Glucose sparing in peritoneal dialysis: Implications and metrics

http://www.kidney-international.org & 26 International Society of Nephrology Glucose sparing in peritoneal dialysis: Implications and metrics C Holmes 1 and S Mujais 1 1 Renal Division, Baxter Healthcare Corporation, McGaw Park, Illinois, USA Glucose sparing is a central component of modern peritoneal dialysis therapy, necessary to reduce the trade-offs of the therapy in terms of membrane protection and alleviation of systemic consequences. We present a detailed exploration of a metric for this approach in the form of the index of ultrafiltration efficiency, that we propose as a guide for designing therapeutic regimens and for the development of new dialysis solutions. Based on insights from exploration of ultrafiltration efficiency with various dialysis solutions, we propose an approach to optimizing dialysis prescription.. doi:1.138/sj.ki.51924 KEYWORDS: peritoneal dialysis; ultrafiltration efficiency; non-glucose osmotic agents Correspondence: S Mujais, Renal Division, Baxter Healthcare Corporation, 162 Waukegan Rd, MPGR-A2, McGaw Park, Illinois 685-9815, USA. E-mail: salim_mujais@baxter.com It is widely accepted that glucose has served very successfully as an osmotic agent in continuous peritoneal dialysis (PD) since its first introduction over 3 years ago. However, concerns over the total amount of glucose that is absorbed systemically has become an increasing focus of attention in recent years, particularly in light of growing number of type II diabetic patients treated with PD. Indeed, the observation that it is the older type II diabetic patients who have a higher relative risk of death when treated with PD versus hemodialysis, irrespective of the presence of co-morbidities, has led numerous investigators to question the role of glucose absorption from the PD solution in this respect. 1 Furthermore, it has also been suggested that excessive glucose absorption may play an important role in many of the metabolic imbalances, such as the dyslipidemia, hyperinsulinemia, insulin resistance, oxidative stress, inflammation, and altered adipokine levels seen in non-diabetic PD patients. 2 In 1994, Holmes and Shockley 3 described strategies to reduce glucose absorption during PD by combining nonglucose solutions with standard glucose formulations. In this paper, we discuss approaches to the quantification of glucose sparing, highlighting the importance of ultrafiltration (UF) efficiency as a critical parameter when considering glucosesparing regimens. Using actual clinical data, the relationship between glucose absorption and UF efficiency within a population of PD patients is provided, including a description of the quantitative impact of icodextrin on UF efficiency from selected patient cohorts. Finally, a summary of demonstrated and emerging clinical benefits with glucose-sparing regimens is provided. QUANTIFYING GLUCOSE SPARING The extent of glucose absorption from glucose-based solutions has been described by several investigators, and ranges from approximately 4 to over 1 kg per year. 2 In 1989, Lindholm and Bergstrom 4 reported that 46 6 g of glucose would be absorbed for a 6-h dwell with 2 l of a 4.25% dextrose solution, 24 4 g for a 2.5% solution, and 15 22 g for a 1.5% solution. Burkhart translated these values into an absorbed range of 1 3 g per day for continuous ambulatory PD (CAPD) patients, presumably by invoking variables such as dextrose concentration, number of exchanges, solutions volumes employed, and membrane transport type. 2 S14

