Study protocol: rationale and design of the community-based prospective cohort study of kidney function and diabetes in rural New Mexico, the COMPASS study.

BACKGROUND: Rural areas in the state of New Mexico have been the "ground-zero" for the epidemic of diabetic Chronic Kidney Disease (CKD) in the United States. However, there is limited research about risk factors of diabetic CKD in this area and scarce data regarding the performance of emerging markers of renal filtration and epigenetic biomarkers of renal function and diabetes in this area with its unique ethnic/racial population. We designed the COMPASS study as a community-based program in rural New Mexico aiming to screen for CKD and to discover CKD-related translational biomarkers. METHODS/DESIGN: The study involves a prospective, longitudinal cohort design involving individuals living in rural New Mexico. Participants undergo a screening for kidney disease using markers of abnormal renal filtration (impaired glomerular filtration rate) or damage (albuminuria). Those found to have CKD on the basis of these tests or those at risk for CKD are enrolled in a prospective longitudinal cohort. We measure markers of renal function, insulin resistance and epigenetics (microRNAs) on patients. Individuals are invited to participate in interviews and focus groups in order to characterize their attitudes towards research and barriers or facilitators to participation in future research studies about kidney disease. DISCUSSION: This study will provide important data about the local epidemiology of kidney disease in a high-risk rural setting and the utility of emerging renal filtration markers (Beta 2 Microglobulin and Cystatin C), while generating data and methods for the analyses of microRNA biomarkers. The qualitative research subproject will identify factors associated with increased willingness to participate in future translational research projects. With its geographical focus, this study will address a critical disparity in kidney disease research, while generating novel epigenetic data that are relevant for future studies in the general population.

Rediscovering Beta-2 Microglobulin As a Biomarker across the Spectrum of Kidney Diseases.

There is currently an unmet need for better biomarkers across the spectrum of renal diseases. In this paper, we revisit the role of beta-2 microglobulin (ß2M) as a biomarker in patients with chronic kidney disease and end-stage renal disease. Prior to reviewing the numerous clinical studies in the area, we describe the basic biology of ß2M, focusing in particular on its role in maintaining the serum albumin levels and reclaiming the albumin in tubular fluid through the actions of the neonatal Fc receptor. Disorders of abnormal ß2M function arise as a result of altered binding of ß2M to its protein cofactors and the clinical manifestations are exemplified by rare human genetic conditions and mice knockouts. We highlight the utility of ß2M as a predictor of renal function and clinical outcomes in recent large database studies against predictions made by recently developed whole body population kinetic models. Furthermore, we discuss recent animal data suggesting that contrary to textbook dogma urinary ß2M may be a marker for glomerular rather than tubular pathology. We review the existing literature about ß2M as a biomarker in patients receiving renal replacement therapy, with particular emphasis on large outcome trials. We note emerging proteomic data suggesting that ß2M is a promising marker of chronic allograft nephropathy. Finally, we present data about the role of ß2M as a biomarker in a number of non-renal diseases. The goal of this comprehensive review is to direct attention to the multifaceted role of ß2M as a biomarker, and its exciting biology in order to propose the next steps required to bring this recently rediscovered biomarker into the twenty-first century.

Depression and all-cause mortality in hemodialysis patients.

BACKGROUND: There are limited data regarding the relationship between depression and mortality in hemodialysis (HD) patients. METHODS: Among 323 patients receiving maintenance HD, depression symptoms were assessed using the Center for Epidemiologic Studies Depression (CES-D) scale, with a score of ≥16 consistent with depression. Adjusted Cox proportional-hazards models with additional analyses incorporating antidepressant medication use were used to evaluate the association between depression and mortality. Baseline CES-D scores were used for the primary analyses, while secondary time-dependent analyses incorporated subsequent CES-D results. RESULTS: The mean age was 62.9 ± 16.5 years, 46% of the subjects were women and 22% were African-American. The mean baseline CES-D score was 10.7± 8.3, and 83 (26%) participants had CES-D scores ≥16. During a median (25th, 75th) follow-up of 25 (13, 43) months, 154 participants died. After adjusting for age, sex, race, primary cause of kidney failure, dialysis vintage and access, baseline depression was associated with an increased risk of all-cause mortality (HR 1.51 and 95% CI 1.06-2.17). This attenuated with further adjustment for cardiovascular disease, smoking, Kt/V, serum albumin, log C-reactive protein and use of antidepressants (HR 1.21 and 95% CI 0.82-1.80). When evaluating time-dependent CES-D, depression remained associated with increased mortality risk in the fully adjusted model (HR 1.44 and 95% CI 1.00-2.06). CONCLUSIONS: Greater symptoms of depression are associated with an increased risk of mortality in HD patients, particularly when accounting for the most proximate assessment. This relationship was attenuated with adjustment for comorbid conditions, suggesting a complex relationship between clinical characteristics and depression symptoms. Future studies should evaluate whether treatment for depression impacts mortality among HD patients.

