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2.  Implementation of Novel Biomarkers in the Diagnosis, Prognosis, and Management of Acute Kidney Injury: Executive Summary from the Tenth Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) 
Contributions to nephrology  2013;182:10.1159/000349962.
Detection of acute kidney injury is undergoing a dynamic revolution of biomarker technology allowing greater, earlier, and more accurate determination of diagnosis, prognosis, and with powerful implication for management. Biomarkers can be broadly considered as any measurable biologic entity or process that allows differentiation between normal function and injury or disease. The ADQI (Acute Dialysis Quality Initiative) had its Ninth Consensus Conference dedicated to synthesis and formulation of the existing literature on biomarkers for the detection of acute kidney injury in a variety of settings. In the papers that accompany this summary, ADQI workgroups fully develop key concepts from a summary of the literature in the domains of early diagnosis, differential diagnosis, prognosis and management, and concurrent physiologic and imaging measures.
PMCID: PMC3856225  PMID: 23689652
3.  Hyperacute drug-induced hepatitis with intravenous amiodarone: case report and review of the literature 
Amiodarone is a benzofuran class III antiarrhythmic drug used to treat a wide spectrum of ventricular tachyarrhythmias. The parenteral formulation is prepared in polysorbate 80 diluent. We report an unusual case of acute elevation of aminotransaminase concentrations after the initiation of intravenous amiodarone. An 88-year-old Caucasian female developed acute hepatitis and renal failure after initiating intravenous amiodarone for atrial fibrillation with a rapid ventricular response in the setting of acutely decompensated heart failure and hepatic congestion. Liver transaminases returned to baseline within 7 days after discontinuing the drug. Researchers hypothesized that this type of injury is related to liver ischemia with possible superimposed direct drug toxicity. The CIOMS/RUCAM scale identifies our patient’s acute hepatitis as a highly probable adverse drug reaction. Future research is needed to understand the mechanisms by which hyperacute drug toxicity occurs in the setting of impaired hepatic perfusion and venous congestion.
PMCID: PMC3792591  PMID: 24109195
intravenous amiodarone; acute hepatotoxicity; liver transaminases; drug-induced liver toxicity
4.  Association Between Lack of Health Insurance and Risk of Death and ESRD: Results From the Kidney Early Evaluation Program (KEEP) 
Uninsured adults in the United States have poor access to health care services and worse health outcomes than insured adults. Little is known about the association between lack of insurance and chronic kidney disease (CKD) progression to end-stage renal disease (ESRD) or death in patients at high risk of kidney disease. We used 2000–2011 data from the National Kidney Foundation’s Kidney Early Evaluation Program (KEEP) to examine this association.
The study population included KEEP participants younger than 65 years. Outcomes were time to ESRD (chronic kidney failure treated by renal replacement therapy) and time to death. Incident ESRD was ascertained by linkage to the US Renal Data System, and vital status, by linkage to the Social Security Administration Death Master File. We used Cox proportional hazard regression to examine the association between insurance and risk of death or ESRD after adjusting for demographic variables.
Of 86,588 participants, 27.8% had no form of insurance, 10.3% had public insurance, and 61.9% had private insurance; 15.0% had CKD (defined as estimated glomerular filtration rate <60 mL/min/1.73 m2 or urine albumin-creatinine ratio ≥30 mg/g), 63.3% had hypertension, and 27.7% had diabetes. Of participants with CKD, 29.3% had no health insurance. Participants without insurance were younger, more likely to be Hispanic and to have 12 or fewer years of education, and less likely to have seen a physician in the past year. After adjustment for demographic characteristics, uninsured KEEP participants were 82% more likely than privately insured participants to die (HR, 1.82; 95% CI, 1.56–2.12; P < 0.001) and 72% more likely to develop ESRD (HR, 1.72; 95% CI, 1.33–2.22; P < 0.001). The association between insurance and outcomes varied by CKD stage.
Lack of insurance is an independent risk factor for early death and ESRD in this population at high risk of kidney disease. Considering the high morbidity and mortality and increasing cost associated with ESRD, access to appropriate health insurance coverage is warranted.
PMCID: PMC3739048  PMID: 23507267
Chronic kidney disease; end-stage renal disease; health insurance; mortality; public health
5.  Awareness of Kidney Disease and Relationship to End-Stage Renal Disease and Mortality 
The American Journal of Medicine  2012;125(7):661-669.
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.
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.
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.
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.
PMCID: PMC3383388  PMID: 22626510
KEEP; CKD; awareness; ESRD; mortality
6.  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
7.  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.
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.
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.
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.
After multivariable adjustment, there was a small positive association between PTH and hemoglobin among diabetics but not among nondiabetics.
