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2.  Effect of More Frequent Hemodialysis on Cognitive Function in the Frequent Hemodialysis Network Trials 
Background
Cognitive impairment is common among patients with end-stage renal disease receiving hemodialysis 3x-per-week.
Study Design
Randomized Clinical Trial
Setting & Participants
218 subjects participating in the Frequent Hemodialysis Network (FHN) Daily Trial and 81 subjects participating in the FHN Nocturnal Trial.
Intervention
The Daily Trial tested in-center hemodialysis 6x-per-week versus 3x-per-week. The Nocturnal Trial tested home nocturnal hemodialysis 6x-per-week versus home or in-center hemodialysis 3x-per-week.
Outcomes
Cognitive function was measured at baseline, month four, and month 12. The primary outcome was performance on the Trail-Making Test, Form B, a measure of executive function, and a secondary outcome was performance on the Modified Mini-Mental State Examination, a measure of global cognition. The domains of attention, psychomotor speed, memory and verbal fluency were assessed in 59 participants in the Daily Trial and 19 participants in the Nocturnal Trial.
Results
We found no benefit of frequent hemodialysis in either trial for the primary cognitive outcome (Daily Trial: OR for improvement, 0.99; 95% CI, 0.59–1.66; Nocturnal Trial: OR, 1.19; 95% CI, 0.48–2.96). Similarly, there was no benefit of frequent hemodialysis in either trial on global cognition, the secondary cognitive outcome. Exploratory analyses in the Daily Trial suggested possible benefits of frequent hemodialysis on memory and verbal fluency, but not on attention and psychomotor speed. Exploratory analyses in the Nocturnal Trial suggested no benefit of frequent hemodialysis on attention, psychomotor speed, memory, or verbal fluency.
Limitations
Unblinded intervention, small sample
Conclusions
Frequent hemodialysis did not improve executive function or global cognition.
doi:10.1053/j.ajkd.2012.09.009
PMCID: PMC3546160  PMID: 23149295
dialysis; end-stage renal disease; cognitive function
3.  Albuminuria, Kidney Function, and the Incidence of Cognitive Impairment Among Adults in the United States 
Background
Albuminuria and estimated glomerular filtration rate (eGFR) are each associated with increased risk for cognitive impairment, but their joint association is unknown.
Study Design
Prospective cohort study.
Setting and Participants
A US national sample of 19,399 adults without cognitive impairment at baseline participating in the REGARDS )REasons for Geographic And Racial Disparities in Stroke) study.
Predictors
Albuminuria was assessed by the urine albumin-creatinine ratio (UACR) and GFR was estimated using the CKD-EPI (CKD Epidemiology Collaboration) equation.
Outcomes
Incident cognitive impairment was defined as a score of 4 or less on the Six-item Screener at the last follow-up visit.
Results
Over a mean follow-up of 3.8 ± 1.5 years, UACR 30 – 299 and ≥300 mg/g were independently associated with 31% and 57% higher risk for cognitive impairment, respectively, relative to individuals with UACR <10 mg/g. This finding was strongest among those with high eGFR and attenuated at lower levels (P=0.04 for trend). Relative an eGFR ≥60 ml/min/1.73m2, eGFR <60 ml/min/1.73m2 was not independently associated with cognitive impairment. However, after stratifying by UACR, eGFR <60 ml/min/1.73m2 was associated with 30% higher risk for cognitive impairment among participants with UACR <10 mg/g but not higher UACR levels (P=0.04 for trend).
Limitations
single measure of albuminuria and eGFR, screening test of cognition
Conclusions
When eGFR was preserved, albuminuria independently associated with incident cognitive impairment. When albuminuria was <10 mg/g, low eGFR independently associated with cognitive impairment. Albuminuria and low eGFR are complementary but not additive risk factors for incident cognitive impairment.
doi:10.1053/j.ajkd.2011.05.027
PMCID: PMC3199339  PMID: 21816528
albuminuria; chronic kidney disease; cognitive impairment
4.  Timing of initiation of dialysis: time for a new direction? 
Purpose of review
The past 15 years have seen tremendous growth in the initiation of dialysis at higher levels of kidney function in the setting of mixed evidence and at great societal economic cost. We review recent data on the early dialysis initiation trend, the clinical and economic impact of early dialysis initiation and the future implications for the management of advanced chronic kidney disease (CKD).
Recent findings
The percentage of patients who initiate dialysis with an estimated glomerular filtration rate (eGFR) above 10 ml/min/1.73m2 is now greater than 50%, including 20% who initiate with an eGFR above 15 ml/min/1.73m2. The drivers behind these findings are probably diverse but recent literature does not seem to support a higher symptom burden among the ageing CKD population as the major cause. The Initiating Dialysis Early And Late (IDEAL) trial provides guidance on the safety of waiting for symptoms or lower levels of estimated glomerular filtration rate prior to beginning dialysis. In addition, economic analyses based on the IDEAL and US Renal Data System findings suggest that significant cost savings could be achieved by reversing the early initiation trend.
