Search

Chronic kidney disease (CKD) is a risk factor for cognitive decline, but evidence is limited on its etiology and morphological manifestation in the brain. We evaluated the association of estimated glomerular filtration rate (eGFR) and urinary albumin-creatinine ratio (UACR) with structural brain abnormalities visible on magnetic resonance imaging (MRI). We also assessed whether this association was altered when different filtration markers were used to estimate GFR.Cross-sectional study nested in a cohort study.1,527 participants in the Atherosclerosis Risk in Communities (ARIC) Study.Log(UACR) and eGFR based on cystatin C, creatinine, cystatin C and creatinine in combination, or βBrain volume reduction, infarcts, microhemorrhages, white matter lesions.Multivariable linear and logistic regression models fit separately for each predictor based on a 1-IQR difference in the predictor value.Each 1-IQR lower eGFR was associated with reduced cortex volume (regression coefficient: -0.07 [95% CI, -0.12 to-0.02]), greater white matter hyperintensity volume (logarithmically transformed; regression coefficient: 0.07 [95% CI, 0.01-0.15]), and lower white matter fractional anisotropy (regression coefficient: -0.08 [95% CI, -0.17 to-0.01]). The results were similar when eGFR was estimated with different equations based on cystatin C, creatinine, a combination of cystatin C and creatinine, or B2M. Higher log(UACR) was similarly associated with these outcomes as well as brain infarcts and microhemorrhages (odds ratios per 1-IQR-fold greater UACR of 1.31 [95% CI, 1.13-1.52] and 1.30 [95% CI, 1.12-1.51], respectively). The degree to which brain volume was lower in regions usually susceptible to Alzheimer disease and LATE (limbic-predominant age-related TDP-43 [Tar DNA binding protein 43] encephalopathy) was similar to that seen in the rest of the cortex.No inference about longitudinal effects due to cross-sectional design.We found eGFR and UACR are associated with structural brain damage across different domains of etiology, and eGFR- and UACR-related brain atrophy is not selective for regions typically affected by Alzheimer disease and LATE. Hence, Alzheimer disease or LATE may not be leading contributors to neurodegeneration associated with CKD.

Anemia is common in chronic kidney disease (CKD); although anemia is associated with adverse outcomes, the available treatments are not ideal. We characterized the burden, risk factors for, and risks associated with anemia by estimated glomerular filtration rate (eGFR) and hemoglobin level.Cross-sectional and prospective cohort study.Outpatient data from 5,004,957 individuals across 57 health care centers in the United States from 2016 to 2019, extracted from the Optum Labs Data Warehouse.Severity of anemia, presence of low iron test results, eGFR.Incident kidney failure with replacement therapy, cardiovascular disease, coronary heart disease, stroke, heart failure, death.The prevalences of anemia, low iron test results, vitamin BThe mean age was 54 years, and 42% were male. Lower eGFR was very strongly associated with increased prevalence of anemia, even after adjustment. Although iron studies were checked infrequently in patients with anemia, low iron test results were highly prevalent in those tested: 60.4% and 81.3% of men and women, respectively. ESA use was uncommon, with a prevalence of use of4%. Lower hemoglobin was independently associated with increased risk of incident kidney failure with replacement therapy, cardiovascular disease, coronary heart disease, stroke, heart failure, and death.Reliance on ICD codes for medical diagnoses, death information obtained from claims data, observational study.Severe anemia was common and strongly associated with lower eGFR and multiple adverse outcomes. Low-iron test results were highly prevalent in those tested despite iron studies being checked infrequently. ESA use in nondialysis CKD patients was uncommon.

Rationale & Objective Arterial stiffness is suggested as a mediator of cardiorenal interaction. However, previous studies reported inconsistent associations between chronic kidney disease (CKD) and arterial stiffness and were limited by using either estimated glomerular filtration rate (eGFR) or albumin-creatinine ratio (ACR) and examining arterial stiffness at limited segments. Study Design Cross-sectional. Setting & Participants 3,424 Atherosclerosis in Communities (ARIC) Study participants aged 66 to 90 years during 2011 to 2013. Predictors eGFR and ACR. Outcome Pulse wave velocity (PWV) at 6 segments: carotid-femoral (cfPWV), heart-carotid (hcPWV), and heart-femoral (hfPWV), reflecting central stiffness; heart-ankle (haPWV) and brachial-ankle (baPWV), representing both central and peripheral stiffness; and femoral-ankle (faPWV), indicating peripheral stiffness. Analytical Approach Multiple linear and logistic regression models to quantify the associations of eGFR and ACR with continuous PWV and elevated PWV (in the highest quartile), respectively. Results After adjusting for age, sex, and race, higher cfPWV and hfPWV were consistently associated with lower eGFR and higher ACR. Higher haPWV and baPWV were also observed with higher ACR. The independent association of both CKD measures with elevated cfPWV remained consistent after adjusting for additional confounders (ORs of elevated cfPWV were 1.09 [95% CI, 1.01-1.18] per 15-mL/min/1.73m2 lower eGFR and 1.20 [95% CI, 1.07-1.33] per 4-fold higher ACR). Higher ACR was also associated with elevated hfPWV and haPWV (ORs per 4-fold higher ACR were 1.25 [95% CI, 1.12-1.39] for elevated hfPWV and 1.19 [95% CI, 1.06-1.33] for elevated haPWV). Lower eGFR was associated with lower odds of elevated baPWV and faPWV (ORs per 15–mL/min/1.73m2 lower eGFR were 0.92 [95% CI, 0.84-0.99] and 0.91 [95% CI, 0.85-0.99], respectively). Limitation Unable to address temporality between CKD measures and arterial stiffness. Conclusions Both lower eGFR and higher ACR are independently associated with measures of central arterial stiffness, with stronger associations for ACR over eGFR. Our findings suggest that central arterial stiffness may be an important pathophysiologic phenotype of vascular disease in CKD.

