Association of Low Glomerular Filtration Rate With Adverse Outcomes at Older Age in a Large Population With Routinely Measured Cystatin C.

BACKGROUND: The commonly accepted threshold of glomerular filtration rate (GFR) to define chronic kidney disease (CKD) is less than 60 mL/min/1.73 m2. This threshold is based partly on associations between estimated GFR (eGFR) and the frequency of adverse outcomes. The association is weaker in older adults, which has created disagreement about the appropriateness of the threshold for these persons. In addition, the studies measuring these associations included relatively few outcomes and estimated GFR on the basis of creatinine level (eGFRcr), which may be less accurate in older adults. OBJECTIVE: To evaluate associations in older adults between eGFRcr versus eGFR based on creatinine and cystatin C levels (eGFRcr-cys) and 8 outcomes. DESIGN: Population-based cohort study. SETTING: Stockholm, Sweden, 2010 to 2019. PARTICIPANTS: 82 154 participants aged 65 years or older with outpatient creatinine and cystatin C testing. MEASUREMENTS: Hazard ratios for all-cause mortality, cardiovascular mortality, and kidney failure with replacement therapy (KFRT); incidence rate ratios for recurrent hospitalizations, infection, myocardial infarction or stroke, heart failure, and acute kidney injury. RESULTS: The associations between eGFRcr-cys and outcomes were monotonic, but most associations for eGFRcr were U-shaped. In addition, eGFRcr-cys was more strongly associated with outcomes than eGFRcr. For example, the adjusted hazard ratios for 60 versus 80 mL/min/1.73 m2 for all-cause mortality were 1.2 (95% CI, 1.1 to 1.3) for eGFRcr-cys and 1.0 (CI, 0.9 to 1.0) for eGFRcr, and for KFRT they were 2.6 (CI, 1.2 to 5.8) and 1.4 (CI, 0.7 to 2.8), respectively. Similar findings were observed in subgroups, including those with a urinary albumin-creatinine ratio below 30 mg/g. LIMITATION: No GFR measurements. CONCLUSION: Compared with low eGFRcr in older patients, low eGFRcr-cys was more strongly associated with adverse outcomes and the associations were more uniform. PRIMARY FUNDING SOURCE: Swedish Research Council, National Institutes of Health, and Dutch Kidney Foundation.

Factors Associated With Non-vaccination for Influenza Among Patients With CKD: Findings From the Chronic Renal Insufficiency Cohort (CRIC) Study.

RATIONALE & OBJECTIVE: Vaccination for influenza is strongly recommended for people with chronic kidney disease (CKD) due to their immunocompromised state. Identifying risk factors for not receiving an influenza vaccine (non-vaccination) could inform strategies for improving vaccine uptake in this high-risk population. STUDY DESIGN: Longitudinal observational study. SETTING & PARTICIPANTS: 3,692 Chronic Renal Insufficiency Cohort Study (CRIC) participants. EXPOSURE: Demographic factors, social determinants of health, clinical conditions, and health behaviors. OUTCOME: Influenza non-vaccination, which was assessed based on a receipt of influenza vaccine ascertained during annual clinic visits in a subset of participants who were under nephrology care. ANALYTICAL APPROACH: Mixed-effects Poisson models to estimate adjusted prevalence ratios (APRs). RESULTS: Between 2009 and 2020, the pooled mean vaccine uptake was 72% (mean age, 66 years; 44% female; 44% Black race). In multivariable models, factors significantly associated with influenza non-vaccination were younger age (APR, 2.16 [95% CI, 1.85-2.52] for<50 vs≥75 years), Black race (APR, 1.58 [95% CI, 1.43-1.75] vs White race), lower education (APR, 1.20 [95% CI, 1.04-1.39 for less than high school vs college graduate]), lower annual household income (APR, 1.26 [95% CI, 1.06-1.49] for <$20,000 vs >$100,000), formerly married status (APR, 1.22 [95% CI, 1.09-1.35] vs currently married), and nonemployed status (APR, 1.13 [95% CI, 1.02-1.24] vs employed). In contrast, participants with diabetes (APR, 0.80 [95% CI, 0.73-0.87] vs no diabetes), chronic obstructive pulmonary disease (COPD) (APR, 0.80 [95% CI, 0.70-0.92] vs no COPD), end-stage kidney disease (APR, 0.64 [0.56 to 0.76] vs estimated glomerular filtration rate≥60mL/min/1.73m2), frailty (APR, 0.86 [95% CI, 0.74-0.99] vs no frailty), and ideal physical activity (APR, 0.90 [95% CI, 0.82-0.99] vs. physically inactive) were less likely to have non-vaccination status. LIMITATIONS: Possible residual confounding. CONCLUSIONS: Among adults with CKD receiving nephrology care, younger adults, Black individuals, and those with adverse social determinants of health were more likely to have the influenza non-vaccination status. Strategies are needed to address these disparities and reduce barriers to vaccination. PLAIN-LANGUAGE SUMMARY: Identifying risk factors for not receiving an influenza vaccine ("non-vaccination") in people living with kidney disease, who are at risk of influenza and its complications, could inform strategies for improving vaccine uptake. In this study, we examined whether demographic factors, social determinants of health, and clinical conditions were linked to the status of not receiving an influenza vaccine among people living with kidney disease and receiving nephrology care. We found that younger adults, Black individuals, and those with adverse social determinants of health were more likely to not receive the influenza vaccine. These findings suggest the need for strategies to address these disparities and reduce barriers to vaccination in people living with kidney disease.

