Impact of Chronic Kidney Disease on Aortic Disease-related Mortality: A Four-year Community-Based Cohort Study

Objective Despite advances in medicine, aortic diseases (ADs), such as aneurysm rupture and aortic dissection, remain fatal and carry extremely high mortality rates. Due to its low frequency, the risk of developing AD has not yet been fully elucidated. Chronic kidney disease (CKD) is an established risk factor for cardiovascular disease and mortality. The aim of the present study was to examine whether or not CKD is a risk for AD-related mortality in the general population. Methods We used a nationwide database of 554,442 subjects (40-75 years old) who participated in the annual “Specific Health Check and Guidance in Japan” checkup between 2008 and 2013. Results There were 131 aortic aneurysm and dissection deaths during the follow-up period of 2,123,512 person-years. A Kaplan-Meier analysis revealed that subjects with CKD had a higher rate of AD-related deaths than those without it. A multivariate Cox proportional hazard regression analysis demonstrated that CKD was an independent risk factor for AD-related death in the general population after adjusting for cardiovascular risk factors. The addition of CKD to cardiovascular risk factors significantly improved the C, net reclassification, and integrated discrimination indexes. Conclusion CKD is an additional risk for AD-related death, suggesting that CKD may be a target for the prevention and early identification of subjects at high risk for AD-related death in the general population.     

高同型半胱氨酸和慢性肾脏疾病死亡原因的相关性研究

研究背景:血浆高半胱氨酸的水平和3、4期慢性肾脏疾病的预后关系目前还尚未被研究。方法和结果: 肾脏疾病饮食调节研究入选了840名患者,测量血浆高半胱氨酸基线水平,患者的生存状况和死亡原因从国家死亡索引中获得。血浆高半胱氨酸分为3个水平(<14．7,14．7 to 19．5,>or=19．6 mmol／／L)和其作为     

Sleep and Activity in Chronic Kidney Disease: A Longitudinal Study

Summary

Background and objectives

Commonly sleep is disrupted and physical activity is restricted among patients with CKD and those on long-term dialysis. However, few studies have assessed patients longitudinally.

Design, setting, participants, & measurements

We compared the prevalence of sleep disturbances measured both subjectively using a questionnaire and objectively using actimetry among patients with CKD (n = 145), those on hemodialysis (n = 116), and people without kidney disease (n = 19). Activity level during the day was measured using actimetry, and patients were then followed for up to 2 years.

Results

Compared with people without kidney disease, patients with CKD not on dialysis had disruption of sleep that was independent of several risk factors. However, disrupted sleep was correlated with neither estimated GFR in cross-sectional nor longitudinal assessment. Those on hemodialysis had sleep disruption that was of much greater severity than that found among those with CKD not on dialysis. Furthermore, missing or shortening the prescribed duration of dialysis was associated with greater severity of sleep disturbance in cross-sectional but not in longitudinal assessment. Day-time activity declined both in duration and intensity from controls to CKD to hemodialysis.

Conclusions

The loss of kidney function is related to both reduced duration and intensity of day time physical activity. Although patients with CKD have disrupted sleep, this is independent of estimated GFR. However, compared with those with CKD, dialysis patients have more severely disrupted sleep; this is related to missing dialysis. Thus, shortening patients'' dialysis may reduce their sleep.     

Association Between Serum Albumin Level and All-Cause Mortality in Patients With Chronic Kidney Disease: A Retrospective Cohort Study

