Publications by authors named "Ziyad Al-Aly"

80 Publications

Association of Ambient Fine Particulate Matter Air Pollution With Kidney Transplant Outcomes.

JAMA Netw Open 2021 Oct 1;4(10):e2128190. Epub 2021 Oct 1.

Institute for Public Health, Washington University School of Medicine in St. Louis, Missouri.

Importance: Increased levels of ambient fine particulate matter (PM2.5) air pollution are associated with increased risks for detrimental health outcomes, but risks for patients with kidney transplants (KTs) remain unknown.

Objective: To investigate the association of PM2.5 exposure with KT outcomes.

Design, Setting, And Participants: This retrospective cohort study was conducted using data on patients who received KTs from 2004 to 2016 who were identified in the national US transplant registry and followed up through March 2021. Multiple databases were linked to obtain data on PM2.5 concentration, KT outcomes, and patient clinical, transplant, and contextual factors. Data were analyzed from April 2020 through July 2021.

Exposures: Exposures included post-KT time-dependent annual mean PM2.5 level (in 10 μg/m3) and mean PM2.5 level in the year before KT (ie, baseline levels) in quartiles, as well as baseline annual mean PM2.5 level (in 10 μg/m3).

Main Outcomes And Measures: Acute kidney rejection (ie, rejection within 1 year after KT), time to death-censored graft failure, and time to all-cause death. Multivariable logistic regression for kidney rejection and Cox analyses with nonlinear assessment of exposure-response for death-censored graft failure and all-cause death were performed. The national burden of graft failure associated with PM2.5 levels greater than the Environmental Protection Agency recommended level of 12 μg/m3 was estimated.

Results: Among 112 098 patients with KTs, 70 522 individuals (62.9%) were older than age 50 years at the time of KT, 68 117 (60.8%) were men, and the median (IQR) follow-up was 6.0 (3.9-8.9) years. There were 37 265 Black patients (33.2%), 17 047 Hispanic patients (15.2%), 48 581 White patients [43.3%]), and 9205 patients (8.2%) of other race or ethnicity. The median (IQR) baseline PM2.5 level was 9.8 (8.3-11.9) μg/m3. Increased baseline PM2.5 level, compared with quartile 1 baseline PM2.5 level, was not associated with higher odds of acute kidney rejection for quartile 2 (adjusted odds ratio [aOR], 0.99; 95% CI, 0.92-1.06) but was associated with increased odds for quartile 3 (aOR, 1.11; 95% CI, 1.04-1.20) and quartile 4 (aOR, 1.13; 95% CI, 1.05-1.23). Nonlinear assessment of exposure-response for graft failure and death showed no evidence for nonlinearity. Increased PM2.5 levels were associated with increased risk of death-censored graft failure (adjusted hazard ratio [aHR] per 10 μg/m3 increase, 1.17; 95% CI, 1.09-1.25) and all-cause death (aHR per 10 μg/m3 increase, 1.21; 95% CI, 1.14-1.28). The national burden of death-censored graft failure associated with PM2.5 above 12 μg/m3 was 57 failures (95% uncertainty interval, 48-67 failures) per year among patients with KTs.

Conclusions And Relevance: This cohort study found that PM2.5 level was an independent risk factor associated with acute rejection, graft failure, and death among patients with KTs. These findings suggest that efforts toward decreasing levels of PM2.5 concentration may be associated with improved outcomes after KT.
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http://dx.doi.org/10.1001/jamanetworkopen.2021.28190DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8498852PMC
October 2021

Kidney Outcomes in Long COVID.

J Am Soc Nephrol 2021 Sep 1. Epub 2021 Sep 1.

Z Al-Aly, Research and Development Service, VA Saint Louis Health Care System Clinical Epidemiology Center, Saint Louis, United States

COVID-19 is associated with increased risk of post-acute sequelae involving pulmonary and extrapulmonary organ systems - referred to as long COVID. However, a detailed assessment of kidney outcomes in long COVID is not yet available. We built a cohort of 1,726,683 US Veterans identified from March 01, 2020 to March 15, 2021 including 89,216 30-day COVID-19 survivors and 1,637,467 non-infected controls. We examined risks of AKI, eGFR decline, ESKD, and major adverse kidney events (MAKE) defined as eGFR decline ≥50%, ESKD, or all-cause mortality using inverse probability weighted survival regressions, adjusting for predefined demographic and health characteristics, and algorithmically selected high-dimensional covariates including diagnoses, medications, and laboratory tests. Linear mixed models characterized intra-individual eGFR trajectory. Beyond the acute illness, 30-day survivors of COVID-19 exhibited a higher risk of AKI (aHR=1.94 (95%CI: 1.86,2.04)), eGFR decline ≥30% (1.25 (1.14,1.37)), eGFR decline ≥40% (1.44 (1.37,1.51)), eGFR decline ≥50% (1.62 (1.51,1.74)), ESKD (2.96 (2.49-3.51)), and MAKE (1.66 (1.58,1.74)). There was a graded increase in risks of post-acute kidney outcomes according to the severity of the acute infection (whether patients were non-hospitalized, hospitalized, or admitted to intensive care). Compared to non-infected controls, 30-day COVID-19 survivors exhibited excess eGFR decline of -3.26 (-3.58, -2.94), -5.20 (-6.24, -4.16), and -7.69 (-8.27, -7.12) mL/min/1.73m/year in non-hospitalized, hospitalized, and those admitted to intensive care during the acute phase of COVID-19 infection. COVID-19 survivors exhibited increased risk of kidney outcomes in the post-acute phase of the disease. Post-acute COVID-19 care should involve attention to kidney disease.
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http://dx.doi.org/10.1681/ASN.2021060734DOI Listing
September 2021

Temporal trends of COVID-19 mortality and hospitalisation rates: an observational cohort study from the US Department of Veterans Affairs.

BMJ Open 2021 08 16;11(8):e047369. Epub 2021 Aug 16.

Clinical Epidemiology Center, VA Saint Louis Health Care System, Saint Louis, Missouri, USA

Objectives: To investigate the temporal trends of 30-day mortality and hospitalisation in US Veterans with COVID-19 and 30-day mortality in hospitalised veterans with COVID-19 and to decompose the contribution of changes in the underlying characteristics of affected populations to these temporal changes.

Design: Observational cohort study.

Setting: US Department of Veterans Affairs.

Participants: 49 238 US veterans with a positive COVID-19 test between 20 March 2020 and 19 September 2020; and 9428 US veterans hospitalised with a positive COVID-19 test during the same period.

Outcome Measures: 30-day mortality rate and hospitalisation rate.

Results: Between 20 March 2020 and 19 September 2020 and in COVID-19 positive individuals, 30-day mortality rate dropped by 9.2% from 13.6% to 4.4%; hospitalisation rate dropped by 16.8% from 33.8% to 17.0%. In hospitalised COVID-19 individuals, 30-day mortality rate dropped by 12.7% from 23.5% to 10.8%. Among COVID-19 positive individuals, decomposition analyses suggested that changes in demographic, health and contextual characteristics, COVID-19 testing capacity, and hospital occupancy rates accounted for 40.2% and 33.3% of the decline in 30-day mortality and hospitalisation, respectively. Changes in the underlying characteristics of hospitalised COVID-19 individuals accounted for 29.9% of the decline in 30-day mortality.

Conclusion: Between March and September 2020, changes in demographic and health characteristics of people infected with COVID-19 contributed measurably to the substantial decline in 30-day mortality and hospitalisation.
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http://dx.doi.org/10.1136/bmjopen-2020-047369DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8370839PMC
August 2021

Predicting the environmental suitability for onchocerciasis in Africa as an aid to elimination planning.

PLoS Negl Trop Dis 2021 07 28;15(7):e0008824. Epub 2021 Jul 28.

Department of Health Policy Planning and Management, University of Health and Allied Sciences, Ho, Ghana.

