Is the Effect of Low-GDP Solutions on Residual Renal Function Mediated by Fluid State? An Enigmatic Question which Still Needs to be Solved

Fluid overload is still a problem in peritoneal dialysis (PD). In a recent international multicenter study of 639 patients on PD, approximately 25% were classified with severe fluid overload according to bioimpedance indices reflecting extracellular hypervolemia, whereas only 40% were classified as normovolemic (1). Two recent studies found that the mean degree of fluid overload in PD was comparable to pre-dialysis values in hemodialysis (HD) patients (2,3). This is of clinical importance, given the relation between fluid overload with hypertension and cardiac congestion, although there is no evidence for an inferiority of PD as compared to HD regarding the effect on blood pressure regulation or cardiac structure (3,4). Recently, a relation between fluid overload and mortality was also observed in PD patients, confirming previous findings in HD patients (5,6). Regulation of fluid balance during PD treatment is dependent upon 3 basic factors: salt and water intake, peritoneal ultrafiltration (or reabsorption), and residual diuresis (6–9). Peritoneal ultrafiltration was inversely related to the extracellular:total body water (ECW:TBW) ratio, assessed by bioimpedance (8). Importantly, both total and peritoneal fluid and sodium removal were related to outcome (9). Due to alterations in the peritoneal membrane based on long-term exposure to unphysiologic concentrations of glucose and glucose degradation products, higher glucose concentrations are often needed to maintain adequate peritoneal ultrafiltration during long-term treatment but at the risk of initiating a vicious cycle leading to further peritoneal membrane damage (10). The relevance of diuresis and residual renal function (RRF) for PD treatment is evident from its relation to survival in prospective observational studies (11). The extent to which the relation between RRF and outcome is mediated by the effect on fluid overload or uremic toxins removal is not completely clear. Residual renal function was found to be inversely associated with the presence of fluid overload (12), although this has not been a uniform finding (1). Still, a recent study subdivided patients according to the median value of the RRF decline during the first year of PD. Whereas left ventricular diameter and mass improved in the subgroup experiencing a slower decline in RRF, these parameters remained stable in the subgroup with the faster decline in RRF (13). As preservation of both peritoneal membrane function and RRF are both of major importance for the success of long-term PD, it would be a great asset if both the decline in RRF and peritoneal membrane function could be positively influenced by modification of the PD strategy. By improving biocompatibility, the use of PD solutions with lower concentrations of glucose degradation products (GDP) and more physiological pH levels (to be called “low-GDP solutions” in this review) may be a further step towards achieving this goal. Despite the variety of low-GDP solutions on the market, common mechanisms behind the beneficial effects of lowGDP solutions on peritoneal membrane function are, amongst others, a lesser peritoneal and systemic toxicity of glyoxidation and advanced glycation end-products (14). Where there is ample evidence for a beneficial effect of low-GDP fluids on cell viability, as well as on peritoneal membrane structure and function from experimental trials, long-term data in humans are more scarce (15,16). In the largest randomized controlled study on this subject, after an increase in the D/P creatinine ratio in the short term, low-GDP solutions were associated with a stabilization of peritoneal membrane function as compared to standard solutions (17,18). Importantly, peritoneal ultrafiltration volume is generally found to be higher with conventional as compared to low-GDP solutions of the same glucose concentrations (17,19). Although the underlying mechanisms have not been fully elucidated, more pronounced vasodilation and peritoneal capillary recruitment with conventional solutions may be implicated (20). Next to the effects on peritoneal membrane, there are data in the literature suggesting a better preservation of RRF with the use of low-GDP solutions. In the balANZ trial, the slope of the decline in RRF was not significantly different between the low-GDP and the conventional group, but the time to anuria was longer in the group treated with low-GDP solutions (17). In a subsequent meta-analysis, RRF and urine volume 12 months after the start of PD were significantly higher in patients treated with low-GDP as compared to conventional solutions (21,22). Whereas the beneficial effect of low-GDP solutions on peritoneal membrane function has strong theoretical underpinnings, the effects on RRF and/or diuresis are more enigmatic, although it has been proposed that the COMMENTARIES