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author:("jar, Bernard")
1.  Effectiveness of Educational and Social Worker Interventions to Activate Patients’ Discussion and Pursuit of Preemptive Living Donor Kidney Transplantation: A Randomized Controlled Trial 
Many patients with chronic kidney disease (CKD) have difficulties becoming actively engaged in the pursuit of pre-emptive living donor kidney transplantation.
Study Design
The Talking About Live Kidney Donation (TALK) study was a randomized controlled trial of the effectiveness of educational and social worker interventions designed to encourage early discussions and active pursuit of pre-emptive LKT among patients with progressive CKD.
Setting & Participants
We recruited participants with progressive CKD from academically affiliated nephrology practices in Baltimore, Maryland.
Participants randomly received 1) “Usual Care” (routine care with their nephrologists), 2) “TALK Education” intervention (video and booklet), or the 3) “TALK Social Worker” intervention (video and booklet plus patient and family social worker visits).
We followed participants for 6 months to assess their self-reported achievement of behaviors reflecting their discussions about LKT and/or pursuit of LKT (discussions with family; discussions with physicians; initiating recipient evaluation; completing recipient evaluation; identifying a potential living donor).
We assessed outcomes via questionnaire at 1, 3, and 6-month follow up.
Participants receiving Usual Care with their nephrologists (n=44), TALK Education (n=43), and the TALK Social Worker (n=43) were similar at baseline. TALK Study interventions improved participants’ LKT discussion and pursuit behaviors, with the Social Worker leading to greater patient activation (participants’ predicted probability (95% confidence interval) of achieving LKT discussions, evaluations, or donor identification over 6 months in Usual Care, TALK Education, and TALK Social Worker groups: 30% (20%–46%), 42% (33% –54%), and 58% (41% –83%), respectively (p=0.03).
Our population was well educated and mostly insured, potentially limiting generalizability of our findings.
TALK interventions improved discussion and active pursuit of LKT among patients with progressive CKD and may improve their utilization of pre-emptive LKT.
PMCID: PMC3710736  PMID: 23089512
2.  African American and Non-African American Patients’ and Families’ Decision Making About Renal Replacement Therapies 
Qualitative health research  2012;22(7):997-1006.
We conducted focus group meetings of African American and non-African American patients with end-stage renal disease (six groups) and their family members (six groups), stratified by race/ethnicity and treatment. We elicited differences in participants’ experiences with shared decision making about initiating renal replacement therapy (RRT; that is, hemodialysis, peritoneal dialysis, or a kidney transplant). Patients were often very sick when initiating RRT, and had little, if any, time to make a decision about what type of RRT to initiate. They also lacked sufficient information about alternative treatment options prior to initiation. Family members played supportive roles and shared in decision making when possible. Reports were similar for African American and non-African American participants. Our findings suggest that a greater emphasis on the improved engagement of patients and their families in shared decision making about RRT initiation is needed for both ethnic/racial minorities and nonminorities.
PMCID: PMC3927418  PMID: 22645225
African Americans; communication; medical; decision making; illness and disease; chronic; illness and disease; experiences; minorities; nephrology
3.  Trends in anemia management in US hemodialysis patients 2004–2010 
BMC Nephrology  2013;14:264.
There have been major changes in the management of anemia in US hemodialysis patients in recent years. We sought to determine the influence of clinical trial results, safety regulations, and changes in reimbursement policy on practice.
We examined indicators of anemia management among incident and prevalent hemodialysis patients from a medium-sized dialysis provider over three time periods: (1) 2004 to 2006 (2) 2007 to 2009, and (3) 2010. Trends across the three time periods were compared using generalized estimating equations.
Prior to 2007, the median proportion of patients with monthly hemoglobin >12 g/dL for patients on dialysis 0 to 3, 4 to 6 and 7 to 18 months, respectively, was 42%, 55% and 46% declined to 41%, 54%, and 40% after 2007, and declined more sharply in 2010 to 34%, 41%, and 30%. Median weekly Epoeitin alpha doses over the same periods were 18,000, 12,400, and 9,100 units before 2007; remained relatively unchanged from 2007 to 2009; and decreased sharply in the patients 3–6 and 6–18 months on dialysis to 10,200 and 7,800 units, respectively in 2010. Iron doses, serum ferritin, and transferrin saturation levels increased over time with more pronounced increases in 2010.
Modest changes in anemia management occurred between 2007 and 2009, followed by more dramatic changes in 2010. Studies are needed to examine the effects of declining erythropoietin use and hemoglobin levels and increasing intravenous iron use on quality of life, transplantation rates, infection rates and survival.
PMCID: PMC3866613  PMID: 24289058
Anemia; Erythropoietin stimulating agents; Hemodialysis
4.  Patterns in blood pressure medication use in US incident dialysis patients over the first 6 months 
BMC Nephrology  2013;14:249.
Several observational studies have evaluated the effect of a single exposure window with blood pressure (BP) medications on outcomes in incident dialysis patients, but whether BP medication prescription patterns remain stable or a single exposure window design is adequate to evaluate effect on outcomes is unclear.
