The definition of peritoneal dialysis (PD) adequacy has

Peritoneal Dialysis International, Vol. 29, pp. 465 471 Printed in Canada. All rights reserved. 0896-8608/09 $3.00 +.00 Copyright 2009 International Society for Peritoneal Dialysis DIALYTIC PHOSPHATE REMOVAL: A MODIFIABLE MEASURE OF DIALYSIS EFFICACY IN AUTOMATED PERITONEAL DIALYSIS Claus P. Schmitt, 1a Dagmara Borzych, 1,2a Barbara Nau, 1 Elke Wühl, 1 Aleksandra Zurowska, 2 and Franz Schaefer 1 Division of Pediatric Nephrology, 1 Center for Pediatric and Adolescent Medicine, University of Heidelberg, Germany; Department of Pediatric Nephrology, 2 Medical University of Gdansk, Poland Background: Although hyperphosphatemia is one of the few established risk factors for cardiovascular mortality in patients on dialysis, the relationship between peritoneal dialysis (PD) prescription and dialytic phosphate removal is largely unexplored. Methods and Patients: We analyzed 24-hour clearances (n = 60) together with peritoneal equilibration tests (PETs) (n = 52) performed in children and adolescents (n = 35) on automated PD. Results: Dialytic phosphate clearance was more closely correlated with 2-hour and 4-hour dialysate-to-plasma ratio (D/P) of phosphate in the PETs (r = 0.44 and r = 0.52, both p < 0.0001) than with 2-hour and 4-hour D/P creatinine (r = 0.26 and r = 0.27, both p < 0.05). Dialytic 24-hour phosphate clearance was independently predicted by total fluid turnover (partial R 2 = 0.48, p < 0.001), the number of cycles (r = 0.52, p < 0.001), 2-hour D/P phosphate (partial R 2 = 0.07, p = 0.001), dwell time (partial R 2 = 0.05, p = 0.01), and achieved ultrafiltration (partial R 2 = 0.05, p = 0.005). 4-hour D/P phosphate and 24-hour phosphate clearance were significantly lower in hyperphosphatemic children (3.38 ± 1.17 vs 4.56 ± 1.99 L/1.73 m 2 /day, p < 0.05), whereas creatinine equilibration and clearance rates were not distinctive. Conclusion: Dialytic phosphate removal is an important modifiable determinant of phosphate control in automated PD. It strongly depends on total dialysate turnover and the prescribed number of cycles and is more adequately predicted by phosphate than by creatinine equilibration characteristics. Due to the deleterious effects of hyperphosphatemia, dialytic phosphate removal should be monitored routinely. Perit Dial Int 2009; 29:465 471 a www.pdiconnect.com These authors contributed equally to this study. KEY WORDS: Phosphate clearance; peritoneal transport; adequacy; children. The definition of peritoneal dialysis (PD) adequacy has long been a matter of controversy. Extending the urea kinetic modeling approach of hemodialysis, small-molecule clearances were originally considered useful prognostically relevant indices of PD dose. Observational studies such as the CANUSA trial suggested a linear relationship between urea and creatinine clearance and patient mortality and morbidity (1), and resulted in the formulation of adequacy guidelines defining dialysis adequacy by certain minimum urea and creatinine clearances (2). However, subsequent interventional trials demonstrated that modification of dialytic smallmolecule removal does not affect patient survival or morbidity (3,4). Hence, the search for a prognostically useful marker of dialysis adequacy continues. Hyperphosphatemia has been identified as a significant risk marker of cardiovascular and all-cause mortality in adult dialysis patients (5 10). Mechanistically, the link between hyperphosphatemia and mortality has been attributed to disseminated vascular calcifications in patients on chronic dialysis. Calcifying large-vessel arteriopathy develops even in young patients with childhood-onset end-stage renal disease (ESRD) and is associated with the prevailing calcium phosphorus ion product (11,12). These findings raise the issue of whether dialytic phosphate removal might provide a more relevant direct measure of dialysis efficacy and adequacy than urea and creatinine clearance. In contrast to the large body of research available on the peritoneal transport kinetics and daily dialytic clearance of urea and creatinine, surprisingly little is known about the capacity to remove phosphate via the peritoneal membrane, although its importance is apparent and has been emphasized (13,14). Previous studies suggest that phosphate removal can be improved by modification of the dwell time (15,16); however, a detailed analysis of the Correspondence to: F. Schaefer, Division of Pediatric Nephrology, University Children s Hospital, Im Neuenheimer Feld 151, 69120 Heidelberg, Germany. franz.schaefer@med.uni-heidelberg.de Received 5 May 2008; accepted 12 September 2008. 465

