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1.  Erythropoiesis-stimulating agents increase the risk of acute stroke in patients with chronic kidney disease 
Kidney international  2011;80(3):10.1038/ki.2011.49.
Erythropoiesis-stimulating agents (ESAs) are effective in ameliorating anemia in chronic kidney disease (CKD). However, a recent trial in diabetic CKD patients suggested a greater stroke risk associated with full correction of anemia using ESAs.
We performed a case-control study examining the association of incident ESA use with acute stroke in CKD patients, using national Veterans Affairs data. Patients with eGFR<60 cc/min/1.73m2 and outpatient hemoglobin (Hb)<12g/dL were included. Acute hospitalized stroke cases (N=2071) were identified using diagnosis codes and matched 1:5 to controls without stroke. Conditional logistic regression was used to estimate the association of ESA use with stroke, adjusting for potential confounders.
After multivariate adjustment, ESA use (N=1026, 8.3%) was associated with 30% greater odds of stroke (odds ratio[OR]=1.30, 95% confidence interval[CI]: 1.06, 1.58). There was significant interaction (p=.015) between ESA use and cancer; ESA use was associated with 85% greater odds of stroke in cancer patients (95% CI: 1.26, 2.65), but not associated with stroke in patients without cancer (OR=1.07, 95% CI: 0.85, 1.35). ESA-treated patients with cancer received a median initial dose 2.5 to 4 times greater than ESA patients without cancer, but pre-ESA Hb and rate of Hb change did not differ between groups.
Among a large national sample of anemic CKD patients, ESA treatment is associated with an increased risk of acute stroke, with the greatest effect among patients with cancer.
doi:10.1038/ki.2011.49
PMCID: PMC3882072  PMID: 21389972
2.  Retinopathy and Chronic Kidney Disease in the Chronic Renal Insufficiency Cohort Study (CRIC) 
Archives of ophthalmology  2012;130(9):1136-1144.
Objectives
Retinal vascular and anatomic abnormalities caused by diabetes, hypertension, and other conditions can be observed directly in the ocular fundus and may reflect severity of chronic renal insufficiency. The purpose of this study was to investigate the association between retinopathy and chronic kidney disease (CKD).
Methods
In this observational, cross-sectional study, 2605 participants of the Chronic Renal Insufficiency Cohort (CRIC) study, a multi-center study of CKD, were offered participation. Non-mydriatic fundus photographs of the disc and macula in both eyes were obtained in 1936 of these subjects.
Photographs were reviewed in a masked fashion at a central photograph reading center using standard protocols. Presence and severity of retinopathy (diabetic, hypertensive or other) and vessel diameter caliber were assessed by trained graders and a retinal specialist using protocols developed for large epidemiologic studies. Kidney function measurements and information on traditional and non-traditional risk factors for decreased kidney function were obtained from the CRIC study.
Results
Greater severity of retinopathy was associated with lower estimated glomerular filtration rate (eGFR) after adjustment for traditional and non-traditional risk factors. Presence of vascular abnormalities usually associated with hypertension was also associated with lower eGFR. We found no strong direct relationship between eGFR and average arteriolar or venular calibers.
Conclusions
Our findings show a strong association between severity of retinopathy and its features and level of kidney function after adjustment for traditional and non-traditional risk factors for CKD, suggesting that retinovascular pathology reflects renal disease.
doi:10.1001/archophthalmol.2012.1800
PMCID: PMC3719171  PMID: 22965589
Retinopathy; Retinal Vascular Diameter; Chronic Kidney Disease
3.  Chronic kidney disease as an under-recognized threat to patient safety 
Chronic kidney disease (CKD) is common, but under-recognized, among patients in the health care system, where improving patient safety is a high priority. Poor disease recognition and several other features of CKD make it a high risk condition for adverse safety events. In this review, we will discuss the unique attributes of CKD, which make it a high risk condition for patient safety mishaps. We will point out that adverse safety events in this disease have the potential to contribute to disease progression; namely, accelerated loss of kidney function and an increased incidence of end-stage renal disease (ESRD). We will also propose a framework in which to consider patient safety in CKD, highlighting the need for disease-specific safety indicators that reflect unsafe practices in this disease. Finally, we will discuss the hypothesis that increased recognition of CKD will reduce disease-specific safety events, and in this way decrease the likelihood of adverse outcomes including an accelerated rate of kidney function loss and an increased incidence of ESRD.
doi:10.1053/j.ajkd.2008.12.016
PMCID: PMC3710448  PMID: 19246142
patient safety; chronic kidney disease; disease recognition; medical errors
4.  The influence of creatinine versus GFR on NSAID prescriptions in CKD 
American journal of nephrology  2012;36(1):19-26.