Background Using change in estimated glomerular filtration rate (eGFR) based on creatinine concentration as a surrogate outcome in clinical trials of chronic kidney disease has been proposed. Risk for end-stage renal disease (ESRD) and all-cause mortality associated with change in concentrations of other filtration markers has not been studied in chronic kidney disease populations. Study Design Observational analysis of 2 clinical trials. Setting & Participants Participants in the MDRD (Modification of Diet in Renal Disease; n=317) Study and AASK (African American Study of Kidney Disease and Hypertension; n=373). Predictors Creatinine, cystatin C, β-trace protein (BTP), and β 2 -microglobulin (B2M) were measured in serum samples collected at the 12- and 24-month follow-up visits, along with measured GFR (mGFR) at these time points. Outcomes ESRD and all-cause mortality. Measurements Poisson regression was used to estimate incidence rate ratios and 95% CIs for ESRD and all-cause mortality during long-term follow-up (10-16 years) per 30% decline in mGFR or eGFR for each filtration marker and the average of all 4 markers. Results 1-year decline in mGFR, eGFR cr , eGFR BTP , and the average of the 4 filtration markers was significantly associated with increased risk for incident ESRD in both studies (all P ≤0.02). Compared to mGFR, only decline in eGFR BTP was statistically significantly more strongly associated with ESRD risk in both studies (both P ≤0.03). Decline in eGFR cr , but not mGFR or the other filtration markers, was significantly associated with risk for all-cause mortality in AASK only (incidence rate ratio per 30% decline, 4.17; 95% CI, 1.78-9.74; P P =0.2). Limitations Small sample size. Conclusions Declines in mGFR, eGFR cr , eGFR BTP , and the average of 4 filtration markers (creatinine, cystatin C, BTP, and B2M) were consistently associated with progression to ESRD.

Background Reported associations of estimated glomerular filtration rate (eGFR) with cancer risk are inconsistent, and data for the proteinuria-cancer relationship are sparse. We sought to quantify the associations of cancer incidence with eGFR and with proteinuria in a large population-based cohort. Study Design A prospective cohort study. Setting & Participants 242,583 adults (30-74 years old) without a diagnosis of cancer at baseline in the Korean Heart Study, based on health checkups in 1996 to 2004 with follow-up until 2012. Predictors Creatinine-based eGFR (≥90, 60-89, 45-59, and 2 ) and dipstick proteinuria (undetectable/trace, 1+, 2+, and ≥3+). Outcomes Overall and site-specific cancer incidence based on ICD-10 codes. Results 15,165 cases of cancer were detected. The relationship between eGFR and incidence of any cancer was J shaped, with the lowest risk at 45 to 59mL/min/1.73m 2 . There was 44% higher risk for any cancer among those with eGFRs 2 compared with those with eGFRs≥90mL/min/1.73m 2 (HR, 1.44; 95% CI, 1.11-1.87). High proteinuria was also associated with cancer risk, showing a dose-response relationship (HRs of 1.24 [95% CI, 1.13-1.35], 1.38 [95% CI, 1.17-1.63], and 1.66 [95% CI, 1.30-2.12] for 1+, 2+, and ≥3+ vs undetectable/trace). Examining site-specific cancer, eGFR 2 was significantly associated with kidney and ureteral cancer, multiple myeloma, and leukemia, whereas proteinuria ≥ 1+ (vs undetectable/trace) was related to a broader set of cancers (ie, stomach, rectal, liver, lung, ovarian, kidney, bladder, and multiple myeloma). After excluding study participants with follow-up less than 3 years, the associations remained consistent for kidney cancer and myeloma with eGFR and for rectal, liver, lung, and ovarian cancer with proteinuria. Limitations Relatively small number of participants with severely reduced eGFR or 70 years or older. Conclusions Kidney measures, particularly proteinuria, were associated with increased incidence of cancer. Future studies are needed to better understand the pathophysiologic mechanisms underlying these associations.