We described patterns of BP medication prescription over 6 months after dialysis initiation in hemodialysis and peritoneal dialysis patients, stratified by cardiovascular comorbidity, diabetes, and other patient characteristics. The cohort included 13,072 adult patients (12,159 hemodialysis, 913 peritoneal dialysis) who initiated dialysis in Dialysis Clinic, Inc., facilities January 1, 2003-June 30, 2008, and remained on the original modality for at least 6 months. We evaluated monthly patterns in BP medication prescription over 6 months and at 12 and 24 months after initiation.
Prescription patterns varied by dialysis modality over the first 6 months; substantial proportions of patients with prescriptions for beta-blockers, renin angiotensin system agents, and dihydropyridine calcium channel blockers in month 6 no longer had prescriptions for these medications by month 24. Prescription of specific medication classes varied by comorbidity, race/ethnicity, and age, but little by sex. The mean number of medications was 2.5 at month 6 in hemodialysis and peritoneal dialysis cohorts.
This study evaluates BP medication patterns in both hemodialysis and peritoneal dialysis patients over the first 6 months of dialysis. Our findings highlight the challenges of assessing comparative effectiveness of a single BP medication class in dialysis patients. Longitudinal designs should be used to account for changes in BP medication management over time, and designs that incorporate common combinations should be considered.
PMCID: PMC3840675  PMID: 24219348
Blood pressure medication; Dialysis; Medication use patterns
5.  Frailty and falls among adult patients undergoing chronic hemodialysis: a prospective cohort study 
BMC Nephrology  2013;14:224.
Patients undergoing hemodialysis are at high risk of falls, with subsequent complications including fractures, loss of independence, hospitalization, and institutionalization. Factors associated with falls are poorly understood in this population. We hypothesized that insights derived from studies of the elderly might apply to adults of all ages undergoing hemodialysis; we focused on frailty, a phenotype of physiological decline strongly associated with falls in the elderly.
In this prospective, longitudinal study of 95 patients undergoing hemodialysis (1/2009-3/2010), the association of frailty with future falls was explored using adjusted Poisson regression. Frailty was classified using the criteria established by Fried et al., as a combination of five components: shrinking, weakness, exhaustion, low activity, and slowed walking speed.
Over a median 6.7-month period of longitudinal follow-up, 28.3% of study participants (25.9% of those under 65, 29.3% of those 65 and older) experienced a fall. After adjusting for age, sex, race, comorbidity, disability, number of medications, marital status, and education, frailty independently predicted a 3.09-fold (95% CI: 1.38-6.90, P=0.006) higher number of falls. This relationship between frailty and falls did not differ for younger and older adults (P=0.57).
Frailty, a validated construct in the elderly, was a strong and independent predictor of falls in adults undergoing hemodialysis, regardless of age. Our results may aid in identifying frail hemodialysis patients who could be targeted for multidimensional fall prevention strategies.
PMCID: PMC3852906  PMID: 24131569
Hemodialysis; Falls; Frailty
6.  Associations of Multiple Metals with Kidney Outcomes in Lead Workers 
Environmental exposure to multiple metals is common. A number of metals cause nephrotoxicity with acute and/or chronic exposure. However, few epidemiologic studies have examined the impact of metal co-exposure on kidney function. Therefore, we evaluated associations of antimony and thallium with kidney outcomes and assessed the impact of cadmium exposure on those associations in lead workers.
Multiple linear regression was used to examine associations between ln-urine thallium, antimony and cadmium levels with serum creatinine- and cystatin-C-based glomerular filtration measures, and ln-urine N-acetyl-β-D-glucosaminidase (NAG).
In 684 participants, median urine thallium and antimony were 0.39 and 0.36 μg/g creatinine, respectively. After adjustment for lead dose, urine creatinine, and kidney risk factors, higher ln-urine thallium was associated with higher serum creatinine- and cystatin-C-based estimates of glomerular filtration rate (eGFR); associations remained significant after adjustment for antimony and cadmium (regression coefficient for serum creatinine-based eGFR = 5.2 mL/min/1.73 m2; 95% confidence interval = 2.4, 8.0). Antimony associations with kidney outcomes were attenuated by thallium and cadmium adjustment; thallium and antimony associations with NAG were attenuated by cadmium.
Urine thallium levels were significantly associated with both serum creatinine- and cystatin-C-based glomerular filtration measures in a direction opposite that expected with nephrotoxicity. Given similarities to associations recently observed with cadmium, these results suggest that interpretation of urine metal values, at exposure levels currently present in the environment, may be more complex than previously appreciated. These results also support multiple metal analysis approaches to decrease the potential for inaccurate risk conclusions.
PMCID: PMC3542392  PMID: 22843435
antimony; cadmium; creatinine; kidney function; thallium
7.  U.S. Centers for Disease Control and Prevention launches new chronic kidney disease surveillance system website 
BMC Nephrology  2013;14:196.
The burden of chronic kidney disease (CKD) is substantial and is associated with poor health outcomes including increase hospitalizations and premature deaths, as well as considerable health care cost. In recognition of this mounting public health problem, the U.S. Centers for Disease Control and Prevention and their collaborators created a national CKD surveillance system. This commentary introduces the national CKD surveillance system and discusses some of its potential uses.
PMCID: PMC3847207  PMID: 24034342
Chronic kidney disease; Centers for Disease Control and Prevention; Epidemiology; Surveillance; Website
8.  Estimating GFR Among Participants in the Chronic Renal Insufficiency Cohort (CRIC) Study 
Glomerular filtration rate (GFR) is considered the best measure of kidney function, but repeated assessment is not feasible in most research studies.
