Dialysis Rounds A Dialysis Case Presentation and Discussion
Series Editor: Roger A. Rodby
Anaphylactic Shock at the End of Hemodialysis Nivin Aziz,* Carla Luna,† Farheen Mirza,† and Mary Tobin†
*Section of Nephrology, Department of Medicine, Rush University Medical Center, Chicago, Illinois, and †Section of Allergy and Immunology, Department of Immunology & Microbiology, Rush University Medical Center, Chicago, Illinois
ABSTRACT Allergic reactions to epoetin alfa, including anaphylaxis, have been described but desensitization in the setting of an IgE-mediated reaction has not been reported. We present a case of a hemodialysis patient who developed symptoms of an IgE-mediated allergic response to epoetin alfa that occurred after each administration. These reactions progressed to a single episode of
anaphylaxis with generalized pruritus, urticaria, oropharyngeal edema, and hypotension that prompted its discontinuation. Intradermal skin testing confirmed an allergic response to this agent. The patient then underwent a desensitization procedure to epoetin alpha after which she was able to tolerate it without further problems.
After its 1984 approval by the Food and Drug Administration (FDA), epoetin alfa became the standard of care for treating anemia associated with chronic kidney disease (CKD). Mild allergic reactions to erythropoiesis-stimulating agents (ESAs) have been described. Even more unusual are anaphylactic reactions following ESA administration, with the timing and severity suggesting the mechanism to be an allergic hypersensitivity reaction (1–3). We report the first case of a patient to receive successful desensitization after development of anaphylaxis to epoetin alfa.
Amgen, Inc.) (4). The patient received epoetin alfa thrice weekly (initially intravenously but subcutaneously for the last few years), usually during the last hour of treatment, with no adverse effect for 12 years. Without any change in medications, addition of herbal medications or contact sensitivities, she developed an urticarial rash at the base of her neck and at the site of access to her arteriovenous fistula (Fig. 1). This reaction occurred toward the end, or shortly after, completing each dialysis
Case Presentation A 44-year-old woman with end-stage renal disease secondary to focal segmental glomerulosclerosis had received hemodialysis since January 1999. At the time of initiating dialysis, she was noted to be anemic and was started on epoetin alpha (Epogen, Address correspondence to: Mary Tobin, MD, Rush University Medical Center, 1725 W. Harrison, Suite 117, Chicago, IL 60612, Tel.: +312-942-6296, Fax: +312-563-2201, or e-mail: [email protected]. Seminars in Dialysis—Vol 28, No 6 (November–December) 2015 pp. 661–664 DOI: 10.1111/sdi.12402 © 2015 Wiley Periodicals, Inc.
Fig. 1. Urticarial rash seen on the neck shortly after the administration of epoetin alfa. 661
662
Aziz et al.
treatment. The rash recurred on several subsequent dialyses and progressed to generalized pruritus. She was given oral diphenhydramine with symptom resolution. She was changed to a single-dose Epogen vial due to the concern that this was a reaction to the presence of a preservative in the multidose vial, but she continued to develop a rash with pruritus following the epoetin alfa administration. Within a few weeks, without any changes in dosing, the patient developed her typical symptoms of generalized pruritus accompanied by urticaria, but this time it was accompanied by a burning sensation of the eyes, swelling of the lips and tongue, and difficulty breathing. Her blood pressure dropped to 68/36 mmHg and the hemodialysis treatment was discontinued; 911 was called. She received treatment for anaphylaxis and was transferred to the Emergency Department (ED) of Rush University Medical Center. On arrival to the ED her symptoms had subsided and her blood pressure had improved to 96/60. Significant lab results in the ED included a hemoglobin value of 10.7 g/dl and white blood cell count of 3.4 9 103 cells/mm3 with 18.2 percent eosinophils (absolute eosinophil count of 619 cells/mm3). A total tryptase level was 56.5 ng/ml (normal than the negative control (saline). Epoetin alfa was positive at a concentration of 1000 units/ml as was darbepoetin alfa, at a concentration of 10 lg/ml (Fig. 2). Desensitization Protocol The patient underwent a desensitization protocol to epoetin alfa in the intensive care unit over 3 hours to achieve a total therapeutic dose of 12,800 units. Starting with 100 units, increasing incremental doses were given subcutaneously every 15 minutes (Table 1). She tolerated desensitization without any complications. Because the half-life of subcutaneously administered epoetin alfa is between 7 and 18 hours, and to ensure maintenance of tolerance, the patient received epoetin alfa 2000 units subcutaneously daily on nondialysis days in addition to 10,000 units of epoetin alfa with each session of dialysis. This was done for a 2-week period and she returned to her previous dosing of epoetin alpha schedule of 12,800 units with dialysis three times a week without daily dosing. Her hemoglobin improved to 10.6 mg/dl and she remained on epoetin alpha without any evidence of an allergic response. Discussion While rare, allergic reactions on hemodialysis typically occur at the beginning of the treatment and are usually associated with exposure to ethylene oxide, heparin, or the dialyzer membrane. Reactions
