Faculty Bibliography

BACKGROUND AND OBJECTIVES:Carotid intima-media thickness has been reported to predict kidney function decline. However, whether carotid intima-media thickness is associated with a hard kidney end point, ESRD, has not been investigated. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS:We studied 13,197 Atherosclerosis Risk in Communities participants at visit 1 (1987-1989) without history of cardiovascular disease, including coronary heart disease, stroke, and heart failure, at baseline and assessed whether carotid intima-media thickness measured by B-mode ultrasound is associated with ESRD risk using Cox proportional hazards models. Regarding carotid intima-media thickness parameters, we investigated the mean and maximum values of overall and segment-specific (common, bifurcation, and internal carotid arteries) measurements. RESULTS:Mean age was 54.0 (SD=5.7) years old, and there were 3373 (25.6%) blacks and 7370 (55.8%) women. During a median follow-up of 22.7 years, 433 participants developed ESRD (1.4/1000 person-years). After adjusting for shared risk factors for atherosclerosis and kidney disease, including baseline kidney function, carotid intima-media thickness was significantly associated with ESRD risk (hazard ratio [HR] between quartiles 4 and 1, 1.46; 95% confidence interval [95% CI], 1.02 to 2.08 for overall mean intima-media thickness and HR between quartiles 4 and 1, 1.75; 95% CI, 1.24 to 2.48 for overall maximum intima-media thickness). The associations were largely consistent in demographic and clinical subgroups. When we explored segment-specific intima-media thicknesses, the associations with ESRD were most robust for bifurcation carotid (e.g., adjusted HR between quartiles 4 and 1 of mean intima-media thickness, 1.49; 95% CI, 1.04 to 2.13 for bifurcation; adjusted HR between quartiles 4 and 1 of mean intima-media thickness, 1.36; 95% CI, 0.94 to 1.97 for common; and adjusted HR between quartiles 4 and 1 of mean intima-media thickness, 0.93; 95% CI, 0.67 to 1.29 for internal). CONCLUSIONS:Carotid intima-media thickness was independently associated with incident ESRD in the general population, suggesting the shared etiology of atherosclerosis and ESRD.

BACKGROUND:Few trials of acute kidney injury (AKI) prevention after surgery have been conducted, and most observational studies focus on AKI following cardiac surgery. The frequency of, risk factors for, and outcomes after AKI following other types of major surgery have not been well characterized and may present additional opportunities for trials in AKI. STUDY DESIGN/METHODS:Observational cohort study. SETTING & PARTICIPANTS/METHODS:3.6 million US veterans followed up from 2004 to 2011 for the receipt of major surgery (cardiac; general; ear, nose, and throat; thoracic; vascular; urologic; and orthopedic) and postoperative outcomes. FACTORS/METHODS:Demographics, health characteristics, and type of surgery. OUTCOMES/RESULTS:Postoperative AKI defined by the KDIGO creatinine criteria, postoperative length of stay, end-stage renal disease, and mortality. RESULTS:Postoperative AKI occurred in 11.8% of the 161,185 major surgery hospitalizations (stage 1, 76%; stage 2, 15%, stage 3 [without dialysis], 7%; and AKI requiring dialysis, 2%). Cardiac surgery had the highest postoperative AKI risk (relative risk [RR], 1.22; 95% CI, 1.17-1.27), followed by general (reference), thoracic (RR, 0.92; 95% CI, 0.87-0.98), orthopedic (RR, 0.70; 95% CI, 0.67-0.73), vascular (RR, 0.68; 95% CI, 0.64-0.71), urologic (RR, 0.65; 95% CI, 0.61-0.69), and ear, nose, and throat (RR, 0.32; 95% CI, 0.28-0.37) surgery. Risk factors for postoperative AKI included older age, African American race, hypertension, diabetes mellitus, and, for estimated glomerular filtration rate < 90mL/min/1.73m(2), lower estimated glomerular filtration rate. Participants with postoperative AKI had longer lengths of stay (15.8 vs 8.6 days) and higher rates of 30-day hospital readmission (21% vs 13%), 1-year end-stage renal disease (0.94% vs 0.05%), and mortality (19% vs 8%), with similar associations by type of surgery and more severe stage of AKI relating to poorer outcomes. LIMITATIONS/CONCLUSIONS:Urine output was not available to classify AKI; cohort included mostly men. CONCLUSIONS:AKI was common after major surgery, with similar risk factor and outcome associations across surgery type. These results can inform the design of clinical trials in postoperative AKI to the noncardiac surgery setting.