Major cardiovascular events and subsequent risk of kidney failure with replacement therapy: a CKD Prognosis Consortium study.

AIMS: Chronic kidney disease (CKD) increases risk of cardiovascular disease (CVD). Less is known about how CVD associates with future risk of kidney failure with replacement therapy (KFRT). METHODS AND RESULTS: The study included 25 903 761 individuals from the CKD Prognosis Consortium with known baseline estimated glomerular filtration rate (eGFR) and evaluated the impact of prevalent and incident coronary heart disease (CHD), stroke, heart failure (HF), and atrial fibrillation (AF) events as time-varying exposures on KFRT outcomes. Mean age was 53 (standard deviation 17) years and mean eGFR was 89 mL/min/1.73 m2, 15% had diabetes and 8.4% had urinary albumin-to-creatinine ratio (ACR) available (median 13 mg/g); 9.5% had prevalent CHD, 3.2% prior stroke, 3.3% HF, and 4.4% prior AF. During follow-up, there were 269 142 CHD, 311 021 stroke, 712 556 HF, and 605 596 AF incident events and 101 044 (0.4%) patients experienced KFRT. Both prevalent and incident CVD were associated with subsequent KFRT with adjusted hazard ratios (HRs) of 3.1 [95% confidence interval (CI): 2.9-3.3], 2.0 (1.9-2.1), 4.5 (4.2-4.9), 2.8 (2.7-3.1) after incident CHD, stroke, HF and AF, respectively. HRs were highest in first 3 months post-CVD incidence declining to baseline after 3 years. Incident HF hospitalizations showed the strongest association with KFRT [HR 46 (95% CI: 43-50) within 3 months] after adjustment for other CVD subtype incidence. CONCLUSION: Incident CVD events strongly and independently associate with future KFRT risk, most notably after HF, then CHD, stroke, and AF. Optimal strategies for addressing the dramatic risk of KFRT following CVD events are needed.

Cigarette Smoking and Risk of Hospitalization With Acute Kidney Injury: The Atherosclerosis Risk in Communities (ARIC) Study.

RATIONALE & OBJECTIVE: Smoking is a modifiable risk factor for various adverse events. However, little is known about the association of smoking with the incidence of acute kidney injury (AKI) in the general population. This study investigated the association of cigarette smoking with the risk of AKI. STUDY DESIGN: Prospective observational study. SETTING & PARTICIPANTS: 14,571 participants (mean age 55±6 years, 55% women, and 25% Black participants) from the ARIC study visit 1 (1987-1989) followed through December 31, 2019. EXPOSURE: Smoking parameters (status, duration, pack-years, intensity, and years since cessation). OUTCOME: Incident hospitalization with AKI, defined by a hospital discharge with a diagnostic code relevant to AKI. ANALYTICAL APPROACH: Multivariable Cox regression models. RESULTS: Over a median follow-up period of 26.3 years, 2,984 participants had an incident hospitalization with AKI. Current and former smokers had a significantly higher risk of AKI compared to never smokers after adjusting for potential confounders (HR, 2.22 [95% CI, 2.02-2.45] and 1.12 [1.02-1.23], respectively). A dose-response association was consistently seen for each of smoking duration, pack-years, and intensity with AKI (eg, HR, 1.19 [95% CI, 1.16-1.22] per 10 years of smoking). When years since cessation were considered as a time-varying exposure, the risk of AKI associated with smoking compared with current smokers began to decrease after 10 years, and became similar to never smokers at 30 years (HR for≥30 years, 1.07 [95% CI, 0.97-1.20] vs never smokers). LIMITATIONS: Self-reported smoking measurements and missing outpatient AKI cases. CONCLUSIONS: In a community-based cohort, all smoking parameters were robustly associated with the risk of AKI. Smoking cessation was associated with decreased risk of AKI, although the excess risk lasted up to 30 years. Our study supports the importance of preventing smoking initiation and promoting smoking cessation for the risk of AKI. PLAIN-LANGUAGE SUMMARY: Smoking is a behavior that is associated with many negative health effects. It is not well understood how smoking relates to the occurrence of acute kidney injury (AKI) in the community. In this study, we looked at data from a group of 14,571 adults who were followed for 26 years to see how different aspects of smoking (such as whether someone smoked, how long they smoked for, how many cigarettes they smoked per day, and whether they quit smoking) were related to AKI. We found that smoking was strongly linked to an increased risk of AKI. This risk decreased after 5-10 years of quitting smoking, but the excess risk lasted up to 30 years. This study shows the importance of preventing people from starting smoking and to encourage smokers to quit to reduce their risk of AKI.