Summary
These findings should help clinicians and policy makers looking to rein in costs while maintaining the quality of CKD care.
doi:10.1097/MNH.0b013e328351c244
PMCID: PMC3458516  PMID: 22388556
dialysis; end-stage renal disease; initiation
5.  Optimizing renal replacement therapy in older adults: a framework for making individualized decisions 
Kidney International  2011;82(3):261-269.
It is often difficult to synthesize information about the risks and benefits of recommended management strategies in older patients with end-stage renal disease since they may have more comorbidity and lower life expectancy than patients described in clinical trials or practice guidelines. In this review, we outline a framework for individualizing end-stage renal disease management decisions in older patients. The framework considers three factors: life expectancy, the risks and benefits of competing treatment strategies, and patient preferences. We illustrate the use of this framework by applying it to three key end-stage renal disease decisions in older patients with varying life expectancy: choice of dialysis modality, choice of vascular access for hemodialysis, and referral for kidney transplantation. In several instances, this approach might provide support for treatment decisions that directly contradict available practice guidelines, illustrating circumstances when strict application of guidelines may be inappropriate for certain patients. By combining quantitative estimates of benefits and harms with qualitative assessments of patient preferences, clinicians may be better able to tailor treatment recommendations to individual older patients, thereby improving the overall quality of end-stage renal disease care.
doi:10.1038/ki.2011.384
PMCID: PMC3396777  PMID: 22089945
dialysis; elderly; end-stage renal disease; transplantation
7.  Comparison of CKD Awareness in a Screening Population Using the Modification of Diet in Renal Disease (MDRD) Study and CKD Epidemiology Collaboration (CKD-EPI) Equations 
Background
Low awareness of chronic kidney disease (CKD) may reflect uncertainty about the accuracy or significance of a CKD diagnosis in individuals otherwise perceived to be low-risk. Whether reclassification of CKD severity using the CKD Epidemiology Collaboration (CKD-EPI) equation to estimate glomerular filtration rate (GFR) modifies estimates of CKD awareness is unknown.
Methods
In this cross-sectional study, we used data collected from 2000 to 2009 for 26,213 participants in the Kidney Early Evaluation Program (KEEP), a community-based screening program, with CKD based on GFR estimated using the 4-variable Modification of Diet in Renal Disease (MDRD) Study equation and measurement of albuminuria. We assessed CKD awareness after CKD stage was reclassified using the CKD-EPI equation.
Results
Of 26,213 participants with CKD based on eGFRMDRD, 23,572 (90%) were also classified with CKD based on eGFRCKD-EPI. Based on eGFRMDRD, 9.5% of participants overall were aware of CKD, as were 4.9%, 6.3%, 9.2%, 41.9%, and 59.2% with Stages 1-5, respectively. Based on eGFRCKD-EPI, 10.0% of participants overall were aware of CKD, as were 5.1%, 6.6%, 10.0%, 39.3%, and 59.4% with Stages 1-5, respectively. Reclassification to a less advanced CKD stage with eGFRCKD-EPI was associated with lower odds for awareness (OR, 0.58; 95% CI, 0.50-0.67); reclassification to a more advanced stage was associated with higher odds for awareness (OR, 1.50; 95% CI, 1.05-2.13) after adjustment for confounding factors. Of participants unaware of CKD, 10.6% were reclassified as not having CKD using eGFRCKD-EPI.
Conclusions
Using eGFRCKD-EPI led to a modest increase in overall awareness rates, primarily due to reclassification of low-risk unaware participants.
doi:10.1053/j.ajkd.2010.11.008
PMCID: PMC3075598  PMID: 21338846
awareness; chronic kidney disease; CKD-EPI; estimated glomerular filtration rate
8.  Should there be an expanded role for palliative care in end-stage renal disease? 
Purpose of review
In this review, we outline the rationale for expanding the role of palliative care in end-stage renal disease (ESRD), describe the components of a palliative care model, and identify potential barriers in implementation.
Recent findings
Patients receiving chronic dialysis have reduced life expectancy and high rates of chronic pain, depression, cognitive impairment, and physical disability. Delivery of prognostic information and advance care planning are desired by patients, but occur infrequently. Furthermore, although hospice care is associated with improved symptom control and lower healthcare costs at the end of life, it is underutilized by the ESRD population, even among patients who withdraw from dialysis. A palliative care model incorporating communication of prognosis, advance care planning, symptom assessment and management, and timely hospice referral may improve quality of life and quality of dying. Resources and clinical practice guidelines are available to assist practitioners with incorporating palliative care into ESRD management.
Summary
There is a large unmet need to alleviate the physical, psychosocial, and existential suffering of patients with ESRD. More fully integrating palliative care into ESRD management by improving end-of-life care training, eliminating structural and financial barriers to hospice use, and identifying optimal methods to deliver palliative care are necessary if we are to successfully address the needs of an aging ESRD population.
doi:10.1097/MNH.0b013e32833d67bc
PMCID: PMC3107069  PMID: 20644475
end-stage renal disease; hospice; palliative care
9.  Dementia and cognitive impairment in ESRD: diagnostic and therapeutic strategies 
Kidney international  2010;79(1):14-22.