Little is known about the frequency and patterns of hyperkalemia in clinical settings. We evaluated the association between baseline antihypertensive medications that may affect potassium levels (angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, β-blockers, loop/thiazide diuretics, and potassium-sparing diuretics) and hyperkalemia, defined by potassium >5 mEq/L and >5.5 mEq/L, over a 3-year time period in 194 456 outpatients in the Geisinger Health System, as well as actions taken after an episode of hyperkalemia. The proportions of patients with 0, <2, 2 to 4, and ≥4 potassium measurements per year were 20%, 58%, 16%, and 6%. Potassium levels >5 mEq/L and >5.5 mEq/L occurred in 10.8% and 2.3% of all patients over the 3-year period; among patients with ≥4 measurements per year, corresponding values were 39.4% and 14.6%. Most cases of hyperkalemia occurred only once during follow-up. The antihypertensive medication class most strongly associated with hyperkalemia was angiotensin-converting enzyme inhibitors. Among patients with a measurement of potassium >5.5 mEq/L, only 24% were seen by a nephrologist and 5.2% were seen by a dietician during the 3-year period. Short-term actions after a potassium measurement >5.5 mEq/L included emergency room visit (3.1% within 7 days), remeasurement of potassium (44.3% with 14 days), and change in a potassium-altering medication (26.4% within 60 days). The most common medication changes were discontinuation/dose reduction of an angiotensin-converting enzyme inhibitor/angiotensin receptor blocker or potassium-sparing diuretic, which occurred in 29.1% and 49.6% of people taking these medications, respectively. In conclusion, hyperkalemia is common. Future research may enable optimal renin-angiotensin-aldosterone system inhibitor use with improved management of hyperkalemia.

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 person's 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.).

BACKGROUND:People with end-stage renal disease are at high risk for bone fracture. Less is known about fracture risk in milder chronic kidney disease and whether chronic kidney disease-associated fracture risk varies by sex or assessment with alternative kidney markers. STUDY DESIGN/METHODS:Prospective cohort study. SETTING & PARTICIPANTS/METHODS:10,955 participants from the Atherosclerosis Risk in Communities (ARIC) Study followed up from 1996 to 2011. PREDICTOR/METHODS:Kidney function as assessed by creatinine-based estimated glomerular filtration rate (eGFRcr), urine albumin-creatinine ratio, and alternative filtration markers. OUTCOMES/RESULTS:Fracture-related hospitalizations determined by diagnostic code. MEASUREMENTS/METHODS:Baseline kidney markers; hospitalizations identified by self-report during annual telephone contact and active surveillance of local hospital discharge lists. RESULTS:Mean age of participants was 63 years, 56% were women, and 22% were black. During a median follow-up of 13 years, there were 722 incident fracture-related hospitalizations. Older age, female sex, and white race were associated with higher risk for fracture (P<0.001). The relationship between eGFRcr and fracture risk was nonlinear: <60mL/min/1.73m(2), lower eGFRcr was associated with higher fracture risk (adjusted HR per 10mL/min/1.73m(2) lower, 1.24; 95% CI, 1.05-1.47); there was no statistically significant association for ≥60mL/min/1.73m(2) in the primary analysis. In contrast, there was a graded association between other markers of kidney function and subsequent fracture, including albumin-creatinine ratio (HR per doubling, 1.10; 95% CI, 1.06-1.14), cystatin C-based eGFR (HR per 1-SD decrease, 1.15; 95% CI, 1.06-1.25), and 1/β2-microglobulin (HR per 1-SD decrease, 1.26, 95% CI, 1.15-1.37). LIMITATIONS/CONCLUSIONS:No bone mineral density assessment; one-time measurement of kidney function. CONCLUSIONS:Both low eGFR and higher albuminuria were significant risk factors for fracture in this community-based population. The shape of the association in the upper ranges of eGFR varied by the filtration marker used in estimation.

