Longitudinal Assessment of Body Composition and Its Association With Survival Among Participants of the ACTIVE/ADIPOSE Study.

OBJECTIVES: The importance of muscle wasting as a predictor of mortality in the hemodialysis population is not clear. Lack of association of muscle mass with survival in some studies could be related to reliance on single measures or to incorporation of excess extracellular water (ECW) into estimates of muscle mass. We examined changes in body composition over a 2-year period and the association of body composition with survival. DESIGN AND METHODS: We analyzed data from 325 adults receiving hemodialysis in the Bay Area. We estimated ECW, intracellular water (ICW), and fat mass by whole-body bioimpedance spectroscopy (BIS) at 0, 12, and 24 months from enrollment. We used linear mixed modeling to examine changes in body mass index and BIS-derived estimates of body composition and Cox modeling with BIS-derived estimates as time-varying independent variables to examine associations between body composition and survival in multivariable analyses. RESULTS: Body mass index declined over time. Considering individual components of body composition, ICW declined (-0.09 kg/m2 per year, 95% confidence interval -0.14 to -0.04), but fat mass and ECW did not change significantly. There were 120 deaths over a median of 5.2 years. The relationship between ICW and mortality was not linear such that the association was steeper at low values of ICW, whereas higher ICW was associated with better survival that was relatively stable above 9 kg/m2. Higher ECW was associated with higher mortality, and fat mass was not associated with survival. These associations were independent of markers of inflammation and nutritional status. CONCLUSIONS: ICW declined over 2 years in this cohort, whereas fat mass and ECW remained relatively stable. Higher ICW was associated with better survival, but higher fat mass was not. Higher ECW was associated with worse survival. These results suggest that muscle mass may predict survival among patients on hemodialysis.

The Predialysis Serum Sodium Level Modifies the Effect of Hemodialysis Frequency on Left-Ventricular Mass: The Frequent Hemodialysis Network Trials.

INTRODUCTION: The Frequent Hemodialysis Network (FHN) Daily and Nocturnal trials aimed to compare the effects of hemodialysis (HD) given 6 versus 3 times per week. More frequent in-center HD significantly reduced left-ventricular mass (LVM), with more pronounced effects in patients with low urine volumes. In this study, we aimed to explore another potential effect modifier: the predialysis serum sodium (SNa) and related proxies of plasma tonicity. METHODS: Using data from the FHN Daily and Nocturnal Trials, we compared the effects of frequent HD on LVM among patients stratified by SNa, dialysate-to-predialysis serum-sodium gradient (GNa), systolic and diastolic blood pressure, time-integrated sodium-adjusted fluid load (TIFL), and extracellular fluid volume estimated by bioelectrical impedance analysis. RESULTS: In 197 enrolled subjects in the FHN Daily Trial, the treatment effect of frequent HD on ∆LVM was modified by SNa. When the FHN Daily Trial participants are divided into lower and higher predialysis SNa groups (less and greater than 138 mEq/L), the LVM reduction in the lower group was substantially higher (-28.0 [95% CI -40.5 to -15.4] g) than in the higher predialysis SNa group (-2.0 [95% CI -15.5 to 11.5] g). Accounting for GNa, TIFL also showed more pronounced effects among patients with higher GNa or higher TIFL. Results in the Nocturnal Trial were similar in direction and magnitude but did not reach statistical significance. DISCUSSION/CONCLUSION: In the FHN Daily Trial, the favorable effects of frequent HD on left-ventricular hypertrophy were more pronounced among patients with lower predialysis SNa and higher GNa and TIFL. Whether these metrics can be used to identify patients most likely to benefit from frequent HD or other dialytic or nondialytic interventions remains to be determined. Prospective, adequately powered studies studying the effect of GNa reduction on mortality and hospitalization are needed.

Correlates and Consequences of High Serum Irisin Concentration in Patients on Hemodialysis: A Longitudinal Analysis.