Methods of Skin Testing Skin testing to undiluted epoetin alfa (10,000 units/ml) and darbepoetin alfa (100 lg/ 0.5 ml) from single-use, preservative-free preparations was performed at increasing concentrations of epoetin alfa (1 unit/ml, 10 units/ml, 100 units/ml, 1000 units/ml) and darbepoetin alfa (0.01 lg/ml, 0.1 lg/ml, 1 lg/ml, 10 lg/ml). Due to the possibility of anaphylaxis, initial dilutions were placed from least concentrated to most concentrated via prick apparatus percutaneously to abrade the skin, accompanied by a positive control (histamine sulfate 10 mg/ml) and a negative control (saline). The positive control ensures that the patient can respond to histamine, a marker of mast cell degranulation, when an antigen is recognized. The negative saline control assesses for dermographism, a nonspecific histamine response that would invalidate the testing. The percutaneous skin testing to epoetin alfa and darbepoetin alfa was negative at all concentrations. Intradermal testing was performed by placing 0.02 ml of each drug and at the defined concentrations, from least to most concentrated at 15 minute
Fig. 2. The arrow on the right forearm indicates the positive wheal to epoetin alfa at a concentration of 1000 units/ml during intradermal testing. The arrow on the left forearm demonstrates a positive response to darbepoetin alpha at 10 lg/ml.
DESENSITIZATION FOR ERYTHROPOIETIN ALLERGY
TABLE 1. Desensitization schedule Desensitization protocol to epoetin alfa Volume (ml) 0.05 0.1 0.15 0.2 0.4 0.5 1 1 1
Concentration (units/ml)
Dose (units)
Cumulative dose (units)
2000 2000 2000 2000 2000 2000 2000 4000 4000
100 200 300 400 800 1000 2000 4000 4000
100 300 600 1000 1800 2800 4800 8800 12,800
can occur later in the treatment and these are usually related to the administration of antibiotics or very rarely to an ESA, both administered toward or at the end of treatment. The timing of our patient’s allergic reaction and the lack of any other potential etiology led us to suspect and discontinue the use of the ESA with the complete resolution of symptoms. Skin testing with epoetin alfa confirmed the diagnosis. Subsequent desensitization was successful in allowing the patient to resume receiving epoetin alfa without any allergic symptoms. This is the first report to demonstrate desensitization to epoetin alfa in the setting of anaphylaxis. Anaphylaxis due to epoetin alfa was first reported in 1993 by Garcia and colleagues (1). They performed skin prick testing and intradermal injections with rHuEPO (Erantin, Boehringer Mannheim, FRG) but this did not produce a skin reaction. They did, however, detect IgE antibodies to rHuEPO by RAST testing (Pharmacia-Sweden) with modified Erantin as the antigen. The rHuEPO in their report was administered intravenously suggesting that the route of sensitization may be important in interpreting the results of skin tests. Certainly, negative skin tests do not eliminate the possibility of an IgE-mediated hypersensitivity reaction. Two other studies demonstrated anaphylaxis to ESA agents which were attributed to stabilizing agents. The first reaction was related to polysorbate 80 sensitivity (2). The patient in that report had previously developed a large local reaction to the influenza vaccine, containing polysorbate 80. Forty minutes after the administration of Eprex (JanssenCilag, Beersa, Belgium), she developed pruritus, generalized erythema, and oral facial edema. She was skin tested with Eprex and Neupogen (Amgen, Thousand Oaks, CA) both of which have polysorbate 80 and was positive to both agents and pharmaceutical grade polysorbate. Skin testing with an ESA agent containing no polysorbate 80 was negative. She received a supervised clinical challenge with no reaction. The other report involved a change in the stabilizer for an EPO product from human serum albumin to a bovine gelatin (3). The authors demonstrated anti-bovine gelatin IgE and no IgE antibodies to EPO by ELISA. Anti-gelatin antibodies are well described as the cause of allergic
663