Background
Non-steroidal anti-inflammatory drugs (NSAIDs), including cyclo-oxygenase-2 (COX-2) inhibitors, are generally contraindicated in chronic kidney disease (CKD). This investigation sought to identify the frequency of NSAID/COX2 prescription and determine the influence of serum Cr versus estimated GFR on this practice pattern.
Methods
An established Veterans Health Administration (VHA) CKD safety cohort (n = 70,154) was examined to determine the frequency of NSAID/COX2 in fiscal year 2005 (FY05) for up to 30 days preceding the index hospitalization and as many as 365 days during that year. Binomial regression was used to determine adjusted prevalence ratios for prescription of NSAID/COX2 with respect to continuous eGFR measurement and serum creatinine (Cr) categories. CKD was defined as eGFR < 60 ml/min/1.73m2.
Results
15.4% of subjects had an NSAID/COX2 prescription during the observation period with the proportion prescribed these agents decreasing with declining renal function, but remained significant at any stage of CKD given the renal harm related to these medications. At specific GFR estimates, serum creatinine (Cr) remained a significant predictor of NSAID/COX prescription. At GFR set at 42 ml/min/1.73, the predicted proportion prescribed NSAID/COX2 was 0.29 (95% CI: 0.24,0.36); 0.23 (95% CI: 0.22,0.26); 0.20 (95%: 0.19,0,22); 0.12 (95% CI: 0.10,0.14) for Cr strata of ≤ 1.3 mg/dl, 1.4 – 1.6 mg/dl, 1.7 –2.1 mg/dl, ≥ 2.2 mg/dl, respectively (all p < 0.05).
Conclusion
A significant proportion of individuals with CKD continue to be prescribed NSAID/COX2 and serum Cr remains an influential guide to NSAID/COX2 prescription, even in GFR ranges where these agents are ill-advised.
doi:10.1159/000339439
PMCID: PMC3417055  PMID: 22699456
chronic kidney disease; safety; recognition; NSAIDs
5.  The frequency of hyperkalemia and its significance in chronic kidney disease 
Archives of internal medicine  2009;169(12):1156-1162.
Background
Hyperkalemia is a potential threat to patient safety in chronic kidney disease (CKD). This study determined the incidence of hyperkalemia in CKD and whether it is associated with excess mortality.
Methods
This retrospective analysis of a national cohort comprised of 2,103,422 records from 245,808 veterans with at least one hospitalization and at least one inpatient or outpatient serum potassium record during fiscal year 2005. CKD and treatment with ACE-I and/or ARBs (RAAS blockers) were the key predictors of hyperkalemia. Death within one day of a hyperkalemic event was the principal outcome.
Results
Of the 66,529 hyperkalemic events (3.2% of records), more occurred inpatient (34937 (52.7%)) versus outpatient (31322 (47.3%)). The adjusted rate of hyperkalemia was higher in patients with CKD than without CKD among individuals treated with RAAS blockers (7.67 vs. 2.30 per 100 patient months, p<0.0001) and those without RAAS blocker treatment (8.22 vs. 1.77 per 100 patient months, p<0.0001). The adjusted odds (OR) of death with a moderate (K+≥ 5.5 and < 6.0mg/dl) and severe (K+≥ 6.0 mg/dl) hyperkalemic event was highest with no CKD (OR: 10.32, 31.64, respectively), versus Stage 3 (5.35, 19.52), Stage 4 (OR: 5.73, 11.56), or Stage 5 CKD (OR: 2.31, 8.02) with all p<0.0001 versus normokalemia and no CKD.
