**5. BPA in chronic kidney disease**

Several studies have reported the leaching of BPA from hemodialyzers. Haishima et al. [30] studied the amount of BPA released from different hemodialyzers composed of a combination of polycarbonate housing and cellulose acetate hollow-fibers, polycarbonate housing and polysulfone fibers, and polystyrene and polysulfone. Water and bovine serum were circulated at room temperature in the four different devices tested. The bovine serum was used as a stimulant for human blood circulating into hollow fibers during

BPA recovered ranged from 3.78 to 141.8 ng/module using water circulation and from 140.7 to 2090 ng/module when bovine serum was used. The highest values of BPA released corre-

Murakami et al. [31] reported a BPA concentration of 8.33 and 12.25 ng extracted from 10 mg of polysulfone and polyester polymer alloy (PEPA) hollow fibers. The fibers, taken from indi-

Fink [32] investigated BPA leaching from five different types of dialyzers and polyvinylchloride blood tubing. All the dialyzers were composed of either polycarbonate or polysulfone: polycarbonate housing and polysulfone-polyvinylpyrrolidone (PVP) blend membranes, PC housing and polyamide-polysulfone blend membrane, and polypropylene housing, polysulfone-PVP blend membrane. Different surface area range was investigated (from 1.3 to 1.8 m<sup>2</sup>

Dialysis was simulated using two different eluents: reverse osmotic water and 17.2% ethanol

In agreement with the study of Haishima et al., the highest levels were measured when 17.2% ethanol was used, ranging from 54.8 to 4299 ng/dialyzer. Using osmotic water as eluent, the

Additional factors influence the BPA released from dialyzers, like the type of dialyzer, surface area, and duration of dialysis session. Generally, large amount of BPA is released in long

The contribution of the PVC tubing to total BPA content in the eluates was negligible, and the

Krieter et al. [33] also reported release of BPA from three different high and low flux dialyz-

free sterile water was circulated through the blood and dialysate compartments at 37°C, and BPA was measured by ELISA method. The amount of BPA eluted was significantly different between dialyzers evaluated, with average levels from 140.8 ± 38.7 to 6.2 ± 2.5 ng/dialyzer. These results are in the range with those reported in other studies when using water as eluent. The highest BPA levels were eluted from the low-flux dialyzer with polysulfone membrane, and the lowest from the dialyzer with polyethersulfone (PES) membrane. A summary of data

**Table 2** summarizes the levels of BPA released by dialyzers and measured in different

) and with polycarbonate housing. BPA-

).

sponded to hemodialyzers consisting of PC housing and PS.

vidual dialyzers, were crushed and dissolved in hexane.

BPA levels measured span from 6.4 to 71.3 ng/dialyzer.

dialysis sessions or in dialyzer with high surface area.

levels found were below the limit of quantification.

ers with different surface area (from 1.3 to 1.7 m<sup>2</sup>

available from the literature is presented in **Table 2**.

hemodialysis.

80 Bisphenol A Exposure and Health Risks

[32].

fluids.

The large number of molecules that accumulate in chronic kidney disease (CKD) are responsible for the uremic symptoms and contribute to increasing comorbidities and mortality in patients undergoing extracorporeal blood purification.

Removal of uremic toxins then is accompanied by an improvement in the clinical situation. They have been classified from the EuTox in differ groups according to their size and molecular weight [34]. A first group of molecules, around 350 toxins, is composed of small uremic toxins with molecular weight below 500 Da. Another group is characterized by medium-size toxins with molecular weight between 500 and 5000 Da. A new, and important, group or uremic toxins are represented by molecules with high affinity for proteins (protein-bound uremic toxins), which hamper their clearance.

One of the best characterized class of protein-bound toxins is phenols and indoles, a metabolite of protein catabolism by intestinal bacteria that have been related to renal failure progression and vascular damage in CKD. Proteins and peptides coming from diet are degraded by proteases and peptidases to simple amino acids. Some part of those amino acids reach the colon and are degraded by intestinal bacteria. This degradation generates potentially toxic metabolites such as ammonium, amines, thiols, phenols, and indoles.

Bisphenol A contains phenolic rings with structural similarity to phenols. While the origin of the toxins differs, the metabolism and side effects of BPA may have common characteristics with phenols of intestinal origin. BPA is eliminated by the kidney, and increased blood levels have been observed in CKD. Like intestinal phenols, after glucuronization in the liver, BPA is rapidly eliminated by the kidneys with a half-life in blood of less than 2 hours after oral ingestion that generally results in low blood levels. On the contrary, patients with impaired renal function could have BPA accumulation due to the less urinary excretion.

The National Health and Nutrition Examination Survey 2003–2006 (NHANES III) observed in 2573 patients a decrease of urinary excretion of BPA with renal function impairment [35]. The meaning of these data is uncertain: low urinary BPA excretion may reflect low exposure to BPA (which would be desirable) or retention of BPA by kidney disease (which would not be desirable).

