AbstractBackgroundChronic kidney disease patients particularly with renal anaemia hyporesponsive to erythropoiesis‐stimulating agents (ESAs) are at a greater risk of having skeletal muscle mass (SMM) loss. Hypoxia‐inducible factor prolyl hydroxylase domain inhibitor (HIF‐PHI), a novel therapeutic agent for renal anaemia, potentially promotes angiogenesis, muscle repair, and homeostasis. However, effects of HIF‐PHIs on SMM remain unknown.MethodsThis retrospective observational cohort study enrolled 292 Japanese adults receiving maintenance haemodialysis at our dialysis centre. The dataset included 11 patients who received daprodustat for 6 months or longer during 1 December 2020 through 30 June 2022. From the previously published pooled cohort, we enrolled 281 participants from 1 August 2018 to 31 July 2019 prior to the approval of HIF‐PHIs for renal anaemia. SMM was assessed using modified creatinine index (mg/kg/day) calculated by age, sex, serum creatinine, and single‐pool Kt/V. Annual changes of SMM [ΔSMM (%)] were analysed with the least squares regression model and mixed‐effects model during 6‐ to 12‐month follow‐up period.ResultsThe median age of the participants was 63 years [interquartile range (IQR), 54–71 years], and 33% were female. The median ΔSMM levels (IQR) in the least squares regression model were 4.0% (−1.7% to 9.3%) in the HIF‐PHI group, 0.20% (−2.1% to 2.1%) in the no ESA group, and −0.94% (−3.0% to 1.3%) in the high ESA group using darbepoetin equivalent to 20 μg or more per week. Those in the mixed‐effects model were −1.7% (−1.2% to 3.8%), 0.09% (−1.4% to 1.3%), and −0.74% (−2.0% to 0.8%), respectively. The multivariable linear regression models revealed that HIF‐PHI use was associated with greater ΔSMM compared with the high ESA group [coefficient, 3.737; 95% confidence interval (CI), 1.216–6.258 in the least squares regression model or coefficient, 1.635; 95% CI, 0.068–3.201 in the mixed‐effects model, respectively].ConclusionsHIF‐PHI use led to greater ΔSMM in maintenance haemodialysis patients. HIF‐PHIs may minimize loss of SMM in patients with end‐stage kidney disease and renal anaemia.
RS reports grants from Japan Heart Foundation/Bayer Yakuhin Research Grant Abroad, during the conduct of the study. SvH has been a paid consultant for and/or received honoraria payments from AstraZeneca, Bayer, Boehringer Ingelheim, BRAHMS, Chugai, Grünenthal, Helsinn, Hexal, Novartis, Novo Nordisk, Pfizer, Pharmacosmos, Respicardia, Roche, Servier, Sorin, and Vifor and reports research support from Amgen, Boehringer Ingelheim, Pharmacosmos, IMI, and the German Centre for Cardiovascular Research (DZHK).
An emerging hypothesis is that the activation of innate immunity in the muscle of patients with chronic kidney disease (CKD) is implicated in the development and progression of wasting and cachexia. We previously observed that Toll-like receptor-4 (TLR4) and its downward NF-κB-dependent pro-inflammatory pathways are activated in CKD muscle. It is however unknown if TLR4 can activate the TLR4/NOD, LRR, and pyrin domain-containing protein 3 (NLRP3) inflammasome pathway, which is implicated in cardiovascular disease and frailty, clinical settings that are commonly observed in CKD patients. In a case–control cohort study, we hypothesized that a TLR4/NLRP3 inflammasome pathway is activated in skeletal muscle in uraemia. First, we studied the regulation TLR4/NLRP3/caspase-1 in skeletal muscle biopsies (20M/11F) obtained from 31 non-diabetic CKD5 patients (eGFR 8 ± 1 mL/min 1.73 m 2 ) scheduled for peritoneal dialysis catheter insertion and 15 controls (10M/5F, eGFR 99 ± 6 mL/min 1.73 m 2 ). Second, the effects of uraemic serum on the TLR4/NLRP3 inflammasome pathway were studied in C2C12 cells. In the muscle of CKD subjects, NLRP3 mRNA as well as its protein were overexpressed (by ~16-fold, respectively, P < 0.05 both vs. controls). Both IL-1β and IL-18 mRNA expressions were also up-regulated (~11.8–3.2-fold, respectively, P < 0.05). Also, cleaved caspase-1 was overexpressed in CKD muscle samples ( P < 0.001 vs. controls). Both muscle NLRP3 mRNA ( n = 22, r = −0.606, P < 0.01) and logIL-1 β protein ( n = 26, r = −0.460, P < 0.02) were inversely associated with residual renal function, which suggests that the inflammasome is progressively activated in skeletal muscle of CKD patients as the residual renal function deteriorates. In addition, we observed that in C2C12 myotubes, uraemic serum up-regulates NLRP3 mRNA (~11-fold increase, P < 0.05), cleaved caspase-1 (by ~5-fold, P < 0.05), Il-1β mRNA (~3-fold increase, P < 0.05) and oxidative stress markers respect to normal serum. These effects were prevented by TAK-242, a selective TLR4 inhibitor. Overall, our data demonstrate the activation of TLR4/NLRP3/caspase-1 inflammasome and its downward inflammatory cascade in the muscle of subjects with advanced-stage CKD and suggest targeting TLR4/NLRP3 inflammasome as a new therapeutic strategy to blunt muscle inflammation in CKD.