Study Design
Cross-sectional study of 1,433 participants from the Chronic Renal Insufficiency Cohort (CRIC) Study (i.e., the GFR subcohort) to derive an internal GFR estimating equation using a split sample approach.
Setting & Participants
Adults from 7 US metropolitan areas with mild to moderate chronic kidney disease; 48% had diabetes and 37% were black.
Index Test
CRIC GFR estimating equation
Reference Test or Outcome
Urinary 125I-iothalamate clearance testing (measured GFR)
Other Measurements
Laboratory measures including serum creatinine and cystatin C, and anthropometrics
In the validation dataset, the model that included serum creatinine, serum cystatin C, age, gender, and race was the most parsimonious and similarly predictive of mGFR compared to a model additionally including bioelectrical impedance analysis phase angle, CRIC clinical center, and 24-hour urinary creatinine excretion. Specifically, the root mean square errors for the separate model were 0.207 vs. 0.202, respectively. The performance of the CRIC GFR estimating equation was most accurate among the subgroups of younger participants, men, non-blacks, non-Hispanics, those without diabetes, those with body mass index <30 kg/m2, those with higher 24-hour urine creatinine excretion, those with lower levels of high-sensitivity C-reactive protein, and those with higher mGFR.
Urinary clearance of 125I-iothalamate is an imperfect measure of true GFR; cystatin C is not standardized to certified reference material; lack of external validation; small sample sizes limit analyses of subgroup-specific predictors.
The CRIC GFR estimating equation predicts measured GFR accurately in the CRIC cohort using serum creatinine and cystatin C, age, gender, and race. Its performance was best among younger and healthier participants.
PMCID: PMC3565578  PMID: 22658574
glomerular filtration rate (GFR); kidney function; GFR estimation
9.  Retinopathy and Chronic Kidney Disease in the Chronic Renal Insufficiency Cohort Study (CRIC) 
Archives of ophthalmology  2012;130(9):1136-1144.
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).
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.
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.
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.
PMCID: PMC3719171  PMID: 22965589
Retinopathy; Retinal Vascular Diameter; Chronic Kidney Disease
10.  Access to Health Care Among Adults Evaluated for CKD: Findings From the Kidney Early Evaluation Program (KEEP) 
Data are scant regarding access to health care in patients with chronic kidney disease (CKD). We performed descriptive analyses using data from the National Kidney Foundation’s Kidney Early Evaluation Program (KEEP), a nationwide health screening program for adults at high risk of CKD.
From 2000–2010, a total of 122,502 adults without end-stage renal disease completed KEEP screenings; 27,927 (22.8%) met criteria for CKD (10,082, stages 1–2; 16,684, stage 3; and 1,161, stages 4–5). CKD awareness, self-rated health status, frequency of physician visits, difficulty obtaining medical care, types of caregivers, insurance status, and medication coverage and estimated costs were assessed.
Participants with CKD were more likely to report fair/poor health status than those without CKD. Health care utilization increased at later CKD stages; ~95% of participants at stages 3–5 had visited a physician during the preceding year compared with 83.7% of participants without CKD. More Hispanic and African American than white participants at all CKD stages reported not having a physician. Approximately 40% of participants younger than 65 years reported fair/poor health status at stages 4–5 compared with ~30% who were 65 years and older. Younger participants at all stages were more likely to report extreme or somewhat/moderate difficulty obtaining medical care. Comorbid conditions (diabetes, hypertension, and prior cardiovascular events) were associated with increased utilization of care. Utilization of nephrology care was poor at all CKD stages; <6% of participants at stage 3 and <30% at stages 4–5 reported ever seeing a nephrologist.
Lack of health insurance and perceived difficulty obtaining medical care with lower health care utilization, both of which are consistent with inadequate access to health care, are more likely for KEEP participants who are younger than 65 years, nonwhite, and without previously diagnosed comorbid conditions. Nephrology care is infrequent in elderly participants with advanced CKD who are nonwhite, have comorbid disease, and have high-risk states for cardiovascular disease.
PMCID: PMC3694584  PMID: 22339901
Chronic kidney disease; health care access; health insurance; medication payment; socioeconomic status; educational status
11.  Selecting renal replacement therapies: what do African American and non-African American patients and their families think others should know? A mixed methods study 
BMC Nephrology  2013;14:9.
Little is known regarding the types of information African American and non-African American patients with chronic kidney disease (CKD) and their families need to inform renal replacement therapy (RRT) decisions.
In 20 structured group interviews, we elicited views of African American and non-African American patients with CKD and their families about factors that should be addressed in educational materials informing patients’ RRT selection decisions. We asked participants to select factors from a list and obtained their open-ended feedback.
Ten groups of patients (5 African American, 5 non-African American; total 68 individuals) and ten groups of family members (5 African American, 5 non-African American; total 62 individuals) participated. Patients and families had a range (none to extensive) of experiences with various RRTs. Patients identified morbidity or mortality, autonomy, treatment delivery, and symptoms as important factors to address. Family members identified similar factors but also cited the effects of RRT decisions on patients’ psychological well-being and finances. Views of African American and non-African American participants were largely similar.