OBJECTIVE: Irisin is a hormone released by muscle in response to exercise that acts on white adipose cells to stimulate browning of adipose tissue. We aimed to examine irisin correlates and consequences of irisin in patients receiving hemodialysis. DESIGN AND METHODS: A prospective cohort study was conducted using data from 749 prevalent patients receiving hemodialysis. Multivariable linear regression and multivariable generalized estimating equations were used to determine correlates of baseline and change in serum irisin concentration. Proportional hazards (Cox) regression was used to assess the association between serum irisin concentration and time to death. RESULTS: Age and body mass index were inversely associated with baseline and change in serum irisin concentration. Lower muscle mass as estimated by serum creatinine concentration was associated with lower irisin concentration (-1.38% per mg/dL (95% confidence interval [CI]: -2.45, -0.21) and with a 0.72% decrease in irisin concentration (95% CI: -1.48, -0.04) from baseline to 12 months. Each 50% higher serum interleukin-6 (IL-6) concentration was associated with 1.52% higher serum irisin concentration (95% CI: 0.38, 2.66) at baseline and an increase of 1.04% in irisin concentration over 1 year (95% CI: 0.47, 1.61). Irisin concentration at baseline was associated with higher hazard of death (hazards ratio: 1.45, 95% CI: 1.05 2.00); an increase in irisin concentration over 1 year was associated with a higher hazard of death (hazards ratio: 1.34, 95% CI: 1.01, 1.79). In formal mediation analysis, serum IL-6 was a mediator in the association between serum irisin and mortality. CONCLUSIONS: Lower serum creatinine (reflecting lower muscle mass) and higher serum IL-6 were associated with higher serum irisin concentrations. Higher serum irisin concentrations were associated with higher mortality, which may be mediated by inflammation.

KDOQI Clinical Practice Guideline for Nutrition in CKD: 2020 Update

The National Kidney Foundation's Kidney Disease Outcomes Quality Initiative (KDOQI) has provided evidence-based guidelines for nutrition in kidney diseases since 1999. Since the publication of the first KDOQI nutrition guideline, there has been a great accumulation of new evidence regarding the management of nutritional aspects of kidney disease and sophistication in the guidelines process. The 2020 update to the KDOQI Clinical Practice Guideline for Nutrition in CKD was developed as a joint effort with the Academy of Nutrition and Dietetics (Academy). It provides comprehensive up-to-date information on the understanding and care of patients with chronic kidney disease (CKD), especially in terms of their metabolic and nutritional milieu for the practicing clinician and allied health care workers. The guideline was expanded to include not only patients with end-stage kidney disease or advanced CKD, but also patients with stages 1-5 CKD who are not receiving dialysis and patients with a functional kidney transplant. The updated guideline statements focus on 6 primary areas: nutritional assessment, medical nutrition therapy (MNT), dietary protein and energy intake, nutritional supplementation, micronutrients, and electrolytes. The guidelines primarily cover dietary management rather than all possible nutritional interventions. The evidence data and guideline statements were evaluated using Grading of Recommendations, Assessment, Development and Evaluation (GRADE) criteria. As applicable, each guideline statement is accompanied by rationale/background information, a detailed justification, monitoring and evaluation guidance, implementation considerations, special discussions, and recommendations for future research.

KDOQI Clinical Practice Guideline for Nutrition in CKD: 2020 Update.

The National Kidney Foundation's Kidney Disease Outcomes Quality Initiative (KDOQI) has provided evidence-based guidelines for nutrition in kidney diseases since 1999. Since the publication of the first KDOQI nutrition guideline, there has been a great accumulation of new evidence regarding the management of nutritional aspects of kidney disease and sophistication in the guidelines process. The 2020 update to the KDOQI Clinical Practice Guideline for Nutrition in CKD was developed as a joint effort with the Academy of Nutrition and Dietetics (Academy). It provides comprehensive up-to-date information on the understanding and care of patients with chronic kidney disease (CKD), especially in terms of their metabolic and nutritional milieu for the practicing clinician and allied health care workers. The guideline was expanded to include not only patients with end-stage kidney disease or advanced CKD, but also patients with stages 1-5 CKD who are not receiving dialysis and patients with a functional kidney transplant. The updated guideline statements focus on 6 primary areas: nutritional assessment, medical nutrition therapy (MNT), dietary protein and energy intake, nutritional supplementation, micronutrients, and electrolytes. The guidelines primarily cover dietary management rather than all possible nutritional interventions. The evidence data and guideline statements were evaluated using Grading of Recommendations, Assessment, Development and Evaluation (GRADE) criteria. As applicable, each guideline statement is accompanied by rationale/background information, a detailed justification, monitoring and evaluation guidance, implementation considerations, special discussions, and recommendations for future research.

The effect of frequent hemodialysis on matrix metalloproteinases, their tissue inhibitors, and FGF23: Implications for blood pressure and left ventricular mass modification in the Frequent Hemodialysis Network trials.

