Association of Prescription With Body Composition and Patient Outcomes in Incident Peritoneal Dialysis Patients

Objective: The nutritional status of patients on peritoneal dialysis (PD) is influenced by patient- and disease-related factors and lifestyle. This analysis evaluated the association of PD prescription with body composition and patient outcomes in the prospective incident Initiative for Patient Outcomes in Dialysis–Peritoneal Dialysis (IPOD-PD) patient cohort.Design and Methods: In this observational, international cohort study with longitudinal follow-up of 1,054 incident PD patients, the association of PD prescription with body composition was analyzed by using the linear mixed models, and the association of body composition with death and change to hemodialysis (HD) by means of a competing risk analysis combined with a spline analysis. Body composition was regularly assessed with the body composition monitor, a device applying bioimpedance spectroscopy.Results: Age, time on PD, and the use of hypertonic and polyglucose solutions were significantly associated with a decrease in lean tissue index (LTI) and an increase in fat tissue index (FTI) over time. Competing risk analysis revealed a U-shaped association of body mass index (BMI) with the subdistributional hazard ratio (HR) for risk of death. High LTI was associated with a lower subdistributional HR, whereas low LTI was associated with an increased subdistributional HR when compared with the median LTI as a reference. High FTI was associated with a higher subdistributional HR when compared with the median as a reference. Subdistributional HR for risk of change to HD was not associated with any of the body composition parameters. The use of polyglucose or hypertonic PD solutions was predictive of an increased probability of change to HD, and the use of biocompatible solutions was predictive of a decreased probability of change to HD.Conclusion: Body composition is associated with non-modifiable patient-specific and modifiable treatment-related factors. The association between lean tissue and fat tissue mass and death and change to HD in patients on PD suggests developing interventions and patient counseling to improve nutritional markers and, ultimately, patient outcomes.Study Registration: The study has been registered at Clinicaltrials.gov (NCT01285726).

Oral sodium bicarbonate in people on haemodialysis: a randomised controlled trial

Background Adverse events and mortality tend to cluster around dialysis sessions, potentially due to the impact of the saw-toothed profile of uraemic toxins such as potassium, peaking pre-dialysis and rapidly dropping during dialysis. Acidosis could be contributing to this harm by exacerbating a rise in potassium. The objectives of this study were to investigate the effects of oral bicarbonate treatment on reducing inter-dialytic potassium gain as well as other clinical consequences of preserving muscle mass and function and reducing intradialytic arrhythmia risk in people on haemodialysis. Methods Open-label randomised controlled trial in a single-centre (London, UK). Forty-three clinically stable adults on haemodialysis were recruited, with a 6 month average pre-dialysis serum bicarbonate level < 22 mmol/l and potassium > 4 mmol/l. Thirty-three participants completed the study. Oral sodium bicarbonate tablets titrated up to a maximum of 3 g bd (6 g total) in intervention group for 12 weeks versus no treatment in the control group. Outcomes compared intervention versus non-intervention phases in the treated group and equivalent time points in the control group: pre- and post-dialysis serum potassium; nutritional assessments: muscle mass and handgrip strength and electrocardiograms (ECGs) pre and post dialysis. Results Participants took an average of 3.7 ± 0.5 g sodium bicarbonate a day. In the intervention group, inter-dialytic potassium gain was reduced from 1.90 ± 0.60 to 1.69 ± 0.49 mmol/l (p = 0.032) and pre-dialysis potassium was reduced from 4.96 ± 0.62 to 4.79 ± 0.49 mmol/l without dietary change. Pre-dialysis bicarbonate increased from 18.15 ± 1.35 to 20.27 ± 1.88 mmol/l, however with an increase in blood pressure. Nutritionally, lean tissue mass was reduced in the controls suggesting less catabolism in the intervention group. There was no change in ECGs. Limitations are small sample size and unblinded study design lacking a placebo, with several participants failing to achieve the target of 22 mmol/l serum bicarbonate levels due mainly to tablet burden. Conclusion Oral sodium bicarbonate reduced bicarbonate loss and potassium gain in the inter-dialytic period, and may also preserve lean tissue mass. Trial registration The study was registered prospectively on 06/08/2015 with EU Clinical Trials Register EudraCT number 2015-001439-20.