Cognitive impairment, including dementia, is a common but poorly recognized problem among patients with end-stage renal disease (ESRD), affecting 16–38% of patients. Dementia is associated with high risks of death, dialysis withdrawal, hospitalization, and disability among patients with ESRD; thus, recognizing and effectively managing cognitive impairment may improve clinical care. Dementia screening strategies should take into account patient factors, the time available, the timing of assessments relative to dialysis treatments, and the implications of a positive screen for subsequent management (for example, transplantation). Additional diagnostic testing in patients with cognitive impairment, including neuroimaging, is largely based on the clinical evaluation. There is limited data on the efficacy and safety of pharmacotherapy for dementia in the setting of ESRD; therefore, decisions about the use of these medications should be individualized. Management of behavioral symptoms, evaluation of patient safety, and advance care planning are important components of dementia management. Prevention strategies targeting vascular risk factor modification, and physical and cognitive activity have shown promise in the general population and may be reasonably extrapolated to the ESRD population. Modification of ESRD-associated factors such as anemia and dialysis dose or frequency require further study before they can be recommended for treatment or prevention of cognitive impairment.
doi:10.1038/ki.2010.336
PMCID: PMC3107192  PMID: 20861818
aging; cognitive impairment; dementia; ESRD
10.  Preferences for dialysis withdrawal and engagement in advance care planning within a diverse sample of dialysis patients 
Background and objectives. Rates of dialysis withdrawal are higher among the elderly and lower among Blacks, yet it is unknown whether preferences for withdrawal and engagement in advance care planning also vary by age and race or ethnicity.
Design, setting, participants and methods. We recruited 61 participants from two dialysis clinics to complete questionnaires regarding dialysis withdrawal preferences in five different health states. Engagement in advance care planning (end-of-life discussions), completion of advance directives and ‘do not resuscitate’ or ‘do not intubate’ (DNR/DNI) orders were ascertained by a questionnaire and from dialysis unit records.
Results. The mean age was 62 ± 15 years; 38% were Black, 11% were Latino, 34% were White and 16% of participants were Asian. Blacks were less likely to prefer dialysis withdrawal as compared with Whites (odds ratio 0.16, 95% confidence interval 0.03–0.88) and other race/ethnicity groups, and this difference was not explained by age, education, comorbidity and other confounders. In contrast, older age was not associated with preferences for withdrawal. Rates of engagement in end-of-life discussions were higher than for documentation of advance care planning for all age and most race/ethnicity groups. Although younger participants and minorities were generally less likely to document treatment preferences as compared with older patients and Whites, they were not less likely to engage in end-of-life discussions.
Conclusions. Preferences for withdrawal vary by race/ ethnicity, whereas the pattern of engagement in advance care planning varies by age and race/ethnicity. Knowledge of these differences may be useful for improving communication about end-of-life preferences and in implementing effective advance care planning strategies among diverse haemodialysis patients.
doi:10.1093/ndt/gfp430
PMCID: PMC2910327  PMID: 19734137
advance care planning; dialysis withdrawal; elderly; race; treatment preferences
11.  Incidence, management, and outcomes of end-stage renal disease in the elderly 
Purpose of review
The elderly constitute a substantial and growing fraction of the end-stage renal disease (ESRD) population. We review recent studies on ESRD incidence, management, and outcomes in the elderly.
Recent findings
Rates of treated ESRD among the elderly (>80 years) have risen by more than 50% in the last decade. In studies with a large number of elderly patients, median survival after dialysis initiation is modest, and although a majority have reasonable life expectancy, a substantial minority of elderly patients experience very high early mortality rates after dialysis initiation. Quality of life results are mixed – compared with younger ESRD patients or non-ESRD elderly, mental well being is similar and physical well being is reduced in elderly patients with ESRD. In several studies, elderly patients with ESRD initiating peritoneal dialysis had higher mortality rates than elderly patients with ESRD initiating hemodialysis. Strategies such as nondialytic management of ESRD or dietary protein restriction and delayed dialysis initiation may be alternatives for elderly patients wishing to avoid dialysis initiation, but further studies are needed to determine the patients best suited for these approaches. Quality improvement initiatives in geriatric ESRD care have been successfully implemented in some centers and may ultimately improve care for elderly patients with ESRD.
Summary
These findings should help to clarify some of the risks and benefits of dialysis in the elderly and may be useful in dialysis decision-making and management.
doi:10.1097/MNH.0b013e328326f3ac
PMCID: PMC2738843  PMID: 19374012
dialysis; elderly; end-stage renal disease
12.  Frailty and Dialysis Initiation 
Seminars in dialysis  2013;26(6):690-696.
