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.

Background Sudden death is a leading cause of death in patients on maintenance hemodialysis therapy. During hemodialysis sessions, the gradient between serum and dialysate levels results in rapid electrolyte shifts, which may contribute to arrhythmias and sudden death. Controversies exist about the optimal electrolyte concentration in the dialysate; specifically, it is unclear whether patient outcomes differ among those treated with a dialysate potassium concentration of 3 mEq/L compared to 2 mEq/L. Study Design Prospective cohort study. Setting & Participants 55,183 patients from 20 countries in the Dialysis Outcomes and Practice Patterns Study (DOPPS) phases 1 to 5 (1996-2015). Predictor Dialysate potassium concentration at study entry. Outcomes Cox regression was used to estimate the association between dialysate potassium concentration and both all-cause mortality and an arrhythmia composite outcome (arrhythmia-related hospitalization or sudden death), adjusting for potential confounders. Results During a median follow-up of 16.5 months, 24% of patients died and 7% had an arrhythmia composite outcome. No meaningful difference in clinical outcomes was observed for patients treated with a dialysate potassium concentration of 3 versus 2 mEq/L (adjusted HRs were 0.96 [95% CI, 0.91-1.01] for mortality and 0.98 [95% CI, 0.88-1.08] for arrhythmia composite). Results were similar across predialysis serum potassium levels. As in prior studies, higher serum potassium level was associated with adverse outcomes. However, dialysate potassium concentration had only minimal impact on serum potassium level measured predialysis (+0.09 [95% CI, 0.05-0.14] mEq/L serum potassium per 1 mEq/L greater dialysate potassium concentration). Limitations Data were not available for delivered (vs prescribed) dialysate potassium concentration and postdialysis serum potassium level; possible unmeasured confounding. Conclusions In combination, these results suggest that approaches other than altering dialysate potassium concentration (eg, education on dietary potassium sources and prescription of potassium-binding medications) may merit further attention to reduce risks associated with high serum potassium levels.

Background and objectives High body mass index appears protective in hemodialysis patients, but uncertainty prevails regarding which components of body composition, fat or lean body mass, are primarily associated with survival. Design, setting, participants, & measurements Data between April 2006 and December 2012 were extracted from the Fresenius Medical Care Europe subset of the international MONitoring Dialysis Outcomes initiative. Fresenius Medical Care Europe archives a unique repository of predialysis body composition measurements determined by multifrequency bioimpedance (BCM Body Composition Monitor). The BCM Body Composition Monitor reports lean tissue indices (LTIs) and fat tissue indices (FTIs), which are the respective tissue masses normalized to height squared, relative to an age- and sex-matched healthy population. The relationship between LTI and FTI and all-cause mortality was studied by Kaplan–Meier analysis, multivariate Cox regression, and smoothing spline ANOVA logistic regression. Results In 37,345 hemodialysis patients, median (25th–75th percentile) LTI and FTI were 12.2 (10.3–14.5) and 9.8 (6.6–12.4) kg/m², respectively. Median (25th–75th percentile) follow-up time was 266 (132–379) days; 3458 (9.2%) patients died during follow-up. Mortality was lowest with both LTI and FTI in the 10th–90th percentile (reference group) and significantly higher at the lower LTI and FTI extreme (hazard ratio [HR], 3.37; 95% confidence interval [95% CI], 2.94 to 3.87; P<0.001). Survival was best with LTI between 15 and 20 kg/m² and FTI between 4 and 15 kg/m² (probability of death during follow-up: <5%). When taking the relation between both compartments into account, the interaction was significant (P=0.01). Higher FTI appeared protective in patients with low LTI (HR, 3.37; 95% CI, 2.94 to 3.87; P<0.001 at low LTI–low FTI, decreasing to HR, 1.79; 95% CI, 1.47 to 2.17; P<0.001 at low LTI–high FTI). Conclusions This large international study indicates best survival in patients with both LTI and FTI in the 10th–90th percentiles of a healthy population. In analyses of body composition, both lean tissue and fat tissue compartments and also their relationship should be considered.

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.