PMCID: PMC3721130  PMID: 23922552
Chronic kidney disease; Anemia; Secondary hyperparathyroidism

8.  Physician Utilization, Risk-Factor Control, and CKD Progression Among Participants in the Kidney Early Evaluation Program (KEEP) 
Chronic kidney disease (CKD) is a well-known risk factor for cardiovascular mortality, but little is known about the association between physician utilization and cardiovascular disease risk-factor control in patients with CKD. We used 2005–2010 data from the National Kidney Foundation’s Kidney Early Evaluation Program (KEEP) to examine this association at first and subsequent screenings.
Control of risk factors was defined as control of blood pressure, glycemia, and cholesterol levels. We used multinomial logistic regression to examine the association between participant characteristics and seeing a nephrologist after adjusting for kidney function and paired t tests or McNemar tests to compare characteristics at first and second screenings.
Of 90,009 participants, 61.3% had a primary care physician only, 2.9% had seen a nephrologist, and 15.3% had seen another specialist. The presence of 3 risk factors (hypertension, diabetes, and hypercholesterolemia) increased from 26.8% in participants with CKD stages 1–2 to 31.9% in those with stages 4–5. Target levels of all risk factors were achieved in 7.2% of participants without a physician, 8.3% of those with a primary care physician only, 9.9% of those with a nephrologist, and 10.3% of those with another specialist. Of up to 7,025 participants who met at least one criterion for nephrology consultation at first screening, only 12.3% reported seeing a nephrologist. Insurance coverage was associated strongly with seeing a nephrologist. Of participants who met criteria for nephrology consultation, 406 (5.8%) returned for a second screening, of whom 19.7% saw a nephrologist. The percentage of participants with all risk factors controlled was higher at the second screening (20.9% vs 13.3%).
Control of cardiovascular risk factors is poor in the KEEP population. The percentage of participants seeing a nephrologist is low, although better after the first screening. Identifying communication barriers between nephrologists and primary care physicians may be a new focus for KEEP.
PMCID: PMC3654535  PMID: 22339899
Cardiovascular disease risk factors; chronic kidney disease; nephrologist care; primary care
9.  In reply 
Mayo Clinic Proceedings  2012;87(11):1133-1134.
PMCID: PMC3532680
11.  Urine Catalytic Iron and Neutrophil Gelatinase-Associated Lipocalin as Companion Early Markers of Acute Kidney Injury after Cardiac Surgery: A Prospective Pilot Study 
Cardiorenal Medicine  2013;3(1):7-16.
Open heart surgery with cardiopulmonary bypass is recognized as a common cause of acute kidney injury (AKI). The conventional biomarker creatinine is not sensitive enough to detect AKI until a significant decline in renal filtration has occurred. Urine neutrophil gelatinase-associated lipocalin (NGAL), part of an acute response to the release of tissue iron from cells, is an early biomarker and a predictor of AKI in a variety of clinical settings. We sought to evaluate the relationship between urine catalytic iron (unbound iron) and NGAL over the course of AKI due to cardiac surgery.
Fourteen patients who underwent open heart surgery had the following measured: serum creatinine (0, 12, 24, 48 and 72 h postoperatively), urine NGAL and urine catalytic iron (0, 8, 24 and 48 h postoperatively). Urine NGAL and urine catalytic iron were quantified by immunoassay and bleomycin-detectable iron assay, respectively. AKI was defined by the Acute Kidney Injury Network (AKIN) criteria.
Urine catalytic iron increased significantly (p < 0.05) within 8 h and peaked at 24 h postoperatively in patients who developed AKI (n = 8, baseline 101.96 ± 177.48, peak 226.35 ± 238.23 nmol/l, p = 0.006), but not in non-AKI patients (n = 6, baseline 131.08 ± 116.21, peak 163.99 ± 109.62 nmol/l, p = 0.380). Urine NGAL levels also peaked at 24 h with significant increase observed only in AKI patients: AKI – baseline 34.88 ± 26.47, peak 65.50 ± 27.03 ng/ml, p = 0.043; non-AKI – baseline 59.33 ± 31.72, peak 71.00 ± 31.76 ng/ml, p = 0.100. The correlation between baseline levels of urine catalytic iron and NGAL and peak levels of urine catalytic iron and NGAL was r = 0.86, p < 0.0001.
Urine catalytic iron appears to rise and fall in concert with NGAL in patients undergoing cardiac surgery and may be indicative of early AKI. Future research into the role that catalytic iron plays in acute organ injury syndromes and its potential diagnostic and therapeutic implications is warranted.