Frailty is a physiologic state of increased vulnerability to stressors that results from decreased physiologic reserves or dysregulation of multiple physiologic systems. The construct of frailty has been operationalized as a composite of poor physical function, exhaustion, low physical activity, and weight loss. Several studies have now examined the prevalence of frailty among chronic kidney disease (CKD) or end-stage renal disease (ESRD) patients and have found frailty to be more common among individuals with CKD than among those without. Furthermore, frailty is associated with adverse outcomes among incident dialysis patients, including higher risk of hospitalization and death. Recent evidence shows that frail patients are started on dialysis earlier (at a higher estimated glomerular filtration rate [eGFR]) on average than nonfrail patients but it is unclear whether these patients’ frailty is a result of uremia or is independent of CKD. The survival disadvantage that has been associated with early initiation of dialysis in observational studies could be mediated in part through confounding on the basis of unmeasured frailty. However, available data do not suggest improvement in frailty upon initiation of dialysis; rather, the trajectory appears to be towards higher levels of dependence in activities of daily living (ADLs) after dialysis initiation. Overall, there is no data to suggest that frail patients derive any benefit from early initiation of dialysis either in the form of improved survival or functional status.
doi:10.1111/sdi.12126
PMCID: PMC3984466  PMID: 24004376
13.  Less Is More 
Archives of internal medicine  2011;171(15):1371-1378.
Background
Little is known about trends in the timing of first nephrology consultation and associated outcomes among older patients initiating dialysis.
Methods
Data from patients aged 67 years or older who initiated dialysis in the United States between January 1, 1996, and December 31, 2006, were stratified by timing of the earliest identifiable nephrology visit. Trends of earlier nephrology consultation were formally examined in light of concurrently changing case mix and juxtaposed with trends in 1-year mortality rates after initiation of dialysis.
Results
Among 323 977 older patients initiating dialysis, the proportion of patients receiving nephrology care less than 3 months before initiation of dialysis decreased from 49.6% (in 1996) to 34.7% (in 2006). Patients initiated dialysis with increasingly preserved kidney function, from a mean estimated glomerular filtration rate of 8 mL/min/1.73 m2 in 1996 to 12 mL/min/1.73 m2 in 2006. Patients were less anemic in later years, which was partly attributable to increased use of erythropoiesis-stimulating agents, and fewer used peritoneal dialysis as the initial modality. During the same period, crude 1-year mortality rates remained unchanged (annual change in mortality rate, +0.2%; 95% confidence interval, 0% to +0.4%). Adjustment for changes in demographic and comorbidity patterns yielded estimated annual reductions in 1-year mortality rates of 0.9% (95% confidence interval, 0.7% to 1.1%), which were explained only partly by concurrent trends toward earlier nephrology consultation (annual mortality reduction after accounting for timing of nephrology care was attenuated to 0.4% [0.2% to 0.6%]).
Conclusions
Despite significant trends toward earlier use of nephrology consultation among older patients approaching maintenance dialysis, we observed no material improvement in 1-year survival rates after dialysis initiation during the same time period.
doi:10.1001/archinternmed.2011.360
PMCID: PMC4123329  PMID: 21824952
14.  Risk Factors for ESRD in Individuals With Preserved Estimated GFR With and Without Albuminuria: Results From the Kidney Early Evaluation Program (KEEP) 
Background
Given the increasing costs and poor outcomes of end-stage renal disease (ESRD), we sought to identify risk factors for ESRD in people with preserved estimated glomerular filtration rate (eGFR), with or without albuminuria, who were at high risk of ESRD.
Methods
This cohort study included participants in the National Kidney Foundation’s Kidney Early Evaluation Program (KEEP) with eGFR ≥60 mL/min/1.73 m2 at baseline stratified by the presence or absence of albuminuria. The Chronic Kidney Disease Epidemiology Collaboration equation was used to calculate eGFR. Urine was tested for albuminuria by semiquantitative dipstick. The outcome was the development of treated chronic kidney failure, defined as initiation of maintenance dialysis therapy or kidney transplantation, determined by linkage to the US Renal Data System. We used a Cox model with the Fine-Gray method to assess risk factors for treated chronic kidney failure while accounting for the competing risk of death.
Results
During a median follow-up of 4.8 years, 126 of 13,923 participants with albuminuria (16/10,000 patient-years) and 56 of 109,135 participants without albuminuria (1.1/10,000 patient-years) developed treated chronic kidney failure. Diabetes was a strong risk factor for developing treated chronic kidney failure in participants with and without albuminuria (adjusted HRs of 9.3 [95% CI, 5.7–15.3] and 7.8 [95% CI, 4.1–14.8], respectively). Black race, lower eGFR, and higher systolic blood pressure also were associated with higher adjusted risks of developing treated chronic kidney failure.
Conclusions
In a diverse high-risk cohort of KEEP participants with preserved eGFR, we showed that diabetes, higher systolic blood pressure, lower eGFR, and black race were risk factors for developing treated chronic kidney failure irrespective of albuminuria status, although the absolute risk of kidney failure in participants without albuminuria was very low. Our findings support testing for kidney disease in high-risk populations, which often have otherwise unrecognized kidney disease.
doi:10.1053/j.ajkd.2012.12.016
PMCID: PMC4117734  PMID: 23507268
Albuminuria; blood pressure; chronic kidney disease; diabetes; dialysis risk factors; end-stage renal disease; public health
15.  Impact of frequent hemodialysis on anemia management: results from the Frequent Hemodialysis Network (FHN) Trials 
Nephrology Dialysis Transplantation  2013;28(7):1888-1898.