Performance of creatinine-based GFR estimating equations in solid-organ transplant recipients.

BACKGROUND: Accurate assessment of kidney function is important for the management of solid-organ transplant recipients. In other clinical populations, glomerular filtration rate (GFR) most commonly is estimated using the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) creatinine or the 4-variable MDRD (Modification of Diet in Renal Disease) Study equation. The accuracy of these equations compared with other GFR estimating equations in transplant recipients has not been carefully studied. STUDY DESIGN: Diagnostic test study. SETTING & PARTICIPANTS: Solid-organ transplant recipients longer than 6 months posttransplantation from 5 clinical populations (N=3,622, including recipients of kidney [53%], liver [35%], and other or multiple organs [12%]). INDEX TEST: Estimated GFR (eGFR) using creatinine-based GFR estimating equations identified from a systematic review of the literature. Performance of the CKD-EPI creatinine and the MDRD Study equations was compared with alternative equations. REFERENCE TEST: Measured GFR (mGFR) from urinary clearance of iothalamate or plasma clearance of iohexol. MEASUREMENTS: Error (difference between mGFR and eGFR) expressed as P30 (proportion of absolute percent error <30%) and mean absolute error. RESULTS: We identified 26 GFR estimating equations. Mean mGFR was 55.1±22.7 (SD) mL/min/1.73 m(2). P30 and mean absolute error for the CKD-EPI and the MDRD Study equations were 78.9% (99.6% CI, 76.9%-80.8%) for both and 10.6 (99.6% CI, 10.1-11.1) versus 11.0 (99.6% CI, 10.5-11.5) mL/min/1.73 m(2), respectively; these equations were more accurate than any of the alternative equations (P <0.001 for all pairwise comparisons for both measures). They performed better than or as well as the alternative equations in most subgroups defined by demographic and clinical characteristics, including type of transplanted organ. LIMITATIONS: Study population included few nonwhites and people with solid-organ transplants other than liver and kidneys. CONCLUSIONS: The CKD-EPI creatinine and the MDRD Study equations perform better than the alternative creatinine-based estimating equations in solid-organ transplant recipients. They can be used for clinical management.

FGF-23 and cognitive performance in hemodialysis patients.

Although cognitive impairment is common in hemodialysis patients, the etiology of and risk factors for its development remain unclear. Fibroblast growth factor 23 (FGF-23) levels are elevated in hemodialysis patients and are associated with increased mortality and left ventricular hypertrophy. Despite FGF-23 being found within the brain, there are no prior studies assessing whether FGF-23 levels are associated with cognitive performance. We measured FGF-23 in 263 prevalent hemodialysis patients in whom comprehensive neurocognitive testing was also performed. The cross-sectional association between patient characteristics and FGF-23 levels was assessed. Principal factor analysis was used to derive two factors from cognitive test scores, representing memory and executive function, which carried a mean of 0 and a standard deviation of 1. Multivariable linear regression adjusting for age, sex, education status, and other relevant covariates was used to explore the relationship between FGF-23 and each factor. Mean age was 63 years, 46% were women and 22% were African American. The median FGF-23 level was 3098 RU/mL. Younger age, lower prevalence of diabetes, longer dialysis vintage, and higher calcium and phosphorus were independently associated with higher FGF-23 levels. Higher FGF-23 was independently associated with a lower memory score (per doubling of FGF-23, ß = -0.08 SD [95% confidence interval, CI: -0.16, -0.01]) and highest quartile vs. lowest quartile (ß = -0.42 SD [-0.82, -0.02]). There was no definite association of FGF 23 with executive function when examined as a continuous variable (ß = -0.03 SD [-0.10, 0.04]); however, there was a trend in the quartile analysis (ß = -0.28 SD [-0.63, 0.07], P = 0.13, for 4th quartile vs. 1st quartile). FGF-23 was associated with worse performance on a composite memory score, including after adjustment for measures of mineral metabolism. High FGF-23 levels in hemodialysis patients may contribute to cognitive impairment.

