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1.  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…”
Background
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.
Methods
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).
Results
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).
Conclusions
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.
doi:10.1093/ndt/gft212
PMCID: PMC3888308  PMID: 24078335
daily hemodialysis; end-stage renal disease; frequent hemodialysis network; heart rate variability; left ventricular mass
2.  Objectives and Design of the Hemodialysis Fistula Maturation Study 
Background
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.
Predictors
Clinical, anatomical, biological, and process-of-care attributes identified pre-operatively, intra-operatively, or post-operatively.
Outcomes
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.
Measurements
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.
Results
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.
Limitations
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.
Conclusions
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.
doi:10.1053/j.ajkd.2013.06.024
PMCID: PMC4134933  PMID: 23992885
3.  Inflammation and Inverse Associations of Body Mass Index and Serum Creatinine With Mortality in Hemodialysis Patients 
Objective
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.
Setting
Prevalent HD patients.
Participants
One-thousand HEMO study participants with data available on C-reactive protein (CRP), body mass index (BMI), and serum creatinine.
Intervention
None.
Main Outcome Measure
The associations of CRP, BMI, and serum creatinine with time to all-cause mortality separately and together in multivariate Cox models.
Results
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.
Conclusion
The associations of markers of nutrition and inflammation with mortality are largely independent of each other in HD patients.
doi:10.1053/j.jrn.2007.08.007
PMCID: PMC4265765  PMID: 17971309
4.  Longitudinal Validation of a Tool for Asthma Self-Monitoring 
Pediatrics  2013;132(6):e1554-e1561.
OBJECTIVES:
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.
METHODS:
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.
RESULTS:
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).
CONCLUSIONS:
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.
doi:10.1542/peds.2013-1389
PMCID: PMC4074668  PMID: 24218469
asthma control; pediatrics; self-monitoring; self-management
5.  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
Rationale
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.
Methods
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.
Results
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.
Conclusion
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.
doi:10.1093/ndt/gfs115
PMCID: PMC3765020  PMID: 22561585
6.  VISIT-TO VISIT SYSTOLIC BLOOD PRESSURE VARIABILITY AND OUTCOMES IN HEMODIALYSIS 
Journal of human hypertension  2013;28(1):10.1038/jhh.2013.49.
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.
doi:10.1038/jhh.2013.49
PMCID: PMC3795854  PMID: 23803593
blood pressure variability; cardiovascular disease; hemodialysis; hypertension; end-stage renal disease
7.  APOL1 Risk Variants, Race, and Progression of Chronic Kidney Disease 
The New England journal of medicine  2013;369(23):2183-2196.
BACKGROUND
Among patients in the United States with chronic kidney disease, black patients are at increased risk for end-stage renal disease, as compared with white patients.
METHODS
In two studies, we examined the effects of variants in the gene encoding apolipoprotein L1 (APOL1) on the progression of chronic kidney disease. In the African American Study of Kidney Disease and Hypertension (AASK), we evaluated 693 black patients with chronic kidney disease attributed to hypertension. In the Chronic Renal Insufficiency Cohort (CRIC) study, we evaluated 2955 white patients and black patients with chronic kidney disease (46% of whom had diabetes) according to whether they had 2 copies of high-risk APOL1 variants (APOL1 high-risk group) or 0 or 1 copy (APOL1 low-risk group). In the AASK study, the primary outcome was a composite of end-stage renal disease or a doubling of the serum creatinine level. In the CRIC study, the primary outcomes were the slope in the estimated glomerular filtration rate (eGFR) and the composite of end-stage renal disease or a reduction of 50% in the eGFR from baseline.
RESULTS
In the AASK study, the primary outcome occurred in 58.1% of the patients in the APOL1 high-risk group and in 36.6% of those in the APOL1 low-risk group (hazard ratio in the high-risk group, 1.88; P<0.001). There was no interaction between APOL1 status and trial interventions or the presence of baseline proteinuria. In the CRIC study, black patients in the APOL1 high-risk group had a more rapid decline in the eGFR and a higher risk of the composite renal outcome than did white patients, among those with diabetes and those without diabetes (P<0.001 for all comparisons).
CONCLUSIONS
Renal risk variants in APOL1 were associated with the higher rates of end-stage renal disease and progression of chronic kidney disease that were observed in black patients as compared with white patients, regardless of diabetes status. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others.)
doi:10.1056/NEJMoa1310345
PMCID: PMC3969022  PMID: 24206458
8.  Serum bicarbonate and mortality in adults in NHANES III 
Nephrology Dialysis Transplantation  2013;28(5):1207-1213.
Background
Low serum bicarbonate concentration is a risk factor for death in people with chronic kidney disease (CKD). Whether low serum bicarbonate is a mortality risk factor for people without CKD is unknown.
