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1.  Higher serum bicarbonate levels within the normal range are associated with better survival and renal outcomes in African Americans 
Kidney international  2010;79(3):356-362.
Recent studies suggest that correcting low serum bicarbonate levels may reduce the progression of kidney disease; however, few patients with chronic kidney disease have low serum bicarbonate. Therefore, we examined whether higher levels of serum bicarbonate within the normal range (20–30 mmol/l) were associated with better kidney outcomes in the African American Study of Kidney Disease and Hypertension (AASK) trial. At baseline and during follow-up of 1094 patients, the glomerular filtration rates (GFR) were measured by iothalamate clearances and events were adjudicated by the outcomes committee. Mean baseline serum bicarbonate, measured GFR, and proteinuria were 25.1 mmol/l, 46 ml/min per 1.73 m2, and 326 mg/g of creatinine, respectively. Each 1 mmol/l increase in serum bicarbonate within the normal range was associated with reduced risk of death, dialysis, or GFR event and with dialysis or GFR event (hazard ratios of 0.942 and 0.932, respectively) in separate multivariable Cox regression models that included errors-in-variables calibration. Cubic spline regression showed that the lowest risk of GFR event or dialysis was found at serum bicarbonate levels near 28–30 mmol/l. Thus, our study suggests that serum bicarbonate is an independent predictor of CKD progression. Whether increasing serum bicarbonate into the high-normal range will improve kidney outcomes during interventional studies will need to be considered.
PMCID: PMC5241271  PMID: 20962743
AASK (African American Study of Kidney Disease and Hypertension); acidosis; chronic kidney disease; survival
2.  GFR Estimation Using β-Trace Protein and β2-Microglobulin in CKD 
β-trace protein (BTP) and β2-microglobulin (B2M) are novel glomerular filtration markers that have stronger associations with adverse outcomes than creatinine. Comparisons of BTP and B2M to creatinine and cystatin C are limited by the absence of rigorously developed GFR estimating equations for the novel markers.
Study Design
Study of diagnostic test accuracy.
Setting & Participants
Pooled database of three populations with chronic kidney disease (CKD) with mean measured GFR of 48 ml/min/1.73m2 (N=3551; MDRD [Modification of Diet in Renal Disease] Study, AASK [African American Study of Kidney Disease and Hypertension], and CRIC [Chronic Renal Insufficiency Cohort] Study).
Index Tests
GFR estimated using creatinine, cystatin C, BTP or B2M
Reference Test
GFR measured as the urinary clearance of iothalamate.
For BTP and B2M, coefficients for age, sex and race were smaller than for creatinine, and were similar or smaller than for cystatin C. For B2M, coefficients for sex, age and race were smaller than for creatinine, and were similar (age and race) or smaller (sex) than for cystatin C. The final equations with BTP (BTP, age and sex) or B2M (B2M alone) were less accurate than either the CKD-EPI (CKD Epidemiology Collaboration) creatinine or cystatin C equations. The combined BTP-B2M equation (BTP and B2M alone) had similar accuracy to the CKD-EPI creatinine or cystatin C equation. The average of the BTP-B2M equation and the CKD-EPI creatinine-cystatin C equation was not more accurate than the CKD-EPI creatinine-cystatin C equation.
No external validation population, study population was restricted to CKD, few participants older than 65 years or non-black, non-white race.
BTP and B2M are less influenced by age, sex and race than creatinine and less influenced by race than cystatin C, but provide less accurate GFR estimates than the CKD-EPI creatinine and cystatin C equations. The CKD-EPI BTP and B2M equation provides a methodological advance for their study as filtration markers and in their associations with risk and adverse outcomes, but further study is required before clinical use.
PMCID: PMC4695294  PMID: 26362696
Beta-trace protein (BTP); beta-2-microglobulin (B2M); filtration marker; chronic kidney disease (CKD); estimated glomerular filtration rate (eGFR); measured GFR; estimating equation; kidney function; diagnostic accuracy
3.  Trends in Antibiotic Use and Nosocomial Pathogens in Hospitalized Veterans With Pneumonia at 128 Medical Centers, 2006–2010 
This national Department of Veterans Affairs study of hospitalizations for pneumonia found a dramatic increase in broad-spectrum antibiotic use from 2006 to 2010, without an increase in nosocomial pathogens or improvement in the match between coverage and pathogen.
Background. In 2005, pneumonia practice guidelines recommended broad-spectrum antibiotics for patients with risk factors for nosocomial pathogens. The impact of these recommendations on the ability of providers to match treatment with nosocomial pathogens is unknown.
Methods. Among hospitalizations with a principal diagnosis of pneumonia at 128 Department of Veterans Affairs medical centers from 2006 through 2010, we measured annual trends in antibiotic selection; initial blood or respiratory cultures positive for methicillin-resistant Staphylococcus aureus (MRSA), Pseudomonas aeruginosa, and Acinetobacter species; and alignment between antibiotic coverage and culture results for MRSA and P. aeruginosa, calculating sensitivity, specificity, and diagnostic odds ratio using a 2 × 2 contingency table.
Results. In 95 511 hospitalizations for pneumonia, initial use of vancomycin increased from 16% in 2006 to 31% in 2010, and piperacillin-tazobactam increased from 16% to 27%, and there was a decrease in both ceftriaxone (from 39% to 33%) and azithromycin (change from 39% to 36%) (P < .001 for all). The proportion of hospitalizations with cultures positive for MRSA decreased (from 2.5% to 2.0%; P < .001); no change was seen for P. aeruginosa (1.9% to 2.0%; P = .14) or Acinetobacter spp. (0.2% to 0.2%; P = .17). For both MRSA and P. aeruginosa, sensitivity increased (from 46% to 65% and 54% to 63%, respectively; P < .001) and specificity decreased (from 85% to 69% and 76% to 68%; P < .001), with no significant changes in diagnostic odds ratio (decreases from 4.6 to 4.1 [P = .57] and 3.7 to 3.2 [P = .95], respectively).
Conclusions. Between 2006 and 2010, we found a substantial increase in the use of broad-spectrum antibiotics for pneumonia despite no increase in nosocomial pathogens. The ability of providers to accurately match antibiotic coverage to nosocomial pathogens remains low.