Salt-Sensitivity of Volume and Blood Pressure in a Mouse with Globally Reduced ENaC γ Subunit Expression

The epithelial Na+ channel (ENaC) promotes the absorption of Na+ in the aldosterone-sensitive distal nephron, colon, and respiratory epithelia. Deletion of genes encoding ENaC's subunits results in early post-natal mortality. We present initial characterization of a mouse with dramatically suppressed expression of ENaC's γ subunit. We used this hypomorphic (γmt) allele to explore the importance of this subunit in homeostasis of electrolytes and body fluid volume. At baseline, γ subunit expression in γmt/mt mice was markedly suppressed in kidney and lung, while electrolytes resembled those of littermate controls. Aldosterone levels in γmt/mt mice exceeded those seen in littermate controls. Quantitative magnetic resonance (QMR) measurement of body composition revealed similar baseline body water, lean tissue mass, and fat tissue mass in γmt/mt mice and controls. γmt/mt mice exhibited a more rapid decline in body water and lean tissue mass in response to a low Na+ diet than controls. Replacement of drinking water with 2% saline selectively and transiently increased body water and lean tissue mass in γmt/mt mice, relative to controls. Lower blood pressures were variably observed in γmt/mt mice on a high salt diet, compared to controls. γmt/mt also exhibited reduced diurnal blood pressure variation, a "non-dipping" phenotype, on a high Na+ diet. While ENaC in renal tubules and colon work to prevent extracellular fluid volume depletion, our observations suggest that ENaC in other tissues may participate in regulating extracellular fluid volume and blood pressure.

272 Effect of Frame Size and Supplementation on Performance and Carcass Characteristics of Beef Cattle Finished on Novel Endophyte-infected Tall Fescue Pastures

Objectives were to investigate the effects of frame score (FS) and supplementation on performance and carcass characteristics of cattle finished on novel endophyte-infected fescue pastures. This 2-yr experiment used 80 Angus-sired, crossbred steers and heifers bred for divergent FS. Cattle were allotted to 5 treatments: 1) non-supplemented small frame (S-NON; FS = 3.0 ± 0.9), 2) supplemented small frame (S-SUPP), 3) non-supplemented large frame (L-NON; FS = 4.7 ± 0.6), 4) supplemented large frame (L-SUPP), and 5) grain-based control feedlot ration (CON; FS = 4.2 ± 0.6; target ADG = 1.36 kg/day). Daily rations were delivered individually using Calan gates. Pasture supplement contained corn gluten feed, a commercially available rumen-protected prilled vegetable fat, and dried molasses fed at 0.5% of BW. Treatments started on 7/8/2019 and 5/21/2020, and ended in November of each yr when cattle were slaughtered at a commercial abattoir. Results were analyzed using PROC MIXED of SAS with main effects of treatment, sire, sex, yr, and yr x treatment, with contrast statements comparing large vs. small frame, pasture supplemented vs. non-supplemented, and control vs. pasture groups. As expected, CON had greater (P &lt; 0.001) growth performance (final BW and ADG) and carcass characteristics (HCW, subcutaneous fat, marbling, dressing percentage (DRESS%) than pasture groups, and tended to have greater (P=0.053) REA. Relative to pasture groups, CON had greater (P &lt; 0.001) Minolta L* and a* lean tissue values, and decreased (P &lt; 0.001) b* values for fat tissue. While non-supplemented cattle had decreased (P = 0.016) yield grades (YG), supplemented cattle had greater (P &lt; 0.050) final BW, ADG, subcutaneous fat, HCW, marbling, and DRESS% compared to non-supplemented cattle. Small framed cattle tender to have decreased (P = 0.056) YG; but, large framed cattle had greater (P = 0.006) HCW, and tended (P = 0.060) to have greater ultrasound subcutaneous fat. Results support low-level supplementation in pasture-finishing systems to improve carcass value.

