Letters to the Editor
* 2014 Lippincott Williams & Wilkins
At the end of the surgery, transplanted upper extremities had good perfusion, and the patient’s hemodynamic and clinical data were normal, except for a lactate level of 4.2 mmol/L. She remained stable at intensive care unit for the next 12 hr. The second dose of ATG (50 mg) was administered 24 hr after the first dose. Ten hours later, her heart rate increased to 110 beats per min, and because her mean arterial blood pressure decreased, norepinephrine was started. Simultaneously, there was indirect data of decreased cardiac output (SvO2, 61%; central venous pressure, 10 cm H2O), and the dobutamine was restarted (Fig. 1C). At this moment, the lactate level was 5.3 mmol/L, potassium level was 4.3 mEq/L, and creatine phosphokinase level was 1248 U/L. Subsequently, she developed Pulseless Electrical Activity, thus, we began cardiopulmonary resuscitation. Subsequently, her chest radiography showed diffuse bilateral interstitial edema, and transthoracic echocardiography showed an ejection fraction of 15% with generalized hypokinesis. Profuse salmoncolored pulmonary secretions were expelled through the endotracheal tube, and the patient ultimately expired. The patient did not undergo necropsy; however, postmortem biopsies were taken. Only the recipient’s shoulder skin showed acute inflammation, and the donor’s skin left arm showed minimal periadnexial and perivascular lymphocyte infiltrate. Cultures of the blood and pulmonary secretions were negative. The reasons for the cardiopulmonary deterioration in our patient are unclear. One possibility is that she developed a transfusion-related acute lung injury. Such reactions usually result in acute respiratory distress syndrome during or within 6 hr after the transfusion
(1). Another possibility is that she developed reperfusion syndrome. Reperfusion of a large fraction of the skeletal muscle mass may result in cardiopulmonary failure and death (2). However, her peak serum potassium level was 5 mEq/L, and peak creatine phosphokinase level was 1248 U/L. A severe case of cytokine release syndrome (CRS) secondary to ATG therapy is also possible. CRS has been described in patients treated for aplastic anemia or who have undergone kidney, liver, or pancreas transplantation (3Y6). Cytokine release syndrome typically begins 4 to 10 hr after the first or second infusion of ATG and may cause fever and cardiorespiratory dysfunction, including hypotension, acute respiratory distress syndrome, pulmonary edema, myocardial infarction, tachycardia, and death (3Y7). The causative factor of CRS is not fully understood (1). The temporal association between the rapid onset of pulmonary infiltration, heart failure, and ATG infusion in our patient was similar to the clinical courses in previously reported cases of severe CRS (4Y6). Even though the specific cause of death may not be clear, it is important to report all complications in patients undergoing vascularized composite tissue allotransplantation. Martı´n Iglesias Paulino Leal Patricia Butro´n Selene Santander-Flores Diego Rican˜o-Enciso Mario A. Gonzalez-Chavez Alberto M. Gonzalez-Chavez Leonardo Bravo-Ruiz Daniela Leo´n-Lopez Sofia Garcia-Mancilla Melina Dı´az-Morales
e17
Mario A. Moran-Romero Israel Espino-Gaucin Elizabeth Rodriguez-Rojas Plastic Surgery Service at Instituto Nacional de Ciencias Me´dicas y Nutricio´n Salvador Zubiran, Mexico DF, Mexico The authors declare no funding or conflicts of interest. Address correspondence to: Martin Iglesias, M.D., Monte de Antisana 47, Jardines en la Montan˜a, Tlalpan, Mexico DF 14210, Mexico. E-mail: [email protected] ‘‘Vascularized Composite Allotransplantation: Upper Extremity’’ was approved by Institutional Review Board for Clinical Trials with reference 84. Received 10 February 2014. Accepted 21 April 2014. Copyright * 2014 by Lippincott Williams & Wilkins ISSN: 0041-1337/14/9803-00 DOI: 10.1097/TP.0000000000000258
REFERENCES 1.
2. 3.
4.
5. 6.
7.