Cognitive performance before and during hemodialysis: a randomized cross-over trial.

BACKGROUND AND AIMS: Hemodialysis (HD) patients are educated and counseled during the HD procedure. There are few studies assessing whether cognitive performance varies with dialysis. METHODS: Using a randomized cross-over design, 40 patients were assigned to one of two sequences: testing 1 h before dialysis followed 1 month later by testing during the first hour of dialysis (n = 21) versus testing during the first hour of dialysis followed 1 month later by 1 h before dialysis (n = 19). Cognitive tests were administered at each testing period. Mixed regression models evaluated for a dialysis effect (difference between test performance before vs. during dialysis) while adjusting for potential learning (difference between first and second tests). RESULTS: In models accounting for period of testing, there was no difference in test performance between 1 h before versus during the first hour of HD for all administered cognitive tests (p > 0.05). A learning effect was detected between first and second test administration in two tests, specifically, the Word List Learning and the Digit Symbol Substitution Test. CONCLUSIONS: We found no difference in cognitive performance depending on the time of testing, suggesting that cognitive tests performed during the first hour of dialysis are a valid assessment of cognitive performance.

Low 25-hydroxyvitamin D levels and cognitive impairment in hemodialysis patients.

BACKGROUND AND OBJECTIVES: 25-hydroxyvitamin D (25[OH]D) deficiency and cognitive impairment are both prevalent in hemodialysis patients in the United States. This study tested the hypothesis that 25(OH)D deficiency may be associated with cognitive impairment because of its vasculoprotective, neuroprotective, and immune-modulatory properties. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This cross-sectional analysis involved 255 patients enrolled in the Dialysis and Cognition Study between 2004 and 2012. In linear regression models, 25(OH)D was the exposure variable; it was used first as a continuous variable and then stratified as deficient (<12 ng/ml), insufficient (12 to <20 ng/ml), and sufficient (≥20 ng/ml). Principal component analysis was used to obtain the memory and the executive function domains from the individual neurocognitive tests. Scores on individual tests as well as on the memory and executive function domains were the outcome variables. Multivariable models were adjusted for age, sex, race, education, and other potential confounding variables. RESULTS: Mean serum 25(OH)D ± SD was 17.2±7.4 ng/ml, with 14%, 55%, and 31% of patients in the deficient, insufficient, and sufficient groups, respectively. Patients in the deficient group were more likely to be women, African American, and diabetic and to have longer dialysis vintage. Higher 25(OH)D levels were independently associated with better performance on several tests of executive function (mean difference on component executive score, 0.16 [95% confidence interval, 0.04-0.28; P=0.01] for each SD higher 25[OH]D). No association was seen with tests assessing memory. CONCLUSIONS: 25(OH)D deficiency in hemodialysis patients is associated with worse cognitive function, particularly in domains that assess executive function.

Frequency of and risk factors for poor cognitive performance in hemodialysis patients.

