Regional Variation in Hemoglobin Distribution Among Individuals With CKD: the ISN International Network of CKD Cohorts.

Introduction: Despite recognized geographic and sex-based differences in hemoglobin in the general population, these factors are typically ignored in patients with chronic kidney disease (CKD) in whom a single therapeutic range for hemoglobin is recommended. We sought to compare the distribution of hemoglobin across international nondialysis CKD populations and evaluate predictors of hemoglobin. Methods: In this cross-sectional study, hemoglobin distribution was evaluated in each cohort overall and stratified by sex and estimated glomerular filtration rate (eGFR). Relationships between candidate predictors and hemoglobin were assessed from linear regression models in each cohort. Estimates were subsequently pooled in a random effects model. Results: A total of 58,613 participants from 21 adult cohorts (median eGFR range of 17-49 ml/min) and 3 pediatric cohorts (median eGFR range of 26-45 ml/min) were included with broad geographic representation. Hemoglobin values varied substantially among the cohorts, overall and within eGFR categories, with particularly low mean hemoglobin observed in women from Asian and African cohorts. Across the eGFR range, women had a lower hemoglobin compared to men, even at an eGFR of 15 ml/min (mean difference 5.3 g/l, 95% confidence interval [CI] 3.7-6.9). Lower eGFR, female sex, older age, lower body mass index, and diabetic kidney disease were all independent predictors of a lower hemoglobin value; however, this only explained a minority of variance (R2 7%-44% across cohorts). Conclusion: There are substantial regional differences in hemoglobin distribution among individuals with CKD, and the majority of variance is unexplained by demographics, eGFR, or comorbidities. These findings call for a renewed interest in improving our understanding of hemoglobin determinants in specific CKD populations.

Association of Kidney Function Measures With Signs of Neurodegeneration and Small Vessel Disease on Brain Magnetic Resonance Imaging: The Atherosclerosis Risk in Communities (ARIC) Study.

RATIONALE & OBJECTIVE: 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. STUDY DESIGN: Cross-sectional study nested in a cohort study. SETTING & PARTICIPANTS: 1,527 participants in the Atherosclerosis Risk in Communities (ARIC) Study. PREDICTORS: Log(UACR) and eGFR based on cystatin C, creatinine, cystatin C and creatinine in combination, or ß2-microglobulin (B2M). OUTCOMES: Brain volume reduction, infarcts, microhemorrhages, white matter lesions. ANALYTICAL APPROACH: Multivariable linear and logistic regression models fit separately for each predictor based on a 1-IQR difference in the predictor value. RESULTS: 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. LIMITATIONS: No inference about longitudinal effects due to cross-sectional design. CONCLUSIONS: 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.

Association Between Acute Kidney Injury and Dementia in the Atherosclerosis Risk in Communities (ARIC) Study.

RATIONALE & OBJECTIVE: Acute kidney injury (AKI) causes biochemical changes in the brain in animal models and is associated with adverse neurological complications in hospitalized patients. This study tested the association between AKI and incident dementia in a community-based cohort. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: Adult participants in the Atherosclerosis Risk in Communities (ARIC) study who experienced hospitalized AKI compared with participants hospitalized for other reasons (primary analysis, mean follow-up period 4.3 years) or participants without hospitalized AKI (secondary analysis). PREDICTORS: Incident AKI, defined by ICD codes from hospital records. OUTCOME: Incident dementia, diagnosed based on a combination of neurocognitive testing, informant interviews, ICD codes, and death certificates. ANALYTICAL APPROACH: In the primary analysis, we estimated the propensity for hospitalized AKI and matched these participants with those hospitalized for another reason to examine the association of AKI with subsequent onset of dementia (N = 1,708). In the secondary analysis, we estimated the association between time-varying hospitalized AKI and subsequent onset of dementia using multivariable Cox proportional hazards regression models, adjusted for age, sex, race/center, education, smoking status, body mass index, baseline estimated glomerular filtration rate, baseline urinary albumin-creatinine ratio, systolic blood pressure, coronary heart disease, diabetes, hypertension, apolipoprotein E (APOE) ε4 allele, and C-reactive protein. RESULTS: The mean age in the propensity-matched cohort was 76.1 ± 6.5 (SD) years, and 53.2% of the participants were women. People who were hospitalized with AKI had a higher risk of dementia (HR, 1.25 [95% CI, 1.02-1.52]; P = 0.03) compared with those without a hospitalization for AKI. The associations were slightly stronger in the time-varying analysis (HR, 1.69 [95% CI, 1.48-1.92]; P < 0.001). Other risk factors for dementia included older age, male sex, higher albuminuria, diabetes, current smoker status, and presence of the APOE risk alleles. LIMITATIONS: Observational study, with AKI identified through diagnosis codes. CONCLUSIONS: Participants who experienced a hospitalization for AKI were at increased risk of dementia.

