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Perit Dial Int 29(4): 422-432
2009
© 2009 International Society for Peritoneal Dialysis
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Icodextrin

ICODEXTRIN IMPROVES METABOLIC AND FLUID MANAGEMENT IN HIGH AND HIGH-AVERAGE TRANSPORT DIABETIC PATIENTS

Ramón Paniagua1, María-de-Jesús Ventura1, Marcela Ávila-Díaz1, Alejandra Cisneros2, Marlén Vicenté-Martínez3, María-del-Carmen Furlong4, Zuzel García-González5, Diana Villanueva5, Oscar Orihuela1, María-del-Carmen Prado-Uribe1, Guadalupe Alcántara1 and Dante Amato1

Unidad de Investigación Médica en Enfermedades Nefrológicas,1 Hospital de Especialidades, Centro Médico Nacional Siglo XXI; Hospital General de Zona 27,2 Hospital General de Zona 47,3 Hospital General de Zona 8,4 Hospital General de Zona 25,5 Instituto Mexicano del Seguro Social, México City, México

Correspondence to: R. Paniagua, Unidad de Investigación Médica en Enfermedades Nefrológicas, Hospital de Especialidades, Centro Médico Nacional Siglo XXI, Av. Cuauhtemoc 330, Col. Doctores, México, D.F., C.P. 06725, México. jpaniaguas{at}cis.gob.mx; ramon.paniagua{at}imss.gob.mx


   ABSTRACT
TOP
 ABSTRACT
MATERIAL AND METHODS
 RESULTS
 DISCUSSION
 DISCLOSURE
 REFERENCES
 

{diamondsuit} Background: Icodextrin-based solutions (ICO) have clinical and theoretical advantages over glucose-based solutions (GLU) in fluid and metabolic management of diabetic peritoneal dialysis (PD) patients; however, these advantages have not yet been tested in a randomized fashion.

{diamondsuit} Objective: To analyze the effects of ICO on metabolic and fluid control in high and high-average transport diabetic patients on continuous ambulatory PD (CAPD).

{diamondsuit} Patients and Methods: A 12-month, multicenter, open-label, randomized controlled trial was conducted to compare ICO (n = 30) versus GLU (n = 29) in diabetic CAPD patients with high-average and high peritoneal transport characteristics. The basic daily schedule was 3 x 2 L GLU (1.5%) and either 1 x 2 L ICO (7.5%) or 1 x 2 L GLU (2.5%) for the long-dwell exchange, with substitution of 2.5% or 4.25% for 1.5% GLU being allowed when clinically necessary. Variables related to metabolic and fluid control were measured each month.

{diamondsuit} Results: Groups were similar at baseline in all measured variables. More than 66% of the patients using GLU, but only 9% using ICO, needed prescriptions of higher glucose concentration solutions. Ultrafiltration (UF) was higher (198 ± 101 mL/day, p < 0.05) in the ICO group than in the GLU group over time. Changes from baseline were more pronounced in the ICO group than in the GLU group for extracellular fluid volume (0.23 ± 1.38 vs –1.0 ± 1.48 L, p < 0.01) and blood pressure (systolic 1.5 ± 24.0 vs –10.4 ± 30.0 mmHg, p < 0.01; diastolic 1.5 ± 13.5 vs –6.2 ± 14.2 mmHg, p < 0.01). Compared to baseline, patients in the ICO group had better metabolic control than those in the GLU group: glucose absorption was more reduced (–17 ± 44 vs –64 ± 35 g/day) as were insulin needs (3.6 ± 3.4 vs – 9.1 ± 4.7 U/day, p < 0.01), fasting serum glucose (8.3 ± 36.5 vs –37 ± 25.8 mg/dL, p < 0.01), triglycerides (54.5 ± 31.9 vs –54.7 ± 39.9 mg/dL, p < 0.01), and glycated hemoglobin (0.79% ± 0.79% vs –0.98% ± 0.51%, p < 0.01). Patients in the ICO group had fewer adverse events related to fluid and glucose control than patients in the GLU group.

{diamondsuit} Conclusion: Icodextrin represents a significant advantage in the management of high transport diabetic patients on PD, improving peritoneal UF and fluid control and reducing the burden of glucose overexposure, thereby facilitating metabolic control.

KEY WORDS: Icodextrin; diabetes; ultrafiltration; extracellular fluid volume; metabolic control; randomized controlled trial.