reactions to vaccines such as the measles, mumps, and rubella vaccine. The only previously described desensitization to epoetin alfa was for acute exanthematic pustulosis, a non-IgE-mediated reaction (5). The skin testing was negative at 20 minutes, 24, 48 and 72 hours. The desensitization was modeled after acetylsalicylic acid desensitization, and was administered with increasing doses over 2 days with premedication the evening before the desensitization with cetirizine 10 mg, ranitidine 150 mg, and prednisone 60 mg. The maintenance dose was epoetin alpha 3000 units administered subcutaneously twice weekly. In contrast, the clinical features of our case are consistent with an IgE-mediated event, which included urticaria, angioedema, and hypotension within minutes of the administration of epoetin alpha; a consistent pattern of symptoms after repeated exposure; a quick resolution of symptoms after administration of antihistamine; and a lasting remission of symptoms after withdrawal of the medication. A concurrent, increase in serum eosinophils in conjunction with a marked elevation in serum tryptase and subsequent positive intradermal testing further support the diagnosis of an IgE-mediated reaction. Our patient had received Epogen in a multidose preparation for several years. All preparations of Epogen contain epoetin alfa, as well as human albumin, sodium citrate, sodium chloride, and citric acid (4). Multidose preparations of Epogen also contain the preservative benzyl alcohol, which is not found in single-dose preparations. Single-dose preparations of Epogen can also contain sodium phosphate monobasic monohydrate and sodium phosphate dibasic anhydrate as buffering agents that are not found in the multidose preparation (4). Human serum albumin alone is not an effective antigen. The patient demonstrated positive intradermal testing to the preservative-free, polysorbate-free, single-dose preparation of Epogen supporting IgE antibodies against epoetin alfa itself. Because darbepoetin alfa represented a possible alternative therapy, skin prick testing and intradermal testing to darbepoetin alfa were also performed. Darbepoetin alfa differs from epoetin alfa in number of oligosaccharide chains, due to amino acid substitutions on the erythropoietin peptide chain (6). The positive intradermal testing to both epoetin alfa and darbepoetin alfa suggests sensitization to a shared structural element, thus eliminating darbepoetin as a substitute ESA option. Because the patient was a transplant candidate, it was important to try to induce tolerance to the epoetin alpha to avoid blood transfusions. We developed a desensitization protocol modeled after antibiotic protocols to induce tolerance for IgEmediated reactions. We started at 100 units of the final dose and gave increasing dose every 15 minutes until the total dose was achieved (Table 1). We continued a daily dose of 2000 units on nondialysis days and 10,000 units on the day of dialysis. After 2 weeks she was able to resume her original
664
Aziz et al.
protocol of 12,800 units three times a week with dialysis. Recombinant erythropoietin is a man-made version of natural erythropoietin and its production was made available through the cloning of the gene for human erythropoietin. Epoetin alfa is similar to the more than 60 other human recombinant proteins now available in that they are immunogenic, although less so than their nonhuman DNA derived predecessors. The reason for the development of antibodies to human DNA produced proteins is thought to be from loss of tolerance to self-antigens. Tolerance to self-antigens is initially induced in the thymus by destruction of self-reactive B cells in utero. Some self-reactive B cells escape but are maintained in a state of anergy outside of the thymus. They can be stimulated in several ways. T helper cells can activate self-reactive B cells. This occurs when T cells perceive “danger signals,” such as those generated by bacterial endotoxin acting through various Toll-like receptors. Alternatively, oligonucleotides, with unmethylated cytosine-guanosine dinucleotides (CpG) in DNA itself can provoke the formation of antibodies. Finally, self-antigens presented on viruses can produce a profound antibody response which is predominantly IgG but in certain hosts could lead to an IgE response eliciting an allergic reaction (6). Multiple factors contribute to the immune response to human DNA derived proteins. These include protein structure, immune modulatory effect of the protein, formulation, contaminants and impurities, route, dose, frequency and duration of administration, the major histocompatibility com-
plex (MHC) genotype of the patient, and associated diseases and therapies (6). Erythropoiesis-stimulating agents have changed the practice of nephrology but are not without side effects. The most common serious effects include hypertension and thrombosis. Typical skin reactions include pruritus and wheals at the injection site; however, significant reactions consistent with an IgE-mediated systemic reaction including anaphylaxis are less common and require the cessation of its use with the accompanying risk of anemia or need for transfusions. We describe the first case of successful desensitization to epoetin alfa for IgEmediated symptoms resulting in ongoing tolerance. We present this protocol as a consideration for patients with significant allergic reactions to this often-essential agent.
