Postacute Sequelae of SARS-CoV-2 Infection in the Pre-Delta, Delta, and Omicron Eras.

BACKGROUND: Postacute sequelae of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (PASC) can affect many organ systems. However, temporal changes during the coronavirus disease 2019 (Covid-19) pandemic, including the evolution of SARS-CoV-2, may have affected the risk and burden of PASC. Whether the risk and burden of PASC have changed over the course of the pandemic is unclear. METHODS: We used health records of the Department of Veterans Affairs to build a study population of 441,583 veterans with SARS-CoV-2 infection between March 1, 2020, and January 31, 2022, and 4,748,504 noninfected contemporaneous controls. We estimated the cumulative incidence of PASC at 1 year after SARS-CoV-2 infection during the pre-delta, delta, and omicron eras of the Covid-19 pandemic. RESULTS: Among unvaccinated persons infected with SARS-CoV-2, the cumulative incidence of PASC during the first year after infection was 10.42 events per 100 persons (95% confidence interval [CI], 10.22 to 10.64) in the pre-delta era, 9.51 events per 100 persons (95% CI, 9.26 to 9.75) in the delta era, and 7.76 events per 100 persons (95% CI, 7.57 to 7.98) in the omicron era (difference between the omicron and pre-delta eras, -2.66 events per 100 persons [95% CI, -2.93 to -2.36]; difference between the omicron and delta eras, -1.75 events per 100 persons [95% CI, -2.08 to -1.42]). Among vaccinated persons, the cumulative incidence of PASC at 1 year was 5.34 events per 100 persons (95% CI, 5.10 to 5.58) during the delta era and 3.50 events per 100 persons (95% CI, 3.31 to 3.71) during the omicron era (difference between the omicron and delta eras, -1.83 events per 100 persons; 95% CI, -2.14 to -1.52). Vaccinated persons had a lower cumulative incidence of PASC at 1 year than unvaccinated persons (difference during the delta era, -4.18 events per 100 persons [95% CI, -4.47 to -3.88]; difference during the omicron era, -4.26 events per 100 persons [95% CI, -4.49 to -4.05]). Decomposition analyses showed 5.23 (95% CI, 4.97 to 5.47) fewer PASC events per 100 persons at 1 year during the omicron era than during the pre-delta and delta eras combined; 28.11% of the decrease (95% CI, 25.57 to 30.50) was attributable to era-related effects (changes in the virus and other temporal effects), and 71.89% (95% CI, 69.50 to 74.43) was attributable to vaccines. CONCLUSIONS: The cumulative incidence of PASC during the first year after SARS-CoV-2 infection decreased over the course of the pandemic, but the risk of PASC remained substantial even among vaccinated persons who had SARS-CoV-2 infection in the omicron era. (Supported by the Department of Veterans Affairs.).

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

The acute clinical manifestations of COVID-19 have been well characterized1,2, 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.

Fine particulate matter components and interstitial lung disease in rheumatoid arthritis.

BACKGROUND: Exposure to ambient fine particulate matter with an aerodynamic diameter <2.5 µg·m-3 (PM2.5) is a risk factor for pulmonary and systemic autoimmune diseases; however, evidence on which PM2.5 chemical components are more harmful is still scant. Our goal is to investigate potential associations between major PM2.5 components and interstitial lung disease (ILD) onset in rheumatoid arthritis (RA). METHODS: New-onset RA subjects identified from a US healthcare insurance database (MarketScan) were followed for new onset of RA-associated ILD (RA-ILD) from 2011 to 2018. Annual concentrations of ambient PM2.5 chemical components (i.e. sulfate, nitrate, ammonium, organic matter, black carbon, mineral dust and sea salt) were estimated by combining satellite retrievals with chemical transport modelling and refined by geographically weighted regression. Exposures from 2006 up to 1 year before ILD onset or end of study were assigned to subjects based on their core-based statistical area or metropolitan division codes. A novel time-to-event quantile-based g (generalised)-computation approach was used to estimate potential associations between RA-ILD onset and the exposure mixture of all seven PM2.5 chemical components adjusting for age, sex and prior chronic obstructive pulmonary disease (as a proxy for smoking). RESULTS: We followed 280 516 new-onset RA patients and detected 2194 RA-ILD cases across 1 394 385 person-years. The adjusted hazard ratio for RA-ILD onset was 1.54 (95% CI 1.47-1.63) per every decile increase in all seven exposures. Ammonium, mineral dust and black carbon contributed more to ILD risk than the other PM2.5 components. CONCLUSION: Exposure to components of PM2.5, particularly ammonium, increases ILD risk in RA.