Guo-Wei TU, Min-jie JU, Ming XU, et al. Antithymocyte globulin-induced acute respiratory distress syndrome after renal transplantation: a case report. Chin Med J 2012; 125: 1664. Blaisdell FW. The pathophysiology of skeletal muscle ischemia and the reperfusion syndrome: a review. Cardiovasc Surg 2002; 10: 620. Loushin MK, Hasinoff IK, Belani KG. A delayed cardiopulmonary reaction to an intravenous immunosuppressant thymoglobulin after pancreas transplant. Anesth Analg 2001; 93: 1260. Goligher EC, Csert-Gazdewich C, Balter M, et al. Acute lung injury during antithymocyte globulin therapy for aplastic anemia. Can Respir J 2009; 16: e3. Dean NC, Amend WC, Matthay MA. Adult respiratory distress syndrome related to antilymphocyte globulin therapy. Chest 1987; 91: 619. Busani S, Rinaldi L, Begliomini B, et al. Thymoglobulin-induced severe cardiovascular reaction and acute renal failure in a patient scheduled for orthotopic liver transplantation. Minerva Anestesiol 2006; 72: 243. Thymoglobulin (Anti-thymocyte Globulin [Rabbit]) Product Monograph. Sanofi-aventis Canada Inc. 2905 Place Louis-R.-Renaud Laval, Quebec H7V 0A3. Version 1.0 dated May 6, 2013.
A Case of Thrombotic Microangiopathy Associated With Antiphospholipid Antibody Syndrome Successfully Treated With Eculizumab
A
case of thrombotic microangiopathy (TMA) associated with antiphospholipid antibody syndrome (APS) successfully treated with eculizumab.
Antiphospholipid antibody syndrome is a multisystem disorder characterized
by vascular thrombosis and presence of circulating autoantibodies. The presence of APS can predispose to macrovascular thrombotic events, such as allograft thrombosis after kidney transplantation as well as microvascular thrombotic
renal disease (1) and is associated with a poor functional outcome in the first posttransplant year (2). Recent data have demonstrated the involvement of complement pathway in the pathogenesis of TMA because of APS nephropathy (3)
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
e18
www.transplantjournal.com
and prevention (4) with a complement C5 inhibitor has been found to be effective. We describe a case of TMA secondary to APS successfully treated with eculizumab. A 26-year-old man was admitted with abdominal discomfort, vomiting, and black stools lasting 3 days. His medical history was significant for class V lupus nephritis with a living related kidney transplant 3 years prior and LibmanSacks endocarditis status post mitral valve replacement. His immunosuppression comprised of thymoglobulin induction and maintenance with tacrolimus, mycophenolate, and prednisone. Physical examination was only remarkable for epigastric tenderness. Two days after admission, there was a fall in hemoglobin and platelets with simultaneous elevation in creatinine and significant evidence of intravascular hemolysis. A renal biopsy showed diffusely congested glomeruli containing fibrin thrombi with extension of thrombi into hilar arterioles and the interstitium contained patchy acute inflammation and hemorrhage with mild to moderate interstitial fibrosis (Fig. 1A). Tubular epithelial cells showed no evidence of viral cytopathic effect, and there was no evidence of vasculitis or peritubular capillaritis. Immunofluorescence microscopy showed no glomerular or vascular staining, but highlighted focal (G10%) peritubular C4d staining. Subsequent serologies showed elevated anticardiolipin and antiA-2 glycoprotein 1 antibodies as well as lupus anticoagulant titers. Heparin-PF4
Transplantation
antibody, serotonin release assay, C3/4, anti-nuclear antibody, anti-dsDNA antibodies, donor specific anti-HLA, and quantitative serologies for polyoma BK virus and cytomegalovirus were negative. A subtherapeutic tacrolimus level made tacrolimus-related TMA unlikely. Treatment with plasma exchange failed to resolve the features of TMA. Eculizumab was subsequently started with improved renal function and normalization of hemoglobin and platelets. A repeat biopsy performed after twice monthly dosing of eculizumab for 7 months demonstrated no evidence of TMA (Fig. 1B) and creatinine stabilized between 2.0 and 2.4 mg/dL. A repeat serological work-up showed no hemolysis or thrombocytopenia, normal levels of anticardiolipin, A-2microglobulin, and lupus anticoagulant. Atypical HUS panel showed no diseasecausing gene variants. This case illustrates a number of clinically important contributions to the literature. Thrombotic microangiopathy occurred de novo 3 years after transplantation in a lupus patient with APS syndrome as opposed to nearly all reported cases occurring within 6 months (3). Additionally, our patient’s favorable prognosis is in keeping with observations by Ponticelli and Banfi (5) who showed a less severe prognosis when TMA occurred later in the posttransplant course or affected recipients of living-donors. As has been demonstrated, APS occurred independent of positive serologies for anti-dsDNA and antinuclear antibodies.