Recent evidence suggests that, in some foci, elimination of onchocerciasis from Africa may be feasible with mass drug administration (MDA) of ivermectin. To achieve continental elimination of transmission, mapping surveys will need to be conducted across all implementation units (IUs) for which endemicity status is currently unknown. Using boosted regression tree models with optimised hyperparameter selection, we estimated environmental suitability for onchocerciasis at the 5 × 5-km resolution across Africa. In order to classify IUs that include locations that are environmentally suitable, we used receiver operating characteristic (ROC) analysis to identify an optimal threshold for suitability concordant with locations where onchocerciasis has been previously detected. This threshold value was then used to classify IUs (more suitable or less suitable) based on the location within the IU with the largest mean prediction. Mean estimates of environmental suitability suggest large areas across West and Central Africa, as well as focal areas of East Africa, are suitable for onchocerciasis transmission, consistent with the presence of current control and elimination of transmission efforts. The ROC analysis identified a mean environmental suitability index of 0·71 as a threshold to classify based on the location with the largest mean prediction within the IU. Of the IUs considered for mapping surveys, 50·2% exceed this threshold for suitability in at least one 5 × 5-km location. The formidable scale of data collection required to map onchocerciasis endemicity across the African continent presents an opportunity to use spatial data to identify areas likely to be suitable for onchocerciasis transmission. National onchocerciasis elimination programmes may wish to consider prioritising these IUs for mapping surveys as human resources, laboratory capacity, and programmatic schedules may constrain survey implementation, and possibly delaying MDA initiation in areas that would ultimately qualify.
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http://dx.doi.org/10.1371/journal.pntd.0008824DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8318275PMC
July 2021

Comparative Effectiveness of Sodium-Glucose Cotransporter 2 Inhibitors vs Sulfonylureas in Patients With Type 2 Diabetes.

JAMA Intern Med 2021 08;181(8):1043-1053

Clinical Epidemiology Center, Research and Development Service, VA St Louis Health Care System, St Louis, Missouri.

Importance: In the treatment of type 2 diabetes, evidence of the comparative effectiveness of sodium-glucose cotransporter 2 (SGLT2) inhibitors vs sulfonylureas-the second most widely used antihyperglycemic class after metformin-is lacking.

Objective: To evaluate the comparative effectiveness of SGLT2 inhibitors and sulfonylureas associated with the risk of all-cause mortality among patients with type 2 diabetes using metformin.

Design, Setting, And Participants: A cohort study used data from the US Department of Veterans Affairs compared the use of SGLT2 inhibitors vs sulfonylureas in individuals receiving metformin for treatment of type 2 diabetes. A total of 23 870 individuals with new use of SGLT2 inhibitors and 104 423 individuals with new use of sulfonylureas were enrolled between October 1, 2016, and February 29, 2020, and followed up until January 31, 2021.

Exposures: New use of SGLT2 inhibitors or sulfonylureas.

Main Outcomes And Measures: This study examined the outcome of all-cause mortality. Predefined variables and covariates identified by a high-dimensional variable selection algorithm were used to build propensity scores. The overlap weighting method based on the propensity scores was used to estimate the intention-to-treat effect sizes of SGLT2 inhibitor compared with sulfonylurea therapy. The inverse probability of the treatment adherence weighting method was used to estimate the per-protocol effect sizes.

Results: Among the 128 293 participants (mean [SD] age, 64.60 [9.84] years; 122 096 [95.17%] men), 23 870 received an SGLT2 inhibitor and 104 423 received a sulfonylurea. Compared with sulfonylureas, SGLT2 inhibitors were associated with reduced risk of all-cause mortality (hazard ratio [HR], 0.81; 95% CI, 0.75-0.87), yielding an event rate difference of -5.15 (95% CI, -7.16 to -3.02) deaths per 1000 person-years. Compared with sulfonylureas, SGLT2 inhibitors were associated with a reduced risk of death, regardless of cardiovascular disease status, in several categories of estimated glomerular filtration rate (including rates from >90 to ≤30 mL/min/1.73 m2) and in participants with no albuminuria (albumin to creatinine ratio [ACR] ≤30 mg/g), microalbuminuria (ACR >30 to ≤300 mg/g), and macroalbuminuria (ACR >300 mg/g). In per-protocol analyses, continued use of SGLT2 inhibitors was associated with a reduced risk of death compared with continued use of sulfonylureas (HR, 0.66; 95% CI, 0.60-0.74; event rate difference, -10.10; 95% CI, -12.97 to -7.24 deaths per 1000 person-years). In additional per-protocol analyses, continued use of SGLT2 inhibitors with metformin was associated with a reduced risk of death compared with SGLT2 inhibitor treatment without metformin (HR, 0.70; 95% CI, 0.50-0.97; event rate difference, -7.62; 95% CI, -17.12 to -0.48 deaths per 1000 person-years).

Conclusions And Relevance: In this comparative effectiveness study analyzing data from the US Department of Veterans Affairs, among patients with type 2 diabetes receiving metformin therapy, SGLT2 inhibitor treatment was associated with a reduced risk of all-cause mortality compared with sulfonylureas. The results provide data from a real-world setting that might help guide the choice of antihyperglycemic therapy.
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http://dx.doi.org/10.1001/jamainternmed.2021.2488DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8240007PMC
August 2021

Clinical Implications of Estimated Glomerular Filtration Rate Dip Following Sodium-Glucose Cotransporter-2 Inhibitor Initiation on Cardiovascular and Kidney Outcomes.

J Am Heart Assoc 2021 06 20;10(11):e020237. Epub 2021 May 20.

Clinical Epidemiology Center Research and Development Service VA Saint Louis Health Care System Saint Louis MO.

Background The frequency of the initial short-term decline in estimated glomerular filtration rate (eGFR), eGFR dip, following initiation of sodium-glucose cotransporter-2 inhibitors (SGLT2i) and its clinical implications in real-world practice are not clear. Methods and Results We built a cohort of 36 638 new users of SGLT2i and 209 025 new users of other antihyperglycemics. Inverse probability weighting was used to estimate the excess rate of eGFR dip, risk of the composite cardiovascular outcome of nonfatal myocardial infarction, nonfatal stroke, hospitalization for heart failure, or all-cause mortality, and risk of the composite kidney outcome of eGFR decline >50%, end-stage kidney disease, or all-cause mortality. In the first 6 months of therapy, compared with other antihyperglycemics, excess rates of eGFR dip >10% and eGFR dip >30% were 9.86 (95% CI: 8.83-11.00) and 1.15 (0.70-1.62) per 100 SGLT2i users, respectively. In mediation analyses that accounted for eGFR dipping, SGLT2i use was associated with reduced risk of cardiovascular and kidney outcomes (hazard ratio, 0.92 [0.84-0.99] and 0.78 [0.71-0.87], respectively); the magnitude of the association reduced by eGFR dipping was small for both outcomes. SGLT2i was associated with reduced risk of both outcomes in those with higher than average probability of eGFR dip >10% or 30%. Compared with discontinuation, continued use of SGLT2i at 6 months was associated with reduced risk of cardiovascular and kidney outcomes in those with no eGFR dip or eGFR dip ≤10%, in those with eGFR dip >10%, and in those with eGFR dip >30%. Conclusions The salutary association of SGLT2i with cardiovascular and kidney outcomes was maintained regardless of eGFR dipping; concerns about eGFR dipping should not preclude use, and occurrence of eGFR dip after SGLT2i initiation may not warrant discontinuation.
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http://dx.doi.org/10.1161/JAHA.120.020237DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8483543PMC
June 2021

Ambient fine particulate matter air pollution and the risk of hospitalization among COVID-19 positive individuals: Cohort study.

Environ Int 2021 09 9;154:106564. Epub 2021 Apr 9.

Clinical Epidemiology Center, Research and Development Service, VA Saint Louis Health Care System, 501 N Grand Blvd, Suite 300, Saint Louis, MO 63103, United States; Veterans Research & Education Foundation of Saint Louis, 501 N Grand Blvd, Suite 300, Saint Louis, MO 63103, United States; Department of Medicine, Washington University in Saint Louis, 4921 Parkview Pl, Saint Louis, MO 63110, United States; Nephrology Section, Medicine Service, VA Saint Louis Health Care System, 915 N Grand Blvd, Saint Louis, MO 63106, United States; Institute for Public Health, Washington University in Saint Louis, 600 S Taylor Ave, Saint Louis, MO 63110, United States. Electronic address:

Background: Ecologic analyses suggest that living in areas with higher levels of ambient fine particulate matter air pollution (PM) is associated with higher risk of adverse COVID-19 outcomes. Studies accounting for individual-level health characteristics are lacking.

