Among the 3286 patients concurrently on diuretics, PPI use was associated with a significant increase of hypomagnesemia (odds ratio 1.54) and 0.028 mg/dl lower serum magnesium concentration. Among those not using diuretics, PPI use was not associated with serum magnesium levels. Histamine-2 receptor antagonist use was not significantly associated with magnesium concentration without or with diuretic use. The use of PPI was not associated with serum phosphate concentration regardless of diuretic use. Thus, we verify case reports of the association between PPI use and hypomagnesemia in those concurrently taking diuretics. Hence, serum magnesium concentrations should be followed in susceptible individuals on chronic PPI therapy.

Urea, the toxic end product of protein catabolism, is elevated in end-stage renal disease (ESRD), although it is unclear whether or how it contributes to disease. Urea can promote the carbamylation of proteins on multiple lysine side chains, including human albumin, which has a predominant carbamylation site on Lys(549). The proportion of serum albumin carbamylated on Lys(549) (%C-Alb) correlated with time-averaged blood urea concentrations and was twice as high in ESRD patients than in non-uremic subjects (0.90% versus 0.42%). Baseline %C-Alb was higher in ESRD subjects who died within 1 year than in those who survived longer than 1 year (1.01% versus 0.77%) and was associated with an increased risk of death within 1 year (hazard ratio, 3.76). These findings were validated in an independent cohort of diabetic ESRD subjects (hazard ratio, 3.73). Decreased concentrations of serum amino acids correlated with higher %C-Alb in ESRD patients, and mice with diet-induced amino acid deficiencies exhibited greater susceptibility to albumin carbamylation than did chow-fed mice. In vitro studies showed that amino acids such as cysteine, histidine, arginine, and lysine, as well as other nucleophiles such as taurine, inhibited cyanate-induced C-Alb formation at physiologic pH and temperature. Together, these results suggest that chronically elevated urea promotes carbamylation of proteins in ESRD and that serum amino acid concentrations may modulate this protein modification. In summary, we have identified serum %C-Alb as a risk factor for mortality in patients with ESRD and propose that this risk factor may be modifiable with supplemental amino acid therapy.

Unlabelled: Although vitamin D deficiency has been associated with increased insulin resistance, a causal link has not been established. Interpreting the relationship has been confounded by a close correlation between vitamin D deficiency and obesity. The current clinical approach of assessing endogenous 25-hydroxyvitamin D (25(OH)D) concentrations in patients with chronic kidney disease (CKD), and independently administering activated vitamin D (AD), allows a unique opportunity to clarify cause and effect in the relationship of vitamin D, obesity and insulin resistance., Methods: We assessed how 25(OH)D and body mass index (BMI) related to fasting insulin concentrations in 120 nondiabetic patients with CKD. In addition, we described how treatment with AD modified these relationships., Results: In the full cohort, fasting insulin concentrations varied inversely with both 25(OH)D (r = -0·22, P = 0·02) and BMI (r = -0·36, P < 0·0001). The administration of AD altered these relationships. In individuals treated with AD, there was no association between 25(OH)D and fasting insulin, and the mean fasting insulin concentrations were significantly lower than in those not receiving AD (40·5 ± 22·0 vs 54·1 ± 30·9 pm, P = 0·01). In a multivariate analysis, both AD treatment and BMI were independent predictors of fasting insulin. Furthermore, obese patients treated with AD had insulin concentrations similar to nonobese patients (46·1 ± 24·9 vs 40·2 ± 21·5 pm), whereas untreated obese patients had markedly higher fasting insulin concentrations (74·4 ± 33·4 pm, P = 0·003)., Conclusion: 25(OH)D deficiency is associated with insulin resistance in CKD. Replacement with pharmacologic doses of AD is associated with lower fasting insulin concentrations, especially in obese patients., (© 2012 Blackwell Publishing Ltd.)

When a massive star explodes as a supernova, substantial amounts of radioactive elements--primarily (56)Ni, (57)Ni and (44)Ti--are produced. After the initial flash of light from shock heating, the fading light emitted by the supernova is due to the decay of these elements. However, after decades, the energy powering a supernova remnant comes from the shock interaction between the ejecta and the surrounding medium. The transition to this phase has hitherto not been observed: supernovae occur too infrequently in the Milky Way to provide a young example, and extragalactic supernovae are generally too faint and too small. Here we report observations that show this transition in the supernova SN 1987A in the Large Magellanic Cloud. From 1994 to 2001, the ejecta faded owing to radioactive decay of (44)Ti as predicted. Then the flux started to increase, more than doubling by the end of 2009. We show that this increase is the result of heat deposited by X-rays produced as the ejecta interacts with the surrounding material. In time, the X-rays will penetrate farther into the ejecta, enabling us to analyse the structure and chemistry of the vanished star.