References 1. Garcia JE, Senent C, Pascual C, Fernandez G, Perez-Carral C, DiazTejeiro R, et al.: Anaphylactic reaction to recombinant human erythropoietin. Nephron 65:636–637, 1993 2. Limaye S, Steele RH, Quin J, Cleland B: An allergic reaction to erythropoietin secondary to polysorbate hypersensitivity. J Allergy Clin Immunol 110:530, 2002 3. Sakaguchi M, Kaneda H, Sakae I: A case of anaphylaxis to gelatin included in erythropoietin products. J Allergy Clin Immunol 103: 349–350, 1999 4. EpogenÒ (Epoetin alfa) prescribing information. June 2011, Amgen, Inc. Available at: http://www.epogen.com, accessed February 23, 2012 5. Ruano FJ, Garciamartin MI, Vazquez de la Torre M, et al.: Desensitization of epoetin-alpha in a confirmed case of acute exanthematic pustulosis. Allergy 64:1797–1798, 2009 6. Hermeling S, Crommelin DJA, Schellekens H, Jiskoot W: Structureimmunogenicity relationships of therapeutic proteins. Pharm Res 21:897–903, 2004
Series Editor: Roger A. Rodby
Anaphylactic Shock at the End of Hemodialysis Nivin Aziz,* Carla Luna,† Farheen Mirza,† and Mary Tobin†
*Section of Nephrology, Department of Medicine, Rush University Medical Center, Chicago, Illinois, and †Section of Allergy and Immunology, Department of Immunology & Microbiology, Rush University Medical Center, Chicago, Illinois
ABSTRACT Allergic reactions to epoetin alfa, including anaphylaxis, have been described but desensitization in the setting of an IgE-mediated reaction has not been reported. We present a case of a hemodialysis patient who developed symptoms of an IgE-mediated allergic response to epoetin alfa that occurred after each administration. These reactions progressed to a single episode of
anaphylaxis with generalized pruritus, urticaria, oropharyngeal edema, and hypotension that prompted its discontinuation. Intradermal skin testing confirmed an allergic response to this agent. The patient then underwent a desensitization procedure to epoetin alpha after which she was able to tolerate it without further problems.
After its 1984 approval by the Food and Drug Administration (FDA), epoetin alfa became the standard of care for treating anemia associated with chronic kidney disease (CKD). Mild allergic reactions to erythropoiesis-stimulating agents (ESAs) have been described. Even more unusual are anaphylactic reactions following ESA administration, with the timing and severity suggesting the mechanism to be an allergic hypersensitivity reaction (1–3). We report the first case of a patient to receive successful desensitization after development of anaphylaxis to epoetin alfa.
Amgen, Inc.) (4). The patient received epoetin alfa thrice weekly (initially intravenously but subcutaneously for the last few years), usually during the last hour of treatment, with no adverse effect for 12 years. Without any change in medications, addition of herbal medications or contact sensitivities, she developed an urticarial rash at the base of her neck and at the site of access to her arteriovenous fistula (Fig. 1). This reaction occurred toward the end, or shortly after, completing each dialysis
Case Presentation A 44-year-old woman with end-stage renal disease secondary to focal segmental glomerulosclerosis had received hemodialysis since January 1999. At the time of initiating dialysis, she was noted to be anemic and was started on epoetin alpha (Epogen, Address correspondence to: Mary Tobin, MD, Rush University Medical Center, 1725 W. Harrison, Suite 117, Chicago, IL 60612, Tel.: +312-942-6296, Fax: +312-563-2201, or e-mail: [email protected]. Seminars in Dialysis—Vol 28, No 6 (November–December) 2015 pp. 661–664 DOI: 10.1111/sdi.12402 © 2015 Wiley Periodicals, Inc.