PMCID: PMC4599396  PMID: 26223995
pneumonia; antibiotic use; HCAP; nosocomial pathogens; drug-resistant pneumonia
4.  The effects of weight change on glomerular filtration rate 
Nephrology Dialysis Transplantation  2015;30(11):1870-1877.
Little is known about the effect of weight loss/gain on kidney function. Analyses are complicated by uncertainty about optimal body surface indexing strategies for measured glomerular filtration rate (mGFR).
Using data from the African-American Study of Kidney Disease and Hypertension (AASK), we determined the association of change in weight with three different estimates of change in kidney function: (i) unindexed mGFR estimated by renal clearance of iodine-125-iothalamate, (ii) mGFR indexed to concurrently measured BSA and (iii) GFR estimated from serum creatinine (eGFR). All models were adjusted for baseline weight, time, randomization group and time-varying diuretic use. We also examined whether these relationships were consistent across a number of subgroups, including tertiles of baseline 24-h urine sodium excretion.
In 1094 participants followed over an average of 3.6 years, a 5-kg weight gain was associated with a 1.10 mL/min/1.73 m2 (95% CI: 0.87 to 1.33; P < 0.001) increase in unindexed mGFR. There was no association between weight change and mGFR indexed for concurrent BSA (per 5 kg weight gain, 0.21; 95% CI: −0.02 to 0.44; P = 0.1) or between weight change and eGFR (−0.09; 95% CI: −0.32 to 0.14; P = 0.4). The effect of weight change on unindexed mGFR was less pronounced in individuals with higher baseline sodium excretion (P = 0.08 for interaction).
The association between weight change and kidney function varies depending on the method of assessment. Future clinical trials should examine the effect of intentional weight change on measured GFR or filtration markers robust to changes in muscle mass.
PMCID: PMC4617373  PMID: 26085555
body surface area; glomerular filtration rate; indexing; obesity; weight
5.  Long-term Effects of Frequent Nocturnal Hemodialysis on Mortality: The Frequent Hemodialysis Network (FHN) Nocturnal Trial 
Little data are available regarding the long-term mortality rate for patients receiving nocturnal home hemodialysis.
Study Design
Post-trial observational study.
Setting & Participants
Frequent Hemodialysis Network (FHN) Nocturnal Trial participants who consented to extended follow-up.
The FHN Nocturnal Trial randomized 87 subjects to 6-times-per-week home nocturnal hemodialysis or to 3-times-per-week hemodialysis for one year. Patients were enrolled starting in March 2006 and follow-up was completed by May 2010. After the one year trial concluded, FHN Nocturnal subjects were free to modify their hemodialysis prescription.
Outcomes & Measurements
We obtained dates of death and kidney transplantation through July 2011 using linkage to the US Renal Data System and queries of study centers. We used log-rank tests and Cox regression to relate mortality to the initial randomization assignment.
Median follow-up for the trial and post trial observational period was 3.7 years. In the nocturnal arm, there were 2 deaths during the 12 month trial period and an additional 12 deaths during the extended follow-up. In the conventional arm, the numbers of deaths were 1 and 4, respectively. In the nocturnal dialysis group, the overall mortality HR was 3.88 (95% CI, 1.27-11.79; p = 0.01). Using as-treated analysis with a 12 month running treatment average, the HR for mortality was 3.06 (95% CI, 1.11-8.43; p = 0.03). Six month running treatment data analysis showed an HR of 1.12 (95% CI, 0.44-3.22; p = 0.7).
These results should be interpreted cautiously due to a surprisingly low (0.03 per patient-year) mortality rate for subjects randomized to conventional home hemodialysis, low statistical power for the mortality comparison due to the small sample size, and the high rate of hemodialysis prescription changes.
Patients randomized to nocturnal hemodialysis had a higher mortality rate than those randomized to conventional dialysis. The implications of this result require further investigation.
PMCID: PMC4549208  PMID: 25863828
Nocturnal hemodialysis; frequent hemodialysis; extended hemodialysis; frequent-long dialysis schedule; clinical trial; mortality; hemodialysis prescription; dialysis dose; dialysis adequacy; dialysis regimen; end-stage renal disease (ESRD); renal replacement therapy; Frequent Hemodialysis Network (FHN) Nocturnal Trial
6.  Longitudinal changes in hematocrit in hypertensive chronic kidney disease: results from the African-American Study of Kidney Disease and Hypertension (AASK) 
Nephrology Dialysis Transplantation  2015;30(8):1329-1335.
Anemia is common in chronic kidney disease (CKD) and associated with poor outcomes. In cross-sectional studies, lower estimated glomerular filtration rate (eGFR) has been associated with increased risk for anemia. The aim of this study was to determine how hematocrit changes as eGFR declines and what factors impact this longitudinal association.
We followed 1094 African-Americans with hypertensive nephropathy who participated in the African-American Study of Kidney Disease and Hypertension. Mixed effects models were used to determine longitudinal change in hematocrit as a function of eGFR. Interaction terms were used to assess for differential effects of age, gender, baseline eGFR, baseline proteinuria, malnutrition and inflammation on eGFR-associated declines in hematocrit. In sensitivity analyses, models were run using iGFR (by renal clearance of I125 iothalamate) in place of eGFR.
At baseline, mean hematocrit was 39% and 441 (40%) individuals had anemia. The longitudinal relationship between eGFR and hematocrit differed by baseline eGFR and was steeper when baseline eGFR was <45 mL/min/1.73 m2. For example, the absolute decline in hematocrit per 10 mL/min/1.73 m2 decline in longitudinal eGFR was −3.7, −1.3 and −0.5% for baseline eGFR values of 20, 40 and 60 mL/min/1.73 m2, respectively (P < 0.001 comparing the longitudinal association between baseline eGFR = 40 or 60 versus baseline eGFR = 20 mL/min/1.73 m2). Similarly, male sex, younger age (<65 years) and higher baseline proteinuria (protein-to-creatinine ratio >0.22) were associated with greater hematocrit declines per unit decrease in longitudinal eGFR compared with female sex, older age and low baseline proteinuria, respectively (P-interaction <0.05 for each comparison). The longitudinal eGFR–hematocrit association did not differ by body mass index, serum albumin or C-reactive protein.
