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Diffuse Alveolar Haemorrhage: A Fatal Complication After Alemtuzumab Induction Therapy in Renal Transplantation
Diffuse Alveolar Haemorrhage: A Fatal Complication After Alemtuzumab Induction Therapy in Renal Transplantation W. Tahira, A. Hakeema, R. Bakerb, and N. Ahmada,* a Division of Surgery, Department of Transplantation and bDepartment of Renal Medicine, St James’s University Hospital, Leeds, United Kingdom
ABSTRACT We report a fatal case of alemtuzumab-induced diffuse alveolar hemorrhage in an 18-year-old male with Alport syndrome. The patient developed acute onset shortness of breath, hemoptysis and fever after renal transplantation. Computed tomography findings were consistent with adult respiratory distress syndrome. Bronchoscopy and broncho-alveolar lavage was performed that showed no evidence of pathogenic bacteria or opportunistic infection. The patient was intubated and ventilated because of worsening respiratory function. The patient received plasma electrophoresis and was maintained on tacrolimus and steroids; however, unfortunately the patient died 31 days post-transplantation due to worsening respiratory function and declining graft function. Although the prevalence and the exact mechanism of this fatal complication remain unknown, an awareness of this complication is important to all clinicians using alemtuzumab. This is a second report of diffuse alveolar hemorrhage secondary to alemtuzumab induction in patients with Alport syndrome.
A
LEMTUZUMAB is a novel, fully humanized immunoglobulin G1 monoclonal antibody directed against CD52 that leads to lymphocyte depletion [1]. Not only has it effectively been used in the treatment of various malignancies [2], but its use for induction immunosuppression in a calcineurin inhibitor (CNI) reducing and steroid-sparing regimen in kidney, liver, and pancreas transplantation has also been widely reported [3,4]. A study by Watson et al concluded satisfactory long-term graft and patient survival rates compared with standard triple immunosuppression containing CNI, mycophenolate mofetil, and steroids [5]. Although alemtuzumab is currently widely used and is an efficacious [3] immunosuppressive agent with reduced allograft rejection rates, it has a side-effect profile that is not completely understood [6]. Diffuse alveolar hemorrhage (DAH) is one such complication that has previously been reported in a single case. We report a fatal case of DAH in an 18-year-old male with Alport syndrome after alemtuzumab induction for renal transplantation. CASE REPORT An 18-year-old male with end-stage renal failure secondary to Alport syndrome who was maintained on ambulatory peritoneal dialysis ª 2015 Published by Elsevier Inc. 360 Park Avenue South, New York, NY 10010-1710
Transplantation Proceedings, 47, 151e154 (2015)
underwent deceased donor renal transplantation. Pretransplantation, there was no history of cardiopulmonary dysfunction. On admission for transplantation, his respiratory examination was normal and the preoperative chest radiograph was unremarkable (Fig 1A). The kidney graft was procured from an 11-year-old female donation-after-brain-death donor with low-grade glioma. The implantation was standard with the left kidney bearing normal anatomy implanted in the right iliac fossa. Vascular anastomoses were to the right external iliac vein and the external iliac artery. The ureter was implanted in an onlay manner to the bladder over an indwelling 6-Fr double-J stent. The operative procedure was uneventful. The patient received alemtuzumab 30 mg subcutaneously 30 minutes after premedication with intravenous methylprednisolone 500 mg, chlorpheniramine 10 mg, and paracetamol 1 g. The graft functioned immediately with good urine output and a significant reduction of serum creatinine in the first 24 hours. On the second postoperative day, the patient developed a wet cough with a decrease in oxygen saturation to 94% on room air and a temperature of 39 . Bilateral anterior chest auscultation was normal. A provisional diagnosis of sepsis was made and a full septic screen was undertaken;
*Address correspondence to Mr Niaz Ahmad, MD, FRCS, Consultant Surgeon, Division of Surgery, Department of Transplantation, St James’s University Hospital, Beckett Street, Leeds LS9 7TF, United Kingdom. E-mail: [email protected] 0041-1345/14 http://dx.doi.org/10.1016/j.transproceed.2014.10.037
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Fig 1. (A) Preoperative chest radiograph with no abnormalities. (B) Plain radiograph 3 days post-transplantation showing bilateral perihilar shadowing.
