Benjamin Bowe

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.

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.

Rate of Kidney Function Decline and Risk of Hospitalizations in Stage 3A CKD

BACKGROUND AND OBJECTIVES Risk of hospitalizations is increased in patients with CKD. We sought to examine the association between rate of kidney function decline and risk of hospitalization in a cohort of patients with early CKD. DESIGN, SETTINGS, PARTICIPANTS, & MEASUREMENTS We built a cohort of 247,888 United States veterans who had at least one eGFR measurement between October 1999 and September 2003 and an additional eGFR between October 2003 and September 2004. We selected patients whose initial eGFR was between 45 and 59 ml/min per 1.73 m2. Rate of eGFR change (in milliliters per minute per 1.73 m2 per year) was categorized as no decline (>0), mild (0 to -1, and served as the referent group), moderate (-1 to -5), or severe (>-5) eGFR decline. We built survival models to examine the association between the rate of kidney function decline and the risk of hospitalization and readmission and linear regression to estimate length of hospital stay. RESULTS Over a median observation of 9 years (interquartile range, 5.28-9.00), patients with moderate and severe eGFR decline exhibited a higher risk of hospitalizations (hazard ratio [HR], 1.22; 95% confidence interval [95% CI], 1.19 to 1.26; and HR, 1.33; 95% CI, 1.28 to 1.39, respectively). Among patients with moderate and severe eGFR decline, the association between the rate of decline and the risk of hospitalizations was more pronounced with an increased number of hospitalizations (P<0.01). Patients with moderate and severe eGFR decline had a higher risk of readmission (HR, 1.19; 95% CI, 1.13 to 1.26; and HR, 1.53; 95% CI, 1.43 to 1.63, respectively). Among patients with severe eGFR decline, the association between the rate of kidney function decline and the risk of readmission was stronger with an increased number of readmissions (P<0.01). Patients with moderate and severe eGFR decline experienced an additional length of stay of 1.40 (95% CI, 0.88 to 1.92) and 5.00 days per year (95% CI, 4.34 to 5.66), respectively. CONCLUSIONS The rate of kidney function decline is associated with a higher risk of hospitalizations, readmissions, and prolonged length of hospital stay.

Renal Function Trajectories in Patients with Prior Improved eGFR Slopes and Risk of Death

Background Multiple prior studies demonstrated that patients with early Chronic Kidney Disease (CKD) and positive estimated Glomerular Filtration Rate (eGFR) slopes experience increased risk of death. We sought to characterize patients with positive eGFR slopes, examine the renal function trajectory that follows the time period where positive slope is observed, and examine the association between different trajectories and risk of death. Methods and Findings We built a cohort of 204,132 United States veterans with early CKD stage 3; eGFR slopes were defined based on Bayesian mixed-effects models using outpatient eGFR measurements between October 1999 and September 2004; to build renal function trajectories, patients were followed longitudinally thereafter (from October 2004) until September 2013. There were 41,410 (20.29%) patients with positive eGFR slope and they exhibited increased risk of death compared to patients with stable eGFR slope (HR = 1.33, CI:1.31–1.35). There was an inverse graded association between severity of albuminuria and the odds of positive eGFR slope (OR = 0.94, CI:0.90–0.98, and OR = 0.76, CI:0.69–0.84 for microalbuminuria and albuminuria; respectively). Following the time period where positive eGFR slope is observed, we characterized 4 trajectory phenotypes: high eGFR intercept and positive trajectory (HIPT) (12.42%), intermediate intercept and mild negative trajectory (IIMNT) (60.04%), low intercept and fast negative trajectory (LIFNT)(23.33%), and high intercept and fast negative trajectory (HIFNT) (4.20%). Compared to IIMNT (reference group), HIPT is associated with younger age, dementia, HIV, chronic lung disease, peripheral artery disease, weight loss, and inversely associated with albuminuria; LIFNT and HIFNT were associated with diabetes, hypertension, cardiovascular disease, peripheral artery disease, and albuminuria. The risk of death at 9 years was lowest in IIMNT (HR = 1.12, CI:1.09–1.14), highest in HIPT (HR = 1.71, CI:1.63–1.79), and intermediate in LIFNT (HR = 1.36, CI:1.32–1.40) and HIFNT (HR = 1.56, CI:1.45–1.68). Conclusions Our results demonstrate that patients with positive eGFR slopes, when followed over longer period of time, follow 4 distinct trajectory phenotypes that have distinct demographic and clinical correlates and are differentially associated with risk of death.

