An increase in left ventricular mass (LVM) is associated with mortality and cardiovascular morbidity in patients with end-stage renal disease.
Methods and Results
The Frequent Hemodialysis Network (FHN) Daily Trial randomized 245 patients to 12 months of 6 times per week daily in-center hemodialysis or conventional hemodialysis; the FHN Nocturnal Trial randomized 87 patients to 12 months of 6 times per week nocturnal hemodialysis or conventional hemodialysis. The main cardiac secondary outcome was change in LVM. In each trial, we examined whether several pre-defined baseline demographic or clinical factors, as well as change in volume removal, blood pressure or solute clearance influenced the effect of frequent hemodialysis on LVM. In the Daily Trial, frequent hemodialysis resulted in a significant reduction in LVM (13.1(95% CI 5.0 to 21.3) g, p=0.002), LVM index (6.9 (2.4 to 11.3) g/m2, p=0.003) and percent change in geometric mean of LVM (7.0 (1.0 to 12.6)%, p =0.02). Similar trends were noted in the Nocturnal Trial but did not reach statistical significance. In the Daily Trial, a more pronounced effect of frequent hemodialysis on LVM was evident among patients with left ventricular hypertrophy at baseline. Changes in LVM were associated with changes in blood pressure (conventional hemodialysis: R=0.28, P=0.01, daily hemodialysis: R=0.54, P<0.001) and were not significantly associated with changes in other parameters.
Frequent in-center hemodialysis reduces LVM. The benefit of frequent hemodialysis on LVM may be mediated by salutary effects on blood pressure.
Left Ventricular Mass; Frequent Hemodialysis; Daily Hemodialysis; Nocturnal Hemodialysis; Blood Pressure
Dietary phosphorus intake is usually restricted in dialysis patients but the associations of dietary phosphorus intake with mortality in moderate chronic kidney disease (CKD) are unknown. Therefore, we examined these associations in National Health and Nutrition Examination Survey III.
Dietary phosphorus intake was estimated from 24-h dietary recalls administered by trained personnel. CKD was defined as estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2. Time to mortality was examined by Cox regression models taking into account the complex survey design.
1105 adults with CKD were studied. Phosphorus intake was 1033 ± 482 mg/day (mean ± SD), eGFR was 49.3 ± 9.5 mL/min/1.73 m2 and serum phosphorus was 3.5 ± 0.5 mg/dL. Compared to those in the lowest tertile of phosphorus intake (mean 532 ± 161 mg/day), those in the highest third (1478 ± 378 mg/day) had similar serum phosphorus levels (3.6 ± 0.5 versus 3.5 ± 0.6 mg/dL, P = 0.113) and modestly higher eGFR (50.0 ± 8.1 versus 47.5 ± 12.0 mL/min/1.73 m2, P = 0.014). After adjustment for demographics, comorbidity, eGFR, physical activity, energy intake and nutritional variables, phosphorus intake was not associated with mortality [hazard ratio (HR) 0.98 per 100 mg/dL increase, 0.93–1.03].
High dietary phosphorus intake is not associated with increased mortality in moderate CKD, presumably because serum phosphorus levels are maintained in the normal range at this level of GFR. Interventional trials are needed to define optimal phosphorus intake in moderate CKD.
dietary phosphorus intake; mortality; moderate chronic kidney disease
Prior small studies have shown multiple benefits of frequent nocturnal hemodialysis compared to conventional three times per week treatments. To study this further, we randomized 87 patients to three times per week conventional hemodialysis or to nocturnal hemodialysis six times per week, all with single-use high-flux dialyzers. The 45 patients in the frequent nocturnal arm had a 1.82-fold higher mean weekly stdKt/Vurea, a 1.74-fold higher average number of treatments per week, and a 2.45-fold higher average weekly treatment time than the 42 patients in the conventional arm. We did not find a significant effect of nocturnal hemodialysis for either of the two coprimary outcomes (death or left ventricular mass (measured by MRI) with a hazard ratio of 0.68, or of death or RAND Physical Health Composite with a hazard ratio of 0.91). Possible explanations for the left ventricular mass result include limited sample size and patient characteristics. Secondary outcomes included cognitive performance, self-reported depression, laboratory markers of nutrition, mineral metabolism and anemia, blood pressure and rates of hospitalization, and vascular access interventions. Patients in the nocturnal arm had improved control of hyperphosphatemia and hypertension, but no significant benefit among the other main secondary outcomes. There was a trend for increased vascular access events in the nocturnal arm. Thus, we were unable to demonstrate a definitive benefit of more frequent nocturnal hemodialysis for either coprimary outcome.
hemodialysis; left ventricular mass; nocturnal hemodialysis; RAND physical health composite (PHC) SF-36; randomized clinical trial; vascular access
Health-related quality of life (HRQOL) is poorly understood in patients with chronic kidney disease (CKD) prior to end-stage renal disease. The association between psychosocial measures and HRQOL has not been fully explored in CKD, especially in African Americans. We performed a cross-sectional analysis of HRQOL and its association with sociodemographic and psychosocial factors in African Americans with hypertensive CKD.