Methods
National Health and Nutrition Examination Survey III (NHANES III) adult participants were categorized into one of four serum bicarbonate categories: <22, 22–25, 26–30 and ≥31 mM. Cox models were used to determine the hazards of death in each serum bicarbonate category, using 26–30 mM as the reference group, in the (i) entire population, (ii) non-CKD subgroup and (iii) CKD subgroup.
Results
After adjusting for age, gender, race, estimated glomerular filtration rate, albuminuria, diuretic use, smoking, C-reactive protein, cardiovascular disease, protein intake, diabetes, hypertension, body mass index, lung disease and serum albumin, the hazards of death in the <22 mM serum bicarbonate category were 1.75 (95% CI: 1.12–2.74), 1.56 (95% CI: 0.78–3.09) and 2.56 (95% CI: 1.49–4.38) in the entire population, non-CKD subgroup and CKD subgroup, respectively, compared with the reference group. Hazard ratios in the other serum bicarbonate categories in the entire population and non-CKD and CKD subgroups did not differ from the reference group.
Conclusions
Among the NHANES III participants, low serum bicarbonate was not observed to be a strong predictor of mortality in people without CKD. However, low serum bicarbonate was associated with a 2.6-fold increased hazard of death in people with CKD.
doi:10.1093/ndt/gfs609
PMCID: PMC3808693  PMID: 23348878
bicarbonate; chronic kidney disease; mortality
9.  Low Body Mass Index and Dyslipidemia in Dialysis Patients linked to Elevated Plasma Fibroblast Growth Factor 23 
American journal of nephrology  2013;37(3):183-190.
Background
Fibroblast growth factor 23 (FGF23) has been associated with death in dialysis patients. Since FGF23 shares structural features with FGF19-subfamily members that exert hormonal control of fat mass, we hypothesized that high circulating FGF23 concentrations would be associated with the development of a uremic lipid profile and lower body mass index.
Methods
This study was conducted among 654 patients receiving chronic hemodialysis. C-terminal FGF23 concentrations were measured in stored plasma samples. Linear regression was used to examine the cross-sectional associations of plasma FGF23 concentrations with body mass index (BMI), total cholesterol (TC), low-density lipoprotein-cholesterol (LDL-C), high-density lipoprotein-cholesterol (HDL-C) and triglycerides (TG). Cox-proportional hazard models were used to examine the association between FGF23 concentrations and all-cause mortality.
Results
Participants had a mean age of 60 ± 11 years and a median [IQR] FGF23 concentration of 4212 [1411-13816] RU/mL. An increase per SD in log10 FGF23 was associated with lower BMI (β= −1.11; p=0.008), TC (β= −6.46; p=0.02), LDL-C (β= −4.73; p=0.04) and HDL-C (β= −2.14; p=0.03); after adjusting for age, gender, race, cardiovascular risk factors, serum albumin, markers of mineral metabolism, and use of lipid lowering drugs. The association of FGF23 with death was attenuated after adjustment for HDL-C (HR of highest quartile 1.53, 95% CI 1.06-2.20 compared to lowest quartile).
Conclusion
These results indicate that higher plasma FGF23 levels are associated with lower BMI and dyslipidemia in dialysis patients. The association between FGF23 and death may be mediated through unexplored metabolic risk factors unrelated to mineral metabolism.
doi:10.1159/000346941
PMCID: PMC3717381  PMID: 23428834
Hemodialysis; fibroblast growth factor 23; dyslipidemia; body mass index
10.  Effect of Dipyridamole plus Aspirin on Hemodialysis Graft Patency 
The New England journal of medicine  2009;360(21):2191-2201.
BACKGROUND
Arteriovenous graft stenosis leading to thrombosis is a major cause of complications in patients undergoing hemodialysis. Procedural interventions may restore patency but are costly. Although there is no proven pharmacologic therapy, dipyridamole may be promising because of its known vascular antiproliferative activity.
METHODS
We conducted a randomized, double-blind, placebo-controlled trial of extended-release dipyridamole, at a dose of 200 mg, and aspirin, at a dose of 25 mg, given twice daily after the placement of a new arteriovenous graft until the primary outcome, loss of primary unassisted patency (i.e., patency without thrombosis or requirement for intervention), was reached. Secondary outcomes were cumulative graft failure and death. Primary and secondary outcomes were analyzed with the use of a Cox proportional-hazards regression with adjustment for prespecified covariates.
RESULTS
At 13 centers in the United States, 649 patients were randomly assigned to receive dipyridamole plus aspirin (321 patients) or placebo (328 patients) over a period of 4.5 years, with 6 additional months of follow-up. The incidence of primary unassisted patency at 1 year was 23% (95% confidence interval [CI], 18 to 28) in the placebo group and 28% (95% CI, 23 to 34) in the dipyridamole–aspirin group, an absolute difference of 5 percentage points. Treatment with dipyridamole plus aspirin significantly prolonged the duration of primary unassisted patency (hazard ratio, 0.82; 95% CI, 0.68 to 0.98; P = 0.03) and inhibited stenosis. The incidences of cumulative graft failure, death, the composite of graft failure or death, and serious adverse events (including bleeding) did not differ significantly between study groups.