BACKGROUND: Frequent hemodialysis modifies serum phosphorus, blood pressure, and left ventricular mass (LVM). We ascertained whether frequent hemodialysis is associated with specific changes in biomarker profile among patients enrolled in the frequent hemodialysis network (FHN) trials. METHODS: This was a post hoc analysis of biomarkers among patients enrolled to the FHN trials. In particular, we hypothesized that frequent hemodialysis is associated with changes in a specific set of biomarkers which are linked with changes in blood pressure or LVM. RESULTS: Among 332 randomized patients, 243 had biomarker data available. Of these, 124 patients were assigned to 3-times-a-week hemodialysis (94 [Daily Trial] and 30 [Nocturnal Trial]) and 119 patients were assigned to 6-times-a-week hemodialysis (87 [Daily Trial] and 32 [Nocturnal Trial]). Frequent hemodialysis lowered phosphate, blood pressures, LVM, log fibroblast growth factor (FGF)23, and tissue inhibitors of metalloproteinase (TIMP)-2 levels. The fall in phosphate was associated with changes in FGF23 (r = 0.48, P < 0.001) [Daily Trial] and (r = 0.55, P < 0.001) [Nocturnal Trial]) and tended to be associated with changes in systolic blood pressure (r = 0.18, P = 0.057) [Daily Trial] and (r = 0.31, P = 0.04) [Nocturnal Trial]. Within the Daily Trial, changes in MMP2 (r = 0.20, P = 0.034) were associated with changes in LVM. In the Nocturnal Trial, changes in TIMP-1 (r = 0.37, P = 0.029) and MMP 9 (r = -0.38, P = 0.01) were associated with LVM changes. MMP2 changes were associated with changes in systolic blood pressure. CONCLUSIONS: Reduction of serum phosphate by frequent hemodialysis may modulate FGF23 levels and systolic blood pressure. Markers of matrix turnover are associated with LVM changes. Frequent hemodialysis may affect pathological mediators of chronic kidney disease-mineral bone-metabolism disorder.

Evaluation of one year of frequent dialysis on fluid load and body composition using calf bioimpedance technique.

OBJECTIVE: The primary aim of this study was to evaluate the effect of increased frequency of dialysis (FHD) on change in fluid status and body composition using segmental bioimpedance. APPROACH: Twelve stable HD patients were switched from 3 times/week to 6 times/week HD (FHD). Systolic blood pressure (SBP), body mass and body mass index (BMI) were measured pre- and post-HD. Calf resistance (R 5) at 5 kHz was measured using a multifrequency bioimpedance device (Hydra 4200). Calf resistivity (ρ = R 5 * area/length), normalized resistivity (CNR = ρ/BMI) and calf extracellular volume (cECV) were calculated. Fat mass was measured by Futrex body composition analyzers (Futrex 6100, Futrex Tech, Inc.). All measurements were performed at baseline (BL) and monthly for up to one year. MAIN RESULTS: Nine patients completed one year of FHD. Compared to BL, body weight and cECV decreased, and CNR increased significantly by the first month but did not change thereafter. SBP pre-HD decreased significantly by the end of the first month with further reduction until month 12. Additionally, antihypertensive medication decreased significantly from baseline by month 4 and remained stable from month 6 throughout the rest of the study. The post-HD CNR in five of nine patients reached the range of normal (>18.5 10-2 * Ohm * m3 kg-1 for males and >19.1 10-2 * Ohm * m3 kg-1 for females) after 1 year FHD. In patients who returned to 3 times/week dialysis, CNR decreased significantly in the first week, and this was associated with increases in body weight and SBP. SIGNIFICANCE: Reduction of fluid overload with no alteration of body composition was observed in this study. Accordingly, improving fluid status was confirmed by reducing BP and use of antihypertensive drugs together with increase in CNR. Measurement of fluid status by CNR in hemodialysis patients is a new method to quantitatively assess hydration potentially creating a target for volume of fluid removal.

The effect of increased frequency of hemodialysis on serum cystatin C and ß2-microglobulin concentrations: A secondary analysis of the frequent hemodialysis network (FHN) trial.