Background
The extent to which anemia management is facilitated by more frequent hemodialysis (HD) is controversial. We hypothesized as a preselected outcome that patients receiving HD six times (6×) compared with three times (3×) per week would require lower doses of erythropoietin-stimulating agents (ESA) and/or achieve higher blood hemoglobin (Hb) concentrations.
Methods
Subjects enrolled in the Frequent Hemodialysis Network (FHN) daily and nocturnal trials were studied. As the primary outcome for anemia, the dose of ESAs was recorded at 4-month intervals and the monthly dose of intravenous iron (IV Fe) was reported. Serum iron, transferrin saturation and ferritin were measured at baseline and then at 4-month intervals, whereas Hb concentration was measured monthly.
Results
There was no significant treatment effect in the 6× versus 3× treatment groups on logESA dose or the ratio of log of ESA dose to Hb concentration in either trial. In the daily trial, Hb concentrations increased significantly in the 6× versus 3× group, at Month 12 compared with baseline (0.3 g/dL; 95% CI: 0.05–0.58, P < 0.021), but both groups had Hb concentrations in the usual target range. In the daily trial, the weekly logESA dose and the logESA dose to Hb concentration ratio tended to decline more in the 6× versus 3× group. This trend was not observed in the nocturnal trial. IV Fe doses were significantly lower in the 6× compared with the 3× group by Month 12 in the nocturnal trial, but not different in the daily trial.
Conclusions
In the FHN Daily and Nocturnal Trials, more frequent HD did not have a significant or clinically important effect on anemia management.
doi:10.1093/ndt/gfs593
PMCID: PMC3707527  PMID: 23358899
anemia; erythropoietin; frequent; hemodialysis; nocturnal
16.  Vitamin D Deficiency and Mortality in Patients Receiving Dialysis: The Comprehensive Dialysis Study 
Objective
Although several studies have shown poorer survival among individuals with 25-hydroxy (OH) vitamin D deficiency, data on patients receiving dialysis are limited. Using data from the Comprehensive Dialysis Study (CDS), we tested the hypothesis that patients new to dialysis with low serum concentrations of 25-OH vitamin D would experience higher mortality and hospitalizations.
Design
The CDS is a prospective cohort study. We recruited participants from 56 dialysis units located throughout the United States.
Subjects and Intervention
We obtained data on demographics, comorbidites, and laboratory values from the CDS Patient Questionnaire as well as the Medical Evidence Form (CMS form 2728). Participants provided baseline serum samples for 25-OH vitamin D measurements.
Main Outcome Measure
We ascertained time to death and first hospitalization as well as number of first-year hospitalizations via the U.S. Renal Data System standard analysis files. We used Cox proportional hazards to determine the association between 25-OH vitamin D tertiles and survival and hospitalization. For number of hospitalizations in the first year, we used negative binomial regression.
Results
The analytic cohort was composed of 256 patients with Patient Questionnaire data and 25-OH vitamin D concentrations. The mean age of participants was 62 (±14.0) years, and mean follow-up was 3.8 years. Patients with 25-OH vitamin D concentrations in the lowest tertile (<10.6 ng/mL) at the start of dialysis experienced higher mortality (adjusted hazard ratio 1.75, 95% confidence interval [CI] 1.03–2.97) as well as hospitalization (adjusted hazard ratio 1.76, 95% CI 1.24–2.49). Patients in the lower 2 tertiles (<15.5 ng/mL) experienced a higher rate of hospitalizations in the first year (incidence rate ratio 1.70 [95% CI 1.06–2.72] for middle tertile, 1.66 [95% CI 1.10–2.51] for lowest tertile).
Conclusion
We found a sizeable increase in mortality and hospitalization for patients on dialysis with severe 25-OH vitamin D deficiency.
doi:10.1053/j.jrn.2013.05.003
PMCID: PMC4077719  PMID: 23876600
18.  Spontaneous BOLD Signal Fluctuations in Young Healthy Subjects and Elderly Patients with Chronic Kidney Disease 
PLoS ONE  2014;9(3):e92539.
Spontaneous fluctuations in blood oxygenation level-dependent (BOLD) images are the basis of resting-state fMRI and frequently used for functional connectivity studies. However, there may be intrinsic information in the amplitudes of these fluctuations. We investigated the possibility of using the amplitude of spontaneous BOLD signal fluctuations as a biomarker for cerebral vasomotor reactivity.
We compared the coefficient of variation (CV) of the time series (defined as the temporal standard deviation of the time series divided by the mean signal intensity) in two populations: 1) Ten young healthy adults and 2) Ten hypertensive elderly subjects with chronic kidney disease (CKD).