PMCID: PMC3743453  PMID: 23946721
Catalytic iron; Marker; Neutrophil gelatinase-associated lipocalin; Acute kidney injury; Heart surgery
12.  Discovery and validation of cell cycle arrest biomarkers in human acute kidney injury 
Critical Care  2013;17(1):R25.
Acute kidney injury (AKI) can evolve quickly and clinical measures of function often fail to detect AKI at a time when interventions are likely to provide benefit. Identifying early markers of kidney damage has been difficult due to the complex nature of human AKI, in which multiple etiologies exist. The objective of this study was to identify and validate novel biomarkers of AKI.
We performed two multicenter observational studies in critically ill patients at risk for AKI - discovery and validation. The top two markers from discovery were validated in a second study (Sapphire) and compared to a number of previously described biomarkers. In the discovery phase, we enrolled 522 adults in three distinct cohorts including patients with sepsis, shock, major surgery, and trauma and examined over 300 markers. In the Sapphire validation study, we enrolled 744 adult subjects with critical illness and without evidence of AKI at enrollment; the final analysis cohort was a heterogeneous sample of 728 critically ill patients. The primary endpoint was moderate to severe AKI (KDIGO stage 2 to 3) within 12 hours of sample collection.
Moderate to severe AKI occurred in 14% of Sapphire subjects. The two top biomarkers from discovery were validated. Urine insulin-like growth factor-binding protein 7 (IGFBP7) and tissue inhibitor of metalloproteinases-2 (TIMP-2), both inducers of G1 cell cycle arrest, a key mechanism implicated in AKI, together demonstrated an AUC of 0.80 (0.76 and 0.79 alone). Urine [TIMP-2]·[IGFBP7] was significantly superior to all previously described markers of AKI (P <0.002), none of which achieved an AUC >0.72. Furthermore, [TIMP-2]·[IGFBP7] significantly improved risk stratification when added to a nine-variable clinical model when analyzed using Cox proportional hazards model, generalized estimating equation, integrated discrimination improvement or net reclassification improvement. Finally, in sensitivity analyses [TIMP-2]·[IGFBP7] remained significant and superior to all other markers regardless of changes in reference creatinine method.
Two novel markers for AKI have been identified and validated in independent multicenter cohorts. Both markers are superior to existing markers, provide additional information over clinical variables and add mechanistic insight into AKI.
Trial registration number NCT01209169.
PMCID: PMC4057242  PMID: 23388612
13.  Relation Between Body Mass Index, Exercise Training, and Outcomes in Chronic Systolic Heart Failure 
The American journal of cardiology  2011;108(12):1754-1759.
Exercise training (ET) in heart failure (HF), as demonstrated in the HF-ACTION trial, was associated with improved exercise tolerance and health status, and a trend towards reduced mortality or hospitalizations. This analysis of the HF-ACTION cohort examines the effect of ET in overweight and obese compared to normal HF subjects. 2,314 of 2,331 systolic HF subjects randomized to aerobic ET vs. usual care in HF-ACTION were analyzed to determine the effect of ET on all cause mortality, hospitalizations, exercise parameters, quality of life (QOL), and body weight changes by subgroups of body mass index (BMI). Strata included normal weight (BMI 18.5 – 24.9 kg/m2), overweight (BMI 25.0 – 29.9 kg/m2), obese I (BMI 30 – 34.9 kg/m2), obese II (BMI 35-39.9 kg/m2), and obese III (BMI ≥ 40 kg/m2). At enrollment, 19.4% of subjects were normal weight, 31.3% overweight, and 49.4% obese. Higher BMI was associated with a non-significant increase in all cause mortality or hospitalization. ET was associated with non-significant reductions in all cause mortality or hospitalization in each weight category (HR 0.98, 0.95, 0.92, 0.89, and 0.86 in normal weight, overweight, obese I, obese II, and obese III categories, respectively [all p>0.05]). Modeled improvement in exercise capacity (peak oxygen consumption) and QOL in the ET group was seen in all BMI categories. In conclusion, aerobic ET in HF was associated with a non-significant trend towards decreased mortality and hospitalizations and a significant improvement in QOL across the range of BMI categories.
PMCID: PMC3229667  PMID: 21907317
heart failure; body mass index; exercise
14.  Potential Adverse Cardiovascular Effects From Excessive Endurance Exercise 
Mayo Clinic Proceedings  2012;87(6):587-595.