There were 639 participants in the African American Study of Kidney Disease and Hypertension Cohort Study. The Short Form-36 was used to measure HRQOL. The Diener Satisfaction with Life Scale measured life satisfaction, the Beck Depression Inventory-II assessed depression, the Coping Skills Inventory-Short Form measured coping, and the Interpersonal Support Evaluation List-16 was used to measure social support.
Mean participant age was 60 years at enrollment, and 61% were male. Forty-two percent reported a household income below $15,000/year. Higher levels of social support, coping skills, and life satisfaction were associated with higher HRQOL, while unemployment and depression were associated with lower HRQOL (p<0.05). There was a significant positive association between higher estimated glomerular filtration rate (eGFR) with the Physical Health Composite (PHC) score (p=0.004) but not the Mental Health Composite (MHC) score (p=0.24).
Unemployment was associated with lower HRQOL, and lower eGFR was associated with lower PHC. African Americans with hypertensive CKD with better social support and coping skills had higher HRQOL. This study demonstrates an association between CKD and low HRQOL and highlights the need for longitudinal studies to further examine this association.
Background and Aims
Cognitive impairment is a risk factor for death in dialysis patients and the general population. We sought to determine if cognitive impairment is associated with death in people with non-dialysis-dependent chronic kidney disease (CKD), and if so, whether this relationship is greater in the CKD population compared to the general population.
National Health and Nutrition Examination Survey-III participants older than 60 years were asked to subtract 3 from 20 five times and to perform immediate and delayed recall of three items. A cognitive score of 0–11 was assigned based on the number of correct responses. Participants were categorized according to cognitive score (11, 9–10, 6–9, and 0–5) and CKD status. Survival analyses were conducted using Cox models.
Within the CKD subpopulation, those in the lowest cognitive score group had a twofold increased hazard of death compared to those with maximum score. Within the non-CKD subpopulation, those in the lowest cognitive score group had a 46% increased hazard of death compared to those with maximum score. However, the difference in the hazards of death in the CKD and non-CKD subpopulations with the lowest cognitive score was not significant (p = 0.99).
Low cognitive score is associated with an increased risk of death in elderly individuals with and without CKD; however, there was no interaction of CKD and low cognitive score in this analysis.
Cognitive function; Cognitive score; Chronic kidney disease; Mortality
We investigated the effects of frequency of hemodialysis on nutritional status by analyzing the data in the Frequent Hemodialysis Network Trial. We compared changes in albumin, body weight and composition among 245 patients randomized to 6- or 3-times per week in-center hemodialysis (Daily Trial) and 87 patients randomized to 6-times per week nocturnal or 3-times per week conventional hemodialysis, performed largely at home (Nocturnal Trial). In the Daily Trial, there were no significant differences between groups in changes in serum albumin or the equilibrated protein catabolic rate by 12 months. There was a significant relative decrease in pre-dialysis body weight of 1.5 ± 0.2 kg in the 6 times per week group at one month, but this significantly rebounded by 1.3 ± 0.5 kg over the remaining 11 months. Extracellular water decreased in the 6 times per week compared to the 3 per week hemodialysis group. There were no significant between-group differences in phase angle, intracellular water or body cell mass. In the Nocturnal Trial, there were no significant between-group differences in any study parameter. Any gain in “dry” body weight corresponded to increased adiposity rather than muscle mass but was not statistically significant. Thus, frequent in-center hemodialysis reduced extracellular water but did not increase serum albumin or body cell mass while frequent nocturnal hemodialysis yielded no net effect on parameters of nutritional status or body composition.
Disorders of the Ras/MAPK pathway have an overlapping skeletal phenotype (eg. scoliosis, osteopenia). The Ras proteins regulate cell proliferation and differentiation and NF1 individuals have osteoclast hyperactivity and increased bone resorption as measured by urine pyridinium crosslinks [pyridinoline (Pyd) and deoxypyridinoline (Dpd)]. Pyd and Dpd are hydroxylysine derived cross-links of collagen found in bone and cartilage and excreted in the urine. Dpd is most abundant in bone. The aim of this study was to evaluate if other syndromes of the Ras/MAPK pathway have increased bone resorption, which may impact the skeletal phenotype.
Methods and Results
Participants: [Noonan syndrome (n=14), Costello syndrome (n=21), and cardiofaciocutaneous (CFC) syndrome (n=14)]. Pyridinium cross-links from two consecutive first morning urines were extracted after acid hydrolysis and analyzed by High Performance Liquid Chromotography. Three separate analyses of covariance (ANCOVA) were performed to compare Pyd, Dpd, and Dpd/Pyd ratio of each group to controls after controlling for age. Data were compared to 99 healthy controls.