Men, younger individuals and those with low baseline eGFR (<45 mL/min/1.73 m2) or baseline proteinuria are particularly at risk for eGFR-related declines in hematocrit.
PMCID: PMC4513895  PMID: 25817226
African-American Study of Kidney Disease and Hypertension (AASK); anemia; chronic kidney disease; hematocrit
7.  Effect of Clopidogrel on Early Failure of Arteriovenous Fistulas for Hemodialysis 
JAMA  2008;299(18):2164-2171.
The arteriovenous fistula is the preferred type of vascular access for hemodialysis because of lower thrombosis and infection rates and lower health care expenditures compared with synthetic grafts or central venous catheters. Early failure of fistulas due to thrombosis or inadequate maturation is a barrier to increasing the prevalence of fistulas among patients treated with hemodialysis. Small, inconclusive trials have suggested that antiplatelet agents may reduce thrombosis of new fistulas.
To determine whether clopidogrel reduces early failure of hemodialysis fistulas.
Design, Setting, and Participants
Randomized, double-blind, placebo-controlled trial conducted at 9 US centers composed of academic and community nephrology practices in 2003–2007. Eight hundred seventy-seven participants with end-stage renal disease or advanced chronic kidney disease were followed up until 150 to 180 days after fistula creation or 30 days after initiation of dialysis, whichever occurred later.
Participants were randomly assigned to receive clopidogrel (300-mg loading dose followed by daily dose of 75 mg; n = 441) or placebo (n = 436) for 6 weeks starting within 1 day after fistula creation.
Main Outcome Measures
The primary outcome was fistula thrombosis, determined by physical examination at 6 weeks. The secondary outcome was failure of the fistula to become suitable for dialysis. Suitability was defined as use of the fistula at a dialysis machine blood pump rate of 300 mL/min or more during 8 of 12 dialysis sessions.
Enrollment was stopped after 877 participants were randomized based on a stopping rule for intervention efficacy. Fistula thrombosis occurred in 53 (12.2%) participants assigned to clopidogrel compared with 84 (19.5%) participants assigned to placebo (relative risk, 0.63; 95% confidence interval, 0.46–0.97; P = .018). Failure to attain suitability for dialysis did not differ between the clopidogrel and placebo groups (61.8% vs 59.5%, respectively; relative risk, 1.05; 95% confidence interval, 0.94–1.17; P = .40).
Clopidogrel reduces the frequency of early thrombosis of new arteriovenous fistulas but does not increase the proportion of fistulas that become suitable for dialysis.
Trial Registration Identifier: NCT00067119
PMCID: PMC4943222  PMID: 18477783
8.  Non-linear heart rate variability indices in the Frequent Hemodialysis Network trials of chronic hemodialysis patients 
Blood purification  2015;40(1):99-108.
Non-linear heart rate variability (HRV) indices were hypothesized to correlate with cardiac function, fluid overload and physical performance in hemodialysis patients
24-hour Holter electrocardiograms were recorded in patients enrolled in the Frequent Hemodialysis Network (FHN) Daily Dialysis Trial. Correlations between nonlinear HRV indices and left-ventricular ejection fraction (LVEF), left-ventricular end-diastolic volume (LVEDV), extracellular volume (ECV)/total-body water (TBW) ratio, the SF-36 Physical Health Composite (PHC) and Physical Functioning scores (PF) were tested.
We studied 210 subjects [average age 49.8±13.5 years, 62% males, 42% diabetics]. In non-diabetic patients, MSE SampEn and MSE ApEn correlated positively with LVEF, PF, PH, and inversely with LVEDV and ECV/TBW. SPS correlated positively with ECV/TBW (r=0.27). Irregularity measures (MSE ApEn, MSE SampEn) correlated positively with LVEDV (r=0.19 and 0.20).
Nonlinear HRV indices indicated an association between a deteriorated heart rate regulatory system and impaired cardiac function, fluid accumulation and poor physical condition.
PMCID: PMC4540641  PMID: 26159747
Cardiac function; cardiac MRI; fluid status; hemodialysis; heart rate variability
9.  Effects of Frequent Hemodialysis on Blood Pressure: Results from the Randomized Frequent Hemodialysis Network Trials 
Hypertension is a common complication of chronic kidney disease (CKD) and persists among most patients with end-stage renal disease (ESRD) despite the provision of conventional thrice weekly hemodialysis.
We analysed the effects of frequent hemodialysis on blood pressure in the randomized controlled Frequent Hemodialysis Network Trials. The Daily Trial randomized 245 patients to 12 months of 6× (“frequent”) versus 3× (“conventional”) weekly in-center hemodialysis; the Nocturnal Trial randomized 87 patients to 12 months of 6× weekly nocturnal hemodialysis versus 3× weekly predominantly home-based hemodialysis.
In the Daily Trial, compared to 3× weekly hemodialysis, two months of frequent hemodialysis lowered pre-dialysis systolic blood pressure by −7.7 mmHg [95%CI: −11.9 to −3.5] and diastolic blood pressure by −3.9 mmHg [95%CI: −6.5 to −1.3]. In the Nocturnal Trial, compared to 3× weekly hemodialysis, two months of frequent hemodialysis lowered systolic blood pressure by −7.3 mmHg [95%CI: −14.2 to −0.3] and diastolic blood pressure by −4.2 mmHg [95%CI: −8.3 to −0.1]). In both trials blood pressure treatment effects were sustained until month 12. Frequent hemodialysis resulted in significantly fewer antihypertensive medications (Daily: −0.36 medications [95%CI: −0.65 to −0.08]; Nocturnal: −0.44 mediations [95%CI: −0.89 to −0.03]). In the Daily Trial, the relative risk per dialysis session for intradialytic hypotension was lower with 6×/week HD but given the higher number of sessions per week, there was a higher relative risk for IDH requiring saline administration.
Frequent hemodialysis reduces blood pressure and the number of prescribed antihypertensive medications.