Mathematical modeling can also provide some information on the impact of substitution with non-glucose formulations on total carbohydrate uptake. A simple model described in 2 calculated an absorption of 12 g of carbohydrate per day in a CAPD average transporter using three 5-h exchanges of 1.5% dextrose and one 9-h long dwell of 4.25% dextrose. 3 By substituting the long dwell with icodextrin, this carbohydrate absorption was reduced by 27%. If one of the 1.5% dextrose exchanges was also replaced with an amino-acid solution, the total reduction in carbohydrate uptake was 42%. Figure 1 provides a more detailed analysis by providing a graphical representation of carbohydrate absorption across membrane transporter types with various glucose-sparing regimens. One concept that is crucial to glucose-sparing approaches, and which has not been explored to any great extent to date, is that of UF efficiency. gm/24 h 16 14 12 1 8 6 4 2 3 1.5% Dextrose+ 1 4.5% Dextrose 3 1.5% Dextrose+ 1 7.5% Icodextrin 2 1.5% Dextrose+ 1 7.5% Icodextrin+ 1 1.1% Amino acids L LA HA H L LA HA H L LA HA H Figure 1 Mathematical modeling of glucose absorption in CAPD patients with various membrane transport characteristics. The model assumes three shorts dwells of 5 h and a long dwell of 9 h. Legend: L ¼ low (MTAC 5.96 ml/min); LA ¼ low-average (MTAC 8.35 ml/min); HA ¼ high-average (MTAC 11.7 ml/min); H ¼ high (MTAC 16.3 ml/min). QUANTIFYING UF EFFICIENCY The concept of UF efficiency was first introduced in the pediatric nephrology literature by Fischbach et al. 5 and is defined as the amount of net UF obtained for every gram of carbohydrate absorbed. It is intuitively obvious that the UF efficiency index will vary between patients and is affected by the conditions of the dwell. Although the index can be studied by kinetic modeling approaches, it is recognized that UF prediction is problematic under usual available parameters entered in modeling approaches. Hence, we decided to approach an evaluation of UF efficiency looking at actual clinical data. Short dwell evaluation To understand the parameters related to UF efficiency during the short dwell, we examined the results of a standard peritoneal equilibration test (PET) in 719 patients evaluated as part of the TARGET program (Baxter Healthcare Corporation) previously described. 6 Patients who had a standardized PET performed with 2 l of 2.5% dextrose and had a complete set of all parameters of interest measured are included in this analysis. The characteristics of the patient population classified by PET categories are summarized in Table 1. The four groups were relatively similar in their demographics and residual renal function, and their proportional distribution into the various PET categories is commensurate with that observed in other studies. 6 Peritoneal UF showed the expected tendency to decline with increasing transport status (Table 1), but significant overlap between the categories was clearly apparent (Figure 2). Glucose absorption mirrored transport status and tended to reflect better separation between the groups than net UF (Figure 3). UF efficiency showed an intermediary separation as the summation effect of glucose absorption and net UF (Figure 4). These relationships are further examined in Table 2. The best correlate of net UF was the amount of glucose absorbed (r ¼.578, Po.1; Figure 5) which was higher than the correlation with the ratio of 4-h to -h dialysate glucose Table 1 Characteristics of population used for short dwell study PET category L LA HA H N 54 286 288 91 Age (years) 51.671.8 53.17.9 57.57.8 53.671.5 Height (cm) 165.271.5 166.77.6 167.47.6 168.171.1 Weight (kg) 71.872.4 75.87.9 76.47.9 7.771.5 BSA (m 2 ) 1.787.3 1.847.1 1.867.1 1.837.2 RRF (ml/min/1.73 m 2 ) 2.57.5 2.77.2 2.87.1 2.77.3 Urine volume (ml/24 h) 415777 383728 488732 47176 Ultrafiltration (ml/4 h) 462718 39979* 28771*,# 172722*,#,$ D 4 /D glucose 517.8 427.4* 347.4*,# 267.7*,#,$ D 4 /P creatinine 447.6 67.3* 737.2*,# 867.5*,#,$ MTAC creatinine (ml/min) 4.27.14 7.57.7* 11.67.9*,# 17.37.25*,#,$ Glucose absorbed (g/4 h) 2.37.4 26.7.1* 31.37.1*,# 35.47.3*,#,$ Ultrafiltration efficiency (ml/g CHO) 23.571.1 15.97.4* 9.57.3*,# 5.17.6*,#,$ BSA, body surface area; CHO, carbohydrate; D 4 /D, ratio of 4-h to -h dialysate glucose ; D 4 /P, 4-h dialysate/plasma creatinine; H, high; HA, high-average; L, low; LA, lowaverage; MTAC, mass transfer area coefficient; PET, peritoneal equilibration test; RRF, residual renal function. Values are mean7s.e. *Po.1 vs L; # Po.1 vs LA; $ Po.1 vs HA. S15

