Obesity prevalence continues to increase worldwide, accompanied by a rising tide of hypertension, diabetes, and chronic kidney disease (CKD). Although body mass index is typically used to assess ...obesity in clinical practice, altered body composition (eg, reduced muscle mass and increased visceral adiposity) are common among patients with CKD. Weight loss achieved through behavioral modification or medications reduces albuminuria and in some cases slows the decline in estimated glomerular filtration rate. Use of medications that promote weight loss with favorable cardiovascular risk profiles should be promoted, particularly in patients with type 2 diabetes, obesity, and CKD. For those who fail to achieve weight loss through lifestyle modification, bariatric surgery should be considered because observational studies have shown reductions in risk for estimated glomerular filtration rate decline and kidney failure. Uncertainty persists on the risk to benefit ratio of intentional weight loss in patients with kidney failure due to the lack of prospective trials and limitations of observational data. Regardless, sleeve gastrectomy is increasingly being used for patients with kidney failure and severe obesity, with success in achieving sustained weight loss, improved access to kidney transplantation, and favorable posttransplantation outcomes. More research is needed assessing long-term cardiovascular and kidney outcomes of most weight loss medications.
Proton pump inhibitors (PPIs) are among the most commonly used drugs worldwide and have been linked to acute interstitial nephritis. Less is known about the association between PPI use and chronic ...kidney disease (CKD).
To quantify the association between PPI use and incident CKD in a population-based cohort.
In total, 10,482 participants in the Atherosclerosis Risk in Communities study with an estimated glomerular filtration rate of at least 60 mL/min/1.73 m(2) were followed from a baseline visit between February 1, 1996, and January 30, 1999, to December 31, 2011. The data was analyzed from May 2015 to October 2015. The findings were replicated in an administrative cohort of 248,751 patients with an estimated glomerular filtration rate of at least 60 mL/min/1.73 m(2) from the Geisinger Health System.
Self-reported PPI use in the Atherosclerosis Risk in Communities study or an outpatient PPI prescription in the Geisinger Health System replication cohort. Histamine2 (H2) receptor antagonist use was considered a negative control and active comparator.
Incident CKD was defined using diagnostic codes at hospital discharge or death in the Atherosclerosis Risk in Communities Study, and by a sustained outpatient estimated glomerular filtration rate of less than 60 mL/min/1.73 m(2) in the Geisinger Health System replication cohort.
Among 10,482 participants in the Atherosclerosis Risk in Communities study, the mean (SD) age was 63.0 (5.6) years, and 43.9% were male. Compared with nonusers, PPI users were more often of white race, obese, and taking antihypertensive medication. Proton pump inhibitor use was associated with incident CKD in unadjusted analysis (hazard ratio HR, 1.45; 95% CI, 1.11-1.90); in analysis adjusted for demographic, socioeconomic, and clinical variables (HR, 1.50; 95% CI, 1.14-1.96); and in analysis with PPI ever use modeled as a time-varying variable (adjusted HR, 1.35; 95% CI, 1.17-1.55). The association persisted when baseline PPI users were compared directly with H2 receptor antagonist users (adjusted HR, 1.39; 95% CI, 1.01-1.91) and with propensity score-matched nonusers (HR, 1.76; 95% CI, 1.13-2.74). In the Geisinger Health System replication cohort, PPI use was associated with CKD in all analyses, including a time-varying new-user design (adjusted HR, 1.24; 95% CI, 1.20-1.28). Twice-daily PPI dosing (adjusted HR, 1.46; 95% CI, 1.28-1.67) was associated with a higher risk than once-daily dosing (adjusted HR, 1.15; 95% CI, 1.09-1.21).
Proton pump inhibitor use is associated with a higher risk of incident CKD. Future research should evaluate whether limiting PPI use reduces the incidence of CKD.
Although phosphorus is an essential nutrient required for multiple physiological functions, recent research raises concerns that high phosphorus intake could have detrimental effects on health. ...Phosphorus is abundant in the food supply of developed countries, occurring naturally in protein-rich foods and as an additive in processed foods. High phosphorus intake can cause vascular and renal calcification, renal tubular injury, and premature death in multiple animal models. Small studies in human suggest that high phosphorus intake may result in positive phosphorus balance and correlate with renal calcification and albuminuria. Although serum phosphorus is strongly associated with cardiovascular disease, progression of kidney disease, and death, limited data exist linking high phosphorus intake directly to adverse clinical outcomes. Further prospective studies are needed to determine whether phosphorus intake is a modifiable risk factor for kidney disease.