PMCID: PMC4490029  PMID: 25560227
blood pressure; hypertension; hemodialysis; frequent hemodialysis; nocturnal hemodialysis
10.  The Phosphate Binder Ferric Citrate and Mineral Metabolism and Inflammatory Markers in Maintenance Dialysis Patients: Results From Prespecified Analyses of a Randomized Clinical Trial 
Phosphate binders are the cornerstone of hyperphosphatemia management in dialysis patients. Ferric citrate is an iron-based oral phosphate binder that effectively lowers serum phosphorus levels.
Study Design
52-week, open-label, phase 3, randomized, controlled trial for safety-profile assessment.
Setting & Participants
Maintenance dialysis patients with serum phosphorus levels ≥6.0 mg/dL after washout of prior phosphate binders.
2:1 randomization to ferric citrate or active control (sevelamer carbonate and/or calcium acetate).
Changes in mineral bone disease, protein-energy wasting/inflammation, and occurrence of adverse events after 1 year.
Serum calcium, intact parathyroid hormone, phosphorus, aluminum, white blood cell count, percentage of lymphocytes, serum urea nitrogen, and bicarbonate.
There were 292 participants randomly assigned to ferric citrate, and 149, to active control. Groups were well matched. For mean changes from baseline, phosphorus levels decreased similarly in the ferric citrate and active control groups (−2.04 ± 1.99 [SD] vs −2.18 ± 2.25 mg/dL, respectively; P = 0.9); serum calcium levels increased similarly in the ferric citrate and active control groups (0.22 ± 0.90 vs 0.31 ± 0.95 mg/dL; P = 0.2). Hypercalcemia occurred in 4 participants receiving calcium acetate. Parathyroid hormone levels decreased similarly in the ferric citrate and active control groups (−167.1 ± 399.8 vs −152.7 ± 392.1 pg/mL; P = 0.8). Serum albumin, bicarbonate, serum urea nitrogen, white blood cell count and percentage of lymphocytes, and aluminum values were similar between ferric citrate and active control. Total and low-density lipoprotein cholesterol levels were lower in participants receiving sevelamer than those receiving ferric citrate and calcium acetate. Fewer participants randomly assigned to ferric citrate had serious adverse events compared with active control.
Open-label study, few peritoneal dialysis patients.
Ferric citrate was associated with similar phosphorus control compared to active control, with similar effects on markers of bone and mineral metabolism in dialysis patients. There was no evidence of protein-energy wasting/inflammation or aluminum toxicity, and fewer participants randomly assigned to ferric citrate had serious adverse events. Ferric citrate is an effective phosphate binder with a safety profile comparable to sevelamer and calcium acetate.
PMCID: PMC4868355  PMID: 25958079
Hemodialysis; hyperphosphatemia; ferric citrate; sevelamer carbonate; calcium acetate; phosphate binder; mineral bone disease; protein-energy wasting (PEW)/inflammation; adverse events; safety; end-stage renal disease (ESRD)
11.  Estimating Time to ESRD Using Kidney Failure Risk Equations: Results From the African American Study of Kidney Disease and Hypertension (AASK) 
Planning for renal replacement therapy, such as referral for arteriovenous fistula placement and transplantation, is often guided by level of estimated glomerular filtration rate (eGFR). The use of risk equations might enable more accurate estimation of time to end-stage renal disease (ESRD), thus improving patient care.
Study Design
Prospective observational study.
Setting & Participants
1,094 participants in the African-American Study of Kidney Disease and Hypertension (AASK) cohort.
Age, sex, urine protein-creatinine ratio ≥1 g/g, APOL1 high-risk status, and 3-year antecedent eGFR decline.
Cumulative incidence of ESRD from five different starting points: eGFR values of 30 and 15 ml/min/1.73 m2, and a 5%, 10%, and 20% 1-year ESRD risk, estimated by a published, 4-variable kidney failure risk equation.
There were 566 participants who developed an eGFR of 30 ml/min/1.73 m2, 244 who developed eGFR of 15 ml/min/1.73 m2, and 437, 336, and 259 who developed a 5%, 10%, and 20% 1-year ESRD risk, respectively. The 1-year cumulative incidence of ESRD was 4.3% from eGFR 30 ml/min/1.73 m2, 49.0% from eGFR 15 ml/min/1.73 m2, 6.7% from 5% ESRD risk, 15.0% from 10% ESRD risk, and 29% from 20% ESRD risk. From eGFR 30 ml/min/1.73 m2, there were several risk factors that predicted ESRD risk. From eGFR 15 ml/min/1.73 m2, only level of proteinuria did; median time to ESRD was 9 and 19 months in those with higher and lower proteinuria, respectively. Median times were less variable from corresponding ESRD risk thresholds. For example, median time to ESRD from 20% ESRD risk was 22 and 25 months among those with higher and lower proteinuria, respectively.
Relatively homogeneous population of African Americans with hypertensive kidney disease.
The results of the present study suggest the potential benefit of incorporating kidney failure risk equations into clinical care, with selection of a specific threshold guided by its intended use.
PMCID: PMC4339439  PMID: 25441435
end-stage renal disease (ESRD); estimated glomerular filtration rate (eGFR); proteinuria; kidney failure risk equations; risk; disease trajectory; disease progression; prognosis; clinical decision making; African-American Study of Kidney Disease and Hypertension (AASK); hypertensive kidney disease
12.  High dietary fiber intake is associated with decreased inflammation and all-cause mortality in patients with chronic kidney disease 
Kidney international  2011;81(3):300-306.
Chronic kidney disease is considered an inflammatory state and a high fiber intake is associated with decreased inflammation in the general population. Here, we determined whether fiber intake is associated with decreased inflammation and mortality in chronic kidney disease, and whether kidney disease modifies the associations of fiber intake with inflammation and mortality. To do this, we analyzed data from 14,543 participants in the National Health and Nutrition Examination Survey III. The prevalence of chronic kidney disease (estimated glomerular filtration rate less than 60 ml/min per 1.73 m2) was 5.8%. For each 10-g/day increase in total fiber intake, the odds of elevated serum C-reactive protein levels were decreased by 11% and 38% in those without and with kidney disease, respectively. Dietary total fiber intake was not significantly associated with mortality in those without but was inversely related to mortality in those with kidney disease. The relationship of total fiber with inflammation and mortality differed significantly in those with and without kidney disease. Thus, high dietary total fiber intake is associated with lower risk of inflammation and mortality in kidney disease and these associations are stronger in magnitude in those with kidney disease. Interventional trials are needed to establish the effects of fiber intake on inflammation and mortality in kidney disease.