Cardiac Structure and Function and Subsequent Kidney Disease Progression in Adults With CKD: The Chronic Renal Insufficiency Cohort (CRIC) Study.

RATIONALE & OBJECTIVE: Heart-kidney crosstalk is recognized as the cardiorenal syndrome. We examined the association of cardiac function and structure with the risk of kidney failure with replacement therapy (KFRT) in a chronic kidney disease (CKD) population. STUDY DESIGN: Prospective observational cohort study. SETTING & PARTICIPANTS: 3,027 participants from the Chronic Renal Insufficiency Cohort Study. EXPOSURE: Five preselected variables that assess different aspects of cardiac structure and function: left ventricular mass index (LVMI), LV volume, left atrial (LA) area, peak tricuspid regurgitation (TR) velocity, and left ventricular ejection fraction (EF) as assessed by echocardiography. OUTCOME: Incident KFRT (primary outcome), and annual estimated glomerular filtration rate (eGFR) slope (secondary outcome). ANALYTICAL APPROACH: Multivariable Cox models and mixed-effects models. RESULTS: The mean age of the participants was 59±11 SD years, 54% were men, and mean eGFR was 43±17mL/min/1.73m2. Between 2003 and 2018 (median follow-up, 9.9 years), 883 participants developed KFRT. Higher LVMI, LV volume, LA area, peak TR velocity, and lower EF were each statistically significantly associated with an increased risk of KFRT, with corresponding HRs for the highest versus lowest quartiles (lowest vs highest for EF) of 1.70 (95% CI, 1.27-2.26), 1.50 (95% CI, 1.19-1.90), 1.43 (95% CI, 1.11-1.84), 1.45 (95% CI, 1.06-1.96), and 1.26 (95% CI, 1.03-1.56), respectively. For the secondary outcome, participants in the highest versus lowest quartiles (lowest vs highest for EF) had a statistically significantly faster eGFR decline, except for LA area (ΔeGFR slope per year, -0.57 [95% CI, -0.68 to-0.46] mL/min/1.73m2 for LVMI, -0.25 [95% CI, -0.35 to-0.15] mL/min/1.73m2 for LV volume, -0.01 [95% CI, -0.12 to-0.01] mL/min/1.73m2 for LA area, -0.42 [95% CI, -0.56 to-0.28] mL/min/1.73m2 for peak TR velocity, and -0.11 [95% CI, -0.20 to-0.01] mL/min/1.73m2 for EF, respectively). LIMITATIONS: The possibility of residual confounding. CONCLUSIONS: Multiple aspects of cardiac structure and function were statistically significantly associated with the risk of KFRT. These findings suggest that cardiac abnormalities and incidence of KFRT are potentially on the same causal pathway related to the interaction between hypertension, heart failure, and coronary artery diseases. PLAIN-LANGUAGE SUMMARY: Heart disease and kidney disease are known to interact with each other. In this study, we examined whether cardiac abnormalities, as assessed by echocardiography, were linked to the subsequent progression of kidney disease among people living with chronic kidney disease (CKD). We found that people with abnormalities in heart structure and function had a greater risk of progression to advanced CKD that required kidney replacement therapy and had a faster rate of decline in kidney function. Our study indicates the potential role of abnormal heart structure and function in the progression of kidney disease among people living with CKD.

Diabetes and the risk of hospitalisation for infection: the Atherosclerosis Risk in Communities (ARIC) study.

AIMS/HYPOTHESIS: The aim of this work was to assess the association between diabetes and risk for infection-related hospitalisation and mortality. METHODS: We conducted a prospective cohort analysis of the Atherosclerosis Risk in Communities (ARIC) study. Diabetes was defined as a fasting glucose ≥7 mmol/l or non-fasting glucose ≥11.1 mmol/l, self-report of a diagnosis of diabetes by a physician, or current diabetes medication use. Hospitalisation for infection was ascertained from hospital discharge records. Participants were followed from 1987-1989 to 2019. RESULTS: We included 12,379 participants (mean age 54.5 years; 24.7% Black race; 54.3% female sex). During a median follow-up of 23.8 years, there were 4229 new hospitalisations for infection. After adjusting for potential confounders, people with (vs without) diabetes at baseline had a higher risk for hospitalisation for infection (HR 1.67 [95% CI 1.52, 1.83]). Results were generally consistent across infection type but the association was especially pronounced for foot infection (HR 5.99 [95% CI 4.38, 8.19]). Diabetes was more strongly associated with hospitalisation for infection in younger participants and Black people. Overall infection mortality was low (362 deaths due to infection) but the adjusted risk was increased for people with diabetes (HR 1.72 [95% CI 1.28, 2.31]). CONCLUSIONS/INTERPRETATION: Diabetes confers significant risk for infection-related hospitalisation. Enhancing prevention and early treatment of infection in those with diabetes is needed to reduce infection-related morbidity and mortality.

High-Sensitivity Cardiac Troponin, Natriuretic Peptide, and Long-Term Risk of Acute Kidney Injury: The Atherosclerosis Risk in Communities (ARIC) Study.