Conclusion
The risk of hyperkalemia is increased with CKD, and its occurrence increases the odds of mortality within one day of the event. These findings underscore the importance of this metabolic disturbance as a threat to patient safety in CKD.
doi:10.1001/archinternmed.2009.132
PMCID: PMC3544306  PMID: 19546417
chronic kidney disease; hyperkalemia; patient safety
6.  Metabolic Syndrome, Components, and Cardiovascular Disease Prevalence in Chronic Kidney Disease: Findings from the Chronic Renal Insufficiency Cohort (CRIC) Study 
American Journal of Nephrology  2011;33(6):477-484.
Background/Aims
Metabolic syndrome may increase the risk for incident cardiovascular disease (CVD) and all-cause mortality in the general population. It is unclear whether, and to what degree, metabolic syndrome is associated with CVD in chronic kidney disease (CKD). We determined metabolic syndrome prevalence among individuals with a broad spectrum of kidney dysfunction, examining the role of the individual elements of metabolic syndrome and their relationship to prevalent CVD.
Methods
We evaluated four models to compare metabolic syndrome or its components to predict prevalent CVD using prevalence ratios in the Chronic Renal Insufficiency Cohort (CRIC) Study.
Results
Among 3,939 CKD participants, the prevalence of metabolic syndrome was 65% and there was a significant association with prevalent CVD. Metabolic syndrome was more common in diabetics (87.5%) compared with non-diabetics (44.3%). Hypertension was the most prevalent component, and increased triglycerides the least prevalent. Using the bayesian information criterion, we found that the factors defining metabolic syndrome, considered as a single interval-scaled variable, was the best of four models of metabolic syndrome, both for CKD participants overall and for diabetics and non-diabetics separately.
Conclusion
The predictive value of this model for future CVD outcomes will subsequently be validated in longitudinal analyses.
doi:10.1159/000327618
PMCID: PMC3095834  PMID: 21525746
Cardiovascular disease; Chronic kidney disease; Chronic Renal Insufficiency Cohort (CRIC) Study; Metabolic syndrome
7.  Endogenous Secretory Receptor for Advanced Glycation End Products and Chronic Kidney Disease in the Elderly Population 
American Journal of Nephrology  2011;33(4):313-318.
Background/Aims
The relationship of circulating endogenous secretory receptor for advanced glycation end products (esRAGE) and chronic kidney disease (CKD) has not been well characterized. The aim of the study was to determine whether plasma esRAGE is associated with CKD and is predictive of developing CKD in older adults.
Methods
The relationship between plasma esRAGE and CKD (more than stage 3 of the National Kidney Foundation classification; estimated glomerular filtration rate <60 ml/min/1.73 m2) and CKD over 6 years of follow-up was examined in a cross-sectional and prospective study design in 1,016 men and women, ≥65 years, in the InCHIANTI study, a population-based cohort study of aging in Tuscany, Italy.
Results
At enrollment, 158 (15.5%) had CKD. Mean (SD) plasma esRAGE was 0.45 (0.24) ng/ml. Plasma esRAGE (ng/ml) was associated with CKD (odds ratio per 1 SD = 1.30; 95% CI 1.1–1.6; p < 0.005) in a multivariable logistic regression model, adjusting for potential confounders. Plasma esRAGE was an independent predictor of incident CKD over 6 years of follow-up (hazard ratio per 1 SD = 1.37; 95% CI 1.1–1.7; p < 0.008) in a multivariable Cox proportional hazards model, adjusting for potential confounders.
Conclusions
Elevated plasma esRAGE is independently associated with CKD and is an independent predictor of incident CKD in older community-dwelling adults.
doi:10.1159/000324846
PMCID: PMC3064940  PMID: 21389696
Advanced glycation end products; Aging; Chronic kidney disease; Endogenous secretory receptor for advanced glycation end products
8.  Pre-Clinical Myocardial Metabolic Alterations in Chronic Kidney Disease 
Cardiology  2010;116(3):160-167.
