A randomized controlled pilot trial of anakinra and pioglitazone for protein metabolism in patients on maintenance haemodialysis.

BACKGROUND: Chronic inflammation and insulin resistance are highly prevalent in patients on maintenance haemodialysis (MHD) and are strongly associated with protein energy wasting. We conducted a pilot, randomized, placebo-controlled trial of recombinant human interleukin-1 receptor antagonist (IL-1ra) and pioglitazone to explore the safety, feasibility and efficacy for insulin-mediated protein metabolism in patients undergoing MHD. METHODS: Twenty-four patients were randomized to receive IL-1ra, pioglitazone or placebo for 12 weeks. Changes in serum inflammatory markers and insulin-mediated protein synthesis, breakdown and net balance in the whole-body and skeletal muscle compartments were assessed using hyperinsulinaemic-hyperaminoacidemic clamp technique at baseline and Week 12. RESULTS: Among 24 patients, median (interquartile range) age was 51 (40, 61), 79% were African American and 21% had diabetes mellitus. All patients initiated on intervention completed the study, and no serious adverse events were observed. There was a statistically significant decrease in serum high-sensitivity C-reactive protein in the pioglitazone group compared with placebo, but not in the IL-1ra group. No significant differences in the changes of whole-body or skeletal muscle protein synthesis, breakdown and net balance were found between the groups. CONCLUSIONS: In this pilot study, there were no statistically significant effects of 12 weeks of IL-1ra or pioglitazone on protein metabolism in patients on MHD. CLINICALTRIALS: gov registration: NCT02278562.

Bradykinin B2 receptor blockade and intradialytic hypotension.

INTRODUCTION: Intradialytic hypotension (IDH) is a common clinical complication and is associated with increased morbidity and mortality in patients undergoing maintenance hemodialysis (MHD). The pathogenesis of IDH has been attributed to the rapid reduction of plasma volume during hemodialysis and the inadequate compensatory mechanisms in response to hypovolemia, such as the lack of vasoconstriction. This may be due to the increased production of vasodilators, such as bradykinin. In this study we test the hypothesis that bradykinin B2 receptor blockade prevents intradialytic hypotension. METHODS: We performed a post-hoc analysis of a double-blind, placebo-controlled, randomized, 2 × 2 crossover clinical trial comparing the continuous infusion of icatibant, a bradykinin B2 receptor blocker, and placebo during hemodialysis. Icatibant or placebo was infused for 30 min before and during hemodialysis in 11 patients on MHD. RESULTS: Seven of the patients had IDH, defined as a reduction of systolic blood pressure equal to or greater than 20 mmHg during hemodialysis. Stratified analysis, based on the presence of IDH, revealed that icatibant prevented the decrease in blood pressure compared to placebo in patients with IDH [blood pressure at average nadir (2.5 h after hemodialysis): Placebo,114.3 ± 8.9 vs. icatibant, 125.6 ± 9.1 mmHg, mean ± S.E.M]. Icatibant did not affect blood pressure in the group of patients without IDH. CONCLUSION: Bradykinin B2 receptor blocker may prevent the occurrence of IDH. Further studies should evaluate the hemodynamic effects of icatibant during hemodialysis and the symptomatology associated with IDH.

Tissue Sodium in Patients With Early Stage Hypertension: A Randomized Controlled Trial.

Background Sodium (Na+) stored in skin and muscle tissue is associated with essential hypertension. Sodium magnetic resonance imaging is a validated method of quantifying tissue stores of Na+. In this study, we evaluated tissue Na+ in patients with elevated blood pressure or stage I hypertension in response to diuretic therapy or low Na+ diet. Methods and Results In a double-blinded, placebo-controlled trial, patients with systolic blood pressure 120 to 139 mm Hg were randomized to low sodium diet (<2 g of sodium), chlorthalidone, spironolactone, or placebo for 8 weeks. Muscle and skin Na+ using sodium magnetic resonance imaging and pulse wave velocity were assessed at the beginning and end of the study. Ninety-eight patients were enrolled to undergo baseline measurements and 54 completed randomization. Median baseline muscle and skin Na+ in 98 patients were 16.4 mmol/L (14.9, 18.9) and 13.1 mmol/L (11.1, 16.1), respectively. After 8 weeks, muscle Na+ increased in the diet and chlorthalidone arms compared with placebo. Skin sodium was decreased only in the diet arm compared with placebo. These associations remained significant after adjustment for age, sex, body mass index, systolic blood pressure, and urinary sodium. No changes were observed in pulse wave velocity among the different groups when compared with placebo. Conclusions Diuretic therapy for 8 weeks did not decrease muscle or skin sodium or improve pulse wave velocity in patients with elevated blood pressure or stage I hypertension. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT02236520.