Fig. 1. Urticarial rash seen on the neck shortly after the administration of epoetin alfa. 661
662
Aziz et al.
treatment. The rash recurred on several subsequent dialyses and progressed to generalized pruritus. She was given oral diphenhydramine with symptom resolution. She was changed to a single-dose Epogen vial due to the concern that this was a reaction to the presence of a preservative in the multidose vial, but she continued to develop a rash with pruritus following the epoetin alfa administration. Within a few weeks, without any changes in dosing, the patient developed her typical symptoms of generalized pruritus accompanied by urticaria, but this time it was accompanied by a burning sensation of the eyes, swelling of the lips and tongue, and difficulty breathing. Her blood pressure dropped to 68/36 mmHg and the hemodialysis treatment was discontinued; 911 was called. She received treatment for anaphylaxis and was transferred to the Emergency Department (ED) of Rush University Medical Center. On arrival to the ED her symptoms had subsided and her blood pressure had improved to 96/60. Significant lab results in the ED included a hemoglobin value of 10.7 g/dl and white blood cell count of 3.4 9 103 cells/mm3 with 18.2 percent eosinophils (absolute eosinophil count of 619 cells/mm3). A total tryptase level was 56.5 ng/ml (normal than the negative control (saline). Epoetin alfa was positive at a concentration of 1000 units/ml as was darbepoetin alfa, at a concentration of 10 lg/ml (Fig. 2). Desensitization Protocol The patient underwent a desensitization protocol to epoetin alfa in the intensive care unit over 3 hours to achieve a total therapeutic dose of 12,800 units. Starting with 100 units, increasing incremental doses were given subcutaneously every 15 minutes (Table 1). She tolerated desensitization without any complications. Because the half-life of subcutaneously administered epoetin alfa is between 7 and 18 hours, and to ensure maintenance of tolerance, the patient received epoetin alfa 2000 units subcutaneously daily on nondialysis days in addition to 10,000 units of epoetin alfa with each session of dialysis. This was done for a 2-week period and she returned to her previous dosing of epoetin alpha schedule of 12,800 units with dialysis three times a week without daily dosing. Her hemoglobin improved to 10.6 mg/dl and she remained on epoetin alpha without any evidence of an allergic response. Discussion While rare, allergic reactions on hemodialysis typically occur at the beginning of the treatment and are usually associated with exposure to ethylene oxide, heparin, or the dialyzer membrane. Reactions
Methods of Skin Testing Skin testing to undiluted epoetin alfa (10,000 units/ml) and darbepoetin alfa (100 lg/ 0.5 ml) from single-use, preservative-free preparations was performed at increasing concentrations of epoetin alfa (1 unit/ml, 10 units/ml, 100 units/ml, 1000 units/ml) and darbepoetin alfa (0.01 lg/ml, 0.1 lg/ml, 1 lg/ml, 10 lg/ml). Due to the possibility of anaphylaxis, initial dilutions were placed from least concentrated to most concentrated via prick apparatus percutaneously to abrade the skin, accompanied by a positive control (histamine sulfate 10 mg/ml) and a negative control (saline). The positive control ensures that the patient can respond to histamine, a marker of mast cell degranulation, when an antigen is recognized. The negative saline control assesses for dermographism, a nonspecific histamine response that would invalidate the testing. The percutaneous skin testing to epoetin alfa and darbepoetin alfa was negative at all concentrations. Intradermal testing was performed by placing 0.02 ml of each drug and at the defined concentrations, from least to most concentrated at 15 minute
Fig. 2. The arrow on the right forearm indicates the positive wheal to epoetin alfa at a concentration of 1000 units/ml during intradermal testing. The arrow on the left forearm demonstrates a positive response to darbepoetin alpha at 10 lg/ml.