the patient was commenced on intravenous antibiotics. Twenty-four hours later, the patient developed sudden onset hemoptysis, shortness of breath, and tachypnea alongside fever and a decrease in oxygen saturation to 70%. On chest auscultation there were bilateral coarse crepitations. The clinical picture indicated a lower respiratory tract infection or a pulmonary embolism. The patient was immediately transferred to a high dependency unit. A repeat chest radiograph showed extensive bilateral perihilar air space shadowing but no evidence of pulmonary edema or pleural effusion (Fig 1B). A computed tomographic pulmonary angiogram showed bilateral upper and lower lobe opacities with bilateral pleural effusions but no evidence of a pulmonary embolism (Fig 2). These findings were consistent with acute respiratory distress syndrome and the patient was initiated on continuous positive airway pressure ventilation. An echocardiogram showed good left ventricular function and cardiac valves were unremarkable. The respiratory failure continued to worsen and the patient was intubated and placed on mechanical ventilation on day 5. A fiber optic bronchoscopy was performed and bronchoalveolar lavage (BAL) was performed for bacteriology and virology cultures, acidfast bacilli cultures, and cytology. BAL fluid analysis was positive for polymorphs but showed no evidence of pathogenic bacteria or opportunistic infection.
Fig 2. Chest computed tomography 3 days transplantation showing bilateral alveolar opacities.
post-
During the period of worsening respiratory function, the patient’s graft function was optimal. However, the graft function started to decline on post-transplantation day 7 and peritoneal dialysis was initiated. A renal biopsy 12 days post-transplantation confirmed the diagnosis of acute kidney injury secondary to acute tubular necrosis; however, there was no evidence of acute rejection, anti-GBM, or other immune complex disease. In the high dependency unit the patient received plasma exchange and was maintained on tacrolimus and steroids. The patient remained intubated and ventilation-dependent and unfortunately died 31 days post-transplantation due to worsening respiratory function and failing graft function.
DISCUSSION
The impact of alemtuzumab on the cardiovascular system has been widely reported, in particular its association with heart failure and hypotension [7,8]. Other major complications include increased risk of opportunistic infections, acute respiratory failure, and hematological toxicity [9,10]. Although DAH has been reported with various drugs [11,12] its association with alemtuzumab, to the authors’ knowledge, has only ever been reported once in the literature [13]. Sachdeva et al [13] described the case of a 26-year-old man with Alport syndrome who developed DAH as a complication of alemtuzumab therapy after renal transplantation in a similar clinical course as our patient. Alemtuzumab therapy was administered as part of an induction regime, and 2 days postoperatively the patient developed hemoptysis and shortness of breath. The patient underwent a CT of the chest that showed diffuse alveolar opacities followed by a BAL that revealed blood in the sequential aliquots. The patient subsequently developed acute respiratory failure and acute renal failure for which mechanical ventilation, plasmapheresis, and hemodialysis were required. The patient was eventually discharged from the hospital 28 days post-transplantation. Clinical suspicion of DAH should be high in patients presenting with the classical symptoms of hemoptysis and pulmonary infiltrates. However, presentation may be varied with symptoms such as chest pain, cough, or fever. Renal
ALEMTUZUMAB-INDUCED ALVEOLAR HEMORRHAGE
