Reactions to the hemodialysis membrane

INTRODUCTION — Dialyzer reactions refer to all of the abnormal sequelae resulting from the interaction between blood constituents and the hemodialysis membrane. There are two types of reactions: type A and type B [1]. In the past, these reactions were grouped under the term "first-use syndrome" because they primarily occurred with new dialyzers. Before discussing the characteristics of these disorders, it is helpful to review the different types of dialyzers since they can affect the frequency and type of reaction seen. The longer-term clinical consequences of exposure to dialysis membranes are discussed separately. (See "Clinical consequences of hemodialysis membrane biocompatibility".)

TYPES OF HEMODIALYSIS MEMBRANES — There are four types of membranes currently used to manufacture dialyzers [2]:

●Cellulose, also called 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.

●Substituted cellulose membranes are obtained by chemical bonding 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.

●Cellulosynthetic membranes are modified by the addition of a synthetic material (such as diethylaminoethyl in the production of hemophane) to liquefied cellulose during its formation.

●Synthetic noncellulose membranes, which have a higher permeability and are more biocompatible (and more expensive) than the cellulose membranes. There are a variety of synthetic membranes available, including polyacrylonitrile (PAN), acrylonitrile-sodium methallyl sulfonate (AN-69), polysulfone, polycarbonate, polyamide, and polymethylmethacrylate (PMMA) membranes.

TYPE A REACTIONS — Type A reactions are estimated to occur in approximately 4 of every 100,000 dialysis treatments. They usually begin in the first few minutes of dialysis, immediately after the return of blood from the dialysis circuit to the patient; in occasional cases, however, the onset is delayed for up to 30 minutes into the treatment [1].

The associated symptoms range from mild to severe [1]. Mild cases may be associated with a variety of symptoms such as itching, burning sensation at the access site, urticaria, flushing, cough, sneezing, wheezing, abdominal cramps, diarrhea, headache, back and chest pain, nausea, vomiting, fever, and chills. More severe reactions lead to dyspnea, a sense of impending doom, and hypotension, potentially resulting in cardiac arrest and death. Patients with an allergic diathesis and eosinophilia appear to be predisposed to this type of reaction.

Etiology — Type A reactions are probably largely caused by leachable substances from the dialyzer or by contamination with bacterial peptides. A classic cause of this type of reaction is ethylene oxide, which is used to sterilize hollow fiber dialyzers. Reactions to ethylene oxide, which are now uncommon, occur exclusively during the first use, usually when there has been inadequate rinsing of the dialyzer prior to use. Immunoglobulin E (IgE) antibodies directed against ethylene oxide are present in some cases, particularly those with more severe reactions [3].

One study, for example, found that 16 of 106 unselected patients developed mild allergic symptoms after hemodialysis; 10 of these patients also developed eosinophilia [4]. Two observations suggested an important role for ethylene oxide in this response: Allergy to ethylene oxide could be demonstrated in seven of the cases, and the symptoms and eosinophilia were ameliorated in three patients by ethylene oxide-free hemodialysis. Patients with eosinophilia also have a greater degree of complement activation and interleukin-2 production after exposure to a cuprophane membrane [4,5]. These exaggerated responses may be related in part to an underlying allergic diathesis.

A high incidence of anaphylactoid reactions is also seen when angiotensin-converting enzyme (ACE) inhibitors are used in patients treated with high-flux hemodialysis using acrylonitrile-sodium methallyl sulfonate (AN-69) dialyzers [6-8]. One report, for example, surveyed dialysis centers reporting anaphylactic reactions [6]. An anaphylactic reaction developed in 41 of 72 patients (57 percent) treated with an ACE inhibitor and dialyzed with an AN-69 membrane. In contrast, an anaphylactic reaction developed in none of the 71 patients taking an ACE inhibitor but dialyzed with other membranes and in only 2 of 519 patients (0.4 percent) dialyzed with AN-69 membrane but not treated with an ACE inhibitor.

These membranes appear to act by increasing the rate of kinin generation [9,10]. The following mechanism has been proposed to explain the susceptibility associated with AN-69 membranes. Contact of blood with a dialysis membrane leads to binding of Hageman factor (factor XII) and circulating complexes of high-molecular-weight kininogen with prekallikrein. Activation of prekallikrein by Hageman factor results in the formation of kallikrein, which cleaves bradykinin from kininogen. Activation of this process is facilitated by a negatively charged surface, which induces conformational changes in Hageman factor. Polyacrylonitrile (PAN) membranes are highly negatively charged, while cellulosic membranes have a neutral charge [9].