BACKGROUND: Cardiac markers such as high-sensitivity cardiac troponin T (hs-cTnT) and N-terminal pro-B natriuretic peptide (NTproBNP) are predictors of developing acute kidney injury (AKI) during hospitalization for surgery or revascularization. However, their associations with the long-term risk of AKI in the general population are uncharacterized. METHODS: We conducted a prospective cohort study in 10 669 participants of the Atherosclerosis Risk in Communities Study (visit 4, 1996-1998, mean age, 63 years, 56% female, 22% black race) to examine the association of plasma concentrations of hs-cTnT and NTproBNP with the incident hospitalization with AKI. We used multivariable Cox regression analysis to estimate hazard ratios (HRs). RESULTS: During follow-up, 1907 participants had an incident hospitalization with AKI. Participants with higher concentrations of hs-cTnT had a higher risk of hospitalization with AKI in a graded fashion (adjusted HR, 1.88 [95%CI , 1.59-2.21] for ≥14 ng/L, 1.36 [1.18-1.57] for 9-13 ng/L, and 1.16 [1.03-1.30] for 5-8 ng/L compared to <5 ng/L). The graded association was also observed for NTproBNP (HR, 2.27 [1.93-2.68] for ≥272.7 pg/mL, 1.67 [1.45-1.93] for 142.4-272.6 pg/mL, and 1.31 [1.17-1.47] for 64.0-142.3 pg/mL compared to <64.0 pg/mL). The addition of hs-cTnT and NTproBNP to a model with established predictors significantly improved 10-year risk prediction for hospitalization with AKI (Δc-statistic, 0.015 [95%CI, 0.006-0.024]). CONCLUSIONS: In middle-aged to older black and white adults in the community, higher concentrations of hs-cTnT and NTproBNP were robustly associated with an increased risk of hospitalization with AKI. These results suggest the usefulness of hs-cTnT and NT-proBNP to identify people at risk of AKI in the general population.

Incident Hospitalization with Major Cardiovascular Diseases and Subsequent Risk of ESKD: Implications for Cardiorenal Syndrome.

BACKGROUND: Cardiorenal syndrome is a well known concept, bolstered by extensive investigations of CKD as a risk factor of cardiovascular disease. However, data on whether cardiovascular disease increases long-term risk of ESKD are sparse. METHODS: We assessed the association of incident hospitalization with major cardiovascular diseases (heart failure, atrial fibrillation, coronary heart disease, and stroke) with subsequent risk of ESKD among individuals enrolled in the Atherosclerosis Risk in Communities study; the analysis included 9047 individuals without prevalent cardiovascular disease at their fourth study visit. Each relevant incident cardiovascular disease event was entered into multivariable Cox proportional hazard models as a time-varying exposure to estimate hazard ratios. RESULTS: During a median follow-up of 17.5 years, there were 2598 cases of hospitalization with cardiovascular disease (heart failure, n=1269; atrial fibrillation, n=1337; coronary heart disease, n=696; and stroke, n=559) and 210 cases of incident ESKD. The incidence of major cardiovascular disease was associated with increased risk of ESKD, with the highest risk for heart failure (hazard ratio, 11.40; 95% confidence interval, 8.38 to 15.50), followed by coronary heart disease, atrial fibrillation, and stroke. When we analyzed heart failure with preserved ejection fraction and heart failure with reduced ejection fraction separately, the risk was nominally higher for heart failure with preserved ejection fraction. CONCLUSIONS: Major incident cardiovascular disease events were associated with ESKD, independent of kidney risk factors. In particular, heart failure showed a very strong association with ESKD. Our findings highlight the importance of monitoring and managing kidney disease in patients with cardiovascular disease. The potentially distinct contribution to ESKD of heart failure with preserved versus reduced ejection fraction deserves future investigation.

Fibroblast Growth Factor 23 and Risk of Hospitalization with Infection in Chronic Kidney Disease: The Chronic Renal Insufficiency Cohort (CRIC) Study.

BACKGROUND: Risk of infectious disease is increased among individuals with CKD. Fibroblast growth factor 23 (FGF23) is often elevated in CKD, and may impair immune function directly or indirectly through proinflammatory and vitamin D-suppressing pathways. Whether FGF23 is associated with risk of infection has not been evaluated in a CKD population. METHODS: In 3655 participants of the Chronic Renal Insufficiency Cohort study, we evaluated the association of baseline plasma levels of C-terminal FGF23 with time to first hospitalization with major infection, defined by hospital discharge with a diagnosis code for urinary tract infection, pneumonia, cellulitis/osteomyelitis, or bacteremia/septicemia. Multivariable Cox models were used to estimate hazard ratios (HRs) and adjust for confounding. RESULTS: During a median follow-up of 6.5 years, 1051 individuals (29%) were hospitalized with major infection. Multivariable Cox analysis indicated a graded increase in the risk of infection with higher levels of FGF23 (HR, 1.51; 95% CI, 1.23 to 1.85 with the highest quartile [≥235.9 RU/ml] versus lowest quartile [<95.3 RU/ml]; HR, 1.26; 95% CI, 1.18 to 1.35 per SD increment in log FGF23). The association was consistent across infection subtypes and demographic and clinical subgroups, and remained significant after additional adjustment for biomarkers of inflammation (IL-6, TNF-α, high-sensitivity C-reactive protein, fibrinogen, and albumin), and bone mineral metabolism (25-hydroxyvitamin D, phosphorus, calcium, and parathyroid hormone). The association was consistent across infection subtypes of urinary tract infection (482 cases), cellulitis/osteomyelitis (422 cases), pneumonia (399 cases), and bacteremia/septicemia (280 cases). CONCLUSIONS: Among individuals with CKD, higher FGF23 levels were independently and monotonically associated with an increased risk of hospitalization with infection.