A routine of regular exercise is highly effective for prevention and treatment of many common chronic diseases and improves cardiovascular (CV) health and longevity. However, long-term excessive endurance exercise may induce pathologic structural remodeling of the heart and large arteries. Emerging data suggest that chronic training for and competing in extreme endurance events such as marathons, ultramarathons, ironman distance triathlons, and very long distance bicycle races, can cause transient acute volume overload of the atria and right ventricle, with transient reductions in right ventricular ejection fraction and elevations of cardiac biomarkers, all of which return to normal within 1 week. Over months to years of repetitive injury, this process, in some individuals, may lead to patchy myocardial fibrosis, particularly in the atria, interventricular septum, and right ventricle, creating a substrate for atrial and ventricular arrhythmias. Additionally, long-term excessive sustained exercise may be associated with coronary artery calcification, diastolic dysfunction, and large-artery wall stiffening. However, this concept is still hypothetical and there is some inconsistency in the reported findings. Furthermore, lifelong vigorous exercisers generally have low mortality rates and excellent functional capacity. Notwithstanding, the hypothesis that long-term excessive endurance exercise may induce adverse CV remodeling warrants further investigation to identify at-risk individuals and formulate physical fitness regimens for conferring optimal CV health and longevity.
PMCID: PMC3538475  PMID: 22677079
CAC, coronary artery calcium; CHD, coronary heart disease; CV, cardiovascular; EF, ejection fraction; ET, exercise training; LV, left ventricular; MRI, magnetic resonance imaging; PA, physical activity; RA, right atrium; RV, right ventricular; SCD, sudden cardiac death; VA, ventricular arrhythmia
15.  Dysglycemia but not lipids is associated with abnormal urinary albumin excretion in diabetic kidney disease: a report from the Kidney Early Evaluation Program (KEEP) 
BMC Nephrology  2012;13:104.
The relationship between glycemic control and lipid abnormalities with urinary albumin-creatinine ratio (ACR) in chronic kidney disease (CKD) patients with diabetes mellitus (DM) is unknown. We sought to investigate the association of dyslipidemia and glycemic control with levels of albuminuria in the National Kidney Foundation (NKF) Kidney Early Evaluation Program (KEEP) participants with DM and CKD stage 3 or higher.
We performed a cross-sectional study of 6639 eligible KEEP patients with DM and CKD Stage 3 to 5 from June 2008 to December 2009. Multivariate logistic regression was used to evaluate the association of lipid parameters (per 10 mg/dl change in serum level) and glycosylated hemoglobin (HbA1c) values with three degrees of albuminuria normo (<30 mg⁄g), micro (30 to 300 mg⁄g) and macro (>300 mg⁄g).
2141 KEEP participants were included. HbA1c levels were strongly associated with micro-albuminuria (compared to normo-albuminuria) and macro-albuminuria (compared to normo-albuminuria and micro-albuminuria). Each 1.0% increase in HbA1c increased the odds of micro-albuminuria by 32% (OR 1.32, 95% CI 1.23-1.42) and the odds of macro-albuminuria (vs. microalbuminuria) by 16% (OR 1.16, 95% CI 1.05-1.28). Only increases in serum HDL were associated with decreased odds of micro-albuminuria; otherwise, the association between other components of the serum lipid profile with urinary ACR did not reach statistical significance.
In this cross-sectional study of 2141 KEEP participants with DM and CKD stages 3–5, overall glycemic control but not lipids were associated with abnormal urinary albumin excretion, a marker of increased risk for progressive disease.
PMCID: PMC3480932  PMID: 22958709
Chronic Kidney Disease; Diabetes Mellitus; Proteinuria; Dyslipidemia; Glycosylated hemoglobin
16.  SELDI-TOF-MS Serum Profiling Reveals Predictors of Cardiac MRI Changes in Marathon Runners 
Purpose. To utilize proteomics to discover proteins associated with significant cardiac magnetic resonance imaging (MRI) changes in marathon runners. Methods. Serum from 25 runners was analyzed by surface enhanced laser desorption ionization time-of-flight mass spectrometry (SELDI-TOF-MS). Proteomic profiles were compared in serum samples obtained prior to the race, at the finish line and within 7 hours after race to identify dynamic proteins correlated with cardiac MRI changes. Results. 693 protein/peptide clusters were identified using two ProteinChip surface chemistries and, of these, 116 were significantly different between the three time points. We identified 7 different patterns of protein expression change within the runners and 5 prerace protein peaks, 16 finish-line protein levels, and 15 postrace proteins which were correlated with significant postrace cardiac MRI changes. Conclusions. This study has identified baseline levels of proteins which may be predictive of risk of significant cardiac damage following a marathon race. Preliminary identification of the significant proteins suggested the involvement of cytokines and other proteins involved in stress and inflammatory response.