Educational resources addressing the influence of RRT selection on patients’ morbidity and mortality, autonomy, treatment delivery, and symptoms could help patients and their families select RRT options closely aligned with their values. Including information about the influence of RRT selection on patients’ personal relationships and finances could enhance resources’ cultural relevance for African Americans.
PMCID: PMC3565884  PMID: 23317336
Decision-making; Renal replacement therapy; Family members; African American
12.  Comparative effectiveness studies to improve clinical outcomes in end stage renal disease: the DEcIDE patient outcomes in end stage renal disease study 
BMC Nephrology  2012;13:167.
Evidence is lacking to inform providers’ and patients’ decisions about many common treatment strategies for patients with end stage renal disease (ESRD).
The DEcIDE Patient Outcomes in ESRD Study is funded by the United States (US) Agency for Health Care Research and Quality to study the comparative effectiveness of: 1) antihypertensive therapies, 2) early versus later initiation of dialysis, and 3) intravenous iron therapies on clinical outcomes in patients with ESRD. Ongoing studies utilize four existing, nationally representative cohorts of patients with ESRD, including (1) the Choices for Healthy Outcomes in Caring for ESRD study (1041 incident dialysis patients recruited from October 1995 to June 1999 with complete outcome ascertainment through 2009), (2) the Dialysis Clinic Inc (45,124 incident dialysis patients initiating and receiving their care from 2003–2010 with complete outcome ascertainment through 2010), (3) the United States Renal Data System (333,308 incident dialysis patients from 2006–2009 with complete outcome ascertainment through 2010), and (4) the Cleveland Clinic Foundation Chronic Kidney Disease Registry (53,399 patients with chronic kidney disease with outcome ascertainment from 2005 through 2009). We ascertain patient reported outcomes (i.e., health-related quality of life), morbidity, and mortality using clinical and administrative data, and data obtained from national death indices. We use advanced statistical methods (e.g., propensity scoring and marginal structural modeling) to account for potential biases of our study designs. All data are de-identified for analyses. The conduct of studies and dissemination of findings are guided by input from Stakeholders in the ESRD community.
The DEcIDE Patient Outcomes in ESRD Study will provide needed evidence regarding the effectiveness of common treatments employed for dialysis patients. Carefully planned dissemination strategies to the ESRD community will enhance studies’ impact on clinical care and patients’ outcomes.
PMCID: PMC3554422  PMID: 23217181
13.  Differences in urine cadmium associations with kidney outcomes based on serum creatinine and cystatin C 
Environmental research  2011;111(8):1236-1242.
Cadmium is a well known nephrotoxicant; chronic exposure increases risk for chronic kidney disease. Recently, however, associations between urine cadmium and higher creatinine-based estimated glomerular filtration rate (eGFR) have been reported. Analyses utilizing alternate biomarkers of kidney function allow evaluation of potential mechanisms for these observations. We compared associations of urine cadmium with kidney function measures based on serum cystatin C to those with serum creatinine in 712 lead workers. Mean (standard deviation) molybdenum-corrected urine cadmium, Modification of Diet in Renal Disease (MDRD) eGFR and multi-variable cystatin C eGFR were 1.02 (0.65) μg/g creatinine, and 97.4 (19.2) and 112.0 (17.7) mL/min/1.73 m2, respectively. The eGFR measures were moderately correlated (rs = 0.5; p less than 0.001). After adjustment, ln(urine cadmium) was not associated with serum cystatin-C-based measures. However, higher ln(urine cadmium) was associated with higher creatinine-based eGFRs including the MDRD and an equation incorporating serum cystatin C and creatinine (beta-coefficient = 4.1 ml/min/1.73 m2; 95% confidence interval =1.6, 6.6). Urine creatinine was associated with serum creatinine-based but not cystatin-C-based eGFRs. These results support a biomarker-specific, rather than a kidney function, effect underlying the associations observed between higher urine cadmium and creatinine-based kidney function measures. Given the routine use of serum and urine creatinine in kidney and biomarker research, additional research to elucidate the mechanism(s) for these associations is essential.
PMCID: PMC3210933  PMID: 21871619
cadmium; cystatin C; kidney function; serum creatinine; urine creatinine
14.  The providing resources to enhance African American patients’ readiness to make decisions about kidney disease (PREPARED) study: protocol of a randomized controlled trial 
BMC Nephrology  2012;13:135.
Living related kidney transplantation (LRT) is underutilized, particularly among African Americans. The effectiveness of informational and financial interventions to enhance informed decision-making among African Americans with end stage renal disease (ESRD) and improve rates of LRT is unknown.
We report the protocol of the Providing Resources to Enhance African American Patients’ Readiness to Make Decisions about Kidney Disease (PREPARED) Study, a two-phase study utilizing qualitative and quantitative research methods to design and test the effectiveness of informational (focused on shared decision-making) and financial interventions to overcome barriers to pursuit of LRT among African American patients and their families. Study Phase I involved the evidence-based development of informational materials as well as a financial intervention to enhance African American patients’ and families’ proficiency in shared decision-making regarding LRT. In Study Phase 2, we are currently conducting a randomized controlled trial in which patients with new-onset ESRD receive 1) usual dialysis care by their nephrologists, 2) the informational intervention (educational video and handbook), or 3) the informational intervention in addition to the option of participating in a live kidney donor financial assistance program. The primary outcome of the randomized controlled trial will include patients’ self-reported rates of consideration of LRT (including family discussions of LRT, patient-physician discussions of LRT, and identification of a LRT donor).