Cardiovascular diseases are the main cause of morbidity and mortality among dialysis patients, in both hemodialysis and peritoneal dialysis (PD) (1–3). Fluid overload and hypertension underlie these disturbances. Fluid retention is the origin of hypertension in most dialysis patients. Adequate control of sodium balance makes antihypertensive drugs largely unnecessary (4–7). Control of extracellular fluid volume (ECFv), and therefore hypertension, retards the loss of residual renal function and decreases morbidity and mortality (8–10). Notwithstanding, control of ECFv is not an easy goal for dialysis patients to achieve.

One of the most important issues in PD therapy today is how to minimize the use of glucose as osmotic agent in PD solutions in order to avoid its metabolic side effects. Use of hypertonic glucose has been associated with hyperglycemia, hyperinsulinemia, and obesity (11–13). Other disadvantages include bioincompatibility, advanced glycated end-product generation, peritoneal damage, and, in the long term, loss of ultrafiltration (UF) capacity (14). In a significant number of patients classified as high transporters, glucose use as osmotic agent has its limitations (15–17) due to rapid peritoneal glucose absorption into the circulation with dissipation of the osmotic gradient. It is common practice when facing such a situation to use solutions with higher glucose content, resulting in increases in the adverse metabolic effects of glucose exposure. The disadvantages of hypertonic glucose are even greater in diabetic patients, many of whom are high transporters (18,19).

In the 1990s, icodextrin, a glucose polymer, began to be used in Europe as a replacement for the traditional glucose in PD solutions for the long dwell in both continuous ambulatory PD (CAPD) and automated PD (20–22). The effectiveness of icodextrin as oncotic agent has been demonstrated, as the gradient can be maintained at adequate UF values for 8 – 12 hours (23). Other advantages of icodextrin-based solutions (ICO) are that they are well tolerated, lack the metabolic side effects of glucose (23), and enhance the clearance of small- and middle-size molecules as a consequence of increased convective flow (24,25). In spite of these potential benefits of icodextrin, there are no randomized controlled trials available in PD patients with both diabetes and high-transport peritoneal membrane characteristics. Such information would be particularly important for PD populations with high diabetes rates, as in Mexico and many other countries (26–28). The objective of the present study was to compare the clinical efficacy of ICO to that of glucose-based solutions (GLU) in diabetic patients on PD with high and high-average peritoneal transport status.


   MATERIAL AND METHODS
TOP
 ABSTRACT
 MATERIAL AND METHODS
RESULTS
 DISCUSSION
 DISCLOSURE
 REFERENCES
 
STUDY DESIGN
A prospective, randomized, controlled, open-label clinical trial was conducted. The study protocol was approved by the Local Research Committees of all the participating hospitals and the National Commission for Scientific Research of the Instituto Mexicano del Seguro Social (registration number: 2004-3601-0004). The study was also registered in the Cochrane Registry for Clinical Trials (CRG040600073).

The ongoing target of the treatment was to reach control of blood pressure (BP; <130/80 mmHg) and edema (no clinical edema) through an increment in peritoneal UF. Patients were randomly assigned to one of the two arms of the study. Assignment was in a 1:1 ratio through a central randomization center. After randomization, all patients received 3 x 2 L 1.5% glucose exchanges. In addition, patients in the control group received GLU, at least 1 bag with 2.5% glucose, in the long dwell and patients in the icodextrin group received ICO (7.5%) in the long dwell. Liberal use of 2.5% or 4.25% GLU was allowed in both groups in order to reach treatment goals. Dietary sodium intake prescription was 50 mmol/day for both groups. To achieve the best compliance with the prescription, patients received seven different menus, with the cooking methods for the usual Mexican meals, suggested by a dietitian. When needed, insulin was administered subcutaneously.

SAMPLE SIZE
Sample size calculation was based on the differences in reduction of ECFv. A net difference of more than 1.0 L and a total standard error of 0.4 were expected. With {alpha} = 0.05 and two tails, the power was calculated to be (1 – β) = 0.80 for a sample of 30 patients per group (Power & Precision v 2.0w; Biostat, Englewood, NJ, USA).

PATIENTS
All the studied patients signed an informed written consent. The participating patients were recruited from four general hospitals belonging to the Instituto Mexicano del Seguro Social and located in the metropolitan area of Mexico City (Zone General Hospitals numbers 8, 25, 27, and 47).

