Shoshana H. Ballew

Decline in estimated glomerular filtration rate and subsequent risk of end-stage renal disease and mortality

IMPORTANCE The established chronic kidney disease (CKD) progression end point of end-stage renal disease (ESRD) or a doubling of serum creatinine concentration (corresponding to a change in estimated glomerular filtration rate [GFR] of −57% or greater) is a late event. OBJECTIVE To characterize the association of decline in estimated GFR with subsequent progression to ESRD with implications for using lesser declines in estimated GFR as potential alternative end points for CKD progression. Because most people with CKD die before reaching ESRD, mortality risk also was investigated. DATA SOURCES AND STUDY SELECTION Individual meta-analysis of 1.7 million participants with 12,344 ESRD events and 223,944 deaths from 35 cohorts in the CKD Prognosis Consortium with a repeated measure of serum creatinine concentration over 1 to 3 years and outcome data. DATA EXTRACTION AND SYNTHESIS Transfer of individual participant data or standardized analysis of outputs for random-effects meta-analysis conducted between July 2012 and September 2013, with baseline estimated GFR values collected from 1975 through 2012. MAIN OUTCOMES AND MEASURES End-stage renal disease (initiation of dialysis or transplantation) or all-cause mortality risk related to percentage change in estimated GFR over 2 years, adjusted for potential confounders and first estimated GFR. RESULTS The adjusted hazard ratios (HRs) of ESRD and mortality were higher with larger estimated GFR decline. Among participants with baseline estimated GFR of less than 60 mL/min/1.73 m2, the adjusted HRs for ESRD were 32.1 (95% CI, 22.3-46.3) for changes of −57% in estimated GFR and 5.4 (95% CI, 4.5-6.4) for changes of −30%. However, changes of −30% or greater (6.9% [95% CI, 6.4%-7.4%] of the entire consortium) were more common than changes of −57% (0.79% [95% CI, 0.52%-1.06%]). This association was strong and consistent across the length of the baseline period (1 to 3 years), baseline estimated GFR, age, diabetes status, or albuminuria. Average adjusted 10-year risk of ESRD (in patients with a baseline estimated GFR of 35 mL/min/1.73 m2) was 99% (95% CI, 95%-100%) for estimated GFR change of −57%, was 83% (95% CI, 71%-93%) for estimated GFR change of −40%, and was 64% (95% CI, 52%-77%) for estimated GFR change of −30% vs 18% (95% CI, 15%-22%) for estimated GFR change of 0%. Corresponding mortality risks were 77% (95% CI, 71%-82%), 60% (95% CI, 56%-63%), and 50% (95% CI, 47%-52%) vs 32% (95% CI, 31%-33%), showing a similar but weaker pattern. CONCLUSIONS AND RELEVANCE Declines in estimated GFR smaller than a doubling of serum creatinine concentration occurred more commonly and were strongly and consistently associated with the risk of ESRD and mortality, supporting consideration of lesser declines in estimated GFR (such as a 30% reduction over 2 years) as an alternative end point for CKD progression.

Kidney Failure Risk Projection for the Living Kidney Donor Candidate

BACKGROUND Evaluation of candidates to serve as living kidney donors relies on screening for individual risk factors for end-stage renal disease (ESRD). To support an empirical approach to donor selection, we developed a tool that simultaneously incorporates multiple health characteristics to estimate a persons probable long-term risk of ESRD if that person does not donate a kidney. METHODS We used risk associations from a meta-analysis of seven general population cohorts, calibrated to the population-level incidence of ESRD and mortality in the United States, to project the estimated long-term incidence of ESRD among persons who do not donate a kidney, according to 10 demographic and health characteristics. We then compared 15-year projections with the observed risk among 52,998 living kidney donors in the United States. RESULTS A total of 4,933,314 participants from seven cohorts were followed for a median of 4 to 16 years. For a 40-year-old person with health characteristics that were similar to those of age-matched kidney donors, the 15-year projections of the risk of ESRD in the absence of donation varied according to race and sex; the risk was 0.24% among black men, 0.15% among black women, 0.06% among white men, and 0.04% among white women. Risk projections were higher in the presence of a lower estimated glomerular filtration rate, higher albuminuria, hypertension, current or former smoking, diabetes, and obesity. In the model-based lifetime projections, the risk of ESRD was highest among persons in the youngest age group, particularly among young blacks. The 15-year observed risks after donation among kidney donors in the United States were 3.5 to 5.3 times as high as the projected risks in the absence of donation. CONCLUSIONS Multiple demographic and health characteristics may be used together to estimate the projected long-term risk of ESRD among living kidney-donor candidates and to inform acceptance criteria for kidney donors. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others.).