Inflammatory Markers and Incidence of Hospitalization With Infection in Chronic Kidney Disease.

Persons with chronic kidney disease (CKD) are at high risk of infection. While low-grade inflammation could impair immune response, it is unknown whether inflammatory markers are associated with infection risk in this clinical population. Using 2003-2013 data from the Chronic Renal Insufficiency Cohort Study (3,597 participants with CKD), we assessed the association of baseline plasma levels of 4 inflammatory markers (interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), interleukin-1 receptor antagonist (IL-1RA), and transforming growth factor-ß (TGF-ß)) with incident hospitalization with major infection (pneumonia, urinary tract infection, cellulitis and osteomyelitis, and bacteremia and sepsis). During follow-up (median 7.5 years), 36% (n = 1,290) had incident hospitalization with major infection. In multivariable Cox analyses with each inflammatory marker modeled as a restricted cubic spline, higher levels of IL-6 and TNF-α were monotonically associated with increased risk of hospitalization with major infection (for 95th vs. 5th percentile, hazard ratio = 2.11 (95% confidence interval: 1.68, 2.66) for IL-6 and 1.88 (95% confidence interval: 1.51, 2.33) for TNF-α), while corresponding associations for IL-1RA or TGF-ß were nonsignificant. Thus, higher plasma levels of IL-6 and TNF-α, but not IL-1RA or TGF-ß, were significantly associated with increased risk of hospitalization with major infection. Future studies should investigate whether inflammatory pathways that involve IL-6 and TNF-α increase susceptibility to infection among individuals with CKD.

Effectiveness of Influenza Vaccination Among Older Adults Across Kidney Function: Pooled Analysis of 2005-2006 Through 2014-2015 Influenza Seasons.

RATIONALE & OBJECTIVE: Influenza vaccination is recommended for all adults but particularly for older adults and those with high-risk conditions. Reduced kidney function is an important high-risk condition, but the effectiveness of influenza vaccination across kidney function is uncharacterized. We assessed the effectiveness of influenza vaccination among older adults with and without reduced kidney function. STUDY DESIGN: Observational cohort study. SETTING & PARTICIPANTS: 454,634 person-seasons among 110,968 individuals 65 years or older in the Geisinger Health System between the 2005 and 2015 influenza seasons, with baseline characteristics matched between those with and without vaccination using inverse probability weighting. EXPOSURES: Status of influenza vaccination. OUTCOMES: Incident hospitalization with pneumonia/influenza, coronary heart disease, and heart failure during influenza season stratified by estimated glomerular filtration rate (eGFR; ≥ 60, 30-59, and < 30mL/min/1.73m2). ANALYTICAL APPROACH: Pooled logistic regression analysis to estimate adjusted ORs. RESULTS: In the 2014-2015 influenza season, the prevalence of influenza vaccination was 63.3% without evident difference across eGFR categories. The incidence of hospitalization was higher in lower eGFRs (eg, 2.2% per person-season among those not vaccinated with eGFR < 30 vs 0.7% with ≥ 60mL/min/1.73m2 for pneumonia/influenza). Overall, influenza vaccination was associated with lower odds of hospitalization with pneumonia/influenza (OR, 0.86; 95% CI, 0.79-0.93), coronary heart disease (OR, 0.93; 95% CI, 0.88-0.97), and heart failure (OR, 0.92; 95% CI, 0.86-0.99). When assessing by eGFR categories, the association was consistent in eGFR ≥ 30, but not significant in < 30mL/min/1.73m2 (ORs of 1.04 [95% CI, 0.79-1.36] for pneumonia/influenza, 1.03 [95% CI, 0.87-1.23] for coronary heart disease, and 1.10 [95% CI, 0.92-1.33] for heart failure). LIMITATIONS: Possible unmeasured confounding. CONCLUSIONS: Influenza vaccination was associated with lower risk for hospitalizations with pneumonia/influenza and major cardiac diseases in eGFR ≥ 30mL/min/1.73m2. Studies are needed to explore optimal vaccination strategies for eGFR < 30mL/min/1.73m2.

Short- and long-term outcomes after incident pneumonia in adults with chronic kidney disease: a time-dependent analysis from the Stockholm CREAtinine Measurement project.