An initial screening was performed among the prevalent CAPD populations of the participating hospitals. Adult patients with diabetes mellitus with high and high-average peritoneal transport status were included without selection by gender, residual renal function, or time on dialysis. A simplified version of the peritoneal equilibration test (29) was performed within a month before randomization. The cutoff point for each category was as previously described in the Mexican population (30). Patients were excluded when seropositive for hepatitis B or HIV, if they had malignancies, or were receiving immunosuppressive medication. Patients that had had a peritonitis episode 1 month or less before being screened were also excluded. Twenty-three patients left the study before completing the scheduled follow-up for the following reasons: patient decision, medical decision, kidney transplant, or address change.

CLINICAL OUTCOMES
Primary outcomes were improvement in peritoneal UF, reduction of ECFv, and metabolic control. Secondary outcomes were hospitalizations and therapy-related complications.

CLINICAL AND BIOCHEMICAL ASSESSMENTS
Visits were scheduled every week during the first month and every month for the remaining 12 months. Clinical evaluations were done in each visit. Laboratory assessments were done at baseline, at weeks 2 and 4, and every month for hematological and glycated hemoglobin data, as well as glucose, urea, and creatinine levels in serum, urine, and peritoneal effluent. Serum samples were also analyzed for total cholesterol and triglycerides. Biochemical analyses were performed by standard methods (Synchron CX-5 analyzer; Beckman, Brea, CA, USA). Serum albumin and glycated hemoglobin levels were measured at baseline and at months 1 – 6, 9, and 12 by nephelometry (Array; Beckman). Body composition analyses were carried out at baseline, week 2, and every month by whole body multiple-frequency bioimpedance spectroscopy and body fluid compartments were derived with the software provided by the manufacturer (Biodynamics, Seattle, WA, USA) (31,32).

STATISTICAL ANALYSIS
Data are presented as mean and standard deviation for continuous variables and as proportions for categorical variables. ANOVA was used to analyze differences between groups in variables recorded repeatedly over time. Analysis of hospitalizations and peritonitis were made by Poisson models. Statistical analysis was made with SPSSw v14 (SPSS Inc., Chicago, IL, USA).


   RESULTS
TOP
 ABSTRACT
 MATERIAL AND METHODS
 RESULTS
DISCUSSION
 DISCLOSURE
 REFERENCES
 
BASELINE CHARACTERISTICS
Fifty-nine patients were randomized and received the treatment. The accrual time was 3 months (10 October 2004 to 1 January 2005): 30 patients were randomized to the ICO group and 29 to the GLU group. Follow-up was at least 12 months; the study was terminated on 2 February 2006. At baseline both groups were similar in all the analyzed variables (Table 1), including demographic and clinical characteristics, as well as comorbidities, laboratory measurements, and dialysis parameters.


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  		TABLE 1 Baseline Clinical Characteristics and Laboratory Measurements for the Two Groups

 

INTERVENTION EFFECTS
At baseline most patients were using at least two 2.5% glucose bags or one 4.25% glucose bag per day. During the first days of the study, patients followed the prescription required by protocol with subsequent adjustments to reach their goals. The actual prescription schedule over time is shown in Figure 1. In the control group, nearly two thirds of the patients needed more than one 2.5% glucose bag or at least one 4.25% glucose bag per day to reach the treatment target. In the ICO group, only 9% of the patients needed a daily bag with a glucose concentration higher than 1.5%. Figure 2 shows changes in peritoneal UF along the study period. Ultrafiltration remained higher in the ICO group than in the GLU group throughout the study.


Figure 1
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  		Figure 1 — Over time, patients using glucose-based dialysis solutions for the long dwell (GLU group) needed more frequent replacement of 1.5% glucose bags with bags with higher glucose concentrations: for 2.5% glucose, >50% of GLU group versus <10% of patients using icodextrin-based dialysis solutions (ICO group) (p < 0.01); for 4.25% glucose, >20% GLU group versus none in ICO group (p < 0.01). GLU > 1 bag 2.5% glucose: open squares on dashed line; ICO ≥ 1 bag 2.5% glucose: closed squares on dashed line; GLU ≥ 1 bag 4.25% glucose: open circles on solid line; ICO ≥ 1 bag 4.25% glucose: closed circles on solid line.