We found a statistically significant increase (P<0.01) in the CV values for the CKD patients compared with the young healthy adults in both gray matter (GM) and white matter (WM). The difference was independent of the exact segmentation method, became more significant after correcting for physiological signals using RETROICOR, and mainly arose from very low frequency components of the BOLD signal fluctuation (f<0.025 Hz). Furthermore, there was a strong relationship between WM and GM signal fluctuation CV's (R2 = 0.87) in individuals, with a ratio of about 1∶3.
These results suggest that amplitude of the spontaneous BOLD signal fluctuations may be used to assess the cerebrovascular reactivity mechanisms and provide valuable information about variations with age and different disease states.
doi:10.1371/journal.pone.0092539
PMCID: PMC3961376  PMID: 24651703
19.  Prevalence and significance of stroke symptoms among patients receiving maintenance dialysis 
Neurology  2012;79(10):981-987.
Objective:
The purpose of this cross-sectional study was to determine the prevalence and potential significance of stroke symptoms among end-stage renal disease (ESRD) patients without a prior diagnosis of stroke or TIA.
Methods:
We enrolled 148 participants with ESRD from 5 clinics. Stroke symptoms and functional status, basic and instrumental activities of daily living (ADL, IADL), were ascertained by validated questionnaires. Cognitive function was assessed with a neurocognitive battery. Cognitive impairment was defined as a score 2 SDs below norms for age and education in 2 domains. IADL impairment was defined as needing assistance in at least 1 of 7 IADLs.
Results:
Among the 126 participants without a prior stroke or TIA, 46 (36.5%) had experienced one or more stroke symptoms. After adjustment for age, sex, race, education, language, diabetes, and cardiovascular disease, participants with stroke symptoms had lower scores on tests of attention, psychomotor speed, and executive function, and more pronounced dependence in IADLs and ADLs (p ≤ 0.01 for all). After adjustment for age, sex, race, education, language, diabetes, and cardiovascular disease, participants with stroke symptoms had a higher likelihood of cognitive impairment (odds ratio [OR] 2.47, 95% confidence interval [CI] 1.03–5.92) and IADL impairment (OR 3.86, 95% CI 1.60–9.28).
Conclusions:
Stroke symptoms are common among patients with ESRD and strongly associated with impairments in cognition and functional status. These findings suggest that clinically significant stroke events may go undiagnosed in this high-risk population.
doi:10.1212/WNL.0b013e31826845e9
PMCID: PMC3430712  PMID: 22875090
20.  Factors Associated With Depressive Symptoms and Use of Antidepressant Medications Among Participants in the Chronic Renal Insufficiency Cohort (CRIC) and Hispanic-CRIC Studies 
Background
Depressive symptoms are correlated with poor health outcomes in adults with chronic kidney disease (CKD). The prevalence, severity, and treatment of depressive symptoms and potential risk factors, including level of kidney function, in diverse populations with CKD have not been well studied.
Study Design
Cross-sectional analysis
Settings and Participants
Participants at enrollment into the Chronic Renal Insufficiency Cohort (CRIC) and Hispanic-CRIC (H-CRIC) Studies. CRIC enrolled Hispanics and non-Hispanics at seven centers from 2003-2007, and H-CRIC enrolled Hispanics at the University of Illinois from 2005-2008.
Measurement
Depressive symptoms measured by Beck Depression Inventory (BDI)
Predictors
Demographic and clinical factors
Outcomes
Elevated depressive symptoms (BDI >= 11) and antidepressant medication use
Results
Among 3853 participants, 28.5% had evidence of elevated depressive symptoms and 18.2% were using antidepressant medications; 30.8% of persons with elevated depressive symptoms were using antidepressants. The prevalence of elevated depressive symptoms varied by level of kidney function: 25.2% among participants with eGFR ≥ 60 ml/min/1.73m2, and 35.1% of those with eGFR < 30 ml/min/1.73m2. Lower eGFR (OR per 10 ml/min/1.73m2 decrease, 1.09; 95% CI, 1.03-1.16), Hispanic ethnicity (OR, 1.65; 95% CI, 1.12-2.45), and non-Hispanic black race (OR, 1.43; 95% CI, 1.17-1.74) were each associated with increased odds of elevated depressive symptoms after controlling for other factors. In regression analyses incorporating BDI score, while female sex was associated with a greater odds of antidepressant use, Hispanic ethnicity, non-Hispanic black race, and higher levels of urine albumin were associated with decreased odds of antidepressant use (p<0.05 for each).
Limitations
Absence of clinical diagnosis of depression and use of non-pharmacologic treatments
Conclusions
Although elevated depressive symptoms were common in individuals with CKD, use of antidepressant medications is low. African Americans, Hispanics, and individuals with more advanced CKD had higher odds of elevated depressive symptoms and lower odds of antidepressant medication use.
doi:10.1053/j.ajkd.2011.12.033
PMCID: PMC3378778  PMID: 22497791
21.  Awareness of Kidney Disease and Relationship to End-Stage Renal Disease and Mortality 
The American Journal of Medicine  2012;125(7):661-669.
