Are Both Creatinine and Urea Clearances Necessary as Indices of Small Solute Clearance Adequacy in Peritoneal Dialysis?

The application of urea clearance as a method for evaluating adequacy of hemodialysis was established by the National Cooperative Dialysis Study. 1,2 A comparable study evaluating methods for assessing adequacy of peritoneal dialysis (PD) has not been done. Therefore, the issue of the most suitable solute clearance for PD adequacy is not resolved. Current guidelines suggest the use of the clearances of two small solutes, urea and creatinine, to assess adequacy of PD. 3–6 The practice of measuring two clearances is a source of problems, because the second clearance is inadequate in approximately 20% of the cases with one adequate clearance. 7–9 Elimination of one clearance would simplify the task of assessing solute clearance adequacy in PD. Recent studies have shed some light on this topic. In this report, we will examine first the evidence for using two clearances and then the evidence suggesting that one clearance is superior. Why Use Clearances of Two Solutes? The continuous use of two solute clearances to evaluate PD adequacy is based on studies finding independent influences of clearances on PD outcomes. We will focus on the CANUSA study, which performed a prospective analysis of the associations between clinical outcomes of CAPD and either urea or creatinine clearance. All other studies either were retrospective or contained relatively small numbers of subjects. The CANUSA study found that both urea and creatinine clearance are predictors of survival, whereas only creatinine clearance is a predictor of hospitalization. 10 These findings seem to suggest that creatinine clearance has an advantage as an index of PD adequacy. An analysis of the CANUSA study raises some doubts about this conclusion. Our purpose is not to criticize the CANUSA study, which we consider to be the most rigorous study of this issue, but to correctly interpret its findings. This study was observational. Clearances were monitored over 3 years without changes in the prescribed daily fill volume. During the study period, peritoneal clearances remained the same, whereas renal clearances progressively decreased leading to parallel decreases in total clearances. Therefore, the associations between outcomes and clearances could reflect the changes in either the renal or the total clearances. Either way, changes in renal function were the only influences on solute clearance during the study period. The question that can be answered by the CANUSA and similar observational studies is whether urea or creatinine clearance is more sensitive to changes in renal function in patients treated with PD. In subjects with normal renal function or early renal insufficiency, the variability of urea clearance makes it unsuitable for estimating renal function, whereas creatinine clearance is an established method estimating renal function. In advanced chronic renal failure, fractional urea clearance is uniformly high and urea clearance represents a high and almost fixed percentage of renal creatinine clearance. It could be argued that urea clearance is an acceptable indicator of renal function under these conditions. Although it substantially overestimates glomerular filtration rate, renal creatinine clearance remains a useful index of advanced renal failure. For example, decisions about initiation of renal replacement therapy are often based on renal creatinine clearance. An examination of the relationship between renal creatinine and urea clearance in PD patients can assist with the identification of the most sensitive index of changes in renal function in this setting. In a cross-sectional study of 438 PD subjects followed for a varying period of time, mean renal creatinine clearance exceeded mean renal urea clearance by 76%. When creatinine clearance was expressed as the average of the renal urea and creatinine clearances, “creatinine” clearance exceeded urea clearance by 50%. The relationship between the two clearances was linear with a correlation of 0.89. 11 Although a longitudinal study would be more appropriate for studying the relationship between the two clearances in PD (and should be carried out in the future), this study provided evidence supporting two conclusions: (1) as renal function decreases in PD, renal creatinine and urea clearance decrease in parallel, and (2) the loss in renal creatinine clearance is 1.7 times that of renal urea clearance. This difference makes creatinine clearance a more sensitive indicator of renal function in PD than urea clearance. The findings of the CANUSA study are consistent with this concept. 12 Which Solute Clearance Is Most Suitable as an Index of PD Adequacy? The issue of adequacy of PD is not about recording changes in renal function, but about examining whether the dose of PD is sufficient to prevent adverse outcomes. The current practice of dosing PD is based on the premise that renal and peritoneal clearances are equivalent in terms of clinically significant small solute clearance. Therefore, the PD prescription aims to increase the peritoneal clearance in proportion to the decrease in renal clearance, so that total clearance remains “adequate.” Intervention in PD causes changes in peritoneal, not renal, function, and it is appropriate to study which clearance is more sensitive in recording the changes in peritoneal function after a change in PD prescription. We will study first the principle of equivalency of renal and peritoneal clearances and then proceed to analyze peritoneal clearances. Equivalency between renal and peritoneal small solute clearance is the cornerstone of prescription of the PD dose in all guidelines. 3–6 The studies testing the principle of clearance equivalency are few and present conflicting results. Diaz-Buxo et al.13 found that renal, but not peritoneal, creatinine clearance was a predictor of mortality in a retrospective multivariate analysis of 2,686 patients on PD. However, these authors noted that the narrow range of peritoneal clearances could have influenced their findings; this problem is common to all observational studies analyzing CAPD. Another potential confounding factor for the study of Diaz-Buxo et al. is the effect of peritoneal transport type on peritoneal creatinine clearance (see below). The answer to the question of whether peritoneal and renal clearances are equivalent can be provided by studies in which renal clearance is replaced by equal amounts of peritoneal clearance as renal function declines during the course of PD. A preliminary report presenting a retrospective analysis of 259 PD patients found that replacement of lost renal function by proportional increases in the dose of PD is an independent predictor of survival. 