Do We Have a Biocompatible Peritoneal Dialysis Fluid?

doi:10.4236/ojneph.2012.23005

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Open Journal of Nephrology, 2012, 2, 29-34

http://dx.doi.org/10.4236/ojneph.2012.23005 Published Online September 2012 (http://www.SciRP.org/journal/ojneph)

Do We Have a Biocompatible Peritoneal Dialysis Fluid?

Shadi Hassan1, Batya Kristal2,3, Khalid Khazim3, Fadi Hassan4, Dunia Hassan5, Kamal Hassan2,3

1Internal Medicine Department, Carmel Medical Center, Haifa, Israel

2Faculty of Medicine in the Galilee, Bar-Ilan University, Safed, Israel

3Nephrology and Hypertension Department, Western Galilee Hospital, Nahariya, Israel

4Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

5The Ruth and Bruce Faculty of Medicine, Technion Israel Institute of Technology, Haifa, Israel

Email: [email protected], [email protected]

Received April 21, 2012; revised June 7, 2012; accepted June 21, 2012

ABSTRACT

Objective: Cardiovascular disease remains the leading cause of morbidity and mortality in patients on maintenance

dialysis. Diabetes mellitus, dyslipidemia, hypertension, inflammation and hyperhomocyteinemia are major cardiovas-

cular risk factors. Aim: To evaluate the effects of Icodextrin and amino acid peritoneal dialysis fluid (AAPDF) on these

major cardiovascular risk factors looking for a more biocompatible PDF formula. Methods: 20 adult stable peritoneal

dialysis patients were included in the study. 10 patients received 2 L Icodextrin and other 10 patients received 2 L

AAPDF in their dialysis prescription for 8 weeks. Results: Icodextrin decreased fasting plasma glucose (p < 0.001),

LDL-C (p = 0.03), SBP (p < 0.01), DBP (p < 0.05) and plasma homocysteine (p = 0.002), and increased HDL-C (p =

0.009), CRP (p = 0.035) and fibrinogen (p = 0.009). AAPDF did not affect fasting plasma glucose, LDL-C, HDL-C,

CRP and fibrinogen but increased serum albumin (p = 0.03), SBP (p < 0.01), DBP (p < 0.05) and PHcy (p = 0.03).

Conclusions: A biocompatible PDF should provide not only adequate dialysis and ultrafiltration but should also

improve nutritional and metabolic status, blood pressure control and reduce inflammation and plasma homocyteine.

Keywords: Icodextrin; Amino Acids PDF; Homocyteine; Carbohydrates; Lipids; Inflammation

1. Introduction

Cardiovascular disease (CVD) remains the leading cause

of morbidity and mortality in end-stage renal disease

patients on maintenance dialysis [1]. Diabetes mellitus,

dyslipidemia, hypertension, inflammation and hyperho-

mocyteinemia are major cardiovascular risk factors. Re-

cent studies have suggested that novel risk factors, ure-

mia or dialysis-related, are of great importance, as they

act synergistically with the highly prevalent traditional

risk factors for CVD in chronic kidney disease (CKD)

patients [2]. Glucose based peritoneal dialysis fluids

(PDFs) are usually associated with progressive loss of

the osmotic gradient, concomitant reduction in ultrafil-

tration (UF) and to the development of hyperglycemia

and dyslipidemia. Dyslipidemia increases the risk of

CVD and becomes worse in peritoneal dialysis (PD) pa-

tients [3]. Up to 80% of peritoneal dialysis patients are

hypertensive [4]. Hypertension plays an important role in

the development of CVD in this population [4]. Elevated

plasma inflammation markers associated with increased

risk for CVD [5]. Almost all (97% - 98%) PD and hemo-

dialysis patients have hyperhomocyteinemia that known

to be associated with an increased risk of cardiovascular,

cerebrovascular and venous thromboembolic diseases

[6-8]. Icodextrin and Amino acid PDF (AAPDF) consid-

ered more biocompatible PDFs. Icodextrin PDF is tar-

geted to have more sustained oncotic effect, to reduce

plasma glucose and glucose-induced lipid abnormalities,

and to avoid the production of glucose degradation

products (GDPs) [9,10]. Generally, there is some concern

that Icodextrin treatment may induce a subclinical in-

flammatory response, both intraperitoneally and sys-

temically [10-12]. AAPDF was designed to correct nu-

triational status by supplying extra nitrogen through the

intraperitoneal route [13]. Although the effects of Ico-

dextrin and AAPDF on metabolic status, blood pressure

control, inflammation and plasma homocyteine were

studied but some issues still controversial. Aim of this

study was to evaluate the effects of Icodextrin and

AAPDF on these major cardiovascular risk factors.

