**6. Biological consideration of dialysis membrane**

Biological consideration of the dialysis membrane is often referred to biocompatibility. Since dialyzers are repeatedly used four hours a session, three times a week, even a small event that repeatedly would occur each time may cause undesired side effects such as chronic inflam‐ mation.

#### **6.1. Improvement of biocompatibility of the regenerated cellulosic membrane**

Up until 1970s, RC membrane dominated over the market, and it was gradually replaced by synthetic polymeric membranes. Transient leukopenia that is an abrupt decease of leukocytes occurs at 15 to 30 minutes after starting the treatment has been one of the best known bioincompatible events [22]. Reprocessing dialyzers was common in 1970's and since bioincompatible events were often found when a dialyzer was used for the first time, this was called the "first use syndrome" [23].

Craddock *et al.* reported that complement activation under the use of RC membrane induced transient accumulation of leukocytes in the blood vessels and in the lung [24]. As shown in section 2, RC has three hydroxyl groups in its backbone, and these hydroxyl groups have been realized to be closely related to undesired complement activation. Then acetate groups was introduced to the one, two, or all three of hydroxyl group(s) to produce cellulose acetate (CA), cellulose diacetate (CDA), and cellulose triacetate (CTA), respectively. Since these semisynthesized cellulosic membranes have not only better biocompatibility but also higher permeabilities for solutes and water transport, they are still on the market.

#### **6.2. Improvement of biocompatibility of synthetic polymeric membrane**

It is well known that the Glomerular basement membrane (GBM) in human kidney is nega‐ tively charged. Although AN-69® is also a negatively charged membrane, one must pay much attention for the use of this membrane because it may cause anaphylaxy shock soon after starting the treatment [25]. Strong negative charge (-70 mV) would activate Hageman (XII) factor to XIIa that eventually produces bradykinin from kininogen as a substrate. Under normal situation bradykinin may be deactivated by kininase II; however, if the patient takes angiotensin-converting enzyme (ACE) inhibitor, it deactivates kininase II. This would induce the cascade reaction with bradykinin, including NO generation, increased vascular permea‐ bility, expansion of blood vessels, suppressing blood pressure, and ending up with shock during the treatment. This is often called "negative charge syndrome" (NCS, Figure 14). Although all dialysis membranes are negatively charged, it is usually a contraindication to prescribe ACE inhibitor to a patient under the use of AN69®.

Figure 5-1. Mechanisms of negative charge syndrome (NCS) **Figure 14.** Mechanisms of negative charge syndrome (NCS).

#### **6.3. Surface improvement technique**

incompatible events were often found when a dialyzer was used for the first time, this was

Craddock *et al.* reported that complement activation under the use of RC membrane induced transient accumulation of leukocytes in the blood vessels and in the lung [24]. As shown in section 2, RC has three hydroxyl groups in its backbone, and these hydroxyl groups have been realized to be closely related to undesired complement activation. Then acetate groups was introduced to the one, two, or all three of hydroxyl group(s) to produce cellulose acetate (CA), cellulose diacetate (CDA), and cellulose triacetate (CTA), respectively. Since these semisynthesized cellulosic membranes have not only better biocompatibility but also higher

It is well known that the Glomerular basement membrane (GBM) in human kidney is nega‐ tively charged. Although AN-69® is also a negatively charged membrane, one must pay much attention for the use of this membrane because it may cause anaphylaxy shock soon after starting the treatment [25]. Strong negative charge (-70 mV) would activate Hageman (XII) factor to XIIa that eventually produces bradykinin from kininogen as a substrate. Under normal situation bradykinin may be deactivated by kininase II; however, if the patient takes angiotensin-converting enzyme (ACE) inhibitor, it deactivates kininase II. This would induce the cascade reaction with bradykinin, including NO generation, increased vascular permea‐ bility, expansion of blood vessels, suppressing blood pressure, and ending up with shock during the treatment. This is often called "negative charge syndrome" (NCS, Figure 14). Although all dialysis membranes are negatively charged, it is usually a contraindication to

permeabilities for solutes and water transport, they are still on the market.

**6.2. Improvement of biocompatibility of synthetic polymeric membrane**

prescribe ACE inhibitor to a patient under the use of AN69®.

*Contact of blood to the negative charged material*

XII XIIa

kininase II

**Figure 14.** Mechanisms of negative charge syndrome (NCS).

kallikrein

kininogen bradykinin

ACE inhibitor

*deactivation*

Figure 5-1. Mechanisms of negative charge syndrome (NCS)

Expansion of blood vessel Anaphylaxis syndrome

NO generation Increased vascular permeability

phospholipid

arachidonic acid

prostanoids

phospholipase

called the "first use syndrome" [23].

180 Updates in Hemodialysis

Hemophan® was developed by introducing a positively charged substance, diethylaminoethyl (DEAE), to RC membrane in order to improve its surface character (Membrana, Germany). Although only a limited amount of DEAE was introduced relative to entire amount of cellulose, complement activation was greatly suppressed. Hemophan®, however, adsorbed heparin, which induced blood coagulation. Because of this fact, the production of this membrane was ceased. Another trial was made by coating the membrane surface with vitamin E in order to make the RC membrane antioxydative (Terumo, Tokyo, Japan). Later, this technique was applied to PSf membrane and the commercial model is still available (Asahi Kasei Medical Co., Tokyo, Japan).

### **6.4. Membranes with polyvinylpyrrolidone**

PSf and the ones whose chemical structures are similar to PSf have the highest market share among all dialysis membranes. They usually include polyvinylpyrrolidone (PVP) as a hydrophilic agent since they are hydrophobic in nature. PVP was once used as a supplement of plasma in medicine. Anaphylaxy shock, however, was reported, the cause of which was strongly doubted to be the PVP included in the membrane. Then we performed the following clinical investigation by using dialyzers with PSf and the ones with PEPA membrane with different amount of PVP [11].

Figure 15. Time course of C3a change during 4 hr HD treatment The same PS dialyzers with PVP(+++) were used in the 1-st and last (7-th) weeks. The same FDY dialyzers with PVP(+) were used from **Figure 15.** Time course of C3a change during four hr treatment. The same PSf dialyzers with PVP(+++) were used in the 1-st and last (7-th) weeks. The same FDY dialyzers with PVP(+) were used from the 2nd to the 6th weeks.

th 2nd t th 6th k The time course of C3a concentration profile in clinical study is shown in Figure 15. PSf with PVP(+++) showed three times higher concentration 15 minutes after the start of treatment. The C3a elevation was slightly lower at the first use of PEPA with PVP(+) and the peak concen‐ trations were approximately halved or even less from the second to the fifth week. The peak concentration, however, returned back to three folds in the first use of PSf after five-week use of PEPA with PVP(+).

According to another clinical data shown in Figure 16, PSf with PVP(+++) showed highest C3a elevation, followed by PEPA with PVP(++), PVP(+), and PVP(-). The degree of C3a elevation was a function of amount of PVP included in the membrane regardless of the main material of the membrane.

Symbols are arranged in the chronological order from the top to the bottom. **Figure 16.** Time course of C3a change during four hr treatment in 1 patient. Symbols are arranged in the chronological order from the top to the bottom.

Figure 16. Time course of C3a change during 4 hr HD treatment in 1 patient

From these results, we learned that PVP may not be the best choice as a hydrophilic agent in terms of blood compatibility.