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≥90mL/min/1.73m 2 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 89mL/min/1.73m 2 , 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 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 Kidney failure disproportionately affects older blacks versus whites. The reasons are unknown and may be related to lower measured glomerular filtration rate (GFR) and higher levels of albuminuria in community-based population samples. Study Design Cross-sectional analysis of a substudy of a prospective cohort. Setting & Participants Ancillary study following Multi-Ethnic Study of Atherosclerosis (MESA) visit 5. Predictor Age, sex, and race. Outcomes & Measurements Measured GFR using plasma clearance of iohexol and urine albumin-creatinine ratio (ACR). Results GFR was measured in 294 participants. Mean age was 71±9 (SD) years, 47% were black, 48% were women, mean GFR was 73±19mL/min/1.73m 2 , and median ACR was 10.0 (IQR, 5.8-20.9) mg/g. Measured GFR was on average 1.02 (95% CI, 0.79-1.24) mL/min/1.73m 2 lower per year older. Mean GFR indexed for body surface area was not different between blacks versus whites (mean difference, 2.94 [95% CI, −1.37 to 7.26] mL/min/1.73m 2 ), but was lower in women than men (mean difference, −9.34 [95% CI, −13.53 to −5.15] mL/min/1.73m 2 ); this difference persisted and remained significant after adjustment for demographics, clinical characteristics, and measures of body size. The difference between men and women, but not between blacks and whites, was substantially greater when GFR was not indexed for body surface area. ACR was higher in older versus younger participants (mean difference, 3.2% [95% CI, 1.5%-4.8%] per year), but geometric mean ratio of ACR did not differ between blacks versus whites (mean difference, 19.7%; 95% CI, −39.1% to 6.1%) or between men versus women (mean difference, −4.4%; 95% CI, −27.7% to 26.3%). Limitations This is a study of survivors. People who agreed to participate were younger than those who refused. Conclusions In this first community-based study that included blacks and whites, no differences in measured GFR between races were found, suggesting that other factors must account for the disproportionately higher burden of kidney failure in older blacks versus whites.

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.Prospective cohort study.Atherosclerosis Risk in Communities (ARIC) Study participants with baseline estimated glomerular filtration rate (eGFR) ≥ 60mL/min/1.73mThe 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.Cases were ascertained based on the development of eGFRs60mL/min/1.73m3,720 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.Potential measurement error due to self-reported dietary intake and lack of data for albuminuria.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 β-Trace protein (BTP) and β 2 -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 48mL/min/1.73m 2 (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 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 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 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.

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 Prospective cohort study. Setting & Participants 10,955 participants from the Atherosclerosis Risk in Communities (ARIC) Study followed up from 1996 to 2011. Predictor Kidney function as assessed by creatinine-based estimated glomerular filtration rate (eGFR cr ), urine albumin-creatinine ratio, and alternative filtration markers. Outcomes Fracture-related hospitalizations determined by diagnostic code. Measurements 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 cr and fracture risk was nonlinear: 2 , lower eGFR cr 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/β 2 -microglobulin (HR per 1-SD decrease, 1.26, 95% CI, 1.15-1.37). Limitations 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.

Estimating glomerular filtration rate (GFR) is essential for clinical practice, research, and public health. Appropriate interpretation of estimated GFR (eGFR) requires understanding the principles of physiology, laboratory medicine, epidemiology and biostatistics used in the development and validation of GFR estimating equations. Equations developed in diverse populations are less biased at higher GFR than equations developed in CKD populations and are more appropriate for general use. Equations that include multiple endogenous filtration markers are more precise than equations including a single filtration marker. The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations are the most accurate GFR estimating equations that have been evaluated in large, diverse populations and are applicable for general clinical use. The 2009 CKD-EPI creatinine equation is more accurate in estimating GFR and prognosis than the 2006 Modification of Diet in Renal Disease (MDRD) Study equation and provides lower estimates of prevalence of decreased eGFR. It is useful as a “first” test for decreased eGFR and should replace the MDRD Study equation for routine reporting of serum creatinine–based eGFR by clinical laboratories. The 2012 CKD-EPI cystatin C equation is as accurate as the 2009 CKD-EPI creatinine equation in estimating eGFR, does not require specification of race, and may be more accurate in patients with decreased muscle mass. The 2012 CKD-EPI creatinine–cystatin C equation is more accurate than the 2009 CKD-EPI creatinine and 2012 CKD-EPI cystatin C equations and is useful as a confirmatory test for decreased eGFR as determined by an equation based on serum creatinine. Further improvement in GFR estimating equations will require development in more broadly representative populations, including diverse racial and ethnic groups, use of multiple filtration markers, and evaluation using statistical techniques to compare eGFR to “true GFR”.

Background: A doubling of serum creatinine value, corresponding to a 57% decline in estimated glomerular filtration rate (eGFR), is used frequently as a component of a composite kidney end point in clinical trials in type 2 diabetes. The aim of this study was to determine whether alternative end points defined by smaller declines in eGFR would improve the statistical power of these clinical trials.Study Design: Post hoc analyses of 2 multinational randomized controlled trials (Reduction of End Points in Non-Insulin-Dependent Diabetes With the Angiotensin II Antagonist Losartan [RENAAL] and Irbesartan Diabetic Nephropathy Trial [IDNT]) that assessed the treatment effect of the angiotensin receptor blockers (ARBs) losartan and irbesartan.Setting & Participants: 1,513 (RENAAL) and 1,715 (IDNT) adult patients with type 2 diabetes and nephropathy.Predictor: Established versus alternative end points defined as a confirmed doubling of serum creatinine level versus confirmed eGFR decline of 57%, 40%, 30%, or 20% as a component of a composite end point of end-stage renal disease or eGFR, 15 mL/min/1.73 m(2). Outcomes: Numbers of patients reaching end points, precision (standard error), and significance (z score) of ARB treatment effect (HR) during follow-up.Results: Lesser eGFR declines resulted in a greater number of patients reaching end points in both treatment groups and lower standard error of the HR, but the effect on z score was counterbalanced by attenuation of the HR. When calculating the eGFR decline from month 3, attenuation of the HR was less pronounced.Limitations: Post hoc analysis.Conclusions: Despite increases in precision of the treatment effect, eGFR declines less than a doubling of serum creatinine value did not consistently improve statistical power of the clinical trials due to attenuation of the treatment effect. Attenuation of the treatment effect appears to be due in part to acute effects of ARB son eGFR. These findings should be taken into account when using lesser eGFR declines as alternative end points for clinical trials. (C) 2014 by the National Kidney Foundation, Inc.