PMCID: PMC3439948  PMID: 22988506
17.  Blood Pressure Components and End-stage Renal Disease in Persons With Chronic Kidney Disease 
Archives of internal medicine  2012;172(1):41-47.
Treatment of hypertension is difficult in chronic kidney disease (CKD), and blood pressure goals remain controversial. The association between each blood pressure component and end-stage renal disease (ESRD) risk is less well known.
We studied associations of systolic and diastolic blood pressure (SBP and DBP, respectively) and pulse pressure (PP) with ESRD risk among 16 129 Kidney Early Evaluation Program (KEEP) participants with an estimated glomerular filtration rate of 60 mL/min/1.73 m2 using Cox proportional hazards. We estimated the prevalence and characteristics associated with uncontrolled hypertension (SBP≥150 or DBP≥90 mm Hg).
The mean (SD) age of participants was 69 (12) years; 25% were black, 6% were Hispanic, and 43% had diabetes mellitus. Over 2.87 years, there were 320 ESRD events. Higher SBP was associated with higher ESRD risk, starting at SBP of 140 mm Hg or higher. After sex and age adjustment, compared with SBP lower than 130 mm Hg, hazard ratios (HRs) were 1.08 (95% CI, 0.74–1.59) for SBP of 130 to 139 mm Hg, 1.72 (95% CI, 1.21–2.45) for SBP of 140 to 149 mm Hg, and 3.36 (95% CI, 2.51–4.49) for SBP of 150 mm Hg or greater. After full adjustment, HRs for ESRD were 1.27 (95% CI, 0.88–1.83) for SBP of 140 to 149 mm Hg and 1.36 (95% CI, 1.02–1.85) for SBP of 150 mm Hg or higher. Persons with DBP of 90 mm Hg or higher were at higher risk for ESRD compared with persons with DBP of 60 to 74 mm Hg (HR, 1.81; 95% CI, 1.33–2.45). Higher PP was also associated with higher ESRD risk (HR, 1.44 [95% CI, 1.00–2.07] for PP≥80 mm Hg compared with PP<50 mm Hg). Adjustment for SBP attenuated this association. More than 33% of participants had uncontrolled hypertension (SBP≥150 mm Hg or DBP≥90 mm Hg), mostly due to isolated systolic hypertension (54%).
In this large, diverse, community-based sample, we found that high SBP seemed to account for most of the risk of progression to ESRD. This risk started at SBP of 140 mm Hg rather than the currently recommended goal of less than 130 mm Hg, and it was highest among those with SBP of at least 150 mm Hg. Treatment strategies that preferentially lower SBP may be required to improve BP control in CKD.
PMCID: PMC3417125  PMID: 22232147
18.  Cardiac and renal function in patients with type 2 diabetes who have chronic kidney disease: potential effects of bardoxolone methyl 
The intracellular and tissue balance of oxidant and antioxidant forces is a potential therapeutic target for a variety of agents in the treatment of complications due to chronic disease including diabetes mellitus and hypertension. There are a myriad of processes controlled at the level of genes, transcription factors, and protein messages that work to control the normal use of oxidative reactions within cells. Loss of control of these processes may lead to reversible dysfunction in many cell lines including the podocyte, renal tubular cells, and cardiac myocytes. Bardoxolone methyl is a novel nuclear regulator factor (Nrf-2) activator which works to tip the balance of effects towards antioxidation and as an observation made serendipitously, improves renal filtration function in humans after approximately 12 weeks of therapy. The improvement in estimated glomerular filtration can be up to 30% in those with stage 3 and 4 chronic kidney disease. However, experimental evidence suggests there may be a consequence of relative hyperfiltration in diseased kidneys as well as potential adverse effects on skeletal and cardiac myocytes. Only large, prospective randomized trials with carefully collected and adjudicated clinical outcomes will inform the research community on the therapeutic risks and benefits of this important new agent.
PMCID: PMC3392144  PMID: 22787387
bardoxolone methyl; chronic kidney disease; diabetes mellitus; glomerular filtration; cardiomyocyte; oxidative stress
19.  Comparison of the CKD Epidemiology Collaboration (CKD-EPI) and Modification of Diet in Renal Disease (MDRD) Study Equations: Risk Factors for and Complications of CKD and Mortality in the Kidney Early Evaluation Program (KEEP) 
American Journal of Kidney Diseases  2011;57(3 Suppl 2):S9-16.
The National Kidney Foundation has recommended that the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation replace the Modification of Diet in Renal Disease (MDRD) Study equation. Before implementing this change in the Kidney Early Evaluation Program (KEEP), we compared characteristics of reclassified individuals and mortality risk predictions using the new equation.
