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 Observational cohort study. Setting & Participants 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 Demographics, health characteristics, and type of surgery. Outcomes 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 < 90 mL/min/1.73 m2 , 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 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.
The US Food and Drug Administration currently accepts halving of glomerular filtration rate (GFR), assessed as doubling of serum creatinine level, as a surrogate end point for the development of ...kidney failure in clinical trials of kidney disease progression. A doubling of serum creatinine level generally is a late event in chronic kidney disease (CKD); thus, there is great interest in considering alternative end points for clinical trials to shorten their duration, reduce sample size, and extend their conduct to patients with earlier stages of CKD. However, the relationship between lesser declines in GFR and the subsequent development of kidney failure has not been well characterized. The National Kidney Foundation and Food and Drug Administration sponsored a scientific workshop to critically examine available data to determine whether alternative GFR-based end points have sufficiently strong relationships with important clinical outcomes of CKD to be used in clinical trials. Based on a series of meta-analyses of cohorts and clinical trials and simulations of trial designs and analytic methods, the workshop concluded that a confirmed decline in estimated GFR of 30% over 2 to 3 years may be an acceptable surrogate end point in some circumstances, but the pattern of treatment effects on GFR must be examined, specifically acute effects on estimated GFR. An estimated GFR decline of 40% may be more broadly acceptable than a 30% decline across a wider range of baseline GFRs and patterns of treatment effects on GFR. However, there are other circumstances in which these end points could lead to a reduction in statistical power or erroneous conclusions regarding benefits or harms of interventions. We encourage careful consideration of these alternative end points in the design of future clinical trials.
Background There are established guidelines for recommended dietary intake for hypertension treatment and cardiovascular disease prevention. Evidence is lacking for effective dietary patterns for ...kidney disease prevention. Study Design Prospective cohort study. Setting & Participants Atherosclerosis Risk in Communities (ARIC) Study participants with baseline estimated glomerular filtration rate (eGFR) ≥ 60 mL/min/1.73 m2 (N = 14,882). Predictor The Dietary Approaches to Stop Hypertension (DASH) diet score was calculated based on self-reported dietary intake of red and processed meat, sweetened beverages, sodium, fruits, vegetables, whole grains, nuts and legumes, and low-fat dairy products, averaged over 2 visits. Outcomes Cases were ascertained based on the development of eGFRs < 60 mL/min/1.73 m2 accompanied by ≥25% eGFR decline from baseline, an International Classification of Diseases, Ninth/Tenth Revision code for a kidney disease−related hospitalization or death, or end-stage renal disease from baseline through 2012. Results 3,720 participants developed kidney disease during a median follow-up of 23 years. Participants with a DASH diet score in the lowest tertile were 16% more likely to develop kidney disease than those with the highest score tertile (HR, 1.16; 95% CI, 1.07-1.26; P for trend < 0.001), after adjusting for sociodemographics, smoking status, physical activity, total caloric intake, baseline eGFR, overweight/obese status, diabetes status, hypertension status, systolic blood pressure, and antihypertensive medication use. Of the individual components of the DASH diet score, high red and processed meat intake was adversely associated with kidney disease and high nuts, legumes, and low-fat dairy products intake was associated with reduced risk for kidney disease. Limitations Potential measurement error due to self-reported dietary intake and lack of data for albuminuria. Conclusions Consuming a DASH-style diet was associated with lower risk for kidney disease independent of demographic characteristics, established kidney risk factors, and baseline kidney function. Healthful dietary patterns such as the DASH diet may be beneficial for kidney disease prevention.