14 Two year survival was 88% in the group that had total clearances in the adequate range throughout the first year, 86% in the group that developed a decrease in total clearance because of loss of renal function but then received an appropriate increase in the PD dose to restore total clearance to the adequate range, and 52% in the group that lost renal clearance and did not increase the dose of PD. More studies will be required to verify this preliminary observation. In the remainder of this report, we will operate under the assumption that peritoneal clearance can replace renal clearance. Creatinine and urea clearances in the peritoneal dialysate and kidneys can be compared by a similar process. Flanigan showed that peritoneal urea and creatinine clearances are mathematically linked. 15 A high linear correlation between peritoneal creatinine and urea clearances was found by Nolph et al. 16 and was subsequently verified by several other studies. 7,8,17 However, there is a consistent quantitative difference between the two peritoneal clearances. Unlike renal clearances, peritoneal urea clearance exceeds peritoneal creatinine clearance. In CAPD, peritoneal urea clearance is, on average, 25% higher than peritoneal creatinine clearance. 17 The difference between peritoneal urea and creatinine clearances is even greater in PD schedules with shorter dwell times. 15,18 Therefore, peritoneal urea clearance is a more sensitive indicator of the changes in the dose of PD than peritoneal creatinine clearance. Clinically, Selgas et al.19 found that urea clearance is a better predictor of outcomes than creatinine clearance in PD patients with negligible residual renal function. Similar findings were recently reported in anuric PD patients by the Toronto group. 20 However, the evidence supporting the superiority of peritoneal urea clearance is from retrospective studies and should not be considered as definitive. There is also a qualitative difference between the peritoneal clearances of the two solutes that impacts the adequacy issue. To achieve an adequate peritoneal clearance, the prescription of PD should provide adequate dialysate drain volume, so that the drain volume normalized by size remains adequate (constant) throughout the range of body size. 21–23 Therefore, the normalized drain volume is a strong index of PD adequacy and the only significant predictor of peritoneal urea clearance by multivariate analysis. 24 In contrast, the significant predictors of peritoneal creatinine clearance include the peritoneal solute transport type, in addition to the normalized drain volume. 8 Confirmation of these influences on peritoneal clearances came from direct clearance measurements in PD patients. In two studies analyzing clearances in large numbers of CAPD patients, peritoneal urea clearances were the same in all four peritoneal transport groups, whereas peritoneal creatinine clearances increased progressively from low to high transport. 17,25 In one study, the size (height, weight, gender distribution, degree of obesity) was almost exactly the same for all four peritoneal transport types. 17 In the same study, peritoneal urea clearance exceeded peritoneal creatinine clearance by 56% in the low transporters, 33% in the low-average transporters, 21% in the high-average transporters, and 10% in the high transporters. The effect of peritoneal transport on peritoneal creatinine clearance complicates the evaluation of “adequate” peritoneal creatinine clearance. It has become clear that a high transport status, which causes relatively greater peritoneal creatinine clearance, is an independent predictor of adverse outcomes in PD. 25–28 The reasons for this association seem to be multiple, including the putative etiologic association between systemic inflammatory syndromes and high transport, 29,30 and the consequences of fluid retention, 26,31 decreased food intake, and abnormal metabolism, 31–33 that characterize high transporters. Regardless of the reasons for the poorer outcomes in high transporters, the association between a high transport state and poor outcomes creates the apparent paradox of higher mortality in subjects with relatively higher creatinine clearances. In subjects with negligible renal function, defining PD adequacy based on creatinine clearance may not be discriminatory except, perhaps, if patients are separated according to peritoneal transport type. In this case, the target creatinine clearance corresponding to the same target urea clearance would have to be different between different transport groups. 6 Therefore, unlike renal clearances, peritoneal creatinine clearance is less sensitive than peritoneal urea clearance in recording changes in the dose of PD and is influenced by a condition (peritoneal transport state) making its interpretation problematic. We propose that creatinine clearance is not a satisfactory measure of PD adequacy. Conclusions The NCDS showed that dialyzer urea clearance is an important predictor of outcomes in hemodialysis. 1,2 Mehrotra et al.34 argued that, because of its relationship with nutritional parameters, urea clearance is superior to creatinine clearance in preESRD and PD patients. Twardowski also concluded that urea clearance is the preferred index of PD adequacy. 35 In this report, we analyzed the evidence supporting this conclusion. We propose that interventions aimed at making small solute clearance adequate in PD should be calculated only with urea clearance in mind. Focus on only urea clearance will eliminate the problems of conflicting guidelines 4,6 and conflicting clearances. 7–9,35 Adoption of urea clearance as the sole index of solute clearance adequacy in PD will leave several questions open. These questions include the outcomes in subjects with adequate urea and inadequate creatinine clearance, whether a declining renal function has adverse effects on the outcomes of PD independent of total clearances (e.g., from increasing difficulties with fluid management), and whether peritoneal urea clearance is affected by peritoneal transport type in PD schedules with short dwell exchanges. 21 Therefore, we propose that although intervention in the dose of PD should be guided by urea clearance only, creatinine clearance should also be monitored, and prospective outcome studies of PD adequacy should continue to include creatinine, as well as urea, clearances. Furthermore, total creatinine excretion provides useful information about somatic nutrition 32,36 and compliance. 4 The ideal index for solute clearance adequacy in PD remains an unresolved question. For example, we do not know whether the clearance of middle molecules is more closely linked to outcomes than the clearance of small molecules with this dialysis modality. We suggest that a study analogous to the NCDS would provide a major insight into the issue of adequacy of PD.