Methods: We leveraged the breadth and depth of the US Department of Veterans Affairs national healthcare databases and built a national cohort of 169,102 COVID-19 positive United States Veterans, enrolled between March 2, 2020 and January 31, 2021, and followed them through February 15, 2021. Annual average 2018 PM exposure, at an approximately 1 km resolution, was linked with residential street address at the year prior to COVID-19 positive test. COVID-19 hospitalization was defined as first hospital admission between 7 days prior to, and 15 days after, the first COVID-19 positive date. Adjusted Poisson regression assessed the association of PM with risk of hospitalization.

Results: There were 25,422 (15.0%) hospitalizations; 5,448 (11.9%), 5,056 (13.0%), 7,159 (16.1%), and 7,759 (19.4%) were in the lowest to highest PM quartile, respectively. In models adjusted for State, demographic and behavioral factors, contextual characteristics, and characteristics of the pandemic a one interquartile range increase in PM (1.9 µg/m) was associated with a 10% (95% CI: 8%-12%) increase in risk of hospitalization. The association of PM and risk of hospitalization among COVID-19 individuals was present in each wave of the pandemic. Models of non-linear exposure-response suggested increased risk at PM concentrations below the national standard 12 µg/m. Formal effect modification analyses suggested higher risk of hospitalization associated with PM in Black people compared to White people (p = 0.045), and in those living in socioeconomically disadvantaged neighborhoods (p < 0.001).

Conclusions: Exposure to higher levels of PM was associated with increased risk of hospitalization among COVID-19 infected individuals. The risk was evident at PM levels below the regulatory standards. The analysis identified those of Black race and those living in disadvantaged neighborhoods as population groups that may be more susceptible to the untoward effect of PM on risk of hospitalization in the setting of COVID-19.
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http://dx.doi.org/10.1016/j.envint.2021.106564DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8040542PMC
September 2021

High-dimensional characterization of post-acute sequelae of COVID-19.

Nature 2021 06 22;594(7862):259-264. Epub 2021 Apr 22.

Clinical Epidemiology Center, Research and Development Service, VA Saint Louis Health Care System, Saint Louis, MO, USA.

The acute clinical manifestations of COVID-19 have been well characterized, but the post-acute sequelae of this disease have not been comprehensively described. Here we use the national healthcare databases of the US Department of Veterans Affairs to systematically and comprehensively identify 6-month incident sequelae-including diagnoses, medication use and laboratory abnormalities-in patients with COVID-19 who survived for at least 30 days after diagnosis. We show that beyond the first 30 days of illness, people with COVID-19 exhibit a higher risk of death and use of health resources. Our high-dimensional approach identifies incident sequelae in the respiratory system, as well as several other sequelae that include nervous system and neurocognitive disorders, mental health disorders, metabolic disorders, cardiovascular disorders, gastrointestinal disorders, malaise, fatigue, musculoskeletal pain and anaemia. We show increased incident use of several therapeutic agents-including pain medications (opioids and non-opioids) as well as antidepressant, anxiolytic, antihypertensive and oral hypoglycaemic agents-as well as evidence of laboratory abnormalities in several organ systems. Our analysis of an array of prespecified outcomes reveals a risk gradient that increases according to the severity of the acute COVID-19 infection (that is, whether patients were not hospitalized, hospitalized or admitted to intensive care). Our findings show that a substantial burden of health loss that spans pulmonary and several extrapulmonary organ systems is experienced by patients who survive after the acute phase of COVID-19. These results will help to inform health system planning and the development of multidisciplinary care strategies to reduce chronic health loss among individuals with COVID-19.
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http://dx.doi.org/10.1038/s41586-021-03553-9DOI Listing
June 2021

Ambient Fine Particulate Matter Air Pollution and Risk of Weight Gain and Obesity in United States Veterans: An Observational Cohort Study.

Environ Health Perspect 2021 04 1;129(4):47003. Epub 2021 Apr 1.

Clinical Epidemiology Center, Research and Development Service, Veterans Affairs Saint Louis Health Care System, Saint Louis, Missouri, USA.

Background: Experimental evidence and studies of children and adolescents suggest that ambient fine particulate matter [particulate matter in aerodynamic diameter ()] air pollution may be obesogenic, but the relationship between and the risk of body weight gain and obesity in adults is uncertain.

Objectives: Our goal was to characterize the association between and the risks of weight gain and obesity.

Methods: We followed 3,902,440 U.S. Veterans from 2010 to 2018 (median 8.1 y, interquartile range: 7.3-8.4) and assigned time-updated exposures by linking geocoded residential street addresses with satellite-based estimates of surface-level mass (at resolution). Associations with were estimated using Cox proportional hazards models for incident obesity [body mass index (] and a increase in weight relative to baseline and linear mixed models for associations with intra-individual changes in BMI and weight.

Results: A higher average annual concentration was associated with risk of incident obesity [; (95% CI: 1.06, 1.11)] and the risk of a () increase in weight [ (95% CI: 1.06, 1.08)] and with higher intra-individual changes in BMI [ (95% CI: 0.139, 0.142)] and weight [ (95% CI: 0.955, 0.981)]. Nonlinear exposure-response models indicated associations at concentrations below the national standard of . As expected, a negative exposure control (ambient air sodium) was not associated with obesity or weight gain. Associations were consistent in direction and magnitude across sensitivity analyses that included alternative outcomes and exposures assigned at different spatial resolutions.

Discussion: air pollution was associated with the risk of obesity and weight gain in a large predominantly male cohort of U.S. Veterans. Discussions about health effects of should include its association with obesity, and deliberations about the epidemiology of obesity should consider its association with . Investigation in other cohorts will deepen our understanding of the relationship between and weight gain and obesity. https://doi.org/10.1289/EHP7944.
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http://dx.doi.org/10.1289/EHP7944DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8016176PMC
April 2021

Temporal Trends in Incidence Rates of Lower Extremity Amputation and Associated Risk Factors Among Patients Using Veterans Health Administration Services From 2008 to 2018.

JAMA Netw Open 2021 01 4;4(1):e2033953. Epub 2021 Jan 4.

Clinical Epidemiology Center, Department of Veterans Affairs, St Louis Health Care Systems, St Louis, Missouri.

Importance: Lower extremity amputation (LEA) is associated with significant morbidity and mortality. However, national temporal trends of LEA incidence rates among US veterans and associated factors have not been well characterized.

Objective: To describe the temporal trends of LEA, characterize associated risk factors, and decompose the associations of these risk factors with changes in temporal trends of LEA among US veterans using Department of Veteran Affairs (VA) services between 2008 and 2018.

Design, Setting, And Participants: This cohort study used VA data from 2008 to 2018 to estimate incidence rates of LEA among veterans using VA services. Cox regression models were used to identify risk factors associated with LEA. Decomposition analyses estimated the associations of changes in prevalence of risk factors with changes in LEA rates. Data were analyzed from October 1, 2007, to September 30, 2018.

Main Outcomes And Measures: Toe, transmetatarsal, below-knee, or above-knee LEA.