FIGURE 1. (A) Glomerulus with endothelial injury and several fibrin thrombi (arrows). Jones silver 400. (B) Glomerulus without evidence of microthrombi. Jones silver 400.
& Volume 98, Number 3, August 15, 2014 As we progress to unravel the pathophysiology of APS-associated TMA, it is thus sensible to consider Eculizumab as an effective treatment first line or in cases which are resistant to plasmapheresis. Omid Bakhtar1 Bijin Thajudeen1 Beth L. Braunhut2 Sarah E. Yost3 Erika R. Bracamonte2 Amy N. Sussman1 Bruce Kaplan4 1 Division of Nephrology University of Arizona Health Sciences Center Tucson, AZ 2 Department of Pathology University of Arizona Health Sciences Center Tucson, AZ 3 Department of Pharmacy University of Arizona Health Sciences Center Tucson, AZ 4 Center for Transplantation University of Kansas Medical Center Kansas City, KS
The authors declare no funding or conflicts of interest. Address correspondence to: Bruce Kaplan, University of Kansas Medical Center, Center for Transplantation, 3901 Rainbow Boulevard, Kansas City, KS 66160. E-mail: [email protected] Received 18 April 2014. Accepted 24 April 2014. Copyright * 2014 by Lippincott Williams & Wilkins ISSN: 0041-1337/14/9803-00 DOI: 10.1097/TP.0000000000000267
REFERENCES 1.
Moroni G, Ventura D, Riva P, et al. Antiphospholipid antibodies are associated with an increased risk for chronic renal insufficiency in patients with lupus nephritis. Am J Kidney Dis 2004; 43: 28.
2.
Canaud G, Bienaime´ F, Noe¨l LH, et al. Severe vascular lesions and poor functional outcome in kidney transplant recipients with lupus anticoagulant antibodies. Am J Transplant 2010; 10: 2051.
3.
Pierangeli SS, Girardi G, Vega-Ostertag M, et al. Requirement of activation of complement C3 and C5 for antiphospholipid antibody-mediated thrombophilia. Arthritis Rheum 2005; 52: 2120.
4.
Lonze BE, Zachary AA, Magro CM, et al. Eculizumab prevents recurrent antiphospholipid antibody syndrome and enables successful renal transplantation. Am J Transplant 2014; 14: 459.
5.
Ponticelli C, Banfi G. Thrombotic microangiopathy after kidney transplantation. Transpl Int 2006; 19: 789.