SCHMITT et al. JULY 2009 VOL. 29, NO. 4 PDI variability of peritoneal phosphate transport and the modifiability of dialytic phosphate removal by PD prescription has not yet been performed. In particular, it is unclear how the various dosing options available with automated PD (APD) affect daily phosphorus removal. In this work, peritoneal phosphorus kinetics and daily dialytic and renal phosphorus elimination in children receiving APD were studied. METHODS Retrospective data were collected from 35 pediatric patients receiving chronic APD for ESRD due to congenital malformations of the kidney and urinary tract (n = 14), hemolytic-uremic syndrome (n = 6), focal segmental glomerulosclerosis (n = 3), diffuse mesangial sclerosis (n = 3), IgA nephropathy (n = 2), congenital nephritic syndrome (n = 2), autosomal recessive polycystic kidney disease (n = 2), perinatal asphyxia (n = 2), and cystinosis (n = 1). Patients ranged in age from 3 months to 17 (median 10.2) years; 9 children were below 2 years of age. Median duration of dialysis at the time of study was 12 (1 44) months. Children performed APD without [nocturnal intermittent PD (NIPD); n = 33] or with [continuous cycling PD (CCPD); n = 27] an additional daytime dwell. Conventional PD fluid (Fresenius CAPD; Fresenius, Bad Homburg, Germany) was used on 38, and double-chamber PD solution on 22 occasions (13 times BicaVera and 9 times Balance; Fresenius). Dialysis efficacy was assessed by dialysate and residual renal clearance measurements. Twenty-six children had one clearance assessment and 17 had a second measurement 13.8 (5 40) months later, resulting in a total of 60 assessments. Thirty of the 35 patients had significant residual renal function; complete clearance studies (i.e., peritoneal and renal) were available from 44 occasions. Total clearances were calculated as the sum of dialytic and renal clearances. For the determination of the clearances of phosphate, creatinine, and glucose, a blood sample was taken and the total amounts of urine and peritoneal drainage were collected, weighed, and sampled during a 24-hour period. Clearances were calculated from plasma and dialysate/urine concentrations and the respective volumes and time intervals, and normalized to body surface area and 24 hours. Blood and dialysate glucose, creatinine, and phosphate were measured according to standard laboratory methods. Dialysate creatinine measurements were corrected for the presence of glucose as described previously (17). Fifty-two peritoneal equilibration test (PET) studies (including 17 repeated tests) were performed using 2.3% 466 glucose solution with a standardized fill volume of 1000 ml/m 2 according to a pediatric protocol (13). Dialysate-to-plasma ratios (D/P) and D/D 0 ratios of creatinine and phosphate were calculated for each patient at each time point. Serum phosphate levels were classified as low or high based on age-dependent limits according to the K/DOQI guidelines (18). Results are given as mean and median values, SDs, and ranges. Differences between two groups were evaluated using Student s t-test or Mann Whitney U test and correlations were tested using Spearman rank correlation and stepwise multiple regression analysis. RESULTS PERITONEAL MEMBRANE TRANSPORT CHARACTERISTICS In the PET studies, mean 2-hour and 4-hour D/P ratios were 0.44 ± 0.14 and 0.62 ± 0.14 for creatinine and 0.39 ± 0.12 and 0.55 ± 0.14 for phosphate respectively (p < 0.05 for 2 and 4 hours). A close correlation between the 2-hour and the 4-hour D/P ratios was observed for both phosphate (r = 0.83, p < 0.0001) and creatinine (r = 0.87, p < 0.0001). Also, both the 2-hour and the 4-hour D/P phosphate ratios were significantly correlated with those of creatinine (Figure 1). PERITONEAL DIALYSIS DOSE The parameters of APD prescription and the clearances achieved are summarized in Table 1. The number of nighttime PD cycles ranged from 3 to 13, dwell times from 45 to 180 minutes, and fill volumes from 625 to 1106 ml/m 2 at night and from 0 to 882 ml/m 2 during the day. The Figure 1 Relationship between creatinine and phosphate equilibration rates. D2/P = dialysate-to-plasma ratio at 2 hours; D4/P = dialysate-to-plasma ratio at 4 hours.