The Dpd and the Dpd/Pyd ratio were elevated (p<0.0001) in all 3 conditions compared to controls suggesting that collagen degradation was predominantly from bone. The data suggest that the Ras/MAPK signal transduction pathway is important in bone homeostasis.
bone; cardiofaciocutaneous syndrome; Costello syndrome; Noonan syndrome; pyridinium
In 2003 the Accreditation Council for Graduate Medical Education mandated work hour restrictions. Violations can results in a residency program being cited or placed on probation. Recurrent violations could results in loss of accreditation. We wanted to determine specific intern and workload factors associated with violation of a specific mandate, the 30-hour duty period requirement.
Retrospective review of interns’ performance against the 30-hour duty period requirement during inpatient ward rotations at a pediatric residency program between June 24, 2008 and June 23, 2009. The analytical plan included both univariate and multivariable logistic regression analyses.
Twenty of the 26 (77%) interns had 80 self-reported episodes of continuous work hours greater than 30 hours. In multivariable analysis, noncompliance was inversely associated with the number of prior inpatient rotations (odds ratio: 0.49, 95% confidence interval (0.38, 0.64) per rotation) but directly associated with the total number of patients (odds ratio: 1.30 (1.10, 1.53) per additional patient). The number of admissions on-call, number of admissions after midnight and number of discharges post-call were not significantly associated with noncompliance. The level of noncompliance also varied significantly between interns after accounting for intern experience and workload factors. Subject to limitations in statistical power, we were unable to identify specific intern characteristics, such as demographic variables or examination scores, which account for the variation in noncompliance between interns.
Both intern and workload factors were associated with pediatric intern noncompliance with the 30-hour duty period requirement during inpatient ward rotations. Residency programs must develop information systems to understand the individual and experience factors associated with noncompliance and implement appropriate interventions to ensure compliance with the duty hour regulations.
Blood pressure (BP) guidelines that set target BP levels often rely on analyses of achieved BP from hypertension treatment trials. The objective of this paper was to compare the results of analyses of achieved BP to intention-to-treat analyses on renal disease progression. Participants (n=1,094) in the African-American Study of Kidney Disease and Hypertension Trial were randomized to either: (1) usual BP goal defined by a mean arterial pressure (MAP) goal of 102–107 mmHg or (2) lower BP goal defined by a MAP goal of ≤ 92 mmHg. Median follow-up was 3.7 years. Primary outcomes were rate of decline in measured glomerular filtration rate (GFR) and a composite of a decrease in GFR by > 50% or >25 ml/min/1.73m2, requirement for dialysis, transplantation, or death. Intention-to-treat analyses showed no evidence of a BP effect on either the rate of decline in GFR or the clinical composite outcome. In contrast, the achieved BP analyses showed that each 10 mm Hg increment in mean follow-up achieved MAP was associated with a 0.35 (95% CI 0.08 – 0.62, p = 0.01) ml/min/1.73m2 faster mean GFR decline and a 17% (95% CI 5% – 32%, p = 0.006) increased risk of the clinical composite outcome. Analyses based on achieved BP lead to markedly different inferences than traditional intention-to-treat analyses, due in part to confounding of achieved BP with co- morbidities, disease severity and adherence. Clinicians and policy makers should exercise caution when making treatment recommendations based on analyses relating outcomes to achieved BP.
blood pressure control; African Americans; hypertension treatment; renal disease
Optimal therapy of patients with steroid-resistant primary focal segmental glomerulosclerosis (FSGS) remains controversial. This report describes the initial study design, baseline characteristics, and quality of life of patients enrolled in the FSGS Clinical Trial, a large multicenter randomized study of this glomerulopathy comparing a 12-month regimen of cyclosporine to the combination of mycophenolate mofetil and oral dexamethasone. Patients with age ranging 2–40 years, with an estimated glomerular filtration rate >40 ml/min per 1.73 m2, a first morning urine protein-to-creatinine ratio over one, and resistant to corticosteroids were eligible. The primary outcome was complete or partial remission of proteinuria over 52 weeks after randomization. In all, 192 patients were screened, of whom 138 were randomized for treatment. Ethnic distributions were 53 black, 78 white, and 7 other. By self- or parent-proxy reporting, 26 of the 138 patients were identified as Hispanic. The baseline glomerular filtration rate was 112.4 (76.5, 180.0) ml/min per 1.73 m2, and urine protein was 4.0 (2.1, 5.3) g/g. Overall, the quality of life of the patients with FSGS was lower than healthy controls and similar to that of patients with end-stage renal disease. Thus, the impact of FSGS on quality of life is significant and this measurement should be included in all trials.