(D 4 /D ) or either of the two parameters of creatinine equilibration (dialysate/plasma (D/P) creatinine and mass transfer area coefficient (MTAC) creatinine). Controlling for D 4 /D glucose, D/P creatinine, and MTAC creatinine did not alter this correlation (r ¼.59, Po.1). In contrast, the correlation between D/P creatinine and net UF lost significance when controlled for glucose absorption or D 4 /D. Ultrafiltration (ml/4 h) 12 1 8 6 4 2 2 4 6 N = 54 L 286 288 LA HA PET category 91 H Figure 2 Net UF during a PET with 2.5% dextrose displayed by PET categories. L ¼ low transport; LA ¼ low-average transport; HA ¼ high-average transport; H ¼ high transport. Long dwell evaluation UF efficiency in CAPD. We evaluated the UF efficiency during the long dwell of CAPD in 94 patients studied with 2. 5% dextrose and then re-evaluated with the alternate osmotic agent icodextrin. These patients are a subset of a previously published study in whom carbohydrate absorption data were available. 7 Net UF, carbohydrate absorbed, dwell time, and UF efficiency were measured while patients were on 2.5% dextrose and 4 weeks after transfer to icodextrin to reflect Ultrafiltration efficiency (ml/g CHO) 5 4 3 2 1 1 2 N = 54 L 286 288 LA HA PET category 91 H Figure 4 UF efficiency during a PET with 2.5% dextrose displayed by PET categories. L ¼ low transport; LA ¼ low-average transport; HA ¼ high-average transport; H ¼ high transport. Glucose absorption (g/4 h) 5 4 3 2 1 N = 54 L 286 288 LA HA PET category 91 H Figure 3 Glucose absorption during a PET with 2.5% dextrose displayed by PET categories. L ¼ low transport; LA ¼ low-average transport; HA ¼ high-average transport; H ¼ high transport. Ultrafiltration (ml/4 h) 1 8 6 4 2 2 4 6 1 15 2 25 3 35 4 Glucose absorbed (g/4 h) Figure 5 Correlation between glucose absorption and net UF during a PET with 2.5% dextrose. 45 5 Table 2 Correlates of glucose absorption and ultrafiltration during a PET Ultrafiltration D 4 /D glucose D 4 /P creatinine MTAC creatinine Glucose absorbed Ultrafiltration efficiency Ultrafiltration 1.358 a.452 a.423 a.578 a.935 a D 4 /D glucose.358 a 1.797 a.774 a.898 a.545 a D 4 /P creatinine.452 a.797 a 1.968 a.846 a.617 a MTAC creatinine.423 a.774 a.968 a 1.88 a.574 a Glucose absorbed.578 a.898 a.846 a.88 a 1.761 a Ultrafiltration efficiency.935 a.545 a.617 a.574 a.761 a 1 D 4 /D, ratio of 4-h to -h dialysate glucose; D 4 /P, 4-h dialysate/plasma creatinine; MTAC, mass transfer area coefficient; PET, peritoneal equilibration test. a Correlation is significant at the.1 level. S16

Table 3 Comparison of icodextrin and 2.5% dextrose during the long dwell in CAPD patients Dwell time (h) Net UF (ml) CHO absorbed (g) UF efficiency (ml/g) 2.5% Dextrose 1.17.16 271742 39.37.7 7.971.3 Icodextrin 1.67.16 599733 34.672. 27.873.3 P-value.1 o o.5 o CAPD, continuous ambulatory peritoneal dialysis; CHO, carbohydrate; UF, ultrafiltration. Values are mean7s.e. Net ultrafiltration (ml) 14 12 1 8 6 4 2 2 4 6 8 1 Carbohydrate absorption (g) Figure 6 Correlation between carbohydrate absorption from an icodextrin solution and net UF during a CAPD long dwell. Table 4 Comparison of icodextrin and 4.25% dextrose during the long dwell in APD patients Dwell time (h) Net UF (ml) CHO absorbed (g) UF efficiency (ml/g) 4.25% 14.27.1 22786 77.771.4 3.171.1 Dextrose Icodextrin 14.17.1 54746 56.272.4 1.971.1 P-value.64 o.1 o.1 o.1 APD, automated peritoneal dialysis; CHO, carbohydrate; UF, ultrafiltration. Values are mean7s.e. Net ultrafiltration (ml) 2 175 15 125 1 75 5 25 25 5 2 3 4 5 6 7 8 Carbohydrate absorption (g) 9 1 Figure 7 Correlation between carbohydrate absorption from an icodextrin solution and net UF during an APD long dwell. steady-state conditions (Table 3). Despite a slightly longer dwell time, net UF was clearly superior with icodextrin (Po) and carbohydrate was absorption lower than with 2.5% dextrose. UF efficiency was threefold higher on icodextrin (Po). Net UF was inversely correlated with carbohydrate absorption, but