The risk for cardiovascular events conferred by decreased renal function is curvilinear with exponentially greater increases in risk as estimated glomerular filtration rate (eGFR) declines. In 13 non-diabetic pre-dialysis chronic kidney disease (CKD) patients, we employed quantitative F-18 fluorodeoxyglucose (FDG) positron emission tomography (PET) as a means to measure myocardial metabolic changes.
Methods
Dynamic cardiac FDG PET images were acquired after 6 h fasting and glucose loading. Corrections for attenuation, scatter, randoms, dead time and decay were applied to the PET data and myocardial glucose utilization (MGU) was calculated using the Patlak method in conjunction with standardized myocardial regions of interest and an image-derived input function (left atrium). MGU was compared with eGFR based on a serum creatinine drawn within 2 weeks of the study date.
Results
MGU was relatively uniform between the myocardial sectors (coefficient of variation = 16.2 ± 6.8%) within each patient. Between patients, whole myocardium MGU varied considerably with a range of 37.3–156.2 μmol/min/100 g and a mean of 68.9 ± 38.3 μmol/min/ 100 g. eGFR ranged from 11–89 ml/min/1.73 m2 with a mean of 42.8 ± 26.9 ml/min/1.73 m2. There was an inverse correlation between whole myocardium MGU and eGFR (Spearman's rho correlation = −0.615, p = 0.025). In multivariate analysis, the relationship between MGU and eGFR was sustained with adjustment for age, race and gender (adjusted β = −1.56 ± 0.48, p = 0.01). There was no correlation between cardiac workload and eGFR (p = NS).
Conclusions
A significant inverse correlation between MGU and eGFR is supportive of the hypothesis that CKD is associated with myocardial metabolic changes, which could not be attributed to demographic factors or cardiac workload. Dynamic FDG PET could provide a sensitive, non-invasive, quantitative tool for investigating pre-clinical myocardial abnormalities in patients with CKD.
doi:10.1159/000318227
PMCID: PMC3202933  PMID: 20606430
Chronic kidney disease; Fluorodeoxyglucose; Glomerular filtration rate; Myocardial metabolism; Positron emission tomography; Uremic cardiomyopathy
9.  Serum Carboxymethyl-lysine, a Dominant Advanced Glycation End Product, is Associated with Chronic Kidney Disease: the Baltimore Longitudinal Study of Aging 
Objective:
Advanced glycation end products (AGEs) are modifiable risk factors for renal disease that have been primarily studied in persons with diabetes or end-stage renal disease. The objective was to characterize the relationship between AGEs and renal function in community-dwelling adults.
Design:
Serum L-carboxymethyl-lysine (CML), a dominant AGE, was compared with renal function in a cross-sectional analysis.
Setting:
The Baltimore Longitudinal Study of Aging (BLSA) in Baltimore, Maryland.
Patients or Other Participants:
Community-dwelling men and women, aged 26-93 years, seen in a regular BLSA follow-up visit between 2002 and 2007.
Main outcome measure:
Chronic kidney disease (CKD), ≥stage 3 of National Kidney Foundation classification (estimated glomerular filtration rate [eGFR] <60 mL/min/1.73 m2), and eGFR.
Results:
Of 750 adults, 121 (16.1%) had CKD. Serum CML was associated with CKD (Odds Ratio [O.R.] expressed per 1 Standard Deviation [S.D.], 1.37, 95% Confidence Interval [C.I.] 1.11-1.67, P = 0.003) in a multivariate logistic regression model adjusting for age, race, smoking, and chronic diseases. Serum CML was associated with eGFR (mL/min/1.73 m2) (beta = −2.21, standard error = 0.57, P = 0.0001) in multivariate linear regression model adjusting for age, race, smoking, and chronic diseases. After excluding patients with diabetes, serum CML was associated with CKD (O.R. per 1 S.D., 1.38, 95% C.I. 1.12-1.70, P = 0.003) and eGFR (beta = −2.09, standard error = 0.59, P = 0.0005), adjusting for the same covariates.
Conclusion:
Serum CML, a dominant AGE, is independently associated with CKD and eGFR.
doi:10.1053/j.jrn.2009.08.001
PMCID: PMC2829356  PMID: 19853477
advanced glycation end products; aging; chronic kidney disease; glomerular filtration rate
10.  Carboxymethyl-lysine, an advanced glycation end product, and decline of renal function in older community-dwelling adults 
European journal of nutrition  2008;48(1):38-44.