focal segmental glomerulosclerosis; proteinuria; quality of life; randomized controlled trial
This NIH-funded multicenter randomized study of focal segmental glomerulosclerosis (FSGS) treatment compared the efficacy of a 12-month course of cyclosporine to a combination of oral pulse dexamethasone and mycophenolate mofetil in children and adults with steroid-resistant primary FSGS. Of the 192 patients enrolled, 138 were randomized to cyclosporine (72) or to mycophenolate/dexamethasone (66). The primary analysis compared the levels of an ordinal variable measuring remission during the first year. The odds ratio (0.59) for achieving at least a partial remission with mycophenolate/dexamethasone compared to cyclosporine was not significant. Partial or complete remission was achieved in 22 mycophenolate/dexamethasone- and 33 cyclosporine-treated patients at 12 months. The main secondary outcome, preservation of remission for 26 weeks following cessation of treatment, was not significantly different between these two therapies. During the entire 78 weeks of study, 8 patients treated with cyclosporine and 7 with mycophenolate/dexamethasone died or developed kidney failure. Thus, our study did not find a difference in rates of proteinuria remission following 12 months of cyclosporine compared to mycophenolate/dexamethasone in patients with steroid-resistant FSGS. However, the small sample size might have prevented detection of a moderate treatment effect.
focal segmental glomerulosclerosis; proteinuria; randomized controlled trial
Background. Proteinuria is a candidate surrogate end point for randomized controlled trials (RCTs) in chronic kidney disease (CKD). There is a reasonably sound biological basis for this hypothesis, but only preliminary empirical evidence currently exists.
Methods. A systematic review and creation of a patient-level dataset of randomized controlled trials (RCTs) in CKD that reported changes in proteinuria and assessed progression of kidney disease as defined by dialysis, transplantation, death, or changes in GFR or creatinine were performed.
Results. Systematic review. Seventy RCTs met the eligibility criteria; 17 eligible RCTs contained analyses of proteinuria as a predictor of outcomes; 15 RCTs concluded that greater proteinuria was associated with adverse outcomes. A majority were studies of diabetic or hypertensive kidney disease and tested renin–angiotensin system blockade. Definitions of predictor and outcome variables were too variable to conduct a meta-analysis of group data. Database creation. Over 4 years was required to create the patient-level dataset. The final dataset included 34 studies and > 9000 patients with a variety of CKD types and interventions.
Conclusions. There are a relatively small number of RCTs designed to rigorously test therapies for kidney disease progression. Current analyses of change in proteinuria as a predictor of CKD progression are heterogeneous and incomplete, indicating further evaluation in a pooled individual patient-level database is necessary to advance knowledge in this field.
chronic kidney disease; proteinuria; randomized clinical trials; surrogate markers; systematic review
This study was designed to examine the impact of elevated depressive affect on health outcomes among participants with hypertensive chronic kidney disease in the African-American Study of Kidney Disease and Hypertension (AASK) Cohort Study. Elevated depressive affect was defined by Beck Depression Inventory II (BDI-II) thresholds of 11 or more, above 14, and by 5-Unit increments in the score. Cox regression analyses were used to relate cardiovascular death/hospitalization, doubling of serum creatinine/end-stage renal disease, overall hospitalization, and all-cause death to depressive affect evaluated at baseline, the most recent annual visit (time-varying), or average from baseline to the most recent visit (cumulative). Among 628 participants at baseline, 42% had BDI-II scores of 11 or more and 26% had a score above 14. During a 5-year follow-up, the cumulative incidence of cardiovascular death/hospitalization was significantly greater for participants with baseline BDI-II scores of 11 or more compared with those with scores <11. The baseline, time-varying, and cumulative elevated depressive affect were each associated with a significant higher risk of cardiovascular death/hospitalization, especially with a time-varying BDI-II score over 14 (adjusted HR 1.63) but not with the other outcomes. Thus, elevated depressive affect is associated with unfavorable cardiovascular outcomes in African Americans with hypertensive chronic kidney disease.
AASK (African American Study of Kidney Disease and Hypertension); cardiovascular events; chronic kidney disease; depression
We assessed reliability and relative validity of a self-administered computer-assisted dietary history questionnaire (DHQ) for use in a prospective study of diet, lifestyle, and chronic disease in American Indians in the Dakotas and Southwestern US and Alaska Native people.
Reliability was assessed by one-month test-retest of the dietary history questionnaire. Validity was assessed by comparison of the weighted average of up to 12 monthly 24-hour recalls collected prospectively and a dietary history questionnaire completed in the 13th month.
Participants were recruited at the baseline visit of the Education and Research Toward Health Study in Alaska, the Northern Plains and the Dakotas.
Reliability (Pearson correlation) of the DHQ ranged from r= 0.43 for vitamin A density to r=0.90 for energy intake. The association of nutrient and food estimates assessed by 24-hour recalls and the DHQ completed at the end of the year reflected no bias towards recent intake. Macronutrients expressed as density (nutrients per 1000 calories) did appear to be valid (r 0.50–0.71) as did several micronutrients (range r=.22 to 0.59), fiber (r=0.51), and servings of red meat (r=0.67). However, the DHQ overestimated intake and gross amounts of nutrients were not strongly associated with the weighted average of the 24-hour recalls.