Particulate Matter Air Pollution and the Risk of Incident CKD and Progression to ESRD

Elevated levels of fine particulate matter <2.5 µm in aerodynamic diameter (PM2.5) are associated with increased risk of cardiovascular outcomes and death, but their association with risk of CKD and ESRD is unknown. We linked the Environmental Protection Agency and the Department of Veterans Affairs databases to build an observational cohort of 2,482,737 United States veterans, and used survival models to evaluate the association of PM2.5 concentrations and risk of incident eGFR <60 ml/min per 1.73 m2, incident CKD, eGFR decline ≥30%, and ESRD over a median follow-up of 8.52 years. County-level exposure was defined at baseline as the annual average PM2.5 concentrations in 2004, and separately as time-varying where it was updated annually and as cohort participants moved. In analyses of baseline exposure (median, 11.8 [interquartile range, 10.1-13.7] µg/m3), a 10-µg/m3 increase in PM2.5 concentration was associated with increased risk of eGFR<60 ml/min per 1.73 m2 (hazard ratio [HR], 1.21; 95% confidence interval [95% CI], 1.14 to 1.29), CKD (HR, 1.27; 95% CI, 1.17 to 1.38), eGFR decline ≥30% (HR, 1.28; 95% CI, 1.18 to 1.39), and ESRD (HR, 1.26; 95% CI, 1.17 to 1.35). In time-varying analyses, a 10-µg/m3 increase in PM2.5 concentration was associated with similarly increased risk of eGFR<60 ml/min per 1.73 m2, CKD, eGFR decline ≥30%, and ESRD. Spline analyses showed a linear relationship between PM2.5 concentrations and risk of kidney outcomes. Exposure estimates derived from National Aeronautics and Space Administration satellite data yielded consistent results. Our findings demonstrate a significant association between exposure to PM2.5 and risk of incident CKD, eGFR decline, and ESRD.

Association between Monocyte Count and Risk of Incident CKD and Progression to ESRD

BACKGROUND AND OBJECTIVES Experimental evidence suggests a role for monocytes in the biology of kidney disease progression; however, whether monocyte count is associated with risk of incident CKD, CKD progression, and ESRD has not been examined in large epidemiologic studies. DESIGN, SETTINGS, PARTICIPANTS, & MEASUREMENTS We built a longitudinal observational cohort of 1,594,700 United States veterans with at least one eGFR during fiscal year 2004 (date of last eGFR during this period designated time zero) and no prior history of ESRD, dialysis, or kidney transplant. Cohort participants were followed until September 30, 2013 or death. Monocyte count closest to and before time zero was categorized in quartiles: quartile 1, >0.00 to ≤0.40 thousand cells per cubic millimeter (k/cmm); quartile 2, >0.40 to ≤0.55 k/cmm; quartile 3, >0.55 to ≤0.70 k/cmm; and quartile 4, >0.70 k/cmm. Survival models were built to examine the association between monocyte count and risk of incident eGFR<60 ml/min per 1.73 m2, risk of incident CKD, and risk of CKD progression defined as doubling of serum creatinine, eGFR decline ≥30%, or the composite outcome of ESRD, dialysis, or renal transplantation. RESULTS Over a median follow-up of 9.2 years (interquartile range, 8.3-9.4); in adjusted survival models, there was a graded association between monocyte counts and risk of renal outcomes. Compared with quartile 1, quartile 4 was associated with higher risk of incident eGFR<60 ml/min per 1.73 m2 (hazard ratio, 1.13; 95% confidence interval, 1.12 to 1.14) and risk of incident CKD (hazard ratio, 1.15; 95% confidence interval, 1.13 to 1.16). Quartile 4 was associated with higher risk of doubling of serum creatinine (hazard ratio, 1.22; 95% confidence interval, 1.20 to 1.24), ≥30% eGFR decline (hazard ratio, 1.18; 95% confidence interval, 1.17 to 1.19), and the composite renal end point (hazard ratio, 1.19; 95% confidence interval, 1.16 to 1.22). Cubic spline analyses of the relationship between monocyte count levels and renal outcomes showed a linear relationship, in which risk was higher with higher monocyte count. Results were robust to changes in sensitivity analyses. CONCLUSIONS Our results show a significant association between higher monocyte count and risks of incident CKD and CKD progression to ESRD.

Geographic Variation and US County Characteristics Associated With Rapid Kidney Function Decline

Introduction Geographic variation in the prevalence of chronic kidney disease and incidence of end-stage renal disease has been previously reported. However, the geographic epidemiology of rapid estimated glomerular filtration rate (eGFR) decline has not been examined. Methods We built a longitudinal cohort of 2,107,570 US veterans to characterize the spatial epidemiology of and examine the associations between US county characteristics and rapid eGFR decline. Results There were 169,029 (8.02%) with rapid eGFR decline (defined as eGFR slope < –5 ml/min per 1.73 m2/year). The prevalence of rapid eGFR decline adjusted for age, race, gender, diabetes, and hypertension varied by county from 4.10%–6.72% in the lowest prevalence quintile to 8.41%–22.04% in the highest prevalence quintile (P for heterogeneity < 0.001). Examination of adjusted prevalence showed substantial geographic variation in those with and without diabetes and those with and without hypertension (P for heterogeneity < 0.001). Cohort participants had higher odds of rapid eGFR decline when living in counties with unfavorable characteristics in domains including health outcomes (odds ratio [OR] = 1.15; confidence interval [CI] = 1.09–1.22), health behaviors (OR = 1.08; CI = 1.03–1.13), clinical care (OR = 1.11; CI = 1.06–1.16), socioeconomic conditions (OR = 1.15; CI = 1.09–1.22), and physical environment (OR = 1.15; CI = 1.01–1.20); living in counties with high percentage of minorities and immigrants was associated with rapid eGFR decline (OR = 1.25; CI = 1.20–1.31). Spatial analyses suggest the presence of cluster of counties with high prevalence of rapid eGFR decline. Discussion Our findings show substantial geographic variation in rapid eGFR decline among US veterans; the variation persists in analyses stratified by diabetes and hypertension status; results show associations between US county characteristics in domains capturing health, socioeconomic, environmental, and diversity conditions, and rapid eGFR decline.