CONCLUSIONS
Treatment with dipyridamole plus aspirin had a significant but modest effect in reducing the risk of stenosis and improving the duration of primary unassisted patency of newly created grafts. (ClinicalTrials.gov number, NCT00067119.)
doi:10.1056/NEJMoa0805840
PMCID: PMC3929400  PMID: 19458364
11.  A TRIAL OF TWO STRATEGIES TO REDUCE NOCTURNAL BLOOD PRESSURE IN AFRICAN AMERICANS WITH CHRONIC KIDNEY DISEASE 
Hypertension  2012;61(1):82-88.
The objective of our study was to determine the effects of two antihypertensive drug dose schedules (‘PM dose’ and ‘Add on dose’) on nocturnal blood pressure (BP) in comparison to usual therapy (‘AM dose’) in African Americans with hypertensive chronic kidney disease (CKD) and controlled office BP. In a three period, cross-over trial, former participants of the African American Study of Kidney Disease were assigned to receive the following three regimens, each lasting 6 weeks, presented in random order: AM dose (once daily antihypertensive medications taken in the morning), PM dose (once daily antihypertensives taken at bedtime) and ‘Add on dose’ (once daily antihypertensives taken in the morning and an additional antihypertensive medication before bedtime [diltiazem 60–120 mg, hydralazine 25 mg, or additional ramipril 5 mg]). Ambulatory BP monitoring was performed at the end of each period. The primary outcome was nocturnal systolic BP. Mean age of the study population (n=147) was 65.4 years, 64% were male, mean estimated GFR was 44.9 ml/min/1.73 m2. At the end of each period, mean (SE) nocturnal systolic BP was 125.6 (1.2) mm Hg in the AM dose, 123.9 (1.2) mm Hg in the PM dose, and 123.5(1.2) mm Hg in the Add-on dose. None of the pairwise differences in nocturnal, 24-hour and daytime systolic BP were statistically significant. Among African Americans with hypertensive CKD, neither PM (bedtime) dosing of once daily antihypertensive nor the addition of drugs taken at bedtime significantly reduced nocturnal BP compared to morning dosing of anti-hypertensive medications.
doi:10.1161/HYPERTENSIONAHA.112.200477
PMCID: PMC3523681  PMID: 23172931
Nocturnal blood pressure; chronic kidney disease; hypertension
12.  Long-term Effects of Renin-Angiotensin System–Blocking Therapy and a Low Blood Pressure Goal on Progression of Hypertensive Chronic Kidney Disease in African Americans 
Archives of internal medicine  2008;168(8):10.1001/archinte.168.8.832.
Background
Antihypertensive drugs that block the renin-angiotensin system (angiotensin-converting enzyme inhibitors [ACEIs] or angiotensin receptor blockers) are recommended for patients with chronic kidney disease (CKD). A low blood pressure (BP) goal (BP, <130/80 mm Hg) is also recommended. The objective of this study was to determine the long-term effects of currently recommended BP therapy in 1094 African Americans with hypertensive CKD.
Methods
Multicenter cohort study following a randomized trial. Participants were 1094 African Americans with hypertensive renal disease (glomerular filtration rate, 20–65 mL/min/1.73 m2). Following a 3×2-factorial trial (1995–2001) that tested 3 drugs used as initial antihypertensive therapy (ACEIs, calcium channel blockers, and β-blockers) and 2 levels of BP control (usual and low), we conducted a cohort study (2002–2007) in which participants were treated with ACEIs to a BP lower than 130/80 mm Hg. The outcome measures were a composite of doubling of the serum creatinine level, end-stage renal disease, or death.
Results
During each year of the cohort study, the annual use of an ACEI or an angiotensin receptor blocker ranged from 83.7% to 89.0% (vs 38.5% to 49.8% during the trial). The mean BP in the cohort study was 133/78 mm Hg (vs 136/82 mm Hg in the trial). Overall, 567 participants experienced the primary outcome; the 10-year cumulative incidence rate was 53.9%. Of 576 participants with at least 7 years of follow-up, 33.5% experienced a slow decline in kidney function (mean annual decline in the estimated glomerular filtration rate, <1 mL/min/1.73 m2).
Conclusion
Despite the benefits of renin-angiotensin system–blocking therapy on CKD progression, most African Americans with hypertensive CKD who are treated with currently recommended BP therapy continue to progress during the long term.
doi:10.1001/archinte.168.8.832
PMCID: PMC3870204  PMID: 18443258
13.  Frequent nocturnal hemodialysis accelerates the decline of residual kidney function 
Kidney international  2013;83(5):10.1038/ki.2012.457.