The DHQ developed for estimation of dietary intake in American Indians and Native people in Alaska is reliable. Estimates of nutrient density appeared to have acceptable relative validity for use in epidemiologic studies.
Dietary Intake; American Indians; Alaska Natives; Diet Measurement
The MDRD Study equation underestimates measured GFR at levels greater than 60 ml/min per 1.73 m2, with variable accuracy among subgroups; consequently estimated GFR (eGFR) ≥ 60 ml/min/1.73 m2 is not reported by clinical laboratories. Here, the performance of a more accurate GFR estimating equation, the CKD-EPI equation, is reported by level of GFR and clinical characteristics.
Test of diagnostic accuracy
Setting and Participants
Pooled dataset of 3896 people from 16 studies with measured GFR (not used for development of either equation). Subgroups were defined by eGFR, age, sex, race, diabetes, prior solid organ transplant, and body mass index.
eGFR from the CKD-EPI and MDRD Study equations and standardized serum creatinine
Measured GFR using urinary or plasma clearance of exogenous filtration markers
Mean (SD) measured GFR was 68 (36) ml/min/1.73 m2. For eGFR less than 30 ml/min/1.73 m2, both equations have similar bias (median difference compared to measured GFR). For eGFR between 30-59 ml/min/1.73 m2, bias was reduced from 4.9 to 2.1 ml/min/1.73 m2 (57% improvement). For eGFR between 60-89 ml/min/1.73 m2, bias was reduced from 11.9 to 4.2 ml/min/1.73 m2 (61 % improvement). For eGFR between 90-119 ml/min/1.73 m2, bias was reduced from 10.0 to 1.9 ml/min/1.73 m2 (75% improvement). Similar or improved performance was noted for most subgroups with eGFR < 90 ml/min/1.73 m2, other than BMI less than 20 kg/m2, with greater variation noted for some subgroups with eGFR ≥ 90 ml/min/1.73 m2.
Limited number of elderly people and racial and ethnic minorities with measured GFR.
The CKD-EPI equation is more accurate than the MDRD Study equation overall and across most subgroups. In contrast to the MDRD Study equation, eGFR ≥ 60 ml/min/1.73 m2 can be reported using the CKD-EPI equation.
Estimating equations; glomerular filtration rate; performance
Depression is common in end-stage renal disease and is associated with poor quality of life and higher mortality; however, little is known about depressive affect in earlier stages of chronic kidney disease. To measure this in a risk group burdened with hypertension and kidney disease, we conducted a cross-sectional analysis of individuals at enrollment in the African American Study of Kidney Disease and Hypertension Cohort Study. Depressive affect was assessed by the Beck Depression Inventory II and quality of life by the Medical Outcomes Study-Short Form and the Satisfaction with Life Scale. Beck Depression scores over 14 were deemed consistent with an increased depressive affect and linear regression analysis was used to identify factors associated with these scores. Among 628 subjects, 166 had scores over 14 but only 34 were prescribed antidepressants. The mean Beck Depression score of 11.0 varied with the estimated glomerular filtration rate (eGFR) from 10.7 (eGFR 50–60) to 16.0 (eGFR stage 5); however, there was no significant independent association between these. Unemployment, low income, and lower quality and satisfaction with life scale scores were independently and significantly associated with a higher Beck Depression score. Thus, our study shows that an increased depressive affect is highly prevalent in African Americans with chronic kidney disease, is infrequently treated with antidepressants, and is associated with poorer quality of life. Sociodemographic factors have especially strong associations with this increased depressive affect. Because this study was conducted in an African-American cohort, its findings may not be generalized to other ethnic groups.
AASK (African American Study of Kidney Disease and Hypertension); chronic kidney disease; clinical epidemiology; depression; quality of life
Seasonal respiratory syncytial virus (RSV) epidemics occur annually in temperate climates and result in significant pediatric morbidity and increased health care costs. Although RSV epidemics generally occur between October and April, the size and timing vary across epidemic seasons and are difficult to predict accurately. Prediction of epidemic characteristics would support management of resources and treatment.
The goals of this research were to examine the empirical relationships among early exponential growth rate, total epidemic size, and timing, and the utility of specific parameters in compartmental models of transmission in accounting for variation among seasonal RSV epidemic curves. RSV testing data from Primary Children's Medical Center were collected on children under two years of age (July 2001-June 2008). Simple linear regression was used explore the relationship between three epidemic characteristics (final epidemic size, days to peak, and epidemic length) and exponential growth calculated from four weeks of daily case data. A compartmental model of transmission was fit to the data and parameter estimated used to help describe the variation among seasonal RSV epidemic curves.
The regression results indicated that exponential growth was correlated to epidemic characteristics. The transmission modeling results indicated that start time for the epidemic and the transmission parameter co-varied with the epidemic season.
