The importance of RRF in dialysis patients can only be appreciated when one considers its influence on nutrition, cardiovascular function, mineral metabolism and maintenance of hemoglobin levels. Loss of RRF increases resting energy expenditure and inflammation and reduces small solute and middle molecule uremic toxin clearance, erythropoietin synthesis, phosphorus, sodium and fluid removal. These effects may result in anemia, malnutrition, cardiac hypertrophy, congestive heart failure, atherosclerosis and arteriosclerosis, vascular and valvular calcification, all of which lead to an increase in overall and cardiovascular mortality and decreased quality of life (1).
RRF and Mortality
The loss of RRF is a powerful predictor of mortality (2,3). In a single-center, multivariate survival analysis of 102 dialysis patients (68 PD and 34 HD patients), Maiorca et al. illustrated that preserving RRF could significantly improve the survival of PD patients (4). For each 1-mL/min increase in the glomerular ﬁltration rate (GFR), there was an associated 40% reduction in the risk of death in the entire cohort and a 50% reduction in PD patients. In a single-center study, Shemin et al. (N=114 HD patients) showed that the presence of any RRF (deﬁned as urine volume >100 mL/d) was independently associated with a 65% decrease in the risk of death (5). Wang and colleagues identified that loss of RRF was closely associated with increased resting energy expenditure, and resting energy expenditure was predictive of higher mortality and cardiovascular death in chronic PD patients (6). The Netherlands Cooperative Study on the Adequacy of Dialysis 2 (NECOSAD-2, N=740 incident HD patients), demonstrated that for each 1-unit/week increase in renal Kt/Vurea, there was a 66% decrease in the relative risk of death (7).
The Canada-USA (CANUSA) Peritoneal Dialysis Study showed a survival beneﬁt with increasing total (renal and peritoneal) small-solute clearance in 680 incident PD patients (8). A secondary analysis of data from the CANUSA study showed that this benefit was due to RRF with each 5-L/wk/1.73 m2 increment in GFR being associated with a 12% decrease in the relative risk of death (9). Additionally, for every 250 mL of urine output, the overall mortality decreased by 36% (9). The initial analysis was performed under the assumption that peritoneal and renal small-solute clearances were equivalent and therefore additive. The re-analysis, however, was unable to identify an independent association between survival and peritoneal clearance of small molecules. The ADEMEX (Adequacy of Peritoneal Dialysis in Mexico) study also demonstrated that residual renal clearance and dialytic clearance were not equivalent or additive (10). In this study, RRF was shown to be the most important factor to directly influence patients’ survival rates. Increasing solute clearance in PD did not result in better survival in anuric patients.
RRF and Inflammation
Chronic inflammation is a common finding in chronically dialyzed patients (12-65%), and may actually be part of the pathophysiology of chronic renal disease (11). It appears that the inflammatory component may be present even in pre-dialysis CKD patients. CKD patients show an inverse relationship between renal function and pro-inﬂammatory mediators (12). Animal and in vitro studies suggest that as RRF declines, inflammation is accentuated due to increased oxidative stress and activation of monocytes and cytokines in the vascular endothelium (13,14). This, in turn, can further perpetuate RRF loss (15). Various studies have demonstrated increased levels of C-reactive protein (CRP) and interleukin-6 (IL-6) in patients with chronic kidney disease (CKD) and end-stage renal failure (ESRD) (11,16). Nephrectomized rats showed impaired cytokine clearance, suggesting that the kidneys may play a role in cytokine handling (17). In incident and prevalent PD patients, loss of RRF was associated with an increased inﬂammatory component that was due to C-reactive protein or vascular cell adhesion molecules (18,19). Although the exact mechanism is as yet unknown, the relationship between RRF and inﬂammation was shown to be independent of the patients’ cardiovascular status (20).
RRF and Nutrition
Several studies have demonstrated that nutritional status in both HD and PD patients is better in the presence of RRF (21-24). Parameters such as appetite, dietary protein and total caloric intake assessed using questionnaires were increased in the presence of RRF. Wang et al. showed that the uptake of micronutrients was also greater when dialysis patients had RRF. Several markers of nutritional status such as subjective global assessment, lean body mass and handgrip strength were all shown to correlate with RRF (25); no such relationship with peritoneal urea clearance was found. It has also been proposed that the link between RRF decline and malnutrition status in PD patients may be due to a close association with the resting energy expenditure (6). A sustained increase in resting energy expenditure may lead to an imbalance in energy and malnutrition, which leads to a catabolic state, if not compensated for by an increase in energy intake.
RRF and Volume Control
The importance of RRF in maintaining fluid balance is becoming increasingly apparent. Extracellular ﬂuid volumes were found to be higher in PD patients with a residual GFR below 2 mL/min/1.73 m2 compared to those above 2 mL/min/1.73 m2 (26). This suggests that the degree of water removal by the diseased kidneys remains very important in determining the survival of patients on PD (27). Patients with a history of volume overload were shown to have more severe cardiovascular issues (28). In addition, blood pressure control was shown to worsen with decreasing RRF (29) and was associated with higher arterial pulse pressure (30). Although the role of RRF in maintaining volume control in patients on dialysis is not fully understood, poor RRF might contribute to a higher amount of extracellular fluid, which has been associated with hypertension and left ventricular hypertrophy (31).
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