2. Patients and Methods

Randomly, 20 adult stable PD patients on continuous

ambulatory peritoneal dialysis (CAPD) or automated

Peritoneal Dialysis (APD) for at least 3 months and with

Kt/V > 1.8 were included in the study. Demographic and

clinical characteristics of the enrolled subjects are listed

in Table 1. The study protocol was approved by the local

S. HASSAN ET AL.

Ethics Committee and all patients gave written informed

consent before participating in the study. The patients

randomly assigned to receive Icodextrin or AAPDF. Ten

patients received 2 L Icodextrin in their dialysis prescrip-

tion for 8 weeks, the night dwells in CAPD subjects were

substituted with 2 L Icodextrin and in APD subjects 2 L

from their regular regimen were substituted with 2 L

Icodextrin given as last fill. Ten patients received 2 L

AAPDF in their dialysis prescription for 8 weeks, the

second dwells in CAPD subjects were substituted with 2

L AAPDF and in APD subjects 2 L from their regular

regimen were substituted with 2 L AAPDF given at noon.

The residual renal function (RRF) was estimated by

mean urea and creatinine clearance (CUC) and by the

Modification of Diet in Renal Disease (MDRD) equation

study [14]. At baseline the standard peritoneal equilibra-

tion test (PET) [15], and estimation of Kt/V were perfor-

med using PD-Adequest 2.0 for Windows program

(Baxter Healthcare Co., Deerfield, IL) [16]. Blood, urine

and dialysate analysis were performed in both groups at

baseline and 8 weeks. Blood analysis included complete

blood count (CBC), glucose, low density lipoprotein

cholesterol (LDL-C), high density lipoprotein cholesterol

(HDL-C), triglycerides, albumin, CRP, fibrinogen, plasma

homocysteine (PHcy), folic acid, vitamin B12, and PTH.

Urine analysis included 24-hour urinary collections for

creatinine (mg/dl) (UCr) and urea (mg/dl) (UUrea). Dialy-

sate analysis included creatinine (mg/dl) (DCr) and glucose

(mg/dl) (DGlu). Daily urinary output (ml/day) (DUO),

PET and Kt/V were also evaluated at baseline and 8

weeks. PHcy was determined using AxSYM Homocysteine

Table 1. Characteristics of the study population.

Icodextrin group AAPDFa group

Number 10 10

Age (years) 61.3 ± 11.9 59.6 ± 20.0

Male/female 5/5 5/5

CAPDb/APDc 5/5 5/5

Dialysis duration (months) 29.2 ± 33.6 28.8 ± 17.3

PETd: HATse/LATsf 5/5 5/5

Kt/V 2.41 ± 0.4 2.39 ± 0.4

Vitamin B12 (pg/ml)

(Normal:160 - 680) 598.3 ± 280.3 610.9 ± 330.5

Folic acid (ng/mL)

(Normal:150 - 700) 760.0 ± 385.0 771.2 ± 318.1

PTH (pg/ml) (normal:10 - 60) 313 ± 185 301 ± 158

Underlying cause:

Diabetes mellitus 5 5

Primary hyperoxaluria type 1 2 2

APKDg 1 1

Unknown 2

a: Amino Acid Peritoneal Dialysis Fluid; b: Continuous ambulatory perito-

neal dialysis; c: Automated peritoneal dialysis; d: Peritoneal equilibration test;

e: High average transporters; f: Low average transporters; g: Adult Polycys-

tic Kidney Disease.

