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Abstract Background Physical performance is low and physical activity declines in people with chronic kidney disease (CKD). Both factors are associated with decreased survival. Our hypothesis was that improved physical performance after 12 months of exercise training would result in better survival in patients with CKD stages 3 to 5 not on kidney replacement therapy (KRT). Our aims in this study were to investigate the survival effects of (1) baseline physical performance and (2) physical performance after 12 months of exercise training. Methods This is a post-hoc analysis of the RENEXC trial, a randomized controlled study comparing 12 months of strength- and balance training both in combination with aerobic training. Both groups improved physical performance with no between group differences. Patients were categorized into five groups: improved ≥ 5%, unchanged, deteriorated ≥ 5%, non-completers, missing data. Univariate and multivariate Cox regression analyses were used and adjusted for age, sex, comorbidity, time on dialysis and time with a kidney transplant. Results 151 patients participated, mean age 66 ± 14 years, 65% men, eGFR 22.5 ± 8.2 ml/min/1.73m2, average follow-up 60 months. Multivariate analyses The baseline 6-minute walk test (6MWT) (HR 0.996; 95% CI [0.993–0.998]) and 30-second sit-to-stand (30s-STS) (HR 0.94 CI [0.89–1.0]) were positively associated with survival. After 12 months of exercise improved handgrip strength (HGS) right (HR 2.66; 95% CI [1.07–6.59]) was associated with better survival compared with deterioration. Improvement compared with noncompletion was associated with better survival (6MWT (HR 2.88; 95% CI [1.4–5.88]), HGS right (HR 4.44; 95% CI [1.79–10.98]), functional reach (HR 3.69; 95% CI [1.82–7.48]), isometric quadriceps strength right (HR 2.86; 95% CI [1.43–5.72]), 30s-STS (HR 3.44; 95% CI [1.66–7.11]). Conclusion Baseline walking distance, muscular strength and endurance in the legs were independently associated with survival in people with CKD stages 3–5 without KRT. After completing 12 months of exercise training improved walking distance, muscular strength and endurance, and balance were positively associated with survival, compared with noncompleters. Better physical performance at baseline and the ability to complete 12 months of exercise training conferred survival benefits. There are probably several factors affecting better survival. These factors require elucidation in future studies. Trial registration ClinicalTrials.gov NCT02041156. Registration date 20,240,107.

Neuroendocrine neoplasms (NENs) are a diverse group originating from endocrine cells/their precursors in pancreas, small intestine, or lung. The key serum marker is chromogranin A (CgA). While commonly elevated in patients with NEN, its prognostic value is still under discussion. Secretion/posttranslational proteolytic cleavage of CgA results in multiple bioactive fragments, which are essential regulators of the cardiovascular and immune system. miR-223, regulator of Nrlp3 inflammasome and neutrophil activation, was recently found to have decreased in patients with NEN. We performed flow cytometry of circulating neutrophils in a patient cohort (n = 10) with NEN, microdissection and histology of tumor tissue. Subsequently, in vitro transfections using the well-established human pancreatic NEN cell line (BON), and co-culture experiments with primary macrophages and neutrophils were performed. Serum miR-223 in patients correlated with the expression of the neutrophil activation marker CD15 in circulating cells. Neutrophilic CD62L/CD63 showed good discrimination compared to healthy controls. Immune cell-derived miR-155, miR-193 and miR-223 colocalize with neutrophil in the extra-tumoral tissue alongside Nlrp3-associated caspase-1 activation. miR-223 knockdown in BON decreased the CgA intracellularly, increased in cellular granularity and caspase-1 activation. Plasmin inhibitor a2-aP reverted those effects. Western Blot showed fragmented CgA following miR-223 knockdown, which altered the inflammatory potential of neutrophils. Our data hence provide initial insights into an immunoregulatory mechanism via miR-223 and CgA in NEN cells, as regulation of miR-223 in NEN may affect tumor-associated inflammation.