Background Individuals on dialysis therapy have a high risk for infection, but risk for infection in earlier stages of chronic kidney disease has not been comprehensively described. Study Design ...Observational cohort study. Setting & Participants 9,697 participants (aged 53-75 years) in the Atherosclerosis Risk in Communities (ARIC) Study. Participants were followed up from 1996 to 1998 through 2011. Predictors Estimated glomerular filtration rate (eGFR) and urinary albumin-creatinine ratio (ACR). Outcomes Risk for hospitalization with infection and death during or within 30 days of hospitalization with infection. Results During follow-up (median, 13.6 years), there were 2,701 incident hospitalizations with infection (incidence rate, 23.6/1,000 person-years) and 523 infection-related deaths. In multivariable analysis, HRs of incident hospitalization with infection as compared to eGFRs ≥ 90 mL/min/1.73 m2 were 2.55 (95% CI, 1.43-4.55), 1.48 (95% CI, 1.28-1.71), and 1.07 (95% CI, 0.98-1.16) for eGFRs of 15 to 29, 30 to 59, and 60 to 89 mL/min/1.73 m2 , respectively. Corresponding HRs were 3.76 (95% CI, 1.48-9.58), 1.62 (95% CI, 1.20-2.19), and 0.99 (95% CI, 0.80-1.21) for infection-related death. Compared to ACRs < 10 mg/g, HRs of incident hospitalization with infection were 2.30 (95% CI, 1.81-2.91), 1.56 (95% CI, 1.36-1.78), and 1.34 (95% CI, 1.20-1.50) for ACRs ≥ 300, 30 to 299, and 10 to 29 mg/g, respectively. Corresponding HRs were 3.44 (95% CI, 2.28-5.19), 1.57 (95% CI, 1.18-2.09), and 1.39 (95% CI, 1.09-1.78) for infection-related death. Results were consistent when separately assessing risk for pneumonia, kidney and urinary tract infections, bloodstream infections, and cellulitis and when taking into account recurrent episodes of infection. Limitations Outcome ascertainment relied on diagnostic codes at time of discharge. Conclusions Increasing provider awareness of chronic kidney disease as a risk factor for infection is needed to reduce infection-related morbidity and mortality.
Background Serum β-trace protein (BTP) and β2 -microglobulin (B2M) are independently associated with end-stage renal disease (ESRD) and mortality in the general population and high-risk groups with ...diabetes or advanced chronic kidney disease (CKD). Less is known about their associations with outcomes and predictive ability in adults with moderate CKD. Study Design Prospective cohort study. Setting & Participants 3,613 adults from the CRIC (Chronic Renal Insufficiency Cohort) Study (45% women; mean age, 57.9 years; 41.0% non-Hispanic black; 51.9% with diabetes). Predictors BTP and B2M levels with a reciprocal transformation to reflect their associations with filtration, creatinine-based estimated glomerular filtration rate (eGFRcr ), measured GFR, and a 4-marker composite score combining BTP, B2M, creatinine, and cystatin C levels. Predictors were standardized as z scores for comparisons across filtration markers. Outcomes ESRD, all-cause mortality, and new-onset cardiovascular disease. Results During a 6-year median follow-up, 755 (21%) participants developed ESRD, 653 died, and 292 developed new-onset cardiovascular disease. BTP, B2M, and the 4-marker composite score were independent predictors of ESRD and all-cause mortality, and B2M and the 4-marker composite score of cardiovascular events, after multivariable adjustment. These associations were stronger than those observed for eGFRcr ( P vs eGFRcr ≤ 0.02). The 4-marker composite score led to improvements in C statistic and 2.5-year risk reclassification beyond eGFRcr for all outcomes. Limitations Filtration markers measured at one time point; measured GFR available in subset of cohort. Conclusions BTP and B2M levels may contribute additional risk information beyond eGFRcr , and the use of multiple markers may improve risk prediction beyond this well-established marker of kidney function among persons with moderate CKD.