PMCID: PMC4704855  PMID: 22012132
all-cause mortality; chronic kidney disease; inflammation
13.  Changes in dietary protein intake has no effect on serum cystatin C levels independent of the glomerular filtration rate 
Kidney international  2010;79(4):471-477.
Cystatin C is being considered as a replacement for serum creatinine for estimating glomerular filtration rate (GFR). Data are limited on the non-GFR determinants of cystatin C and their relationship with protein intake. We compared creatinine and cystatin C levels at baseline (N=741) and at 24 months post-randomization (N=426) for participants in the Modification of Diet in Renal Disease Study. Participants in Study A (GFR 25-55 ml/min/1.73 m2) were assigned a low (0.58 g/kg/day) vs. usual (1.3 g/kg/day) protein intake, and in Study B (GFR 13-24 ml/min/1.73 m2), a very low (0.28 g/kg/day) vs. low protein intake. We associated creatinine, cystatin C and estimated protein intake at baseline and compared randomized groups to examine the effect of protein intake on creatinine and cystatin C independent of GFR. The mean (SD) measured GFR, creatinine and cystatin C at baseline was 38.6 (8.9) ml/min/1.73 m2, 1.9 (0.5) mg/dl, 1.9 (0.4) mg/l in Study A and 18.5 (3.4) ml/min/1.73 m2, 3.4 (0.9) mg/dl, 3.0 (0.5) mg/l in Study B. Lower dietary protein intake reduced change in creatinine, but did not affect change in cystatin C [Δ(CI) creatinine vs. cystatin C, −0.22 (−0.36, −0.08) mg/dl vs. 0.02 (−0.08, 0.13) mg/l in Study A, −0.28 mg/dl (−0.82, 0.21) vs. 0.10 (−0.15, 0.26) mg/l in Study B]. Creatinine, but not cystatin C, is affected by dietary protein intake independent of GFR. Cystatin C may allow more accurate GFR estimates than creatinine for patients with reduced protein intake.
PMCID: PMC4557795  PMID: 20980977
14.  Factors Other than GFR Affecting Serum Cystatin C Levels 
Kidney international  2008;75(6):652-660.
Cystatin C is gaining acceptance as an endogenous filtration marker. Factors other than glomerular filtration rate (GFR) that affect the serum level have not been carefully studied. In a cross-sectional analysis of a pooled dataset of participants from clinical trials and a clinical population with chronic kidney disease (N=3418), we related serum levels of cystatin C and creatinine to clinical and biochemical variables after adjustment for GFR using errors-in-variables models to account for GFR measurement error. GFR was measured as urinary clearance of 125I-iothalamate and 15Cr-EDTA. Cystatin C was assayed at a single laboratory and creatinine was standardized to reference methods. Mean (SD) creatinine and cystatin C were 2.1 (1.1) mg/dL and 1.8 (0.8) mg/L, respectively. After adjustment for GFR, cystatin C was 4.3% lower for every 20 years of age, 9.2% lower for female sex but only 1.9% lower in blacks. Diabetes was associated with 8.5% higher levels of cystatin C and 3.9% lower levels of creatinine. Higher C-reactive protein and white blood cell count and lower serum albumin were associated with higher levels of cystatin C and lower levels of creatinine. Adjustment for age, sex and race had a greater effect on association of factors with creatinine than cystatin C. In conclusion, cystatin C is affected by factors other than GFR. Clinicians should consider these factors when interpreting the serum levels or GFR estimates from cystatin C.
PMCID: PMC4557800  PMID: 19119287
15.  Relationship Between Body Mass Index and Proteinuria in Hypertensive Nephrosclerosis: Results From the African American Study of Kidney Disease and Hypertension (AASK) Cohort 
Few studies have examined the association between obesity and markers of kidney injury in a chronic kidney disease population. We hypothesized that obesity is independently associated with proteinuria, a marker of chronic kidney disease progression.
Study Design
Observational cross-sectional analysis.
Setting & Participants
Post hoc analysis of baseline data for 652 participants in the African American Study of Kidney Disease (AASK).
Obesity, determined using body mass index (BMI).
Measurements & Outcomes
Urine total protein–creatinine ratio and albumin-creatinine ratio measured in 24-hour urine collections.
AASK participants had a mean age of 60.2 ± 10.2 years and serum creatinine level of 2.3 ± 1.5 mg/dL; 61.3% were men. Mean BMI was 31.4 ± 7.0 kg/m2. Approximately 70% of participants had a daily urine total protein excretion rate <300 mg/d. In linear regression analyses adjusted for sex, each 2-kg/m2 increase in BMI was associated with a 6.7% (95% CI, 3.2-10.4) and 9.4% (95% CI, 4.9-14.1) increase in urine total protein–creatinine and urine albumin-creatinine ratios, respectively. In multivari-able models adjusting for age, sex, systolic blood pressure, serum glucose level, uric acid level, and creatinine level, each 2-kg/m2 increase in BMI was associated with a 3.5% (95% CI, 0.4-6.7) and 5.6% (95% CI, 1.5-9.9) increase in proteinuria and albuminuria, respectively. The interaction between older age and BMI was statistically significant, indicating that this relationship was driven by younger AASK participants.
May not generalize to other populations; cross-sectional analysis precludes statements regarding causality.
BMI is associated independently with urine total protein and albumin excretion in African Americans with hypertensive nephrosclerosis, particularly in younger patients.
PMCID: PMC4517588  PMID: 20801567
Obesity; body mass index; chronic kidney disease; proteinuria; hypertension
16.  Early Change in Proteinuria as a Surrogate Endpoint for Kidney Disease Progression: An Individual Patient Meta-analysis 
It is controversial whether proteinuria is a valid surrogate endpoint for randomized trials in chronic kidney disease.
Study Design
Meta-analysis of individual patient level data.
Setting & Population
Individual patient data on 9008 patients from 32 randomized trials evaluating five intervention types.