Of 123,704 eligible KEEP participants, 116,321 with data available for this analysis were included. Glomerular filtration rate (GFR) was estimated using the MDRD Study (eGFRMDRD) and CKD-EPI (eGFRCKD-EPI) equations with creatinine level calibrated to standardized methods. Participants were characterized by eGFR category: >120, 90-119, 60-89, 45-59, 30-44, and <30 mL/min/1.73 m2. Clinical characteristics ascertained included age, race, sex, diabetes, hypertension, coronary artery disease, congestive heart failure, cerebrovascular disease, peripheral vascular disease, and anemia. Mortality was determined over a median of 3.7 years of follow-up.
The prevalence of eGFRCKD-EPI <60 mL/min/1.73 m2 was 14.3% compared with 16.8% using eGFRMDRD. Using eGFRCKD-EPI, 20,355 participants (17.5%) were reclassified to higher eGFR categories, and 3,107 (2.7%), to lower categories. Participants reclassified upward were younger and less likely to have chronic conditions, with a lower risk of mortality. A total of 3,601 deaths (3.1%) were reported. Compared with participants classified to eGFR of 45-59 mL/min/1.73 m2 using both equations, those with eGFRCKD-EPI of 60-89 mL/min/1.73 m2 had a lower mortality incidence rate (6.4 [95% CI, 5.1-7.7] vs 18.5 [95% CI, 17.1-19.9]). Results were similar for all eGFR categories. Net reclassification improvement was 0.159 (P < 0.001).
The CKD-EPI equation reclassifies people at lower risk of CKD and death into higher eGFR categories, suggesting more accurate categorization. The CKD-EPI equation will be used to report eGFR in KEEP.
PMCID: PMC3298760  PMID: 21338849
Chronic kidney disease; glomerular filtration rate estimation; mortality; risk factors
20.  Comparison of the CKD Epidemiology Collaboration (CKD-EPI) and Modification of Diet in Renal Disease (MDRD) Study Equations: Prevalence of and Risk Factors for Diabetes Mellitus in CKD in the Kidney Early Evaluation Program (KEEP) 
Diabetes is a leading cause of chronic kidney disease (CKD). Whether reclassification of CKD stages based on glomerular filtration rate estimated using the CKD Epidemiology Collaboration (CKD-EPI) equation versus the Modification of Diet in Renal Disease (MDRD) Study equation modifies estimates of prevalent risk factors across stages is unknown.
This is a cross-sectional analysis of data from the Kidney Early Evaluation Program (KEEP), a community-based health screening program targeting individuals 18 years and older with diabetes, hypertension, or a family history of diabetes, hypertension, or kidney disease. Of 109,055 participants, 68.2% were women and 31.8% were African American. Mean age was 55.3 ± 0.05 years. Clinical, demographic, and laboratory data were collected from August 2000 through December 2009. Glomerular filtration rate was estimated using the CKD-EPI and MDRD Study equations.
CKD was present in 25.6% and 23.5% of the study population using the MDRD Study and CKD-EPI equations, respectively. Diabetes was present in 42.4% and 43.8% of participants with CKD, respectively. Prevalent risk factors for diabetes included obesity (body mass index >30 kg/m2), 44.0%; hypertension, 80.5%; cardiovascular disease, 23.2%; family history of diabetes, 55.9%; and dyslipidemia, 43.0%. In a logistic regression model after adjusting for age and other risk factors, odds for diabetes increased significantly compared with no CKD with each CKD stage based on the CKD-EPI equation and similarly with stages based on the MDRD Study equation. Using a CKD-EPI–adjusted model, ORs were: stage 1, 2.08 (95% CI, 1.90–2.27); stage 2, 1.86 (95% CI, 1.72–2.02); stage 3, 1.23 (95% CI, 1.17–1.30); stage 4, 1.69 (95% CI, 1.42–2.03); and stage 5, 2.46 (95% CI, 1.46–4.14).
Using the CKD-EPI equation led to a lower prevalence of CKD but to similar diabetes prevalence rates associated with CKD across all stages compared with the MDRD Study equation. Diabetes and other CKD risk factor prevalence was increased compared with the non-CKD population.
PMCID: PMC3237700  PMID: 21338847
Chronic kidney disease; diabetes mellitus; estimated glomerular filtration rate
21.  Gestational Diabetes Mellitus Alone in the Absence of Subsequent Diabetes Is Associated With Microalbuminuria 
Diabetes Care  2010;33(12):2586-2591.
Women with gestational diabetes mellitus (GDM) maintain a higher risk for recurrent GDM and overt diabetes. Overt diabetes is a risk factor for development of chronic kidney disease (CKD), but GDM alone, without subsequent development of overt diabetes, may also pose a risk for CKD.