The conclusions were that exponential growth was somewhat empirically related to seasonal epidemic characteristics and that variation in epidemic start date as well as the transmission parameter over epidemic years could explain variation in seasonal epidemic size. These relationships are useful for public health, health care providers, and infectious disease researchers.
The lack of adequate randomized clinical trials (RCT) has hindered identification of new therapies that are safe and effective for patients with primary focal segmental glomerulosclerosis (FSGS), especially in patients who fail to respond to corticosteroids and immunosuppressive therapies. Recent basic science advances have led to development of alternative treatments that specifically target aberrant pathways of fibrosis which are relevant to disease progression in FSGS. There is a need for a flexible Phase II study design which will test such novel antifibrotic strategies in order to identify agents suitable for phase III testing.
The Novel Therapies for Resistant Focal Segmental Glomerulosclerosis (FONT) project is a multicenter Phase I/II RCT designed to investigate the potential efficacy of novel therapies for resistant FSGS. Adalimumab and galactose will be evaluated against conservative therapy consisting of the combination of lisinopril, losartan and atorvastatin. The sample size is defined to assure that if one of the treatments has a superior response rate compared to that of the other treatments, it will be selected with high probability for further evaluation. Comparison of primary and secondary endpoints in each study arm will enable a choice to be made of which treatments are worthy of further study in future Phase III RCT.
This report highlights the key features of the FONT II RCT including the two-step outcome analysis that will expedite achievement of the study objectives. The proposed phase II study design will help to identify promising agents for further testing while excluding ineffective agents. This staged approach can help to prevent large expenditures on unworthy therapeutic agents in the management of serious but rare kidney diseases
Background. We have reported a new equation (CKD-EPI equation) that reduces bias and improves accuracy for GFR estimation compared to the MDRD study equation while using the same four basic predictor variables: creatinine, age, sex and race. Here, we describe the development and validation of this equation as well as other equations that incorporate diabetes, transplant and weight as additional predictor variables.
Methods. Linear regression was used to relate log-measured GFR (mGFR) to sex, race, diabetes, transplant, weight, various transformations of creatinine and age with and without interactions. Equations were developed in a pooled database of 10 studies [2/3 (N = 5504) for development and 1/3 (N = 2750) for internal validation], and final model selection occurred in 16 additional studies [external validation (N = 3896)].
Results. The mean mGFR was 68, 67 and 68 ml/min/ 1.73 m2 in the development, internal validation and external validation datasets, respectively. In external validation, an equation that included a linear age term and spline terms in creatinine to account for a reduction in the magnitude of the slope at low serum creatinine values exhibited the best performance (bias = 2.5, RMSE = 0.250) among models using the four basic predictor variables. Addition of terms for diabetes and transplant did not improve performance. Equations with weight showed a small improvement in the subgroup with BMI <20 kg/m2.
Conclusions. The CKD-EPI equation, based on creatinine, age, sex and race, has been validated and is more accurate than the MDRD study equation. The addition of weight, diabetes and transplant does not significantly improve equation performance.
creatinine; development; estimating equation; glomerular filtration rate; validation
Background. Insulin resistance is associated with increased sympathetic and reduced parasympathetic activity. Resting heart rate reflects autonomic activity. Therefore, we examined the associations of resting heart rate with insulin resistance, cardiovascular events and mortality in the moderate chronic kidney disease (CKD) population.
Methods. Four hundred and sixty participants with MDRD GFR <60 ml/min/1.73 m2 in the limited access Atherosclerosis Risk in Communities (ARIC) study database were divided into four resting heart rate groups: <60, 60–74, 75–89 and ≥90/min. The prevalence of metabolic syndrome at baseline across the groups was examined. Time to cardiovascular composite (myocardial infarction or fatal coronary artery disease event or stroke or coronary revascularization procedure) and time to all-cause death were examined in multivariate Cox models.
Results. The prevalence of metabolic syndrome in the <60, 60–74, 75–89 and ≥90/min groups were 41, 44, 69 and 82% (P < 0.001), respectively. In a multivariate Cox model adjusted for demographics, comorbidity, haemoglobin and physical activity, compared to the 60–74/min group, the hazard ratios of cardiovascular composite in <60, 75–89 and ≥90/min groups were 1.27 (95% CI 0.75–2.16), 1.79 (95% CI 1.07–2.99) and 1.37 (95% CI 0.54–3.44), respectively. In a similar model, the hazard ratios of death were 1.47 (95% CI 0.85–2.53), 3.11 (95% CI 1.93–5.02) and 3.97 (95% CI 1.99–7.94), respectively.