the degree of correlation was higher with icodextrin (r ¼.456, Po; Figure 6) than with 2.5% dextrose (r ¼.38, Po.1). We surmise that this is due to the fact that glucose absorption during the long dwell continues beyond the point at which glucose-induced transcapillary UF has ceased. With icodextrin, however, transcapillary UF continues long into the long dwell. This interpretation is supported by comparing the correlation between glucose absorption and net UF when using 2.5% dextrose in the short dwell (r ¼.578, Po.1; Table 2) and the long dwell (r ¼.38, Po.1). UF efficiency in automated PD. The use of 4.25% dextrose for the long dwell in automated PD (APD) in high and highaverage (H/HA) transporters is aimed at avoiding negative net UF, but it is associated with a metabolically expensive consequence from the large amount of carbohydrate absorbed. We evaluated the UF efficiency during the long dwell of APD in two groups of high and high-average patients randomized to receive either 4.25% dextrose (45 patients) or icodextrin (47 patients) as previously described. 8 Net UF, carbohydrate absorbed, dwell time, and UF efficiency were measured after patients were on 4.25% dextrose or icodextrin for 2 weeks (Table 4). Despite an equal dwell time, icodextrin resulted in a superior net UF than 4.25% dextrose (more than twofold). Carbohydrate absorption was significantly lower with icodextrin than with 4.25% dextrose. The metabolic cost of UF was clearly higher with the dextrose solution as reflected in the superior UF efficiency of icodextrin. The UF efficiency of icodextrin was more than threefold that of dextrose, so for every gram of carbohydrate absorbed from the icodextrin solution, three times more UF is obtained than for a gram of carbohydrate from 4.25% dextrose solution. Considering the major metabolic complications attendant on the use of 4.25% dextrose, the functional and metabolic superiorities of icodextrin become strong imperatives for its use. Net UF was inversely correlated with carbohydrate absorption for both icodextrin (r ¼.536, Po; Figure 7) and 4.25% dextrose (r ¼.44, Po.1). We again observed a higher level of correlation in the icodextrin group than in the 4.25% dextrose group attesting to the sustained nature of UF with icodextrin. DEMONSTRATED AND EMERGING BENEFITS OF GLUCOSE SPARING PRESCRIPTIONS Icodextrin and amino acids are non-glucose osmotic agents that have been used in the clinical management of PD patients, at least in some geographies, for over a decade. The benefits of improved UF during the long dwell with 7.5% icodextrin solution, and the effect of amino-acid solution on S17

Table 5 A summary of demonstrated and emerging clinical benefits of glucose-sparing prescriptions in peritoneal dialysis patients Patient population Prescription Observations Authors Year Non-diabetic CAPD Icodextrin vs glucose Decreased serum insulin Amici et al. 9 21 Improved insulin sensitivity (HOMA) Non-diabetic CAPD Icodextrin vs glucose Decreased plasma total cholesterol Bredie et al. 1 21 Decreased LDL Diabetic Icodextrin vs glucose HbA1c decreased with icodextrin use (8.7.7 to 7.97.7%, Johnson et al. 11 21 Po.5) CAPD with Icodextrin vs glucose Significant fall in triglycerides in icodextrin group only Sisca and Maggiore 22 hypertriglyceridemia et al. 12 All PD Icodextrin vs glucose Gastric emptying time significantly shorter with icodextrin Van et al. 13 22 group All PD Icodextrin vs glucose No increase in non-fluid weight gain in icodextrin group Davies et al. 14 23 unlike glucose group Diabetic CAPD Icodextrin, amino acids and Significantly improved glycemic control Marshall et al. 15 23 glucose vs all glucose All PD Icodextrin and amino acids Improved glucose and lipid metabolism (increased glucose Martikainen et al. 16 25 vs glucose oxidation, decreased lipid oxidation) CAPD Icodextrin vs 3.86% glucose Increased heart rate, stroke volume and thus cardiac output Selby et al. 17 25 leading to increased blood pressure during dwell with glucose vs icodextrin Non-diabetic