Frequent hemodialysis can alter volume status, blood pressure and the concentration of osmotically active solutes, each of which might affect residual kidney function (RKF). In the Frequent Hemodialysis Network Daily and Nocturnal Trials, we examined the effects of assignment to 6 compared to 3 times per week hemodialysis on follow up RKF. In both trials, baseline RKF was inversely correlated with number of years since onset of ESRD. In the Nocturnal Trial, 63 participants had non-zero RKF at baseline (mean urine volume 0.76 l/d, urea clearance 2.3 ml/min, and creatinine clearance 4.7 ml/min). In those assigned to frequent nocturnal dialysis, these indices were all significantly lower at month 4 and were mostly so at month 12 compared to controls. In the frequent dialysis group, urine volume had declined to zero in 52% and 67% of patients at months 4 and 12, respectively, compared to 18% and 36% in controls. In the Daily Trial, 83 patients had non-zero RKF at baseline (mean urine volume 0.43 l/d, urea clearance 1.2 ml/min, and creatinine clearance 2.7 ml/min). Here, treatment assignment did not significantly influence follow-up levels of the measured indices, although the range in baseline RKF was narrower, potentially limiting power to detect differences. Thus, frequent nocturnal hemodialysis appears to promote a more rapid loss of RKF, the mechanism of which remains to be determined. Whether RKF also declines with frequent daily treatment could not be determined.
doi:10.1038/ki.2012.457
PMCID: PMC3855839  PMID: 23344474
14.  Nonparametric Multi-state Representations of Survival and Longitudinal Data with Measurement Error 
Statistics in medicine  2012;31(21):10.1002/sim.5369.
This paper proposes a nonparametric procedure to describe the progression of longitudinal cohorts over time from a population averaged perspective, leading to multi-state probability curves with the states defined jointly by survival and longitudinal outcomes measured with error. To account for the challenges of informative dropout and nonlinear shapes of the longitudinal trajectories, a bias corrected penalized spline regression is applied to estimate the unobserved longitudinal trajectory for each subject. The multi-state probability curves are then estimated based on the survival data and the estimated longitudinal trajectories. Simulation Extrapolation (SIMEX) is further used to reduce the estimation bias caused by the randomness of the estimated trajectories. A bootstrap test is developed to compare multi-state probability curves between groups. We present theoretical justification of the estimation procedure along with a simulation study to demonstrate finite sample performance. The procedure is illustrated by data from the African American Study of Kidney Disease and Hypertension, and it can be widely applied in longitudinal studies.
doi:10.1002/sim.5369
PMCID: PMC3845220  PMID: 22535711
Multi-state representations; penalized spline; SIMEX
15.  25-hydroxyvitamin D Deficiency is Associated with an Increased Risk of Metabolic Syndrome in Patients with Non-Diabetic Chronic Kidney Disease 
Clinical nephrology  2012;78(6):432-441.
Background
Patients with chronic kidney disease (CKD) not requiring dialysis have a high prevalence of 25(OH)D deficiency but the relationship between 25(OH)D levels and metabolic syndrome is unknown in this population.
Methods
This study analyzed stored plasma samples from 495 non-diabetic subjects with severe kidney disease, not yet on dialysis, who participated in the Homocysteine in Kidney and End Stage Renal Disease study. Metabolic syndrome was defined as the presence of all three of the following: (1) Serum triglycerides ≥150 mg/dL or drug treatment for hypertriglyceridemia; (2) serum high density lipoprotein-cholesterol (HDL-C) < 50 mg/dL for women or < 40 mg/dL for men or drug treatment for dyslipidemia; and (3) blood pressure ≥130/85 mmHg or drug treat ment for hypertension. Multivariate logistic regression models were used to evaluate the cross-sectional association between plasma 25(OH)D levels and metabolic syndrome.
Results
The prevalence of metabolic syndrome increased as 25(OH)D levels declined, with the highest prevalence in participants with 25(OH)D levels < 20 ng/mL. Participants with 25(OH)D levels < 20 ng/mL had a significantly increased risk of metabolic syndrome compared to subjects with levels > 30 ng/mL after adjustment for multiple confounders (OR 2.25, 95% CI 1.25–4.07). Plasma 25(OH)D levels were inversely associated with diastolic blood pressure (R= −0.10, p=0.029) and serum triglyceride levels (R= −0.14, p=0.002).
Conclusion
25(OH)D deficiency is strongly associated with an increas ed risk of metabolic syndromein non-diabetic patients with severe CKD not yet on dialysis, independent of cardiometabolic risk factors and other important regulators of mineral metabolism.
doi:10.5414/CN107498
PMCID: PMC3697908  PMID: 22784560
25-hydroxyvitamin D; Chronic kidney disease; Metabolic Syndrome
16.  Baseline Predictors of Renal Disease Progression in the African American Study of Hypertension and Kidney Disease 
Journal of the American Society of Nephrology : JASN  2006;17(10):10.1681/ASN.2005101101.