Abstract P330: Growth Differentiation Factor 15 Causes Cardiac Cachexia In Heart Failure

Background: Cachexia is wasting of normal body tissue and occurs in chronic medical diseases. It is a common complication of heart failure (HF) that is associated with very high mortality. Growth differentiation factor 15 (GDF15) regulates food intake and can cause cancer cachexia. GDF15 is a sensitive biomarker in humans, though its biologic function in HF is unknown. This study investigated the role of GDF15 in HF. Methods: We utilized a genetic mouse model of dilated cardiomyopathy (DCM) caused by a mutation in the phospholamban gene (PLN R9C ). PLN R9C mice have dysregulated cardiac calcium handling (a common feature of nearly all forms of HF) and develop progressive DCM that leads to HF and premature death. Q-PCR and ELISA were performed to assess expression, tissue distribution and circulating levels of GDF15 in PLN R9C and age-matched wild type (WT) mice. A double transgenic mouse was created by crossing our DCM model with a constitutive Gdf15 knock-out (KO). Using this novel model, we quantified food intake, and assessed fat and lean tissue mass by tissue weight at necropsy and by dual-energy X-ray absorptiometry (DXA). Cardiac function was assessed using echocardiography, and histochemistry performed to quantify cardiac fibrosis. Survival was assessed by Kaplan-Meier. Results: GDF15 mRNA (43-fold; p<0.01) and protein (54-fold; p<0.01) were increased in LV tissue, and circulating GDF15 was elevated (8.3-fold; p=0.03) in PLN R9C mice. Gdf15 was expressed at low levels and was not increased in other organs in PLN R9C mice. PLN R9C mice developed cachexia (reduced fat and lean mass by tissue weight, reduced fat mass by DXA vs. WT; p<0.01 for all) and consumed less food (p<0.01 vs. WT). Gdf15 KO in PLN R9C preserved fat and lean tissue mass and resulted in higher food intake (p≤0.01 for all). Gdf15 KO had no effect on cardiac structure or function by echocardiography and PLN R9C / Gdf15 KO mice displayed only a small reduction in cardiac fibrosis relative to PLN R9C mice (3%; p<0.01). Despite this, Gdf15 KO prolonged survival in PLN R9C (29±3 vs. 25±3 weeks; p<0.01). Conclusions: GDF15 is a novel cardiac hormone produced in HF that triggers anorexia and cachexia in HF by an extra-cardiac mechanism.

Wnt16 exerts pleiotropic effects on bone and lean mass in zebrafish

Identifying the mechanisms by which genetic variants exert pleiotropic effects on muscle and bone is a promising strategy to reveal molecular pathways that stimulate coupled bone and muscle growth, and which can be targeted to treat osteoporosis and sarcopenia simultaneously. Previously, it has been shown that genetic variants at the CPED1-WNT16 locus have pleiotropic effects on bone mineral density (BMD) and lean tissue mass in humans. While it is known that WNT16 is required for normal bone mass, our current functional understanding of WNT16 cannot account for dual effects on bone and lean mass at this locus. Using single cell analysis, microCT imaging, and genetic approaches, we reveal that wnt16 exerts pleiotropic effects on bone and lean tissue in zebrafish. We show an early influence of wnt16 on axial bone and lean tissue during skeletogenesis, and provide evidence that wnt16+ cells are myogenic precursors during embryonic development. We also show that wnt16 is a gene of major effect at the CPED1-WNT16 locus. Our findings indicate a critical function for wnt16 in muscle and lean tissue development and support WNT16 as the principal gene driving pleiotropic effects on bone and lean mass at this locus.

Intestinal-derived FGF15 protects against deleterious effects of vertical sleeve gastrectomy in mice

Bariatric surgeries such as the Vertical Sleeve Gastrectomy (VSG) are invasive but provide the most effective improvements in obesity and Type 2 diabetes. We hypothesized a potential role for the gut hormone Fibroblast-Growth Factor 15/19 which is increased after VSG and pharmacologically can improve energy homeostasis and glucose handling. We generated intestinal-specific FGF15 knockout (FGF15INT-KO) mice which were maintained on high-fat diet. FGF15INT-KO mice lost more weight after VSG as a result of increased lean tissue loss. FGF15INT-KO mice also lost more bone density and bone marrow adipose tissue after VSG. The effect of VSG to improve glucose tolerance was also absent in FGF15INT-KO. VSG resulted in increased plasma bile acid levels but were considerably higher in VSG-FGF15INT-KO mice. These data point to an important role after VSG for intestinal FGF15 to protect the organism from deleterious effects of VSG potentially by limiting the increase in circulating bile acids.