Results from the PREPARED study will provide needed evidence on ways to enhance the decision to pursue LRT among African American patients with ESRD.
Trial registration NCT01439516
PMCID: PMC3489555  PMID: 23057616
Shared decision-making; Live kidney transplantation; Live kidney donation; Chronic kidney disease; End stage renal disease
15.  Associations of blood lead with estimated glomerular filtration rate using MDRD, CKD-EPI and serum cystatin C-based equations 
Nephrology Dialysis Transplantation  2011;26(9):2786-2792.
Background. Low-level lead exposure is widespread and has been implicated as a chronic kidney disease (CKD) risk factor. However, studies evaluating associations of lead dose with newer, potentially more accurate, estimates of kidney function, in participants with a wide range of glomerular filtration rates (GFRs), are scarce.
Methods. We compared associations of blood lead and estimated glomerular filtration rate (eGFR) using the Modification of Diet in Renal Disease (MDRD), Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) and cystatin C single variable, multivariable and combined creatinine/cystatin C equations in 3941 adults who participated in the 1999–2002 National Health and Nutrition Examination Survey cystatin C subsample.
Results. Geometric mean blood lead was 1.7 μg/dL. After multivariable adjustment, differences [95% confidence interval (CI)] in mean eGFR for a doubling of blood lead were −1.9 (−3.2, −0.7), −1.7 (−3.0, −0.5) and −1.4 (−2.3, −0.5) mL/min/1.73 m2, using the cystatin C single variable, multivariable and combined creatinine/cystatin C equations, respectively, reflecting lower eGFR with increased blood lead. The corresponding differences (95% CI) were −0.9 (−1.9, 0.02) and −0.9 (−1.8, 0.01) using the creatinine-based MDRD and CKD-EPI equations, respectively. In participants aged ≥60 years, differences in mean eGFR ranged from −3.0 to −4.5 mL/min/1.73 m2, and odds of reduced eGFR (<60 mL/min/1.73 m2) were increased for all estimates of GFR.
Conclusions. These results support the inclusion of cystatin C-based eGFR in future lead research and provide additional evidence for environmental lead exposure as a CKD risk factor.
PMCID: PMC3203408  PMID: 21248295
blood lead; kidney function; lead exposure; NHANES
16.  Soluble P-Selectin Levels Are Associated with Cardiovascular Mortality and Sudden Cardiac Death in Male Dialysis Patients 
American Journal of Nephrology  2011;33(3):224-230.
P-selectin is released by activated platelets and endothelium contributing to inflammation and thrombosis. We evaluated the association between soluble P-selectin and atherosclerotic cardiovascular disease (ASCVD) in dialysis patients.
We measured soluble P-selectin in serum from 824 incident dialysis patients. Using Cox proportional hazards models, we modeled the association of P-selectin levels with ASCVD events, cardiovascular mortality and sudden cardiac death.
After adjustment for demographics, comorbidity and traditional cardiovascular risk factors, higher P-selectin levels were associated with increased risk of ASCVD and cardiovascular mortality among males (p = 0.02 and p = 0.01, respectively), but not females (p = 0.52 and p = 0.31, respectively; p interaction = 0.003), over a median of 38.2 months. Higher P-selectin was associated with a greater risk of sudden cardiac death among males (p = 0.05). The associations between increasing P-selectin and cardiovascular mortality as well as sudden cardiac death in males persisted after adjustment for C-reactive protein, interleukin-6, serum albumin and platelet count (p = 0.01 and p = 0.03, respectively). The risk for sudden cardiac death was more than 3 times greater for males in the highest tertile of soluble P-selectin compared with the lowest tertile after adjustment (HR: 3.19; 95% CI: 1.18 – 8.62; p = 0.02).
P-selectin is associated with ASCVD, cardiovascular mortality and sudden cardiac death among male dialysis patients.
PMCID: PMC3064942  PMID: 21346329
Cardiovascular disease; Dialysis; End-stage renal disease; Inflammation; Sudden cardiac death; P-selectin
17.  Association of Residual Urine Output with Mortality, Quality of Life, and Inflammation in Incident Hemodialysis Patients: The CHOICE (Choices for Healthy Outcomes in Caring for End-Stage Renal Disease) Study 
Residual kidney function (RKF) is associated with improved survival in peritoneal dialysis patients but its role in hemodialysis patients is less well known. Urine output may provide an estimate of RKF. The aim of our study was to determine the association of urine output with mortality, quality of life (QOL) and inflammation in incident hemodialysis patients.
Study Design
Nationally representative prospective cohort study
Setting & Participants
734 incident hemodialysis participants treated in 81 clinics; enrollment, 1995-1998, follow-up until December 2004.
Urine output, defined as producing at least 250 mL (1 cup) of urine daily, ascertained by questionnaires at baseline and year 1.
Outcomes & Measurements
Primary outcomes were all-cause and cardiovascular (CVD) mortality, analyzed using Cox regression adjusted for demographic, clinical and treatment characteristics. Secondary outcomes were QOL, inflammation (CRP and interleukin-6 [IL-6] levels) and erythropoietin (EPO) requirements.
