Clinical consequences of hemodialysis membrane biocompatibility

INTRODUCTION — Interaction of the dialysis membrane with the components of blood has the potential to induce an inflammatory response and to lead to numerous long-term clinical sequelae that are in part determined by the degree of membrane biocompatibility. A biocompatible membrane (BCM) has traditionally been defined as "one that elicits the least amount of inflammatory response in patients exposed to it" [1]. (See "Biochemical mechanisms involved in blood-hemodialysis membrane interactions".)

However, there is no standard technique for the measurement of biocompatibility. As a result, there are wide-ranging claims for biocompatibility by manufacturers of dialysis membranes based upon the testing method utilized, such as the generation of leukotrienes or the degree of complement activation.

Issues related to the clinical consequences of hemodialysis membrane biocompatibility are discussed in this topic review. Acute reactions to the hemodialysis membrane, such as that induced by ethylene oxide and complement activation are discussed separately. (See "Reactions to the hemodialysis membrane".)

TYPES OF HEMODIALYSIS MEMBRANES — There are three types of membranes currently used to manufacture dialyzers: cellulose, substituted cellulose, and synthetic noncellulose.

Cellulose — Cellulose, primarily manufactured as cuprophan (or cuprophane), is a polysaccharide-based membrane obtained from pressed cotton. It is composed of chains of glucosan rings with abundant free hydroxyl groups. Cupammonium is primarily used in the manufacturing process of this membrane (hence the name), but other methods of manufacturing exist.

These membranes, which are generally low flux, are best considered to be bioincompatible. However, reuse techniques that avoid bleach tend to greatly increase their biocompatibility due to the plating of plasma proteins across the membranes. (See "Reuse of dialyzers".)

Substituted cellulose — Substituted cellulose membranes are obtained by chemical bonding or substitution of a material to the free hydroxyl groups at the surface of the cellulose polymer. The most common type is cellulose acetate, in which acetate replaces 80 percent of the hydroxyl groups. Such membranes can also be modified by the addition of a synthetic material (such as diethylaminoethyl in the production of Hemophane) to liquefied cellulose during its formation.

This class of membranes has a broad range of biocompatibility, ranging from relatively bioincompatible (as with cellulose acetate) to extremely biocompatible (as with cellulose triacetate). As with nonsubstituted cellulose membranes, improved biocompatibility is observed with reuse techniques that avoid bleach. The permeabilities of these membranes range from high to low flux.

Synthetic noncellulose — Synthetic noncellulose membranes have a higher permeability and are more biocompatible than the cellulose membranes. There are a variety of synthetic membranes available including polyacrylonitrile (PAN), polysulfone, polycarbonate, polyamide, and polymethylmethacrylate (PMMA) membranes. They have permeabilities that range from low to high flux.

Determinants of biocompatibility — The free hydroxyl groups on the cellulosic dialysis membrane activate the alternate pathway of complement, leading to neutrophil activation and subsequent sequestration in the pulmonary circulation and infiltration in other organs [2,3]. The side-group modifications on substituted cellulose membranes and the high adsorptive capacity of synthetic membranes generally lead to a decrease in the intensity of blood membrane interactions. As an example, the PAN membrane can vigorously activate the complement system; however, it also has a high adsorptive capacity for complement, resulting in a low net level of complement activation products reaching the systemic circulation. (See "Biochemical mechanisms involved in blood-hemodialysis membrane interactions", section on 'Composition of dialysis membranes'.)

ACUTE KIDNEY INJURY — Studies in experimental animals with acute kidney injury (AKI) have shown that hemodialysis with cuprophane membranes (but not more compatible membranes) can lead to neutrophilic infiltration into the kidney (and other tissues) and delayed recovery from AKI.

These findings may also be applicable to humans as some prospective randomized trials have shown that the survival rate and the rate of recovery of critically ill patients from AKI were significantly higher and that recovery occurred earlier when hemodialysis was performed with biocompatible membranes (BCMs) rather than bioincompatible cuprophane membranes. Other studies, however, have failed to detect a difference in survival with these different membranes. (See "Dialysis-related factors that may influence recovery of kidney function in acute kidney injury (acute renal failure)", section on 'Characteristics of the dialysis membrane'.)

CHRONIC KIDNEY DISEASE — There are no prospective randomized studies suggesting that using biocompatible membranes (BCMs) for maintenance hemodialysis is associated with a lower morbidity and mortality when compared with dialysis with bioincompatible membranes (BICMs). However, several nonrandomized studies and post-hoc analyses support this possibility [1,4-7]:

●One report, for example, compared the survival of patients who were switched from hemodialysis with a cellulosic membrane to hemodialysis with a high-flux polysulfone BCM [4]. Multivariate analysis, adjusted for all known comorbid conditions, showed that annual mortality was substantially less in patients treated with the polysulfone membrane (7 versus 20 percent). There was no difference in the overall rate of hospital admissions between the two groups, but infection-related admissions were twice as high in patients treated with the cellulosic membranes.