Results: A total of 6 493 141 veterans were included (median [interquartile range] age, 64 [54-76] years; 6 060 390 [93.4%] men). Veterans were studied for a median (interquartile range) of 10.9 (5.6-11.0) years. Between 2008 and 2018, rates of LEA increased from 12.89 (95% CI, 12.53-13.25) LEA per 10 000 persons to 18.12 (95% CI, 17.70-18.54) LEA per 10 000 persons, representing a net increase of 5.23 (95% CI, 4.68-5.78) LEA per 10 000 persons. Between 2008 and 2018, toe amputation rates increased by 3.24 (2.89-3.59) amputations per 10 000 persons, accounting for 62.0% of the total increase in LEA rates. Transmetatarsal amputations increased by 1.54 (95% CI, 1.27-1.81) amputations per 10 000 persons; below-knee amputation rates increased by 0.81 (95% CI, 0.56-1.05) amputations per 10 000 persons; and above-knee amputation rates decreased by 0.37 (95% CI, 0.14-0.59) amputations per 10 000 persons. Compared with men, women had decreased risk of any LEA (hazard ratio [HR], 0.34 [95% CI, 0.31-0.37]). Factors associated with increased risk of any LEA included Black race (HR, 1.25 [95% CI, 1.21-1.28]) or another non-White race (ie, Asian, Latino, or other; HR, 2.36 [95% CI, 2.30-2.42]), obesity (HR, 1.59 [95% CI, 1.55-1.63]), diabetes (HR, 6.38 [95% CI, 6.22-6.54]), chronic kidney disease (CKD; eg, CKD stage 5: HR, 3.94 [95% CI, 3.22-4.83]), and smoking status (eg, current smoking: HR, 1.97 [95% CI, 1.92-2.03]). Decomposition analyses suggested that while changes in demographic composition, primarily driven by increased proportion of women veterans, associated with a decrease of 0.18 (95% CI, 0.14-0.22) LEA per 10 000 persons, and decreases in smoking rates, associated with a decrease of 0.88 (95% CI, 0.79-0.97) LEA per 10 000 persons. However, these were overwhelmed by increased rates of diabetes, associated with an increase of 1.86 (95% CI, 1.72-1.99) LEA per 10 000 persons; peripheral arterial disease, associated with an increase of 1.53 (95% CI, 1.41-1.65) LEA per 10 000 persons; CKD, associated with an increase of 1.45 (95% CI, 1.33-1.57) LEA per 10 000 persons; and other clinical factors, including body mass index, cancer, cardiovascular disease, cerebrovascular disease, chronic lung disease, dementia, and hypertension, associated with an increase of 1.45 (95% CI, 1.33-1.57) LEA per 10 000 persons.

Conclusions And Relevance: This cohort study found that incidence rates of LEA among veterans using VA services increased between 2008 and 2018. Efforts aimed at reducing burden of LEA should target the reduction of diabetes, peripheral arterial disease, and CKD at the individual and population levels.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.33953DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7823225PMC
January 2021

The Road Ahead for Research on Air Pollution and Kidney Disease.

J Am Soc Nephrol 2021 02 18;32(2):260-262. Epub 2021 Jan 18.

Clinical Epidemiology Center, Research and Development Service, Veterans Affairs St. Louis Health Care System, St. Louis, Missouri.

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http://dx.doi.org/10.1681/ASN.2020121713DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8054881PMC
February 2021

County-Level Contextual Characteristics and Disparities in Life Expectancy.

Mayo Clin Proc 2021 01;96(1):92-104

Clinical Epidemiology Center, Research and Education Service, VA Saint Louis Health Care System, Saint Louis, MO; Veterans Research & Education Foundation of Saint Louis, Saint Louis, MO; Department of Medicine, Washington University School of Medicine, Saint Louis, MO; Nephrology Section, Medicine Service, VA Saint Louis Health Care System, Saint Louis, MO; Institute for Public Health, Washington University in Saint Louis, Saint Louis, MO. Electronic address:

Objective: To estimate the contribution of county-level contextual factors to differences in life expectancy in the United States.

Methods: We used a counterfactual approach to estimate the years of life expectancy lost associated with 45 potentially modifiable county-level contextual characteristics in the United States in the year 2016. Contextual data and life expectancy data were obtained from the County Health Ranking Project and the U.S. Small-Area Life Expectancy Estimates Project, respectively.

Results: Median census-tract-level life expectancy was 78.90 (interquartile range, 76.30-81.00) years, and the range across census tracts spanned 41.20 years. Large variations in life expectancy existed within and between states and within and between counties; the gap between counties was 20.30 years and gaps within counties ranged from 0 to 34.60 years. An array of 45 county-level factors was associated with 4.30 years of life expectancy loss. County-level adult smoking, food insecurity, adult obesity, physical inactivity, college education, and median household income were associated with 1.24-, 0.89-, 0.58-, 0.35-, 0.33-, and 0.14-year losses in life expectancy, respectively; and altogether were associated with a 3.53-year loss in life expectancy. The contribution of contextual factors to years of life expectancy lost varied among states and was more pronounced in states with lower life expectancy and in areas of increased socioeconomic deprivation and increased percentage of Black race.

Conclusion: Substantial geographic variation in life expectancy was observed. Six county-level contextual factors were associated with a 3.53-year loss in life expectancy. The findings may inform and help prioritize approaches to reduce inequalities in life expectancy in the United States.
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http://dx.doi.org/10.1016/j.mayocp.2020.04.043DOI Listing
January 2021

Comparative evaluation of clinical manifestations and risk of death in patients admitted to hospital with covid-19 and seasonal influenza: cohort study.

BMJ 2020 12 15;371:m4677. Epub 2020 Dec 15.

Clinical Epidemiology Center, Research and Development Service, VA Saint Louis Health Care System, Saint Louis, MO, USA

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http://dx.doi.org/10.1136/bmj.m4677DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7735416PMC
December 2020

Acute Kidney Injury in a National Cohort of Hospitalized US Veterans with COVID-19.

Clin J Am Soc Nephrol 2020 12 16;16(1):14-25. Epub 2020 Nov 16.

Clinical Epidemiology Center, Research and Development Service, Veterans Affairs St. Louis Health Care System, St. Louis, Missouri

Background And Objectives: Coronavirus disease 2019 (COVID-19) is associated with higher risk of AKI. We aimed to describe rates and characterize predictors and health outcomes associated with AKI in a national cohort of US veterans hospitalized with COVID-19.

Design, Setting, Participants, & Measurements: In a cohort of 5216 US veterans hospitalized with COVID-19 identified through July 23, 2020, we described changes in serum creatinine and examined predictors of AKI and the associations between AKI, health resource utilization, and death, utilizing logistic regressions. We characterized geographic and temporal variations in AKI rates and estimated variance explained by key variables utilizing Poisson regressions.

Results: In total, 1655 (32%) participants had AKI; 961 (58%), 223 (13%), and 270 (16%) met Kidney Disease Improving Global Outcomes definitions of stage 1, 2, and 3 AKI, respectively, and 201 (12%) received KRT. Eight percent of participants had AKI within 1 day of hospitalization, and 47% did not recover to baseline serum creatinine by discharge. Older age, Black race, male gender, obesity, diabetes, hypertension, and lower eGFR were significant predictors of AKI during hospitalization with COVID-19. AKI was associated with higher mechanical ventilation use (odds ratio, 6.46; 95% confidence interval, 5.52 to 7.57) and longer hospital stay (5.56 additional days; 95% confidence interval, 4.78 to 6.34). AKI was also associated with higher risk of death (odds ratio, 6.71; 95% confidence interval, 5.62 to 8.04); this association was stronger in Blacks ( value of interaction <0.001). Hospital-level rates of AKI exhibited substantial geographic variability, ranging from 10% to 56%. Between March and July 2020, AKI rates declined from 40% to 27%; proportions of AKI stage 3 and AKI requiring KRT decreased from 44% to 17%. Both geographic and temporal variabilities were predominately explained by percentages of Blacks (31% and 49%, respectively).

Conclusions: AKI is common during hospitalization with COVID-19 and associated with higher risk of health care resource utilization and death. Nearly half of patients with AKI did not recover to baseline by discharge. Substantial geographic variation and temporal decline in rates and severity of AKI were observed.

Podcast: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2020_11_16_CJN09610620_final.mp3.
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http://dx.doi.org/10.2215/CJN.09610620DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7792643PMC
December 2020

Sustainable Development Goals relevant to kidney health: an update on progress.

Nat Rev Nephrol 2021 01 13;17(1):15-32. Epub 2020 Nov 13.

Munson Nephrology, Munson Healthcare, Traverse City, MI, USA.