BACKGROUND: Little is known about the health sequelae of pneumonia in persons with chronic kidney disease (CKD). METHODS: We studied adults with CKD in Stockholm during 2006-11, who not previously been diagnosed with lower respiratory tract infections. We used multivariable-adjusted Cox regression with pneumonia as a time-varying exposure to estimate hazard ratios (HRs) [95% confidence intervals (CIs)] for the events of death, major adverse cardiovascular events (MACEs), acute kidney injury (AKI), CKD progression or hospitalization for urinary tract infections (UTIs)/sepsis. Cataract and knee/joint replacement served as negative control outcomes. RESULTS: We identified 71 931 adults (mean age 79 years, 59% women), of whom 8379 (12%) were diagnosed with pneumonia during follow-up; incident pneumonia was associated with 10 times higher adjusted mortality risk during the first 90 days [HR = 10.0, 95% confidence interval (CI) 9.5-10.5] and double the mortality beyond 90 days from pneumonia diagnosis (HR = 2.0; 95% CI 1.9-2.1). Incident pneumonia was similarly associated with higher adjusted risk of MACE (<90 days: HR = 12.6; 95% CI 12.0-13.3; ≥90 days: HR = 1.5; 95% CI 1.4-1.6). The adjusted risk of CKD progression and UTI/sepsis hospitalization was highest within 90 days from pneumonia but remained elevated thereafter. For AKI, the association with incident pneumonia was only seen within 90 days. Neither cataract nor knee/joint replacement was related to pneumonia. CONCLUSIONS: Incident pneumonia was associated with increased risks of MACE, CKD progression, severe UTI/sepsis and death, with risks highest soon after pneumonia diagnosis but extending beyond 90 days. Our findings highlight the susceptibility for adverse outcomes of CKD patients following pneumonia diagnosis, and may inform clinical decisions regarding vaccination strategies.

Additional prognostic value of toe-brachial index beyond ankle-brachial index in hemodialysis patients.

BACKGROUND: Ankle-brachial index (ABI), the first-line diagnostic test for peripheral artery disease, can be falsely elevated when ankle arteries are incompressible, showing a J-shaped association with mortality. In this situation, toe-brachial index (TBI) is the recommended test. However, whether TBI provides additional prognostic information beyond ABI in patients on hemodialysis is unknown. METHODS: In this retrospective cohort study of 247 Japanese prevalent hemodialysis patients (mean age 66.8 [SD 11.6] years), we evaluated mortality (116 deaths over a median follow-up of 5.2 years) related to quartiles of ABI and TBI, as well as three categories of low ABI (≤0.9), normal/high ABI (> 0.9) + low TBI (≤0.6), and normal/high ABI + normal TBI (> 0.6) using multivariable Cox models. RESULTS: ABI showed a J-shaped association with mortality (adjusted hazard ratio 2.72 [95% CI, 1.52-4.88] in the lowest quartile and 1.59 [95% CI, 0.87-2.90] in the highest quartile vs. the second highest). Lower TBI showed a potentially dose-response association with mortality (e.g., adjusted hazard ratios 2.63 [95% CI, 1.36-5.12] and 2.89 [95% CI, 1.49-5.61] in the lowest two quartiles vs. the highest). When three categories by both ABI and TBI were analyzed, those with low ABI (≤0.9) experienced the highest risk followed by normal/high ABI (> 0.9) + low TBI (≤0.6). Among patients with normal/high ABI (> 0.9), the increased mortality risk in individuals with low TBI (≤0.6) compared to those with normal TBI (> 0.6) were significant (adjusted hazard ratio 1.84 [95% CI, 1.12-3.02]). CONCLUSIONS: Lower TBI was independently associated with mortality in patients on hemodialysis and has the potential to classify mortality risk in patients with normal/high ABI. Our results support the importance of evaluating TBI in addition to ABI in this clinical population.

Associations of High-Sensitivity Cardiac Troponin and Natriuretic Peptide With Subsequent Risk of Infection in Persons Without Cardiovascular Disease: The Atherosclerosis Risk in Communities Study.

Whether persons without prevalent cardiovascular disease (CVD) but elevated levels of high-sensitivity cardiac troponin T (hs-cTnT) or N-terminal pro-B-type natriuretic peptide (NT-proBNP) are at high risk of infection is unknown. Using 1996-2013 data from the Atherosclerosis Risk in Communities Study, we estimated hazard ratios for incident hospitalization with infection in relation to plasma hs-cTnT and NT-proBNP concentrations among participants without prevalent CVD and contrasted them with hazard ratios for persons with prevalent CVD (coronary heart disease, heart failure, or stroke). In a multivariable Cox model, prevalent CVD was significantly associated with risk of hospitalization with infection (hazard ratio (HR) = 1.31, 95% confidence interval (CI): 1.19, 1.45). Among participants without prevalent CVD, hs-cTnT and NT-proBNP were independently associated with infection risk in a graded fashion (e.g., HR = 1.44 (95% CI: 1.24, 1.69) for hs-cTnT ≥14 ng/L and HR = 1.28 (95% CI: 1.14, 1.44) for hs-cTnT 9-13 ng/L vs. <3 ng/L; HR = 1.57 (95% CI: 1.35, 1.81) for NT-proBNP ≥248.1 pg/mL and HR = 1.19 (95% CI: 1.06, 1.34) for NT-proBNP 137.2-248.0 pg/mL vs. <48.1 pg/mL). The 15-year cumulative incidences of hospitalization with infection were similar for participants with prevalent CVD and participants who did not have prevalent CVD but had hs-cTnT ≥14 ng/L or NT-proBNP ≥248.1 pg/mL. Thus, hs-cTnT and NT-proBNP were independently associated with infection risk. Persons without CVD but with elevated hs-cTnT or NT-proBNP levels should be recognized to have similar infection risks as persons with prevalent CVD.