Background Our objective was to quantify short-term total within-person variability in standard and nontraditional kidney measures using national data. Study Design Repeated examination study of serum and urine kidney measures. Setting & Participants Participants 18 years or older in the Third National Health and Nutrition Examination Survey (NHANES III) who had repeated blood and urine samples collected during visits occurring approximately 18 days apart. Measurements Standardized serum creatinine, standardized cystatin C, β-trace protein (BTP), β 2 -microglobulin (B2M), and urine albumin and creatinine. We calculated the within-person coefficient of variation (CV w ), which includes both biological and analytical variability. We also evaluated the impact of variability on estimates of the prevalence of reduced estimated glomerular filtration rate and albuminuria. Results Serum cystatin C level demonstrated the lowest short-term within-person variability (CV w = 6.8%). Serum creatinine and B2M levels (CV w = 7.6% and 8.4%, respectively) also had low variability. BTP level had the most variability of the serum markers (CV w = 11.6%). As expected, urine albumin and urine creatinine measurements showed high variability (CV w >30% for both); however, albumin-creatinine ratio performed much better than either measure alone, with CV w of 11.3%. The effect of short-term variability on the prevalence of reduced estimated glomerular filtration rate was moderate, with an ∼20% lower prevalence when defined based on single measurements compared to repeated application of the same test approximately 18 days apart. Repeated testing for albuminuria had a larger effect, showing a 33% lower prevalence of albuminuria when repeated testing was applied. Limitations Only 2 measurements available. General population with low prevalence of kidney disease. Conclusions Our results suggest that creatinine, cystatin C, and B2M levels have similarly low short-term variability. BTP level was more variable compared with the other serum filtration markers. Urine albumin and creatinine levels were highly variable and may benefit from repeated assessments to reduce the misclassification of albuminuria.

Diabetes is the leading cause of kidney disease in the developed world. Over time, the prevalence of diabetic kidney disease (DKD) may increase due to the expanding size of the diabetes population or decrease due to the implementation of diabetes therapies.To define temporal changes in DKD prevalence in the United States.Cross-sectional analyses of the Third National Health and Nutrition Examination Survey (NHANES III) from 1988-1994 (N = 15,073), NHANES 1999-2004 (N = 13,045), and NHANES 2005-2008 (N = 9588). Participants with diabetes were defined by levels of hemoglobin A(1c) of 6.5% or greater, use of glucose-lowering medications, or both (n = 1431 in NHANES III; n = 1443 in NHANES 1999-2004; n = 1280 in NHANES 2005-2008).Diabetic kidney disease was defined as diabetes with albuminuria (ratio of urine albumin to creatinine ≥30 mg/g), impaired glomerular filtration rate (60 mL/min/1.73 m(2) estimated using the Chronic Kidney Disease Epidemiology Collaboration formula), or both. Prevalence of albuminuria was adjusted to estimate persistent albuminuria.The prevalence of DKD in the US population was 2.2% (95% confidence interval [CI], 1.8%-2.6%) in NHANES III, 2.8% (95% CI, 2.4%-3.1%) in NHANES 1999-2004, and 3.3% (95% CI, 2.8%-3.7%) in NHANES 2005-2008 (P.001 for trend). The prevalence of DKD increased in direct proportion to the prevalence of diabetes, without a change in the prevalence of DKD among those with diabetes. Among persons with diabetes, use of glucose-lowering medications increased from 56.2% (95% CI, 52.1%-60.4%) in NHANES III to 74.2% (95% CI, 70.4%-78.0%) in NHANES 2005-2008 (P.001); use of renin-angiotensin-aldosterone system inhibitors increased from 11.2% (95% CI, 9.0%-13.4%) to 40.6% (95% CI, 37.2%-43.9%), respectively (P.001); the prevalence of impaired glomerular filtration rate increased from 14.9% (95% CI, 12.1%-17.8%) to 17.7% (95% CI, 15.2%-20.2%), respectively (P = .03); and the prevalence of albuminuria decreased from 27.3% (95% CI, 22.0%-32.7%) to 23.7% (95% CI, 19.3%-28.0%), respectively, but this was not statistically significant (P = .07).Prevalence of DKD in the United States increased from 1988 to 2008 in proportion to the prevalence of diabetes. Among persons with diabetes, prevalence of DKD was stable despite increased use of glucose-lowering medications and renin-angiotensin-aldosterone system inhibitors.