The ensuing enhancement of bradykinin production is generally well tolerated, unless the patient is taking an ACE inhibitor. ACE is also a kininase. Thus, blocking converting enzyme prevents inactivation of bradykinin, thereby raising bradykinin levels as much as 20- to 30-fold and increasing the likelihood of an anaphylactoid reaction [10].

The association of anaphylactoid reaction with hypochlorite (bleach)-reprocessed, but not formalin-reprocessed, AN-69 dialyzers is also consistent with the importance of surface activation of Hageman factor [11]. Hypochlorite, a strong, oxidizing agent, removes the protein coat from the used dialysis membranes and is therefore likely to activate factor XII. On the other hand, formaldehyde fixes the protein layer on the surface, thereby reducing the chance for further activation of the Hageman factor.

The use of AN-69 membranes for continuous kidney replacement therapy (CKRT) has moved the occurrence of this type of reaction from the dialysis unit to the critical care setting. Priming of the CKRT circuit with packed red blood cells has been associated with severe hypotension, which was only responsive to the removal of the CKRT circuit in two pediatric patients [12]. Neither of these children was on an ACE inhibitor. The reaction was prevented by buffering the blood to a physiologic pH prior to priming the CKRT circuit or by infusing the packed red blood cells after the dialyzer (postdilution). The authors postulated that an acid pH enhanced the generation of bradykinins at the time of the blood-membrane interaction. This raises the possibility that alkali administration may prevent anaphylactoid reactions in patients on ACE inhibitors dialyzed with the AN-69 membrane [13].

Surface treatment of AN-69 membranes with a biocompatible polymer (AN-69 ST) results in partial neutralization of the surface electronegativity, dramatically reducing bradykinin release [14]. Patients with a history of anaphylactoid reaction to AN-69 membranes while taking ACE inhibitors have been successfully dialyzed with AN-69 ST membranes while still taking the ACE inhibitors [15]. This experience further confirms the role of the electronegative charge and the generation of bradykinins as the causative factor for these reactions.

Anaphylactoid reactions have also been associated with reused polysulfone and cellulose acetate dialyzers [16]. However, the role of ACE inhibitors in this setting is less certain.

Anaphylactoid reactions have also been reported among patients receiving angiotensin II receptor blockers (ARBs) during hemodialysis with AN69 membranes [17,18]. However, since ARBs do not affect bradykinin levels, the exact underlying mechanism is unclear.

Type A reactions can also be seen in a number of other settings [1]:

●High-flux dialyzers used in conjunction with bicarbonate dialysate are susceptible to contamination with bacterial peptides.

●Rarely, type A reactions are seen with reused dialyzers. No association was found with the disinfectant, the reprocessing method (manual or automated), or type of dialysate (bicarbonate or acetate). Multivariate analysis showed an increased risk with the practice of washing the hemodialyzer blood compartment with either bleach or hydrogen peroxide [19].

●Heparin and acetate can precipitate type A reactions, potentially causing severe bronchospasm.

●Formaldehyde [20] and natural rubber latex [21] have also been linked to anaphylactoid reactions.

●A type A reaction was reported in a patient with acute kidney injury requiring dialysis with a NxStage machine using a PUREMA polyethersulfone filter sterilized with gamma radiation [22]. The patient was rechallenged the following day with the same membrane and again experienced a reaction. Transitioning to another synthetic membrane (Prismaflex) was well tolerated, without recurrence.

This case illustrates the importance of having a high index of suspicion in identifying these potentially life-threatening reactions, even if membranes not sterilized with ethylene oxide are used.

Treatment and prevention — The dialysis treatment is immediately stopped without returning the blood to the patient. The patient is then treated, depending upon the severity of the symptoms, with antihistamines, steroids, epinephrine, bronchodilators, and/or pressors.

Type A reactions can usually be prevented by proper rinsing of the dialyzer, adequate sterilization techniques for the dialysis machine, reuse of the dialyzer, and avoiding PAN membranes in patients treated with an ACE inhibitor. Sterilization of the dialyzer with gamma irradiation or steam and pretreatment with antihistamines and/or steroids may be necessary during the first use in patients with a previous history of a type A reaction.

Reuse of the dialyzer with proper sterilization techniques prevents most reactions, probably because the dialyzer membrane is coated with proteins from the patient plasma. (See "Reuse of dialyzers".)

TYPE B REACTIONS — Type B reactions are more common and fortunately less severe than type A reactions [1]. They occur in 3 to 5 percent of patients dialyzed with new cellulosic membranes. The most common symptoms are chest and back pain, dyspnea, nausea, vomiting, and hypotension. Anaphylaxis is extremely rare.