BackgroundThe association between serum albumin and all-cause mortality (ACM) in patients with chronic kidney disease (CKD) is presently unclear.MethodsThe study subjects included 201 patients diagnosed with CKD, eliminating those with end-stage renal disease, who were admitted to our hospital from January 2014 to January 2015. The patients were divided into 4 groups according to serum albumin level (Q1: 1.60–3.88 g/dL; Q2: 3.89–4.13 g/dL; Q3: 4.14–4.43 g/dL, and Q4: 4.44–5.51 g/dL). The clinical outcome was ACM, and the difference was compared using odds ratio (OR) and 95% confidence interval (CI).ResultsAfter a median follow-up of 1480 days, 32 patients died (15.92%). The ACM was found to be 28.00%, 20.00%, 8.00%, and 7.84% in the 4 groups (P = 0.012). Pearson correlation analysis revealed a positive association between the serum albumin level and glomerular filtration rate (GFR) (r = 0.22, P = 0.001). Once the potential confounding factors were adjusted, the results indicated that decreased serum albumin was a risk factor for ACM (Q2 vs Q1: OR = 0.50, 95% CI: 0.17–1.47; Q3 vs Q1: OR = 0.12, 95% CI: 0.03–0.48; Q4 vs Q1: OR = 0.26, 95% CI: 0.07–0.98). The receiver operating characteristic curve indicated that the optimum threshold of serum albumin to predict ACM was 4 g/dL, and the area under the curve was 0.69 (95% CI: 0.60–0.79).ConclusionsDecreased serum albumin is a risk factor for ACM in patients with CKD, with the optimal threshold being 4 g/dL.     

Hemoglobin Decline in Children with Chronic Kidney Disease: Baseline Results from the Chronic Kidney Disease in Children Prospective Cohort Study

Background and objectives: The level of glomerular filtration rate at which hemoglobin declines in chronic kidney disease is poorly described in the pediatric population.Design, setting, participants, & measurements: This cross-sectional study of North American children with chronic kidney disease examined the association of glomerular filtration rate, determined by the plasma disappearance of iohexol, and hemoglobin concentration.Results: Of the 340 patients studied, the mean age was 11 ± 4 yr, the mean glomerular filtration rate was 42 ± 14 ml/min per 1.73 m², and the mean hemoglobin was 12.5 ± 1.5. Below a glomerular filtration rate of 43, the hemoglobin declined by 0.3 g/dl (95% confidence interval −0.2 to −0.5) for every 5-ml/min per 1.73 m² decrease in glomerular filtration rate. Above a glomerular filtration rate of 43 ml/min per 1.73 m², the hemoglobin showed a nonsignificant decline of 0.1 g/dl for every 5-ml/min per 1.73 m² decrease in glomerular filtration rate.Conclusions: In pediatric patients with chronic kidney disease, hemoglobin declines as an iohexol-determined glomerular filtration rate decreases below 43 ml/min per 1.73 m². Because serum creatinine–based estimated glomerular filtration rates may overestimate measured glomerular filtration rate in this population, clinicians need to be mindful of the potential for hemoglobin decline and anemia even at early stages of chronic kidney disease, as determined by current Schwartz formula estimates. Future longitudinal analyses will further characterize the relationship between glomerular filtration rate and hemoglobin, including elucidation of reasons for the heterogeneity of this association among individuals.The adverse health effects of anemia in adult and pediatric patients with chronic kidney disease (CKD) are both common and profound. Anemia has been associated with increased mortality, limitations in physical activity, and adverse effects on quality of life. Among children in the 2005 End Stage Renal Disease Clinical Performance Measures Project, 95% of 1598 prevalent pediatric patients with ESRD were anemic; 95% of patients who were receiving hemodialysis and 94% of patients who were receiving peritoneal dialysis were prescribed erythropoiesis-stimulating agents (ESA) (1). A lower prevalence of anemia is observed at earlier stages of CKD in pediatric patients. The National Kidney Foundation Kidney Disease Outcomes Quality Initiative (KDOQI) stages CKD as follows: Stage 1, evidence of kidney damage with normal or increased GFR; stage 2, GFR 60 to 89 ml/min per 1.73 m²; stage 3, GFR 30 to 59 ml/min per 1.73 m²; stage 4, GFR 15 to 29 ml/min per 1.73 m²; stage 5, GFR <15 ml/min per 1.73 m² or on dialysis (2). In a recent single-center, cross-sectional study of 366 children and adolescents with CKD, approximately 30% of patients with stages 1 and 2 CKD reported prevalent anemia, defined as hemoglobin <12 mg/dl or medical treatment for anemia, whereas 66% of patients with stage 3 and 93% of patients with stages 4 and 5 CKD were anemic. GFR was estimated from serum cystatin C in this study (3).The lower prevalence of anemia in patients with earlier stages of CKD suggests an association between hemoglobin and GFR. In adults, hemoglobin has been reported to decline below a GFR threshold of 40 to 60 ml/min per 1.73 m² as measured by the Modification of Diet in Renal Disease (MDRD) or Cockcroft-Gault equation (4,5). This association, including the existence of a “GFR threshold,” has not been clearly described in children. This study aimed to define more clearly the relationship between hemoglobin and GFR in the pediatric CKD population. To accomplish this, we used the relatively large sample size and precise measurement of GFR offered by the Chronic Kidney Disease in Children Prospective Cohort Study (CKiD).     