OBJECTIVE: There are few detailed data on cognition in patients undergoing dialysis. We evaluated the frequency of and risk factors for poor cognitive performance using detailed neurocognitive testing. METHODS: In this cross-sectional cohort study, 314 hemodialysis patients from 6 Boston-area hemodialysis units underwent detailed cognitive assessment. The neuropsychological battery assessed a broad range of functions, with established age-, sex-, and education-matched normative scores. Principal component analysis was used to derive composite scores for memory and executive function domains. Risk factors for each domain were evaluated using linear regression adjusting for age, sex, race, and education status. Analyses were repeated in those with Mini-Mental State Examination (MMSE) score ≥ 24. RESULTS: Compared with population norms, patients on dialysis had significantly poorer executive function but not memory performance, a finding that persisted in the subgroup with MMSE score ≥ 24. In adjusted analyses, vascular risk factors and vascular disease were associated with lower executive function (p < 0.01). CONCLUSIONS: There is a high frequency of poor cognitive performance in hemodialysis patients, primarily affecting executive function. Risk factors for worse executive function include vascular risk factors as well as vascular disease. Normal performance on the MMSE does not preclude impaired cognitive function, because individuals with MMSE score ≥ 24 also have a high frequency of poor cognitive performance.

Anatomic brain disease in hemodialysis patients: a cross-sectional study.

BACKGROUND: Although dialysis patients are at high risk of stroke and have a high burden of cognitive impairment, there are few reports of anatomic brain findings in the hemodialysis population. Using magnetic resonance imaging of the brain, we compared the prevalence of brain abnormalities in hemodialysis patients with that in a control population without known kidney disease. STUDY DESIGN: Cross-sectional cohort. SETTING & PARTICIPANTS: 45 maintenance hemodialysis patients and 67 controls without reported kidney disease, both without history of known stroke. PREDICTOR: The primary predictor was dialysis status. Covariates included demographics (age, race, and sex), vascular risk factors (diabetes and hypertension), and cardiovascular disease (coronary artery disease and congestive heart failure). OUTCOMES: Magnetic resonance imaging of the brain features, including severity of white matter disease and cerebral atrophy (sulcal prominence and ventricular atrophy), hippocampal size, and small-/large-vessel infarcts. MEASUREMENTS: Semiquantitative scale (0-9 for white matter disease and cerebral atrophy, 0-3 for hippocampal size) and infarct prevalence. RESULTS: Mean ages of hemodialysis patients and controls were 55 ± 17 (SD) and 53 ± 13 years, respectively. In comparison to controls, hemodialysis patients had more severe white matter disease (1.6 vs 0.7) and cerebral atrophy (sulcal prominence, 2.3 vs 0.6; ventricular enlargement, 2.3 vs 0.9; hippocampal size, 1.3 vs 1.0), with all P < 0.001. In multivariable analyses, hemodialysis status was associated independently with worse white matter disease and atrophy grades. Hemodialysis patients also had a higher prevalence of small- (17.8%) and large- (7.8%) vessel infarcts than controls (combined, 22% vs 0%; P < 0.001). LIMITATIONS: The dialysis cohort likely is healthier than the overall US hemodialysis population, partly limiting generalizability. CONCLUSIONS: Hemodialysis patients have more white matter disease and cerebral atrophy compared with controls without known kidney disease. Hemodialysis patients also have a high prevalence of unrecognized infarcts.

Measures of blood pressure and cognition in dialysis patients.

There are few reports on the relationship of blood pressure with cognitive function in maintenance dialysis patients. The Cognition and Dialysis Study is an ongoing investigation of cognitive function and its risk factors in six Boston area hemodialysis units. In this analysis, we evaluated the relationship between different domains of cognitive function with systolic and diastolic blood pressure, pulse pressure, and intradialytic changes in systolic blood pressure, using univariate and multivariable linear regression models adjusted for age, sex, race, education, and primary cause of end-stage renal disease. Among 314 participants, mean age was 63 years; 47% were female, 22% were African American, and 48% had diabetes. The mean (SD) of systolic blood pressure, diastolic blood pressure, pulse pressure, and intradialytic change in systolic blood pressure were 141 (21), 73 (12), 68 (15), and -10 (24) mmHg, respectively. In univariate analyses, the performance on cognitive tests primarily assessing executive function and processing speeds was worse among participants with lower diastolic blood pressure and higher pulse pressure. These relationships were not statistically significant, however, in multivariable analyses. There was no association between cognitive function and systolic blood pressure or intradialytic change in systolic blood pressure in either univariate or multivariable analyses. We found no association between different measures of blood pressure and cognitive function in cross-sectional analysis. Longitudinal studies are needed to confirm these results.