In addition to the difference in symptoms, there are two other important characteristics that distinguish these reactions from type A reactions:

●Symptoms are delayed, as opposed to the usual occurrence within the first few minutes with type A reactions. Type B reactions typically begin within the first 15 to 30 minutes of the dialysis treatment but occasionally much later.

●There is generally an improvement in symptoms with continuation of the dialysis treatment.

Pathogenesis — Type B reactions are believed to be mediated by complement. The free hydroxyl groups on the dialysis membrane activate the alternate pathway of complement, leading to neutrophil activation and subsequent sequestration in the pulmonary circulation [23,24] (see "Biochemical mechanisms involved in blood-hemodialysis membrane interactions"). These changes are frequently associated with marked and transient neutropenia, beginning as early as one minute after the start of dialysis, with the nadir in the white cell count being reached within 15 minutes. This is followed by an increased number of immature neutrophils (bands) appearing in the circulation, returning the neutrophil count to predialysis values by one hour. At this time, however, the band count may reach levels three times normal, an effect that may persist for as long as five hours (figure 1).

The lymphocyte count is also affected during this response. It tends to remain stable for the first 30 minutes of dialysis and then increases during the next 30 minutes to levels averaging twice the baseline value.

Animal studies have shown that the neutropenia is almost entirely explained by the sequestration of neutrophils in the pulmonary capillary bed [23]. Furthermore, the timing of activation of the complement parallels the changes in leukocyte count. C3a formation begins immediately after blood is exposed to a new cuprophane dialyzer; maximal plasma C3a levels are seen at 15 minutes and return to normal values within 10 minutes of completing dialysis (figure 2) [25]. Patients who exhibit the first-use syndrome consistently activate complement and raise the serum levels of C3a to a greater degree than patients who do not have this reaction [24].

Although C3a levels most accurately reflect the extent of complement activation, it is C5a that is responsible for promoting leukocyte sequestration in the lungs [26]. C5a binds to plasma membrane receptors on neutrophils, leading to activation, aggregation, and adherence [27]. This is followed by downregulation of the receptor sites with resultant cellular unresponsiveness and release of deactivated granulocytes from the pulmonary capillaries back into the circulation [26].

Complement activation is importantly determined by the type of membrane used, being progressively less as the biocompatibility of the membrane increases (figure 2). The types of dialysis membranes listed above can be listed in decreasing order of biocompatibility:

●Synthetic membranes (most biocompatible)

●Reused cellulose

●Cellulosynthetic (Hemophan)

●Substituted cellulose (cellulose acetate)

●Cellulose (cuprophane) (least biocompatible)

Cellulose acetate dialyzers appear to possess only approximately one-half the complement-activating property of new cuprophane dialyzers, while polyacrylonitrile (PAN) membranes induce minimal complement activation and do not lead to leukopenia [26]. Synthetic polysulfone membranes are able to activate the complement pathway, but the complement products are then absorbed, thereby blunting their effect. The degree of complement activation is also proportional to dialyzer size but not to the blood flow rate [28,29].

In contrast to the transient release of C3a and C5a, ongoing generation of the terminal complement components (C5b-9) continues throughout the dialysis session and possibly for several hours afterward [30]. The terminal complement components are able to activate mononuclear cells to release various cytokines, such as tumor necrosis factor and interleukin-1 [31]. This may contribute to other complications associated with hemodialysis such as enhanced tissue catabolism, a greater risk of infection, increased beta-2 microglobulin generation, and perhaps more rapid loss of residual kidney function. (See "Clinical consequences of hemodialysis membrane biocompatibility".)

Treatment and prevention — The treatment of type B reactions is typically supportive since the symptoms characteristically resolve as dialysis is continued. The syndrome can be minimized or prevented by reuse of the dialyzer, which reduces complement activation and leukopenia by 90 percent [23] (see "Reuse of dialyzers"). This protective effect is thought to result from coating of the free hydroxyl groups by plasma proteins. In some cases, it may be necessary to change to a more biocompatible membrane to relieve symptoms.

OTHER REACTIONS — Seven dialysis patients at one center developed unusual clinical features after exposure to old cellulose acetate membranes [32]. These manifestations, which appeared 7 to 24 hours after a dialysis treatment, variably included decreased vision and hearing, conjunctivitis, headache, confusion, corneal opacification, and cardiac arrest. An investigation by the Centers for Disease Control and Prevention and the Food and Drug Administration (both of the United States) concluded that the outbreak was due to exposure to cellulose acetate degradation products resulting from the use of very old (11.5 years) cellulose acetate dialyzer membranes. Thus, the stock of dialysis membranes should be properly rotated, and the manufacturers should clear the use of membranes suspected of being old. The date of manufacture is now required to be placed on all new dialyzers.