Mortality Associated with Metformin Versus Sulfonylurea Initiation: A Cohort Study of Veterans with Diabetes and Chronic Kidney Disease

Background

For patients with type 2 diabetes and chronic kidney disease (CKD), high-quality evidence about the relative benefits and harms of oral glucose-lowering drugs is limited.

Objective

To evaluate whether mortality risk differs after the initiation of monotherapy with either metformin or a sulfonylurea in Veterans with type 2 diabetes and CKD.

Design

Observational, national cohort study in the Veterans Health Administration (VHA).

Participants

Veterans who received care from the VHA for at least 1 year prior to initiating monotherapy treatment for type 2 diabetes with either metformin or a sulfonylurea between 2004 and 2009.

Main Measures

Metformin and sulfonylurea use was assessed from VHA electronic pharmacy records. The CKD-EPI equation was used to estimate glomerular filtration rate (eGFR). The outcome of death from January 1, 2004, through December 31, 2009, was assessed from VHA Vital Status files.

Key Results

Among 175,296 new users of metformin or a sulfonylurea monotherapy, 5121 deaths were observed. In primary analyses adjusted for all measured potential confounding factors, metformin monotherapy was associated with a lower mortality hazard ratio (HR) compared with sulfonylurea monotherapy across all ranges of eGFR evaluated (HR ranging from 0.59 to 0.80). A secondary analysis of mortality risk differences favored metformin across all eGFR ranges; the greatest risk difference was observed in the eGFR category 30–44 mL/min/1.73m² (12.1 fewer deaths/1000 person-years, 95% CI 5.2–19.0).

Conclusions

Initiation of metformin versus a sulfonylurea among individuals with type 2 diabetes and CKD was associated with a substantial reduction in mortality, in terms of both relative and absolute risk reduction. The largest absolute risk reduction was observed among individuals with moderately–severely reduced eGFR (30–44 mL/min/1.73m²).

     

Serum Phosphate and Mortality in Patients with Chronic Kidney Disease

Background and objectives: Higher phosphate is associated with mortality in dialysis patients but few prospective studies assess this in nondialysis patients managed in an outpatient nephrology clinic. This prospective longitudinal study examined whether phosphate level was associated with death in a referred population.Design, setting, participants & measurements: Patients (1203) of nondialysis chronic kidney disease (CKD) in the Chronic Renal Insufficiency Standards Implementation Study were assessed. Survival analyses were performed for quartiles of baseline phosphate relative to GFR, 12-month time-averaged phosphate, and baseline phosphate according to published phosphate targets.Results: Mean (SD) eGFR was 32 (15) ml/min per 1.73 m², age 64 (14) years, and phosphate 1.2 (0.30) mmol/L. Cox multivariate adjusted regression in CKD stages 3 to 4 patients showed an increased risk of all-cause and cardiovascular mortality in the highest quartile compared with that in the lowest quartile of phosphate. No association was found in CKD stage 5 patients. Patients who had values above recommended targets for phosphate control had increased risk of all-cause and cardiovascular death compared with patients below target. The highest quartile compared with the lowest quartile of 12-month time-averaged phosphate was associated with an increased risk of mortality.Conclusions: In CKD stages 3 to 4 patients, higher phosphate was associated with a stepwise increase in mortality. As phosphate levels below published targets (as opposed to within them) are associated with better survival, guidelines for phosphate in nondialysis CKD patients should be re-examined. Intervention trials are required to determine whether lowering phosphate will improve survival.Higher serum phosphate is associated with mortality in hemodialysis patients (1–3). There have been three studies in patients with chronic kidney disease (CKD), not on dialysis, evaluating the association of serum phosphate with mortality; two of these found a positive association (4–6). The relationship between serum phosphate and mortality in patients with CKD stages 3 to 5 (eGFR <60 ml/min per 1.73 m²) who are not on dialysis, and who are under regular nephrological review, has not previously been examined in a prospective systematic way. Survival data according to follow-up phosphate results are also lacking in CKD patients.The aims of this single-center study were to investigate whether an association of serum phosphate with all-cause and cardiovascular mortality could be shown prospectively in outpatients with advanced CKD (stage 5) not receiving dialysis and also in those with earlier (stages 3 and 4) CKD. The relationship of 12-month time-averaged phosphate and mortality and the influence upon survival of a serum phosphate within guideline targets was examined in this population.     