Globally, more than 5 million people die annually from lack of access to critical treatments for kidney disease - by 2040, chronic kidney disease is projected to be the fifth leading cause of death worldwide. Kidney diseases are particularly challenging to tackle because they are pathologically diverse and are often asymptomatic. As such, kidney disease is often diagnosed late, and the global burden of kidney disease continues to be underappreciated. When kidney disease is not detected and treated early, patient care requires specialized resources that drive up cost, place many people at risk of catastrophic health expenditure and pose high opportunity costs for health systems. Prevention of kidney disease is highly cost-effective but requires a multisectoral holistic approach. Each Sustainable Development Goal (SDG) has the potential to impact kidney disease risk or improve early diagnosis and treatment, and thus reduce the need for high-cost care. All countries have agreed to strive to achieve the SDGs, but progress is disjointed and uneven among and within countries. The six SDG Transformations framework can be used to examine SDGs with relevance to kidney health that require attention and reveal inter-linkages among the SDGs that should accelerate progress.
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http://dx.doi.org/10.1038/s41581-020-00363-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7662029PMC
January 2021

Comparative Effectiveness of SGLT2 Inhibitors, GLP-1 Receptor Agonists, DPP-4 Inhibitors, and Sulfonylureas on Risk of Kidney Outcomes: Emulation of a Target Trial Using Health Care Databases.

Diabetes Care 2020 11 16;43(11):2859-2869. Epub 2020 Sep 16.

Clinical Epidemiology Center, Research and Development Service, VA St. Louis Health Care System, St. Louis, MO

Objective: To examine the comparative effectiveness of sodium-glucose cotransporter 2 inhibitors (SGLT2i), glucagon-like peptide 1 receptor agonists (GLP-1), dipeptidyl peptidase 4 inhibitors (DPP-4), and sulfonylureas on risk of kidney outcomes among people with type 2 diabetes.

Research Design And Methods: U.S. veterans initiated on SGLT2i ( = 18,544), GLP-1 ( = 23,711), DPP-4 ( = 39,399), or sulfonylureas ( = 134,904) were followed for up to 3 years to evaluate the risk of the composite outcome of estimated glomerular filtration rate (eGFR) decline >50%, end-stage kidney disease (ESKD), or all-cause mortality. Risks were estimated using survival models adjusted for predefined covariates as well as covariates identified by a high-dimensional variable selection algorithm through application of generalized propensity scores.

Results: Compared with those treated with sulfonylureas, treatment with SGLT2i, GLP-1, and DPP-4 was associated with a lower risk of the composite outcome (hazard ratio 0.68 [95% CI 0.63, 0.74], 0.72 [0.67, 0.77], and 0.90 [0.86, 0.95], respectively). While we did not observe a statistically significant difference in risk between the SGLT2i and GLP-1 arms (0.95 [0.87, 1.04]), both SGLT2i and GLP-1 had a lower risk of the composite outcome than DPP-4 (0.76 [0.70, 0.82] and 0.79 [0.74, 0.85], respectively). Analyses by eGFR category suggested that compared with the sulfonylurea arm, those in the SGLT2i and GLP-1 arms exhibited a lower risk of the composite outcome in all eGFR categories, including eGFR <45 mL/min/1.73 m. Compared with DPP-4, both SGLT2i and GLP-1 exhibited a reduced risk of the composite outcome in eGFR <90 to ≥60, <60 to ≥45, and <45 mL/min/1.73 m.

Conclusions: In type 2 diabetes, treatment with SGLT2i or GLP-1 compared with DPP-4 or sulfonylureas was associated with a lower risk of adverse kidney outcomes.
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http://dx.doi.org/10.2337/dc20-1890DOI Listing
November 2020

Comparative Effectiveness of the Sodium-Glucose Cotransporter 2 Inhibitor Empagliflozin Versus Other Antihyperglycemics on Risk of Major Adverse Kidney Events.

Diabetes Care 2020 11 10;43(11):2785-2795. Epub 2020 Sep 10.

Clinical Epidemiology Center, Research and Development Service, VA St. Louis Health Care System, St. Louis, MO

Objective: To examine the comparative effectiveness of the sodium-glucose cotransporter 2 inhibitor (SGLT2i) empagliflozin and other non-SGLT2i antihyperglycemics on the risk of major adverse kidney events (MAKE) of estimated glomerular filtration rate (eGFR) decline >50%, end-stage kidney disease, or all-cause mortality.

Research Design And Methods: In a cohort study of 379,033 new users of empagliflozin or other non-SGLT2i antihyperglycemics, predefined variables and covariates identified by a high-dimensional variable selection algorithm were used to build propensity scores. Weighted survival analyses were then applied to estimate the risk of MAKE.

Results: Compared with other antihyperglycemics, empagliflozin use was associated with 0.99 (95% CI 0.51, 1.55) mL/min/1.73 m less annual reduction in eGFR, 0.25 (95% CI 0.16, 0.33) kg/m more annual decrease in BMI, and reduced risk of MAKE (hazard ratio [HR] 0.68 [95% CI 0.64, 0.73]). Empagliflozin use was associated with reduced risk of MAKE in eGFR ≥90, ≥60 to <90, ≥45 to <60, and ≥30 to <45 mL/min/1.73 m (HR 0.70 [95% CI 0.60, 0.82], 0.66 [0.60, 0.73], 0.78 [0.69, 0.89]), and 0.71 [0.55, 0.92], respectively), in participants without albuminuria, with microalbuminuria and macroalbuminuria (HR 0.65 [95% CI 0.57, 0.75], 0.72 [0.66. 0.79], and 0.74 [0.62, 0.88], respectively), and in participants with and without cardiovascular disease (HR 0.67 [95% CI 0.61, 0.74] and 0.76 [0.69, 0.83], respectively). The association was evident in per-protocol analyses, which required continuation of the assigned antihyperglycemic medication (empagliflozin or other antihyperglycemics) during follow-up (HR 0.64 [95% CI 0.60, 0.70]), and in analyses requiring concurrent use of metformin in at least the first 90 days of follow-up (HR 0.63 [0.57-0.69]).

Conclusions: Among people with type 2 diabetes, empagliflozin use was associated with eGFR preservation, a greater decline in BMI, and a reduced risk of MAKE compared with other non-SGLT2i antihyperglycemics.
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http://dx.doi.org/10.2337/dc20-1231DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7576413PMC
November 2020

The global and national burden of chronic kidney disease attributable to ambient fine particulate matter air pollution: a modelling study.

BMJ Glob Health 2020 25;5(3):e002063. Epub 2020 Mar 25.

Clinical Epidemiology Center, VA Saint Louis Health Care System, Saint Louis, Missouri, USA.

Introduction: We aimed to integrate all available epidemiological evidence to characterise an exposure-response model of ambient fine particulate matter (PM) and the risk of chronic kidney disease (CKD) across the spectrum of PM concentrations experienced by humans. We then estimated the global and national burden of CKD attributable to PM.

Methods: We collected data from prior studies on the association of PM with CKD and used an integrative meta-regression approach to build non-linear exposure-response models of the risk of CKD associated with PM exposure. We then estimated the 2017 global and national incidence, prevalence, disability-adjusted life-years (DALYs) and deaths due to CKD attributable to PM in 194 countries and territories. Burden estimates were generated by linkage of risk estimates to Global Burden of Disease study datasets.

Results: The exposure-response function exhibited evidence of an increase in risk with increasing PM concentrations, where the rate of risk increase gradually attenuated at higher PM concentrations. Globally, in 2017, there were 3 284 358.2 (95% UI 2 800 710.5 to 3 747 046.1) incident and 122 409 460.2 (108 142 312.2 to 136 424 137.9) prevalent cases of CKD attributable to PM, and 6 593 134.6 (5 705 180.4 to 7 479 818.4) DALYs and 211 019.2 (184 292.5 to 236 520.4) deaths due to CKD attributable to PM. The burden was disproportionately borne by low income and lower middle income countries and exhibited substantial geographic variability, even among countries with similar levels of sociodemographic development. Globally, 72.8% of prevalent cases of CKD attributable to PM and 74.2% of DALYs due to CKD attributable to PM were due to concentrations above 10 µg/m, the WHO air quality guidelines.

Conclusion: The global burden of CKD attributable to PM is substantial, varies by geography and is disproportionally borne by disadvantaged countries. Most of the burden is associated with PM levels above the WHO guidelines, suggesting that achieving those targets may yield reduction in CKD burden.
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http://dx.doi.org/10.1136/bmjgh-2019-002063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7173767PMC
June 2021

Biomarkers of CKD in Children.

