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Chronic kidney disease (CKD) shares many phenotypic similarities with other chronic diseases, including heart failure, chronic obstructive pulmonary disease, HIV infection and rheumatoid arthritis. The most apparent similarity is premature ageing, involving accelerated vascular disease and muscle wasting. We propose that in addition to a sedentary lifestyle and psychosocial and socioeconomic determinants, four major disease-induced mechanisms underlie premature ageing in CKD: an increase in allostatic load, activation of the 'stress resistance response', activation of age-promoting mechanisms and impairment of anti-ageing pathways. The most effective current interventions to modulate premature ageing-treatment of the underlying disease, optimal nutrition, correction of the internal environment and exercise training-reduce systemic inflammation and oxidative stress and induce muscle anabolism. Deeper mechanistic insight into the phenomena of premature ageing as well as early diagnosis of CKD might improve the application and efficacy of these interventions and provide novel leads to combat muscle wasting and vascular impairment in chronic diseases.

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Overhydration is a risk factor for hypertension and left ventricular hypertrophy in peritoneal dialysis patients. Recently, a high prevalence of subclinical overhydration was observed in peritoneal dialysis patients. Aim of the present open-label randomized study was to assess the effect of a icodextrin 7.5% solution on fluid status [extracellular water (ECW) bromide dilution], blood pressure regulation (24-hour ambulatory measurements) and echocardiographic parameters during a study period of 4 months, and to relate the effect to peritoneal membrane characteristics (dialysate/plasma creatinine ratio). Forty peritoneal dialysis patients (22 treated with icodextrin, 18 controls) were randomized to either treatment with icodextrin during the long dwell or standard glucose solutions. Thirty-two patients (19 treated with icodextrin, 13 controls] completed the study. The use of icodextrin resulted in a significant increase in daily ultrafiltration volume (744 +/- 767 mL vs. 1670 +/- 1038 mL; P = 0.012) and a decrease in ECW (17.5 +/- 5.2 L vs. 15.8 +/- 3.8 L; P = 0.035). Also the change in ECW between controls and patients treated with icodextrin was significant (-1.7 +/- 3.3 L vs. +0.9 +/- 2.2 L; P = 0.013). The effect of icodextrin on ECW was not related to peritoneal membrane characteristics, but significantly related to the fluid state of the patients (ECW:height) (r = -0.72; P < 0.0001). Left ventricular mass (LVM) decreased significantly in the icodextrin-treated group (241 +/- 53 grams vs. 228 +/- 42 grams; P = 0.03), but not in the control group. In this randomized open-label study, the use of icodextrin resulted in a significant reduction in ECW and LVM. The effect of icodextrin on ECW was not related to peritoneal membrane characteristics, but was related to the initial fluid state of the patient.

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Systemic inflammation in end-stage renal disease is an established risk factor for mortality and a catalyst for other complications, which are related to a premature aging phenotype, including muscle wasting, vascular calcification, and other forms of premature vascular disease, depression, osteoporosis, and frailty. Uremic inflammation is also mechanistically related to mechanisms involved in the aging process, such as telomere shortening, mitochondrial dysfunction, and altered nutrient sensing, which can have a direct effect on cellular and tissue function. In addition to uremia-specific causes, such as abnormalities in the phosphate-Klotho axis, there are remarkable similarities between the pathophysiology of uremic inflammation and so-called "inflammaging" in the general population. Potentially relevant, but still somewhat unexplored in this respect, are abnormal or misplaced protein structures, as well as abnormalities in tissue homeostasis, which evoke danger signals through damage-associated molecular patterns, as well as the senescence-associated secretory phenotype. Systemic inflammation, in combination with the loss of kidney function, can impair the resilience of the body to external and internal stressors by reduced functional and structural tissue reserves, and by impairing normal organ crosstalk, thus providing an explanation for the greatly increased risk of homeostatic breakdown in this population. In this review, the relationship between uremic inflammation and a premature aging phenotype, as well as potential causes and consequences, are discussed.

In hemodialysis patients extracellular fluid overload is a predictor of all-cause and cardiovascular mortality, and a relation with inflammation has been reported in previous studies. The magnitude and nature of this interaction and the effects of moderate fluid overload and extracellular fluid depletion on survival are still unclear. We present the results of an international cohort study in 8883 hemodialysis patients from the European MONDO initiative database where, during a three-month baseline period, fluid status was assessed using bioimpedance and inflammation by C-reactive protein. All-cause mortality was recorded during 12 months of follow up. In a second analysis a three-month baseline period was added to the first baseline period, and changes in fluid and inflammation status were related to all-cause mortality during six-month follow up. Both pre-dialysis estimated fluid overload and fluid depletion were associated with an increased mortality, already apparent at moderate levels of estimated pre-dialysis fluid overload (1.1-2.5L); hazard ratio 1.64 (95% confidence interval 1.35-1.98). In contrast, post-dialysis estimated fluid depletion was associated with a survival benefit (0.74 [0.62-0.90]). The concurrent presence of fluid overload and inflammation was associated with the highest risk of death. Thus, while pre-dialysis fluid overload was associated with inflammation, even in the absence of inflammation, fluid overload remained a significant risk factor for short-term mortality, even following improvement of fluid status.