Prediction of Incident Atrial Fibrillation in Chronic Kidney Disease: The Chronic Renal Insufficiency Cohort Study

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Hemoglobin Variability in Nondialysis Chronic Kidney Disease: Examining the Association with Mortality

Background and objectives: Anemia and hemoglobin (Hb) variability are associated with mortality in hemodialysis patients who are on erythropoiesis-stimulating agents (ESA). Our aim was to describe the degree of Hb variability present in nondialysis patients with chronic kidney disease (CKD), including those who were not receiving ESA, and to investigate the association between Hb variability and mortality.Design, setting, participants, & measurements: Hb variability was determined using 6 mo of “baseline” data between January 1, 2003, and October 31, 2005. A variety of definitions for Hb variability were examined to ensure consistency and robustness.Results: A total of 6165 patients from 22 centers in seven countries were followed for a mean of 34.0 ± 15.8 mo; 49% were prescribed an ESA. There was increased Hb variability with ESA use; the residual SD of Hb was 4.9 ± 4.4 g/L in patients who were not receiving an ESA, compared with 6.8 ± 4.8 g/L. Hb variability was associated with a small but significantly increased risk for death per g/L residual SD, irrespective of ESA use. Multivariate linear regression model explained only 11% of the total variance of Hb variability.Conclusions: Hb variability is increased in patients who have CKD and are receiving ESA and is associated with an increased risk for death (even in those who are not receiving ESAs). This analysis cannot determine whether Hb variability causally affects mortality. Thus, the concept of targeting Hb variability with specific agents needs to be examined within the context of factors that affect both Hb variability and mortality.Substantial numbers of epidemiologic studies have described the association of anemia with worse outcomes in all populations, including chronic kidney disease (CKD) populations. More recently, the identified phenomenon of hemoglobin (Hb) variability (the oscillations or fluctuations of an individual dialysis patient''s Hb over time) (1–5) has also been associated with adverse outcomes and has received increasing attention as a therapeutic target (4,6–9). It remains unclear what the best method is to define or measure Hb variability and whether its association with adverse outcomes is simply an epiphenomenon or a causal relationship. Furthermore, CKD studies to date have been primarily restricted almost exclusively to hemodialysis patients who were receiving erythropoiesis-stimulating agents (ESA) (1–8)Debate exists on which factors may influence the severity and frequency of Hb variability. Identification of these factors is necessary if manipulation of Hb variability in experimental or clinical settings is a goal (3,4,8,10,11,12). There are some data to suggest that physician prescribing patterns of ESA and the type of ESA affect variability; however, because both may be confounded by other factors, the specific contribution of these and other factors to Hb variability remains uncertain (3,4,10,11,12).The goal of this analysis was to assess the presence of anemia and Hb variability within a culturally diverse, nondialysis CKD population that included patients who were not receiving ESA therapy. We assessed the association of Hb variability with mortality and explored factors that are associated with Hb variability.     

Casual Blood Pressure and Neurocognitive Function in Children with Chronic Kidney Disease: A Report of the Children with Chronic Kidney Disease Cohort Study

Summary

Background and objectives

Children with chronic kidney disease (CKD) are at risk for cognitive dysfunction, and over half have hypertension. Data on the potential contribution of hypertension to CKD-associated neurocognitive deficits in children are limited. Our objective was to determine whether children with CKD and elevated BP (EBP) had decreased performance on neurocognitive testing compared with children with CKD and normal BP.

Design, setting, participants, & measurements

This was a cross-sectional analysis of the relation between auscultatory BP and neurocognitive test performance in children 6 to 17 years enrolled in the Chronic Kidney Disease in Children (CKiD) project.