Rapid correction of severe hyponatremia can result in serious neurologic complications, including osmotic demyelination. Few data exist on incidence and risk factors of rapid correction or osmotic ...demyelination.
In a retrospective cohort of 1490 patients admitted with serum sodium <120 mEq/L to seven hospitals in the Geisinger Health System from 2001 to 2017, we examined the incidence and risk factors of rapid correction and osmotic demyelination. Rapid correction was defined as serum sodium increase of >8 mEq/L at 24 hours. Osmotic demyelination was determined by manual chart review of all available brain magnetic resonance imaging reports.
Mean age was 66 years old (SD=15), 55% were women, and 67% had prior hyponatremia (last outpatient sodium <135 mEq/L). Median change in serum sodium at 24 hours was 6.8 mEq/L (interquartile range, 3.4-10.2), and 606 patients (41%) had rapid correction at 24 hours. Younger age, being a woman, schizophrenia, lower Charlson comorbidity index, lower presentation serum sodium, and urine sodium <30 mEq/L were associated with greater risk of rapid correction. Prior hyponatremia, outpatient aldosterone antagonist use, and treatment at an academic center were associated with lower risk of rapid correction. A total of 295 (20%) patients underwent brain magnetic resonance imaging on or after admission, with nine (0.6%) patients showing radiologic evidence of osmotic demyelination. Eight (0.5%) patients had incident osmotic demyelination, of whom five (63%) had beer potomania, five (63%) had hypokalemia, and seven (88%) had sodium increase >8 mEq/L over a 24-hour period before magnetic resonance imaging. Five patients with osmotic demyelination had apparent neurologic recovery.
Among patients presenting with severe hyponatremia, rapid correction occurred in 41%; nearly all patients with incident osmotic demyelination had a documented episode of rapid correction.
This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2018_06_05_CJASNPodcast_18_7_G.mp3.
Decline in eGFR is a biologically plausible surrogate end point for the progression of CKD in clinical trials. However, it must first be tested to ensure strong associations with clinical outcomes in ...diverse populations, including patients with higher eGFR.
To investigate the association between 1-, 2-, and 3-year changes in eGFR (slope) with clinical outcomes over the long term, we conducted a random effects meta-analysis of 3,758,551 participants with baseline eGFR≥60 ml/min per 1.73 m
and 122,664 participants with eGFR<60 ml/min per 1.73 m
from 14 cohorts followed for an average of 4.2 years.
Slower eGFR decline by 0.75 ml/min per 1.73 m
per year over 2 years was associated with lower risk of ESKD in participants with baseline eGFR≥60 ml/min per 1.73 m
(adjusted hazard ratio, 0.70; 95% CI, 0.68 to 0.72) and eGFR<60 ml/min per 1.73 m
(0.71; 95% CI, 0.68 to 0.74). The relationship was stronger with 3-year slope. For a rapidly progressing population with predicted 5-year risk of ESKD of 8.3%, an intervention that reduced eGFR decline by 0.75 ml/min per 1.73 m
per year over 2 years would reduce the ESKD risk by 1.6%. For a hypothetical low-risk population with a predicted 5-year ESKD risk of 0.58%, the same intervention would reduce the risk by only 0.13%.
Slower decline in eGFR was associated with lower risk of subsequent ESKD, even in participants with eGFR≥60 ml/min per 1.73 m
, but those with the highest risk would be expected to benefit the most.
β-Arrestins (βarrs) interact with G protein-coupled receptors (GPCRs) to desensitize G protein signaling, to initiate signaling on their own, and to mediate receptor endocytosis. Prior structural ...studies have revealed two unique conformations of GPCR–βarr complexes: the “tail” conformation, with βarr primarily coupled to the phosphorylated GPCR C-terminal tail, and the “core” conformation, where, in addition to the phosphorylated C-terminal tail, βarr is further engaged with the receptor transmembrane core. However, the relationship of these distinct conformations to the various functions of βarrs is unknown. Here, we created a mutant form of βarr lacking the “finger-loop” region, which is unable to form the core conformation but retains the ability to form the tail conformation. We find that the tail conformation preserves the ability to mediate receptor internalization and βarr signaling but not desensitization of G protein signaling. Thus, the two GPCR–βarr conformations can carry out distinct functions.