Performance and Limitations of Administrative Data in the Identification of AKI

BACKGROUND AND OBJECTIVES Billing codes are frequently used to identify AKI events in epidemiologic research. The goals of this study were to validate billing code-identified AKI against the current AKI consensus definition and to ascertain whether sensitivity and specificity vary by patient characteristic or over time. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS The study population included 10,056 Atherosclerosis Risk in Communities study participants hospitalized between 1996 and 2008. Billing code-identified AKI was compared with the 2012 Kidney Disease Improving Global Outcomes (KDIGO) creatinine-based criteria (AKIcr) and an approximation of the 2012 KDIGO creatinine- and urine output-based criteria (AKIcr_uop) in a subset with available outpatient data. Sensitivity and specificity of billing code-identified AKI were evaluated over time and according to patient age, race, sex, diabetes status, and CKD status in 546 charts selected for review, with estimates adjusted for sampling technique. RESULTS A total of 34,179 hospitalizations were identified; 1353 had a billing code for AKI. The sensitivity of billing code-identified AKI was 17.2% (95% confidence interval [95% CI], 13.2% to 21.2%) compared with AKIcr (n=1970 hospitalizations) and 11.7% (95% CI, 8.8% to 14.5%) compared with AKIcr_uop (n=1839 hospitalizations). Specificity was >98% in both cases. Sensitivity was significantly higher in the more recent time period (2002-2008) and among participants aged 65 years and older. Billing code-identified AKI captured a more severe spectrum of disease than did AKIcr and AKIcr_uop, with a larger proportion of patients with stage 3 AKI (34.9%, 19.7%, and 11.5%, respectively) and higher in-hospital mortality (41.2%, 18.7%, and 12.8%, respectively). CONCLUSIONS The use of billing codes to identify AKI has low sensitivity compared with the current KDIGO consensus definition, especially when the urine output criterion is included, and results in the identification of a more severe phenotype. Epidemiologic studies using billing codes may benefit from a high specificity, but the variation in sensitivity may result in bias, particularly when trends over time are the outcome of interest.

Subclinical Atherosclerosis Measures for Cardiovascular Prediction in CKD

Whether inclusion of the coronary artery calcium score improves cardiovascular risk prediction in individuals with CKD, a population with unique calcium-phosphate homeostasis, is unknown. Among 6553 participants ages 45-84 years without prior cardiovascular disease in the Multi-Ethnic Study of Atherosclerosis, coronary artery calcium score was assessed for cardiovascular risk prediction beyond the Framingham predictors in those with (n=1284) and without CKD and contrasted with carotid intima-media thickness and ankle-brachial index (two other measures of subclinical atherosclerosis). During a median follow-up of 8.4 years, 650 cardiovascular events (coronary heart disease, stroke, heart failure, and peripheral artery disease) occurred (236 events in subjects with CKD). In Cox proportional hazards models adjusted for Framingham predictors, each subclinical measure was independently associated with cardiovascular outcomes, with larger adjusted hazard ratios (HRs; per 1 SD) for coronary artery calcium score than carotid intima-media thickness or ankle-brachial index in subjects without and with CKD (HR, 1.69; 95% confidence interval [95% CI], 1.45 to 1.97 versus HR, 1.12; 95% CI, 1.00 to 1.25 and HR, 1.20; 95% CI, 1.08 to 1.32, respectively). Compared with inclusion of carotid intima-media thickness or ankle-brachial index, inclusion of the coronary artery calcium score led to greater increases in C statistic for predicting cardiovascular disease and net reclassification improvement. Coronary artery calcium score performed best for the prediction of coronary heart disease and heart failure, regardless of CKD status. In conclusion, each measure improved cardiovascular risk prediction in subjects with CKD, with the greatest improvement observed with coronary artery calcium score.