 

Figure 2
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  		Figure 2 — Ultrafiltration was higher in patients using icodextrin-based dialysis solutions for the long dwell (ICO group; closed circles) than in patients using glucose-based dialysis solutions (GLU group; open circles), even with more frequent use of solutions with glucose concentration higher than 1.5% in the latter group. Mean difference between groups over time was 197 mL/day (p < 0.006).

 
OUTCOMES
Changes in body weight and body fluids are shown in Figure 3. During the first days of the study, patients in the GLU group had increments in both body weight and ECFv, probably due to the change in dialysis regimen, which could seem weaker in comparison to the basal schedule, causing a temporary change in fluid control. Body weight remained stable in the ICO group throughout the study; in contrast, it increased progressively in the GLU group. Total body water (TBW) decreased in both groups but the change was more pronounced and faster in the ICO group. ECFv decreased significantly in the ICO group from the first week of treatment, whereas it remained unchanged in the control group (GLU). Reductions in TBW were more pronounced than those observed in ECFv, probably due to the reduction in intracellular water. It is known that end-stage renal disease patients, as well as those with primary malnutrition, show increments in intracellular water and in intracellular concentrations of sodium. In this condition, we attributed the difference between TBW and ECFv to a reduction in intracellular edema.


Figure 3
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  		Figure 3 — Significant changes were found in body composition and edema. Body weight is shown in panel A. Patients using glucose-based dialysis solutions for the long dwell (GLU group; open symbols) had significant increments over baseline. Changes in total body water (TBW; B: solid lines) and extracellular fluid volume (ECFv; dashed lines) are shown in panel B. A faster and deeper reduction in TBW was seen in patients using icodextrin-based dialysis solutions for the long dwell (ICO group; closed symbols) than in the GLU group. For ECFv, ICO patients had a significant and stable reduction from baseline values; ECFv remained unchanged from baseline values in GLU patients. *p < 0.05 GLU versus ICO; +p < 0.01 GLU versus ICO.

 
Systolic and diastolic BP decreased in the ICO group from soon after beginning treatment to the ninth month, after which BP differences from baseline were less pronounced [Figure 4(a)]. In the GLU group, systolic and diastolic BP remained essentially unchanged at the beginning of the study. For a brief period from month 5 to month 8, diastolic BP decreased, and from month 7 to month 8, systolic BP decreased. After that, diastolic BP returned to baseline and systolic BP had significant increments over the initial values. It is remarkable that the early changes in BP were in accordance with those observed in TBW and with ECFv in the ICO group (r = 0.32, p < 0.01). However, the changes in BP in the late follow-up period were inconsistent with the body fluid data. This finding suggests a mechanism of overhydration-independent hypertension due perhaps to stimulation of the renin–angiotensin system. Changes in antihypertensive therapy were consistent with the changes in BP [Figure 4(b)].


Figure 4
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  		Figure 4 — Systolic (solid lines) and diastolic (dashed lines) blood pressure (BP) values were significantly lower in the patients using icodextrin-based dialysis solutions for the long dwell (ICO group; closed symbols) throughout the study; *p < 0.05 GLU versus ICO; +p < 0.01 GLU versus ICO (A). In patients using glucose-based dialysis solutions for the long dwell (GLU group; open symbols), systolic BP rose at the end of follow-up. Changes in antihypertensive therapy resembled those seen in BP: *p < 0.05 ICO versus GLU; +p < 0.01 ICO versus GLU (B).

 
Soon after the beginning of the treatment, peritoneal clearances of small-size molecules increased in the ICO group. After month 6, both Kt/V and creatinine clearance returned to baseline (Figure 5). In the control group, Kt/V and creatinine clearance decreased significantly over time. In the ICO group, glomerular filtration rate (GFR; calculated as mean urea and creatinine renal clearance) and urine volume dropped from the initial values of the first week. This reduction was statistically significant compared to the control group, but GFR remained stable for the remainder of the study period [Figure 5(c)]. These changes were consistent with the reduction in body fluids.


Figure 5
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  		Figure 5 — Changes in small-size molecule peritoneal clearances increased from baseline after the beginning of follow-up in patients using icodextrin-based dialysis solutions for the long dwell (ICO group; closed circles), and were higher than in patients using glucose-based dialysis solutions (GLU group; open circles) throughout the follow-up [panel A for peritoneal Kt/V (pKt/V); panel B for peritoneal creatinine clearance (pCrCl)]. Changes in glomerular filtration rate (GFR) are shown in panel C. Patients in the ICO group had a significant and sustained decrease compared to patients in the GLU group. The effect was mainly during the first week of treatment and was related to contraction in extracellular fluid volume. *p < 0.05 GLU versus ICO; +p < 0.01 GLU versus ICO.