It is unknown to what degree of sarcopenia related to heart failure (HF) is reversible with resolution of the HF syndrome. We evaluated whether (1) weight loss prior to left ventricular assist device (LVAD) is associated with pre-operative sarcopenia as quantified on pre-operative chest CTs and (2) determine the relationship between weight recovery (increase) after LVAD implantation and reduction of NT-proBNP levels. In a large single-centre cohort ( n = 502), CT measures of sarcopenia (pectoralis muscle mass indexed to body surface area and tissue attenuation) were correlated with pre-LVAD BMI trend ( n = 190). BMI and NT-proBNP trends before and after LVAD implantation were evaluated ( n = 403). Linear effects modelling was performed to test the association between NT-proBNP and BMI trends. A downtrending BMI prior to LVAD was associated with pectoralis muscle tissue attenuation ( P < 0.05). BMI declined prior to LVAD, declined further early post-implant, and then increased between 100 and 300 days post-implant (average per cent change in BMI in Year 1, 7.6%, 95% CI: 6.3–8.8%). NT-proBNP decreased during the first 100 post LVAD days (−5.4%, 95% CI: −6.6 to −4.2%). Post-LVAD NT-proBNP and BMI trends were significantly associated, with a decrease of 1 unit log NT-proBNP associated with an increase in BMI of 0.81 kg/m 2 (CI: 0.53–1.09, P < .001). The rise in post-LVAD BMI occurred after the reduction in NT-proBNP levels. Patients who failed to gain weight post-LVAD had the highest 6-month post-LVAD natriuretic peptides (lowest per cent BMI gain tertile NT-proBNP: 2208 vs. highest 1635 pg/mL, P < 0.001). Weight recovery during LVAD support occurs after the reduction in natriuretic peptide levels. Failure to gain weight during LVAD support was associated with persistently elevated natriuretic peptide levels. These data collectively suggest that recovery of body mass may be dependent upon recovery of the HF syndrome.
Patients with pancreatic cancer often lose weight during chemotherapy with associated changes in body composition. The goal of the present analysis was to describe changes in body composition in pancreatic cancer patients on an exercise regimen. The long-term goal is to determine whether an exercise intervention may attenuate changes in body composition and function. Twenty-two pancreatic cancer patients of all stages who were to receive chemotherapy were recruited into a pre-post exercise intervention study. A standard exercise prescription was individualized to include aerobic, resistance, stretch, and balance exercises. Pre- and post-intervention computed tomography-derived measures of body composition [skeletal muscle index (SMI), skeletal muscle density, visceral fat area, and subcutaneous fat area] and physical function measures (grip strength, timed up and go, 30-s chair stand, and tandem balance stand) were evaluated using paired t -tests, χ 2 tests, and Pearson correlation coefficients. The subjects were, on average, 62 years of age, 55% were female, 95% non-Hispanic White, and 45% were Stage IV. Body composition changes included a median 4.6% decrease in SMI ( P = 0.04), 7.91% increase in skeletal muscle density ( P = 0.05), 25.07% decrease in visceral fat area ( P = 0.0001), and 22.08% decrease in subcutaneous fat area ( P = 0.001). Adherence to aerobic and strength exercise was 65% and 57%, respectively. Some physical function measures improved, though not significantly: chair stands increased from a mean of 11.5 to 13.0 ( P = 0.59) and timed up and go improved from a mean of 11.7 to 10.3 ( P = 0.26). Change in right hand grip strength was marginally positively associated with changes in SMI ( r = 0.53, P = 0.06). Improvements in skeletal muscle density were seen in 63% of patients, including Stage IV patients but did not correlate with change in function. Exercise is feasible during neoadjuvant chemotherapy for pancreatic cancer patients of all stages and may assist with maintaining physical function and improving body composition. Further research is needed.