Background Serum phosphorus levels have been associated with mortality in some but not all studies. Because dietary intake prior to measurement can affect serum phosphorus levels, we hypothesized ...that the association between serum phosphorus level and mortality is strongest in those who have fasted longer. Study Design Prospective cohort study. Setting & Participants Nationally representative sample of 12,984 participants 20 years or older in the Third National Health and Nutrition Examination Survey (1988-1994). Factors Serum phosphorus level, fasting duration (dichotomized as ≥12 or <12 hours). Outcomes All-cause and cardiovascular mortality determined by death certificate data from the National Death Index. Measurements Serum phosphorus measured in a central laboratory and fasting duration recorded as time since food or drink other than water was consumed. Results Individuals fasting 12 or more hours had lower serum phosphorus levels than those fasting less than 12 hours (3.34 vs 3.55 mg/dL; P < 0.001) and higher correlation with repeat measurement (0.66 vs 0.53; P = 0.002). In multivariable-adjusted Cox regression models, the highest quartile of serum phosphorus was associated with increased mortality in participants fasting 12 or more hours (adjusted HR, 1.74; 95% CI, 1.38-2.20; reference, lowest quartile) but not in participants fasting less than 12 hours (adjusted HR, 1.08; 95% CI, 0.89-1.32; P for interaction = 0.002). Relationships were consistent using 8 hours as the fasting cutoff point or cardiovascular mortality as the outcome. Limitations Observational study, lack of fibroblast growth factor 23 or intact parathyroid hormone measurements. Conclusions Fasting but not nonfasting serum phosphorus levels were associated with increased mortality. Risk prognostication based on serum phosphorus may be improved using fasting levels.
Interest in the health effects of dietary phosphorus is burgeoning, yet sources and trends in phosphorus consumption have not been well characterized. We describe trends in and primary sources of ...dietary phosphorus in a nationally representative sample of 34,741 US adults, 20+ years old (NHANES 2001-2014). Dietary sources of phosphorus were estimated in nine food groups and 26 food categories. Phosphorus consumption was expressed in absolute intake, phosphorus density, and proportion contributed by dietary sources. Between 2001 and 2014, dietary phosphorus intake increased from 1345 to 1399 mg/day (p-trend = 0.02), while calorie intake slightly declined (p-trend = 0.1). Grains were the largest dietary phosphorus source, followed by meats, and milk products. Soft drinks accounted for just 3.3% of total dietary phosphorus. Phosphorus intake from grains increased 68 mg/day (p < 0.001), 25 mg/day from meats (p = 0.02), and decreased 75 mg/day (p < 0.001) from milk products. Dietary phosphorus intake and the phosphorus density of the diet are increasing. Grains are an important dietary phosphorus source that has increased in total consumption and phosphorus density. Further research is needed to determine if this is due to individuals' selection of grains or the composition of those available.
Background: Elevated serum phosphorus is associated with all-cause mortality, but little is known about risk associated with dietary phosphorus intake.Objective: We investigated the association ...between phosphorus intake and mortality in a prospective cohort of healthy US adults (NHANES III; 1998–1994).Design: Study participants were 9686 nonpregnant adults aged 20–80 y without diabetes, cancer, or kidney or cardiovascular disease. Exposure to dietary phosphorus, which was assessed by using a 24-h dietary recall, was expressed as the absolute intake and phosphorus density (phosphorus intake divided by energy intake). All-cause and cardiovascular mortality was assessed through 31 December 2006.Results: Median phosphorus intake was 1166 mg/d (IQR: 823–1610 mg/d); median phosphorus density was 0.58 mg/kcal (0.48–0.70 mg/kcal). Individuals who consumed more phosphorus-dense diets were older, were less often African American, and led healthier lifestyles (smoking, physical activity, and Healthy Eating Index). In analyses adjusted for demographics, cardiovascular risk factors, kidney function, and energy intake, higher phosphorus intake was associated with higher all-cause mortality in individuals who consumed >1400 mg/d adjusted HR (95% CI): 2.23 (1.09, 4.5) per 1-unit increase in ln(phosphorus intake); P = 0.03. At <1400 mg/d, there was no association. A similar association was seen between higher phosphorus density and all-cause mortality at a phosphorus density amount >0.35 mg/kcal adjusted HR (95% CI): 2.27 (1.19, 4.33) per 0.1-mg/kcal increase in phosphorus density; P = 0.01. At <0.35 mg/kcal (approximately the fifth percentile), lower phosphorus density was associated with increased mortality risk. Phosphorus density was associated with cardiovascular mortality adjusted HR (95% CI): 3.39 (1.43, 8.02) per 0.1 mg/kcal at >0.35 mg/kcal; P = 0.01, whereas no association was shown in analyses with phosphorus intake. Results were similar by subgroups of diet quality and in analyses adjusted for sodium and saturated fat intakes.Conclusions: High phosphorus intake is associated with increased mortality in a healthy US population. Because of current patterns in phosphorus consumption in US adults, these findings may have important public health implications.