INTRODUCTION: Small molecular weight toxin clearance is the main method of assessment of hemodialysis efficiency. Middle molecules including cystatin C (CysC) and Beta-2 microglobulin (ß2-M) are understudied. We hypothesized that lowering of predialysis CysC and ß2-M serum concentrations would be affected by switching to more frequent hemodialysis. METHODS: Predialysis CysC and ß2-M serum concentrations were measured from serum samples of the Frequent Hemodialysis Network (FHN) Daily and Nocturnal Trials. The differences between predialysis concentrations at baseline (while on conventional thrice weekly dialysis) and those after 12-months of study (on more frequent dialysis) were compared separately by trial (Nocturnal, Daily). We tested the associations between predialysis serum CysC and ß2-M concentrations and outcomes. FINDINGS: Forty-nine percent and 52% of the patients from the FHN Daily and Nocturnal Trials respectively were included in this ancillary study. Predialysis serum CysC concentrations remained unchanged after intensifying hemodialysis dose by either modality. There was significant lowering of the serum ß2-M concentrations in the frequent Daily Trial hemodialysis group at 12 months in all patients and in patients without residual renal function at baseline (-3.8 ± 12.62 µg/mL, P = 0.004; -5.9 ± 12.99 µg/mL, P = 0.02, respectively). There were no significant differences between the baseline and the 12-months predialysis ß2-M serum concentrations in the two control groups (Daily 3× and Nocturnal 3× groups). No association between the changes in the two biomarkers between baseline and 12-months and in changes in left ventricular mass, physical-health composite scores, hospitalization rate, and death were found. The numbers of hospitalizations and deaths were small. DISCUSSION: ß2-M may be a better biomarker of dialysis dose than CysC. Reduction in the concentration of potentially toxic long-lived proteins of the size of ß-2M is one potential long-term benefit of more intensive dialysis that may be explored.

Frailty Among Patients Receiving Hemodialysis: Evolution of Components and Associations With Mortality.

BACKGROUND: Understanding how components of frailty change over time and how they can be modeled as time-dependent predictors of mortality could lead to better risk prediction in the dialysis population. METHODS: We measured frailty at baseline, 12 months, and 24 months among 727 patients receiving hemodialysis in Northern California and Atlanta. We examined the likelihood of meeting frailty components (weight loss, exhaustion, low physical activity, weak grip strength, and slow gait speed) as a function of time in logistic regression analysis and association of frailty components with mortality in time-updated multivariable Cox models. RESULTS: Physical activity and gait speed declined, exhaustion and grip strength did not change, and the odds of meeting the weight loss criterion declined with time. All five components were associated with higher mortality in multivariable analyses, but gait speed was the strongest individual predictor. All frailty components except physical inactivity were independently associated with mortality when all five components were included in the same model. The number of frailty components met was associated with mortality in a gradient that ranged from a hazard ratio of 2.73 for one component to 10.07 for five components met; the model including all five components was the best model based on Akaike information criterion. CONCLUSIONS: Measurement of all frailty components was necessary for optimal mortality prediction, and the number of components met was strongly associated with mortality in this cohort.

Low testosterone is associated with frailty, muscle wasting and physical dysfunction among men receiving hemodialysis: a longitudinal analysis.

BACKGROUND: Despite the high prevalence of frailty among patients receiving hemodialysis, few preventable or treatable contributing causes have been identified. Hypogonadism is also common in this population and low serum testosterone concentrations share several clinical phenotypes with frailty. We hypothesized that low serum testosterone concentrations would be associated with frailty and several of its individual components. METHODS: We used data from 440 men from A Cohort Study To Investigate the Value of Exercise in ESRD/Analysis Designed to Investigate the Paradox of Obesity and Survival in ESRD, a longitudinal study that recruited participants from 14 dialysis centers in Atlanta, GA and the San Francisco, CA Bay Area from 2009 to 2011. We assessed frailty using the Fried Frailty Phenotype. We examined the association between free testosterone (as a continuous and dichotomous variable) and frailty, individual frailty components, sarcopenia, lower extremity function and muscle mass estimation by creatinine and body impedance spectroscopy over 12 months using generalized estimating equations. RESULTS: The mean age was 56.1 ± 14.2 years and 27% were white. A 50% lower concentration of free testosterone was associated with 1.40-fold higher odds of being frail [95% confidence interval (CI) 1.05-1.53] and 1.40-fold higher odds of becoming frail over 12 months (95% CI 1.07-1.73). This association was mainly due to an association with two components of frailty: grip strength and gait speed. In addition, 50% lower free testosterone concentration was associated with a 1.55-fold higher odds of having sarcopenia (95% CI 1.09-2.02) and 1.72-fold higher odds for developing sarcopenia (95% CI 1.13-2.33) as well as with lower muscle mass and a decrease in muscle mass over 12 months as estimated by serum creatinine and by bioelectrical impedance spectroscopy. CONCLUSION: Serum free testosterone concentration was associated with frailty, physical function, sarcopenia and muscle mass as well as with changes in these outcomes over 12 months. Testosterone replacement may be a feasible therapeutic target toward prevention of frailty, although clinical trials are needed to test this possibility.