Selection Criteria for Studies
Randomized controlled trials of kidney disease progression until 2007 with measurements of proteinuria both at baseline and during the first year of follow-up, with at least one further year of follow-up for the clinical outcome.
Early change in proteinuria.
Doubling of serum creatinine, end stage renal disease or death.
Early decline in proteinuria was associated with a lower risk of the clinical outcome (pooled HR, 0.74 per 50% reduction in proteinuria); this association was stronger at higher levels of baseline proteinuria. Pooled estimates for the proportion of treatment effect on the clinical outcome explained by early decline in proteinuria ranged from −7.0% (95% CI, −40.6% to 26.7%) to 43.9% (95% CI, 25.3% to 62.6%) across five intervention types. The direction of the pooled treatment effects on early change in proteinuria agreed with the direction of the treatment effect on the clinical outcome for all 5 intervention types, with the magnitudes of the pooled treatment effects on the two endpoints agreeing for 4 of the 5 intervention types. The pooled treatment effects on both endpoints were simultaneously stronger at higher levels of proteinuria. However, statistical power was insufficient to determine if differences in treatment effects on the clinical outcome corresponded to differences in treatment effects on proteinuria between individual studies.
Limited variety of interventions tested and low statistical power for many chronic kidney disease clinical trials.
These results provide new evidence supporting the use of an early reduction in proteinuria as a surrogate endpoint, but do not provide sufficient evidence to establish its validity in all settings.
PMCID: PMC4070618  PMID: 24787763
proteinuria; surrogate endpoint; kidney disease progression; disease trajectory; end-stage renal disease (ESRD); prognostic marker
17.  Supervised oral protein supplementation during dialysis in patients with elevated C-reactive protein levels: a two phase, longitudinal, single center, open labeled study 
BMC Nephrology  2015;16:87.
Inflammation is considered one of the major causes of protein-energy wasting in maintenance hemodialysis (MHD) patients. It is unclear whether dietary interventions can impact nutritional status and quality of life in MHD patients with elevated C-reactive protein (CRP) levels. Therefore, we examined the hypothesis that supervised intra-dialysis protein supplementation in MHD patients with elevated plasma CRP will improve protein stores and quality of life.
A 24 week, two phase, longitudinal, single center, open labeled study of 50 MHD patients with plasma CRP > 3 mg/L was conducted. During the 12-week observation phase dietary advice was provided to increase protein intake to 1.2 g/kg/day. In the 12-week treatment phase 45 g of liquid protein supplement was provided at each dialysis treatment. Protein nitrogen appearance (PNA), mid-arm muscle circumference (MAMC), serum albumin, body mass index (BMI) and quality of life (assessed by Short Form-12 questionnaire) were measured at baseline, 12 and 24 weeks.
Median plasma CRP at baseline was 16.0 (IQR 7.7 to 25.1) mg/L. The mean MAMC was 26.5 ± 3.9 cm, BMI 29.2 ± 6.9 kg/m2 and plasma albumin 3.8 ± 0.3 g/dl. During the intervention period, mean PNA increased by 0.13 g/kg/d (p = 0.01) under a mixed effects model. However, there were no clinically or statistically significant effects on MAMC (p = 0.87), plasma albumin (p = 0.70), BMI (p = 0.09), physical (p = 0.32) or mental (p = 0.96) composite scores.
In MHD patients with elevated plasma CRP but otherwise mostly normal nutritional parameters, intra-dialytic oral protein supplement was effective in increasing protein intake but did not provide a detectable impact on nutritional status or quality of life.
Electronic supplementary material
The online version of this article (doi:10.1186/s12882-015-0070-0) contains supplementary material, which is available to authorized users.
PMCID: PMC4477490  PMID: 26099512
Hemodialysis; Inflammation; Protein supplement; Quality of life
18.  Effect of Naturally Occurring Ozone Air Pollution Episodes on Pulmonary Oxidative Stress and Inflammation 
This study aimed to determine if naturally occurring episodes of ozone air pollution in the Salt Lake Valley in Utah, USA, during the summer are associated with increased pulmonary inflammation and oxidative stress, increased respiratory symptoms, and decreased lung function in individuals with chronic obstructive pulmonary disease (COPD) compared to controls. We measured biomarkers (nitrite/nitrate (NOx), 8-isoprostane) in exhaled breath condensate (EBC), spirometry, and respiratory symptoms in 11 former smokers with moderate-to-severe COPD and nine former smokers without airflow obstruction during periods of low and high ozone air pollution. High ozone levels were associated with increased NOx in EBC in both COPD (8.7 (±8.5) vs. 28.6 (±17.6) μmol/L on clean air vs. pollution days, respectively, p < 0.01) and control participants (7.6 (±16.5) vs. 28.5 (±15.6) μmol/L on clean air vs. pollution days, respectively, p = 0.02). There was no difference in pollution effect between COPD and control groups, and no difference in EBC 8-isoprostane, pulmonary function, or respiratory symptoms between clean air and pollution days in either group. Former smokers both with and without airflow obstruction developed airway oxidative stress and inflammation in association with ozone air pollution episodes.
PMCID: PMC4454954  PMID: 25985308
air pollution; ozone; chronic obstructive pulmonary disease; exhaled breath condensate; oxidative stress; airway inflammation
19.  Estimating Glomerular Filtration Rate from Serum Creatinine and Cystatin C 
Estimates of glomerular filtration rate (GFR) that are based on serum creatinine are routinely used; however, they are imprecise, potentially leading to the overdiagnosis of chronic kidney disease. Cystatin C is an alternative filtration marker for estimating GFR.
Using cross-sectional analyses, we developed estimating equations based on cystatin C alone and in combination with creatinine in diverse populations totaling 5352 participants from 13 studies. These equations were then validated in 1119 participants from 5 different studies in which GFR had been measured. Cystatin and creatinine assays were traceable to primary reference materials.