Background Diabetes mellitus and hypertension are risk factors for acute kidney injury (AKI). Whether estimated glomerular filtration rate (eGFR) and urine albumin-creatinine ratio (ACR) remain risk ...factors for AKI in the presence and absence of these conditions is uncertain. Study Design Meta-analysis of cohort studies. Setting & Population 8 general-population (1,285,045 participants) and 5 chronic kidney disease (CKD; 79,519 participants) cohorts. Selection Criteria for Studies Cohorts participating in the CKD Prognosis Consortium. Predictors Diabetes and hypertension status, eGFR by the 2009 CKD Epidemiology Collaboration creatinine equation, urine ACR, and interactions. Outcome Hospitalization with AKI, using Cox proportional hazards models to estimate HRs of AKI and random-effects meta-analysis to pool results. Results During a mean follow-up of 4 years, there were 16,480 episodes of AKI in the general-population and 2,087 episodes in the CKD cohorts. Low eGFRs and high ACRs were associated with higher risks of AKI in individuals with or without diabetes and with or without hypertension. When compared to a common reference of eGFR of 80 mL/min/1.73 m2 in nondiabetic patients, HRs for AKI were generally higher in diabetic patients at any level of eGFR. The same was true for diabetic patients at all levels of ACR compared with nondiabetic patients. The risk gradient for AKI with lower eGFRs was greater in those without diabetes than with diabetes, but similar with higher ACRs in those without versus with diabetes. Those with hypertension had a higher risk of AKI at eGFRs > 60 mL/min/1.73 m2 than those without hypertension. However, risk gradients for AKI with both lower eGFRs and higher ACRs were greater for those without than with hypertension. Limitations AKI identified by diagnostic code. Conclusions Lower eGFRs and higher ACRs are associated with higher risks of AKI among individuals with or without either diabetes or hypertension.
Background Recent studies suggest that potassium levels may differ by race. The basis for these differences and whether associations between potassium levels and adverse outcomes differ by race are ...unknown. Study Design Observational study. Setting & Participants Associations between race and potassium level and the interaction of race and potassium level with outcomes were investigated in the Racial and Cardiovascular Risk Anomalies in Chronic Kidney Disease (RCAV) Study, a cohort of US veterans (N = 2,662,462). Associations between African ancestry and potassium level were investigated in African Americans in the Atherosclerosis Risk in Communities (ARIC) Study (N = 3,450). Predictors Race (African American vs non–African American and percent African ancestry) for cross-sectional analysis; serum potassium level for longitudinal analysis. Outcomes Potassium level for cross-sectional analysis; mortality and end-stage renal disease for longitudinal analysis. Results The RCAV cohort was 18% African American (N = 470,985). Potassium levels on average were 0.162 mmol/L lower in African Americans compared with non–African Americans, with differences persisting after adjustment for demographics, comorbid conditions, and potassium-altering medication use. In the ARIC Study, higher African ancestry was related to lower potassium levels (−0.027 mmol/L per each 10% African ancestry). In both race groups, higher and lower potassium levels were associated with mortality. Compared to potassium level of 4.2 mmol/L, mortality risk associated with lower potassium levels was lower in African Americans versus non–African Americans, whereas mortality risk associated with higher levels was slightly greater. Risk relationships between potassium and end-stage renal disease were weaker, with no difference by race. Limitations No data for potassium intake. Conclusions African Americans had slightly lower serum potassium levels than non–African Americans. Consistent associations between potassium levels and percent African ancestry may suggest a genetic component to these differences. Higher and lower serum potassium levels were associated with mortality in both racial groups.