assay (Produced by Axis-Shied, Dundee, UK for Abbott

laboratories, Abbott park, IL 60064, USA). Statistical

methods: Qualitative variables were described as incide-

nces and percentages. Quantitative variables were descri-

bed as means and standard deviations. Repeated Measures

tests were used to evaluate the effects of Icodextrin and

AAPDF on RRF, DUO, UF, D/PCr, DGlu, DCr, fasting

glucose, plasma lipids, plasma inflammation markers,

body weight, blood pressure and PHcy. Repeated Measures

tests were also used to evaluate the effects of PD

modality, peritoneal membrane characteristics, Kt/V, ge-

nder, cause of CKD and hemoglobin on PHcy. Linear

regression was used to evaluate the correlation between

PHcy and RRF, DUO, PD duration, age, body weight,

PTH and hemoglobin levels. Linear regression was also

used to evaluate the correlation between degree of incre-

ment in UF (∆Net UF) and the degree of reduction in PHcy

(∆PHcy) as well as between the degree of increment in

D/PCr (∆D/PCr ) and ∆PHcy.

3. Results

Repeated measures analysis revealed that Icodextrin and

AAPDF did not affect the RRF or DUO (Table 2). No

linear correlation was found between the RRF and PHcy.

Icodextrin increased UF (p = 0.003) and D/PCr (p < 0.001)

(Table 2). Icodextrin, as well AAPDF decreased DGlu (p

= 0.02) (Table 2).

Table 2. Effects of Icodextrin and AAPDF on RRF, DUO,

UF, D/PCr and DGlu.

Icodextrin group

Baseline 8 Weeks p

PHcy (µmol/L) 29.1 ± 21.8 14.8 ± 5.3 0.002

CUC (ml/min/1.73m2) 10.1 ± 2.3 9.5 ± 2.9 n.s.

eGFRMDRD

(ml/min/1.73m2) 8.3 ± 2.4 8.1 ± 2.0 n.s.

DUO (L/day) 0.8 ± 0.4 0.75 ± 0.3 n.s.

UF (L/day) 0.98 ± 0.1 1.22 ± 1.3 0.003

D/PCr 0.54 ± 0.1 0.79 ± 0.1 <0.001

DGlu (mg/dl) 1035.8 ± 438.1 901.8 ± 354.90.016

AAPDF group

Baseline 8 weeks p

PHcya (µmol/L) 26.6 ± 17.0 36.4 ± 15.6 0.03

CUCb (ml/min/1.73m2) 10.2 ± 3.7 9.7 ± 3.3 n.s.

eGFRMDRDc

(ml/min/1.73m2) 8.1 ± 2.3 8.0 ± 2.0 n.s.

DUOd (L/day) 0.7 ± 0.3 0.6 ± 0.4 n.s.

UFe (L/day) 0.99 ± 0.2 0.97 ± 0.2 n.s.

D/PCrf 0.64 ± 0.1 0.61 ± 0.2 n.s.

DGlug (mg/dl) 981.4 ± 446.8 854.5 ± 435.50.02

a: Plasma homocysteine; b: Mean urea and creatinine clearance; c: estimated

GFR using the Modification of Diet in Renal Disease equation study; d:

Daily Urinary Output; e: Ultrafiltration, f: Dialysate creatinine/plasma creat-

inine; g: Dialysate glucose level.

S. HASSAN ET AL. 31

The basal levels of HbA1C in the two study groups

were similar (4.9% ± 0.7% in Icodextrin group and 5.1%

± 1.5% in AAPDF group). Icodextrin decreased fasting

glucose (p < 0.001), LDL-C (p = 0.03) and triglycerides

(p = 0.04), and increased HDL-C levels (p = 0.009)

(Table 3). AAPDF did not affect glucose and lipid

metabolism (Table 3).

Basal levels of inflammation markers were similar in

both study groups. Basal serum CRP and fibrinogen

levels were elevated in both study groups. Compared to

AAPDF, Icodextrin increased serum CRP (p = 0.035) and

fibrinogen levels (p = 0.009) (Table 3). AAPDF, in con-

trast to Icodextrin, increased serum albumin (p = 0.03)

(Table 3). Icodextrin decreased body weight (p=0.002),

SBP (p < 0.01) and DBP (p < 0.05) while AAPDF incre-

ased body weight (p = 0.002), SBP (p < 0.01) and DBP

(p < 0.05) (Table 3).

Table 3. Effects of Icodextrin and AAPDF on carbohydrates,

lipids, inflammation and blood pressure.