PDI JULY 2009 VOL. 29, NO. 4 DIALYTIC PHOSPHATE REMOVAL IN APD TABLE 1 Automated Peritoneal Dialysis (PD) Modalities and Achieved Dialytic Phosphate and Creatinine Clearances All patients NIPD CCPD p Value Clearance studies (n) 60 33 27 NS Nighttime cycles (n) 6.0±2.1 6.4±2.4 5.5±1.4 NS Cycle dwell time (minutes) 94±31 93±33 96±28 NS Total cycler time (hours) 8.85±1.66 9.9±1.65 9.0±1.13 <0.05 Nighttime fill volume (ml/m 2 ) 996±109 992±87 1003±132 NS Daytime fill volume (ml/m 2 ) 0 540±220 Net ultrafiltration (ml/m 2 /day) 496±333 489±334 524±351 NS Nighttime dialysate turnover (L/m 2 /day) 5.93±1.92 6.28±2.22 5.49±1.37 NS Total dialysate turnover (L/m 2 /day) 6.17±1.89 6.28±2.22 6.03±1.40 NS Dialytic phosphate clearance (L/1.73 m 2 /week) 28.42±12.79 30.44±14.45 27.00±9.05 NS Dialytic creatinine clearance (L/1.73 m 2 /week) 29.23±15.27 30.74±16.37 29.66±12.25 NS Renal phosphate clearance (L/1.73 m 2 /week) 26.33±24.48 27.64±29.52 26.28±19.04 NS Renal creatinine clearance (L/1.73 m 2 /week) 43.01±37.70 49.40±44.44 38.80±32.94 NS Total phosphate clearance (L/1.73 m 2 /week) 55.96±24.23 59.82±28.15 52.28±19.75 NS Total creatinine clearance (L/1.73 m 2 /week) 67.19±36.92 66.37±41.02 67.13±34.86 NS NIPD = nocturnal intermittent PD; CCPD = continuous cycling PD; NS = not significant. 30 of the 35 patients had significant residual renal function. Complete clearance studies (i.e., peritoneal and renal) were available for 44 occasions. additional daytime dwell in the CCPD patients was offset by slightly shorter cycler dialysis with fewer automated cycles, resulting in similar total dialysate fluid turnover and 24-hour phosphate and creatinine clearances in the two groups. In the 9 children below the age of 2 years, dialytic phosphate clearance was 29.8 ± 11.1 and in the older children 28.6 ± 12.8 L/1.73 m 2 /week (p = NS); mean fill volume was 944 ± 127 and 1011 ± 99 ml/m 2 respectively (p = NS). Phosphate clearance did not differ in patients with conventional and bicarbonate- or lactatebased double-chamber solutions. FACTORS AFFECTING PHOSPHATE CLEARANCE Dialytic phosphate clearance was more closely correlated with 2-hour and 4-hour D/P phosphate in the PET (r = 0.44, r = 0.52; both p < 0.0001) than with 2-hour and 4-hour D/P creatinine (r = 0.26, p = 0.045 and r = 0.27, p = 0.036; Figure 2). Dialytic phosphate clearance was positively correlated with total (r = 0.53, p < 0.0001; Figure 3) and nighttime fluid turnover (r = 0.5, p < 0.0001), the number of cycles (r = 0.52, p < 0.001), total cycler time (r = 0.33, p < 0.01), and net ultrafiltration (r = 0.30, p < 0.05), and negatively with dwell time (r = 0.43, p < 0.001) but not with age. Patients with high dialysate volume had more exchanges (r = 0.89, p < 0.0001) and a longer daily dialysis time (r = 0.28, p < 0.05). Stepwise multiple linear regression analysis was performed to identify those variables among the univariate Figure 2 Association between dialytic phosphate clearance and dialysate-to-plasma ratios (D/P) of creatinine and phosphate. correlates listed above that independently affected dialytic phosphate clearance. Four variables that explained 65% of the overall variability of dialytic 24-hour phosphate clearance were retained in the model: total fluid turnover (partial R 2 = 0.48, p < 0.001), 2-hour D/P phosphate (partial R 2 = 0.07, p = 0.001), dwell time (partial R 2 = 0.05, p = 0.01), and total net ultrafiltration (partial R 2 = 0.05, p = 0.005). When individual prescription characteristics were considered, dialytic phosphate clearance was positively affected by the number of nighttime exchanges (partial R 2 = 0.48, p < 0.001) and 467