involvement is the most common extrapulmonary manifestation with the risk of developing DAH increased in those with active renal disease [14]. Diagnosis is usually confirmed with a combination of radiological evidence (perihilar alveolar infiltrates) and BAL fluid sample analysis (increased red blood cell count or hemosiderin-laden macrophages). In this case, a combination of clinical and radiological evidence indicated DAH. A temporal relationship to alemtuzumab administration implicated this to be the likely causative agent. This was further supported by lack of evidence both clinically and in the published literature towards an alternative diagnosis such as tacrolimus-induced DAH. Tacrolimus instead has been shown to be effective in the treatment of antineutrophil cytoplasmic antibody positive DAH [15]. Paracetamol, chlorpheniramine, and methylprednisolone used as premedication agents before alemtuzumab administration, and none of the new-generation anesthetic agents used intra-operatively have been reported to cause DAH; hence, alemtuzumab is likely to be the causative agent in this case. The severity of respiratory failure and subsequent mechanical ventilation prevented us from attaining a bronchial lung biopsy for confirmatory purposes. There was no clinical or histologic evidence of vasculitis. In both the reported cases of DAH secondary to alemtuzumab, the patient suffered from Alport syndrome suggesting that patients with Alport syndrome may have a predisposition to developing DAH when exposed to alemtuzumab. In the 1960s, Lerner et al [16] induced glomerulonephritis by introducing anti-GBM antibodies in a primate model thereby showing the involvement of an autoantibody in causing the disease. Since then, various studies [17,18] have shown that patients with Goodpasture syndrome exhibit autoantibodies to the NC1 domain of a3, a4, and a5 (IV) collagen in both kidneys and lungs. The a345 collagen network is also a target for alloantibodies in Alport post-transplantation nephritis. As their immune system has never seen the normal human renal GBM, it is recognized as “foreign” in these patients and they develop post-transplantation nephritis (patients with Alport syndrome do not develop anti-GBM disease pretransplantation because their GBMs retain a fetal distribution of a1 and a2 isoforms) [19]. For this reason they will not experience pulmonary hemorrhage unless they also have a lung transplantation as the pulmonary basement membrane is still of the Alport syndrome phenotype. However, Kalluri et al [20] have suggested that a345 collagen chains may have protective properties and prevent proteolytic degradation at the site of glomerular filtration in those with anti-GBM disease, but their relative absence in those with Alport syndrome may explain basement membrane splitting and increased kidney damage. Thus, it is possible that increased susceptibility to protease/oxidants may play a role in disrupting the alveolar-capillary barrier and predispose those with Alport syndrome to increased pulmonary toxicity. In conclusion, we describe a fatal case of alemtuzumabinduced pulmonary hemorrhage in the setting of Alport
153
syndrome. Although the prevalence and the exact mechanism of this fatal complication remain unknown, an awareness of this complication is important to all clinicians involved in alemtuzumab induction therapy for transplantation and for other indications.
REFERENCES [1] Hale G, Waldmann H. From laboratory to the clinic: The story of CAMPATH-1. In: George A, Urch C, editors. Methods in molecular medicine: diagnostic and therapeutic antibodies, vol 40. Totowa, NJ: Humana Press Inc; 2000. p. 243. [2] Moreton P, Kennedy B, Lucas G, Leach M, Rassam SM, Haynes A, et al. Eradication of minimal residual disease in B-cell chronic lymphocytic leukemia after alemtuzumab therapy is associated with prolonged survival. J Clin Oncol 2005;23:2971. [3] Magliocca JF, Knechtle SJ. The evolving role of alemtuzumab (Campath-1H) for immunosuppressive therapy in organ transplantation. Transpl Int 2006;19:705e14. [4] Morris PJ, Russell NK. Alemtuzumab (Campath-1H): a systematic review in organ transplantation. Transplantation 2006;81:1361e7. [5] Watson CJ, Bradley JA, Friend PJ, Firth J, Taylor CJ, Bradley JR, et al. Alemtuzumab (Campath 1H) induction therapy in cadaveric kidney transplantation d efficacy and safety at five years. Am J