By contrast, increased serum BPA with decreasing renal function and higher levels in hemodialysis was observed in different studies, suggesting that BPA may accumulate in CKD [31–33].

Additionally, the fractions of protein-bound and free plasma BPA in the maintenance of dialysis patients are 74 ± 5 and 26 ± 5%, respectively [33]. Moreover, a tissue/blood partition coefficient of 1.4 for nonadipose tissues and 3.3 for fat tissues further compromises the dialyzability of BPA [36], implying a concentration gradient highly in favor of driving BPA from dialysate to patient's blood.

Besides the other environmental sources, patients with end-stage renal disease on hemodialysis are repeatedly exposed to BPA from components of the dialyzer, more specifically polycarbonate housings and some dialysis membranes, resulting in a higher BPA blood levels of ESRD patients than healthy subjects.

BPA is found in the housing (polycarbonate) and membranes of some commonly used dialyzers; in **Table 3**, a summary of BPA contents in different dialyzers available on the market is provided.

Dialyzer BPA content is variable and depends on the manufacturer. All housings made with polycarbonate contain BPA (as a starting material), while the BPA contents in the fibers are variable. Generally, polysulfone membrane contains BPA in different amounts depending on the dialyzer surface. Other membranes such as polyethersulfone, polyarylethersulfone, polyamide, and polymethyl methacrylate are "naturally" BPA free.

The amount of BPA released depends on the experimental conditions and is higher in dialyzers perfused with blood than when perfused with saline. This difference has been attributed to the effect of blood hydrophobic components such as lipids or lipoproteins to extract BPA from the medical devices. An additional source of uncertainty on the quantitative determination of BPA is the analytical method used for determination. The most sensitive analytical method is represented by HPLC coupled with mass spectroscopy. Recently, simple ELISA methods are available on the market for BPA determination in biological fluids.

BPA may leach into aqueous solutions due to hydrolysis of the ester bonds in BPA-based polymers. With respect to the clinical situation, blood and water may differ in their ability to leach BPA. However, Krieter et al. [33] showed that considerable amounts of BPA were eluted from dialyzers with polysulfone membranes in 180 min of simulating (*in vitro*) dialysis conditions


with phenols of intestinal origin. BPA is eliminated by the kidney, and increased blood levels have been observed in CKD. Like intestinal phenols, after glucuronization in the liver, BPA is rapidly eliminated by the kidneys with a half-life in blood of less than 2 hours after oral inges

tion that generally results in low blood levels. On the contrary, patients with impaired renal

The National Health and Nutrition Examination Survey 2003–2006 (NHANES III) observed in 2573 patients a decrease of urinary excretion of BPA with renal function impairment [35]. The meaning of these data is uncertain: low urinary BPA excretion may reflect low exposure to BPA (which would be desirable) or retention of BPA by kidney disease (which would not

By contrast, increased serum BPA with decreasing renal function and higher levels in hemodi

Additionally, the fractions of protein-bound and free plasma BPA in the maintenance of dial

ysis patients are 74 ± 5 and 26 ± 5%, respectively [33]. Moreover, a tissue/blood partition coeffi

Besides the other environmental sources, patients with end-stage renal disease on hemodialy

sis are repeatedly exposed to BPA from components of the dialyzer, more specifically poly

BPA is found in the housing (polycarbonate) and membranes of some commonly used dialyz

Dialyzer BPA content is variable and depends on the manufacturer. All housings made with polycarbonate contain BPA (as a starting material), while the BPA contents in the fibers are variable. Generally, polysulfone membrane contains BPA in different amounts depending on the dialyzer surface. Other membranes such as polyethersulfone, polyarylethersulfone, poly

The amount of BPA released depends on the experimental conditions and is higher in dialyz

ers perfused with blood than when perfused with saline. This difference has been attributed to the effect of blood hydrophobic components such as lipids or lipoproteins to extract BPA from the medical devices. An additional source of uncertainty on the quantitative determina

tion of BPA is the analytical method used for determination. The most sensitive analytical method is represented by HPLC coupled with mass spectroscopy. Recently, simple ELISA

BPA may leach into aqueous solutions due to hydrolysis of the ester bonds in BPA-based poly

mers. With respect to the clinical situation, blood and water may differ in their ability to leach BPA. However, Krieter et al. [33] showed that considerable amounts of BPA were eluted from dialyzers with polysulfone membranes in 180 min of simulating (*in vitro*) dialysis conditions

methods are available on the market for BPA determination in biological fluids.

amide, and polymethyl methacrylate are "naturally" BPA free.