617/734 (84%) participants reported urine output at baseline and 163/579 (28%) at year 1. Baseline urine output was not associated with survival. Urine output at year 1, indicating preserved RKF, was independently associated with lower all-cause mortality (Hazard Ratio [HR], 0.70; 95% Confidence Interval [CI], 0.52-0.93; p=0.02) and a trend towards lower CVD mortality (HR, 0.69; 95% CI, 0.45-1.05; p=0.09). Participants with urine output at baseline reported better QOL and had lower CRP (p=0.02) and IL-6 (p=0.03) levels. Importantly, EPO dose was 12,000 units/week lower in those with urine output at year 1 compared with those without (p=0.001).
Urine volume was measured in only a subset of patients (42%) but was in agreement with self-report (p<0.001).
RKF in hemodialysis patients is associated with better survival and QOL, lower inflammation and significantly less EPO use. RKF should be monitored routinely in hemodialysis patients. Development of methods to assess and preserve RKF is important and may improve dialysis care.
PMCID: PMC2910835  PMID: 20605303
End-stage Renal Disease; Hemodialysis; Residual Kidney Function; Mortality; Quality of Life; Inflammation
18.  Associations of low-level urine cadmium with kidney function in lead workers 
Low-level cadmium exposure, e.g., urinary cadmium < 2.0 μg/g creatinine, is widespread; recent data suggest nephrotoxicity even at these lower levels. Few studies have examined the impact of low-level cadmium exposure in workers who are occupationally exposed to other nephrotoxicants such as lead.
We evaluated associations of urine cadmium, a measure of cumulative dose, with four glomerular filtration measures and N-acetyl-β-D-glucosaminidase (NAG) in lead workers. Recent and cumulative lead dose was assessed via blood and tibia lead, respectively.
In 712 lead workers, mean (SD) blood and tibia lead, urine cadmium, and estimated glomerular filtration rate (eGFR) using the Modification of Diet in Renal Disease equation were 23.1 (14.1) μg/dl, 26.6 (28.9) μg Pb/g bone mineral, 1.15 (0.66) μg/g creatinine, and 97.4 (19.2) ml/min/1.73m2, respectively. After adjustment for age, sex, body mass index, urine creatinine, smoking, alcohol, education, annual income, diastolic blood pressure, current or former lead worker job status, new or returning study participant, and blood and tibia lead, higher ln-urine cadmium was associated with higher calculated creatinine clearance, eGFR (β = 8.7 ml/min/1.73 m2; 95% CI = 5.4, 12.1) and ln-NAG but lower serum creatinine.
Potential explanations for these results include a normal physiologic response in which urine cadmium levels reflect renal filtration; the impact of adjustment for urine dilution with creatinine in models of kidney outcomes; and cadmium-related hyperfiltration.
PMCID: PMC3053421  PMID: 20974743
cadmium; kidney function; lead exposure; urine creatinine
19.  Inpatient Hemodialysis Initiation: Reasons, Risk Factors and Outcomes 
Nephron. Clinical Practice  2009;114(1):c19-c28.
Inpatient initiation of chronic hemodialysis is considered undesirable because of cost and possible harms of hospitalization. We examined the patient characteristics and outcomes associated with inpatient initiation.
In a prospective cohort study of incident dialysis patients, the independent association of inpatient hemodialysis initiation with patient outcomes was assessed in multivariable analyses with adjustment for patient characteristics and propensity for inpatient initiation.
A total of 410 of 652 (63%) hemodialysis patients began as inpatients; uremia and volume overload were the most commonly documented reasons. Compared to outpatients, inpatients were more likely to be unmarried, report less social support, have multiple comorbidities and be referred to a nephrologist 4 months or less prior to initiation. Inpatient initiation was protective for subsequent all-cause hospitalization (incidence rate ratio (IRR) = 0.92, confidence interval (CI) 0.89–0.94); this was most pronounced among those who had the highest propensity for inpatient initiation (IRR = 0.66, CI 0.56–0.78), including those referred late to nephrology. Similar results were found for infectious hospitalization. Mortality [hazard ratio = 1.03, CI 0.82–1.30] and cardiovascular events were not significantly different for inpatients versus outpatients.
Inpatient hemodialysis initiation has a protective association with hospitalization among those patients referred late to nephrology, with multiple comorbidities and/or little social support.
PMCID: PMC2842162  PMID: 19816040
End-stage renal disease; Hospitalization; Late referral; Mortality; Social support
20.  Effect of primary care physicians' use of estimated glomerular filtration rate on the timing of their subspecialty referral decisions 
BMC Nephrology  2011;12:1.
Primary care providers' suboptimal recognition of the severity of chronic kidney disease (CKD) may contribute to untimely referrals of patients with CKD to subspecialty care. It is unknown whether U.S. primary care physicians' use of estimated glomerular filtration rate (eGFR) rather than serum creatinine to estimate CKD severity could improve the timeliness of their subspecialty referral decisions.
We conducted a cross-sectional study of 154 United States primary care physicians to assess the effect of use of eGFR (versus creatinine) on the timing of their subspecialty referrals. Primary care physicians completed a questionnaire featuring questions regarding a hypothetical White or African American patient with progressing CKD. We asked primary care physicians to identify the serum creatinine and eGFR levels at which they would recommend patients like the hypothetical patient be referred for subspecialty evaluation. We assessed significant improvement in the timing [from eGFR < 30 to ≥ 30 mL/min/1.73m2) of their recommended referrals based on their use of creatinine versus eGFR.