Transplant 2005;5:1347. [6] Muthusamy ASR, Vaidya AC, Sinha S, Roy D, Elker DE, Friend PJ. Alemtuzumab induction and steroid-free immunosuppression in pancreas transplantation. Am J Transplant 2008;8:2126. [7] Oshima K, Sakata-Yanagimoto M, Asano-Moriy Y, Izutsu K, Watanabe T, Shoda E, et al. Cardiac complications after haploidentical HLA-mismatched hematopoietic stem cell transplantation using in vivo alemtuzumab. Bone Marrow Transplant 2005;36:821. [8] Lenihan DJ, Alencar AJ, Yang D, Kurzrock R, Keating MJ, Duvic M. Cardiac toxicity of alemtuzumab in patients with mycosis fungoides/Sezary syndrome. Blood 2004;104:655. [9] US Food and Drug Administration. FDA alert for healthcare professionals: alemtuzumab. Available at: http://www.fda.gov/ Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsand Providers/ucm125216.htm. Accessed July 28, 2014. [10] Afessa B, Tefferi A, Litzow MR, Peters SG. Outcomes of diffuse alveolar hemorrhage in hematopoeitic stem cell transplant recipients. Am J Respir Crit Care Med 2002;166:1364e8. [11] Ikeda S, Sekine A, Kato T, Yoshida M, Ogata R, Baba T, et al. Diffuse alveolar hemorrhage as a fatal adverse effect of bevacizumab: an autopsy case. Jpn J Clin Oncol 2014;44:497e500. [12] Mal H, Veyradier A, Brugiere O, Da Silva D, Colombat M, Azoulay E, et al. Thrombotic microangiopathy with acquired deficiency of ADAMTS 13 activity in lung transplant recipients. Transplantation 2006;81:1628e32. [13] Sachdeva A, Matuschak G. Diffuse alveolar hemorrhage following alemtuzumab. Chest 2008;133:1476. [14] Badsha H, The CL, Kong KO, Lian TY, Chng HH. Pulmonary hemorrhage in systemic lupus erythematosus. Semin Arthritis Rheum 2004;33:414e21. [15] Kawasaki S, Nakamura H, Honda E, Iwanaga N, Kawakami A, Ida H, et al. Tacrolimus as a reinforcement therapy for a patient with MPO-ANCA associated diffuse alveolar hemorrhage. Clin Rheumatol 2007;26:1211e4. [16] Lerner RA, Glassock RJ, Dixon FJ. The role of antiglomerular basement membrane antibody in the pathogenesis of human glomerulonephritis. J Exp Med 1967;126:989e1004. [17] Turner N, Mason PJ, Brown R, Fox M, Povey S, Rees A, et al. Molecular cloning of the human Goodpasture antigen demonstrates it to be the alpha 3 chain of type IV collagen. J Clin Invest 1992;89:592e601.
154 [18] Saus J, Wieslander J, Langeveld JP, Quinones S, Hudson BG. Identification of the Goodpasture antigen as the alpha 3(IV) chain of collagen IV. J Biol Chem 1988;263: 13374e80. [19] Kang JS, Kashtan CE, Turner AN, Heidet L, Hudson BG, Borza DB. The alloantigenic sites of alpha3alpha4alpha5 (IV) collagen: pathogenic X-linked Alport alloantibodies target two
TAHIR, HAKEEM, BAKER ET AL accessible conformational epitopes in the alpha5NC1 domain. J Biol Chem 2007;282:10670e7. [20] Kalluri R, Shield CF, Todd P, Hudson BG, Neilson EG. Isoform switching of type IV collagen is developmentally arrested in X-linked Alport syndrome leading to increased susceptibility of renal basement membrane to endoproteolysis. J Clin Invest 1997;99:2470e8.
ABSTRACT We report a fatal case of alemtuzumab-induced diffuse alveolar hemorrhage in an 18-year-old male with Alport syndrome. The patient developed acute onset shortness of breath, hemoptysis and fever after renal transplantation. Computed tomography findings were consistent with adult respiratory distress syndrome. Bronchoscopy and broncho-alveolar lavage was performed that showed no evidence of pathogenic bacteria or opportunistic infection. The patient was intubated and ventilated because of worsening respiratory function. The patient received plasma electrophoresis and was maintained on tacrolimus and steroids; however, unfortunately the patient died 31 days post-transplantation due to worsening respiratory function and declining graft function. Although the prevalence and the exact mechanism of this fatal complication remain unknown, an awareness of this complication is important to all clinicians using alemtuzumab. This is a second report of diffuse alveolar hemorrhage secondary to alemtuzumab induction in patients with Alport syndrome.