Identifying individuals at risk of chronic kidney disease (CKD) is critical for timely treatment initiation to slow progression of the disease. Neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule 1 (KIM-1) are known biomarkers of acute kidney injury, but it is unknown whether these markers are associated with incident CKD stage 3 in the general population.Matched case-control study.African American and white participants from the Atherosclerosis Risk in Communities (ARIC) Study who at baseline had an estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73 m(2) and urinary albumin-creatinine ratio ≤30 mg/g. 143 controls were matched for age, sex, and race to 143 cases of incident CKD stage 3 after 8.6 years of follow-up.Quartile of NGAL and KIM-1.Incident CKD stage 3 (eGFR60 mL/min/1.73 m(2) at follow-up and a decrease in eGFR from baseline to follow-up ≥25%).Both NGAL (P = 0.05) and KIM-1 levels (P0.001) were correlated positively with baseline urinary albumin-creatinine ratio; neither was associated with baseline eGFR. Participants with NGAL concentrations in the fourth quartile had more than 2-fold higher odds (adjusted OR, 2.11; 95% CI, 0.96-4.64) of incident CKD stage 3 compared with participants in the first quartile after multivariable adjustment (P-trend = 0.03). Adjustment for urinary creatinine and albumin levels resulted in a nonsignificant association (highest quartile adjusted OR, 1.52; 95% CI, 0.64-3.58; P = 0.2). No significant association between KIM-1 level and incident CKD was observed in crude or adjusted models.The relatively small sample size of the study limits precision and power to detect weak associations.Higher NGAL, but not KIM-1, levels were associated with incident CKD stage 3. Adjustment for urinary creatinine and albumin concentration attenuated this association. Additional studies are needed to confirm these findings and assess the utility of urinary NGAL as a marker of CKD risk.

Identification of persons with chronic kidney disease (CKD) who are at highest risk to progress to end-stage renal disease (ESRD) is necessary to reduce the burden of kidney failure. The relative utility of traditional markers of kidney function, including estimated glomerular filtration rate (eGFR) and serum creatinine level, and emerging markers of kidney function, including cystatin C and beta-trace protein (BTP) levels, to predict ESRD and mortality has yet to be established.Randomized clinical trial followed by an observational cohort study.865 African American individuals with hypertensive CKD enrolled in a clinical trial of 2 levels of blood pressure control and 3 different antihypertensive drugs as initial therapy and subsequently followed by an observational cohort study.Quintile of measured GFR (mGFR) by iothalamate clearance, serum creatinine, serum creatinine-based eGFR, cystatin C, and BTP values.Incidence of ESRD and mortality.246 participants reached ESRD during a median follow-up of 102 months. The incidence rate of ESRD was higher with higher quintiles of each marker. The association between higher BTP level and ESRD was stronger than those for the other markers, including mGFR. All markers remained significantly associated with ESRD after adjustment for mGFR and relevant covariates (all P0.05), with BTP level retaining the strongest association (HR for highest vs lowest quintile, 5.7; 95% CI, 2.2-14.9). Associations with the combined end point of ESRD or mortality (n = 390) were weaker, but remained significant for cystatin C (P = 0.05) and BTP levels (P = 0.004).The ability of these markers to predict ESRD and mortality in other racial and ethnic groups and in individuals with CKD due to other causes is unknown.Plasma BTP and cystatin C levels may be useful adjuncts to serum creatinine level and mGFR in evaluating risk of progression of kidney disease.

Background The calibration of serum creatinine values to standardized creatinine and the commutability of serum creatinine across surveys are essential to the correct use of National Health and Nutrition Examination Survey (NHANES) data for kidney function and for generating estimates of the burden of kidney disease in the United States. Study Design Calibration study of serum creatinine in NHANES III (1988-1994) and NHANES 1999-2000, 2001-2002, and 2003-2004 to directly compare creatinine measurements from the original surveys with standard creatinine measured using an assay traceable to known gold-standard methods. We also assessed predictors of differences between methods (potential interferences) in this general population. Setting & Participants The NHANES are ongoing cross-sectional surveys of the civilian noninstitutionalized population of the United States. We selected random samples of approximately 200 stored specimens from persons aged 60 years or older from each survey (NHANES III, 1999-2000, 2001-2002, and 2003-2004). Measurements Stored serum specimens from the 4 NHANES surveys were analyzed for serum creatinine by using a Roche enzymatic assay implemented at the Cleveland Clinic Research Laboratory (CCRL). The Roche assay is traceable to gold-standard reference methods. The original NHANES serum creatinine values were obtained using the Jaffe method (kinetic alkaline picrate) implemented in several different laboratories. Results Overall agreement between the original NHANES values (Jaffe method) and CCRL measurements (Roche enzymatic) was high, but substantial biases were observed in NHANES III and 1999-2000. No bias was observed in NHANES 2001-2002 and 2003-2004. Final calibration equations to correct serum creatinine values in the relevant surveys are provided. Assay differences were independent of sex, race/ethnicity, and bilirubin and triglyceride levels, but weakly related to age and glucose concentration. Limitations We were not able to examine drift in measurements over time within each survey or directly evaluate freeze-thaw effects. Conclusions The magnitude of differences in serum creatinine measurements in NHANES III and 1999-2000 from standard creatinine would result in large differences in estimates of kidney function (10% to 20%). Thus, correction of original creatinine values in NHANES III and 1999-2000 is essential, but no correction is needed for NHANES 2001-2002 or 2003-2004.

