Ziyad Al-Aly

Aortic Msx2-Wnt Calcification Cascade Is Regulated by TNF-α–Dependent Signals in Diabetic Ldlr−/− Mice

Objective—Aortic calcification is prevalent in type II diabetes (T2DM), enhancing morbidity and tracking metabolic syndrome parameters. Ldlr−/− mice fed high-fat “Westernized” diets (HFD) accumulate aortic calcium primarily in the tunica media, mediated via osteogenic morphogens and transcriptional programs that induce aortic alkaline phosphatase (ALP). Because elevated TNF-&agr; is characteristic of obesity with T2DM, we examined contributions of this inflammatory cytokine. Methods and Results—HFD promoted obesity, hyperglycemia, and hyperlipidemia, and upregulated serum TNF-&agr; in Ldlr−/− mice. Serum haptoglobin (inflammatory marker) was increased along with aortic expression of BMP2, Msx2, Wnt3a, and Wnt7a. Dosing with the TNF-&agr; neutralizing antibody infliximab did not reduce obesity, hypercholesterolemia, or hyperglycemia; however, haptoglobin, aortic BMP2, Msx2, Wnt3a, and Wnt7a and aortic calcium accumulation were downregulated by infliximab. Mice with vascular TNF-&agr; augmented by a transgene (SM22-TNF&agr;Tg) driven from the SM22 promoter upregulated aortic Msx2, Wnt3a, and Wnt7a. Furthermore, SM22-TNF&agr;Tg;TOPGAL mice exhibited greater aortic &bgr;-galactosidase reporter staining versus TOPGAL sibs, indicating enhanced mural Wnt signaling. In aortic myofibroblast cultures, TNF-&agr; upregulated Msx2, Wnt3a, Wnt7a, and ALP. ALP induction was inhibited by Dkk1, an antagonist of paracrine Wnt actions. Conclusions—TNF-&agr; promote aortic Msx2-Wnt programs that contribute to aortic calcium accumulation in T2DM.

Global, regional, and national age-sex specific mortality for 264 causes of death, 1980-2016