A Meta-analysis of the Association of Estimated GFR, Albuminuria, Age, Race, and Sex With Acute Kidney Injury

BACKGROUND Acute kidney injury (AKI) is a serious global public health problem. We aimed to quantify the risk of AKI associated with estimated glomerular filtration rate (eGFR), albuminuria (albumin-creatinine ratio [ACR]), age, sex, and race (African American and white). STUDY DESIGN Collaborative meta-analysis. SETTING & POPULATION 8 general-population cohorts (1,285,049 participants) and 5 chronic kidney disease (CKD) cohorts (79,519 participants). SELECTION CRITERIA FOR STUDIES Available eGFR, ACR, and 50 or more AKI events. PREDICTORS Age, sex, race, eGFR, urine ACR, and interactions. OUTCOME Hospitalized with or for AKI, using Cox proportional hazards models to estimate HRs of AKI and random-effects meta-analysis to pool results. RESULTS 16,480 (1.3%) general-population cohort participants had AKI over a mean follow-up of 4 years; 2,087 (2.6%) CKD participants had AKI over a mean follow-up of 1 year. Lower eGFR and higher ACR were strongly associated with AKI. Compared with eGFR of 80mL/min/1.73m(2), the adjusted HR of AKI at eGFR of 45mL/min/1.73m(2) was 3.35 (95% CI, 2.75-4.07). Compared with ACR of 5mg/g, the risk of AKI at ACR of 300mg/g was 2.73 (95% CI, 2.18-3.43). Older age was associated with higher risk of AKI, but this effect was attenuated with lower eGFR or higher ACR. Male sex was associated with higher risk of AKI, with a slight attenuation in lower eGFR but not in higher ACR. African Americans had higher AKI risk at higher levels of eGFR and most levels of ACR. LIMITATIONS Only 2 general-population cohorts could contribute to analyses by race; AKI identified by diagnostic code. CONCLUSIONS Reduced eGFR and increased ACR are consistent strong risk factors for AKI, whereas associations of AKI with age, sex, and race may be weaker in more advanced stages of CKD.

CKD and Cardiovascular Disease in the Atherosclerosis Risk in Communities (ARIC) Study: Interactions With Age, Sex, and Race

BACKGROUND Estimated glomerular filtration rate (eGFR) and albuminuria are central for diagnosis, staging, and risk evaluation in chronic kidney disease (CKD). Universal thresholds regardless of age, sex, and race are recommended, but relatively little is known about how these demographic factors alter the relationship of eGFR and albuminuria to cardiovascular outcomes. STUDY DESIGN Observational cohort study. SETTING & PARTICIPANTS 11,060 whites and blacks aged 52-75 years in the Atherosclerosis Risk in Communities (ARIC) Study with median follow-up of 11.2 years. PREDICTORS eGFR by the CKD-EPI (CKD Epidemiology Collaboration) creatinine equation (reference, 95 mL/min/1.73 m(2)) and urinary albumin-creatinine ratio (ACR; reference, 5 mg/g). OUTCOMES Cardiovascular events (coronary disease, stroke, and heart failure) and all-cause mortality. MEASUREMENTS Adjusted HRs associated with eGFR and ACR in subgroups according to age, sex, and race. RESULTS Cardiovascular risk significantly increased at eGFR <70 mL/min/1.73 m(2) in all subgroups according to age (<65 vs ≥65 years), sex, and race (P for interaction >0.2 for these subgroups; eg, at eGFR of 30 mL/min/1.73 m(2), the adjusted HR was 2.19 [95% CI, 1.10-4.35] at age 52-64 years vs 2.23 [95% CI, 1.33-3.72] at age 65-75 years). Results were similar for mortality. Log(ACR) was associated linearly with cardiovascular risk without threshold effects in all subgroups, with some quantitative interactions. HRs according to ACR tended to be lower in men versus women (eg, at ACR of 40 mg/g, 1.18 [95% CI, 0.98-1.41] vs 1.77 [95% CI, 1.45-2.15]) and in the older versus younger population (1.24 [95% CI, 1.04-1.49] vs 1.73 [95% CI, 1.42-2.12]; P for interaction <0.01 for sex and age). Less evident interactions were observed for mortality. LIMITATIONS Single measurement of eGFR with creatinine and ACR and relatively narrow age range. CONCLUSIONS The associations of eGFR and ACR with cardiovascular events were largely similar, with some quantitative interactions, in age, sex, and racial subgroups, generally supporting universal thresholds of GFR and ACR for CKD definition/staging.

Identification of incident CKD stage 3 in research studies.