Background
Advanced glycation end products (AGEs) are bioactive molecules found in greater concentrations in foods that have been processed at high temperatures. AGEs have been associated with impaired renal function in diabetes and in uremia. The relationship between AGEs and renal function in community-dwelling adults has not been well characterized.
Aim of the Study
The objective was to determine whether plasma AGEs are independently associated with chronic kidney disease (CKD) and predictive of renal function in older adults.
Methods
The relationship between plasma carboxymethyl-lysine (CML), an AGE, and CKD (≥stage 3 of National Kidney Foundation classification; estimated glomerular filtration rate [eGFR] <60 mL/min/1.73 m2) and eGFR at 3- and 6-years follow-up was examined in a population-based study of aging, the InCHIANTI study, in Tuscany, Italy.
Results
Of 1,008 adults, aged ≥65 years, 153 (15.2%) had CKD at enrollment. Mean (Standard Deviation [S.D.]) plasma CML was 365 (110) ng/mL. Plasma CML was associated with CKD (Odds Ratio [O.R.] expressed per 1 S.D., 1.53, 95% Confidence Interval [C.I.] 1.27-1.84, P <0.0001) in a multivariate logistic regression model, adjusting for potential confounders. Plasma CML was associated with eGFR (beta = -2.77, standard error [S.E.] = 0.51, P <0.0001) at baseline, 3-year (beta = -2.54, S.E. = 0.61, P <0.0001) and 6-year follow-up visits (beta = -1.21, S.E. = 0.70, P = 0.08) in multivariate linear regression models, adjusting for potential confounders. The associations between plasma CML and prevalent CKD, eGFR, and eGFR at 3- and 6-year follow-up were significant and nearly unchanged after exclusion of adults with diabetes.
Conclusion
Plasma CML is independently associated with CKD and is an independent predictor of decline in renal function in older community-dwelling adults.
doi:10.1007/s00394-008-0757-0
PMCID: PMC2637810  PMID: 19031098
advanced glycation end products; aging; carboxymethyl-lysine; chronic kidney disease; renal function
11.  Advanced Glycation End Products and Their Circulating Receptors and Level of Kidney Function in Older Community-Dwelling Women 
Background
Advanced glycation end products (AGEs) and the receptor for AGE (RAGE) are implicated in the pathogenesis of renal disease but their relation with level of kidney function has not been well characterized.
Study Design
Cross-sectional and prospective.
Setting and Participants
548 moderately to severely disabled community-dwelling women in the Women's Health and Aging Study I in Baltimore, Maryland.
Predictor
Serum L-carboxymethyl-lysine (CML), a dominant AGE, total RAGE (sRAGE), and endogenous secretory RAGE (esRAGE).
Outcomes & Measurements
Glomerular filtration rate (GFR), prevalent and incident reduced GFR (GFR <60 mL/min/1.73 m2). Serum CML, sRAGE, and esRAGE.
Results
Of 548 women, 283 (51.6%) had reduced GFR at baseline. Serum CML was associated with reduced GFR (Odds Ratios [O.R.; all expressed per 1 Standard Deviation], 1.98, 95% Confidence Interval [C.I.] 1.41-2.76, P <0.001) in a multivariate logistic regression model adjusting for age, race, hemoglobin A1c, and chronic diseases. Serum sRAGE (ng/mL) and esRAGE (ng/mL), respectively, were associated with reduced GFR (O.R. 1.42, 95% C.I. 1.12-1.79, P = 0.003; O.R. 1.42, 95% C.I. 1.14-1.77, P = 0.001) in separate multivariate logistic regression models, adjusting for potential confounders. Of 230 women without reduced GFR at baseline, 32 (13.9%) developed reduced GFR by the follow-up visit 12 months later. Serum CML (μg/mL), sRAGE (ng/mL), and esRAGE (ng/mL), respectively, at baseline was associated with the prevalence of reduced GFR 12 months later (O.R. 1.80, 95% C.I. 1.19-2.71, P = 0.005; O.R. 1.32, 95% C.I. 1.01-1.74, P = 0.05; O.R. 1.33, 95% C.I. 1.01-1.77, P = 0.05) in separate multivariate logistic regression models adjusting for potential confounders.