Kidney Outcomes in Long COVID.

BACKGROUND: 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. METHODS: We built a cohort of 1,726,683 US Veterans identified from March 1, 2020 to March 15, 2021, including 89,216 patients who were 30-day survivors of COVID-19 and 1,637,467 non-infected controls. We examined risks of AKI, eGFR decline, ESKD, and major adverse kidney events (MAKE). MAKE was defined as eGFR decline ≥50%, ESKD, or all-cause mortality. We used inverse probability-weighted survival regression, 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. RESULTS: Beyond the acute illness, 30-day survivors of COVID-19 exhibited a higher risk of AKI (aHR, 1.94; 95% CI, 1.86 to 2.04), eGFR decline ≥30% (aHR, 1.25; 95% CI, 1.14 to 1.37), eGFR decline ≥40% (aHR, 1.44; 95% CI, 1.37 to 1.51), eGFR decline ≥50% (aHR, 1.62; 95% CI, 1.51 to 1.74), ESKD (aHR, 2.96; 95% CI, 2.49 to 3.51), and MAKE (aHR, 1.66; 95% CI, 1.58 to 1.74). Increase in risks of post-acute kidney outcomes was graded according to the severity of the acute infection (whether patients were non-hospitalized, hospitalized, or admitted to intensive care). Compared with non-infected controls, 30-day survivors of COVID-19 exhibited excess eGFR decline (95% CI) of -3.26 (-3.58 to -2.94), -5.20 (-6.24 to -4.16), and -7.69 (-8.27 to -7.12) ml/min per 1.73 m2 per year, respectively, in non-hospitalized, hospitalized, and those admitted to intensive care during the acute phase of COVID-19 infection. CONCLUSIONS: Patients who survived COVID-19 exhibited increased risk of kidney outcomes in the post-acute phase of the disease. Post-acute COVID-19 care should include attention to kidney disease.

Estimated Global Proportions of Individuals With Persistent Fatigue, Cognitive, and Respiratory Symptom Clusters Following Symptomatic COVID-19 in 2020 and 2021.