DESENSITIZATION FOR ERYTHROPOIETIN ALLERGY
TABLE 1. Desensitization schedule Desensitization protocol to epoetin alfa Volume (ml) 0.05 0.1 0.15 0.2 0.4 0.5 1 1 1
Concentration (units/ml)
Dose (units)
Cumulative dose (units)
2000 2000 2000 2000 2000 2000 2000 4000 4000
100 200 300 400 800 1000 2000 4000 4000
100 300 600 1000 1800 2800 4800 8800 12,800
can occur later in the treatment and these are usually related to the administration of antibiotics or very rarely to an ESA, both administered toward or at the end of treatment. The timing of our patient’s allergic reaction and the lack of any other potential etiology led us to suspect and discontinue the use of the ESA with the complete resolution of symptoms. Skin testing with epoetin alfa confirmed the diagnosis. Subsequent desensitization was successful in allowing the patient to resume receiving epoetin alfa without any allergic symptoms. This is the first report to demonstrate desensitization to epoetin alfa in the setting of anaphylaxis. Anaphylaxis due to epoetin alfa was first reported in 1993 by Garcia and colleagues (1). They performed skin prick testing and intradermal injections with rHuEPO (Erantin, Boehringer Mannheim, FRG) but this did not produce a skin reaction. They did, however, detect IgE antibodies to rHuEPO by RAST testing (Pharmacia-Sweden) with modified Erantin as the antigen. The rHuEPO in their report was administered intravenously suggesting that the route of sensitization may be important in interpreting the results of skin tests. Certainly, negative skin tests do not eliminate the possibility of an IgE-mediated hypersensitivity reaction. Two other studies demonstrated anaphylaxis to ESA agents which were attributed to stabilizing agents. The first reaction was related to polysorbate 80 sensitivity (2). The patient in that report had previously developed a large local reaction to the influenza vaccine, containing polysorbate 80. Forty minutes after the administration of Eprex (JanssenCilag, Beersa, Belgium), she developed pruritus, generalized erythema, and oral facial edema. She was skin tested with Eprex and Neupogen (Amgen, Thousand Oaks, CA) both of which have polysorbate 80 and was positive to both agents and pharmaceutical grade polysorbate. Skin testing with an ESA agent containing no polysorbate 80 was negative. She received a supervised clinical challenge with no reaction. The other report involved a change in the stabilizer for an EPO product from human serum albumin to a bovine gelatin (3). The authors demonstrated anti-bovine gelatin IgE and no IgE antibodies to EPO by ELISA. Anti-gelatin antibodies are well described as the cause of allergic
663
reactions to vaccines such as the measles, mumps, and rubella vaccine. The only previously described desensitization to epoetin alfa was for acute exanthematic pustulosis, a non-IgE-mediated reaction (5). The skin testing was negative at 20 minutes, 24, 48 and 72 hours. The desensitization was modeled after acetylsalicylic acid desensitization, and was administered with increasing doses over 2 days with premedication the evening before the desensitization with cetirizine 10 mg, ranitidine 150 mg, and prednisone 60 mg. The maintenance dose was epoetin alpha 3000 units administered subcutaneously twice weekly. In contrast, the clinical features of our case are consistent with an IgE-mediated event, which included urticaria, angioedema, and hypotension within minutes of the administration of epoetin alpha; a consistent pattern of symptoms after repeated exposure; a quick resolution of symptoms after administration of antihistamine; and a lasting remission of symptoms after withdrawal of the medication. A concurrent, increase in serum eosinophils in conjunction with a marked elevation in serum tryptase and subsequent positive intradermal testing further support the diagnosis of an IgE-mediated reaction. Our patient had received Epogen in a multidose preparation for several years. All preparations of Epogen contain epoetin alfa, as well as human albumin, sodium citrate, sodium chloride, and citric acid (4). Multidose preparations of Epogen also contain the preservative benzyl alcohol, which is not found in single-dose preparations. Single-dose preparations of Epogen can also contain sodium phosphate monobasic monohydrate and sodium phosphate dibasic anhydrate as buffering agents that are not found in the multidose preparation (4). Human serum albumin alone is not an effective antigen. The patient demonstrated positive intradermal testing to the preservative-free, polysorbate-free, single-dose preparation of Epogen supporting IgE antibodies against epoetin alfa itself. Because darbepoetin alfa represented a possible alternative therapy, skin prick testing and intradermal testing to darbepoetin alfa were also performed. Darbepoetin alfa differs from epoetin alfa in number of oligosaccharide chains, due to amino acid substitutions on the erythropoietin peptide chain (6). The positive intradermal testing to both epoetin alfa and darbepoetin alfa suggests sensitization to a shared structural element, thus eliminating darbepoetin as a substitute ESA option. Because the patient was a transplant candidate, it was important to try to induce tolerance to the epoetin alpha to avoid blood transfusions. We developed a desensitization protocol modeled after antibiotic protocols to induce tolerance for IgEmediated reactions. We started at 100 units of the final dose and gave increasing dose every 15 minutes until the total dose was achieved (Table 1). We continued a daily dose of 2000 units on nondialysis days and 10,000 units on the day of dialysis. After 2 weeks she was able to resume her original
664
Aziz et al.