Conclusions. Resting heart rate is associated with metabolic syndrome in moderate CKD. Higher resting heart is associated with increased mortality and possibly cardiovascular events in this population. Interventional studies to examine whether a target resting heart rate of 60–74/min improves cardiovascular outcomes and survival in moderate CKD are warranted.
chronic kidney disease; heart rate; insulin resistance; metabolic syndrome; mortality
To assess the utility and precision of GFR measurements in multicenter trials, the test performance and variability of GFR were analyzed in 2,250 patients enrolled in 44 clinical centers participating in either the Modification of Diet in Renal Disease (MDRD) Study or the Diabetes Control and Complications Trial (DCCT). GFR was measured as the renal clearance of (125I)iothalamate after an sc injection without epinephrine. The studies used similar protocols for obtaining blood and urine, training clinical center staff, and processing specimens in central laboratories. The performance of GFR measurements, assessed from adherence to protocol and quality control analyses, was excellent. The variability among the four clearance periods (intratest coefficient of variation (CV)) was acceptable; the median intratest CV for GFR was 9.4% in the MDRD Study and 11.7% in the DCCT. The pattern of decline in serum counts was better approximated by an exponential rather than a linear relationship. The cause of the intratest variability in GFR measurements was explored by univariate and multivariate analysis. The intratest CV was highest at the extremes of GFR. Among patients with a high GFR (>90 mL/min per 1.73 m2), most of whom were participants in the DCCT, the higher intratest GFR was due, in part, to a systematic decline in GFR during the test. Among patients with a very low GFR (<13 mL/min per 1.73 m2), technical difficulties in urine collections contributed substantially to the higher intratest CV. Other patient characteristics, including age, gender, weight, serum glucose, renal diagnosis, and use of diuretics, were not strongly correlated with the intratest CV. The precision of GFR measurements was assessed from the variability from measurement to measurement (intertest CV). Among MDRD Study subjects, in whom two measurements of GFR were performed over a 3-month interval, the median intertest CV was relatively low (6.3%) and was only weakly related to the intratest CV. Thus, GFR measurements are reasonably precise, even if the intratest CV is high. Given the relatively high intratest CV that is characteristic of GFR measurements, the estimate of GFR in an individual is more precise if multiple clearance periods, rather than a single period, are included. Similarly, the estimate of mean GFR for a population is also more precise if multiple clearance periods are included. In conclusion, by the use of standardized methods, an acceptable precision of GFR results can be obtained in multicenter trials. The same methods can be applied in clinical practice. The usefulness of GFR measurements in practice depends, in part, on the results of these and other ongoing clinical trials investigating therapeutic interventions to prevent the onset or retard the progression of renal disease.
Renal function; GFR; diabetes; chronic renal disease; clinical trial
Hyperuricemia is prevalent in chronic kidney disease (CKD); however data are limited on the relationship of uric acid levels with long term outcomes in this patient population.
Setting & Participants
The Modification of Diet in Renal Disease (MDRD) Study was a randomized controlled trial (N=840), conducted 1989–1993, to examine the effects of strict blood pressure control and dietary protein restriction on progression of stage 3–4 CKD. This analysis included 838 patients.
Outcomes & Measurements
The study evaluated the association of baseline uric acid levels with all-cause mortality, cardiovascular (CVD) mortality, and kidney failure.
Mean (SD) age was 52 (12) years, glomerular filtration rate was 33 (12) ml/min/1.73m2, and uric acid was 7.63 (1.66) mg/dl. During a median follow-up of 10 years, 208 (25%) participants died of any cause, 127 (15%) from CVD, and 553 (66%) reached kidney failure. In multivariate models, the highest tertile of uric acid was associated with increased risk of all-cause (HR, 1.57 [95% CI, 1.07–2.32]) mortality, a trend towards CVD mortality (HR, 1.47 [95% CI, 0.90–2.39]) and no association with kidney failure (HR, 1.20 [95% CI, 0.95–1.51), compared to the lowest tertile. In continuous analyses, a 1-mg/dl higher uric acid was associated with 17% increased risk of all-cause (HR, 1.17 [95% CI, 1.05–1.30]), and 16% increased risk of CVD mortality (HR, 1.16 [95% CI, 1.01–1.33]), but was not associated with kidney failure (HR, 1.02 [95% CI, 0.97–1.07]).
Primary analyses were based on single measurement of uric acid. The results are primarily generalizable to relatively young white patients with predominantly non-diabetic CKD.
In stage 3–4 CKD, hyperuricemia appears to be an independent risk factor for all-cause and CVD mortality but not kidney failure.
Equations to estimate glomerular filtration rate (GFR) are routinely used to assess kidney function. Current equations have limited precision and systematically underestimate measured GFR at higher levels.
To develop a new estimating equation (CKD-EPI creatinine equation).
Cross-sectional analysis. Separate pooled databases for equation development and validation. Representative U.S. population for prevalence estimates.
Research studies and clinical populations (“studies”) with measured GFR. National Health and Nutrition Examination Survey (NHANES) 1999-2006.
Equation development in 10 studies (8254 people) and validation in 16 studies (3896 people). Prevalence estimates based on 16,032 people.
GFR measured as the clearance of exogenous filtration markers (iothalamate in the development dataset; iothalamate and other markers in the validation dataset). Linear regression to estimate the logarithm of measured GFR from standardized creatinine, sex, race and age.