SCHMITT et al. JULY 2009 VOL. 29, NO. 4 PDI oral phosphate binders less frequently than the hyperphosphatemic patients. Whereas renal phosphate removal did not differ between the groups, the hyperphosphatemic children had significantly lower 24-hour dialytic phosphate clearances than the normophosphatemic patients (p < 0.05). In contrast, neither D/P creatinine nor dialytic creatinine clearance differed between normo- and hyperphosphatemic children. Low phosphate transport did not correlate with age or duration of dialysis. DISCUSSION Figure 3 Total fluid turnover and dialytic phosphate clearance in 60 children on automated peritoneal dialysis. net ultrafiltration (partial R 2 = 0.08, p = 0.005), with an additional negative impact of dwell time (partial R 2 = 0.06, p = 0.001). Children with longer dwell time had fewer exchanges and less total fluid turnover. Age did not independently affect dialytic phosphate clearance or serum phosphate levels. EFFECT OF DIALYTIC PHOSPHATE REMOVAL ON SERUM PHOSPHATE LEVELS To account for the age dependency of serum phosphorus levels, the patients with both PET and clearance studies available were divided into normophosphatemic (n = 30) and hyperphosphatemic subgroups (n = 22; Table 2). Normophosphatemic children were younger and received Dialytic phosphate clearance is the product of nonmodifiable peritoneal transport characteristics and the modifiable components of dialysis prescription. Our study demonstrates that, in children treated with APD, both intrinsic peritoneal phosphate transport characteristics and PD dosing have a significant impact on daily phosphate removal. Creatinine is an inadequate surrogate marker of phosphate transport and cannot replace direct measurements of peritoneal phosphate handling. Creatinine and glucose were used as markers to describe small-molecule transport across the peritoneal membrane in the original description of the PET, and creatinine and urea clearances have been utilized for a long time as indices of dialysis adequacy. While the validity of these markers has been questioned increasingly in recent years (3), it has become obvious that phosphate is both an important marker and a mediator of morbidity and mortality in ESRD (5,6). In the present study, we measured phosphate equilibration during standardized pediatric PETs, assessed the relationship TABLE 2 Clinical, Biochemical, and Dialytic Characteristics in Normophosphatemic Children (Thirty Occasions) Compared to Children with Elevated Serum Phosphate Levels for Age (Twenty-Two Occasions) 468 Hyperphosphatemic Normophosphatemic p Value Age (years) 12.1±4.8 6.26±4.9 <0.001 Time on PD (months) 9.7±12.2 12.3±11.6 NS Patients receiving oral phosphate binders 18/22 (82%) 13/30 (43%) <0.05 Serum phosphate (mmol/l) 1.89±0.32 1.44±0.24 <0.001 Serum Ca P ion product (mmol 2 /L 2 ) 4.3±0.7 3.5±0.8 <0.001 Renal phosphate clearance (L/1.73 m 2 /week) 27.35±24.92 23.87±24.57 NS 2-hour D/P creatinine 0.39±0.12 0.45±0.14 NS 4-hour D/P creatinine 0.57±0.13 0.65±0.15 NS Dialytic creatinine clearance (L/1.73 m 2 /week) 26.89±8.90 31.28±16.05 NS 2-hour D/P phosphate 0.37±0.11 0.40±0.12 NS 4-hour D/P phosphate 0.51±0.14 0.60±0.16 <0.05 Dialytic phosphate clearance (L/1.73 m 2 /week) 23.78±8.00 31.38±11.60 <0.05 PD = peritoneal dialysis; Ca P = calcium phosphate product; D/P = dialysate-to-plasma ratio; NS = not significant.