Patients with chronic kidney disease have an increased risk for progression to ESRD. The purpose of this study was to examine factors that predict increased risk for adverse renal outcomes. Cox regression was performed to assess the potential of 38 baseline risk factors to predict the clinical renal composite outcome of 50% or 25-ml/min per 1.73 m2 GFR decline or ESRD among 1094 black patients with hypertensive nephrosclerosis (GFR 20 to 65 ml/min per 1.73 m2). Patients were trial participants who had been randomly assigned to one of two BP goals and to one of three antihypertensive regimens and followed for a range of 3 to 6.4 yr. In unadjusted and adjusted analyses, baseline proteinuria was consistently associated with an increased risk for adverse renal outcomes, even at low levels of proteinuria. The relationship of proteinuria with adverse renal outcomes also was evident in analyses that were stratified by level of GFR, which itself was associated with adverse renal outcomes but only at levels <40 ml/min. Other factors that were significantly associated with increased renal events after adjustment for baseline GFR, age, and gender, both with and without adjustment for baseline proteinuria, included serum creatinine, urea nitrogen, and phosphorus. In black patients with hypertensive nephrosclerosis, increased proteinuria, reduced GFR, and elevated levels of serum creatinine, urea nitrogen and phosphorus were directly associated with adverse clinical renal events. These findings identify a subset of this high-risk population that might benefit from even more aggressive treatment.
doi:10.1681/ASN.2005101101
PMCID: PMC3833081  PMID: 16959828
17.  Risk of Hyperkalemia in Nondiabetic Patients With Chronic Kidney Disease Receiving Antihypertensive Therapy 
Transplantation  2011;92(7):10.1097/TP.0b013e31822dc36b.
Background
The incidence and factors associated with hyperkalemia in patients with chronic kidney disease (CKD) treated with angiotensin converting enzyme inhibitors (ACEIs) and other antihypertensive drugs was investigated using the African American Study of Kidney Disease and Hypertension (AASK) database.
Methods
A total of 1094 nondiabetic adults with hypertensive CKD (glomerular filtration rate [GFR], 20–65 mL/min/1.73 m2) were followed for 3.0 to 6.4 years in the AASK trial. Participants were randomly assigned to ACEI, β-blocker (BB), or dihydropyridine calcium channel blocker (CCB). The outcome variables for this analysis were a serum potassium level higher than 5.5 mEq/L (to convert to millimoles per liter, multiply by 1.0), or a clinical center initiated hyperkalemia stop point.
Results
A total of 6497 potassium measurements were obtained, and 80 events in 51 subjects were identified (76 events driven by a central laboratory result and 4 driven by a clinical center–initiated hyperkalemia stop point). Compared with a GFR higher than 50 mL/min/1.73 m2, after multivariable adjustment, the hazard ratio (HR) for hyperkalemia in patients with a GFR between 31 and 40 mL/min/1.73 m2 and a GFR lower than 30 mL/min/1.73 m2 was 3.61 (95% confidence interval [CI], 1.42–9.18 [P=.007]) and 6.81 (95% CI, 2.67–17.35 [P<.001]), respectively; there was no increased risk of hyperkalemia if GFR was 41 to 50 mL/min/1.73 m2. Use of ACEIs was associated with more episodes of hyperkalemia compared with CCB use (HR, 7.00; 95% CI, 2.29–21.39 [P<.001]) and BB group (HR, 2.85; 95% CI, 1.50–5.42 [P=.001]). Diuretic use was associated with a 59% decreased risk of hyperkalemia.
Conclusions
In nondiabetic patients with hypertensive CKD treated with ACEIs, the risk of hyperkalemia is small, particularly if baseline and follow-up GFR is higher than 40 mL/min/1.73 m2. Including a diuretic in the regimen may markedly reduce risk of hyperkalemia.
doi:10.1097/TP.0b013e31822dc36b
PMCID: PMC3831506  PMID: 21832957
18.  Associations of Plasma 25-Hydroxyvitamin D and 1,25-Dihydroxyvitamin D Concentrations With Death and Progression to Maintenance Dialysis in Patients With Advanced Kidney Disease 
Background
Low vitamin D concentrations are prevalent in chronic kidney disease (CKD) patients. We investigated the relationship between plasma 25-hydroxyvitamin D (25(OH)D) or 1,25-dihydroxyvitamin D (1,25(OH)2D) concentrations with death, cardiovascular events (CVE) and dialysis initiation in patients with advanced CKD. Study Design: The Homocysteine Study was a randomized double-blind trial evaluating the effects of high doses of folic acid on death and chronic dialysis initiation in patients with advanced CKD (stage 4 and 5 not yet on dialysis). 25(OH)D and 1,25(OH)2D concentrations were measured in stored plasma samples obtained 3 months after trial initiation and evaluated at clinically defined cutoffs (<10, 10-30, and >30 ng/mL) and tertiles (< 15, 15-22, and >22 pg/mL), respectively. Cox-proportional hazard models were used to examine the association between vitamin D concentrations and clinical outcomes.