Background Variation in performance of glomerular filtration rate (GFR) estimating equations is related to variation in calibration of the creatinine assay across clinical laboratories. Study Design Cross-sectional analysis. Setting & Participants 6 research studies and 4 clinical populations including 5,504 participants who had GFR measured using urinary clearance of iothalamate. Measurements Standardized serum creatinine values obtained by means of calibration to the Cleveland Clinic Research Laboratory using frozen specimens, a calibration panel, and/or survey results from the College of American Pathologists. Predictor Noncalibrated serum creatinine assayed in research and clinical laboratories compared with standardized serum creatinine. Outcome Difference between measured GFR versus GFR estimated from the Modification of Diet in Renal Disease (MDRD) Study and Cockcroft-Gault equations. Results For a noncalibrated serum creatinine value of 1 mg/dL (88.4 μmol/L), standardized serum creatinine value was 0.07 mg/dL (6.2 μmol/L) less than noncalibrated values. In the pooled data set, for the MDRD Study equation, calibration improved median percentage of difference between measured and estimated GFR from 9.0% (interquartile range [IQR], 28%) to 5.8% (IQR, 28%) and improved the percentage of estimates within 30% of measured GFR (P 30 ) from 80% to 83%. The effect of calibration was greater at higher levels of GFR and varied across studies. For the Cockcroft-Gault equation, calibration worsened the median percentage of difference from −2.0% (IQR, 38%) to −11.4% (IQR, 39%), and the P 30 , from 74% to 69%. Limitations College of American Pathologist samples were used for calibration of clinical populations; calibration factors do not account for drift over time in the serum creatinine assay; calibration cannot account for variation in assay performance among individuals. Conclusion Calibration improves the performance of the MDRD Study equation. After calibration, larger errors remain for GFR estimates greater than 60 mL/min/1.73 m 2 (>1 mL/s/1.73 m 2 ).

Background C-Reactive protein ( CRP ) gene variation has been associated with serum CRP levels in the general population. We examined the associations of CRP gene variation with longitudinal CRP measurements and incident cardiovascular disease (CVD) risk in a cohort of 504 white and 244 African-American incident dialysis patients. Methods Seven tagging single-nucleotide polymorphisms in the CRP gene were selected by using the Carlson method ( r 2 > 0.65). High-sensitivity CRP was measured every 6 months (mean, 4.6 months). Haplo.glm was used to determine the association of haplotypes with serum CRP levels and CVD risk. Global tests from Haplo.score were conducted to determine statistical significance. Results Compared with the most common haplotype, 1 haplotype was associated with a 52% lower CRP level at baseline among African Americans (ratio, 0.48; 95% confidence interval [CI], 0.28 to 0.82; global P -value = 0.0005). Furthermore, this haplotype was associated significantly with lower serum CRP levels during 36 months of follow-up. Among whites, this haplotype was associated with an 18% (ratio, 0.82; 95% CI, 0.56 to 1.22; n=6 carriers) lower CRP level compared with the most common haplotype with a frequency of 1% (global P -value = 0.048). No association was detected between CRP gene variation and CVD risk in either whites or African Americans. Conclusion Compared with the most common haplotype of the CRP gene, 1 haplotype predicts a lower serum CRP level over time, but no association exists between haplotype of CRP gene and incident CVD in this incident dialysis population. Serum CRP level might be a biomarker, rather than a causal factor, in CVD development. CRP variation may lead to susceptibility to inflammation, but not risk for CVD; however, replication in multiple settings is necessary.

Background: Individual-level socioeconomic status (SES) has been found to be associated inversely with progressive chronic kidney disease (CKD); the effect of area-level SES on progressive CKD is less known. We conducted a cohort study of 12,856 Atherosclerosis Risk in Communities Study participants to examine the independent risk for progressive CKD associated with living in a low SES area. Methods: Progressive CKD is defined as a creatinine level elevation of 0.4 mg/dL or greater (≥35 μmol/L) during a 9-year follow-up, hospitalization for CKD, or death. Area-level SES was characterized by using measures of income, wealth, education, and occupation for 1990 US Census block groups of residence. Results: Age- and center-adjusted incidence rates (per 1,000 person-years) of progressive CKD by quartiles of area-level SES score showed increasing rates with decreasing SES for African-American women: quartile 1 (Q1; low) = 11.1, Q2=10.5, Q3=6.4, and Q4=7.1 and white men: Q1=6.6, Q2=4.8, Q3=4.0, and Q4 (high) = 3.5, but not for African-American men or white women. Cox proportional hazards models showed that living in the lowest versus the highest SES-area quartile was associated with a 60% greater risk for progressive CKD in white men after adjusting for age, center, baseline creatinine level, body mass index, and individual-level SES (hazard ratio, 1.6; 95% confidence interval, 1.0 to 2.5). This risk and trend persisted after adjusting for such potential mediators as health awareness, health care access, and behavioral and physiological factors. We found no significant association of progressive CKD risk and area SES in white women, African-American women, or African-American men after adjustment. Conclusion: For white men, living in a low SES area is independently associated with greater risk for progressive CKD. Future research is needed to examine this association, considering the disparate effects found by race/sex groups.