This cross-sectional analysis included Kidney Early Evaluation Program (KEEP) participants from 2000 to 2009. Patient characteristics and kidney function among three categories (GDM alone, overt diabetes, and no history of diabetes) were compared. The prevalence of microalbuminuria, macroalbuminuria, and CKD stages 1–2 and 3–5 was assessed using logistic regression.
Of 37,716 KEEP female participants, 571 (1.5%) had GDM alone and 12,100 (32.1%) had overt diabetes. Women with GDM had a higher rate of microalbuminuria but not macroalbuminuria than their nondiabetic peers (10.0 vs. 7.7%) that was substantially lower than the 13.6% prevalence in diabetic women. In multivariate analysis, women with GDM alone, compared with nondiabetic women, demonstrated increased odds of CKD stages 1–2 (multivariate odds ratio 1.54 [95% CI 1.16–2.05]) similar to the odds for women with overt diabetes (1.68 [1.55–1.82]). In stratified analyses, age, race, BMI, and hypertension modified the odds for CKD stages 1 –2 but not CKD stages 3–5 among women with GDM.
Women with GDM alone have a higher prevalence of microalbuminuria than women without any history of diabetes, translating to higher rates of CKD stages 1–2. These results suggest that GDM, even in the absence of subsequent overt diabetes, may increase the risk for future cardiovascular and kidney disease.
PMCID: PMC2992195  PMID: 20807871
22.  Kidney Function, Albuminuria, and All-Cause Mortality in the REGARDS (Reasons for Geographic and Racial Differences in Stroke) Study 
Chronic kidney disease (CKD) and albuminuria are associated with increased risk of all-cause mortality.
Study Design
Prospective observational cohort study
Setting and Participants
17,393 participants (mean age, 64.3 ± 9.6 years) in the REGARDS (Reasons for Geographic and Racial Differences in Stroke) Study.
Estimated glomerular filtration rate (eGFR), urinary albumin-creatinine ratio (ACR).
All-cause mortality (710 deaths); median duration of follow-up: 3.6 years.
Measurements and Analysis
Categories of eGFR (90– <120, 60–<90, 45–<60, 30–<45, and 15–<30 mL/min/1.73 m2) and urinary ACR (<10 mg/g or normal, 10–<30 mg/g or high normal, 30–300 mg/g or high, and >300 mg/g or very high). Cox’s proportional hazards models were adjusted for demographic factors, cardiovascular covariates, and hemoglobin.
The background all-cause mortality rate for participants with normal ACR, eGFR of 90–<120 mL/min/1.73 m2 and no CHD was 4.3 deaths/1,000 person-years. Higher ACR was associated with an increased multivariable adjusted hazard ratio for all-cause mortality within each eGFR category. Reduced eGFR was associated with higher adjusted hazard ratio for all-cause mortality for participants with high normal (P value = 0.01) and high (P value <0.001) ACR values, but not for those with normal or very high ACR values.
Only one laboratory assessment for serum creatinine and ACR was available
Increased albuminuria was an independent risk factor for all-cause mortality. Reduced eGFR was associated with increased mortality risk among those with high normal and high ACR. The mortality rate was low in the normal ACR group and increased in the very high ACR group but did not vary with eGFR in these groups.
PMCID: PMC2963678  PMID: 20692752
23.  Cardiovascular Disease in Chronic Kidney Disease: Data from the Kidney Early Evaluation Program (KEEP) 
Current diabetes reports  2011;11(1):47-55.
Diabetes mellitus (DM) and hypertension (HTN) are leading joint risk factors for both cardiovascular disease (CVD) and chronic kidney disease (CKD). In the nationwide KEEP (Kidney Early Evaluation Program) an estimated glomerular filtration rate less than 60 mL/min/1.73 m2 or a urine albumin:creatinine ratio ≥30 mg/g (3.4 mg/mmol) defines CKD. Overall in KEEP, the rates of identified CKD and self-reported CVD are 25.7% and 22.1%, respectively. The presence of CKD has been associated with younger ages of self-reported myocardial infarction and stroke. The combination of CVD and CKD in KEEP has been associated with shorter survival time. Finally, the presence of CVD or a prior history of coronary revascularization has been associated with modestly better rates of CVD risk factor control; however, the majority of patients with CKD have suboptimally controlled blood pressure, glucose, or lipids. These data suggest that patients with CKD are not only at higher risk for CVD and subsequent mortality, but are also ideal for targeted community—and practice-based interventions to improve risk factor control and, hopefully, reduce rates of subsequent cardiovacular events.