Estimated GFR and Hospital-Acquired Infections Following Major Surgery.

RATIONALE & OBJECTIVE: Low estimated glomerular filtration rate (eGFR) increases infection risk, but its contribution to hospital-acquired infection following major surgery is unknown. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: Residents of Stockholm, Sweden, 18 years or older with at least 1 recorded serum creatinine measurement, no recent diagnoses of infection, and hospitalized for orthopedic, abdominal, cardiothoracic and vascular, or neurologic surgery between January 2007 and December 2011. EXPOSURES: eGFR<60mL/min/1.73m2 (termed low eGFR) and other clinical comorbid conditions at admission: cancer, cerebrovascular disease, chronic obstructive pulmonary disease (COPD), coronary heart disease, diabetes, heart failure (HF), and liver disease. OUTCOMES: Incidence and population-attributable fractions of 4 major types of hospital-acquired infections: pneumonia, urinary tract infection, surgical-site infection, and bloodstream infection. ANALYTICAL APPROACH: Logistic regression analysis. RESULTS: 66,126 patients with a history of orthopedic (n=31,630), abdominal (n=26,317), cardiothoracic and vascular (n=6,266), or neurologic (n=1,913) surgery were studied. Cancer (21%) and low eGFR (18%) were the most prevalent comorbid conditions at admission, followed by diabetes, HF, and COPD (12%). Overall, 3,617 patients (5.5%) had at least 1 type of hospital-acquired infection (1,650 cases of urinary tract infection, 1,196 cases of pneumonia, 635 cases of surgical site infection, and 411 cases of bloodstream infection). The OR of hospital-acquired infection was highest for low eGFR (1.64; 95% CI, 1.51-1.77), followed by HF (1.60; 95% CI, 1.46-1.76), cerebrovascular disease (1.47; 95% CI, 1.34-1.61), cancer (1.43; 95% CI, 1.33-1.55), and COPD (1.37; 95% CI, 1.25-1.50). Low eGFR demonstrated the highest population-attributable fraction for hospital-acquired infections (0.13), followed by cancer (0.10), HF (0.09), and cerebrovascular disease (0.06). When assessed by type of infection, low eGFR particularly contributed to pneumonia (0.15) and urinary tract infection (0.10). LIMITATIONS: Outcome ascertainment based on diagnostic codes. CONCLUSIONS: These findings highlight the association between low eGFR and hospital-acquired infection and may inform evidence-based hospital-acquired infection prevention policies following major surgery.

Cost-effectiveness of Pneumococcal Vaccination Among Patients With CKD in the United States.

RATIONALE & OBJECTIVE: Pneumococcal vaccine is recommended for adults 65 years and older and those younger than 65 years with clinical indications (eg, diabetes, lung/heart disease, kidney failure, and nephrotic syndrome). Its cost-effectiveness in less severe chronic kidney disease (CKD) is uncharacterized. STUDY DESIGN: Cost-effectiveness analysis. SETTING & POPULATION: US adults aged 50 to 64 and 65 to 79 years stratified by CKD risk status: no CKD (estimated glomerular filtration rate≥60mL/min/1.73m2 and urinary albumin-creatinine ratio<30mg/g), CKD with moderate risk, CKD with high risk, and kidney failure (estimated glomerular filtration rate<15mL/min/1.73m2) or nephrotic-range albuminuria (urinary albumin-creatinine ratio≥2,000mg/g). Data sources were the National Health and Nutrition Examination Survey (NHANES) 1999 to 2004, Centers for Disease Control and Prevention, and the Atherosclerosis Risk in Communities (ARIC) Study. INTERVENTION(S): Vaccination compared to no vaccination. OUTCOMES: Incremental cost-effectiveness ratios based on US dollars per quality-adjusted life-year (QALY). MODEL, PERSPECTIVE, & TIMEFRAME: Markov model, US health sector perspective, and lifetime horizon. RESULTS: The prevalence of pneumococcal vaccination in NHANES 1999 to 2004 was 56.6% (aged 65-79 years), 28.5% (aged 50-64 years with an indication), and 9.7% (aged 50-64 years without an indication), with similar prevalences across CKD risk status. Pneumococcal vaccination was overall cost-effective (

Hospitalization Risk among Older Adults with Chronic Kidney Disease.