Background: Levels of lipoprotein(a) [Lp(a)], an atherogenic lipoprotein, are elevated in patients with end-stage renal disease and inversely related to the size of apolipoprotein(a) [apo(a)], a glycoprotein bound to Lp(a). We studied the association of Lp(a) level and apo(a) size with prevalent atherosclerotic cardiovascular disease (ASCVD) in 871 incident dialysis patients (261 blacks, 565 whites, 45 other). Methods: Lp(a) was measured by an apo(a) size-independent enzyme-linked immunoassay; and apo(a) size was measured by sodium dodecyl sulfate-agarose gel electrophoresis. Prevalent ASCVD, derived from medical records, was defined as coronary heart disease or cerebral or peripheral vascular disease. Adjustment variables included age, sex, race, dialysis modality, diabetes, serum creatinine level, albumin level, and low-density lipoprotein cholesterol level. Results: ASCVD prevalence was 58%. Median Lp(a) levels for those with compared with those without ASCVD were 38 versus 35 nmol/L for whites ( P = 0.49) and 100 versus 74 nmol/L for blacks, respectively ( P = 0.35). Lp(a) level was associated with ASCVD among those younger than 60 years (odds ratio [OR] for +1 interquartile range of Lp(a), 1.5; P = 0.02), but not among those 60 years and older (OR, 1.0; P = 0.82; P interaction by age, 0.08). ORs were 1.3 for all whites ( P = 0.03) and 1.1 for all blacks ( P = 0.87; P interaction by race=0.53). ORs of ASCVD were 1.7 for whites younger than 60 years ( P = 0.01) and 1.2 for blacks younger than 60 years ( P = 0.77; P interaction by race=0.42). No association between apo(a) isoform size and ASCVD was present. Conclusion: In an incident dialysis cohort, Lp(a) level was associated with prevalent ASCVD among whites younger than 60 years, but not among blacks or those older than 60 years. Apo(a) isoform size was not associated with prevalent ASCVD. These data suggest that baseline ASCVD is unlikely to strongly confound the potential associations of Lp(a) level and prospectively ascertained ASCVD among incident dialysis patients.

Background: Recently developed clinical practice guidelines and calibration of the Third National Health and Nutrition Examination Survey (NHANES III) serum creatinine assay provide a basis for estimating the prevalence and distribution of chronic kidney disease (CKD) in the United States using standardized criteria based on estimated glomerular filtration rate (GFR) and persistent albuminuria. Methods: A nationally representative sample of 15,625 noninstitutionalized adults aged 20 years and older from the NHANES III was analyzed. Kidney function (GFR), kidney damage (albuminuria), and stages of CKD (GFR and albuminuria) were estimated from calibrated serum creatinine level, spot urine albumin level, age, sex, and race. GFR was estimated using the simplified Modification of Diet in Renal Disease Study equation and compared with the Cockcroft-Gault equation for creatinine clearance (CCr). Results: The prevalence of CKD in the US adult population was 11% (19.2 million). By stage, an estimated 5.9 million individuals (3.3%) had stage 1 (persistent albuminuria with a normal GFR), 5.3 million (3.0%) had stage 2 (persistent albuminuria with a GFR of 60 to 89 mL/min/1.73 m 2 ), 7.6 million (4.3%) had stage 3 (GFR, 30 to 59 mL/min/1.73 m 2 ), 400,000 individuals (0.2%) had stage 4 (GFR, 15 to 29 mL/min/1.73 m 2 ), and 300,000 individuals (0.2%) had stage 5, or kidney failure. Aside from hypertension and diabetes, age is a key predictor of CKD, and 11% of individuals older than 65 years without hypertension or diabetes had stage 3 or worse CKD. Compared with GFR estimates, CCr estimates showed a steeper decline with age and were lower in non-Hispanic blacks. Conclusion: CKD is common and warrants improved detection and classification using standardized criteria to improve outcomes. Am J Kidney Dis 41:1-12. © 2003 by the National Kidney Foundation, Inc.

Background: Few studies have performed a comprehensive comparison of the prognostic importance of comorbidity to that of other case-mix factors influencing incident dialysis patients' survival. Longitudinal change in the comorbid illness burden of incident dialysis patients has not been measured. Comorbidity severity and its change may serve as important prognostic markers of survival, independent of other case-mix factors. Methods: The Choices for Healthy Outcomes in Caring for End-Stage Renal Disease Cohort Study used the Index of Coexistent Disease (ICED) to assess comorbidity at the initiation of chronic dialysis treatment (1,039 incident patients) and during follow-up (733 patients). Using proportional hazards regression analyses, the relationship to survival of baseline ICED level and change in ICED level was examined. Results: At the initiation of chronic dialysis treatment, 36% of patients were at ICED level 0 to 1 (least comorbidity severity); 35%, level 2; and 29%, level 3. After multivariable adjustment, baseline ICED level was the strongest predictor of subsequent mortality. Compared with ICED level 0 to 1, relative risks for mortality were 1.9 (95% confidence interval, 1.3 to 2.6) for ICED level 2 and 2.8 (95% confidence interval, 2.0 to 3.9) for ICED level 3. The prevalence and severity of most comorbid conditions increased during follow-up. After controlling for baseline ICED level and other factors, change in ICED level over time was significantly associated with mortality ( P = 0.01). Conclusion: Indexing comorbidity when patients begin chronic dialysis therapy and recording the evolution of index scores yields a predictor of mortality risk that is independent of other case-mix factors. Am. J Kidney Dis 41:149-161. © 2003 by the National Kidney Foundation, Inc.