PMCID: PMC3206095  PMID: 21076895
Cardiovascular disease; Chronic kidney disease; Atherosclerosis; Myocardial infarction; Percutaneous coronary intervention; Microalbuminuria; Bypass surgery; Risk factors
24.  Effects of Intra-Arterial and Intravenous Iso-Osmolar Contrast Medium (Iodixanol) on the Risk of Contrast-Induced Acute Kidney Injury: A Meta-Analysis 
Cardiorenal Medicine  2011;1(4):220-234.
The iso-osmolar contrast agent iodixanol may be associated with a lower incidence of contrast-induced acute kidney injury (CI-AKI) than low-osmolar contrast media (LOCM), but previous meta-analyses have yielded mixed results. Objectives: To compare the incidence of CI-AKI between iodixanol and LOCM.
Studies were identified from literature searches to December 2009,, and conference abstracts from the past 2 years including 2010. Only prospective, randomized comparisons between iodixanol and LOCM with CI-AKI [increase in serum creatinine (sCr) ≥0.5 mg/dl or ≥25% from baseline, as defined in the trial] as a primary and/or secondary endpoint and a Jadad score ≥2 were included. A random-effects model was used to obtain pooled relative risks (RRs) for CI-AKI in analyses based on route of administration [intra-arterial (IA) or intravenous (IV)], definition of CI-AKI, and timing of sCr measurements.
145 potential articles were identified, of which 25 were included in the meta-analysis. Following IA administration (n = 19), the RR for CI-AKI (≥0.5 mg/dl definition) with iodixanol, compared with LOCM, was 0.462 [95% confidence interval (CI): 0.272–0.786, p = 0.004, 15 studies]. Using the ≥25% definition, there was a lower incidence of CI-AKI with iodixanol versus LOCM, but the difference was not statistically significant (RR: 0.577, 95% CI: 0.297–1.12, p = 0.104, 11 studies). In the IV trials, there was no significant difference in the incidence of CI-AKI using either definition (≥0.5 mg/dl definition: RR: 0.967, 95% CI: 0.188–4.972, p = 0.968, 3 trials; ≥25% definition: RR: 0.656, 95% CI: 0.316–1.360, p = 0.257, 4 trials).
IA but not IV administration of iodixanol is associated with a significantly lower risk of CI-AKI than LOCM.
PMCID: PMC3222111  PMID: 22164156
Acute kidney injury; Clinical trials; Contrast agents; Iodixanol; Iso-osmolar contrast agent; Low-osmolar contrast agent; Meta-analysis
25.  Impact of Reduced Kidney Function on Cardiopulmonary Fitness in Patients with Systolic Heart Failure 
American Journal of Nephrology  2010;32(3):226-233.
Decreased renal function has been consistently associated with increased mortality among patients with systolic heart failure. The relationship between estimated glomerular filtration rate (eGFR) and other high-risk features including reduced cardiorespiratory fitness has not been previously reported in this patient population.
The HF-ACTION trial was a prospective, randomized trial of exercise therapy versus usual care in patients with systolic heart failure. Patients with class 2–4 heart failure and a left ventricular ejection fraction of ≤35% were recruited. Serum creatinine was measured up to 1 year prior to entry. The 4-variable modified Modification of Diet in Renal Disease equation was used to calculate eGFR. Peak oxygen consumption (peak VO2) was directly measured using gas exchange analysis during progressive exercise testing to volitional fatigue or adverse signs/symptoms.
Of 2,091 subjects (mean age 59 ± 13 years, with serum creatinine available at baseline), 72% were men, and 61, 33, and 5% were Caucasians, African Americans, and others, respectively. Older age, diabetes, and hypertension were all more frequent with declining eGFR. The Pearson correlation between eGFR and peak VO2 was 0.22 (p < 0.0001). Age was negatively correlated with both eGFR (r = −0.44, p < 0.0001) and peak VO2 (r = −0.27, p < 0.0001). The peak VO2 tended to decline across decreasing levels of eGFR. Individuals with an eGFR <30 ml/min/1.73 m2 had, on average, 2.1 high-risk features including peak VO2 <14 ml/kg/min, age >75 years, diabetes, and functional class 3–4 symptoms. Conversely, those with an eGFR >90 ml/min/1.73 m2 had relatively few (1.0) high-risk characteristics.
Reduced renal filtration is associated with impaired cardiorespiratory fitness and a clustering of high-risk features in systolic heart failure patients which portend a more complicated course and higher all-cause mortality.
PMCID: PMC2980519  PMID: 20664198
Heart failure; Chronic kidney disease; Cardiopulmonary fitness; Glomerular filtration rate; Renal insufficiency; Mortality risk

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