Results

Of 383 subjects, 132 (34%) had EBP (systolic BP and/or diastolic BP ≥90^th percentile). Subjects with EBP had lower mean (SD) scores on Wechsler Abbreviated Scales of Intelligence (WASI) Performance IQ than those with normal BP (normal BP versus EBP, 96.1 (16.7) versus 92.4 (14.9), P = 0.03) and WASI Full Scale IQ (97.0 (16.2) versus 93.4 (16.5), P = 0.04). BP index (subject''s BP/95^th percentile BP) correlated inversely with Performance IQ score (systolic, r = −0.13, P = 0.01; diastolic, r = −0.19, P < 0.001). On multivariate analysis, the association between lower Performance IQ score and increased BP remained significant after controlling for demographic and disease-related variables (EBP, β = −3.7, 95% confidence interval [CI]: −7.3 to −0.06; systolic BP index, β = −1.16 to 95% CI: −2.1, −0.21; diastolic BP index, β = −1.17, 95% CI: −1.8 to −0.55).

Conclusions

Higher BP was independently associated with decreased WASI Performance IQ scores in children with mild-to-moderate CKD.     

Epidemiological Study of Chronic Kidney Disease Progression: A Large-Scale Population-Based Cohort Study

The prognostic information about CKD progression, particularly for GFR categories 1 and 2, is still limited. This cohort was therefore conducted to determine the CKD progression using a competing risk approach.We conducted a retrospective cohort study linking community health screening with hospitals and death registry data in a province of Thailand, from 1997 to 2011. A competing risk model was applied by treating death as a competing risk factor to estimate 2-, 5-, and 10-year probability of kidney failure and median time for CKD progression from lower to higher GFR category.There were 17,074 non-diabetic and 15,032 diabetic CKD subjects. Diabetic subjects progressed more rapidly through GFR categories with the median times for CKD progression from GFR categories G1 to G2, G2 to G3a, G3a to G3b, G3b to G4, and G4 to G5 of 4.4, 6.1, 4.9, 6.3, and 9.0 years, respectively. Non-diabetic subjects took longer to progress with the corresponding median time of 9.4, 14.0, 11.0, 13.8, and >14.3 years. After adjusting for confounders, diabetic subjects were 49% (cause-specific hazard ratio (_cHR) = 1.49, 95% CI: 1.37, 1.62) more likely to develop kidney failure than non-diabetic subjects. Albuminuria categories A3 and A2 were, respectively, 3.40 (95% CI: 3.07, 3.76) and 1.71 (95% CI: 1.53, 1.92) higher risk of kidney failure when compared to A1.For each albumin category, death rate increased as albuminuria increased particularly in diabetic subjects, which was approximately 2 times higher in A3 compared to A1. Considering GFR category, it gradually increased from G1 to G4 and sharply increased from G4 to G5 in both non-diabetic and diabetic subjects.This study has quantified CKD progression in an Asian population within ordinary practice. Diabetic subjects progress through GFR and albuminuria categories and reach kidney failure about twice as rapidly as non-diabetic subjects.     

Combined Effect of Chronic Kidney Disease and Peripheral Arterial Disease on All-Cause Mortality in a High-Risk Population