Background β-Trace protein (BTP) and β2 -microglobulin (B2M) are novel glomerular filtration markers that have stronger associations with adverse outcomes than creatinine. Comparisons of BTP and B2M ...to creatinine and cystatin C are limited by the absence of rigorously developed glomerular filtration rate (GFR) estimating equations for the novel markers. Study Design Study of diagnostic test accuracy. Setting & Participants Pooled database of 3 populations with chronic kidney disease (CKD) with mean measured GFR of 48 mL/min/1.73 m2 (N = 3,551; MDRD Modification of Diet in Renal Disease Study, AASK African American Study of Kidney Disease and Hypertension, and CRIC Chronic Renal Insufficiency Cohort Study). Index Tests GFR estimated using creatinine, cystatin C, BTP, or B2M level. Reference Test GFR measured as the urinary clearance of iothalamate. Results For BTP and B2M, coefficients for age, sex, and race were smaller than for creatinine and were similar or smaller than for cystatin C. For B2M, coefficients for sex, age, and race were smaller than for creatinine and were similar (age and race) or smaller (sex) than for cystatin C. The final equations with BTP (BTP, age, and sex) or B2M (B2M alone) were less accurate than either the CKD-EPI (CKD Epidemiology Collaboration) creatinine or cystatin C equations. The combined BTP-B2M equation (BTP and B2M alone) had similar accuracy to the CKD-EPI creatinine or cystatin C equation. The average of the BTP-B2M equation and the CKD-EPI creatinine–cystatin C equation was not more accurate than the CKD-EPI creatinine–cystatin C equation. Limitations No external validation population, study population was restricted to CKD, few participants older than 65 years, or nonblack nonwhite race. Conclusions BTP and B2M are less influenced by age, sex, and race than creatinine and less influenced by race than cystatin C, but provide less accurate GFR estimates than the CKD-EPI creatinine and cystatin C equations. The CKD-EPI BTP and B2M equation provides a methodological advance for their study as filtration markers and in their associations with risk and adverse outcomes, but further study is required before clinical use.
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 80 mL/min/1.73 m2 , the adjusted HR of AKI at eGFR of 45 mL/min/1.73 m2 was 3.35 (95% CI, 2.75-4.07). Compared with ACR of 5 mg/g, the risk of AKI at ACR of 300 mg/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.
Background Serum cystatin C was proposed as a potential replacement for serum creatinine in glomerular filtration rate (GFR) estimation. We report the development and evaluation of GFR-estimating ...equations using serum cystatin C alone and serum cystatin C, serum creatinine, or both with demographic variables. Study Design Test of diagnostic accuracy. Setting & Participants Participants screened for 3 chronic kidney disease (CKD) studies in the United States (n = 2,980) and a clinical population in Paris, France (n = 438). Reference Test Measured GFR (mGFR). Index Test Estimated GFR using the 4 new equations based on serum cystatin C alone, serum cystatin C, serum creatinine, or both with age, sex, and race. New equations were developed by using linear regression with log GFR as the outcome in two thirds of data from US studies. Internal validation was performed in the remaining one third of data from US CKD studies; external validation was performed in the Paris study. Measurements GFR was measured by using urinary clearance of iodine-125–iothalamate in the US studies and chromium-51–EDTA in the Paris study. Serum cystatin C was measured by using Dade-Behring assay, standardized serum creatinine values were used. Results Mean mGFR, serum creatinine, and serum cystatin C values were 48 mL/min/1.73 m2 (5th to 95th percentile, 15 to 95), 2.1 mg/dL, and 1.8 mg/L, respectively. For the new equations, coefficients for age, sex, and race were significant in the equation with serum cystatin C, but 2- to 4-fold smaller than in the equation with serum creatinine. Measures of performance in new equations were consistent across the development and internal and external validation data sets. Percentages of estimated GFR within 30% of mGFR for equations based on serum cystatin C alone, serum cystatin C, serum creatinine, or both levels with age, sex, and race were 81%, 83%, 85%, and 89%, respectively. The equation using serum cystatin C level alone yields estimates with small biases in age, sex, and race subgroups, which are improved in equations including these variables. Limitations Study population composed mainly of patients with CKD. Conclusions Serum cystatin C level alone provides GFR estimates that are nearly as accurate as serum creatinine level adjusted for age, sex, and race, thus providing an alternative GFR estimate that is not linked to muscle mass. An equation including serum cystatin C level in combination with serum creatinine level, age, sex, and race provides the most accurate estimates.
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