BACKGROUND In epidemiologic research, incident chronic kidney disease (CKD) commonly is determined by laboratory tests performed at planned study visits. Given the morbidity and mortality associated with CKD, persons with incident disease may be less likely to attend scheduled visits, affecting observed associations. The objective of this study was to quantify loss to follow-up by CKD status and determine whether supplementation with diagnostic code data improves capture of incident CKD. STUDY DESIGN Prospective cohort study. SETTING & PARTICIPANTS 11,560 participants in the Atherosclerosis Risk in Communities (ARIC) Study underwent continuous surveillance for hospitalizations and death from baseline visit (1996-1999) to follow-up visit (2011-2013). A subset of hospitalizations in Washington County, MD, was used in diagnostic code validation (n=2,540). PREDICTOR Baseline demographics and comorbid conditions. OUTCOMES Incident CKD stage 3 ascertained by follow-up visit (visit-based definition) or hospitalization surveillance (hospitalization-based definition). MEASUREMENTS Visit-based definition: ≥25% decline from baseline estimated glomerular filtration rate to <60 mL/min/1.73 m2 at follow-up visit; hospitalization-based definition: hospitalization CKD diagnostic code. RESULTS Of 11,560 participants, 5,951 attended the follow-up visit and 9,264 were hospitalized. Never-hospitalized participants were younger, more often female, and had fewer comorbid conditions; 73.5% attended the follow-up visit. Incident CKD stage 3 occurred in 1,172 participants by the visit-based definition (251 were never hospitalized) and 1,078 participants by the hospitalization-based definition (237 attended the follow-up study visit). Sensitivity of the hospitalization-based CKD definition was 35.5% (95% CI, 31.6%-39.7%); specificity was 95.7% (95% CI, 94.2%-96.8%). Sensitivity was higher with later time period, older participant age, and baseline prevalent diabetes and CKD. LIMITATIONS A subset of hospitalizations was used for validation; 15-year gap between study visits. CONCLUSIONS The sensitivity of diagnostic code-identified CKD is low and varies by certain factors; however, supplementing a visit-based definition with hospitalization information can increase disease identification during periods of follow-up without study visits.

Cohort Profile: The Chronic Kidney Disease Prognosis Consortium

The Chronic Kidney Disease Prognosis Consortium (CKD-PC) was established in 2009 to provide comprehensive evidence about the prognostic impact of two key kidney measures that are used to define and stage CKD, estimated glomerular filtration rate (eGFR) and albuminuria, on mortality and kidney outcomes. CKD-PC currently consists of 46 cohorts with data on these kidney measures and outcomes from >2 million participants spanning across 40 countries/regions all over the world. CKD-PC published four meta-analysis articles in 2010-11, providing key evidence for an international consensus on the definition and staging of CKD and an update for CKD clinical practice guidelines. The consortium continues to work on more detailed analysis (subgroups, different eGFR equations, other exposures and outcomes, and risk prediction). CKD-PC preferably collects individual participant data but also applies a novel distributed analysis model, in which each cohort runs statistical analysis locally and shares only analysed outputs for meta-analyses. This distributed model allows inclusion of cohorts which cannot share individual participant level data. According to agreement with cohorts, CKD-PC will not share data with third parties, but is open to including further eligible cohorts. Each cohort can opt in/out for each topic. CKD-PC has established a productive and effective collaboration, allowing flexible participation and complex meta-analyses for studying CKD.

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.

Past Decline Versus Current eGFR and Subsequent ESRD Risk

eGFR is a robust predictor of ESRD risk. However, the prognostic information gained from the past trajectory (slope) beyond that of the current eGFR is unclear. We examined 22 cohorts to determine the association of past slopes and current eGFR level with subsequent ESRD. We modeled hazard ratios as a spline function of slopes, adjusting for demographic variables, eGFR, and comorbidities. We used random effects meta-analyses to combine results across studies stratified by cohort type. We calculated the absolute risk of ESRD at 5 years after the last eGFR using the weighted average baseline risk. Overall, 1,080,223 participants experienced 5163 ESRD events during a mean follow-up of 2.0 years. In CKD cohorts, a slope of -6 versus 0 ml/min per 1.73 m(2) per year over the previous 3 years (a decline of 18 ml/min per 1.73 m(2) versus no decline) associated with an adjusted hazard ratio of ESRD of 2.28 (95% confidence interval, 1.88 to 2.76). In contrast, a current eGFR of 30 versus 50 ml/min per 1.73 m(2) (a difference of 20 ml/min per 1.73 m(2)) associated with an adjusted hazard ratio of 19.9 (95% confidence interval, 13.6 to 29.1). Past decline contributed more to the absolute risk of ESRD at lower than higher levels of current eGFR. In conclusion, during a follow-up of 2 years, current eGFR associates more strongly with future ESRD risk than the magnitude of past eGFR decline, but both contribute substantially to the risk of ESRD, especially at eGFR<30 ml/min per 1.73 m(2).