Icodextrin vs glucose Decreased plasma leptin, insulin, and triglycerides in icodextrin group Increased adiponectin and HDL, and improved insulin sensitivity (HOMA) in icodextrin group Furuya et al. 18 25 CAPD, continuous ambulatory peritoneal dialysis; HbA1c, hemoglobin A1c; HDL, high-density lipoprotein; HOMA, Homeostasis Model Assessment; LDL, low-density lipoprotein. nutritional parameters have been the subject of much research. It has been only of late, however, that the benefits of glucose sparing offered by these formulations have started to be explored. Table 5 provides a summary of more recent clinical observations that suggest that both diabetic and non-diabetic patients may benefit from a glucose-sparing approach, in terms of the PD solutions prescription. By employing icodextrin to achieve a reduction in total carbohydrate absorption while maintaining adequate UF, it appears that a less atherogenic lipid profile can be attained and avoidance of weight gain that is often observed in glucose-using patients. 14 At least two independent studies have also identified the potential for improving insulin sensitivity. 9,18 In diabetic patients, a well-designed, albeit small study by Marshall et al. 15 demonstrated much improved glycemic control with a glucose-sparing regimen, and Johnson et al. 11 have reported a preliminary observation of reduced hemoglobin (Hb) A1c. Recent research illustrates the numerous avenues for further exploration of glucose-sparing regimens: beneficial changes in plasma adipokine levels, 18 glucose and lipid oxidation, 16 and systemic hemodynamic effects. 17 The accumulated experience to date is promising, but clearly there is a need for further well-designed studies to confirm and to extend these observations. IMPLEMENTING GLUCOSE SPARING Two complementary strategies can be envisaged for the implementation of glucose sparing in a clinical setting: first, reduction for the need for peritoneal UF and second optimization of peritoneal UF with minimization of glucose Table 6 Strategies for implementation of glucose sparing 1. Reduction for the need for peritoneal ultrafiltration (a) Dietary salt and water restriction (b) Use of diuretics 2. Optimization of peritoneal ultrafiltration with minimization of glucose use (a) Appropriate design of prescription (b) Use of icodextrin for the long dwell (c) Use of amino-acids-based solution in short dwells use. The first strategy is best achieved with reduction in dietary salt and water intake and the use of diuretics. Dietary salt restriction can significantly reduce the fluid burden and has been shown to be successful in the absence of any change in dialysis prescription. 19,2 Diuretic use in non-oliguric patients is also successful, but requires use of appropriate doses of loop diuretics with or without thiazides or thiazidecongeners. 21 23 Interventions under this first strategy can be considered to have infinite UF efficiency as no glucose is involved! The second strategy relies on the use of physiologic principles to optimize the conditions for UF by matching patients peritoneal transport characteristics with the design of the prescription. Additionally, use of icodextrin in the long dwell will readily lead to better UF efficiency as illustrated above. The impact of icodextrin in glucose sparing may go beyond the long dwell as enhanced UF during the long dwell may lessen the burden of required UF during the short dwell and consequently lower glucose use in the short dwells is feasible. 24 Use of amino-acid-based solutions during the short dwell in either CAPD 25 or APD 26 provides also for maximization of glucose sparing (Table 6). S18