Primary care physicians recommended subspecialty referrals later (CKD more advanced) when using creatinine versus eGFR to assess kidney function [median eGFR 32 versus 55 mL/min/1.73m2, p < 0.001]. Forty percent of primary care physicians significantly improved the timing of their referrals when basing their recommendations on eGFR. Improved timing occurred more frequently among primary care physicians practicing in academic (versus non-academic) practices or presented with White (versus African American) hypothetical patients [adjusted percentage(95% CI): 70% (45-87) versus 37% (reference) and 57% (39-73) versus 25% (reference), respectively, both p ≤ 0.01).
Primary care physicians recommended subspecialty referrals earlier when using eGFR (versus creatinine) to assess kidney function. Enhanced use of eGFR by primary care physicians' could lead to more timely subspecialty care and improved clinical outcomes for patients with CKD.
PMCID: PMC3033812  PMID: 21235763
21.  Blood Cadmium and Lead and Chronic Kidney Disease in US Adults: A Joint Analysis 
American Journal of Epidemiology  2009;170(9):1156-1164.
Environmental cadmium and lead exposures are widespread, and both metals are nephrotoxic at high exposure levels. Few studies have evaluated the associations between low-level cadmium and clinical renal outcomes, particularly with respect to joint cadmium and lead exposure. The geometric mean levels of blood cadmium and lead were 0.41 μg/L (3.65 nmol/L) and 1.58 μg/dL (0.076 μmol/L), respectively, in 14,778 adults aged ≥20 years who participated in the National Health and Nutrition Examination Survey (1999–2006). After adjustment for survey year, sociodemographic factors, chronic kidney disease risk factors, and blood lead, the odds ratios for albuminuria (≥30 mg/g creatinine), reduced estimated glomerular filtration rate (eGFR) (<60 mL/minute/1.73 m2), and both albuminuria and reduced eGFR were 1.92 (95% confidence interval (CI): 1.53, 2.43), 1.32 (95% CI: 1.04, 1.68), and 2.91 (95% CI: 1.76, 4.81), respectively, comparing the highest with the lowest blood cadmium quartiles. The odds ratios comparing participants in the highest with the lowest quartiles of both cadmium and lead were 2.34 (95% CI: 1.72, 3.18) for albuminuria, 1.98 (95% CI: 1.27, 3.10) for reduced eGFR, and 4.10 (95% CI: 1.58, 10.65) for both outcomes. These findings support consideration of cadmium and lead as chronic kidney disease risk factors in the general population and provide novel evidence of risk with environmental exposure to both metals.
PMCID: PMC2781739  PMID: 19700501
albuminuria; cadmium; creatinine; glomerular filtration rate; kidney diseases; lead; metals; nutrition surveys
22.  Cerebrovascular Disease Incidence, Characteristics, and Outcomes in Patients Initiating Dialysis: The CHOICE (Choices for Healthy Outcomes in Caring for ESRD) Study 
Stroke is the third most common cause of cardiovascular disease death in patients on dialysis; however, characteristics of cerebrovascular disease, including clinical subtypes and subsequent consequences, have not been well described.
Study Design
Prospective national cohort study, the Choices for Healthy Outcomes in Caring for ESRD (CHOICE) study.
Settings & Participants
1,041 incident dialysis patients treated in 81 clinics, enrolled from 10/95–7/98, followed until 12/31/2004.
Time from dialysis initiation.
Outcomes & Measurements
Cerebrovascular disease events were defined as non-fatal (hospitalized stroke, carotid endarterectomy) and fatal (stroke death) events after dialysis initiation. Stroke subtypes were classified using standardized criteria from the Trial of ORG 10172 in Acute Stroke Treatment (TOAST) system. Incidence of cerebrovascular event subtypes were analyzed using time-to-event analyses accounting for competing risk of death. Clinical outcomes after stroke were abstracted from medical records.
A total of 165 participants experienced a cerebrovascular event with an overall incidence of 4.9 per 100 person-years. Ischemic stroke was the most common (76% of all 200 events) with cardioembolism subtype accounting for 28% of the 95 abstracted ischemic events. The median time from onset of symptoms to first stroke evaluation was 8.5 hours (25th and 75th percentiles 1, 42 hours), with only 56% of patients successfully escaping death, nursing home, or a skilled nursing facility.
Relatively small sample size limits power to determine risk factors.
Cerebrovascular disease is common in dialysis patients, is identified late, and carries a significant risk of morbidity and mortality. Stroke etiologic subtypes on dialysis are multifactorial, suggesting risk factors may change the longer one has ESRD. Further studies are needed to address the poor prognosis through prevention, early identification, and treatment.
PMCID: PMC2744381  PMID: 19376618
Cerebrovascular disease; Stroke; Dialysis; Prognosis; Epidemiology
23.  Clinical testing patterns and cost implications of variation in the evaluation of chronic kidney disease among U.S. physicians 
Clinical practice guidelines were established to improve the diagnosis and management of chronic kidney disease (CKD), but the extent, determinants, and cost implications of guideline adherence and variation in adherence have not been evaluated.