BACKGROUND:The link of low estimated glomerular filtration rate (eGFR) and high proteinuria to cardiovascular disease (CVD) mortality is well known. However, its link to mortality due to other causes is less clear. METHODS:We studied 367,932 adults (20-93 years old) in the Korean Heart Study (baseline between 1996-2004 and follow-up until 2011) and assessed the associations of creatinine-based eGFR and dipstick proteinuria with mortality due to CVD (1,608 cases), cancer (4,035 cases), and other (non-CVD/non-cancer) causes (3,152 cases) after adjusting for potential confounders. RESULTS:Although cancer was overall the most common cause of mortality, in participants with chronic kidney disease (CKD), non-CVD/non-cancer mortality accounted for approximately half of cause of death (47.0%for eGFR <60 ml/min/1.73 m2 and 54.3% for proteinuria ≥1+). Lower eGFR (<60 vs. ≥60 ml/min/1.73 m2) was significantly associated with mortality due to CVD (adjusted hazard ratio 1.49 [95% CI, 1.24-1.78]) and non-CVD/non-cancer causes (1.78 [1.54-2.05]). The risk of cancer mortality only reached significance at eGFR <45 ml/min/1.73 m2 when eGFR 45-59 ml/min/1.73 m2 was set as a reference (1.62 [1.10-2.39]). High proteinuria (dipstick ≥1+ vs. negative/trace) was consistently associated with mortality due to CVD (1.93 [1.66-2.25]), cancer (1.49 [1.32-1.68]), and other causes (2.19 [1.96-2.45]). Examining finer mortality causes, low eGFR and high proteinuria were commonly associated with mortality due to coronary heart disease, any infectious disease, diabetes, and renal failure. In addition, proteinuria was also related to death from stroke, cancers of stomach, liver, pancreas, and lung, myeloma, pneumonia, and viral hepatitis. CONCLUSION/CONCLUSIONS:Low eGFR was associated with CVD and non-CVD/non-cancer mortality, whereas higher proteinuria was consistently related to mortality due to CVD, cancer, and other causes. These findings suggest the need for multidisciplinary prevention and management strategies in individuals with CKD, particularly when proteinuria is present.

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/METHODS:Collaborative meta-analysis. SETTING & POPULATION/METHODS:8 general-population cohorts (1,285,049 participants) and 5 chronic kidney disease (CKD) cohorts (79,519 participants). SELECTION CRITERIA FOR STUDIES/METHODS:Available eGFR, ACR, and 50 or more AKI events. PREDICTORS/METHODS:Age, sex, race, eGFR, urine ACR, and interactions. OUTCOME/RESULTS: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/CONCLUSIONS: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.

Chronic kidney disease (CKD), the presence of kidney dysfunction and/or damage, is a worldwide public health issue. Although CKD is independently associated with various subtypes of cardiovascular diseases, a recent international collaborative meta-analysis demonstrates that CKD is particularly strongly associated with heart failure, suggesting its critical impact on cardiac structure and function. Although numerous studies have investigated the association of CKD and cardiac structure and function, these studies substantially vary regarding source populations and methodology (e.g., measures of CKD and/or parameters of cardiac structure and function), making it difficult to reach universal conclusions. Nevertheless, in this review, we comprehensively examine relevant studies, discuss potential mechanisms linking CKD to alteration of cardiac structure and function, and demonstrate clinical implications as well as potential future research directions. We exclusively focus on studies investigating both CKD measures, kidney function (i.e., glomerular filtration rate [GFR], creatinine clearance, or levels of filtration markers), and kidney damage represented by albuminuria, since current international clinical guidelines of CKD recommend staging CKD and assessing its clinical risk based on both GFR and albuminuria.