Limitations
Small number of incident cases, limited follow-up interval, creatinine not standardized.
Conclusions
AGEs and circulating RAGE are independently associated with reduced GFR and seem to predict reduced GFR. AGEs are amenable to interventions, as serum AGEs can be lowered by change in dietary pattern and pharmacological treatment.
doi:10.1053/j.ajkd.2008.06.018
PMCID: PMC2637807  PMID: 18789567
advanced glycation end products; reduced glomerular filtration rate
12.  Renal Function and Cardiovascular Response to Mental Stress 
American Journal of Nephrology  2007;28(2):304-310.
Background/Aims
Cardiovascular reactivity (CVR), defined as an exaggerated hemodynamic response to mental stress, is a putative vascular risk factor and may reflect sympathetic hyperactivity. Chronic kidney disease (CKD) is also associated with sympathetic hyperactivity and vascular risk, but its relationship with CVR is unknown.
Methods
CVR was assessed in 107 individuals without overt cardiovascular disease or diabetes. Blood pressure and heart rate responses were elicited by three experimental tasks designed to evoke mental stress. Glomerular filtration rate (eGFR) was estimated using the MDRD formula. General linear models estimated the association between renal function and CVR, adjusting for potential confounders.
Results
Mean age was 66 years and 11% had eGFR of <60 ml/min/1.73 m2. After multivariate adjustment, a low eGFR was associated with a greater stress response of systolic blood pressure, heart rate, and pulse pressure. Associations were only partially attenuated after adjustment for lipids and glucose tolerance. When considered as a continuous variable, lower eGFR was associated with a greater blood pressure response after adjustment for glycemia.
Conclusion
Although there were relatively few participants with CKD, these results suggest a relationship between CKD and greater CVR. Further investigation is warranted into factors that mediate this relationship and potential clinical consequences of this exaggerated response to stress in CKD.
doi:10.1159/000111386
PMCID: PMC2785907  PMID: 18025779
Renal function; Cardiovascular reactivity; Blood pressure
13.  Directed Use of the Internet for Health Information by Patients With Chronic Kidney Disease: Prospective Cohort Study 
Background
Health information technology has become common in the care of patients with chronic diseases; however, there are few such applications employed in kidney disease.
Objective
The aim of the study was to evaluate the use of a website providing disease-specific safety information by patients with predialysis chronic kidney disease.
Methods
As part of the Safe Kidney Care (SKC) study, an educational website was designed to provide information on safety concerns in chronic kidney disease. Phase I study participants were provided a medical alert accessory with a unique ID number, the Safe Kidney Care website, and an in-person tutorial on the use of the Internet and accessing the SKC website at baseline. Participants were asked to visit the website and enter their unique ID as frequently as they desired over the next 365 days or until their annual follow-up visit, whichever occurred first. Participants’ visits and dwell times on specific safety modules were tracked using embedded webpage PHP scripts linked to a MySQL database, enabling the collection of website usage statistics.
Results
Of 108 Phase I participants, 28.7% (31/108) visited the website from 1-6 times during the observation period (median follow-up 365 days). Median access time was 7 minutes per visit (range <1-46) and 13 minutes per person (range <1-123). The three most frequently visited pages were “Renal function calculator”, “Pills to avoid”, and “Foods to avoid”. High school education and frequent Internet use were significantly associated with website entry (P=.02 and P=.03, respectively).
Conclusions
Preliminary results show general interest in a Web-based platform designed to improve patient safety in chronic kidney disease.
Trial Registration
Clinicaltrials.gov NCT01407367; http://clinicaltrials.gov/show/NCT01407367 (Archived by WebCite at http://www.webcitation.org/6KvxFKA6M).
doi:10.2196/jmir.2848
PMCID: PMC3841367  PMID: 24240617
chronic kidney disease; health information technology; patient safety

Results 1-13 (13)