Association between change in serum bicarbonate and change in thyroid hormone levels in patients receiving conventional or more frequent maintenance haemodialysis.

AIM: Correction of metabolic acidosis in patients with chronic kidney disease has been associated with improvement in thyroid function. We examined whether changes in bicarbonate were associated with changes in thyroid function in patients with end-stage renal disease receiving conventional or more frequent haemodialysis. METHODS: In the Frequent Hemodialysis Network Trials, the relationship between changes in serum bicarbonate, free triiodothyronine (FT3) and free thyroxine (FT4) was examined among 147 and 48 patients with endogenous thyroid function who received conventional (3×/week) or more frequent (6×/week) haemodialysis (Daily Trial) or who received conventional or more frequent nocturnal haemodialysis (Nocturnal Trial). Equilibrated normalized protein catabolic rate (enPCR) was examined to account for nutritional factors affecting both acid load and thyroid function. RESULTS: Increasing dialysis frequency was associated with increased bicarbonate level. Baseline bicarbonate level was not associated with baseline FT3 and FT4. Change in bicarbonate level was not associated with changes in FT3 and FT4 in the Daily Trial nor for FT4 in the Nocturnal Trial (r ≤ 0.14, P > 0.21). While, a significant correlation between change in serum bicarbonate and change in FT3 (r = 0.44, P = 0.02) was observed in the Nocturnal Trial; findings were no longer significant after adjusting for change in enPCR (r = 0.37, P = 0.08). For participants with baseline bicarbonate <23 mmol/L, no association between change in bicarbonate and change in thyroid indices were seen in the Daily Trial; for the Nocturnal Trial, findings were also not significant for change in FT3 and the association between change in bicarbonate and change in FT4 (r = 0.54, P = 0.03) was no longer significant after adjusting for enPCR (r = 0.45, P = 0.11). CONCLUSION: Changes in bicarbonate were not associated with changes in thyroid hormone levels after adjusting for enPCR, as a marker of nutritional status. Future studies should examine whether improvement in acid base status improves thyroid function in haemodialysis patients with evidence of thyroid hypofunction.

Lipid levels are inversely associated with infectious and all-cause mortality: international MONDO study results.

Cardiovascular (CV) events are increased 36-fold in patients with end-stage renal disease. However, randomized controlled trials to lower LDL cholesterol (LDL-C) and serum total cholesterol (TC) have not shown significant mortality improvements. An inverse association of TC and LDL-C with all-cause and CV mortality has been observed in patients on chronic dialysis. Lipoproteins also may protect against infectious diseases. We used data from 37,250 patients in the international Monitoring Dialysis Outcomes (MONDO) database to evaluate the association between lipids and infection-related or CV mortality. The study began on the first day of lipid measurement and continued for up to 4 years. We applied Cox proportional models with time-varying covariates to study associations of LDL-C, HDL cholesterol (HDL-C), and triglycerides (TGs) with all-cause, CV, infectious, and other causes of death. Overall, 6,147 patients died (19.2% from CV, 13.2% from infection, and 67.6% from other causes). After multivariable adjustment, higher LDL-C, HDL-C, and TGs were independently associated with lower all-cause death risk. Neither LDL-C nor TGs were associated with CV death, and HDL-C was associated with lower CV risk. Higher LDL-C and HDL-C were associated with a lower risk of death from infection or other non-CV causes. LDL-C was associated with reduced all-cause and infectious, but not CV mortality, which resulted in the inverse association with all-cause mortality.

Fibroblast Growth Factor 23 is Associated With Adiposity in Patients Receiving Hemodialysis: Possible Cross Talk Between Bone and Adipose Tissue.