Study Design
Cross-sectional survey
Settings & Participants
Nationally representative sample of 301 U.S. primary care physicians and nephrologists
Provider and patient characteristics
Outcomes & Measurements
Guideline adherence was assessed as present if physicians recommended at least 5 of 6 clinical tests prescribed by the National Kidney Foundation-Kidney Disease Outcomes and Quality Initiative (KDOQI) guidelines for a hypothetical patient with newly identified CKD. We also assessed patterns and cost of additional non-recommended tests for the initial clinical evaluation of CKD.
Most of the 86 family medicine, 89 internal medicine, and 126 nephrology physicians practiced greater than 10 years (54%), were in non-academic practices (76%), spent greater than 80% of their time performing clinical duties (78%), and correctly estimated kidney function (73%). Overall, 35% of participants were guideline adherent. Compared to nephrologists, internal medicine and family physicians had lower odds of adherence for all recommended testing (Odds Ratio (OR) [95% CI]:0.6[0.3–1.1] and 0.3[0.1–0.6], respectively). Participants practicing greater than 10 years had lower odds of ordering all recommended testing compared to participants practicing less than 10 years (OR[95% CI]: 0.5[0.3–0.9]). Eighty-five percent of participants recommended additional tests, which resulted in a 23% increased total per patient cost of the clinical evaluation.
Recommendations for a hypothetical case scenario may differ from that of actual patients.
Adherence to the recommended clinical testing for the diagnosis and management of CKD was poor and additional testing was associated with substantially increased cost of the clinical evaluation. Improved clarity, dissemination, and uptake of existing guidelines are needed to improve quality and decrease costs of care for patients with CKD.
PMCID: PMC2714476  PMID: 19371991
chronic kidney disease; primary care providers; guidelines; KDOQI; cost
24.  Association of Single-Nucleotide Polymorphisms in JAK3, STAT4, and STAT6 With New Cardiovascular Events in Incident Dialysis Patients 
Increasing evidence supports a role for cell-mediated immunity in the pathogenesis of cardiovascular disease. Single nucleotide polymorphisms (SNPs) in JAK3, STAT4, and STAT6 of the Janus kinase–signal transducer and activator of transcription (Jak-Stat) signal transduction pathway were examined for association with time to new cardiovascular events in incident dialysis patients from the Choices for Healthy Outcomes in Caring for End-Stage Renal Disease study.
Study Design
Prospective cohort study.
Setting & Participants
764 White (n=518) and Black (n=246) participants from 79 dialysis centers.
SNPs in JAK3, STAT4, and STAT6 selectedusing a pairwise approach to identify a maximally informative set of tag SNPs for populations of European and African descent.
Outcomes and Measurements
Cox proportional hazards models were used to estimate unadjusted and multivariable adjusted hazard ratios (HR) for incident cardiovascular disease events after dialysis initiation associated with each race-specific SNP.
Two European tag SNPs (rs3212780 and rs3213409) were associated with new cardiovascular disease events in White patients in JAK3, with unadjusted HR 1.92 (p<0.001) and 1.82 (p=0.07), respectively. One dual-tag SNP (rs3212752) in JAK3 was associated with new cardiovascular events in White patients with unadjusted HR 2.09 (p<0.001) and in Black patients with HR 2.07 (p=0.007). SNP rs3213409 codes for a valine to isoleucine change at amino acid 722, a potentially functional mutation. SNPs in STAT4 and STAT6 were not associated with cardiovascular events after the initiation of dialysis.
This study does not provide direct evidence for the mechanism of increased risk. Replication in independent cohorts is necessary.
Genetic polymorphisms in the Jak-Stat signaling pathway are associated with an increased risk of new cardiovascular events in incident dialysis patients.
PMCID: PMC2744364  PMID: 19282076
dialysis; cardiovascular diseases; inflammation; genes
25.  Longitudinal associations between lead dose and renal function in lead workers 
Environmental research  2008;109(1):101-107.
Existing research on the lead dose range associated with nephrotoxicity in the occupational setting is inconsistent and primarily cross-sectional in design.
To determine if lead dose predicts change in renal function in a large population of current and former lead workers.
Three evaluations were performed between 1997 and 2001. Lead dose was assessed with blood and tibia lead. Renal outcomes included blood urea nitrogen, serum creatinine, and calculated creatinine clearance. We used generalized estimating equations to model change in renal function between each evaluation in relation to tibia lead at the beginning of each follow-up period and concurrent change in blood lead, while adjusting for baseline lead dose and other covariates.
At baseline, mean (SD) age and duration of occupational lead exposure were 42.0 (9.3) and 8.8 (6.3) years, respectively, in 537 current and former lead workers followed over a mean of 2.1 years. Mean (SD) blood and tibia lead were 31.3 (14.4) μg/dL and 35.0 (37.8) μg/g bone mineral, respectively. Women (25.9%) were older and more likely to be former lead workers than men. In males, serum creatinine decreased and calculated creatinine clearance increased over the course of the study. Mean blood lead was not significantly different between evaluations 1 and 3 in either sex, however, tibia lead decreased in women. Blood and tibia lead were significantly associated with change in renal function. In males, serum creatinine decreases and calculated creatinine clearance increases were greatest in participants whose blood lead declined.
Both acute and chronic occupational lead dose measures were associated with change in renal function measures prospectively.
PMCID: PMC2722941  PMID: 19038382
blood lead; renal function; lead exposure; longitudinal; tibia lead

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