Importance: Some individuals experience persistent symptoms after initial symptomatic SARS-CoV-2 infection (often referred to as Long COVID). Objective: To estimate the proportion of males and females with COVID-19, younger or older than 20 years of age, who had Long COVID symptoms in 2020 and 2021 and their Long COVID symptom duration. Design, Setting, and Participants: Bayesian meta-regression and pooling of 54 studies and 2 medical record databases with data for 1.2 million individuals (from 22 countries) who had symptomatic SARS-CoV-2 infection. Of the 54 studies, 44 were published and 10 were collaborating cohorts (conducted in Austria, the Faroe Islands, Germany, Iran, Italy, the Netherlands, Russia, Sweden, Switzerland, and the US). The participant data were derived from the 44 published studies (10 501 hospitalized individuals and 42 891 nonhospitalized individuals), the 10 collaborating cohort studies (10 526 and 1906), and the 2 US electronic medical record databases (250 928 and 846 046). Data collection spanned March 2020 to January 2022. Exposures: Symptomatic SARS-CoV-2 infection. Main Outcomes and Measures: Proportion of individuals with at least 1 of the 3 self-reported Long COVID symptom clusters (persistent fatigue with bodily pain or mood swings; cognitive problems; or ongoing respiratory problems) 3 months after SARS-CoV-2 infection in 2020 and 2021, estimated separately for hospitalized and nonhospitalized individuals aged 20 years or older by sex and for both sexes of nonhospitalized individuals younger than 20 years of age. Results: A total of 1.2 million individuals who had symptomatic SARS-CoV-2 infection were included (mean age, 4-66 years; males, 26%-88%). In the modeled estimates, 6.2% (95% uncertainty interval [UI], 2.4%-13.3%) of individuals who had symptomatic SARS-CoV-2 infection experienced at least 1 of the 3 Long COVID symptom clusters in 2020 and 2021, including 3.2% (95% UI, 0.6%-10.0%) for persistent fatigue with bodily pain or mood swings, 3.7% (95% UI, 0.9%-9.6%) for ongoing respiratory problems, and 2.2% (95% UI, 0.3%-7.6%) for cognitive problems after adjusting for health status before COVID-19, comprising an estimated 51.0% (95% UI, 16.9%-92.4%), 60.4% (95% UI, 18.9%-89.1%), and 35.4% (95% UI, 9.4%-75.1%), respectively, of Long COVID cases. The Long COVID symptom clusters were more common in women aged 20 years or older (10.6% [95% UI, 4.3%-22.2%]) 3 months after symptomatic SARS-CoV-2 infection than in men aged 20 years or older (5.4% [95% UI, 2.2%-11.7%]). Both sexes younger than 20 years of age were estimated to be affected in 2.8% (95% UI, 0.9%-7.0%) of symptomatic SARS-CoV-2 infections. The estimated mean Long COVID symptom cluster duration was 9.0 months (95% UI, 7.0-12.0 months) among hospitalized individuals and 4.0 months (95% UI, 3.6-4.6 months) among nonhospitalized individuals. Among individuals with Long COVID symptoms 3 months after symptomatic SARS-CoV-2 infection, an estimated 15.1% (95% UI, 10.3%-21.1%) continued to experience symptoms at 12 months. Conclusions and Relevance: This study presents modeled estimates of the proportion of individuals with at least 1 of 3 self-reported Long COVID symptom clusters (persistent fatigue with bodily pain or mood swings; cognitive problems; or ongoing respiratory problems) 3 months after symptomatic SARS-CoV-2 infection.

Health Effects of Overweight and Obesity in 195 Countries over 25 Years.

BACKGROUND: Although the rising pandemic of obesity has received major attention in many countries, the effects of this attention on trends and the disease burden of obesity remain uncertain. METHODS: We analyzed data from 68.5 million persons to assess the trends in the prevalence of overweight and obesity among children and adults between 1980 and 2015. Using the Global Burden of Disease study data and methods, we also quantified the burden of disease related to high body-mass index (BMI), according to age, sex, cause, and BMI in 195 countries between 1990 and 2015. RESULTS: In 2015, a total of 107.7 million children and 603.7 million adults were obese. Since 1980, the prevalence of obesity has doubled in more than 70 countries and has continuously increased in most other countries. Although the prevalence of obesity among children has been lower than that among adults, the rate of increase in childhood obesity in many countries has been greater than the rate of increase in adult obesity. High BMI accounted for 4.0 million deaths globally, nearly 40% of which occurred in persons who were not obese. More than two thirds of deaths related to high BMI were due to cardiovascular disease. The disease burden related to high BMI has increased since 1990; however, the rate of this increase has been attenuated owing to decreases in underlying rates of death from cardiovascular disease. CONCLUSIONS: The rapid increase in the prevalence and disease burden of elevated BMI highlights the need for continued focus on surveillance of BMI and identification, implementation, and evaluation of evidence-based interventions to address this problem. (Funded by the Bill and Melinda Gates Foundation.).

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

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.

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.

Mortality in Patients Hospitalized for COVID-19 vs Influenza in Fall-Winter 2023-2024.

This cohort study evaluates the risk of death in patients hospitalized for COVID-19 or seasonal influenza following the emergence of the JN.1 variant in winter 2023.

Higher blood urea nitrogen is associated with increased risk of incident diabetes mellitus.