Background: Elevated lipoprotein(a) (Lp[a]) levels have been observed in patients on dialysis therapy. However, few studies explored the relationship between kidney function and Lp(a) levels in patients with mild to moderate chronic kidney disease. Methods: We examined the association of estimated glomerular filtration rate (GFR) with Lp(a) level in 7,675 participants in the second phase of the Third National Health and Nutrition Examination Survey. Results: There was no association between Lp(a) level and estimated GFR in the overall sample (geometric mean, 10.4 mg/dL [95% confidence interval (CI), 9.2 to 11.8] in the group with a GFR of 90 to 149 mL/min/1.73 m 2 versus 9.3 mg/dL [95% CI, 7.9 to 11.0] in the group with a GFR of 60 to 89 mL/min/1.73 m 2 versus 12.1 mg/dL [95% CI, 9.0 to 15.9] in the group with a GFR of 15 to 59 mL/min/1.73 m 2 ; P = 0.77 for linear trend) or non-Hispanic whites (geometric mean, 8.9 mg/dL [95% CI, 7.8 to 10.2] versus 8.5 mg/dL [95% CI, 7.1 to 10.2] versus 10.9 mg/dL [95% CI, 8.1 to 14.7]; P = 0.54 for linear trend). However, non-Hispanic blacks (geometric mean, 30.4 mg/dL [95% CI, 28.0 to 33.0] versus 35.2 mg/dL [95% CI, 31.4 to 39.4] versus 40.2 mg/dL [95% CI, 27.7 to 58.2]; P = 0.01 for linear trend) and Mexican Americans (geometric mean, 6.2 mg/dL [95% CI, 5.3 to 7.2] versus 7.4 mg/dL [95% CI, 6.4 to 8.5] versus 11.0 mg/dL [95% CI, 5.7 to 20.3]; P = 0.04 for linear trend) showed modestly, but significantly, greater Lp(a) levels with lower GFRs. In a weighed quantile regression model adjusted for age, sex, and race, a lower GFR was associated with greater 95th percentile serum Lp(a) values in the overall sample and non-Hispanic whites and with greater median Lp(a) levels in Mexican Americans. Conclusion: In a cross-section of the US population, a low GFR is associated with only moderately greater Lp(a) levels, and this association may differ by race-ethnicity. Am J Kidney Dis 40:899-908. © 2002 by the National Kidney Foundation, Inc.

Case-mix factors influence both the selection of dialysis modality and outcomes in end-stage renal disease (ESRD). A detailed characterization of the case-mix differences between peritoneal dialysis (PD) and hemodialysis (HD) patients at the onset of dialysis therapy has not been performed, despite the importance of accounting for baseline differences in future comparisons of outcomes across modality groups. We compared baseline characteristics of 279 PD and 759 HD patients enrolled in the Choices for Healthy Outcomes in Caring for End-Stage Renal Disease (CHOICE) Cohort Study, a prospective study of incident dialysis patients. Comorbidity was assessed using the Index of Coexistent Diseases (ICED), consisting of a medical record review of 19 medical conditions and an observer-based assessment of 11 physical functions. ICED scores range from 0 to 3, with higher levels reflecting more severe comorbidity. Comorbidity was less severe in PD patients than in HD patients: the proportions of patients with ICED 0-1, ICED 2, and ICED 3 were 52%, 26%, and 22%, respectively, among the PD patients and 30%, 39%, and 31%, respectively, among the HD patients (P0.001). After controlling for all other factors, the differences in comorbidity remained significant. As compared with patients with ICED 0-1, the odds of being treated with PD for patients with ICED 2 and ICED 3 were less (odds ratio [OR] and 95% confidence intervals) 0.31 (0.17 to 0.56) and 0.50 (0.28 to 0.90), respectively. The number and severity of comorbid conditions at the onset of ESRD is significantly lower in patients choosing PD, independent of other factors influencing modality selection. The increased survival of PD patients reported in recent studies may simply reflect the self- or physician-directed selection of healthier patients to PD. Adjustment for case-mix differences in patients treated with PD versus HD is essential to the assessment of the independent effect of the dialysis modality on outcomes.

c Recent clinical practice guidelines recommend the creation of an arteriovenous (AV) vascular access (ie, native fistula or synthetic graft) before the start of chronic hemodialysis therapy to prevent the need for complicationprone dialysis catheters. We report on the association of referral to a nephrologist with duration of dialysis-catheter use and type of vascular access used in the first 6 months of hemodialysis therapy. The study population is a representative cohort of 356 patients with questionnaire, laboratory, and medical record data collected as part of the Choices for Healthy Outcomes in Caring for End-Stage Renal Disease Center Study. Patients who reported being seen by a nephrologist at least 1 month before starting hemodialysis therapy (75%) were more likely than those referred later to use an AV access at initiation (39% versus 10%; P < 0.001) and 6 months after starting hemodialysis therapy (74% versus 56%; P < 0.01). Patients referred within 1 month of initiating hemodialysis therapy used a dialysis catheter for a median of 202 days compared with 64, 67, and 19 days for patients referred 1 to 4, 4 to 12, and greater than 12 months before initiating hemodialysis therapy, respectively (P trend < 0.001). Patients referred at least 4 months before initiating hemodialysis therapy were more likely than patients referred later to use an AV fistula, rather than a synthetic graft, as their first AV access (45% versus 31%;P < 0.01). These associations remained after adjustment for age, sex, race, marital status, education, insurance coverage, comorbid disease status, albumin level, body mass index, and underlying renal diagnosis. These data show that late referral to a nephrologist substantially increases the likelihood of dialysis-catheter use at the initiation of hemodialysis therapy and is associated with prolonged catheter use. Regardless of the time of referral, only a minority of patients used an AV access at the initiation of treatment, and greater than 25% had not used an AV access 6 months after initiation. Thus, further efforts to improve both referral patterns and preparation for dialysis after referral are needed. © 2001 by the National Kidney Foundation, Inc.