Icodextrin group

Baseline 8 weeks p

Fasting glucose (mg/dl) 141.1 ± 39.9 119.3 ± 29.1 <0.00

LDL-C (mg/dl) 102.3 ± 33.3 89.6 ± 22.0 0.03

HDL-C (mg/dl) 35.6 ± 10.1 40.7 ± 11.8 0.009

TG (mg/dl) 272.4 ± 67.0 221.4 ± 74.8 0.04

Albumin(gr/dl) 3.6 ± 0.4 3.6 ± 0.3 n.s.

CRP (0 - 5 mg/L) 9.5 ± 6.5 22.4 ± 16.5 0.035

Fibrinogen

(200 - 400 mg/dl) 835.1 ± 126.5 1066.1 ± 199.80.009

Body weight (kg) 80.4 ± 14.1 78.5 ± 14.7 0.002

SBP (mmHg) 149.5 ± 35.5 131.4 ± 21.9 <0.01

DBP (mmHg) 79.0 ± 14.5 72.8 ± 9.9 <0.05

AAPDF group

Baseline 8 weeks p

Fasting glucose (mg/dl) 138.4 ± 76.2 142.2 ± 86.6 n.s.

LDL-Ca (mg/dl) 117.6 ± 25.9 112.97 ± 21.1n.s.

HDL-Cb (mg/dl) 42.0 ± 9.4 45.0 ± 11.6 n.s.

TGc (mg/dl) 186.4 ± 96.6 176.3 ± 62.7 n.s.

Albumin (gr/dl) 3.5 ± 0.4 4.3 ± 0.5 0.03

CRP (0 - 5 mg/L) 12.6 ± 26.0 10.4 ± 18.3 n.s.

Fibrinogen

(200 - 400 mg/dl) 999.6 ± 189.6 973.0 ± 231.4n.s.

Body weight (kg) 71.6 ± 15.0 72.5 ± 15.0 0.002

SBPd (mmHg) 138.7 ± 28.4 146.6 ± 26.4 <0.01

DBPe (mmHg) 75.4 ± 12.3 80.1 ± 11.8 <0.05

a: Low density lipoprotein cholesterol; b: High density lipoprotein cholest-

erol; c: Triglycerides; d: Systolic blood pressure; e: Diastolic blood pressure.

Hyperhomocysteinemia was identified in 84% of the

study subjects at baseline. Icodextrin decreased PHcy (p =

0.002) (Table 2). AAPDF increased PHcy (p = 0.03) (Table

2). Furthermore, in Icodextrin group, a linear corre-

lation was found between the degree of increment in UF

(∆UF) and the degree of reduction in PHcy (∆PHcy) (p <

0.001, R2 = 0.962) (Figure 1), and between the degree of

increment in D/PCr (∆D/PCr) and ∆PHcy (p < 0.001, R2 =

0.836) (Figure 2).

Icodextrin decreased PHcy in both CAPD and APD

patients (p = 0.033), in low average transporter patients

(LATs) (p = 0.006), in PD patients with Kt/V > 2 (p =

0.04) or Kt/V ≤ 2 (p = 0.003) and in non diabetic patients

(p = 0.039) (Table 4). LATs had a higher basal PHcy

compared with high-average transporter patients (HATs)

(p = 0.015) (Table 4). HATs had lower PHcy which were

in the upper normal limits (Table 4).

Figure 1. The correlation between ∆PHcy and ∆Net UF in the

extraneal group.

Figure 2. The correlation between ∆PHcy and ∆D/PCr in the

extraneal group.

S. HASSAN ET AL.

Table 4. Effects of PDa modality, peritoneal membrane

characteristics, Kt/V, gender and diabetes mellitus on PHcy.

PHcyb (µmol/L) in Icodextrin group

Baseline 8 weeks p

CAPDc 33.0 ± 26.3 14.7 ± 6.2 0.033

APDd 24.3 ± 17.0 14.8 ± 5.0 0.033

p n.s.

LATse 46.4 ± 23.2 17.2 ± 5.3 0.006

HATsf 15.3 ± 3.0 12.8 ± 5.1 n.s.

P 0.015

Kt/V ≤ 2 46.9 ± 32.5 19.5 ± 2.7 0.003

Kt/V > 2 20.2 ± 7.3 15.9 ± 6.2 0.04

p 0.05

DMg 24.5 ± 7.9 17.0 ± 7.4 n.s.