A
LEMTUZUMAB is a novel, fully humanized immunoglobulin G1 monoclonal antibody directed against CD52 that leads to lymphocyte depletion [1]. Not only has it effectively been used in the treatment of various malignancies [2], but its use for induction immunosuppression in a calcineurin inhibitor (CNI) reducing and steroid-sparing regimen in kidney, liver, and pancreas transplantation has also been widely reported [3,4]. A study by Watson et al concluded satisfactory long-term graft and patient survival rates compared with standard triple immunosuppression containing CNI, mycophenolate mofetil, and steroids [5]. Although alemtuzumab is currently widely used and is an efficacious [3] immunosuppressive agent with reduced allograft rejection rates, it has a side-effect profile that is not completely understood [6]. Diffuse alveolar hemorrhage (DAH) is one such complication that has previously been reported in a single case. We report a fatal case of DAH in an 18-year-old male with Alport syndrome after alemtuzumab induction for renal transplantation. CASE REPORT An 18-year-old male with end-stage renal failure secondary to Alport syndrome who was maintained on ambulatory peritoneal dialysis ª 2015 Published by Elsevier Inc. 360 Park Avenue South, New York, NY 10010-1710
Transplantation Proceedings, 47, 151e154 (2015)
underwent deceased donor renal transplantation. Pretransplantation, there was no history of cardiopulmonary dysfunction. On admission for transplantation, his respiratory examination was normal and the preoperative chest radiograph was unremarkable (Fig 1A). The kidney graft was procured from an 11-year-old female donation-after-brain-death donor with low-grade glioma. The implantation was standard with the left kidney bearing normal anatomy implanted in the right iliac fossa. Vascular anastomoses were to the right external iliac vein and the external iliac artery. The ureter was implanted in an onlay manner to the bladder over an indwelling 6-Fr double-J stent. The operative procedure was uneventful. The patient received alemtuzumab 30 mg subcutaneously 30 minutes after premedication with intravenous methylprednisolone 500 mg, chlorpheniramine 10 mg, and paracetamol 1 g. The graft functioned immediately with good urine output and a significant reduction of serum creatinine in the first 24 hours. On the second postoperative day, the patient developed a wet cough with a decrease in oxygen saturation to 94% on room air and a temperature of 39 . Bilateral anterior chest auscultation was normal. A provisional diagnosis of sepsis was made and a full septic screen was undertaken;
*Address correspondence to Mr Niaz Ahmad, MD, FRCS, Consultant Surgeon, Division of Surgery, Department of Transplantation, St James’s University Hospital, Beckett Street, Leeds LS9 7TF, United Kingdom. E-mail: [email protected] 0041-1345/14 http://dx.doi.org/10.1016/j.transproceed.2014.10.037
151
152
TAHIR, HAKEEM, BAKER ET AL
Fig 1. (A) Preoperative chest radiograph with no abnormalities. (B) Plain radiograph 3 days post-transplantation showing bilateral perihilar shadowing.
the patient was commenced on intravenous antibiotics. Twenty-four hours later, the patient developed sudden onset hemoptysis, shortness of breath, and tachypnea alongside fever and a decrease in oxygen saturation to 70%. On chest auscultation there were bilateral coarse crepitations. The clinical picture indicated a lower respiratory tract infection or a pulmonary embolism. The patient was immediately transferred to a high dependency unit. A repeat chest radiograph showed extensive bilateral perihilar air space shadowing but no evidence of pulmonary edema or pleural effusion (Fig 1B). A computed tomographic pulmonary angiogram showed bilateral upper and lower lobe opacities with bilateral pleural effusions but no evidence of a pulmonary embolism (Fig 2). These findings were consistent with acute respiratory distress syndrome and the patient was initiated on continuous positive airway pressure ventilation. An echocardiogram showed good left ventricular function and cardiac valves were unremarkable. The respiratory failure continued to worsen and the patient was intubated and placed on mechanical ventilation on day 5. A fiber optic bronchoscopy was performed and bronchoalveolar lavage (BAL) was performed for bacteriology and virology cultures, acidfast bacilli cultures, and cytology. BAL fluid analysis was positive for polymorphs but showed no evidence of pathogenic bacteria or opportunistic infection.
Fig 2. Chest computed tomography 3 days transplantation showing bilateral alveolar opacities.
post-
During the period of worsening respiratory function, the patient’s graft function was optimal. However, the graft function started to decline on post-transplantation day 7 and peritoneal dialysis was initiated. A renal biopsy 12 days post-transplantation confirmed the diagnosis of acute kidney injury secondary to acute tubular necrosis; however, there was no evidence of acute rejection, anti-GBM, or other immune complex disease. In the high dependency unit the patient received plasma exchange and was maintained on tacrolimus and steroids. The patient remained intubated and ventilation-dependent and unfortunately died 31 days post-transplantation due to worsening respiratory function and failing graft function.