PDI JULY 2009 VOL. 29, NO. 4 DIALYTIC PHOSPHATE REMOVAL IN APD between phosphate and creatinine equilibration, and analyzed the predictive value of D/P phosphate for daily phosphate removal and serum phosphate levels in children receiving APD. We noted that, while the equilibration characteristics of creatinine and phosphate were significantly correlated, D/P phosphate was a better predictor of 24-hour phosphate clearance than was D/P creatinine. The mechanisms of phosphate transport across the peritoneal membrane have received little attention to date. Kinetic modeling in a small number of diabetic patients suggested that diffusion is the major physical principle of phosphate elimination, with some additional impact by non-lymphatic convective transport but no appreciable lymphatic transport (19). As charged ions, phosphate molecules are subject to facilitated diffusion along the electrochemical gradient between plasma and dialysate in addition to size-restricted diffusive transport. Another level of complexity is added by the fact that some 20% of circulating phosphate ions are bound to plasma proteins. Finally, several families of transmembranous phosphate transporters have been discovered in recent years (20), providing a mechanistic basis for transcellular phosphate transport across endothelial cells. In addition, phosphate ions can reversibly shift into erythrocytes, depending on the prevailing electrophysiological milieu (21). These differences in biophysical handling at the peritoneal membrane readily explain the marked heterogeneity of phosphate and creatinine equilibration ratios observed in the PET. As a consequence of these differential transport kinetics, the peritoneal transporter state defined by the creatinine equilibration pattern is poorly predictive of daily phosphate clearances. This becomes particularly evident in patients undergoing APD, where dialysate is drained well before full equilibration is achieved. Our findings clearly indicate that direct measurement of D/P phosphate in the PET is a better indicator of the phosphate clearance achieved with a given PD prescription than D/P creatinine. According to our results and in analogy to the usual definition of transport categories, patients with a D/P phosphate less than 0.27 after 2 hours or 0.41 after 4 hours could be considered low phosphate transporters (i.e., D/P < 1 SD below the mean). Of note, close correlations between 2- and 4-hour ratios have already been reported for glucose and creatinine (22) and suggest that sufficient accuracy for the assessment of peritoneal membrane transport capacity can be achieved with a shortened PET. In addition to the effect of peritoneal transport characteristics, dialytic clearance in APD is a function of the number, volume, and duration of dialysis cycles. Total PD fluid turnover is the major determinant of phosphate clearance. Stepwise linear regression analysis suggested approximately 50% of the variance would be explained by fluid turnover and 10% by the individual membrane characteristics as reflected by D/P phosphate in the PET. At a given D/P phosphate, dialytic phosphate clearance increased by 0.7 L/1.73 m 2 /day with every 1 L/m 2 prescribed PD fluid turnover. In a child with a serum phosphate of 6 mg/dl, this translates into 4.2 mg/1.73 m 2 phosphate removal per day, or 29.5 mg (9.5 mmol) per week, the average amount removed by one APD session (23). These results are in keeping with studies in adults, where 8 and 8.8 mmol phosphate removal per 1 L dialysate volume were reported (24,25). When the individual prescription variables were analyzed in the stepwise prediction model, the number of cycles performed was the strongest independent predictor of phosphate clearance, with smaller contributions by cycle duration, D/P phosphate, and net ultrafiltration, the latter likely reflecting the additional impact of convective phosphate transport. These