J Am Soc Nephrol 2020 05 31;31(5):894-896. Epub 2020 Mar 31.

Clinical Epidemiology Center, Research and Development Service, Veterans Affairs St. Louis Health Care System, St. Louis, Missouri.

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http://dx.doi.org/10.1681/ASN.2020020212DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7217413PMC
May 2020

Diabetes Minimally Mediated the Association Between PM Air Pollution and Kidney Outcomes.

Sci Rep 2020 03 12;10(1):4586. Epub 2020 Mar 12.

Clinical Epidemiology Center, Research and Education Service, VA Saint Louis Health Care System, Saint Louis, Missouri, USA.

Epidemiologic observations suggest that exposure to ambient fine particulate matter (PM) is associated with increased risk of chronic kidney disease (CKD) and diabetes, a causal driver of CKD. We evaluated whether diabetes mediates the association between PM and CKD. A cohort of 2,444,157 United States veterans were followed over a median 8.5 years. Environmental Protection Agency data provided PM exposure levels Regression models assessed associations and their proportion mediated. A 10 µg/m increase in PM was associated with increased odds of having a diabetes diagnosis (odds ratio: 1.18, 95% CI: 1.06-1.32), use of diabetes medication (1.22, 1.07-1.39), and increased risk of incident eGFR <60 ml/min/1.73 m (hazard ratio:1.20, 95% CI: 1.13-1.29), incident CKD (1.28, 1.18-1.39), ≥30% decline in eGFR (1.23, 1.15-1.33), and end-stage renal disease (ESRD) or ≥50% decline in eGFR (1.17, 1.05-1.30). Diabetes mediated 4.7% (4.3-5.7%) of the association of PM with incident eGFR <60 ml/min/1.73 m, 4.8% (4.2-5.8%) with incident CKD, 5.8% (5.0-7.0%) with ≥30% decline in eGFR, and 17.0% (13.1-20.4%) with ESRD or ≥50% decline in eGFR. Diabetes minimally mediated the association between PM and kidney outcomes. The findings will help inform more accurate estimates of the burden of diabetes and burden of kidney disease attributable to PM pollution.
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http://dx.doi.org/10.1038/s41598-020-61115-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7067761PMC
March 2020

Air Pollution and Kidney Disease.

Clin J Am Soc Nephrol 2020 03 27;15(3):301-303. Epub 2020 Feb 27.

Clinical Epidemiology Center, Research and Development Service, Saint Louis, Missouri.

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http://dx.doi.org/10.2215/CJN.16031219DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7057298PMC
March 2020

Burden of Cause-Specific Mortality Associated With PM2.5 Air Pollution in the United States.

JAMA Netw Open 2019 11 1;2(11):e1915834. Epub 2019 Nov 1.

Research and Education Service, Clinical Epidemiology Center, Veterans Affairs St Louis Health Care System, St Louis, Missouri.

Importance: Ambient fine particulate matter (PM2.5) air pollution is associated with increased risk of several causes of death. However, epidemiologic evidence suggests that current knowledge does not comprehensively capture all causes of death associated with PM2.5 exposure.

Objective: To systematically identify causes of death associated with PM2.5 pollution and estimate the burden of death for each cause in the United States.

Design, Setting, And Participants: In a cohort study of US veterans followed up between 2006 and 2016, ensemble modeling was used to identify and characterize morphology of the association between PM2.5 and causes of death. Burden of death associated with PM2.5 exposure in the contiguous United States and for each state was then estimated by application of estimated risk functions to county-level PM2.5 estimates from the US Environmental Protection Agency and cause-specific death rate data from the Centers for Disease Control and Prevention.

Main Outcomes And Measures: Nonlinear exposure-response functions of the association between PM2.5 and causes of death and burden of death associated with PM2.5.

Exposures: Annual mean PM2.5 levels.

Results: A cohort of 4 522 160 US veterans (4 243 462 [93.8%] male; median [interquartile range] age, 64.1 [55.7-75.5] years; 3 702 942 [82.0%] white, 667 550 [14.8%] black, and 145 593 [3.2%] other race) was followed up for a median (interquartile range) of 10.0 (6.8-10.2) years. In the contiguous United States, PM2.5 exposure was associated with excess burden of death due to cardiovascular disease (56 070.1 deaths [95% uncertainty interval {UI}, 51 940.2-60 318.3 deaths]), cerebrovascular disease (40 466.1 deaths [95% UI, 21 770.1-46 487.9 deaths]), chronic kidney disease (7175.2 deaths [95% UI, 5910.2-8371.9 deaths]), chronic obstructive pulmonary disease (645.7 deaths [95% UI, 300.2-2490.9 deaths]), dementia (19 851.5 deaths [95% UI, 14 420.6-31 621.4 deaths]), type 2 diabetes (501.3 deaths [95% UI, 447.5-561.1 deaths]), hypertension (30 696.9 deaths [95% UI, 27 518.1-33 881.9 deaths]), lung cancer (17 545.3 deaths [95% UI, 15 055.3-20 464.5 deaths]), and pneumonia (8854.9 deaths [95% UI, 7696.2-10 710.6 deaths]). Burden exhibited substantial geographic variation. Estimated burden of death due to nonaccidental causes was 197 905.1 deaths (95% UI, 183 463.3-213 644.9 deaths); mean age-standardized death rates (per 100 000) due to nonaccidental causes were higher among black individuals (55.2 [95% UI, 50.5-60.6]) than nonblack individuals (51.0 [95% UI, 46.4-56.1]) and higher among those living in counties with high (65.3 [95% UI, 56.2-75.4]) vs low (46.1 [95% UI, 42.3-50.4]) socioeconomic deprivation; 99.0% of the burden of death due to nonaccidental causes was associated with PM2.5 levels below standards set by the US Environmental Protection Agency.

Conclusions And Relevance: In this study, 9 causes of death were associated with PM2.5 exposure. The burden of death associated with PM2.5 was disproportionally borne by black individuals and socioeconomically disadvantaged communities. Effort toward cleaner air might reduce the burden of PM2.5-associated deaths.
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http://dx.doi.org/10.1001/jamanetworkopen.2019.15834DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6902821PMC
November 2019

Proton Pump Inhibitors and the Kidney: Implications of Current Evidence for Clinical Practice and When and How to Deprescribe.

Am J Kidney Dis 2020 04 10;75(4):497-507. Epub 2019 Oct 10.

Clinical Epidemiology Center, Research and Education Service, VA Saint Louis Health Care System, Saint Louis, MO; Veterans Research & Education Foundation of St. Louis, Saint Louis, MO.

Proton pump inhibitors (PPIs), long thought to be safe, are associated with a number of nonkidney adverse health outcomes and several untoward kidney outcomes, including hypomagnesemia, acute kidney injury, acute interstitial nephritis, incident chronic kidney disease, kidney disease progression, kidney failure, and increased risk for all-cause mortality and mortality due to chronic kidney disease. PPIs are abundantly prescribed, rarely deprescribed, and frequently purchased over the counter. They are frequently used without medical indication, and when medically indicated, they are often used for much longer than needed. In this In Practice review, we summarize evidence linking PPI use with adverse events in general and adverse kidney outcomes in particular. We review the literature on the association of PPI use and risk for hypomagnesemia, acute kidney injury, acute interstitial nephritis, incident chronic kidney disease, kidney disease progression, end-stage kidney disease, and death. We provide an assessment of how this evidence should inform clinical practice. We review the impact of this evidence on patients' perception of risk, synthesize PPI deprescription literature, and provide our recommendations on how to approach PPI use and deprescription.
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http://dx.doi.org/10.1053/j.ajkd.2019.07.012DOI Listing
April 2020

Global, Regional, and National Cancer Incidence, Mortality, Years of Life Lost, Years Lived With Disability, and Disability-Adjusted Life-Years for 29 Cancer Groups, 1990 to 2017: A Systematic Analysis for the Global Burden of Disease Study.

JAMA Oncol 2019 12;5(12):1749-1768

Department of Family and Community Medicine, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia.