Background: Physical performance is low and physical activity declines in people with chronic kidney disease (CKD). Both factors are associated with decreased survival. Our hypothesis was that improved physical performance after 12 months of exercise training would result in better survival in patients with CKD stages 3 to 5 not on kidney replacement therapy (KRT). Our aims in this study were to investigate the survival effects of (1) baseline physical performance and (2) physical performance after 12 months of exercise training. Methods: This is a post-hoc analysis of the RENEXC trial, a randomized controlled study comparing 12 months of strength- and balance training both in combination with aerobic training. Both groups improved physical performance with no between group differences. Patients were categorized into five groups: improved ≥ 5%, unchanged, deteriorated ≥ 5%, non-completers, missing data. Univariate and multivariate Cox regression analyses were used and adjusted for age, sex, comorbidity, time on dialysis and time with a kidney transplant. Results: 151 patients participated, mean age 66 ± 14 years, 65% men, eGFR 22.5 ± 8.2 ml/min/1.73m2, average follow-up 60 months. Multivariate analyses: The baseline 6-minute walk test (6MWT) (HR 0.996; 95% CI [0.993–0.998]) and 30-second sit-to-stand (30s-STS) (HR 0.94 CI [0.89–1.0]) were positively associated with survival. After 12 months of exercise improved handgrip strength (HGS) right (HR 2.66; 95% CI [1.07–6.59]) was associated with better survival compared with deterioration. Improvement compared with noncompletion was associated with better survival (6MWT (HR 2.88; 95% CI [1.4–5.88]), HGS right (HR 4.44; 95% CI [1.79–10.98]), functional reach (HR 3.69; 95% CI [1.82–7.48]), isometric quadriceps strength right (HR 2.86; 95% CI [1.43–5.72]), 30s-STS (HR 3.44; 95% CI [1.66–7.11]). Conclusion: Baseline walking distance, muscular strength and endurance in the legs were independently associated with survival in people with CKD stages 3–5 without KRT. After completing 12 months of exercise training improved walking distance, muscular strength and endurance, and balance were positively associated with survival, compared with noncompleters. Better physical performance at baseline and the ability to complete 12 months of exercise training conferred survival benefits. There are probably several factors affecting better survival. These factors require elucidation in future studies. Trial registration: ClinicalTrials.gov NCT02041156. Registration date 20,240,107. [ABSTRACT FROM AUTHOR]

Neuroendocrine neoplasms (NENs) are a diverse group originating from endocrine cells/their precursors in pancreas, small intestine, or lung. The key serum marker is chromogranin A (CgA). While commonly elevated in patients with NEN, its prognostic value is still under discussion. Secretion/posttranslational proteolytic cleavage of CgA results in multiple bioactive fragments, which are essential regulators of the cardiovascular and immune system. miR-223, regulator of Nrlp3 inflammasome and neutrophil activation, was recently found to have decreased in patients with NEN. We performed flow cytometry of circulating neutrophils in a patient cohort (n = 10) with NEN, microdissection and histology of tumor tissue. Subsequently, in vitro transfections using the well-established human pancreatic NEN cell line (BON), and co-culture experiments with primary macrophages and neutrophils were performed. Serum miR-223 in patients correlated with the expression of the neutrophil activation marker CD15 in circulating cells. Neutrophilic CD62L/CD63 showed good discrimination compared to healthy controls. Immune cell-derived miR-155, miR-193 and miR-223 colocalize with neutrophil in the extra-tumoral tissue alongside Nlrp3-associated caspase-1 activation. miR-223 knockdown in BON decreased the CgA intracellularly, increased in cellular granularity and caspase-1 activation. Plasmin inhibitor a2-aP reverted those effects. Western Blot showed fragmented CgA following miR-223 knockdown, which altered the inflammatory potential of neutrophils. Our data hence provide initial insights into an immunoregulatory mechanism via miR-223 and CgA in NEN cells, as regulation of miR-223 in NEN may affect tumor-associated inflammation. [ABSTRACT FROM AUTHOR]

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