Natriuretic Peptides as Predictors of Protein-Energy Wasting in Hemodialysis Population.

OBJECTIVE: Imbalance between anabolism and catabolism is linked to cachexia and protein-energy wasting (PEW), especially in frail populations such as patients with chronic kidney disease. PEW is responsible of poor outcomes with increased morbidity and mortality. Several causes are involved in PEW such as insulin resistance, acidosis, or hyperparathyroidism. Natriuretic peptides (NPs) have recently been described as activators of resting energy expenditure through the induction of browning of white adipose tissue in rodents with chronic kidney disease. The present study was therefore implemented to investigate whether NPs could be associated with PEW criteria and predict clinical outcomes. METHODS: We quantified serum N-terminal pro-B-type natriuretic peptide (NT-proBNP) in a prospective cohort of 231 patients undergoing maintenance hemodialysis and atrial natriuretic peptide in a subgroup of 35 patients. Body composition parameters were measured with bioimpedance spectroscopy. RESULTS: NT-proBNP was inversely associated with serum albumin, prealbumin, and body mass index and, conversely, positively associated with age and C-reactive protein. NT-proBNP as well as atrial natriuretic peptide were significantly higher in patients with PEW criteria. NT-proBNP was negatively associated with body fat mass. In multiple linear regression, NT-proBNP remained associated with body mass index. Kaplan-Meier analysis revealed a significant correlation between serum NT-proBNP concentrations and all-cause mortality and cardiovascular events. This association remained significant after multivariable Cox regression models adjusted for demographic factors and cardiovascular risk factors. CONCLUSION: Accumulation of NPs seems to be associated with poor nutritional status and reduced survival among hemodialysis patients. Further studies are needed to confirm this association using resting energy expenditure measurement and adipose tissue biopsy.

Accumulation of natriuretic peptides is associated with protein energy wasting and activation of browning in white adipose tissue in chronic kidney disease.

Protein energy wasting is a common feature of patients with chronic kidney disease (CKD) and is associated with poor outcomes. Protein energy wasting and cachexia, a severe form of protein energy wasting, are characterized by increased resting energy expenditure but the underlying mechanisms are unclear. Browning corresponds to the activation of inducible brown adipocytes in white adipose tissue and occurs in states of cachexia associated with hypermetabolic disease such as cancer. Here we tested the hypothesis that CKD-associated protein energy wasting could result from browning activation as a direct effect of the uremic environment on adipocytes. In a murine model of CKD (5/6 nephrectomy), there was increased resting energy expenditure, expression of uncoupling protein 1 (a thermogenic protein uncoupling oxidative phosphorylation in mitochondria) and citrate synthase activity (a proxy of mitochondrial density in white adipose tissue). Mice with CKD also exhibited increased levels of atrial natriuretic peptide, a well known activator of browning. The incubation of primary adipose cells with plasma from patients receiving dialysis treatment and having signs of protein energy wasting led to an increased synthesis of uncoupling protein 1. Similarly, primary adipose cells exposed to atrial natriuretic peptide at concentrations relevant of CKD led to a significant increase of uncoupling protein 1 content. Thus, accumulation of cardiac natriuretic peptides during CKD could contribute to the browning of white adipose tissue and protein energy wasting.

Serum levels of the adipokine zinc-alpha2-glycoprotein (ZAG) predict mortality in hemodialysis patients.

Wasting has been associated with increased cardiovascular and all-cause mortality in chronic kidney disease (CKD). We investigated whether serum zinc-alpha2-glycoprotein (ZAG), a potent cachectic and lipid-mobilizing factor that is increased in patients with CKD, predicts clinical outcomes in patients on chronic hemodialysis. We quantified serum ZAG at baseline in a prospective cohort of 252 patients undergoing maintenance hemodialysis. Serum ZAG concentrations were inversely associated with serum albumin, creatinine, and triglycerides and, conversely, positively associated with age. Although ZAG is strongly linked to protein energy wasting (PEW) in patients with cancer, higher ZAG concentrations were not associated with PEW in our cohort. During a mean study follow-up of 954 days, 49 patients died and 62 patients experienced a cardiovascular event. Kaplan-Meier analysis revealed a significant correlation between serum ZAG concentrations and all-cause mortality and cardiovascular events. In separate multivariable Cox regression models, serum ZAG concentrations remained significantly associated with all-cause mortality and cardiovascular events after adjustment for demographic factors (age, sex, and dialysis vintage), metabolic parameters (serum albumin, prealbumin, triglycerides, cholesterol, normalized protein catabolic rate, and body mass index), and cardiovascular risk factors (diabetes, dyslipidemia, history of cardiovascular disease, smoking, and diuretic use as a proxy of residual renal function). Thus, serum ZAG appears to be a strong and independent predictor of mortality and cardiovascular events in patients with end-stage renal disease. Further studies are necessary to confirm this association and to elucidate the underlying mechanisms.

[Secondary hyperparathyroidism and anemia. Effects of a calcimimetic on the control of anemia in chronic hemodialysed patients. Pilot Study]. / Hyperparathyroïdie secondaire et anémie. Effets d'un calcimimétique sur le contrôle de l'anémie des hémodialysés chroniques. Étude pilote.