DIFFERENTIAL DIAGNOSIS — Acute complications are common during hemodialysis (see "Acute complications during hemodialysis"). Most of these intradialytic events are relatively easy to recognize and treat, and potentially fatal reactions rarely occur.

The following are specific events and their general time of onset of symptoms with respect to the initiation of the dialysis session. This is an important clue to properly diagnose and treat these events [33].

●Type A dialyzer reactions most frequently occur within the first 10 minutes; they occur less often later but still during the first hour.

●The onset of type B dialyzer reactions is after 30 minutes and up to the first hour; it is uncommon after this period.

●Although it can happen at any time, hemolysis most often occurs during the first hour. Multiple patients may be simultaneously involved.

●Air embolism most frequently occurs at dialysis initiation in patients with central venous catheters. It is uncommon otherwise but can happen at any time.

●Dialysis-associated episodic hypotension is rare at initiation unless pericardial tamponade or valvular heart disease is present. It is more common in the later stages of treatment.

●Dialysis-induced hypoxemia peaks at 30 minutes and improves after the second hour.

●Dialysis dysequilibrium most frequently occurs toward the end of the treatment or immediately thereafter. It may happen sooner if dialysate is hypotonic.

SUMMARY

●Types of dialyzer reactions – Dialyzer reactions refer to all the abnormal sequelae resulting from the interaction between blood constituents and the hemodialysis membrane. There are two types of reactions: type A and type B. Type A is far less common but more severe than type B. (See 'Introduction' above and 'Type A reactions' above.)

●Type A reactions – Type A reactions are estimated to occur in approximately 4 of every 100,000 dialysis treatments.

•Timing and symptoms – Type A reactions usually begin in the first few minutes of dialysis, although the onset may be delayed for up to 30 minutes. Mild symptoms include itching, burning sensation at the access site, urticaria, flushing, cough, sneezing, wheezing, abdominal cramps, diarrhea, headache, back and chest pain, nausea, vomiting, fever, and chills. More severe reactions lead to dyspnea, a sense of impending doom, and hypotension, potentially resulting in cardiac arrest and death. (See 'Type A reactions' above.)

•Etiology – Type A reactions are probably caused by leachable substances from the dialyzer (such as ethylene oxide) or by contamination with bacterial peptides. A high incidence of anaphylactoid reactions is seen when angiotensin-converting enzyme (ACE) inhibitors are used in patients treated with high-flux hemodialysis using acrylonitrile-sodium meth allyl sulfonate (AN-69) dialyzers. These membranes increase bradykinin levels. Since ACE is also a kininase, blocking the enzyme prevents inactivation of bradykinin, which increases the likelihood of an anaphylactoid reaction. (See 'Etiology' above.)

•Treatment – The treatment of a type A reaction is stopping dialysis immediately without returning the blood to the patient. Other therapies that may be used include antihistamines, steroids, epinephrine, bronchodilators, and/or pressors, depending upon the severity of symptoms. (See 'Treatment and prevention' above.)

•Prevention – Type A reactions can usually be prevented by proper rinsing of the dialyzer, adequate sterilization techniques for the dialysis machine, reuse of the dialyzer, and avoiding polyacrylonitrile (PAN) membranes in patients treated with an ACE inhibitor. Sterilization of the dialyzer with gamma irradiation or steam and pretreatment with antihistamines and/or steroids may be necessary during the first use in patients with a previous history of a type A reaction. (See 'Treatment and prevention' above.)

●Type B reactions – Type B reactions occur in 3 to 5 percent of patients dialyzed with new cellulosic membranes.

•Timing and symptoms – In contrast to type A reactions, type B symptoms typically do not occur until 15 to 30 minutes into the dialysis treatment, and there is generally an improvement in symptoms with continuation of the dialysis treatment. The most common symptoms are chest and back pain, dyspnea, nausea, vomiting, and hypotension. Anaphylaxis is extremely rare. (See 'Type B reactions' above.)

•Pathogenesis – Type B reactions are mediated by complement. (See 'Pathogenesis' above.)

•Treatment and prevention – The treatment of type B reactions is typically supportive since the symptoms characteristically resolve as dialysis is continued. The syndrome can be minimized or prevented by reuse of the dialyzer. (See 'Treatment and prevention' above.)

●Differential diagnosis of dialyzer reactions – The differential diagnosis of type A and B reactions include other acute complications of dialysis such as hemolysis, air embolism, dialysis-associated episodic hypotension, dialysis-induced hypoxemia, and dialysis dysequilibrium. (See 'Differential diagnosis' above.)