OBJECTIVE: Fibroblast growth factor 23 (FGF-23) may be involved in signaling between bone and adipose tissue in dialysis patients, but its role is uncertain. We sought to examine the association between FGF-23 and adiposity and whether this association is mediated in part by leptin. DESIGN/SETTING: We performed univariate and multivariate linear regression analyses using data from 611 participants in a cohort of prevalent hemodialysis patients recruited from dialysis centers in Atlanta, GA and San Francisco, CA from 2009 to 2011. We also investigated the role of leptin in these relationships. SUBJECTS: Participants were aged ≥18 years, English or Spanish speaking, and receiving hemodialysis for at least 3 months. MAIN OUTCOME MEASURES: Outcome measures of adiposity included body mass index, waist circumference, and body fat measured by bioelectrical impedance spectroscopy. RESULTS: Mean age was 56 ± 14 years, 39.8% were female, and median serum FGF-23 was 807 pg/mL. In fully adjusted models, FGF-23 was inversely associated with body mass index (-0.24 kg/m2 per 50% higher FGF-23, 95% confidence interval [CI]: -0.38 to -0.10), waist circumference (-0.44 cm per 50% higher FGF-23, 95% CI: -0.79 to -0.08), and percent body fat (-0.58% per 50% higher FGF-23, 95% CI: -0.79 to -0.37). Leptin was inversely associated with FGF-23. Addition of leptin to body composition models attenuated the associations between FGF-23 and measures of adiposity, but FGF-23 remained significantly associated with percent body fat (-0.17% per 50% higher FGF-23, 95% CI: -0.32 to -0.02). CONCLUSION: We found a negative association between FGF-23 and adiposity that appears to be mediated in part by leptin. As adipose tissue provides a "protective energy depot" for patients with chronic illness, a decrease in adipose tissue may be one mechanism in which higher FGF-23 levels may contribute to increased mortality in dialysis patients.

Changes in Biomarker Profile and Left Ventricular Hypertrophy Regression: Results from the Frequent Hemodialysis Network Trials.

BACKGROUND: Regression of left ventricular hypertrophy (LVH) is feasible with more frequent hemodialysis (HD). We aimed to ascertain pathways associated with regression of left ventricular mass (LVM) in patients enrolled in the Frequent HD Network (FHN) trials. METHODS: This was a post hoc observational cohort study. We hypothesized LVH regression with frequent HD was associated with a different cardiovascular biomarker profile. Regressors were defined as patients who achieved a reduction of more than 10% in LVM at 12 months. Progressors were defined as patients who had a minimum of 10% increase in LVM at 12 months. RESULTS: Among 332 randomized patients, 243 had biomarker data available. Of these, 121 patients did not progress or regress, 77 were regressors, and 45 were progressors. Mean LVM change differed between regressors and progressors by -65.6 (-74.0 to -57.2) g, p < 0.001. Regressors had a median (interquartile range) increase in dialysis frequency (from 3.0 [3.0-3.0] to 4.9 [3-5.7] per week, p = 0.001) and reductions in pre-dialysis systolic (from 149.0 [136.0-162.0] to 136.0 [123.0-152.0] mm Hg, p < 0.001) and diastolic (from 83.0 [71.0-91.0] to 76.0 [68.0-84.0] mm Hg, p < 0.001) blood pressures. Klotho levels increased in regressors versus progressors (76.9 [10.5-143.3] pg/mL, p = 0.024). Tissue inhibitors of metalloproteinase (TIMP)-2 levels fell in regressors compared to progressors (-7,853 [-14,653 to -1,052] pg/mL, p = 0.024). TIMP-1 and log (brain natriuretic -peptide [BNP]) levels also tended to fall in regressors. Changes in LVM correlated inversely with changes in klotho (r = -0.24, p = 0.014). -Conclusions: Markers of collagen turnover and changes in klotho levels are potential novel pathways associated with regression of LVH in the dialysis population, which will require further prospective validation.

Associations of lipoproteins with cardiovascular and infection-related outcomes in patients receiving hemodialysis.