 

At baseline, values of metabolic control parameters were similar in both groups; two thirds of patients were using insulin. During the follow-up, insulin medication was individually reconsidered and adjusted according to fasting serum glucose values. Metabolic control was better in the ICO group, which presented lower glucose exposure and glucose absorption, than in the GLU group (Figure 6). Insulin requirements decreased significantly and progressively in the ICO group, whereas an inverse pattern was observed for the control group (Figure 6). Fasting serum glucose levels decreased over time in the ICO group and were statistically different from baseline after month 6 [Figure 7(a)], whereas glucose levels did not change in the control group. The changes in triglyceride levels were less consistent [Figure 7(b)] during the first 6 months; however, thereafter a divergent trend was observed, with triglyceride levels decreasing in the ICO group and increasing in the GLU group. This decrease in triglyceride levels in the ICO group after month 6 was parallel to the significant decrease in fasting serum glucose levels observed in the same group after month 6. Total cholesterol levels were similar in the two groups at baseline and remained statistically unchanged during the follow-up. Glycated hemoglobin rose in the control group and dropped in the ICO group [Figure 7(c)], with the changes being statistically significant from month 3 to the end of follow-up.


Figure 6
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  		Figure 6 — Significant reductions were seen in peritoneal glucose exposure (A), peritoneal glucose absorption (B), and insulin requirements (C) in patients using icodextrin-based dialysis solution for the long dwell (ICO; larger closed circles). GLU = patients using glucose-based dialysis solutions (smaller or open circles). +p < 0.01 GLU versus ICO; *p < 0.05 GLU versus ICO.

 

Figure 7
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  		Figure 7 — Reduced glucose load was associated with lower levels of fasting serum glucose (A), serum triglycerides (B), and glycated hemoglobin (Hb a1c) (C) in patients using icodextrin-based dialysis solution for the long dwell (ICO; closed circles). GLU = patients using glucose-based dialysis solutions (open circles). *p < 0.05 GLU versus ICO; +p < 0.01 GLU versus ICO.

 

The numbers of dropouts were 11 in the GLU group and 12 in the ICO group; the remaining patients completed the scheduled follow-up and were available for statistical evaluation. Adverse events related to fluid overload and metabolic control were more frequent in the GLU group compared to the ICO group (Table 2). There were no skin rashes, aseptic peritonitis, or allergic symptoms in the studied patients. Infectious peritonitis rates were similar in both groups. Overall causes of hospitalizations and days of hospitalization did not differ between the groups (Table 3).


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  		TABLE 2 More Frequent Adverse Events

 

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  		TABLE 3 Hospitalization/Days of Hospitalization as Events/Patient-Year Due to All Causes

 


   DISCUSSION
TOP
 ABSTRACT
 MATERIAL AND METHODS
 RESULTS
 DISCUSSION
DISCLOSURE
 REFERENCES
 
The data here presented suggest that ICO treatment is superior to GLU treatment, allowing for better metabolic control and improved ECFv control in diabetic patients on PD. This is probably the first randomized trial evaluating the effect of icodextrin versus glucose as osmotic agent for the long-dwell exchange in high and high-average transport diabetic patients treated with PD.

Since its introduction, ICO has proven its utility in UF management in PD patients. Icodextrin solution has been compared to GLU of different glucose concentrations and with different periods of follow-up. In most of these studies, ICO was superior to GLU in fluid removal, even in patients with high or high-average peritoneal transport status (21,23,33). Furthermore, ICO was more effective than the GLU with the highest glucose concentration (34) in improving UF in the long dwell exchange in patients on automated PD. The data presented here are consistent with published papers. The group using ICO exhibited higher UF volumes than the GLU group. With most of those studies, there was a by-design difference related to the treatment target. ICO has been previously compared to f ixed GLU prescriptions (21,25,34). In this study, as in the aforementioned study by Davies et al. (33), ICO was compared to the optimal PD schedule to achieve the treatment target of maintaining the patient without hypertension and edema. In the actual prescription for the GLU group, patients received one extra 2.5% glucose bag (more than 60% of the patients) or one 4.25% glucose bag (a third of the patients) instead of one or more of the 1.5% glucose bags. On the other hand, less than 10% of the patients in the ICO group needed replacement of 1.5% glucose solutions. Ultrafiltration declined equally in both groups over time. In the GLU group, the changes may have been due to increased glucose exposure but not so in the ICO group (35,36). Therefore, an alternative explanation for the ICO group is contraction in fluid compartments, as suggested by reduction in urine volume after initiation of ICO treatment (37).