Background and objectives: Chronic kidney disease (estimated glomerular filtration rate <60 ml/min per 1.73 m²) and peripheral arterial disease (ankle-brachial index <0.9) independently predict mortality. It was hypothesized that the risk for death is higher in patients with both chronic kidney disease and peripheral arterial disease compared with those with chronic kidney disease or peripheral arterial disease alone.Design, setting, participants, & measurements: A total of 1079 patients who had an ankle-brachial index and serum creatinine recorded within 90 d of each other in 1999 were studied retrospectively. Glomerular filtration rate was estimated using the Modification of Diet in Renal Disease equation. Patients were categorized into four groups: Chronic kidney disease and peripheral arterial disease, chronic kidney disease alone, peripheral arterial disease alone, or no chronic kidney disease or peripheral arterial disease.Results: The overall 6-yr mortality rate was 28% (n = 284). Patients with both chronic kidney disease and peripheral arterial disease had the highest mortality rate (45%) compared with patients with chronic kidney disease alone (28%), peripheral arterial disease alone (26%), and neither condition (18%). After adjustment for clinical and demographic variables, the chronic kidney disease and peripheral arterial disease group had an increased odds for death when compared with the no chronic kidney disease or peripheral arterial disease group or the single disease groups.Conclusions: These findings indicate that patients with both chronic kidney disease and peripheral arterial disease have a significantly higher risk for death than patients with either disease alone.Both peripheral arterial disease (PAD) and chronic kidney disease (CKD) are prevalent in the general population, especially in patients who are older than 65 yr and have other cardiovascular risk factors. The data from the Third National Health and Nutrition Examination Survey (NHANES III) suggest that there are more than 8 million people in the United States with reduced kidney function (defined by a GFR <60 ml/min per 1.73 m²) (1). PAD is a common disease with a prevalence rate of 14.5% among those aged ≥70 yr and affects approximately 5 million adults aged ≥40 yr in the United States (2).According to recent reports, even mild to moderate CKD is a powerful independent predictor of cardiovascular mortality and all-cause mortality (3–9). Despite the current recommendation for regular laboratory testing for serum creatinine in patients who are at increased risk for CKD (elderly, those with diabetes, and those with cardiovascular disease [CVD] or other CVD risk factors), the frequency of testing is still significantly low and therefore results in underdetection (10). Moreover, patients with CKD are at an increased risk for cardiovascular events and mortality yet often receive inadequate disease prevention and management (11–13).Like CKD, PAD is underdiagnosed and undertreated in the general population (14,15). An ankle-brachial index (ABI) cutoff of <0.9 not only has been shown to be a good screening tool for PAD (90% sensitivity and 98% specificity) (14,16) but is also associated with increased cardiovascular and all-cause mortality (17–20).PAD is very common in the CKD population (GFR <60 ml/min) with prevalence rates of 24 to 37% (21–23). Both CKD and PAD share the same cardiovascular risk factors and are clinical manifestations of diffuse atherosclerosis. Patients with PAD and ESRD have increased mortality and morbidity. These individuals may present with critical limb ischemia, which is associated with lower successful revascularization rates and higher mortality (24–27); however, the mortality data on PAD in the earlier stages of CKD is still limited. One recent study by O''Hare et al. (28) reported that moderate to severe predialysis CKD significantly increases mortality in patients with advanced PAD; however, that study was limited by its short follow-up (1 yr) and that the PAD population contained only those with advanced PAD (rest pain, ischemic ulceration, or gangrene). In this study, we hypothesized that the risk for death is higher in patients with both CKD and PAD than in those with CKD or PAD alone.     

Chronic Kidney Disease Japan Cohort (CKD-JAC) study: design and methods

The prevalence and incidence of end-stage renal disease (ESRD) in Japan are the highest and the third highest, respectively, in the world, while the incidence of cardiac death in Japan is the lowest among developed countries. A recent study showed that the prevalence of chronic kidney disease (CKD), defined as an estimated glomerular filtration rate (GFR) of less than 60 mL/min/1.73 m(2), is extremely high in Japan, about 20% of the adult population. However, the risk of ESRD and cardiovascular disease (CVD) in the CKD population has not been determined nationwide. For this observational study, we will establish a Chronic Kidney Disease Japan Cohort (CKD-JAC) by enrolling 3,000 patients with CKD in 17 clinical centers around Japan, which will be used to determine the incidence of ESRD and CVD in Japanese CKD patients. Risk factors associated with the development of CVD will also be examined. Comorbidity of diabetes in CKD patients will be analyzed to determine whether it is a risk for rapid progression of CKD and high incidence of CVD. In addition, we will study whether the burden of CKD decreases the QOL of patients, and increases hospitalization or health resource utilization. Insights from the CKD-JAC study will provide a basis for future interventional trials focused on reducing the burden of ESRD and CVD in patients with CKD in Japan.     