**3**, a summary of BPA contents in different dialyzers available on the market is

carbonate housings and some dialysis membranes, resulting in a higher BPA blood levels of

cient of 1.4 for nonadipose tissues and 3.3 for fat tissues further compromises the dialyzability of BPA [36], implying a concentration gradient highly in favor of driving BPA from dialysate

alysis was observed in different studies, suggesting that BPA may accumulate in CKD [31

function could have BPA accumulation due to the less urinary excretion.

be desirable).

82 Bisphenol A Exposure and Health Risks

to patient's blood.

ers; in **Table**

provided.

ESRD patients than healthy subjects.












–33].

**Table 3.**

Summary of BPA contents in different dialyzers available on the market.

with sterile water at body temperature. Previous studies had already shown that different polysulfone membranes leach varying amounts of BPA [31–37]. Obviously, this is also true for polysulfone membranes from the same manufacturer, indicating variations in different polysulfone lots or different extraction processes during fiber spinning. Additionally, a different amount of BPA is eluted from low-flux polysulfone membranes compared with highflux polysulfone membranes. This difference, higher in HF membranes, may be attributed to a higher polymer content; usually less permeable low-flux membranes have a tighter wall structure compared with high-flux membranes. Since BPA is not a starting material of polyethersulfone membranes, the very small amounts of BPA eluted from this dialyzer most likely originate, in some cases, from the polycarbonate housing. Moreover, Krieter in his study also found that no differences in BPA levels were determined between the blood and dialysate compartments. This was because the unbound BPA can easily pass the dialysis membrane and equilibrate during recirculation. In vitro experiment suggests that dialyzers differing in elutable BPA used during chronic hemodialysis would have an impact on plasma BPA levels.

Recently, Bosch-Panadero et al. [38] performed a cross-over study to evaluate the impact of the dialyzer choice (BPA-free versus BPA-containing) on serum and intracellular BPA levels and on inflammation and oxidative stress markers in a group of 69 prevalent patients on hemodialysis.

The main finding of this study was that the choice of dialyzer in terms of BPA content impacts on acute (after a single dialysis session) and chronic (after 3 months of continuous use of the same type of dialyzer) changes in serum BPA levels. This reinforces the hypothesis of Krieter et al. that dialyzer BPA content may contribute to BPA burden in patients on hemodialysis.

The expression of oxidative stress markers was significantly higher after 3 months of hemodialysis with BPA-containing membranes with respect to BPA-free dialyzers. Three months of hemodialysis with BPA-containing membranes increased significantly circulating C-reactive protein (CRP) and IL-6 with respect to BPA-free dialyzers. These patients are more sensitive to BPA accumulation and potential toxicity due to the loss of the physiologic BPA excretion mechanisms in urine. In this same work, authors indicated that the serum BPA levels were 35-fold higher in patients on hemodialysis than in healthy controls confirming that serum BPA levels increased with decreasing renal function and are highest in individuals on hemodialysis.

A particular group of hemodialysis patients are those with diabetes. Recently, in a cross-over study, values of serum BPA have been measured in a group of 47 patients in which 12 had diabetes [39]. All patients were treated with low-flux polysulfone dialyzers.

In this study, postdialysis serum levels of BPA were significantly higher than predialysis levels. Additionally, diabetic patients showed higher predialytic BPA levels compared with those without diabetes. This difference disappeared for postdialysis measurement.

Unfortunately, no association was found between serum BPA levels and age, body mass index, dialytic vintage, blood pressure, and other medical parameters, probably due to the small number of subject investigated.

Up to now, we analyzed the dialyzer contribution to BPA in the blood of hemodialyzed patients, but recently, Bacle et al. [40] evaluated the potential exposure to BPA via the entire process of hemodialysis treatment, from production of purified water to dialysate and dialyzers. In their work, they could confirm that no BPA leaching is observed from bloodlines, confirming the information provided by the European PVC manufacturers who no longer use BPA in polyvinylchloride (PVC) production. At the same time, no leaching was observed from rinsing bags (0.9% sodium chloride), but larger amounts of BPA were found in dialyzers based on polysulfone and polycarbonate, as described by other authors and confirming the hypothesis that the dialyzers used during hemodialysis treatment may expose patients to a significant amount of BPA.

Concerning the water purification process, BPA has been detected in over 90% of collected samples, with significant amounts of BPA found after each step of the water treatment process. This suggests that none of the different processes applied in water purification is able to totally remove BPA. An additional source of BPA contamination already found in water of BPA could come from dialysis machine and dialysate cartridges, slightly increasing the BPA content in the dialysate.

In **Table 4**, a summary of selected study cited with the number of patients evaluated as well as BPA concentration in the serum samples is reported. Up to now, information provided by scientific literature on specific hemodialyzed population is scarce. Nevertheless, all studies reported showed an increase of BPA serum concentration in patients treated with BPAcontaining dialyzers.


**Table 4.** Levels of BPA measured in serum samples reported in the literature.