The last 37 years have featured declining rates of communicable, maternal, neonatal, and nutritional diseases across all quintiles of SDI, with faster than expected gains for many locations relative to their SDI. A global shift towards deaths at older ages suggests success in reducing many causes of early death. YLLs have increased globally for causes such as diabetes mellitus or some neoplasms, and in some locations for causes such as drug use disorders, and conflict and terrorism. Increasing levels of YLLs may reflect outcomes from conditions that required high levels of care but for which effective treatments remain elusive, potentially increasing costs to health systems.Summary Background Monitoring levels and trends in premature mortality is crucial to understanding how societies can address prominent sources of early death. The Global Burden of Disease 2016 Study (GBD 2016) provides a comprehensive assessment of cause-specific mortality for 264 causes in 195 locations from 1980 to 2016. This assessment includes evaluation of the expected epidemiological transition with changes in development and where local patterns deviate from these trends. Methods We estimated cause-specific deaths and years of life lost (YLLs) by age, sex, geography, and year. YLLs were calculated from the sum of each death multiplied by the standard life expectancy at each age. We used the GBD cause of death database composed of: vital registration (VR) data corrected for under-registration and garbage coding; national and subnational verbal autopsy (VA) studies corrected for garbage coding; and other sources including surveys and surveillance systems for specific causes such as maternal mortality. To facilitate assessment of quality, we reported on the fraction of deaths assigned to GBD Level 1 or Level 2 causes that cannot be underlying causes of death (major garbage codes) by location and year. Based on completeness, garbage coding, cause list detail, and time periods covered, we provided an overall data quality rating for each location with scores ranging from 0 stars (worst) to 5 stars (best). We used robust statistical methods including the Cause of Death Ensemble model (CODEm) to generate estimates for each location, year, age, and sex. We assessed observed and expected levels and trends of cause-specific deaths in relation to the Socio-demographic Index (SDI), a summary indicator derived from measures of average income per capita, educational attainment, and total fertility, with locations grouped into quintiles by SDI. Relative to GBD 2015, we expanded the GBD cause hierarchy by 18 causes of death for GBD 2016. Findings The quality of available data varied by location. Data quality in 25 countries rated in the highest category (5 stars), while 48, 30, 21, and 44 countries were rated at each of the succeeding data quality levels. Vital registration or verbal autopsy data were not available in 27 countries, resulting in the assignment of a zero value for data quality. Deaths from non-communicable diseases (NCDs) represented 72·3% (95% uncertainty interval [UI] 71·2–73·2) of deaths in 2016 with 19·3% (18·5–20·4) of deaths in that year occurring from communicable, maternal, neonatal, and nutritional (CMNN) diseases and a further 8·43% (8·00–8·67) from injuries. Although age-standardised rates of death from NCDs decreased globally between 2006 and 2016, total numbers of these deaths increased; both numbers and age-standardised rates of death from CMNN causes decreased in the decade 2006–16—age-standardised rates of deaths from injuries decreased but total numbers varied little. In 2016, the three leading global causes of death in children under-5 were lower respiratory infections, neonatal preterm birth complications, and neonatal encephalopathy due to birth asphyxia and trauma, combined resulting in 1·80 million deaths (95% UI 1·59 million to 1·89 million). Between 1990 and 2016, a profound shift toward deaths at older ages occurred with a 178% (95% UI 176–181) increase in deaths in ages 90–94 years and a 210% (208–212) increase in deaths older than age 95 years. The ten leading causes by rates of age-standardised YLL significantly decreased from 2006 to 2016 (median annualised rate of change was a decrease of 2·89%); the median annualised rate of change for all other causes was lower (a decrease of 1·59%) during the same interval. Globally, the five leading causes of total YLLs in 2016 were cardiovascular diseases; diarrhoea, lower respiratory infections, and other common infectious diseases; neoplasms; neonatal disorders; and HIV/AIDS and tuberculosis. At a finer level of disaggregation within cause groupings, the ten leading causes of total YLLs in 2016 were ischaemic heart disease, cerebrovascular disease, lower respiratory infections, diarrhoeal diseases, road injuries, malaria, neonatal preterm birth complications, HIV/AIDS, chronic obstructive pulmonary disease, and neonatal encephalopathy due to birth asphyxia and trauma. Ischaemic heart disease was the leading cause of total YLLs in 113 countries for men and 97 countries for women. Comparisons of observed levels of YLLs by countries, relative to the level of YLLs expected on the basis of SDI alone, highlighted distinct regional patterns including the greater than expected level of YLLs from malaria and from HIV/AIDS across sub-Saharan Africa; diabetes mellitus, especially in Oceania; interpersonal violence, notably within Latin America and the Caribbean; and cardiomyopathy and myocarditis, particularly in eastern and central Europe. The level of YLLs from ischaemic heart disease was less than expected in 117 of 195 locations. Other leading causes of YLLs for which YLLs were notably lower than expected included neonatal preterm birth complications in many locations in both south Asia and southeast Asia, and cerebrovascular disease in western Europe. Interpretation The past 37 years have featured declining rates of communicable, maternal, neonatal, and nutritional diseases across all quintiles of SDI, with faster than expected gains for many locations relative to their SDI. A global shift towards deaths at older ages suggests success in reducing many causes of early death. YLLs have increased globally for causes such as diabetes mellitus or some neoplasms, and in some locations for causes such as drug use disorders, and conflict and terrorism. Increasing levels of YLLs might reflect outcomes from conditions that required high levels of care but for which effective treatments remain elusive, potentially increasing costs to health systems. Funding Bill & Melinda Gates Foundation.

Rate of Kidney Function Decline Associates with Mortality

The effect of rate of decline of kidney function on risk for death is not well understood. Using the Department of Veterans Affairs national databases, we retrospectively studied a cohort of 4171 patients who had rheumatoid arthritis and early stage 3 chronic kidney disease (CKD; estimated GFR 45 to 60 ml/min) and followed them longitudinally to characterize predictors of disease progression and the effect of rate of kidney function decline on mortality. After a median of 2.6 years, 1604 (38%) maintained stable kidney function; 426 (10%), 1147 (28%), and 994 (24%) experienced mild, moderate, and severe progression of CKD, respectively (defined as estimated GFR decline of 0 to 1, 1 to 4, and >4 ml/min per yr). Peripheral artery disease predicted moderate progression of CKD progression. Black race, hypertension, diabetes, cardiovascular disease, and peripheral artery disease predicted severe progression of CKD. After a median of 5.7 years, patients with severe progression had a significantly increased risk for mortality (hazard ratio 1.54; 95% confidence interval 1.30 to 1.82) compared with those with mild progression; patients with moderate progression exhibited a similar trend (hazard ratio 1.10; 95% confidence interval 0.98 to 1.30). Our results demonstrate an independent and graded association between the rate of kidney function decline and mortality. Incorporating the rate of decline into the definition of CKD may transform a static definition into a dynamic one that more accurately describes the potential consequences of the disease for an individual.