four parameters explained up to 65% of the variability of dialytic phosphate clearance. The age of the patients was not predictive. Peritoneal phosphate transport did not differ with acid or ph-neutral, lactate- or bicarbonate-buffered double-chamber solutions. Impact of ph on cellular phosphate balance (26) and acute phosphate removal with hemodialysis (27) and PD (28) has been demonstrated. These subtle differences, however, could not be reconfirmed in extended clinical trials (29). An impact of the initial ph of the PD solutions on dialysate phosphate determination is also unlikely. Mean dwell time was 95 ± 30 minutes in our patients; even with acidic PD solution (ph 5.5), effluent ph increased to ph 7.2 within only 60 minutes of dwell time (28). Fill volume did not exert an independent effect, probably due to the minor variation of dwell volumes in the given setting of routine APD prescriptions with a standardized target of 1000 ml/m 2. Daytime fill volumes, averaging 430 ml/m 2 in those patients following a wet day prescription, also did not impact significantly on 24-hour dialytic phosphate clearance. The efficacy of single long daytime dwells of conventional dextrose PD fluid may be compromised by their partial resorption and the limited intra-abdominal volumes tolerated by children during the daytime. Moreover, patients with a daytime dwell tended to have shorter cycler sessions, which may level off effects of the daytime dwell. It would be interesting to study whether a more marked effect on dialytic phosphate clearance might be achieved using icodextrin daytime dwells when added to an unchanged NIPD prescription. 469

SCHMITT et al. JULY 2009 VOL. 29, NO. 4 PDI A subgroup of 17 of the 35 patients had a second determination 13.8 ± 10.2 months later, which harbors the danger of overestimation of individual patients. Similar findings, however, were obtained when these repeat determinations were excluded from the analysis, thus ruling out a respective bias. The second issue addressed in this study concerned possible association between dialytic phosphate removal and serum phosphate levels. Since the normal range of serum phosphate is strongly age dependent, reaching up to 2.7 mmol/l in healthy infants, patients were categorized as normo- or hyperphosphatemic and the groups were compared with respect to their clinical and dialysis-related characteristics. Hyperphosphatemic children were, on average, older than normophosphatemic subjects, reflecting the better control of phosphate intake in tube and formula fed infants in contrast to the variable nutritional compliance observed in adolescents. Individual growth rate may also have influenced net phosphate balance. Whereas residual renal phosphate clearance, albeit considerable, showed no relationship with serum phosphate levels, the daily dialytic phosphate clearance was 33% higher in normophosphatemic than in hyperphosphatemic children. In contrast, creatinine clearance and creatinine D/P ratios were not distinctive. This is different from findings in adult PD patients (30) and provides a strong rationale for direct monitoring of peritoneal phosphate elimination. We conclude that dialytic phosphate elimination can be modified in APD by the number of PD cycles, dwell time, and total dialysate turnover. Dialytic phosphate clearance represents an important contribution to serum phosphate control. Since hyperphosphatemia is a major cardiovascular risk factor in uremia, dialytic phosphate removal should be monitored routinely. Adequacy studies defining the impact on patient outcome are mandatory. 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