Asymmetric Dimethylarginine and Mortality in Stages 3 to 4 Chronic Kidney Disease

Background and objectives: Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, reduces bioavailability of nitric oxide and induces endothelial dysfunction. This dimethylated amino acid accumulates in chronic kidney disease and may be involved in the pathophysiology of cardiovascular disease (CVD) in this population.Design, settings, participants, & methods: The Modification of Diet in Renal Disease Study was a randomized, controlled trial conducted between 1989 and 1993. We measured ADMA in frozen samples collected at baseline (n = 820) and obtained survival status, up to December 31, 2000, from the National Death Index. We examined the relationship of ADMA with prevalent CVD and performed multivariable Cox models to examine the relationship of ADMA with all-cause and CVD mortality.Results: Mean (SD) age was 52 (12) yr, GFR was 32 ± 12 ml/min per 1.73 m², and ADMA was 0.70 ± 0.25 μmol/L. A 1-SD increase in ADMA was associated with a 31% increased odds of prevalent CVD in an adjusted logistic regression model. During the 10-yr follow-up period, 202 (25%) participants died of any cause, 122 (15%) from CVD, and 545 (66%) reached kidney failure. In multivariable Cox models, a 1-SD increase in ADMA was associated with a 9% increased risk for all-cause and 19% increased risk for CVD mortality.Conclusions: In this cohort of patients with predominantly nondiabetic, stages 3 to 4 chronic kidney disease, there was a strong association of ADMA with prevalent CVD and a modest association with all-cause and CVD mortality.Endothelium-derived nitric oxide, an important mediator of vascular tone and BP regulation, is produced via a reaction catalyzed by nitric oxide synthase (1). Asymmetric dimethylarginine (ADMA), a byproduct of the breakdown of arginine methylated proteins, is an endogenous inhibitor of this reaction (2). Increased ADMA levels lead to nitric oxide depletion, impaired endothelium-dependent vasodilation, reduced free radical scavenging, and plaque rupture with thrombus formation (3–5). Plasma concentrations of ADMA are elevated in cardiovascular high-risk states such as hypertension (6,7), obesity (8), and diabetes (9) and seem to be related to endothelial dysfunction in patients with these conditions. High ADMA levels were an index of carotid intima-media thickness and were associated with future acute coronary events in general population studies (10,11).Levels of ADMA are elevated in chronic kidney disease (CKD) (12,13). This 202-Da amino acid is eliminated unchanged in the urine but is also taken up and degraded in the kidney by the enzyme dimethylarginine dimethylaminohydrolase (DDAH); ADMA accumulation in kidney failure is due to both decreased elimination and reduced DDAH activity (14). High ADMA was an independent risk factor for cardiovascular disease (CVD) and all-cause mortality in a cohort of patients who were on hemodialysis (13,15) and was associated with faster rates of kidney disease progression in patients in the earlier stages of CKD (16); however, data are limited on the relationship between ADMA levels and CVD in patients with CKD before reaching kidney failure (17,18). We therefore examined the relationship of ADMA with prevalent CVD and with all-cause and CVD mortality during long-term follow-up of a cohort of patients with stages 3 to 4 CKD.     

Physical Activity and Mortality in Chronic Kidney Disease (NHANES III)

Background and objectives: Chronic kidney disease (CKD) is associated with impaired physical activity. However, it is unclear whether the associations of physical activity with mortality are modified by the presence of CKD. Therefore, we examined the effects of CKD on the associations of physical activity with mortality.Design, setting, participants, & measurements: This was an observational study of 15,368 adult participants in the National Health and Nutrition Examination Survey III; 5.9% had CKD (eGFR < 60 ml/min per 1.73 m²). Based on the frequency and intensity of leisure time physical activity obtained by a questionnaire, participants were divided into inactive, insufficiently active, and active groups. Time to mortality was examined in Cox models, taking into account the complex survey design.Results: Inactivity was present in 13.5% of the non-CKD and 28.0% of the CKD groups (P < 0.001). In two separate multivariable Cox models, compared with the physically inactive group, hazard ratios (95% confidence intervals) of mortality for insufficiently active and active groups were 0.60 (0.45 to 0.81) and 0.59 (0.45 to 0.77) in the non-CKD subpopulation and 0.58 (0.42 to 0.79) and 0.44 (0.33 to 0.58) in the CKD subpopulation. These hazard ratios did not differ significantly between the CKD and non-CKD subpopulations (P > 0.3).Conclusions: Physical inactivity is associated with increased mortality in CKD and non-CKD populations. As in the non-CKD population, increased physical activity might have a survival benefit in the CKD population.There are >16 million U.S. adults with stage III and IV chronic kidney disease (CKD) (1), yet there are only ∼400,000 in stage V CKD. A vast majority of those with moderate CKD die before they reach ESRD (2). However, the current focus of the providers taking care of the stage III and IV CKD population is on measures to slow the progression of kidney disease rather than on measures that could reduce the mortality in this population.Increased physical activity is associated with better survival in the general population. A previous analysis of the Modification of Diet in Renal Disease (MDRD) Study suggested that higher levels of physical activity were not significantly associated with reduced mortality in the CKD population (3). To our knowledge, there are no other data on exercise and survival in the CKD population. Therefore, we examined whether the presence of CKD modifies the association of exercise with mortality in the National Health and Nutrition Examination Survey (NHANES) III.     