Mean measured GFRs were 68 and 70 ml per minute per 1.73 m2 of body-surface area in the development and validation data sets, respectively. In the validation data set, the creatinine–cystatin C equation performed better than equations that used creatinine or cystatin C alone. Bias was similar among the three equations, with a median difference between measured and estimated GFR of 3.9 ml per minute per 1.73 m2 with the combined equation, as compared with 3.7 and 3.4 ml per minute per 1.73 m2 with the creatinine equation and the cystatin C equation (P = 0.07 and P = 0.05), respectively. Precision was improved with the combined equation (inter-quartile range of the difference, 13.4 vs. 15.4 and 16.4 ml per minute per 1.73 m2, respectively [P = 0.001 and P<0.001]), and the results were more accurate (percentage of estimates that were >30% of measured GFR, 8.5 vs. 12.8 and 14.1, respectively [P<0.001 for both comparisons]). In participants whose estimated GFR based on creatinine was 45 to 74 ml per minute per 1.73 m2, the combined equation improved the classification of measured GFR as either less than 60 ml per minute per 1.73 m2 or greater than or equal to 60 ml per minute per 1.73 m2 (net reclassification index, 19.4% [P<0.001]) and correctly reclassified 16.9% of those with an estimated GFR of 45 to 59 ml per minute per 1.73 m2 as having a GFR of 60 ml or higher per minute per 1.73 m2.
The combined creatinine–cystatin C equation performed better than equations based on either of these markers alone and may be useful as a confirmatory test for chronic kidney disease. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases.)
PMCID: PMC4398023  PMID: 22762315
20.  Effects of daily hemodialysis on heart rate variability: results from the Frequent Hemodialysis Network (FHN) Daily Trial 
…we are starting to acknowledge the ability of modified dialysis procedures (in particular extended dialysis schedules) over the current conventional norms of frequency and duration to provide a range of benefits cutting across the range of relevant domains…”
End-stage renal disease is associated with reduced heart rate variability (HRV), components of which generally are associated with advanced age, diabetes mellitus and left ventricular hypertrophy. We hypothesized that daily in-center hemodialysis (HD) would increase HRV.
The Frequent Hemodialysis Network (FHN) Daily Trial randomized 245 patients to receive 12 months of six versus three times per week in-center HD. Two hundred and seven patients had baseline Holter recordings. HRV measures were calculated from 24-h Holter electrocardiograms at both baseline and 12 months in 131 patients and included low-frequency power (LF, a measure of sympathetic modulation), high-frequency power (HF, a measure of parasympathetic modulation) and standard deviation (SD) of the R–R interval (SDNN, a measure of beat-to-beat variation).
Baseline to Month 12 change in LF was augmented by 50% [95% confidence interval (95% CI) 6.1–112%, P =0.022] and LF + HF was augmented by 40% (95% CI 3.3–88.4%, P = 0.03) in patients assigned to daily hemodialysis (DHD) compared with conventional HD. Changes in HF and SDNN were similar between the randomized groups. The effects of DHD on LF were attenuated by advanced age and diabetes mellitus (predefined subgroups). Changes in HF (r = −0.20, P = 0.02) and SDNN (r = −0.18, P = 0.04) were inversely associated with changes in left ventricular mass (LVM).
DHD increased the LF component of HRV. Reduction of LVM by DHD was associated with increased vagal modulation of heart rate (HF) and with increased beat-to-beat heart rate variation (SDNN), suggesting an important functional correlate to the structural effects of DHD on the heart in uremia.
PMCID: PMC3888308  PMID: 24078335
daily hemodialysis; end-stage renal disease; frequent hemodialysis network; heart rate variability; left ventricular mass
21.  Objectives and Design of the Hemodialysis Fistula Maturation Study 
A large proportion of newly created arteriovenous fistulas cannot be used for dialysis because they fail to mature adequately to support the hemodialysis blood circuit. The Hemodialysis Fistula Maturation (HFM) Study was designed to elucidate clinical and biological factors associated with fistula maturation outcomes.
Study Design
Multicenter prospective cohort study.
Setting & Participants
Approximately 600 patients undergoing creation of a new hemodialysis fistula will be enrolled at 7 centers in the United States and followed up for as long as 4 years.
Clinical, anatomical, biological, and process-of-care attributes identified pre-operatively, intra-operatively, or post-operatively.
The primary outcome is unassisted clinical maturation defined as successful use of the fistula for dialysis for four weeks without any maturation-enhancing procedures. Secondary outcomes include assisted clinical maturation, ultrasound-based anatomical maturation, fistula procedures, fistula abandonment, and central venous catheter use.
Pre-operative ultrasound arterial and venous mapping, flow-mediated and nitroglycerin-mediated brachial artery dilation, arterial pulse wave velocity, and venous distensibility; intra-operative vein tissue collection for histopathological and molecular analyses; post-operative ultrasounds at 1 day, 2 weeks, 6 weeks, and prior to fistula intervention and initial cannulation.
Assuming complete data, no covariate adjustment, and unassisted clinical maturation of 50%, there will be 80% power to detect ORs of 1.83 and 1.61 for dichotomous predictor variables with exposure prevalences of 20% and 50%, respectively.
Exclusion of two-stage transposition fistulas limits generalizability. The requirement for study visits may result in a cohort that is healthier than the overall population of patients undergoing fistula creation.
The HFM Study will be of sufficient size and scope to 1) evaluate a broad range of mechanistic hypotheses, 2) identify clinical practices associated with maturation outcomes, 3) assess the predictive utility of early indicators of fistula outcome, and 4) establish targets for novel therapeutic interventions to improve fistula maturation.
PMCID: PMC4134933  PMID: 23992885
22.  Inflammation and Inverse Associations of Body Mass Index and Serum Creatinine With Mortality in Hemodialysis Patients 
Protein-energy wasting and inflammation are common and associated with an increased risk of mortality in hemodialysis (HD) patients. We examined the extent to which they mediate the associations of each other with death in this population.
Study Design
Retrospective analysis of the Hemodialysis (HEMO) Study data.
Prevalent HD patients.
One-thousand HEMO study participants with data available on C-reactive protein (CRP), body mass index (BMI), and serum creatinine.
Main Outcome Measure
The associations of CRP, BMI, and serum creatinine with time to all-cause mortality separately and together in multivariate Cox models.