Importance: Cancer and other noncommunicable diseases (NCDs) are now widely recognized as a threat to global development. The latest United Nations high-level meeting on NCDs reaffirmed this observation and also highlighted the slow progress in meeting the 2011 Political Declaration on the Prevention and Control of Noncommunicable Diseases and the third Sustainable Development Goal. Lack of situational analyses, priority setting, and budgeting have been identified as major obstacles in achieving these goals. All of these have in common that they require information on the local cancer epidemiology. The Global Burden of Disease (GBD) study is uniquely poised to provide these crucial data.

Objective: To describe cancer burden for 29 cancer groups in 195 countries from 1990 through 2017 to provide data needed for cancer control planning.

Evidence Review: We used the GBD study estimation methods to describe cancer incidence, mortality, years lived with disability, years of life lost, and disability-adjusted life-years (DALYs). Results are presented at the national level as well as by Socio-demographic Index (SDI), a composite indicator of income, educational attainment, and total fertility rate. We also analyzed the influence of the epidemiological vs the demographic transition on cancer incidence.

Findings: In 2017, there were 24.5 million incident cancer cases worldwide (16.8 million without nonmelanoma skin cancer [NMSC]) and 9.6 million cancer deaths. The majority of cancer DALYs came from years of life lost (97%), and only 3% came from years lived with disability. The odds of developing cancer were the lowest in the low SDI quintile (1 in 7) and the highest in the high SDI quintile (1 in 2) for both sexes. In 2017, the most common incident cancers in men were NMSC (4.3 million incident cases); tracheal, bronchus, and lung (TBL) cancer (1.5 million incident cases); and prostate cancer (1.3 million incident cases). The most common causes of cancer deaths and DALYs for men were TBL cancer (1.3 million deaths and 28.4 million DALYs), liver cancer (572 000 deaths and 15.2 million DALYs), and stomach cancer (542 000 deaths and 12.2 million DALYs). For women in 2017, the most common incident cancers were NMSC (3.3 million incident cases), breast cancer (1.9 million incident cases), and colorectal cancer (819 000 incident cases). The leading causes of cancer deaths and DALYs for women were breast cancer (601 000 deaths and 17.4 million DALYs), TBL cancer (596 000 deaths and 12.6 million DALYs), and colorectal cancer (414 000 deaths and 8.3 million DALYs).

Conclusions And Relevance: The national epidemiological profiles of cancer burden in the GBD study show large heterogeneities, which are a reflection of different exposures to risk factors, economic settings, lifestyles, and access to care and screening. The GBD study can be used by policy makers and other stakeholders to develop and improve national and local cancer control in order to achieve the global targets and improve equity in cancer care.
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http://dx.doi.org/10.1001/jamaoncol.2019.2996DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6777271PMC
December 2019

Estimates of all cause mortality and cause specific mortality associated with proton pump inhibitors among US veterans: cohort study.

BMJ 2019 05 29;365:l1580. Epub 2019 May 29.

Clinical Epidemiology Center, Department of Veterans Affairs St Louis Health Care System, 915 North Grand Boulevard, St Louis, MO 63106, USA

Objective: To estimate all cause mortality and cause specific mortality among patients taking proton pump inhibitors (PPIs).

Design: Longitudinal observational cohort study.

Setting: US Department of Veterans Affairs.

Participants: New users of PPIs (n=157 625) or H2 blockers (n=56 842).

Main Outcome Measures: All cause mortality and cause specific mortality associated with taking PPIs (values reported as number of attributable deaths per 1000 patients taking PPIs).

Results: There were 45.20 excess deaths (95% confidence interval 28.20 to 61.40) per 1000 patients taking PPIs. Circulatory system diseases (number of attributable deaths per 1000 patients taking PPIs 17.47, 95% confidence interval 5.47 to 28.80), neoplasms (12.94, 1.24 to 24.28), infectious and parasitic diseases (4.20, 1.57 to 7.02), and genitourinary system diseases (6.25, 3.22 to 9.24) were associated with taking PPIs. There was a graded relation between cumulative duration of PPI exposure and the risk of all cause mortality and death due to circulatory system diseases, neoplasms, and genitourinary system diseases. Analyses of subcauses of death suggested that taking PPIs was associated with an excess mortality due to cardiovascular disease (15.48, 5.02 to 25.19) and chronic kidney disease (4.19, 1.56 to 6.58). Among patients without documented indication for acid suppression drugs (n=116 377), taking PPIs was associated with an excess mortality due to cardiovascular disease (22.91, 11.89 to 33.57), chronic kidney disease (4.74, 1.53 to 8.05), and upper gastrointestinal cancer (3.12, 0.91 to 5.44). Formal interaction analyses suggested that the risk of death due to these subcauses was not modified by a history of cardiovascular disease, chronic kidney disease, or upper gastrointestinal cancer. Taking PPIs was not associated with an excess burden of transportation related mortality and death due to peptic ulcer disease (as negative outcome controls).

Conclusions: Taking PPIs is associated with a small excess of cause specific mortality including death due to cardiovascular disease, chronic kidney disease, and upper gastrointestinal cancer. The burden was also observed in patients without an indication for PPI use. Heightened vigilance in the use of PPI may be warranted.
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http://dx.doi.org/10.1136/bmj.l1580DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6538974PMC
May 2019

Estimates of the 2016 global burden of kidney disease attributable to ambient fine particulate matter air pollution.

BMJ Open 2019 05 9;9(5):e022450. Epub 2019 May 9.

Clinical Epidemiology Center, Research and Education Service, VA Saint Louis Health Care System, Saint Louis, Missouri, USA.

Objective: To quantitate the 2016 global and national burden of chronic kidney disease (CKD) attributable to ambient fine particulate matter air pollution ≤ 2.5 μm in aerodynamic diameter (PM).

Design: We used the Global Burden of Disease (GBD) study data and methodologies to estimate the 2016 burden of CKD attributable to PM in 194 countries and territories. Population-weighted PM levels and incident rates of CKD for each country were curated from the GBD study publicly available data sources.

Setting: GBD global and national data on PM and CKD.

Participants: 194 countries and territories.

Main Outcome Measures: We estimated the attributable burden of disease (ABD), years living with disability (YLD), years of life lost (YLL) and disability-adjusted life-years (DALYs).

Results: The 2016 global burden of incident CKD attributable to PM was 6 950 514 (95% uncertainty interval: 5 061 533-8 914 745). Global YLD, YLL and DALYs of CKD attributable to PM were 2 849 311 (1 875 219-3 983 941), 8 587 735 (6 355 784-10 772 239) and 11 445 397 (8 380 246-14 554 091), respectively. Age-standardised ABD, YLL, YLD and DALY rates varied substantially among geographies. Populations in Mesoamerica, Northern Africa, several countries in the Eastern Mediterranean region, Afghanistan, Pakistan, India and several countries in Southeast Asia were among those with highest age-standardised DALY rates. For example, age-standardised DALYs per 100 000 were 543.35 (391.16-707.96) in El Salvador, 455.29 (332.51-577.97) in Mexico, 408.41 (283.82-551.84) in Guatemala, 238.25 (173.90-303.98) in India and 178.26 (125.31-238.47) in Sri Lanka, compared with 5.52 (0.82-11.48) in Sweden, 6.46 (0.00-14.49) in Australia and 12.13 (4.95-21.82) in Canada. Frontier analyses showed that Mesoamerican countries had significantly higher CKD DALY rates relative to other countries with comparable sociodemographic development.

Conclusions: Our results demonstrate that the global toll of CKD attributable to ambient air pollution is significant and identify several endemic geographies where air pollution may be a significant driver of CKD burden. Air pollution may need to be considered in the discussion of the global epidemiology of CKD.
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http://dx.doi.org/10.1136/bmjopen-2018-022450DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6528010PMC
May 2019

Changes in the US Burden of Chronic Kidney Disease From 2002 to 2016: An Analysis of the Global Burden of Disease Study.

JAMA Netw Open 2018 11 2;1(7):e184412. Epub 2018 Nov 2.

Clinical Epidemiology Center, Research and Education Service, Veterans Affairs St Louis Health Care System, St Louis, Missouri.

Introduction: Over the past 15 years, changes in demographic, social, and epidemiologic trends occurred in the United States. These changes likely contributed to changes in chronic kidney disease (CKD) epidemiology.

Objective: To describe the change in burden of CKD at the US state level from 2002 to 2016.