Serum Alkaline Phosphatase and Mortality in African Americans with Chronic Kidney Disease

Background and objectives: Serum alkaline phosphatase has been associated with increased mortality in hemodialysis patients but its associations with mortality in chronic kidney disease (CKD) stages III and IV are unknown.Design, settings, participants & measurements: In 1094 participants in the African-American Study of Kidney Disease and Hypertension (AASK) database, the associations of serum alkaline phosphatase with mortality and cardiovascular events were examined in Cox models.Results: The mean (±SD) age was 54 ± 11 yr, and 61% were men. The median alkaline phosphatase was 80 IU/L, and interquartile range was 66 to 97 IU/L. The mean follow-up was 4.6 yr. There were 105 (9.6%) all-cause deaths and 149 (13.6%) cardiovascular events. Each doubling of serum alkaline phosphatase was significantly associated with increased hazard [hazard ratio (HR) 1.60, 95% confidence interval (CI) 1.08 −2.36] of all-cause mortality adjusted for demographics, drug and blood pressure groups, and comorbidity. With further adjustment for liver function tests as well as serum calcium and phosphorus, each doubling of serum alkaline phosphatase remained significantly associated with increased mortality (HR 1.55, 95% CI 1.03 to 2.33). Serum alkaline phosphatase was not significantly associated with increased risk of cardiovascular events.Conclusions: Independent of liver function tests and serum calcium and phosphorus, higher levels of serum alkaline phosphatase are associated with increased mortality in the CKD population. Further studies are warranted to identify the potential mechanisms for this association.Experimental studies suggest alkaline phosphatase might promote vascular calcification (1,2). Indeed, higher levels of serum alkaline phosphatase were independently associated with progressive arterial calcification in a longitudinal study of stage IV and V chronic kidney disease (CKD) patients (3). Furthermore, serum alkaline phosphatase was independently associated with increased mortality in hemodialysis patients (4–6). However, there is a paucity of data on whether serum alkaline phosphatase is an independent predictor of mortality in CKD stages III and IV. Therefore, we examined the associations of serum alkaline phosphatase with cardiovascular events and mortality in the African-American Study of Kidney Disease and Hypertension (AASK) database.     

GFR Decline and Mortality Risk among Patients with Chronic Kidney Disease

Summary

Background and objectives

Estimates of the effect of estimated GFR (eGFR) decline on mortality have focused on populations with normal kidney function, or have included limited information on factors previously shown to influence the risk of death among patients with CKD.

Design, setting, participants, & measurements

We retrospectively assessed the effect of rate of eGFR decline on survival of patients with CKD receiving primary care through a large integrated health care system in central Pennsylvania between January 1, 2004, and December 31, 2009.

Results

A total of 15,465 patients were followed for a median of 3.4 years. Median rates of eGFR change by those in the lower, middle, and upper tertiles of eGFR slope were −4.8, −0.6, and 3.5 ml/min per 1.73 m²/yr, respectively. In Cox proportional hazard modeling for time to death, adjusted for baseline proteinuria, changes in nutritional parameters, and episodes of acute kidney injury during follow-up (among other covariates), the hazard ratio for those in the lower (declining) and upper (increasing) eGFR tertiles (relative to the middle, or stable, tertile) was 1.84 and 1.42, respectively. Longitudinal changes in nutritional status as well as episodes of acute kidney injury attenuated the risk only modestly. These findings were consistent across subgroups.

Conclusions

eGFR change over time adds prognostic information to traditional mortality risk predictors among patients with CKD. The utility of incorporating eGFR trends into patient-risk assessment should be further investigated.