In the validation dataset, the CKD-EPI performed better than the MDRD Study equation (p<0.001 for all subsequent comparisons), especially at higher GFR: lesser bias (median difference between measured and estimated GFR of 2.5 vs. 5.5 mL/min/1.73 m2, respectively); improved precision (interquartile range of the differences of 16.6 vs. 18.3 mL/min/1.73 m2, respectively); and greater accuracy (percent of estimated GFR within 30% of measured GFR of 84.1 vs. 80.6%, respectively. In NHANES, median (interquartile range) estimated GFR was 94.5 (79.7 – 108.1) vs. 85.0 (72.9 – 98.5) mL/min/1.73 m2, and the prevalence (95% confidence interval) of CKD was 11.5 (10.6, 12.4) % vs. 13.1 (12.1, 14.0) %, respectively.
Limited number of elderly people and racial and ethnic minorities with measured GFR.
The CKD-EPI creatinine equation is more accurate than the MDRD Study equation and could replace it for routine clinical use.
Malnutrition is a powerful predictor of mortality in chronic kidney disease (CKD); however, its etiology is unclear. We hypothesized that adipocyte-derived proteins leptin and adiponectin, inflammation (C-reactive protein –CRP), and insulin resistance (Homeostasis Model Assessment –HOMA); implicated in the malnutrition-inflammation complex syndrome commonly seen in maintenance dialysis patients, would be associated with the loss of muscle mass in earlier stages of CKD. Arm muscle area was used as an indicator of muscle mass.
The Modification of Diet in Renal Disease (MDRD) Study cohort of people with CKD stages 3 and 4 was used for analysis.
Main Outcome Measures
Regression models were carried out to examine the relationships of leptin, adiponectin, CRP, and HOMA with arm muscle area (the main study outcome).
Arm muscle area was 39 ± 15 cm2 (mean ± standard deviation, SD) and adiponectin levels were 13 ± 7 μg/mL. Median and (inerquartile range, IQR) concentrations were: 9.0 (13.6) ng/mL for leptin, 2.3 (4.9) mg/L for CRP, and 2.4 (2.0) form HOMA. Higher leptin [beta coefficient and (95% confidence interval): −6.9 (−8.7, −5.1), P<0.001] and higher CRP [−2.7 (−3.9, −1.4), P<0.001] were associated with lower arm muscle area. There was a trend toward lower arm muscle area with higher adiponectin (P=0.07) but no association with HOMA (P=0.80).
Leptin and CRP were associated with lower muscle mass in subjects with CKD stages 3–4. Further studies are needed to understand the mechanisms underlying these associations and to develop targeted interventions for this patient population.
Chronic kidney disease; arm muscle area; adipokines; inflammation; insulin resistance
Dialysis is measured as Kt/V, which scales the dose (Kt) to body water content (V). Scaling dialysis dose to body surface area (Sdub) has been advocated, but the implications of such rescaling have not been examined. We developed a method of rescaling measured Kt/V to Sdub and studied the effect of such alternative scaling on the minimum adequacy values that might then be applied in male and female patients of varying body size. We examined anthropometric estimates of V and S (Watson vs. Dubois estimates) in 1765 patients enrolled in the HEMO study after excluding patients with amputations. An S-normalized target stdKt/V was defined, and an adequacy ratio (R) was computed for each patient as R = D/N where D = delivered stdKt/V (calculated using the Gotch–Leypoldt equation for stdKt/V) and N = the S-normalized minimum target value. In the HEMO data set, we determined the extent to which baseline (prerandomization) stdKt/V values would have exceeded such an S-based minimum target stdKt/V. The median Vwat:Sdub ratios were significantly higher in men (21.34) than in women (18.50). The average of these (20) was used to normalize the current suggested minimally adequate value (stdKt/V ≥ 2.0 / week) to the S-normalized target value (stdKt/S ≥ 40 L/M2), assuming that average modeled V = average anthropometric V. To achieve this S-normalized target, the required single-pool (sp) Kt/V was always higher in women than in men at any level of body size. For small patients (Vwat = 25L), required stdKt/V values were 2.05 and 2.21/week for men and women, respectively, corresponding to spKt/V values of 1.31 and 1.52/session. On the other hand, large (Vwat = 50L) male patients would need spKt/V values of only 1.0/session. Prerandomization baseline dialysis sessions in the HEMO study were found to meet such a new S-based standard in almost all (766/773) men and in 885/992 women. An analysis of scaling dose to anthropometrically estimated liver size (L) showed similar gender ratios for Vwat:L and Vwat:Sdub, providing a potential physiologic explanation underpinning S-based scaling. S-based scaling of the dialysis dose would require considerably higher doses in small patients and in women, and would allow somewhat lower doses in larger male patients. Current dialysis practice would largely meet such an S-based adequacy standard if the dose were normalized to a Vwat:Sdub ratio of 20.