BACKGROUND:Linkage to the US Renal Data System (USRDS) registry commonly is used to identify end-stage renal disease (ESRD) cases, or kidney failure treated with dialysis or transplantation, but it underestimates the total burden of kidney failure. This study validates a kidney failure definition that includes both kidney failure treated and not treated by dialysis or transplantation. It compares kidney failure risk factors and outcomes using this broader definition with USRDS-identified ESRD risk factors and outcomes. STUDY DESIGN/METHODS:Diagnostic test study with stratified random sampling of hospitalizations for chart review. SETTING & PARTICIPANTS/METHODS:Atherosclerosis Risk in Communities Study (n=11,530; chart review, n=546). INDEX TEST/METHODS:USRDS-identified ESRD; treated or untreated kidney failure defined by USRDS-identified ESRD or International Classification of Diseases, Ninth or Tenth Revision, Clinical Modification (ICD-9-CM/ICD-10-CM) code for hospitalization or death. REFERENCE TEST/METHODS:For ESRD, determination of permanent dialysis therapy or transplantation; for kidney failure, determination of permanent dialysis therapy, transplantation, or estimated glomerular filtration rate < 15 mL/min/1.73 m(2). RESULTS:During 13 years' median follow-up, 508 kidney failure cases were identified, including 173 (34.1%) from the USRDS registry. ESRD and kidney failure incidence were 1.23 and 3.66 cases per 1,000 person-years in the overall population and 1.35 and 6.59 cases per 1,000 person-years among participants older than 70 years, respectively. Other risk-factor associations were similar between ESRD and kidney failure, except diabetes and albuminuria, which were stronger for ESRD. Survivals at 1 and 5 years were 74.0% and 24.0% for ESRD and 59.8% and 31.6% for kidney failure, respectively. Sensitivity and specificity were 88.0% and 97.3% comparing the kidney failure ICD-9-CM/ICD-10-CM code algorithm to chart review; for USRDS-identified ESRD, sensitivity and specificity were 94.9% and 100.0%. LIMITATIONS/CONCLUSIONS:Some medical charts were incomplete. CONCLUSIONS:A kidney failure definition including treated and untreated disease identifies more cases than linkage to the USRDS registry alone, particularly among older adults. Future studies might consider reporting both USRDS-identified ESRD and a more inclusive kidney failure definition.

BACKGROUND:The usefulness of estimated glomerular filtration rate (eGFR) and albuminuria for prediction of cardiovascular outcomes is controversial. We aimed to assess the addition of creatinine-based eGFR and albuminuria to traditional risk factors for prediction of cardiovascular risk with a meta-analytic approach. METHODS:We meta-analysed individual-level data for 637 315 individuals without a history of cardiovascular disease from 24 cohorts (median follow-up 4·2-19·0 years) included in the Chronic Kidney Disease Prognosis Consortium. We assessed C statistic difference and reclassification improvement for cardiovascular mortality and fatal and non-fatal cases of coronary heart disease, stroke, and heart failure in a 5 year timeframe, contrasting prediction models for traditional risk factors with and without creatinine-based eGFR, albuminuria (either albumin-to-creatinine ratio [ACR] or semi-quantitative dipstick proteinuria), or both. FINDINGS/RESULTS:The addition of eGFR and ACR significantly improved the discrimination of cardiovascular outcomes beyond traditional risk factors in general populations, but the improvement was greater with ACR than with eGFR, and more evident for cardiovascular mortality (C statistic difference 0·0139 [95% CI 0·0105-0·0174] for ACR and 0·0065 [0·0042-0·0088] for eGFR) and heart failure (0·0196 [0·0108-0·0284] and 0·0109 [0·0059-0·0159]) than for coronary disease (0·0048 [0·0029-0·0067] and 0·0036 [0·0019-0·0054]) and stroke (0·0105 [0·0058-0·0151] and 0·0036 [0·0004-0·0069]). Dipstick proteinuria showed smaller improvement than ACR. The discrimination improvement with eGFR or ACR was especially evident in individuals with diabetes or hypertension, but remained significant with ACR for cardiovascular mortality and heart failure in those without either of these disorders. In individuals with chronic kidney disease, the combination of eGFR and ACR for risk discrimination outperformed most single traditional predictors; the C statistic for cardiovascular mortality fell by 0·0227 (0·0158-0·0296) after omission of eGFR and ACR compared with less than 0·007 for any single modifiable traditional predictor. INTERPRETATION/CONCLUSIONS:Creatinine-based eGFR and albuminuria should be taken into account for cardiovascular prediction, especially when these measures are already assessed for clinical purpose or if cardiovascular mortality and heart failure are outcomes of interest. ACR could have particularly broad implications for cardiovascular prediction. In populations with chronic kidney disease, the simultaneous assessment of eGFR and ACR could facilitate improved classification of cardiovascular risk, supporting current guidelines for chronic kidney disease. Our results lend some support to also incorporating eGFR and ACR into assessments of cardiovascular risk in the general population. FUNDING/BACKGROUND:US National Kidney Foundation, National Institute of Diabetes and Digestive and Kidney Diseases.