Early nephrologist involvement in hospital-acquired acute kidney injury: a pilot study.

BACKGROUND The optimal timing of nephrology consultation in patients with hospital-acquired acute kidney injury (AKI) is unknown. STUDY DESIGN Prospective controlled nonrandomized intervention study. SETTING & PARTICIPANTS We screened daily serum creatinine (SCr) levels of 4,296 patients admitted to the St. Louis Veterans Affairs Medical Center between September and November 2008 (control group) and January to May 2009 (intervention group). 354 patients (8.2%) met the definition of in-hospital AKI (SCr level increase of 0.3 mg/dL over 48 hours); 176 of whom met all inclusion criteria; 85 and 91 patients were enrolled in the control (standard care) and intervention groups, respectively. INTERVENTION Early renal service involvement (EARLI), defined as a 1-time nephrology consultation within 18 hours of the onset of AKI. OUTCOME Primary outcome defined as 2.5-fold increase in SCr level from admission. MEASUREMENT Daily SCr until discharge. RESULTS The 2 groups had similar characteristics at baseline and at the time of AKI. The intervention was completed at a mean of 13.1 ± 0.8 hours from the onset of AKI. Nephrology recommendations in the EARLI group included specific diagnostic, therapeutic, and preventative components. The primary outcome occurred in 12.9% of patients in the control group compared with 3.3% of patients in the EARLI group (P = 0.02). Patients in the EARLI group had a lower peak SCr level of 1.8 ± 0.1 versus 2.1 ± 0.2 mg/dL in controls (P = 0.01). LIMITATIONS Single-center nonrandomized study of mostly US male veterans. CONCLUSIONS Early nephrologist involvement in patients with AKI may reduce the risk of a further decrease in kidney function. A larger randomized trial is needed to confirm the findings.

Proton Pump Inhibitors and Risk of Incident CKD and Progression to ESRD

The association between proton pump inhibitors (PPI) use and risk of acute interstitial nephritis has been described. However, whether exposure to PPI associates with incident CKD, CKD progression, or ESRD is not known. We used Department of Veterans Affairs national databases to build a primary cohort of new users of PPI (n=173,321) and new users of histamine H2-receptor antagonists (H2 blockers; n=20,270) and followed these patients over 5 years to ascertain renal outcomes. In adjusted Cox survival models, the PPI group, compared with the H2 blockers group, had an increased risk of incident eGFR<60 ml/min per 1.73 m2 and of incident CKD (hazard ratio [HR], 1.22; 95% confidence interval [95% CI], 1.18 to 1.26; and HR, 1.28; 95% CI, 1.23 to 1.34, respectively). Patients treated with PPI also had a significantly elevated risk of doubling of serum creatinine level (HR, 1.53; 95% CI, 1.42 to 1.65), of eGFR decline >30% (HR, 1.32; 95% CI, 1.28 to 1.37), and of ESRD (HR, 1.96; 95% CI, 1.21 to 3.18). Furthermore, we detected a graded association between duration of PPI exposure and risk of renal outcomes among those exposed to PPI for 31-90, 91-180, 181-360, and 361-720 days compared with those exposed for ≤30 days. Examination of risk of renal outcomes in 1:1 propensity score-matched cohorts of patients taking H2 blockers versus patients taking PPI and patients taking PPI versus controls yielded consistent results. Our results suggest that PPI exposure associates with increased risk of incident CKD, CKD progression, and ESRD.