●A similar benefit was suggested in two reports from the United States Renal Data System (USRDS) case mix adequacy study, which compared the outcomes in patients dialyzed with cellulose or more compatible modified cellulose or synthetic membranes [5,7]. Compared with dialysis with cellulosic BICMs, the last two membranes were associated with an adjusted relative risk (RR) of overall mortality of 0.75 to 0.80 [5], as well as an adjusted RR of mortality due to coronary artery disease or infection of 0.74 and 0.69, respectively [7]. The relative roles of biocompatibility and higher flux in the apparent benefit could not be determined; furthermore, this type of study cannot prove a cause-and-effect relationship.

●In a post-hoc analysis of the 4D study, dialysis was performed with four different types of dialysis membranes: high-flux synthetic, low-flux synthetic, low-flux semisynthetic, or cellulosic low-flux membranes [8]. Compared with low-flux synthetic membranes (biocompatible), there was a significantly greater risk of death with low-flux cellulosic (hazard ratio [HR] 1.73, CI 95% 1.04-2.87) and low-flux semisynthetic membranes (HR 1.42, CI 95% 1.01-2.00).

In response in part to the data suggesting possible outcomes benefit (or at least no increased harm) with the use of BCMs, nephrologists in the United States have increased the use of modified cellulose or synthetic membranes [1]. It should be remembered, however, that simultaneous improvement in other features of dialysis treatment, such as increasing the delivered dose of dialysis, increasing the time on dialysis, or improving blood pressure control may mask or override adverse reactions to cellulosic membranes. (See "Patient survival and maintenance dialysis".)

BETA-2 MICROGLOBULIN AND DIALYSIS-RELATED AMYLOIDOSIS — Amyloidosis in patients on maintenance dialysis is related to the accumulation and tissue deposition of beta-2 microglobulin. This is discussed separately. (See "Dialysis-related amyloidosis".)

PROTEIN CATABOLISM — There is some evidence that the nutritional status of the hemodialysis patient can be influenced by the biocompatibility of the membrane [9-11]. In particular, the release of cytokines from cells activated after contact with bioincompatible membranes (BICMs) may be responsible for increased protein catabolism.

One report, for example, demonstrated net protein catabolism when normal subjects were exposed to (not dialyzed by) cellulosic membranes, but not when exposed to biocompatible (BCM) polysulfone or polyacrylonitrile (PAN) membranes [12]. A 150-minute exposure to the cuprophane membrane resulted in the net degradation of approximately 15 to 20 g of muscle protein (measured by the release of amino acids). The net release of amino acids occurred three hours after the end of dialysis, not during dialysis, and continued for as long as six and one-half hours after dialysis. This time course is similar to that of monocyte activation, the release of cytokines, and their subsequent action on muscle cells [9].

Two other observations reported a beneficial effect of BCMs on nutritional status:

●One study found that, for a given dose of dialysis, protein intake (reflected by the protein catabolic rate) increased to a greater extent in patients dialyzed with PAN membranes compared with those treated with cuprophane membranes [10].

●A multicenter trial randomly assigned 159 patients newly initiated on dialysis to a BCM or BICM [11]. Patients treated with BCMs had higher plasma levels of albumin and insulin-like growth factor-1 and a greater degree of body-mass weight gain during the 18 months of the study.

However, large protein losses have also been reported among patients who are dialyzed with BCM [13].

INFECTION — Uremic patients have enhanced susceptibility to infection due in part to impaired neutrophil function [14,15]. Neutrophils eliminate bacteria through a series of carefully orchestrated events, including adherence to vascular endothelium, migration through the endothelium to the sites of infection, ingestion of bacteria, and killing the bacteria by the generation of reactive oxygen species and the release of microbial enzymes [16].

The hemodialysis membrane may play a role in this enhanced susceptibility to infection [14,15,17-21].

●One retrospective study compared the major causes of mortality in approximately 1000 patients before and after their hemodialysis membranes were changed from cellulosic to a biocompatible polysulfone membrane [22]. The most significant difference in the cause of death between these two time periods was in the incidence of infection, which was decreased by approximately one-half during therapy with the polysulfone membrane. Similar results were noted in another report, in which the rate of hospitalization for infection in patients switched to a polysulfone membrane was one-half that in patients dialyzed with a cellulosic membrane [4].