Non DM 31.4 ± 6.7 13.7 ± 4.4 0.039

p n.s.

PHcy (µmol/L) in AAPDF group

Baseline 8 weeks p

CAPD 26.72 ± 7.2 33.6 ± 15.7 n.s.

APD 26.52 ± 24.5 31.12 ± 34.9 n.s.

p n.s.

LATs 37.5 ± 18.8 48.5 ± 28.5 n.s.

HATs 15.8 ± 2.1 16.2 ± 3.1 n.s.

p 0.015

Kt/V ≤ 2 32.3 ± 25.5 38.5 ± 36.6 n.s.

Kt/V > 2 22.8 ± 9.4 28.3 ± 17.9 n.s.

p 0.05

DM 28.7 ± 5.1 37.0 ± 3.9 n.s.

Non DM 30.0 ± 19.5 38.9 ± 28.4 n.s.

p n.s.

a: Peritoneal dialysis; b: Plasma homocysteine; c: Continuous ambulatory

peritoneal dialysis; d: Automated peritoneal dialysis, HATs = High average

transporters; e: Low average transporters; f: High average transporters; g:

Diabetes mellitus.

AAPDF increased PHcy (p = 0.03) (Table 2).

Linear regression analysis did not show any correla-

tion between PHcy and age, gender, body weight, duration

of PD, DUO, hemoglobin and PTH levels in both Icode-

xtrin and AAPDF groups.

4. Discussion

Long-term systemic exposure of glucose caused by con-

ventional PD solutions has been well recognized to cause

metabolic and cardiovascular abnormalities, which con-

tribute to the morbidities seen in PD patients. Several

studies have shown that conventional solutions damage

mesothelial cells and peritoneal blood vessels leading to

functional impairment [17,18]. Besides its effects on the

peritoneal membrane, rapid absorption of glucose during

a dwell leads to loss of osmotic gradient and diminished

ultrafiltration as well as to the development of hypergly-

cemia and associated hyperinsulinemia in both diabetic

as well as nondiabetic patients [19]. The high levels of

dextrose and the lactate acidic buffer make the conven-

tional solutions nonphysiologic and nonbiocompatible.

Introducing the newer solutions that designed to be more

biocompatible by either, containing physiologic buffer

bicarbonate, or having lower GDP concentration, and/or

substituting glucose with alternative osmotic agents, like

polyglucose or amino acids were targeted to ameliorate

the complications of conventional dextrose solutions

[20-22]. It is postulated that newer PD solutions contain-

ing lower levels of GDPs are less nephrotoxic, and hence

may preserve RRF longer. Additionally, the effect of

fluid status on preservation of RRF cannot be ignored.

In the present study, Icodextrin and AAPDF did not

affect RRF (Table 2). Icodextrin improved glucose con-

trol and lipid profile including significant decrease in

LDL-C and triglyceride levels as well as significant in-

crease in HDL-C (Table 3). Similar results were reported

by Bredie et al. [23].

It is well known that the major reason for the elevation

of blood pressure in PD patients is volume overload.

Icodextrin improved blood pressure control by improving

UF and decreasing body weight (Tables 2 and 3).

The effects of Icodextrin on inflammation status in PD

patients are controversial [11,12]. Martikainen et al.

showed that Icodextrin use was resulted in subclinical

inflammatory response [11]. In contrast, Lin et al. re-

ported that Icodextrin decreased CRP [12]. In this study

the basal serum CRP and fibrinogen levels were similar

and elevated in both study groups (Table 3). Icodextrin

use was accompanied by a rise in plasma CRP and fi-

brinogen levels (Table 3). There is a concern that Ico-

dextrin use may induce a subclinical inflammatory re-

sponse, both intraperitoneally and systemically. Accord-

ingly, Icodextrin that lowered GDPs levels and designed

to preserve the peritoneal membrane and to improve

glucose and lipid control, seems to intensify systemic

inflammation.

Hyperhomocysteinemia was identified in 84% of our

study subjects compared to the 97% - 98% reported by

Van Guldener [24]. The significant rise in D/PCr and UF

as well as the linear correlations between ∆PHcy and

∆NetUF, and between ∆PHcy and ∆D/PCr in the Icodextrin

group, suggest better peritoneal clearances of Hcy com-

pared to standard glucose-based fluids and AAPDF (Ta-

ble 2, Figures 1 and 2). Similar results were reported by

Czupryniak et al. [25].