Risk of death among users of Proton Pump Inhibitors: A longitudinal observational cohort study of United States veterans

Objective Proton pump inhibitors (PPIs) are widely used, and their use is associated with increased risk of adverse events. However, whether PPI use is associated with excess risk of death is unknown. We aimed to examine the association between PPI use and risk of all-cause mortality. Design Longitudinal observational cohort study. Setting US Department of Veterans Affairs. Participants Primary cohort of new users of PPI or histamine H2 receptor antagonists (H2 blockers) (n=349 312); additional cohorts included PPI versus no PPI (n=3 288 092) and PPI versus no PPI and no H2 blockers (n=2 887 030). Main outcome measures Risk of death. Results Over a median follow-up of 5.71 years (IQR 5.11–6.37), PPI use was associated with increased risk of death compared with H2 blockers use (HR 1.25, CI 1.23 to 1.28). Risk of death associated with PPI use was higher in analyses adjusted for high-dimensional propensity score (HR 1.16, CI 1.13 to 1.18), in two-stage residual inclusion estimation (HR 1.21, CI 1.16 to 1.26) and in 1:1 time-dependent propensity score-matched cohort (HR 1.34, CI 1.29 to 1.39). The risk of death was increased when considering PPI use versus no PPI (HR 1.15, CI 1.14 to 1.15), and PPI use versus no PPI and no H2 blockers (HR 1.23, CI 1.22 to 1.24). Risk of death associated with PPI use was increased among participants without gastrointestinal conditions: PPI versus H2 blockers (HR 1.24, CI 1.21 to 1.27), PPI use versus no PPI (HR 1.19, CI 1.18 to 1.20) and PPI use versus no PPI and no H2 blockers (HR 1.22, CI 1.21 to 1.23). Among new PPI users, there was a graded association between the duration of exposure and the risk of death. Conclusions The results suggest excess risk of death among PPI users; risk is also increased among those without gastrointestinal conditions and with prolonged duration of use. Limiting PPI use and duration to instances where it is medically indicated may be warranted.

Tumor necrosis factor-α blockade, cardiovascular outcomes, and survival in rheumatoid arthritis

The effect of TNF-α blockade on the risk of cardiovascular outcomes and long-term survival in patients with rheumatoid arthritis (RA) is not known. We assembled a cohort of 20,811 (75,329 person-years) U.S. veterans who were diagnosed with RA between October 1998 and September 2005, and who were treated with a disease-modifying anti-rheumatic drug (DMARD). Cox survival models were built to examine the effect of TNF-α antagonists on the risk of a composite endpoint of cardiovascular outcomes defined as the occurrence of atherosclerotic heart disease, congestive heart failure, peripheral artery disease, or cerebrovascular disease, and on the risk of death. Treatment with TNF-α antagonists was not associated with a significant effect on the composite endpoint of cardiovascular outcomes. When each outcome was examined separately, the use TNF-α antagonists was not associated with an increased risk of atherosclerotic heart disease, congestive heart failure, or peripheral artery disease, but it was associated with decreased risk of cerebrovascular disease (hazard ratio [HR] = 0.83; confidence interval [CI] = 0.70-0.98). The use of TNF-α antagonists did not affect the risk of death (HR = 0.99; CI = 0.87-1.14). In subgroup analyses, the use TNF-α antagonists was associated with a reduced risk of cardiovascular outcomes (HR = 0.90, CI = 0.83-0.98) in patients younger than the median age of our cohort (63 years). The use TNF-α antagonists was not associated with a change in the risk of death in any other subgroup. These results show that the risk of cardiovascular events and survival in patients who receive TNF-α antagonists is not different than those who receive other DMARDs.

Mental health disorders and the risk of AIDS-defining illness and death in HIV-infected veterans.