Background
Patients with chronic kidney disease are often reported to be unaware. We prospectively evaluated the association between awareness of kidney disease to end-stage renal disease and mortality.
Methods
We utilized 2000–2009 data from the National Kidney Foundation-Kidney Early Evaluation Program (KEEP™). Mortality was determined by cross reference to the Social Security Administration Death Master File, and development of end-stage by cross reference with the United States Renal Data System.
Results
Of 109,285 participants, 28,244 (26%) had chronic kidney disease defined by albuminuria or eGFR <60ml/min/1.73m2. Only 9% (n=2660) reported being aware of kidney disease. Compared to those who were not aware, participants aware of chronic kidney disease had lower eGFR (49 vs 62ml/min/1.73m2) and a higher prevalence of albuminuria (52 vs 46%), diabetes (47 vs 42%), cardiovascular disease (43 vs 28%) and cancer (23 vs 14%). Over 8.5 years of follow-up, aware participants compared to those unaware had a lower rate of survival for end-stage (83% and 96%) and mortality (78 vs 81%), p<0.001 respectively. After adjustment for demographics, socioeconomic factors, comorbidity, and severity of kidney disease, aware participants continued to demonstrate an increased risk for end-stage renal disease [hazard ratio (95% CI) 1.37(1.07–1.75); p<0.0123] and mortality [1.27(1.07–1.52); p<0.0077] relative to unaware participants with chronic kidney disease.
Conclusions
Among persons identified as having chronic kidney disease at a health screening, only a small proportion had been made aware of their diagnosis previously by clinicians. This subgroup was at a disproportionately high risk for mortality and end-stage renal disease.
doi:10.1016/j.amjmed.2011.11.026
PMCID: PMC3383388  PMID: 22626510
KEEP; CKD; awareness; ESRD; mortality
22.  The Association between Parathyroid Hormone Levels and Hemoglobin in Diabetic and Nondiabetic Participants in the National Kidney Foundation's Kidney Early Evaluation Program 
Cardiorenal Medicine  2013;3(2):120-127.
Background
Both anemia and secondary hyperparathyroidism are reflections of hormonal failure in chronic kidney disease (CKD). While the association of elevated levels of parathyroid hormone (PTH) and anemia has been studied among those with advanced CKD, less is known about this association in mild-to-moderate CKD.
Methods
In a cross-sectional analysis, the relationship between PTH and hemoglobin levels was investigated in 10,750 participants in the National Kidney Foundation's Kidney Early Evaluation Program with an estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m2.
Results
In the unadjusted analysis, higher PTH levels were associated with lower hemoglobin levels. However, after multivariable adjustment for age, race, gender, smoking status, education, cardiovascular disease, diabetes, hypertension, cancer, albuminuria, BMI, baseline eGFR, calcium, and phosphorus, the direction of association changed. As compared to the first PTH quintile, hemoglobin levels were 0.09 g/dl (95% CI: 0.01-0.18), 0.15 g/dl (95% CI: 0.07-0.24), 0.18 g/dl (95% CI: 0.09-0.26), and 0.13 g/dl (95% CI: 0.07-0.25) higher for the second, third, fourth, and fifth quintiles, respectively. Similarly, each standard deviation increase in natural log transformed PTH was associated with a 0.06 g/dl (95% CI: 0.03-0.09, p = 0.0003) increase in hemoglobin. However, a significant effect modification was seen for diabetes (p = 0.0003). Each standard deviation increase in natural log transformed PTH was associated with a 0.10 g/dl (95% CI: 0.054-0.138, p < 0.0001) increase in hemoglobin, while no association was seen among those without diabetes mellitus.
Conclusion
After multivariable adjustment, there was a small positive association between PTH and hemoglobin among diabetics but not among nondiabetics.
doi:10.1159/000351229
PMCID: PMC3721130  PMID: 23922552
Chronic kidney disease; Anemia; Secondary hyperparathyroidism

23.  Association of Self-Reported Physical Activity with Laboratory Markers of Nutrition and Inflammation: the Comprehensive Dialysis Study 
Objective
Patients on dialysis maintain extremely low levels of physical activity. Prior studies have demonstrated a direct correlation between nutrition and physical activity but provide conflicting data on the link between inflammation and physical activity. Using a cohort of patients new to dialysis from the Comprehensive Dialysis Study (CDS), we examined associations of self-reported physical activity with laboratory markers of nutrition and inflammation.
Design, setting & patients
Between September 2005 and June 2007, CDS collected data on self-reported physical activity, nutrition and health-related quality of life from patients starting dialysis in 296 facilities located throughout the United States. Baseline serum samples were collected from participants in a nutrition sub-study of CDS.
Measures
Serum albumin and prealbumin were measured as markers of nutrition and C-reactive protein and α-1-acid glycoprotein as markers of inflammation. Self-reported physical activity was characterized by the maximal activity score (MAS) and adjusted activity score (AAS) of the Human Activity Profile.