Associations of ambient coarse particulate matter, nitrogen dioxide, and carbon monoxide with the risk of kidney disease: a cohort study

BACKGROUND Experimental evidence and preliminary clinical evidence suggest that environmental air pollution adversely effects kidney health. Previous work has examined the association between fine particulate matter and risk of kidney disease; however, the association between ambient coarse particulate matter (PM10; ≤10 μm in aerodynamic diameter), nitrogen dioxide (NO2), and carbon monoxide (CO) and risk of incident chronic kidney disease, chronic kidney disease progression, and end-stage renal disease is not clear. METHODS We merged multiple large databases, including those of the Environmental Protection Agency and the Department of Veterans Affairs, to build a cohort of US veterans, and used survival models to evaluate the association between PM10, NO2, and CO concentrations and risk of incident estimated glomerular filtration rate (eGFR) of less than 60 mL/min per 1·73 m2, incident chronic kidney disease, eGFR decline of 30% or more, and end-stage renal disease. We treated exposure as time-varying when it was updated annually and as cohort participants moved. FINDINGS Between Oct 1, 2003, and Sept 30, 2012, 2 010 398 cohort participants were followed up over a median of 8·52 years (IQR 8·05-8·80). An increased risk of eGFR of less than 60 mL/min per 1·73 m2 was associated with an IQR increase in concentrations of PM10 (hazard ratio 1·07, 95% CI 1·06-1·08), NO2 (1·09, 1·08-1·10), and CO (1·09, 1·08-1·10). An increased risk of incident chronic kidney disease was associated with an IQR increase in concentrations of PM10 (1·07, 1·05-1·08), NO2 (1·09, 1·08-1·11), and CO (1·10, 1·08-1·11). An increased risk of an eGFR decline of 30% or more was associated with an IQR increase in concentrations of PM10 (1·08, 1·07-1·09), NO2 (1·12, 1·10-1·13), and CO (1·09, 1·08-1·10). An increased risk of end-stage renal disease was associated with an IQR increase in concentrations of PM10 (1·09, 1·06-1·12), NO2 (1·09, 1·06-1·12), and CO (1·05, 1·02-1·08). Spline analyses suggested a monotonic increasing association between PM10, NO2, and CO concentrations and risk of kidney outcomes. INTERPRETATION Environmental exposure to higher concentrations of PM10, NO2, and CO is associated with increased risk of incident chronic kidney disease, eGFR decline, and end-stage renal disease. FUNDING US Department of Veterans Affairs.

Serum phosphorus levels and risk of incident dementia

Higher serum phosphorous is associated with cerebral small vessel disease, an important driver of cognitive decline and dementia. Whether serum phosphorous, a potentially modifiable parameter, associates with risk of incident dementia is not known. We aimed to examine the association between serum phosphorous and risk of incident dementia and to determine if the association is modified by age. We used the United States Department of Veterans Affairs national databases to build a longitudinal observational cohort of US veterans without prior history of dementia and with at least one outpatient serum phosphorus between October 2008 and September 2010 and followed them until September 2014. Serum phosphorus was categorized into quintiles: ≤2.9, >2.9 to ≤3.2, >3.2 to ≤3.5, >3.5 to ≤3.9, >3.9 mg/dL. There were 744,235 participants in the overall cohort. Over a median follow-up of 5.07 years (Interquartile range [IQR]: 4.28, 5.63), adjusted Cox models show that compared to quintile 2, the risk of incident dementia was increased in quintile 4 (Hazard Ratio [HR] = 1.05; CI = 1.01–1.10) and quintile 5 (HR = 1.14; CI = 1.09–1.20). In cohort participants ≤60 years old, the risk of incident dementia was increased in quintile 4 (HR = 1.29; CI = 1.12–1.49) and 5 (HR = 1.45; CI = 1.26–1.68). In participants > 60 years old, the risk was not significant in quintile 4, and was attenuated in quintile 5 (HR = 1.10; CI = 1.05–1.16). Formal interaction analyses showed that the association between phosphorous and dementia was more pronounced in those younger than 60, and attenuated in those older than 60 (P for interaction was 0.004 and <0.0001 in quintiles 4 and 5; respectively). We conclude that higher serum phosphorous is associated with increased risk of incident dementia. This association is stronger in younger cohort participants. The identification of serum phosphorous as a risk factor for incident dementia has public health relevance and might inform the design and implementation of risk reduction strategies.