DISCUSSION
The impact of alemtuzumab on the cardiovascular system has been widely reported, in particular its association with heart failure and hypotension [7,8]. Other major complications include increased risk of opportunistic infections, acute respiratory failure, and hematological toxicity [9,10]. Although DAH has been reported with various drugs [11,12] its association with alemtuzumab, to the authors’ knowledge, has only ever been reported once in the literature [13]. Sachdeva et al [13] described the case of a 26-year-old man with Alport syndrome who developed DAH as a complication of alemtuzumab therapy after renal transplantation in a similar clinical course as our patient. Alemtuzumab therapy was administered as part of an induction regime, and 2 days postoperatively the patient developed hemoptysis and shortness of breath. The patient underwent a CT of the chest that showed diffuse alveolar opacities followed by a BAL that revealed blood in the sequential aliquots. The patient subsequently developed acute respiratory failure and acute renal failure for which mechanical ventilation, plasmapheresis, and hemodialysis were required. The patient was eventually discharged from the hospital 28 days post-transplantation. Clinical suspicion of DAH should be high in patients presenting with the classical symptoms of hemoptysis and pulmonary infiltrates. However, presentation may be varied with symptoms such as chest pain, cough, or fever. Renal
ALEMTUZUMAB-INDUCED ALVEOLAR HEMORRHAGE
involvement is the most common extrapulmonary manifestation with the risk of developing DAH increased in those with active renal disease [14]. Diagnosis is usually confirmed with a combination of radiological evidence (perihilar alveolar infiltrates) and BAL fluid sample analysis (increased red blood cell count or hemosiderin-laden macrophages). In this case, a combination of clinical and radiological evidence indicated DAH. A temporal relationship to alemtuzumab administration implicated this to be the likely causative agent. This was further supported by lack of evidence both clinically and in the published literature towards an alternative diagnosis such as tacrolimus-induced DAH. Tacrolimus instead has been shown to be effective in the treatment of antineutrophil cytoplasmic antibody positive DAH [15]. Paracetamol, chlorpheniramine, and methylprednisolone used as premedication agents before alemtuzumab administration, and none of the new-generation anesthetic agents used intra-operatively have been reported to cause DAH; hence, alemtuzumab is likely to be the causative agent in this case. The severity of respiratory failure and subsequent mechanical ventilation prevented us from attaining a bronchial lung biopsy for confirmatory purposes. There was no clinical or histologic evidence of vasculitis. In both the reported cases of DAH secondary to alemtuzumab, the patient suffered from Alport syndrome suggesting that patients with Alport syndrome may have a predisposition to developing DAH when exposed to alemtuzumab. In the 1960s, Lerner et al [16] induced glomerulonephritis by introducing anti-GBM antibodies in a primate model thereby showing the involvement of an autoantibody in causing the disease. Since then, various studies [17,18] have shown that patients with Goodpasture syndrome exhibit autoantibodies to the NC1 domain of a3, a4, and a5 (IV) collagen in both kidneys and lungs. The a345 collagen network is also a target for alloantibodies in Alport post-transplantation nephritis. As their immune system has never seen the normal human renal GBM, it is recognized as “foreign” in these patients and they develop post-transplantation nephritis (patients with Alport syndrome do not develop anti-GBM disease pretransplantation because their GBMs retain a fetal distribution of a1 and a2 isoforms) [19]. For this reason they will not experience pulmonary hemorrhage unless they also have a lung transplantation as the pulmonary basement membrane is still of the Alport syndrome phenotype. However, Kalluri et al [20] have suggested that a345 collagen chains may have protective properties and prevent proteolytic degradation at the site of glomerular filtration in those with anti-GBM disease, but their relative absence in those with Alport syndrome may explain basement membrane splitting and increased kidney damage. Thus, it is possible that increased susceptibility to protease/oxidants may play a role in disrupting the alveolar-capillary barrier and predispose those with Alport syndrome to increased pulmonary toxicity. In conclusion, we describe a fatal case of alemtuzumabinduced pulmonary hemorrhage in the setting of Alport
153
syndrome. Although the prevalence and the exact mechanism of this fatal complication remain unknown, an awareness of this complication is important to all clinicians involved in alemtuzumab induction therapy for transplantation and for other indications.