Tissue sodium stores in peritoneal dialysis and hemodialysis patients determined by 23-sodium magnetic resonance imaging.

BACKGROUND: Tissue sodium content in patients on maintenance hemodialysis (MHD) and peritoneal dialysis (PD) were previously explored using 23Sodium magnetic resonance imaging (23NaMRI). Larger studies would provide a better understanding of sodium stores in patients on dialysis as well as the factors influencing this sodium accumulation. METHODS: In this cross-sectional study, we quantified the calf muscle and skin sodium content in 162 subjects (10 PD, 33 MHD patients, and 119 controls) using 23NaMRI. Plasma levels of interleukin-6 (IL-6) and high-sensitivity C-reactive protein (hsCRP) were measured to assess systemic inflammation. Sixty-four subjects had repeat 23NaMRI scans that were analyzed to assess the repeatability of the 23NaMRI measurements. RESULTS: Patients on MHD and PD exhibited significantly higher muscle and skin sodium accumulation compared to controls. African American patients on dialysis exhibited greater muscle and skin sodium content compared to non-African Americans. Multivariable analysis showed that older age was associated with both higher muscle and skin sodium. Male sex was also associated with increased skin sodium deposition. Greater ultrafiltration was associated with lower skin sodium in patients on PD (Spearman's rho=-0.68, P = 0.035). Higher plasma IL-6 and hsCRP levels correlated with increased muscle and skin sodium content in the overall study population. Patients with higher baseline tissue sodium content exhibited greater variability in tissue sodium stores on repeat measurements. CONCLUSIONS: Our findings highlight greater muscle and skin sodium content in dialysis patients compared to controls without kidney disease. Tissue sodium deposition and systemic inflammation seen in dialysis patients might influence one another bidirectionally.

Effects of long-term intradialytic oral nutrition and exercise on muscle protein homeostasis and markers of mitochondrial content in patients on hemodialysis.

Patients with end-stage kidney disease on maintenance hemodialysis commonly develop protein-energy wasting, a syndrome characterized by nutritional and metabolic abnormalities. Nutritional supplementation and exercise are recommended to prevent protein-energy wasting. In a 6-mo prospective randomized, open-label, clinical trial, we reported that the combination of resistance exercise and nutritional supplementation does not have an additive effect on lean body mass measured by dual-energy X-ray absorptiometry. To provide more mechanistic data, we performed a secondary analysis where we hypothesized that the combination of nutritional supplementation and resistance exercise would have additive effects on muscle protein accretion by stable isotope protein kinetic experiments, muscle mass by MRI, and mitochondrial content markers in muscle. We found that 6 mo of nutritional supplementation during hemodialysis increased muscle protein net balance [baseline: 2.5 (-17.8, 13.0) µg·100 mL-1·min-1 vs. 6 mo: 43.7 (13.0, 98.5) µg·100 mL-1·min-1, median (interquartile range), P = 0.04] and mid-thigh fat area [baseline: 162.3 (104.7, 226.6) cm2 vs. 6 mo: 181.9 (126.3, 279.2) cm2, median (interquartile range), P = 0.04]. Three months of nutritional supplementation also increased markers of mitochondrial content in muscle. Although the study is underpowered to detected differences, the combination of nutritional supplementation and exercise failed to show further benefit in protein accretion or muscle cross-sectional area. We conclude that long-term nutritional supplementation increases the skeletal muscle anabolic effect, the fat cross-sectional area of the thigh, and markers of mitochondrial content in skeletal muscle.