Objective:Mental health comorbidities are common in HIV-infected veterans and can impact clinical outcomes for HIV. We examined the impact of mental health diagnoses on progression to AIDS-defining illness (ADI) and death in a large cohort of HIV-infected veterans who accessed care between 2001 and 2006. Design:Retrospective cohort study using the national Veterans Health Administration (VHA) HIV Clinical Case Registry. Methods:We identified HIV-infected veterans initiating combination antiretroviral therapy (cART) within the VHA between 2000 and 2006. The prevalences of the following mental health diagnoses were examined: schizophrenia, bipolar disorder, depression, anxiety, and substance use disorder. Cox proportional hazards models were constructed to examine the relationship between mental health conditions and two outcomes, all-cause mortality and ADI. Models were computed before and after adjusting for confounding factors including age, race, baseline CD4 cell count, comorbidities and cART adherence. Results:Among 9003 veterans receiving cART, 31% had no mental health diagnosis. Age, race, baseline comorbidity score, CD4, and cART adherence were associated with shorter time to ADI or death. All-cause mortality was more likely among veterans with schizophrenia, bipolar disorder and substance use, and ADI was more likely to occur among veterans with substance use disorder. Conclusions:Our results demonstrate the high prevalence of mental health diagnoses among HIV-infected veterans. In the era of highly active antiretroviral therapy, presence of psychiatric diagnoses impacted survival and development of ADI. More aggressive measures addressing substance abuse and severe mental illness in HIV-infected veterans are necessary.

Greater variability in kidney function is associated with an increased risk of death

Intra-individual variability in kidney function is a common phenomenon; however, predictors of kidney function variability and its prognostic significance are not known. To examine this question, we assembled a cohort of 51,304 US veterans with an estimated glomerular filtration rate (eGFR) <60 ml/min at the end of the study period and who had at least two eGFR measurements during the previous 3 years. Variability in kidney function was defined for each patient as the coefficient of variation of the regression line fitted to all outpatient measures of eGFR during this time frame. In adjusted analyses, blacks, women, and those with Current Procedural Terminology and ICD-9-CM diagnostic codes for hypertension, diabetes, cardiovascular disease, peripheral artery disease, chronic lung disease, hepatitis C, dementia, acute kidney injury, and those with a greater number of hospitalizations had greater variability in eGFR. After a median follow-up of 4.9 years, there were 23.66%, 25.68%, and 31.23% deaths among patients in the lowest, intermediate, and highest tertiles of eGFR variability, respectively. Compared with the referent (those in the lowest tertile), patients in the highest tertile had a significantly increased risk of death with a hazard ratio of 1.34 (1.28-1.40), an association consistently present in all sensitivity analyses. Thus, our results demonstrate that greater variability in kidney function is independently associated with increased risk of death.

High Density Lipoprotein Cholesterol and the Risk of All-Cause Mortality among U.S. Veterans

BACKGROUND AND OBJECTIVES The relationship between HDL cholesterol and all-cause mortality in patients with kidney disease is not clear. We sought to characterize the relationship of HDL cholesterol and risk of death and examine the association by eGFR levels. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS We built a cohort of 1,764,986 men who were United States veterans with at least one eGFR between October of 2003 and September of 2004 and followed them until September of 2013 or death. RESULTS Patients with low HDL cholesterol and low eGFR had a higher burden of comorbid illnesses. Over a median of 9.1 years (interquartile range, 7.7-9.4 years), 26,247 (40.1%), 109,222 (32.3%), 152,625 (29.2%), 113,785 (28.5%), and 139,803 (31.8%) participants with HDL cholesterol ≤25, >25 to <34, ≥34 to ≤42, >42 to <50, and ≥50 mg/dl died. In adjusted survival models, compared with the referent group of patients with low HDL cholesterol (≤25 mg/dl), intermediate HDL cholesterol levels (>25 to <34, ≥34 to ≤42, and >42 to <50 mg/dl) were associated with lower risk of death across all levels of eGFR. The lower risk was partially abrogated in those with high HDL cholesterol (≥50 mg/dl), and the risk of death was similar to the referent category among those with eGFR<30 or ≥90 ml/min per 1.73 m2. Analysis by HDL cholesterol deciles and spline analyses suggest that the relationship between HDL cholesterol and death follows a U-shaped curve. There was a significant interaction between eGFR and HDL cholesterol in that lower eGFR attenuated the salutary association of HDL cholesterol and risk of death (P for interaction <0.01). Presence of coronary artery disease attenuated the lower risk of high HDL cholesterol and all-cause mortality in those with eGFR≥60 ml/min per 1.73 m2 (P for interaction <0.05). CONCLUSIONS Our results show a U-shaped relationship between HDL cholesterol and risk of all-cause mortality across all eGFR categories. The risk is modified by eGFR and cardiovascular disease.