REFERENCES [1] Hale G, Waldmann H. From laboratory to the clinic: The story of CAMPATH-1. In: George A, Urch C, editors. Methods in molecular medicine: diagnostic and therapeutic antibodies, vol 40. Totowa, NJ: Humana Press Inc; 2000. p. 243. [2] Moreton P, Kennedy B, Lucas G, Leach M, Rassam SM, Haynes A, et al. Eradication of minimal residual disease in B-cell chronic lymphocytic leukemia after alemtuzumab therapy is associated with prolonged survival. J Clin Oncol 2005;23:2971. [3] Magliocca JF, Knechtle SJ. The evolving role of alemtuzumab (Campath-1H) for immunosuppressive therapy in organ transplantation. Transpl Int 2006;19:705e14. [4] Morris PJ, Russell NK. Alemtuzumab (Campath-1H): a systematic review in organ transplantation. Transplantation 2006;81:1361e7. [5] Watson CJ, Bradley JA, Friend PJ, Firth J, Taylor CJ, Bradley JR, et al. Alemtuzumab (Campath 1H) induction therapy in cadaveric kidney transplantation d efficacy and safety at five years. Am J Transplant 2005;5:1347. [6] Muthusamy ASR, Vaidya AC, Sinha S, Roy D, Elker DE, Friend PJ. Alemtuzumab induction and steroid-free immunosuppression in pancreas transplantation. Am J Transplant 2008;8:2126. [7] Oshima K, Sakata-Yanagimoto M, Asano-Moriy Y, Izutsu K, Watanabe T, Shoda E, et al. Cardiac complications after haploidentical HLA-mismatched hematopoietic stem cell transplantation using in vivo alemtuzumab. Bone Marrow Transplant 2005;36:821. [8] Lenihan DJ, Alencar AJ, Yang D, Kurzrock R, Keating MJ, Duvic M. Cardiac toxicity of alemtuzumab in patients with mycosis fungoides/Sezary syndrome. Blood 2004;104:655. [9] US Food and Drug Administration. FDA alert for healthcare professionals: alemtuzumab. Available at: http://www.fda.gov/ Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsand Providers/ucm125216.htm. Accessed July 28, 2014. [10] Afessa B, Tefferi A, Litzow MR, Peters SG. Outcomes of diffuse alveolar hemorrhage in hematopoeitic stem cell transplant recipients. Am J Respir Crit Care Med 2002;166:1364e8. [11] Ikeda S, Sekine A, Kato T, Yoshida M, Ogata R, Baba T, et al. Diffuse alveolar hemorrhage as a fatal adverse effect of bevacizumab: an autopsy case. Jpn J Clin Oncol 2014;44:497e500. [12] Mal H, Veyradier A, Brugiere O, Da Silva D, Colombat M, Azoulay E, et al. Thrombotic microangiopathy with acquired deficiency of ADAMTS 13 activity in lung transplant recipients. Transplantation 2006;81:1628e32. [13] Sachdeva A, Matuschak G. Diffuse alveolar hemorrhage following alemtuzumab. Chest 2008;133:1476. [14] Badsha H, The CL, Kong KO, Lian TY, Chng HH. Pulmonary hemorrhage in systemic lupus erythematosus. Semin Arthritis Rheum 2004;33:414e21. [15] Kawasaki S, Nakamura H, Honda E, Iwanaga N, Kawakami A, Ida H, et al. Tacrolimus as a reinforcement therapy for a patient with MPO-ANCA associated diffuse alveolar hemorrhage. Clin Rheumatol 2007;26:1211e4. [16] Lerner RA, Glassock RJ, Dixon FJ. The role of antiglomerular basement membrane antibody in the pathogenesis of human glomerulonephritis. J Exp Med 1967;126:989e1004. [17] Turner N, Mason PJ, Brown R, Fox M, Povey S, Rees A, et al. Molecular cloning of the human Goodpasture antigen demonstrates it to be the alpha 3 chain of type IV collagen. J Clin Invest 1992;89:592e601.
154 [18] Saus J, Wieslander J, Langeveld JP, Quinones S, Hudson BG. Identification of the Goodpasture antigen as the alpha 3(IV) chain of collagen IV. J Biol Chem 1988;263: 13374e80. [19] Kang JS, Kashtan CE, Turner AN, Heidet L, Hudson BG, Borza DB. The alloantigenic sites of alpha3alpha4alpha5 (IV) collagen: pathogenic X-linked Alport alloantibodies target two
TAHIR, HAKEEM, BAKER ET AL accessible conformational epitopes in the alpha5NC1 domain. J Biol Chem 2007;282:10670e7. [20] Kalluri R, Shield CF, Todd P, Hudson BG, Neilson EG. Isoform switching of type IV collagen is developmentally arrested in X-linked Alport syndrome leading to increased susceptibility of renal basement membrane to endoproteolysis. J Clin Invest 1997;99:2470e8.