BACKGROUND: In hemodialysis (HD) patients, higher lipid levels are associated with lower mortality. Lipid-lowering therapy does not reduce all-cause mortality or cardiovascular (CV) mortality. Lipoproteins play a role in the innate immune system. Our objective was to determine whether protection from infection might counterbalance adverse CV outcomes associated with lipoproteins. METHODS: We examined associations between serum apolipoprotein (Apo) A1, B, C2, C3, high-density lipoprotein and low-density lipoprotein (LDL) cholesterol and triglyceride levels and infectious mortality or hospitalization, CV mortality or hospitalization, and all-cause mortality in 433 prevalent HD patients. Cox models with time-varying apolipoprotein concentrations collected every 6 months for up to 2 years were used for analyses. RESULTS: Median follow-up time for all-cause mortality was 2.7 years (25th-75th percentile range: 2.2-3.4 years). One hundred seventy-nine (41%) patients had an infection-related event. In multivariable models, higher Apo B and LDL were associated with lower risks of infection-related outcomes (hazard ratio Apo B 0.92 [95% confidence interval 0.86-0.99 per 10 mg/dL, P = .03]; hazard ratio LDL 0.93 [95% confidence interval 0.87-1.00 per 10 mg/dL, P = .05]). Sixty-three (15%) participants had a CV-related event. No significant associations were observed between lipoproteins and CV outcomes. Eighty-seven (20%) participants died. Higher Apo A1, Apo B, and Apo C3 were associated with lower risks of all-cause mortality. There was no interaction between the use of lipid-lowering medication and any of the outcomes. CONCLUSION: Associations of lipoproteins with lower risk of serious infection accompanied by no significant association with CV events may help to explain the paradoxical association between lipids and survival and lack of benefit of lipid-lowering therapies in HD.

Albumin handling in different hemodialysis modalities.

Hypoalbuminemia is a major risk factor for morbidity and mortality in dialysis patients. With increasing interest in highly permeable membranes and convective therapies to improve removal of middle molecules, transmembrane albumin loss increases accordingly. Currently, the acceptable upper limit of albumin loss for extracorporeal renal replacement therapies is unknown. In theory, any additional albumin loss should be minimized because it may contribute to hypoalbuminemia and adversely affect the patient's prognosis. However, hypoalbuminemia-associated mortality may be a consequence of inflammation and malnutrition, rather than low albumin levels per se. The purpose of this review is to give an overview of albumin handling with different extracorporeal renal replacement strategies. We conclude that the acceptable upper limit of dialysis-related albumin loss remains unknown. Whether enhanced middle molecule removal outweighs the potential adverse effects of increased albumin loss with novel highly permeable membranes and convective therapies is yet to be determined.

Associations of Body Mass Index and Body Fat With Markers of Inflammation and Nutrition Among Patients Receiving Hemodialysis.

BACKGROUND: Understanding the extent to which visceral and subcutaneous body fat are associated with markers of nutrition and inflammation in patients on dialysis therapy could shed light on the obesity paradox and the biology of subcutaneous fat. STUDY DESIGN: Cross-sectional. SETTING & PARTICIPANTS: 609 adults receiving hemodialysis who participated in the ACTIVE/ADIPOSE Study. PREDICTORS: Body mass index (BMI), waist circumference, and bioelectrical impedance spectroscopy-derived estimates of percent body fat. OUTCOMES: C-Reactive protein (CRP), interleukin 6 (IL-6), prealbumin, albumin, leptin, and adiponectin concentrations. MEASUREMENTS: We performed linear regression analyses to examine the extent to which proxies of visceral and subcutaneous fat were associated with inflammation, nutrition, and adiposity-related hormones. RESULTS: BMI was directly associated with markers of inflammation (standardized estimate for ln[CRP in mg/L]: 0.30 [95% CI, 0.22-0.38] per 10kg/m2; for ln[IL-6 in pg/mL]: 0.10 [95% CI, 0.02-0.18] per 10kg/m2), but was not associated with markers of nutrition. BMI was also inversely associated with adiponectin and directly associated with leptin. With waist circumference and percent body fat (as a proxy of visceral and subcutaneous fat, respectively) modeled together, waist circumference was associated with markers of inflammation (standardized estimate for ln[CRP in mg/L]: 0.21 [95% CI, 0.09-0.34] per 10cm; for ln[IL-6 in pg/mL]: 0.18 [95% CI, 0.07-0.29] per 10cm), whereas percent body fat was not associated with CRP (standardized estimate for ln[CRP in mg/L]: 0.03 [95% CI, -0.10 to 0.15] per 1%) and was inversely associated with IL-6 (standardized estimate for ln[IL-6 in pg/mL]: -0.15 [95% CI, -0.27 to -0.02] per 1%). In addition, waist circumference was inversely associated with prealbumin and albumin (standardized estimates of -0.12 [95% CI, -0.23 to -0.02] mg/dL per 10cm and -0.17 [95% CI, -0.28 to -0.06] g/dL per 10cm, respectively), and percent body fat was directly associated with prealbumin and albumin (0.20 [95% CI, 0.07-0.32] mg/dL and 0.15 [95% CI, 0.02-0.28] g/dL per 1%, respectively). Higher waist circumference was associated indirectly with adiponectin and directly with leptin concentrations. LIMITATIONS: Although the observed associations implicate visceral fat as the cause of inflammation, it cannot be determined in this cross-sectional study. CONCLUSIONS: Proxies of visceral and subcutaneous fat appear to have opposing associations with biomarkers of inflammation and nutrition. Subcutaneous fat may be an indicator of nutritional status, and visceral fat, an indicator of inflammation.