Setting & Participants
1,099 patients with advanced CKD from 36 Veteran Affairs Medical Centers
Predictors
25(OH)D and 1,25(OH)2D concentrations
Outcomes
Death, CVE and time to initiation of chronic dialysis.
Results
After a median follow-up period of 2.9 years, 41% (n=453) died, while 56% (n=615) initiated dialysis. Mean 25(OH)D and 1,25(OH)2D concentrations were 21±10 ng/mL and 20±11 pg/mL, respectively. After adjustment for potential confounders, the lowest tertile of 1,25(OH)2D was associated with death (HR, 1.33; 95% CI, 1.01-1.74) and initiation of chronic dialysis (HR, 1.78; 95% CI, 1.40-2.26), compared to the highest tertile. The association with death and initiation of dialysis was moderately attenuated after adjustment for plasma fibroblast growth factor-23 (FGF23) concentrations (HRs of lower tertiles of 1.20 [95% CI, 0.91-1.58] and 1.56 [95% CI, 1.23-1.99], respectively, compared to highest tertile). There was no association between 25(OH)D concentrations and outcomes.
Limitations
Participants were mostly male.
Conclusions
Low plasma 1,25(OH)2D concentrations are associated with death and initiation of chronic dialysis in advanced CKD. Fibroblast growth factor-23 may attentuate this relationship.
doi:10.1053/j.ajkd.2012.04.014
PMCID: PMC3439559  PMID: 22621970
19.  Effect of Intensive Blood Pressure Control on Cardiovascular Remodeling in Hypertensive Patients with Nephrosclerosis 
Pulse pressure (PP), a marker of arterial system properties, has been linked to cardiovascular (CV) complications. We examined (a) association between unit changes of PP and (i) composite CV outcomes and (ii) development of left-ventricular hypertrophy (LVH) and (b) effect of mean arterial pressure (MAP) control on rate of change in PP. We studied 1094 nondiabetics with nephrosclerosis in the African American Study of Kidney Disease and Hypertension. Subjects were randomly assigned to usual MAP goal (102–107 mmHg) or a lower MAP goal (≤92 mmHg) and randomized to beta-blocker, angiotensin converting enzyme inhibitor, or calcium channel blocker. After covariate adjustment, a higher PP was associated with increased risk of CV outcome (RR = 1.28, CI = 1.11–1.47, P < 0.01) and new LVH (RR = 1.26, CI = 1.04–1.54, P = 0.02). PP increased at a greater rate in the usual than in lower MAP groups (slope ± SE: 1.08 ± 0.15 versus 0.42 ± 0.15 mmHg/year, P = 0.002), but not by the antihypertensive treatment assignment. Observations indicate that control to a lower MAP slows the progression of PP, a correlate of cardiovascular remodeling and complications, and may be beneficial to CV health.
doi:10.1155/2013/120167
PMCID: PMC3786477  PMID: 24102027
20.  The Joint Commission Children’s Asthma Care Quality Measures and Asthma Readmissions 
Pediatrics  2012;130(3):482-491.
BACKGROUND AND OBJECTIVES:
The Joint Commission introduced 3 Children’s Asthma Care (CAC 1–3) measures to improve the quality of pediatric inpatient asthma care. Validity of the commission’s measures has not yet been demonstrated. The objectives of this quality improvement study were to examine changes in provider compliance with CAC 1–3 and associated asthma hospitalization outcomes after full implementation of an asthma care process model (CPM).
METHODS:
The study included children aged 2 to 17 years who were admitted to a tertiary care children’s hospital for acute asthma between January 1, 2005, and December 31, 2010. The study was divided into 3 periods: preimplementation (January 1, 2005–December 31, 2007), implementation (January 1, 2008–March 31, 2009), and postimplementation (April 1, 2009–December 31, 2010) periods. Changes in provider compliance with CAC 1–3 and associated changes in hospitalization outcomes (length of stay, costs, PICU transfer, deaths, and asthma readmissions within 6 months) were measured. Logistic regression was used to control for age, gender, race, insurance type, and time.
RESULTS:
A total of 1865 children were included. Compliance with quality measures before and after the CPM implementation was as follows: 99% versus 100%, CAC-1; 100% versus 100%, CAC-2; and 0% versus 87%, CAC-3 (P < .01). Increased compliance with CAC-3 was associated with a sustained decrease in readmissions from an average of 17% to 12% (P = .01) postimplementation. No change in other outcomes was observed.