●Neutrophils harvested predialysis from patients chronically dialyzed with cellulosic membranes have a significantly attenuated metabolic response to phagocytic stimuli such as latex or zymosan when compared with neutrophils from patients treated with a polysulfone membrane [23]. During a follow-up of approximately six months, there was a higher incidence of clinically apparent infections in patients dialyzed with a bioincompatible membrane (BICM).

●Serum from patients dialyzed with BICMs may improve the adherence ability of hematopoietic cells. As an example, one study found that serum collected from patients being dialyzed with cuprophane hemodialysis membranes significantly increased the ability of granulocytes and monocytes to adhere to human saphenous vein endothelial cells [24]. This finding may be due to the presence of active complement fragments, which increase expression of neutrophil and monocyte adhesion receptors. No significant effect was observed with serum from patients undergoing dialysis with polysulfone hemodialysis membranes.

There is also evidence that lymphopenia and impaired natural killer cell (NKC) function occur in patients dialyzed with BICMs. Switching to a biocompatible membrane (BCM) can improve the lymphopenia [25] and NKC function [19]. NKCs can spontaneously lyse target cells without prior sensitization; they are important in providing resistance to viral infection and destroying tumor cells. The impairment in NKC function with cellulosic membranes may explain, in part, why hemodialysis patients have immune defects (such as a decreased responsiveness to vaccines) and an increased incidence of malignancy.

GENERAL INFLAMMATION — The aggravation of general inflammatory processes in those undergoing maintenance hemodialysis may occur with exposure to dialysis tubing and dialysis membranes, particularly less biocompatible membranes. (See "Inflammation in patients with kidney function impairment".)

LOSS OF RESIDUAL KIDNEY FUNCTION — The initiation of hemodialysis is associated with a rapid decrease in residual kidney function at a rate that is approximately twice as fast as in patients starting peritoneal dialysis. There are conflicting data on the effect of biocompatible membranes (BCMs) compared with bioincompatible membranes (BICMs). (See "Residual kidney function in kidney failure".)

PULMONARY CHANGES — A large increase in the concentration of elastin fragments (most likely from lung parenchyma) is seen in patients dialyzed with cellulosic membranes. It has been suggested that patients chronically dialyzed with cellulosic membranes have increased release of elastase from activated neutrophils, resulting in breakdown of pulmonary elastin fibrils [26]. Reduced function of the inhibitory proteins of elastase in the presence of reactive oxygen species also may contribute to the rise in elastase activity. The clinical consequences of these changes are not known.

In addition to these chronic changes, sequestration of neutrophils in the lungs during cuprophane dialysis has been partially incriminated in the hypoxemia seen in the early phase of dialysis in association with concurrent leukopenia [2,3,27]. (See "Reactions to the hemodialysis membrane", section on 'Type B reactions'.)

SUMMARY

●Interaction of the dialysis membrane with blood components may induce an inflammatory response with long-term clinical sequelae. The degree to which this occurs may in part be determined by membrane biocompatibility. A biocompatible membrane (BCM) is defined as one that elicits the least amount of inflammatory response. There is no standard technique for the measurement of biocompatibility. (See "Biochemical mechanisms involved in blood-hemodialysis membrane interactions".)

●There are three types of membranes used to manufacture dialyzers: cellulose, substituted cellulose, and synthetic noncellulose. Cellulose membranes are best considered to be bioincompatible, although reuse techniques that avoid bleach increase their biocompatibility. Substituted cellulose membranes vary in the degree of biocompatibility, and, as with nonsubstituted cellulose membranes, biocompatibility is increased with reuse techniques. Synthetic noncellulose membranes are more biocompatible than the cellulose membranes. Available synthetic membranes include polyacrylonitrile (PAN), polysulfone, polycarbonate, polyamide, and polymethylmethacrylate (PMMA) membranes. (See 'Types of hemodialysis membranes' above.)

●Hemodialysis with cuprophane membranes (but not more compatible membranes) may lead to neutrophilic infiltration into the kidney (and other tissues) and delayed recovery from acute kidney injury. Some studies suggest that the use of BCMs is associated with a lower morbidity and mortality. As a result of these data, nephrologists in the United States have increased the use of modified cellulose or synthetic membranes. (See 'Acute Kidney Injury' above and 'Chronic kidney disease' above.)

●The biocompatibility of the membrane may influence the accumulation of beta-2 microglobulin, nutritional status, susceptibility to infection, and the loss of residual kidney function. (See 'Beta-2 microglobulin and dialysis-related amyloidosis' above and 'Protein catabolism' above and 'Infection' above and 'Loss of residual kidney function' above and 'Pulmonary changes' above.)