In 1,437 patient-years of follow-up, there were 265 (26.5%) all-cause deaths. Compared with the lowest CRP quartile, the highest quartile was associated with a hazard ratio (HR) of 2.02 (95% confidence interval [CI], 1.31–3.10) for all-cause mortality. This association of highest CRP quartile with mortality was not attenuated with further adjustment for BMI and serum creatinine (HR, 2.13; 95% CI, 1.38–3.30). When serum albumin was added to the model, the hazard of death associated with highest CRP quartile was modestly attenuated (HR, 1.88; 95% CI, 1.21–2.92). In contrast, both BMI (for each kg/m2 increase; HR, 0.94; 95% CI, 0.91–0.96 for all-cause mortality) and serum creatinine (for each mg/dL increase; HR, 0.85; 95% CI, 0.79–0.90 for all-cause mortality) had strong, independent protective effects. Further adjustment with CRP had a negligible effect on these associations.
The associations of markers of nutrition and inflammation with mortality are largely independent of each other in HD patients.
PMCID: PMC4265765  PMID: 17971309
23.  Longitudinal Validation of a Tool for Asthma Self-Monitoring 
Pediatrics  2013;132(6):e1554-e1561.
To establish longitudinal validation of a new tool, the Asthma Symptom Tracker (AST). AST combines weekly use of the Asthma Control Test with a color-coded graph for visual trending.
Prospective cohort study of children age 2 to 18 years admitted for asthma. Parents or children (n = 210) completed baseline AST assessments during hospitalization, then over 6 months after discharge. Concurrent with the first 5 AST assessments, the Asthma Control Questionnaire (ACQ) was administered for comparison.
Test–retest reliability (intraclass correlation) was moderate, with a small longitudinal variation of AST measurements within subjects during follow-ups. Internal consistency was strong at baseline (Cronbach’s α 0.70) and during follow-ups (Cronbach’s α 0.82–0.90). Criterion validity demonstrated a significant correlation between AST and ACQ scores at baseline (r = −0.80, P < .01) and during follow-ups (r = −0.64, −0.72, −0.63, and −0.69). The AST was responsive to change over time; an increased ACQ score by 1 point was associated with a decreased AST score by 2.65 points (P < .01) at baseline and 3.11 points (P < .01) during follow-ups. Discriminant validity demonstrated a strong association between decreased AST scores and increased oral corticosteroid use (odds ratio 1.13, 95% confidence interval, 1.10–1.16, P < .01) and increased unscheduled acute asthma visits (odds ratio 1.23, 95% confidence interval, 1.18–1.28, P < .01).
The AST is reliable, valid, and responsive to change over time, and can facilitate ongoing monitoring of asthma control and proactive medical decision-making in children.
PMCID: PMC4074668  PMID: 24218469
asthma control; pediatrics; self-monitoring; self-management
24.  Improved equation for estimating single-pool Kt/V at higher dialysis frequencies 
Nephrology Dialysis Transplantation  2012;28(8):2156-2160.
we need a standard method of calculating dialysis dose, taking all the required factors into account. This would be a dialysis-equivalent GFR
To measure adequacy in patients dialyzed other than three times per week, guidelines recommend the use of ‘standard’ Kt/V, which commonly is estimated from treatment Kt/V, time and frequency; however, the accuracy of equations that predict treatment Kt/V in patients being dialyzed other than three times per week has not been evaluated.
In patients enrolled in the Frequent Hemodialysis Network (FHN) Daily and Nocturnal Trials who were being dialyzed three, four or six times per week, we tested the accuracy of the following Kt/V prediction equation: Kt/V = −ln(R − GFAC × T_hours) + (4–3.5 × R) × 0.55 × weight loss/V, where R = post-dialysis/pre-dialysis blood urea nitrogen and GFAC, originally set to 0.008 for a 3/week schedule (Daugirdas, J Am Soc Nephrol 1993), is a factor that adjusts for urea generation.
With the above equation, there was <0.1% mean error in predicted treatment Kt/V for 3/week patients, but mean errors were −5, −9 and −13% for the 6/week daily, 4/week nocturnal and 6/week nocturnal patients. Modeling simulations were performed to optimize the GFAC term for dialysis schedule and length of the preceding interdialysis interval (PIDI). After substituting schedule- and interval-optimized GFAC terms, the treatment Kt/V prediction errors were reduced to −0.81, +0.1 and −1.3% for the three frequent dialysis schedules tested.
For frequent dialysis schedules, the urea generation factor (GFAC) of one commonly used Kt/V prediction equation should be adjusted based on length in days of the PIDI and number of treatments per week.
PMCID: PMC3765020  PMID: 22561585
Journal of human hypertension  2013;28(1):18-24.
Visit-to-visit blood pressure variation (VTV-BPV) is an independent risk factor for cardiovascular events and death in the general population. We sought to determine the association of VTV-BPV with outcomes in patients on hemodialysis, using data from a National Institutes of Health-sponsored randomized trial (the HEMO Study). We used the coefficient of variation (CV) and the average real variability (ARV) in systolic blood pressure (SBP) as metrics of VTV-BPV. 1844 of 1846 randomized subjects had at least three visits with SBP measurements and were included in the analysis. Median follow-up was 2.5 years (interquartile range [IQR] 1.3 to 4.3 years), during which time there were 869 deaths from any cause and 408 (adjudicated) cardiovascular deaths. The mean pre-dialysis SBP CV was 9.9% ± 4.6%. In unadjusted models, we found a 31% higher risk of death from any cause per 10% increase in VTV-BPV. This association was attenuated after multivariable adjustment but remained statistically significant. Similarly, we found a 28% higher risk of cardiovascular death per 10% increase in VTV-BPV, which was attenuated and no longer statistically significant in fully adjusted models. The associations among VTV-BPV, death and cardiovascular death were modified by baseline SBP. In a diverse, well-dialyzed cohort of patients on maintenance hemodialysis, VTV-BPV, assessed using metrics of variability in pre-dialysis SBP, was associated with a higher risk of all-cause mortality and a trend towards higher risk of cardiovascular mortality, particularly in patients with a lower baseline SBP.
PMCID: PMC3795854  PMID: 23803593
blood pressure variability; cardiovascular disease; hemodialysis; hypertension; end-stage renal disease

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