Design, Setting, And Participants: This systematic analysis used data and methodologies from the 2016 Global Burden of Disease study in the United States. Data on CKD from 2002 to 2016 were examined at the state level.

Main Outcomes And Measures: Disability-adjusted life years (DALYs) and death due to CKD.

Results: In this analysis of data from individuals in the United States, from 2002 to 2016, CKD DALYs increased by 52.6%, from 1 269 049 DALYs (95% uncertainty interval [UI], 1 154 521-1 387 008) to 1 935 954 DALYs (95% UI, 1 747 356-2 124 795). Death due to CKD increased by 58.3%, from 52 127 deaths (95% UI, 51 082-53 076) to 82 539 deaths (95% UI, 80 298-84 652). All states exhibited increases in CKD burden, but the rate of change (2002-2016) and the burden in 2016 varied by state. States in the southern United States (including Mississippi and Louisiana) exhibited more than twice the burden seen in other states (eg, the age-standardized CKD DALY rate in Vermont was 321 [95% UI, 281-363] per 100 000 population, whereas the rate in Mississippi was 697 [95% UI, 620-779] per 100 000 population). In the United States, the increase in CKD DALYs was attributable to increased risk exposure (40.3%), aging (32.3%), and population growth (27.4%). Age-standardized CKD DALY rates increased by 18.6% where increases in metabolic, and to a lesser extent dietary, risk factors contributed 93.8% and 5.3% of this change, respectively. Chronic kidney disease due to diabetes was the primary contributor for the 26.8% increased probability of death due to CKD among the population aged 20 to 54 years; among the population aged 55 to 89 years, the probability of death due to CKD increased by 25.6% and was driven by CKD due to diabetes and decreased probability of death from causes other than CKD. Improvement in sociodemographic development was coupled with an increase in age-standardized CKD DALY rates that occurred at a faster pace than that of other noncommunicable diseases in the United States.

Conclusions And Relevance: Our findings revealed that between 2002 and 2016, the burden of CKD in the United States appeared to be increasing and variable among states. These changes may be associated with increased risk exposure and demographic expansion leading to increased probability of death due to CKD, especially among young adults. The findings suggest that an effort to target the reduction of CKD through greater attention to metabolic and dietary risks, especially among younger adults, is necessary.
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http://dx.doi.org/10.1001/jamanetworkopen.2018.4412DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6324659PMC
November 2018

Analysis of the Global Burden of Disease study highlights the global, regional, and national trends of chronic kidney disease epidemiology from 1990 to 2016.

Kidney Int 2018 09 3;94(3):567-581. Epub 2018 Aug 3.

Clinical Epidemiology Center, Research and Education Service, VA St. Louis Health Care System, St. Louis, Missouri, USA; Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA; Nephrology Section, Medicine Service, VA St. Louis Health Care System, St. Louis, Missouri, USA; Institute for Public Health, Washington University in St. Louis, St. Louis, Missouri, USA. Electronic address:

The last quarter century witnessed significant population growth, aging, and major changes in epidemiologic trends, which may have shaped the state of chronic kidney disease (CKD) epidemiology. Here, we used the Global Burden of Disease study data and methodologies to describe the change in burden of CKD from 1990 to 2016 involving incidence, prevalence, death, and disability-adjusted-life-years (DALYs). Globally, the incidence of CKD increased by 89% to 21,328,972 (uncertainty interval 19,100,079- 23,599,380), prevalence increased by 87% to 275,929,799 (uncertainty interval 252,442,316-300,414,224), death due to CKD increased by 98% to 1,186,561 (uncertainty interval 1,150,743-1,236,564), and DALYs increased by 62% to 35,032,384 (uncertainty interval 32,622,073-37,954,350). Measures of burden varied substantially by level of development and geography. Decomposition analyses showed that the increase in CKD DALYs was driven by population growth and aging. Globally and in most Global Burden of Disease study regions, age-standardized DALY rates decreased, except in High-income North America, Central Latin America, Oceania, Southern Sub-Saharan Africa, and Central Asia, where the increased burden of CKD due to diabetes and to a lesser extent CKD due to hypertension and other causes outpaced burden expected by demographic expansion. More of the CKD burden (63%) was in low and lower-middle-income countries. There was an inverse relationship between age-standardized CKD DALY rate and health care access and quality of care. Frontier analyses showed significant opportunities for improvement at all levels of the development spectrum. Thus, the global toll of CKD is significant, rising, and unevenly distributed; it is primarily driven by demographic expansion and in some regions a significant tide of diabetes. Opportunities exist to reduce CKD burden at all levels of development.
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http://dx.doi.org/10.1016/j.kint.2018.04.011DOI Listing
September 2018

The 2016 global and national burden of diabetes mellitus attributable to PM air pollution.

Lancet Planet Health 2018 07;2(7):e301-e312

Clinical Epidemiology Center, Research and Education Service, VA Saint Louis Health Care System, Saint Louis, Missouri, MO, USA; Nephrology Section, Medicine Service, VA Saint Louis Health Care System, Saint Louis, Missouri, MO, USA; Department of Medicine, Washington University School of Medicine, Saint Louis, MO, USA; Institute for Public Health, Washington University in Saint Louis, Saint Louis, MO, USA. Electronic address:

Background: PM air pollution is associated with increased risk of diabetes; however, a knowledge gap exists to further define and quantify the burden of diabetes attributable to PM air pollution. Therefore, we aimed to define the relationship between PM and diabetes. We also aimed to characterise an integrated exposure response function and to provide a quantitative estimate of the global and national burden of diabetes attributable to PM.

Methods: We did a longitudinal cohort study of the association of PM with diabetes. We built a cohort of US veterans with no previous history of diabetes from various databases. Participants were followed up for a median of 8·5 years, we and used survival models to examine the association between PM and the risk of diabetes. All models were adjusted for sociodemographic and health characteristics. We tested a positive outcome control (ie, risk of all-cause mortality), negative exposure control (ie, ambient air sodium concentrations), and a negative outcome control (ie, risk of lower limb fracture). Data for the models were reported as hazard ratios (HRs) and 95% CIs. Additionally, we reviewed studies of PM and the risk of diabetes, and used the estimates to build a non-linear integrated exposure response function to characterise the relationship across all concentrations of PM exposure. We included studies into the building of the integrated exposure response function if they scored at least a four on the Newcastle-Ottawa Quality Assessment Scale and were only included if the outcome was type 2 diabetes or all types of diabetes. Finally, we used the Global Burden of Disease study data and methodologies to estimate the attributable burden of disease (ABD) and disability-adjusted life-years (DALYs) of diabetes attributable to PM air pollution globally and in 194 countries and territories.

Findings: We examined the relationship of PM and the risk of incident diabetes in a longitudinal cohort of 1 729 108 participants followed up for a median of 8·5 years (IQR 8·1-8·8). In adjusted models, a 10 μg/m increase in PM was associated with increased risk of diabetes (HR 1·15, 95% CI 1·08-1·22). PM was associated with increased risk of death as the positive outcome control (HR 1·08, 95% CI 1·03-1·13), but not with lower limb fracture as the negative outcome control (1·00, 0·91-1·09). An IQR increase (0·045 μg/m) in ambient air sodium concentration as the negative exposure control exhibited no significant association with the risk of diabetes (HR 1·00, 95% CI 0·99-1·00). An integrated exposure response function showed that the risk of diabetes increased substantially above 2·4 μg/m, and then exhibited a more moderate increase at concentrations above 10 μg/m. Globally, ambient PM contributed to about 3·2 million (95% uncertainty interval [UI] 2·2-3·8) incident cases of diabetes, about 8·2 million (95% UI 5·8-11·0) DALYs caused by diabetes, and 206 105 (95% UI 153 408-259 119) deaths from diabetes attributable to PM exposure. The burden varied substantially among geographies and was more heavily skewed towards low-income and lower-to-middle-income countries.

Interpretation: The global toll of diabetes attributable to PM air pollution is significant. Reduction in exposure will yield substantial health benefits.

Funding: US Department of Veterans Affairs.
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http://dx.doi.org/10.1016/S2542-5196(18)30140-2DOI Listing
July 2018
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