It is well known that AAPDF improve nutritional

status in malnourished PD patients. Although increased

serum albumin levels and did not affect UF, glucose and

lipid metabolism, and inflammation status, AAPDF in-

creased body weight, SBP, DBP and PHcy levels (p =

S. HASSAN ET AL. 33

0.002, p < 0.01, p < 0.05, p = 0.03—respectively) (Ta-

bles 2 and 3). The increase in PHcy in the AAPDF group

is, most likely, related to methionine, a precursor of Hcy,

absorption as well as to the decrease in D/PCr and UF in

the AAPDF group (Table 2). Then, AAPDF that intro-

duced to improve nutritional status and survival may

contribute to the unfavorable rise of PHcy. The rise in PHcy

in PD patients treated with AAPDF described also in

previous studies [26,27].

End stage renal disease patients are unable to excrete

the daily acid load. The standard PDFs, Icodextrin and

AAPDF use lactate as a buffer that, by its acidic pH,

causes harmful effects on the peritoneal cells [17]. In

contrast, bicarbonate-based PDFs include a physiologic

buffer with neutral pH, cause less peritoneal damage [28].

The relationships between the PD modality, the peri-

toneal membrane characteristics and Kt/V, and PHcy re-

main a controversial issue [29,30]. Basal PHcy was elevated

and not different in the two study groups and all sub-

groups apart from HATs (Table 4). In the Icodextrin

group PHcy decreased in both PD modalities (p = 0.033)

(Table 3). On the other hand, AAPDF increase PHcy (p =

0.033) (Table 2). This may be due to its low osmotic

drive and as a result of the absorption of methionine

through the peritoneal membrane. These results suggest

that the peritoneal membrane characteristics and the

composition of the PDF have an important role in the

peritoneal elimination of Hcy.

Basal PHcy in HATs were near normal in both study

groups (Table 4). It may be related to the higher solute

clearances across the peritoneal membrane in HATs.

Basal PHcy was marginally lower in subjects with Kt/V

> 2 compared to those with Kt/V ≤ 2 (p = 0.05) (Table 4).

Icodextrin, but not AAPDF, significantly decreased PHcy

in PD patients with Kt/V > 2, in those with Kt/V ≤ 2 and

in non diabetic patients (Table 4). Therefore, Icodextrin

may influence the atherosclerotic outcomes through

Hcy-lowering effects, as it was stated previously by Do-

cloux et al [29].

No associations between age, gender, body weight, du-

ration of PD, hemoglobin, PTH, RRF and DUO and PHcy

were found.

In summary: Higher UF, higher D/PCr, HATs, Kt/V >

2, non diabetic patients and Icodextrin use were associ-

ated with decline in PHcy. Conversely, lower UF, lower

D/PCr, LATs, Kt/V ≤ 2, diabetic patients and AAPDF use

were associated with rise in PHcy.

Although it exhibited favorable effects on metabolic

status, blood pressure control and PHcy levels, Icodextrin

seems to intensify systemic inflammation. On the other

hand, although it did not seem to affect adversely the

metabolic status and systemic inflammation, AAPDF

increased PHcy and blood pressure.

The results of the present study suggested that the use

of Icodextrin and AAPDF was associated with beneficial

effects as well as with considerable harmful consequences

that may adversely affect the prognosis and survival of

PD patients.

5. Conclusion

A new PDF containing a mixture of a biocompatible sub-

stance, amino acids without methionine, lower glucose

and GDPs content, and neutral pH will provide sustained

oncotic effect, adequate dialysis and ultrafiltration as

well as will improve nutritional status and metabolic

profile, reduce inflammation, plasma homocyteine and

blood pressure. A PDF with those properties will preserve

the peritoneal membrane and improve the prognosis and

survival of peritoneal dialysis patients.

6. Acknowledgements

The authors would like to thank Prof. Ben Ami Sela,

Clinical Biochemistry Laboratory-Sheba Medical Center,

Tel Hashomer, Israel for his assistance in determination

of PHcy. We also would like to thank Tobie Kuritsky for

her assistance in editing our manuscript.

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