Results
The mean age of participants in the analytic cohort (n=201) was 61 years. The MAS and AAS were below the 10th and first percentile respectively in comparison to healthy 60 year-old norms. Both activity scores were directly correlated with albumin (r2=0.3, p<0.0001) and prealbumin (r2=0.3, p<0.0001), and inversely correlated with C-reactive protein (r2=-0.2, p=0.01 for AAS and r2 = -0.1, p=0.08 for MAS). In multivariable analyses adjusting for age, sex, race/ethnicity, diabetes status and center, both activity scores were directly correlated with prealbumin and inversely correlated with C-reactive protein.
Conclusions
Patients new to dialysis with laboratory-based evidence of malnutrition and/or inflammation are likely to report lower levels of physical activity.
doi:10.1053/j.jrn.2010.09.007
PMCID: PMC3124610  PMID: 21239185
Physical activity; albumin; prealbumin; C-reactive protein; inflammation
24.  Regional Variation in Health Care Intensity and Treatment Practices for End-stage Renal Disease in Older Adults 
Context
An increasing number of older adults are being treated for end-stage renal disease (ESRD) with long-term dialysis.
Objectives
To determine how ESRD treatment practices for older adults vary across regions with differing end-of-life intensity of care.
Design, Setting, and Participants
Retrospective observational study using a national ESRD registry to identify a cohort of 41 420 adults (of white or black race), aged 65 years or older, who started long-term dialysis or received a kidney transplant between June 1, 2005, and May 31, 2006. Regional end-of-life intensity of care was defined using an index from the Dartmouth Atlas of Healthcare.
Main Outcome Measures
Incidence of treated ESRD (dialysis or transplant), preparedness for ESRD (under the care of a nephrologist, having a fistula [vs graft or catheter] at time of hemodialysis initiation), and end-of-life care practices.
Results
Among whites, the incidence of ESRD was progressively higher in regions with greater intensity of care and this trend was most pronounced at older ages. Among blacks, a similar relationship was present only at advanced ages (men aged ≥80 years and women aged ≥85 years). Patients living in regions in the highest compared with lowest quintile of end-of-life intensity of care were less likely to be under the care of a nephrologist before the onset of ESRD (62.3% [95% confidence interval {CI}, 61.3%–63.3%] vs 71.1% [95% CI, 69.9%–72.2%], respectively) and less likely to have a fistula (vs graft or catheter) at the time of hemodialysis initiation (11.2% [95% CI, 10.6%–11.8%] vs 16.9% [95% CI, 15.9%–17.8%]). Among patients who died within 2 years of ESRD onset (n=21 190), those living in regions in the highest compared with lowest quintile of end-of-life intensity of care were less likely to have discontinued dialysis before death (22.2% [95% CI, 21.1%–23.4%] vs 44.3% [95% CI, 42.5%–46.1%], respectively), less likely to have received hospice care (20.7% [95% CI, 19.5%–21.9%] vs 33.5% [95% CI, 31.7%–35.4%]), and more likely to have died in the hospital (67.8% [95% CI, 66.5%–69.1%] vs 50.3% [95% CI, 48.5%–52.1%]). These differences persisted in adjusted analyses.
Conclusion
There are pronounced regional differences in treatment practices for ESRD in older adults that are not explained by differences in patient characteristics.
doi:10.1001/jama.2010.924
PMCID: PMC3477643  PMID: 20628131
25.  Association of Educational Attainment With Chronic Disease and Mortality: The Kidney Early Evaluation Program (KEEP) 
Background
Recent reports have suggested a close relationship between education and health, including mortality, in the United States.
Study Design
Observational cohort
Setting and Participants
We studied 61,457 participants enrolled in a national health screening initiative, the National Kidney Foundation’s Kidney Early Evaluation Program (KEEP).
Predictor
Self-reported educational attainment
Outcomes
Chronic diseases (hypertension, diabetes, cardiovascular disease, reduced kidney function, and albuminuria) and mortality
Measurements
We evaluated the cross-sectional associations between self-reported educational attainment with the chronic diseases listed above using logistic regression models adjusted for demographics, access to care, behaviors, and co-morbidities. The association of educational attainment with survival was determined by multivariable Cox proportional hazards regression.
Results
Higher educational attainment was associated with lower prevalence of each of the chronic conditions listed above. In multivariable models, compared with persons not completing high school, college graduates had a lower risk of each chronic condition, ranging from 11% lower odds of reduced kidney function to 37% lower odds of cardiovascular disease. Over a mean follow-up time of 3.9 years (median, 3.7 years), 2,384 (4%) deaths occurred. In the fully adjusted Cox model, those who had completed college had a 24% lower mortality, compared to participants who had completed at least some high school.
Limitations
A lack of income data does not allow us to disentangle the independent effects of education from income.
Conclusions
In this diverse, contemporary cohort, higher educational attainment was independently associated with lower prevalence of chronic diseases and short-term mortality among all age and race/ethnicity groups.
doi:10.1053/j.ajkd.2011.02.388
PMCID: PMC3144262  PMID: 21601328
education; mortality; chronic kidney disease

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