INTRODUCTION: Chronic kidney disease (CKD) risk staging is based on estimated glomerular filtration rate (eGFR) and albumin-creatinine ratio (ACR). However, the relationship between all-cause hospitalization risk and the current CKD staging system has not been well studied among older adults, despite a high prevalence of CKD and a high risk of hospitalization in old age. METHODS: Among 4,766 participants of the Atherosclerosis Risk in Communities study, CKD was staged according to Kidney Disease Improving Global Outcomes (KDIGO) criteria, using creatinine-based eGFR (eGFRcr) and ACR. Incidence rates of all-cause hospitalization associated with each CKD risk group were analyzed using negative binomial regression. Additionally, cause-specific hospitalization risks for cardiovascular, infectious, kidney, and other diseases were estimated. The impacts of using cystatin C-based eGFR (eGFRcys) to estimate the prevalence of CKD and risks of hospitalization were also quantified. RESULTS: Participants experienced 5,548 hospitalizations and 29% had CKD. Hospitalization rates per 1,000 person-years according to KDIGO risk categories were 208-223 ("low risk"), 288-376 ("moderately increased risk"), 363-548 ("high risk"), and 499-1083 ("very high risk"). The increased risk associated with low eGFR and high ACR persisted in adjusted analyses, examinations of cause-specific hospitalizations, and when CKD was staged by eGFRcys or eGFRcr-cys, a combined equation based on both creatinine and cystatin C. In comparison to eGFRcr, staging by eGFRcys increased the prevalence of CKD to 50%, but hospitalization risks remained similarly high. DISCUSSION/CONCLUSION: In older adults, decreased eGFR, increased ACR, and KDIGO risk stages based on a combination of these measures, were strong risk factors for hospitalization. These relationships were consistent, regardless of the marker used to estimate GFR, but the use of cystatin C resulted in a substantially higher prevalence of CKD than the use of creatinine. Older adults in the population with very high risk stages of CKD have hospitalization rates exceeding 500 per 1,000 person-years.

Clinical epidemiology of infectious disease among patients with chronic kidney disease.

Infectious disease is recognized as an important complication among patients with end-stage renal disease, contributing to excess morbidity and health care costs. However, recent epidemiological studies have revealed that even mild to moderate stages of chronic kidney disease (CKD) substantially increase risk of infection. Regarding underlying mechanisms, evidence suggests various aspects of altered immune response in patients with CKD including impaired function of T cells, B cells and neutrophil. Multiple conditions surrounding CKD, such as older age, diabetes, and cardiovascular disease are important contributors in the increased susceptibility to infection in this population. In addition, several mechanisms impairing immune function have been hypothesized including accumulated uremic toxins, increased oxidative stress, endothelial dysfunction, low-grade inflammation, and mineral and bone disorders. In terms of prevention strategies, influenza and pneumococcal vaccines are most feasible and important. Nevertheless, the extent of vaccine utilization in CKD has not been well documented. In addition, antibody response to vaccination may be reduced in CKD patients, and thus a vaccine delivery strategy (e.g., dose and frequency) may need to be optimized among patients with CKD. Through this review, we demonstrate that infection is a major but underrecognized complication of CKD. As CKD is recognized as a serious public health issue, dedicated research is needed to better characterize the burden of infectious disease associated with CKD, understand the pathophysiology of infection in patients with CKD, and develop effective strategies to prevent infection and its sequela in this high risk population.

Correction to: Clinical epidemiology of infectious disease among patients with chronic kidney disease.

The article "Clinical epidemiology of infectious disease among patients with chronic kidney disease", written by Junichi Ishigami and Kunihiro Matsushita, was originally published electronically on the publisher's internet portal (currently SpringerLink) on 3rd September 2018 without open access.

Predictors of withdrawal from renal replacement therapy among patients with acute kidney injury requiring renal replacement therapy.

BACKGROUND: Although recovery of renal function after an episode of acute kidney injury (AKI) is an important clinical measure of morbidity, predictors of withdrawal from renal replacement therapy (RRT) among AKI patients remain unclear. METHODS: In this single-center retrospective cohort study, we examined the clinical records of AKI patients requiring RRT who were hospitalized in the ICU or general wards at our hospital from January 2010 to December 2013. A priori-determined covariates of age, sex, cardiovascular disease, chronic kidney disease (CKD), mean arterial pressure (MAP), sepsis, nephrotoxic agents, and hypoalbuminemia were assessed in Cox hazard models to estimate hazard ratio (HR). RESULTS: A total of 334 patients were enrolled (median age, 68 years; interquartile range [IQR], 57-77 years; male, 71.6%). During follow-up 157 (47.0%) patients achieved RRT withdrawal. Multivariable Cox regression analysis revealed that CKD, MAP between 95 and 105 mmHg and MAP ≥ 105 mmHg, compared with MAP between 65 and 75 mmHg, ventilator use and hypoalbuminemia, were significantly associated with RRT withdrawal. CONCLUSION: Among patients with AKI requiring RRT, CKD, ventilator use, hypoalbuminemia, and high MAP were associated with RRT withdrawal. Furthermore, keeping a higher MAP at RRT initiation can potentially lead to dependence on RRT.