ACKNOWLEDGMENTS We thank Sujatha Karoor PhD for the glucose absorption modeling. REFERENCES 1. Vonesh EF, Snyder JJ, Foley RN, Collins AJ. The differential impact of risk factors on mortality in hemodialysis and peritoneal dialysis. Kidney Int 24; 66: 2389 241. 2. Burkart J. Metabolic consequences of peritoneal dialysis. Semin Dial 24; 17: 498 54. 3. Holmes CJ, Shockley TR. Strategies to reduce glucose exposure in peritoneal dialysis patients. Perit Dial Int 2; 2(Suppl 2): S37 S41. 4. Lindholm B, Bergstrom J. Nutritional management of patients undergoing peritoneal dialysis. In: KD N (ed). Peritoneal Dialysis. Kluwer: Dordecht, 1989, pp 32 328. 5. Fischbach M, Desprez P, Donnars F et al. Optimization of CCPD prescription in children using peritoneal equilibration test. Adv Perit Dial 1 1994; 9, 1:37 39. 6. Mujais S, Vonesh E. Profiling of peritoneal ultrafiltration. Kidney Int 22; S81: S17 S22. 7. Wolfson M, Ogrinc F, Mujais S. Review of clinical trial experience with icodextrin. Kidney Int 22; S81: S46 S52. 8. Finkelstein F, Healy H, Abu-Alfa A et al. Superiority of icodextrin compared with 4.25% dextrose for peritoneal ultrafiltration. J Am Soc Nephrol 25; 16: 546 554. 9. Amici G, Orrasch M, Da Rin G, Bocci C. Hyperinsulinism reduction associated with icodextrin treatment in continuous ambulatory peritoneal dialysis patients. Adv Perit Dial 21; 17: 8 83. 1. Bredie SJ, Bosch FH, Demacker PN. Effects of peritoneal dialysis with an overnight icodextrin dwell on parameters of glucose and lipid metabolism. Perit Dial Int 21; 21: 275 281. 11. Johnson DW, Arndt M, O Shea A et al. Icodextrin as salvage therapy in peritoneal dialysis patients with refractory fluid overload. BMC Nephrol 21; 2: 2. 12. Sisca S, Maggiore U. Beneficial effect of icodextrin on the hypertriglyceridemia of CAPD patients. Perit Dial Int 22; 22: 727 729. 13. Van V, Schoonjans RS, Struijk DG et al. Influence of dialysate on gastric emptying time in peritoneal dialysis patients. Perit Dial Int 22; 22: 32 38. 14. Davies SJ, Woodrow G, Donovan K et al. Icodextrin improves the fluid status of peritoneal dialysis patients: results of a double-blind randomized controlled trial. J Am Soc Nephrol 23; 14: 2338 2344. 15. Marshall J, Jennings P, Scott A et al. Glycemic control in diabetic CAPD patients assessed by continuous glucose monitoring system (CGMS). Kidney Int 23; 64: 148 1486. 16. Martikainen T, Teppo AM, Gronhagen-Riska C, Ekstrand A. Benefit of glucose-free dialysis solutions on glucose and lipid metabolism in peritoneal dialysis patients. Blood Purif 25; 23: 33 31. 17. Selby NM, Fonseca S, Hulme L et al. Hypertonic glucose-based peritoneal dialysate is associated with higher blood pressure and adverse haemodynamics as compared with icodextrin. Nephrol Dial Transplant 25; 2: 1848 1853. 18. Furuya R, Odamaki M, Kumagai H, Hishida A. Beneficial effects of icodextrin on plasma level of adipocytokines in peritoneal dialysis patients. Nephrol Dial Transplant 26; 21: 494 498. 19. Gunal AI, Duman S, Ozkahya M et al. Strict volume control normalizes hypertension in peritoneal dialysis patients. Am J Kidney Dis 21; 37: 588 593. 2. Asci G, Ozkahya M, Duman S et al. Volume control associated with better cardiac function in long-term peritoneal dialysis patients. Perit Dial Int 26; 26: 85 88. 21. Medcalf JF, Harris KP, Walls J. What place diuretics in long-term CAPD? Nephrol Dial Transplant 1998; 13: 2193 2194. 22. Medcalf JF, Harris KP, Walls J. Role of diuretics in the preservation of residual renal function in patients on continuous ambulatory peritoneal dialysis. Kidney Int 21; 59: 1128 1133. 23. Wollam GL, Tarazi RC, Bravo EL, Dustan HP. Diuretic potency of combined hydrochlorothiazide and furosemide therapy in patients with azotemia. Am J Med 1982; 72: 929 938. 24. Bajo MA, Selgas R, del Peso G et al. Use of icodextrin for diurnal exchange in patients undergoing automatic peritoneal dialysis. Comparison with glucose solutions. Nefrologia 22; 22: 348 355. 25. le Poole CY, van Ittersum FJ, Weijmer MC et al. Clinical effects of a peritoneal dialysis regimen low in glucose in new peritoneal dialysis patients: a randomized crossover study. Adv Perit Dial 24; 2: 17 176. 26. Tjiong HL, van den Berg JW, Wattimena JL et al. Dialysate as food: combined amino acid and glucose dialysate improves protein anabolism in renal failure patients on automated peritoneal dialysis. JAmSoc Nephrol 25; 16: 1486 1493. S19