Albuminuria and Estimated GFR as Risk Factors for Dementia in Midlife and Older Age: Findings From the ARIC Study.

RATIONALE & OBJECTIVE: Evidence is limited on how estimated glomerular filtration rate (eGFR) and urinary albumin-creatinine ratio (UACR) relate to dementia at different ages. We evaluated eGFR and UACR in midlife and older age as risk factors for dementia. Additionally, we assessed whether the association between eGFR and dementia is altered when cystatin C and ß2-microglobulin (B2M) levels are used for GFR estimation. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: Two baselines from the Atherosclerosis Risk in Communities (ARIC) Study were used: visit 4 (1996-1998), including 9,967 participants 54 to 74 years old, and visit 5 (2011-2013), including 4,626 participants 70 to 90 years old. Participants were followed up until 2017. PREDICTORS: Log(UACR); eGFR based on creatinine, cystatin C, creatinine and cystatin C, or B2M levels (denoted as eGFRcr, eGFRcys, eGFRcr-cys, and eGFRB2M). OUTCOME: Incident dementia. ANALYTICAL APPROACH: Multivariable Cox proportional hazards regression models fit separately for each of the 5 predictors and based on a change in the predictor equivalent to the interquartile range for that predictor at visit 4 (IQRV4). eGFR models were adjusted for log(UACR) and log(UACR) models were adjusted for eGFRcys. RESULTS: We observed 1,821 dementia cases after visit 4 and 438 cases after visit 5. Dementia risk increased with higher albuminuria levels (HRs per IQRV4 [equivalent to 4.2-fold greater log albuminuria] of 1.15 [95% CI, 1.09-1.21] after visit 4 and 1.27 [95% CI, 1.13-1.42] after visit 5). An association with lower eGFR was seen for only eGFRcys (HRs per IQRV4 [equivalent to 24.3mL/min/1.73m2 lesser eGFRcys] of 1.12 [95% CI, 1.04-1.21] after visit 4 and 1.30 [95% CI, 1.12-1.52] after visit 5) and eGFRB2M (HRs per IQRV4 [equivalent to 18.3mL/min/1.73m2 lesser eGFRB2M] of 1.15 [95% CI, 1.07-1.23] after visit 4 and 1.34 [95% CI, 1.17-1.55] after visit 5). Differences between these associations in midlife and older age were not statistically significant. LIMITATIONS: Changes in potentially time-varying covariates were not measured. Dementia was not subclassified by cause. CONCLUSIONS: Albuminuria was consistently associated with dementia incidence. Lower eGFR based on cystatin C or B2M, but not creatinine, levels was also associated with dementia. Risk associations were similar when kidney measures were assessed at midlife and older age.

Left Ventricular Structure in Patients With Mild-to-Moderate CKD-a Magnetic Resonance Imaging Study.

INTRODUCTION: The high burden of left ventricular (LV) abnormalities in patients with advanced chronic kidney disease (CKD) is well established. However, less is known about the prevalence, patterns, and determinants of LV abnormalities in patients with early CKD. METHODS: We examined LV structure in 290 patients with a median estimated glomerular filtration rate (eGFR) of 51 ml/min per 1.73 m2 by magnetic resonance imaging (MRI). We explored associations with clinical and hemodynamic parameters, hydration (bioimpedance), endothelial function, inflammation (including C-reactive protein and tumor necrosis factor-α and its soluble receptors) and mineral bone disease (MBD) markers (including vitamin D, parathyroid hormone, α-klotho and fibroblast growth factor-23). RESULTS: Normal geometry was found in 56% of patients, dilation in 4%, concentric remodeling in 10%, and LV hypertrophy in 29%. Linear regression analysis revealed that greater LV mass was independently associated with male sex, greater body mass index (BMI), and higher 24-hour systolic blood pressure (24-hour SBP). Concentric remodeling was independently associated with age, male sex, higher 24-hour SBP, and greater hemoglobin levels. Surprisingly, neither hydration status, nor endothelial function, nor any of the inflammatory or MBD parameters added significantly to these models. CONCLUSION: Abnormal LV structure was found in almost one-half of the patients. Reducing BMI and 24-hour SBP and avoiding high hemoglobin concentrations appear to be the key factors to prevent abnormal LV remodeling in patients with mild-to-moderate CKD.

Blood Pressure Pattern and Target Organ Damage in Patients With Chronic Kidney Disease.