UNLABELLED: The main cause of resistance to erythropoiesis-stimulating agents (ESA) used for treatment of anemia in chronic hemodialysed patients (CHP) is the iron deficiency, absolute or functional. Secondary hyperparathyroidism (SHPT) is a secondary factor of resistance. Indeed, it has been reported in the literature an improvement of anemia parameters after surgical parathyroidectomy (PTX). The objective of this study is to assess in CHP, the impact of the correction of SHPT by a calcimimetic, cinacalcet (CI), (which is considered as a pharmacological PTX) on the response to ESA, measured by the erythropoietin resistance index (ERI). Twenty-two CHP with severe SHPT documented by an intact parathyroid hormone (iPTH) above 800pg/mL were included in this prospective pilot study. Mineral bone metabolism, anemia and nutritional parameters were measured baseline and after 6 months of treatment by CI. The effect on anemia was assessed at the end of study by the ERI, the change in Hb concentration, and the proportion of patients with Hb levels above 11g/dL. RESULTS: At the end of study there was a significant decrease (M6 vs M0) in iPTH (1302 vs 674pg/mL or -48%, p=0.006), serum calcium (2.39 vs 2.15mmol/L or -10%), serum phosphate (2 vs 1.7mmol/L or -15%), serum calcium-phosphorus product (CaxP) (4.8 vs 3.8mmol(2)/L(2) or - 20% (p<0.05), and the number of patients with CaxP>4.4mmol(2)/L(2) (64 vs 32%, p<0.05). The level of bone alkaline phosphatase remained stable during the study (28 vs 27 IU/L). The Hb levels increased from 11 to 11.4g/dL, as did the proportion of patients whose Hb concentration reached 11g/dL or higher (50 vs 70%, p<0.05) without important change of the median weekly ESA dosis in the majority of patients, 18 cases (81%) vs four (19%). Two subgroups were identified from the median decreases in iPTH (delta iPTH) between M0 and M6, Group 1 (delta iPTH≥400pg/mL, n=10) and group 2 (delta iPTH<400pg/mL, n=12): in group 1, we found a correlation between the decrease in iPTH by CI and the stability or decrease in ERI (group 1), at comparable dose of dialysis, nutritional and iron intakes and inflammatory profiles; in group 2 without a significant effect of CI on PTH reduction the levels of ERI and ESA dosis were more elevated. CONCLUSION: A treatment by calcimimetic improves the control of anemia by ESA in CHP and interferes positively on a cause of secondary resistance to ESA represented by SHPT. The mechanism of these effects could be linked to the decreased of bone marrow fibrosis and inflammation and to the triptych formed by the reduction in iPTH, CaxP and phosphate.

Influence of inflammation on total energy expenditure in hemodialysis patients.

BACKGROUND AND OBJECTIVES: Studies show that inflammation can contribute to an increase in resting energy expenditure in patients with chronic kidney disease; however, findings about total energy expenditure (TEE) have not been reported. The aim of this study was to evaluate the effects of inflammation on TEE and physical activity energy expenditure in hemodialysis (HD) patients. DESIGN: This was a cross-sectional study. SETTING: This study was conducted from Hôpital Edouard Herriot, Lyon, France. PATIENTS: This study included 24 HD patients and 18 healthy subjects. MAIN OUTCOME MEASURE: TEE and step counts were measured over a 7-day period by the SenseWear Pro2 Armband in 24 HD patients (15 patients with C-reactive protein <5 mg/L, aged 67.0 ± 14.7 years, and 9 with C-reactive protein >5 mg/L, aged 69.0 ± 18.0 years) and compared with 18 healthy subjects (62.3 ± 15.3 years). RESULTS: Mean estimated TEE measured with SenseWear Pro2 Armband was significantly lower (25.5 ± 4.1 kcal/kg/day) in patients with inflammation when compared with those without inflammation (32.0 ± 6.7 kcal/kg/day) and with healthy subjects (31.8 ± 7.0 kcal/kg/day) (P = .012). There was a difference in the physical activity (step counts) between patient groups (P < .05). Healthy subjects and patients without inflammation walked more (8,107 ± 5,419 and 6,016 ± 3,752 steps/day, respectively) as compared with patients with inflammation (2,801 ± 2,754 steps/day, P = .001). CONCLUSION: Our findings suggest that patients with inflammation have a lower TEE when compared with healthy subjects and patients without inflammation. TEE is influenced by physical activity because patients with inflammation appear to be less active.

New measurements of energy expenditure and physical activity in chronic kidney disease.

The accurate estimation of total daily energy expenditure (TEE) in chronic kidney patients is essential to allow the provision of nutritional requirements; however, it remains a challenge to collect actual physical activity and resting energy expenditure in maintenance dialysis patients. The direct measurement of TEE by direct calorimetry or doubly labeled water cannot be used easily so that, in clinical practice, TEE is usually estimated from resting energy expenditure and physical activity. Prediction equations may also be used to estimate resting energy expenditure; however, their use has been poorly documented in dialysis patients. Recently, a new system called SenseWear Armband (BodyMedia, Pittsburgh, PA) was developed to assess TEE, but so far no data have been published in chronic kidney disease patients. The aim of this review is to describe new measurements of energy expenditure and physical activity in chronic kidney disease patients.