Experimental evidence suggests that higher levels of urea may increase insulin resistance and suppress insulin secretion. However, whether higher levels of blood urea nitrogen (BUN) are associated with increased risk of incident diabetes mellitus in humans is not known. To study this, we built a national cohort of 1,337,452 United States Veterans without diabetes to characterize the association of BUN and risk of incident diabetes. Over a median follow-up of 4.93 years, there were 172,913 cases of incident diabetes. In joint risk models of estimated glomerular filtration rate (eGFR) and BUN. there was no association between eGFR and the risk of incident diabetes in those with a BUN of 25 mg/dl or less. However, the risk was significantly increased in those with a BUN over 25 mg/dl at all eGFR levels, even in those with an eGFR of 60 ml/min/1.73m2 or more (hazard ratio 1.27; confidence interval 1.24-1.31). The risk of incident diabetes was highest in those with BUN over 25 mg/dL and an eGFR under 15 ml/min/1.73m2 (1.68; 1.51-1.87). Spline analyses of the relationship between BUN and risk of incident diabetes showed that risk was progressively higher as BUN increased. In models where eGFR was included as a continuous covariate, compared to a BUN of 25 mg/dl or less, a BUN over 25 mg/dl was associated with increased risk of incident diabetes (1.23; 1.21-1.25). Every 10 ml/min/1.73m2 decrease in eGFR was not associated with risk of incident diabetes (1.00; 1.00-1.01). Two-stage residual inclusion analyses showed that, independent of the impact of eGFR, every 10 mg/dL increase in BUN concentration was associated with increased risk of incident diabetes (1.15; 1.14-1.16). Thus, higher levels of BUN are associated with increased risk of incident diabetes mellitus.

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

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.

The association of proton pump inhibitors and chronic kidney disease: cause or confounding?

PURPOSE OF REVIEW: To discuss whether the recently described relationship between proton pump inhibitor (PPI) use and the risk of adverse kidney outcomes represents a causal relationship or is merely the result of confounding. RECENT FINDINGS: A wave of observational studies has described an association between PPI use and the risk of development of chronic kidney disease and its progression to end-stage renal disease. The results are generally robust and remarkably consistent across different studies. The application of modern pharmacoepidemiologic methods to estimate the effect of a putative unmeasured or unknown confounder or set of confounders on the relationship of PPI use and risk of adverse renal outcomes suggests that confounding is unlikely to explain away the reported association. SUMMARY: The constellation of evidence from all available studies suggests that PPI use is associated with increased risk of adverse kidney outcomes. Exercising vigilance in the use of PPI is warranted.

Monocyte count modifies the association between chronic kidney disease and risk of death
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BACKGROUND: Chronic kidney disease (CKD) is associated with increased all-cause mortality. How non-traditional risk factors modify the mortality risk associated with CKD has not been studied. We approached this question using elevated monocyte count, which is associated with increased risk of death in the general population; however, there is very limited data in CKD. MATERIALS AND METHODS: A national cohort of 1,706,589 U.S. veterans without end-stage renal disease (ESRD) was followed over a median of 9.16 years. Estimated glomerular filtration rate (eGFR; mL/min/1.73m2) was divided into 6 categories: 15 - 30, 30 - 45, 45 - 60, 60 - 90, 90 - 105 (reference), and > 105. Monocyte count (k/cmm) was grouped into quartiles: 0.00 - 0.40 (reference), 0.40 - 0.56, 0.56 - 0.70, and > 0.70. Multinomial logistic regression, Cox proportional hazard regression, and formal interaction analyses on both the multiplicative and additive scales were undertaken. RESULTS: Monocyte count > 0.56 k/cmm was associated with increased risk of death overall (hazard ratio (HR) 1.40, confidence interval (CI) 1.38, 1.41 in monocyte quartile 4) and across each eGFR category. Very high (> 105 mL/min/1.73m2) and low (15 - 30 mL/min/1.73m2) eGFR categories were associated with increased mortality risk (HR 1.40, CI 1.38, 1.42 and HR 2.07, CI 2.03, 2.11, respectively). The mortality risk associated with high monocyte count and low eGFR exhibited a strong negative interaction (p < 0.001). No interaction was noted at very high eGFR. CONCLUSION: While low and very high eGFR were both associated with increased mortality risk, a monocyte count > 0.56 k/cmm only modified the risk associated with low eGFR. This suggests a shared underlying mechanism of death between CKD and high monocyte count.
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Global Cardiovascular and Renal Outcomes of Reduced GFR.