In patients with chronic kidney disease, data on blood pressure (BP) pattern and its association with target organ damage, which indicates elevated cardiovascular risk, are sparse. In 305 treated hypertensive chronic kidney disease patients, we assessed BP pattern, left ventricular mass (magnetic resonance imaging), intima-media thickness (ultrasound), 24-hour-pulse wave velocity and 24-hour-central augmentation index (Mobil-O-Graph). Controlled hypertension (normal office and ambulatory BP) was found in 41% and sustained uncontrolled hypertension (elevated office and ambulatory BP) in 30% of patients. Misclassification of BP status occurred in 29%: white coat uncontrolled hypertension (elevated office but normal ambulatory BP) was detected in 11% and masked uncontrolled hypertension (normal office but elevated ambulatory BP) in 18% of patients. Left ventricular mass was increased in white coat uncontrolled hypertension (+11.2 g), masked uncontrolled hypertension (+9.4 g), and sustained uncontrolled hypertension (+16.6 g) compared with controlled hypertension. Intima-media thickness was similar across all 4 BP groups. Twenty-four hour-pulse wave velocity and 24-hour-central augmentation index were increased in masked uncontrolled hypertension (+0.5 m/sec and +2.5%) and sustained uncontrolled hypertension (+0.5 m/sec and +2.9%) compared with controlled hypertension. In conclusion, based on office BP measurements, misclassification of true BP status occurred in almost one-third of chronic kidney disease patients. Both types of misclassification (white coat uncontrolled hypertension and masked uncontrolled hypertension) were associated with parameters of target organ damage. Ambulatory BP monitoring should be used routinely to identify chronic kidney disease patients at high cardiovascular risk.

Retinal capillary and arteriolar changes in patients with chronic kidney disease.

RATIONALE: Premature cardiovascular disease is a leading cause of death in patients with chronic kidney disease (CKD). In animal models CKD has been shown to cause renal and extrarenal vascular remodeling and capillary rarefaction, but data in humans with CKD are sparse. Retinal arteriolar wall-to-lumen ratio (WLR) is an established marker of early end-organ damage and there is evidence that arteriolar and capillary changes in the retinal circulation mirror those in the general and in particular the cerebrovascular microcirculation. OBJECTIVE: The aim of this study was to compare retinal capillary density and arteriolar structure between patients with CKD and healthy individuals. METHODS: We compared 76 patients with CKD stage 3+ or proteinuria >500 mg/g creatinine in the presence of a normal GFR from the German Chronic Kidney Disease cohort to 53 healthy control subjects, who participated in clinical trials during 2007 and 2015 in our Clinical Research Center. Retinal vascular parameters were measured non-invasively in vivo by scanning laser Doppler Flowmetry (SLDF, Heidelberg Engineering, Germany). Capillary rarefaction was assessed by intercapillary distance. RESULTS: Patients with CKD showed greater WLR (0.403 ±â€¯0.11 vs 0.351 ±â€¯0.11, p = 0.010) and greater wall thickness (WT) (15.1 ±â€¯4.1 vs 13.5 ±â€¯3.8, p = 0.026) compared to healthy individuals. Intercapillary distance (ICD) (22.4 ±â€¯5.7 vs 20.2 ±â€¯4.1, p = 0.008) was greater in the CKD group compared to the healthy control group. After adjustment for differences in clinical characteristics of the groups (age, gender, BMI, serum cholesterol) WLR (p = 0.046), WT (p = 0.025) and ICD (p = 0.003) remained significantly different between the two groups. There was a correlation between serum phosphate level and WLR in the CKD group (r = 0.288, p = 0.013). CONCLUSION: Patients with moderately severe CKD show retinal signs of end-organ damage indicated by an increased wall-to-lumen ratio and capillary rarefaction.

Skin Sodium Concentration Correlates with Left Ventricular Hypertrophy in CKD.

The pathogenesis of left ventricular hypertrophy in patients with CKD is incompletely understood. Sodium intake, which is usually assessed by measuring urinary sodium excretion, has been inconsistently linked with left ventricular hypertrophy. However, tissues such as skin and muscle may store sodium. Using 23sodium-magnetic resonance imaging, a technique recently developed for the assessment of tissue sodium content in humans, we determined skin sodium content at the level of the calf in 99 patients with mild to moderate CKD (42 women; median [range] age, 65 [23-78] years). We also assessed total body overhydration (bioimpedance spectroscopy), 24-hour BP, and left ventricular mass (cardiac magnetic resonance imaging). Skin sodium content, but not total body overhydration, correlated with systolic BP (r=0.33, P=0.002). Moreover, skin sodium content correlated more strongly than total body overhydration did with left ventricular mass (r=0.56, P<0.001 versus r=0.35, P<0.001; P<0.01 between the two correlations). Linear regression analysis demonstrated that skin sodium content is a strong explanatory variable for left ventricular mass, unaffected by BP and total body overhydration. In conclusion, we found skin sodium content to be closely linked to left ventricular mass in patients with CKD. Interventions that reduce skin sodium content might improve cardiovascular outcomes in these patients.