CONCLUSIONS:
Implementation of the asthma CPM was associated with improved compliance with CAC-3 and with a delayed, yet significant and sustained decrease in hospital asthma readmission rates, validating CAC-3 as a quality measure. Due to high baseline compliance, CAC-1 and CAC-2 are of questionable value as quality measures.
doi:10.1542/peds.2011-3318
PMCID: PMC4074621  PMID: 22908110
asthma; compliance; hospitalization; quality improvement; quality of care
21.  Estimating GFR Among Participants in the Chronic Renal Insufficiency Cohort (CRIC) Study 
Background
Glomerular filtration rate (GFR) is considered the best measure of kidney function, but repeated assessment is not feasible in most research studies.
Study Design
Cross-sectional study of 1,433 participants from the Chronic Renal Insufficiency Cohort (CRIC) Study (i.e., the GFR subcohort) to derive an internal GFR estimating equation using a split sample approach.
Setting & Participants
Adults from 7 US metropolitan areas with mild to moderate chronic kidney disease; 48% had diabetes and 37% were black.
Index Test
CRIC GFR estimating equation
Reference Test or Outcome
Urinary 125I-iothalamate clearance testing (measured GFR)
Other Measurements
Laboratory measures including serum creatinine and cystatin C, and anthropometrics
Results
In the validation dataset, the model that included serum creatinine, serum cystatin C, age, gender, and race was the most parsimonious and similarly predictive of mGFR compared to a model additionally including bioelectrical impedance analysis phase angle, CRIC clinical center, and 24-hour urinary creatinine excretion. Specifically, the root mean square errors for the separate model were 0.207 vs. 0.202, respectively. The performance of the CRIC GFR estimating equation was most accurate among the subgroups of younger participants, men, non-blacks, non-Hispanics, those without diabetes, those with body mass index <30 kg/m2, those with higher 24-hour urine creatinine excretion, those with lower levels of high-sensitivity C-reactive protein, and those with higher mGFR.
Limitations
Urinary clearance of 125I-iothalamate is an imperfect measure of true GFR; cystatin C is not standardized to certified reference material; lack of external validation; small sample sizes limit analyses of subgroup-specific predictors.
Conclusions
The CRIC GFR estimating equation predicts measured GFR accurately in the CRIC cohort using serum creatinine and cystatin C, age, gender, and race. Its performance was best among younger and healthier participants.
doi:10.1053/j.ajkd.2012.04.012
PMCID: PMC3565578  PMID: 22658574
glomerular filtration rate (GFR); kidney function; GFR estimation
22.  Updated comorbidity assessments and outcomes in prevalent hemodialysis patients 
When evaluating clinical characteristics and outcomes in patients on hemodialysis, the prevalence and severity of comorbidity may change over time. Knowing whether updated assessments of comorbidity enhance predictive power will assist the design of future studies. We conducted a secondary data analysis of 846 prevalent hemodialysis patients from 5 US clinical centers enrolled in the HEMO study. Our primary explanatory variable was the Index of Coexistent Diseases score, which aggregates comorbidities, as a time-constant and time-varying covariate. Our outcomes of interest were all-cause mortality, time to first hospitalization, and total hospitalizations. We used Cox proportional hazards regression. Accounting for an updated comorbidity assessment over time yielded a more robust association with mortality than accounting for baseline comorbidity alone. The variation explained by time-varying comorbidity assessments on time to death was greater than age, baseline serum albumin, diabetes, or any other covariates. There was a less pronounced advantage of updated comorbidity assessments on determining time to hospitalization. Updated assessments of comorbidity significantly strengthen the ability to predict death in patients on hemodialysis. Future studies in dialysis should invest the necessary resources to include repeated assessments of comorbidity.
doi:10.1111/j.1542-4758.2010.00468.x
PMCID: PMC3683592  PMID: 20955281
Comorbidity; hemodialysis; HEMO study; hospitalization; mortality; Index of Coexistent Diseases (ICED)
23.  Imprecision of Urinary Iothalamate Clearance as a Gold Standard Measure of GFR Decreases the Diagnostic Accuracy of Kidney Function Estimating Equations 
Background
Evaluating the accuracy of estimated glomerular filtration rate (eGFR) derived from serum creatinine (SCr) and serum cystatin C (SCysC) equations requires gold standard measures of GFR. However, the influence of imprecise measured GFRs (mGFRs) on estimates of equation error is unknown.
Study Design
Diagnostic test study
Setting & Participants
1995 participants from the Modification of Diet in Renal Disease (MDRD) Study and African American Study of Kidney Disease (AASK) with at least two baseline mGFRs from125I-iothalamate urinary clearances, one standardized Scr value, and one SCysC value.