protocol of 12,800 units three times a week with dialysis. Recombinant erythropoietin is a man-made version of natural erythropoietin and its production was made available through the cloning of the gene for human erythropoietin. Epoetin alfa is similar to the more than 60 other human recombinant proteins now available in that they are immunogenic, although less so than their nonhuman DNA derived predecessors. The reason for the development of antibodies to human DNA produced proteins is thought to be from loss of tolerance to self-antigens. Tolerance to self-antigens is initially induced in the thymus by destruction of self-reactive B cells in utero. Some self-reactive B cells escape but are maintained in a state of anergy outside of the thymus. They can be stimulated in several ways. T helper cells can activate self-reactive B cells. This occurs when T cells perceive “danger signals,” such as those generated by bacterial endotoxin acting through various Toll-like receptors. Alternatively, oligonucleotides, with unmethylated cytosine-guanosine dinucleotides (CpG) in DNA itself can provoke the formation of antibodies. Finally, self-antigens presented on viruses can produce a profound antibody response which is predominantly IgG but in certain hosts could lead to an IgE response eliciting an allergic reaction (6). Multiple factors contribute to the immune response to human DNA derived proteins. These include protein structure, immune modulatory effect of the protein, formulation, contaminants and impurities, route, dose, frequency and duration of administration, the major histocompatibility com-
plex (MHC) genotype of the patient, and associated diseases and therapies (6). Erythropoiesis-stimulating agents have changed the practice of nephrology but are not without side effects. The most common serious effects include hypertension and thrombosis. Typical skin reactions include pruritus and wheals at the injection site; however, significant reactions consistent with an IgE-mediated systemic reaction including anaphylaxis are less common and require the cessation of its use with the accompanying risk of anemia or need for transfusions. We describe the first case of successful desensitization to epoetin alfa for IgEmediated symptoms resulting in ongoing tolerance. We present this protocol as a consideration for patients with significant allergic reactions to this often-essential agent.
References 1. Garcia JE, Senent C, Pascual C, Fernandez G, Perez-Carral C, DiazTejeiro R, et al.: Anaphylactic reaction to recombinant human erythropoietin. Nephron 65:636–637, 1993 2. Limaye S, Steele RH, Quin J, Cleland B: An allergic reaction to erythropoietin secondary to polysorbate hypersensitivity. J Allergy Clin Immunol 110:530, 2002 3. Sakaguchi M, Kaneda H, Sakae I: A case of anaphylaxis to gelatin included in erythropoietin products. J Allergy Clin Immunol 103: 349–350, 1999 4. EpogenÒ (Epoetin alfa) prescribing information. June 2011, Amgen, Inc. Available at: http://www.epogen.com, accessed February 23, 2012 5. Ruano FJ, Garciamartin MI, Vazquez de la Torre M, et al.: Desensitization of epoetin-alpha in a confirmed case of acute exanthematic pustulosis. Allergy 64:1797–1798, 2009 6. Hermeling S, Crommelin DJA, Schellekens H, Jiskoot W: Structureimmunogenicity relationships of therapeutic proteins. Pharm Res 21:897–903, 2004