Factors Associated with Frailty and Its Trajectory among Patients on Hemodialysis.

BACKGROUND AND OBJECTIVES: Frailty is common among patients on hemodialysis and associated with adverse outcomes. However, little is known about changes in frailty over time and the factors associated with those changes. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: To address these questions, we examined 762 participants in the A Cohort to Investigate the Value of Exercise/Analyses Designed to Investigate the Paradox of Obesity and Survival in ESRD cohort study, among whom frailty was assessed at baseline and 12 and 24 months. We used ordinal generalized estimating equations analyses and modeled frailty (on a scale from zero to five possible components) and death during follow-up. RESULTS: The mean frailty score at baseline was 1.9, and the distribution of frailty scores was similar at each evaluation. However, most participants' scores changed, with patients improving almost as often as worsening (overall change, 0.2 points per year; 95% confidence interval, 0.1 to 0.3). Hispanic ethnicity (0.6 points per year; 95% confidence interval, 0.0 to 1.1) and diabetes (0.7 points per year; 95% confidence interval, 0.3 to 1.0) were associated with higher frailty scores and higher serum albumin concentration with lower frailty scores (-1.1 points per g/dl; 95% confidence interval, -1.5 to -0.7). In addition, patients whose serum albumin increased over time were less likely to become frail, with each 1-g/dl increase in albumin associated with a 0.4-point reduction in frailty score (95% confidence interval, -0.80 to -0.05). To examine the underpinnings of the association between serum albumin and frailty, we included serum IL-6, normalized protein catabolic rate, and patient self-report of hospitalization within the last year in a second model. Higher IL-6 and hospitalization were statistically significantly associated with worse frailty at any point and worsening frailty over time, whereas normalized protein catabolic rate was not independently associated with frailty. CONCLUSIONS: There was substantial year to year variability in frailty scores, with approximately equal numbers of patients improving and worsening. Markers of inflammation and hospitalization were independently associated with worsening frailty. Studies should examine whether interventions to address inflammation or posthospitalization rehabilitation can improve the trajectory of frailty.

Sarcopenia and its individual criteria are associated, in part, with mortality among patients on hemodialysis.

The relative importance of sarcopenia and its individual components as independent predictors of mortality in the dialysis population has not been determined. We estimated whole-body muscle mass using pre-dialysis bioimpedance spectroscopy measurements in 645 ACTIVE/ADIPOSE-enrolled prevalent hemodialysis patients from San Francisco and Atlanta. Low muscle mass was defined as two standard deviations below sex-specific means for young adults from NHANES and indexed to height2, body weight, body surface area, or body mass index. We evaluated the association of sarcopenia (low muscle mass) by four indexing methods, weak hand grip strength, and slow gait speed with mortality. Seventy-eight deaths were observed during a mean follow-up of 1.9 years. Sarcopenia was not significantly associated with mortality after adjusting for covariates. No muscle mass criteria were associated with death, regardless of indexing metrics. In contrast, having weak grip strength or slow walking speed was associated with mortality in the adjusted model. Only gait slowness significantly improved the predictive accuracy for death with an increase in C-statistic from 0.63 to 0.68. However, both gait slowness and hand grip weakness significantly improved the net reclassification index compared to models without performance measures (50.5% for slowness and 33.7% for weakness), whereas models with muscle size did not. Neither sarcopenia nor low muscle mass by itself was a better predictor of mortality than functional limitation alone in patients receiving hemodialysis. Thus, physical performance measures, including slow gait speed and weak hand grip strength, were associated with mortality even after adjustment for muscle size and other confounders.