The burden of premature death and health loss from ESRD is well described. Less is known regarding the burden of cardiovascular disease attributable to reduced GFR. We estimated the prevalence of reduced GFR categories 3, 4, and 5 (not on RRT) for 188 countries at six time points from 1990 to 2013. Relative risks of cardiovascular outcomes by three categories of reduced GFR were calculated by pooled random effects meta-analysis. Results are presented as deaths for outcomes of cardiovascular disease and ESRD and as disability-adjusted life years for outcomes of cardiovascular disease, GFR categories 3, 4, and 5, and ESRD. In 2013, reduced GFR was associated with 4% of deaths worldwide, or 2.2 million deaths (95% uncertainty interval [95% UI], 2.0 to 2.4 million). More than half of these attributable deaths were cardiovascular deaths (1.2 million; 95% UI, 1.1 to 1.4 million), whereas 0.96 million (95% UI, 0.81 to 1.0 million) were ESRD-related deaths. Compared with metabolic risk factors, reduced GFR ranked below high systolic BP, high body mass index, and high fasting plasma glucose, and similarly with high total cholesterol as a risk factor for disability-adjusted life years in both developed and developing world regions. In conclusion, by 2013, cardiovascular deaths attributed to reduced GFR outnumbered ESRD deaths throughout the world. Studies are needed to evaluate the benefit of early detection of CKD and treatment to decrease these deaths.

Risk of Death in Patients Hospitalized for COVID-19 vs Seasonal Influenza in Fall-Winter 2022-2023.

This study uses data from the US Department of Veterans Affairs to assess whether SARS-CoV-2 remains associated with higher risk of death compared with seasonal influenza in fall-winter 2022-2023.

Long-term kidney outcomes among users of proton pump inhibitors without intervening acute kidney injury.

Proton pump inhibitor (PPI) use is associated with an increased risk of acute kidney injury (AKI), incident chronic kidney disease (CKD), and progression to end-stage renal disease (ESRD). PPI-associated CKD is presumed to be mediated by intervening AKI. However, whether PPI use is associated with an increased risk of chronic renal outcomes in the absence of intervening AKI is unknown. To evaluate this we used the Department of Veterans Affairs national databases to build a cohort of 144,032 incident users of acid suppression therapy that included 125,596 PPI and 18,436 Histamine H2 receptor antagonist (H2 blockers) consumers. Over 5 years of follow-up in survival models, cohort participants were censored at the time of AKI occurrence. Compared with incident users of H2 blockers, incident users of PPIs had an increased risk of an estimated glomerular filtration rate (eGFR) under 60 ml/min/1.73m2 (hazard ratio 1.19; 95% confidence interval 1.15-1.24), incident CKD (1.26; 1.20-1.33), eGFR decline over 30% (1.22; 1.16-1.28), and ESRD or eGFR decline over 50% (1.30; 1.15-1.48). Results were consistent in models that excluded participants with AKI either before chronic renal outcomes, during the time in the cohort, or before cohort entry. The proportion of PPI effect mediated by AKI was 44.7%, 45.47%, 46.00%, and 46.72% for incident eGFR under 60 ml/min/1.73m2, incident CKD, eGFR decline over 30%, and ESRD or over 50% decline in eGFR, respectively. Thus, PPI use is associated with increased risk of chronic renal outcomes in the absence of intervening AKI. Hence, reliance on antecedent AKI as warning sign to guard against the risk of CKD among PPI users is not sufficient as a sole mitigation strategy.