Changes in TBW and ECFv were congruent with those in UF. A more effective fluid removal by ICO caused a larger and faster reduction in TBW and ECFv. Similar findings have been reported elsewhere (33).

Blood pressure had a paradoxical behavior. Systolic and diastolic values decreased until month 6 in the ICO group and followed the same trend as reductions in TBW and ECFv. After that, BP reductions were less significant in spite of reductions in fluid compartments. Increments in natriuretic peptides with the long-term use of ICO have been reported (38,39), suggesting that icodextrin metabolites may exert an oncotic effect and increase blood volume. We did not measure blood volume in order to support this hypothesis. An alternative explanation is excessive fluid removal beyond dry weight and a secondary activation of vasoactive hormones, as was found in intradialytic hypertension in hemodialysis patients (40,41). Unchanged BP values and late BP increments in the GLU group may be explained by the hemodynamic effects of hyperglycemia, such as increased heart rate and systolic volume (42).

Changes in UF may explain variations in some dialysis adequacy-related measurements. Peritoneal creatinine clearance and peritoneal Kt/V increased significantly, while urine volume and GFR decreased. Association of peritoneal removal of small-size molecules with convective diffusion has been previously reported (24,25,43). As UF increases, more effective removal of urea and creatinine is expected. Increments in UF and a secondary reduction in ECFv have been proposed to explain the drop in urine volume and residual renal function in patients treated with ICO (37). It is very likely that the initial decrease in GFR in the ICO group may be related to an initial excessive UF, as denoted by the accentuated parallel initial decrease in TBW in the ICO group, thereby leading to an initial dehydration in some patients. The fact that GFR remained stable thereafter in the ICO group would reinforce this hypothesis and its clinical importance.

Intuitively, the improvement in metabolic control associated with ICO treatment could be expected. However, controversial results have been published in noninterventional studies and in studies with small numbers of patients with respect to continuously monitored glucose values, fasting serum glucose levels, or other metabolic markers (44–47). Data from the present study showed a clear advantage of ICO in metabolic control. Peritoneal glucose exposure and peritoneal glucose absorption were reduced in the ICO group and, in spite of reduced needs for insulin, lower levels of fasting serum glucose and triglycerides could be demonstrated. In addition, glycated hemoglobin increased in the GLU group and decreased in the ICO group.

Fluid overload and metabolic control-related adverse events were seen less frequently in the ICO group, which is in accordance with the physical and biochemical findings. There were no differences in peritonitis rates between the groups. Some adverse events specifically related to ICO, such as skin reactions and noninfectious peritonitis (23), did not occur. The improved quality control in the manufacture of icodextrin by measuring peptidoglycan levels (48) may be one possible contributing factor.

In summary, icodextrin-based solutions may represent a significant advantage for the management of high and high-average transport diabetic patients treated with CAPD, as demonstrated in this randomized trial. Improvements in metabolic control, reduction of the burden of glucose exposure, and optimization of fluid management in these patients are important evidence of the clinical benefits of icodextrin for diabetic PD patients.


   DISCLOSURE
TOP
 ABSTRACT
 MATERIAL AND METHODS
 RESULTS
 DISCUSSION
 DISCLOSURE
REFERENCES
 
The sponsors did not participate in the study design, data collection, data analysis, data interpretation, or writing of this report. The authors did not have any kind of relationship, commercial or otherwise, with Baxter, S.A. de R.L., México. The authors are employees of the IMSS. The corresponding author had full access to all data and had final responsibility for submitting for publication.


   ACKNOWLEDGMENTS
 
We thank Baxter, S.A. de R.L., México (grant 2005/23-585), and Instituto Mexicano del Seguro Social (IMSS) for their financial support.

The authors also thank Ms. Susan Drier for her assistance in preparing the manuscript. Part of this paper was presented in abstract form at the 11th Congress of the ISPD.

Received 8 May 2008; accepted 17 November 2008.


   REFERENCES
TOP
 ABSTRACT
 MATERIAL AND METHODS
 RESULTS
 DISCUSSION
 DISCLOSURE
 REFERENCES
 

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