Index Tests
eGFRs calculated from the 4-variable IDMS-traceable MDRD Study equation, the CKD-EPI SCysC equation, the CKD-EPI SCr-SCysC equation, and mGFRs collected from another pre-randomization visit
Reference Tests
A single reference mGFR, average of two, and average of three mGFRs; additional analysis limited to consistent mGFRs (difference fl 25% from the reference mGFR)
Results
We found that mGFRs had stable means but substantial variability across visits. Of all the mGFRs collected a mean of 62 days apart from the reference visit, 8.0% fell outside 30% of the single reference mGFR (1-P30). The estimation equations were less accurate as 12.1%, 17.1% and 8.3% of the eGFR from MDRD Study, CKD-EPI SCysC, and CKD-EPI SCr-SCysC equations fell outside 30% of the same gold standard (1-P30). However, improving the precision of the reference test from a single mGFR to the average of three consistent mGFRs reduced these error estimates (1-P30) to 8.0%, 12.5% and 3.9% respectively.
Limitations
Study population limited to those with CKD.
Conclusions
Imprecision in gold standard measures of GFR contribute to an appreciable proportion of the cases where estimated and measured GFR differs by more than 30%. Reducing and quantifying errors in gold standard measurements of GFR is critical to fully estimating the accuracy of GFR estimates.
doi:10.1053/j.ajkd.2010.02.347
PMCID: PMC3671926  PMID: 20537455
gold standard; measured glomerular filtration rate; kidney function estimation equations; cystatin C; creatinine
24.  Intensive Blood-Pressure Control in Hypertensive Chronic Kidney Disease 
The New England journal of medicine  2010;363(10):918-929.
BACKGROUND
In observational studies, the relationship between blood pressure and end-stage renal disease (ESRD) is direct and progressive. The burden of hypertension-related chronic kidney disease and ESRD is especially high among black patients. Yet few trials have tested whether intensive blood-pressure control retards the progression of chronic kidney disease among black patients.
METHODS
We randomly assigned 1094 black patients with hypertensive chronic kidney disease to receive either intensive or standard blood-pressure control. After completing the trial phase, patients were invited to enroll in a cohort phase in which the blood-pressure target was less than 130/80 mm Hg. The primary clinical outcome in the cohort phase was the progression of chronic kidney disease, which was defined as a doubling of the serum creatinine level, a diagnosis of ESRD, or death. Follow-up ranged from 8.8 to 12.2 years.
RESULTS
During the trial phase, the mean blood pressure was 130/78 mm Hg in the intensive-control group and 141/86 mm Hg in the standard-control group. During the cohort phase, corresponding mean blood pressures were 131/78 mm Hg and 134/78 mm Hg. In both phases, there was no significant between-group difference in the risk of the primary outcome (hazard ratio in the intensive-control group, 0.91; P = 0.27). However, the effects differed according to the baseline level of proteinuria (P = 0.02 for interaction), with a potential benefit in patients with a protein-to-creatinine ratio of more than 0.22 (hazard ratio, 0.73; P = 0.01).
CONCLUSIONS
In overall analyses, intensive blood-pressure control had no effect on kidney disease progression. However, there may be differential effects of intensive blood-pressure control in patients with and those without baseline proteinuria. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases, the National Center on Minority Health and Health Disparities, and others.)
doi:10.1056/NEJMoa0910975
PMCID: PMC3662974  PMID: 20818902
25.  Longitudinal Progression Trajectory of GFR Among Patients With CKD 
Background
The traditional paradigm of glomerular filtration rate (GFR) progression among chronic kidney disease (CKD) patients is a steady, nearly linear decline over time. We describe individual GFR progression trajectories over twelve years of follow-up among participants in the African American Study of Kidney Disease and Hypertension (AASK).
Study Design
Longitudinal, observational study
Setting & Participants
846 AASK patients with at least 3 years of follow-up and 8 GFR estimates.
Measurements
Longitudinal GFR estimates (eGFR) from creatinine-based equations.
Predictors
Patient demographic and clinical features.
Outcomes
Probability of a nonlinear trajectory and probability of a period of nonprogression, calculated for each patient from a Bayesian model of individual eGFR trajectories.
Results
Three hundred and fifty-two (41.6%) patients exhibited a greater than 0.9 probability of having either a nonlinear trajectory or a prolonged nonprogression period; in 559 (66.1%), the probability was larger than 0.5. Baseline eGFR > 40 mL/min/1.73m2 and urine protein-creatinine < 0.22 g/g were associated with a higher likelihood of a nonprogression period. Seventy-four patients (8.7%) had both a substantial period of stable or increasing eGFR and a substantial period of rapid eGFR decline.
Limitations
Clinical trial population; absence of direct GFR measurements.
Conclusions
In contrast to the traditional paradigm of steady GFR progression over time, many CKD patients have a non-linear GFR trajectory or a prolonged period of nonprogression. These findings highlight the possibility that stable kidney disease progression can accelerate, and, conversely provide hope that CKD need not be relentlessly progressive. These results should encourage researchers to identify time-dependent factors associated with periods of nonprogression and other desirable trajectories.
doi:10.1053/j.ajkd.2011.12.009
PMCID: PMC3312980  PMID: 22284441
Chronic kidney disease; estimated glomerular filtration rate; nonlinear progression; longitudinal cohort study; African American; slope

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