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
* 2014 Lippincott Williams & Wilkins
At the end of the surgery, transplanted upper extremities had good perfusion, and the patient’s hemodynamic and clinical data were normal, except for a lactate level of 4.2 mmol/L. She remained stable at intensive care unit for the next 12 hr. The second dose of ATG (50 mg) was administered 24 hr after the first dose. Ten hours later, her heart rate increased to 110 beats per min, and because her mean arterial blood pressure decreased, norepinephrine was started. Simultaneously, there was indirect data of decreased cardiac output (SvO2, 61%; central venous pressure, 10 cm H2O), and the dobutamine was restarted (Fig. 1C). At this moment, the lactate level was 5.3 mmol/L, potassium level was 4.3 mEq/L, and creatine phosphokinase level was 1248 U/L. Subsequently, she developed Pulseless Electrical Activity, thus, we began cardiopulmonary resuscitation. Subsequently, her chest radiography showed diffuse bilateral interstitial edema, and transthoracic echocardiography showed an ejection fraction of 15% with generalized hypokinesis. Profuse salmoncolored pulmonary secretions were expelled through the endotracheal tube, and the patient ultimately expired. The patient did not undergo necropsy; however, postmortem biopsies were taken. Only the recipient’s shoulder skin showed acute inflammation, and the donor’s skin left arm showed minimal periadnexial and perivascular lymphocyte infiltrate. Cultures of the blood and pulmonary secretions were negative. The reasons for the cardiopulmonary deterioration in our patient are unclear. One possibility is that she developed a transfusion-related acute lung injury. Such reactions usually result in acute respiratory distress syndrome during or within 6 hr after the transfusion
(1). Another possibility is that she developed reperfusion syndrome. Reperfusion of a large fraction of the skeletal muscle mass may result in cardiopulmonary failure and death (2). However, her peak serum potassium level was 5 mEq/L, and peak creatine phosphokinase level was 1248 U/L. A severe case of cytokine release syndrome (CRS) secondary to ATG therapy is also possible. CRS has been described in patients treated for aplastic anemia or who have undergone kidney, liver, or pancreas transplantation (3Y6). Cytokine release syndrome typically begins 4 to 10 hr after the first or second infusion of ATG and may cause fever and cardiorespiratory dysfunction, including hypotension, acute respiratory distress syndrome, pulmonary edema, myocardial infarction, tachycardia, and death (3Y7). The causative factor of CRS is not fully understood (1). The temporal association between the rapid onset of pulmonary infiltration, heart failure, and ATG infusion in our patient was similar to the clinical courses in previously reported cases of severe CRS (4Y6). Even though the specific cause of death may not be clear, it is important to report all complications in patients undergoing vascularized composite tissue allotransplantation. Martı´n Iglesias Paulino Leal Patricia Butro´n Selene Santander-Flores Diego Rican˜o-Enciso Mario A. Gonzalez-Chavez Alberto M. Gonzalez-Chavez Leonardo Bravo-Ruiz Daniela Leo´n-Lopez Sofia Garcia-Mancilla Melina Dı´az-Morales
e17
Mario A. Moran-Romero Israel Espino-Gaucin Elizabeth Rodriguez-Rojas Plastic Surgery Service at Instituto Nacional de Ciencias Me´dicas y Nutricio´n Salvador Zubiran, Mexico DF, Mexico The authors declare no funding or conflicts of interest. Address correspondence to: Martin Iglesias, M.D., Monte de Antisana 47, Jardines en la Montan˜a, Tlalpan, Mexico DF 14210, Mexico. E-mail: [email protected] ‘‘Vascularized Composite Allotransplantation: Upper Extremity’’ was approved by Institutional Review Board for Clinical Trials with reference 84. Received 10 February 2014. Accepted 21 April 2014. Copyright * 2014 by Lippincott Williams & Wilkins ISSN: 0041-1337/14/9803-00 DOI: 10.1097/TP.0000000000000258
REFERENCES 1.
2. 3.
4.
5. 6.
7.
Guo-Wei TU, Min-jie JU, Ming XU, et al. Antithymocyte globulin-induced acute respiratory distress syndrome after renal transplantation: a case report. Chin Med J 2012; 125: 1664. Blaisdell FW. The pathophysiology of skeletal muscle ischemia and the reperfusion syndrome: a review. Cardiovasc Surg 2002; 10: 620. Loushin MK, Hasinoff IK, Belani KG. A delayed cardiopulmonary reaction to an intravenous immunosuppressant thymoglobulin after pancreas transplant. Anesth Analg 2001; 93: 1260. Goligher EC, Csert-Gazdewich C, Balter M, et al. Acute lung injury during antithymocyte globulin therapy for aplastic anemia. Can Respir J 2009; 16: e3. Dean NC, Amend WC, Matthay MA. Adult respiratory distress syndrome related to antilymphocyte globulin therapy. Chest 1987; 91: 619. Busani S, Rinaldi L, Begliomini B, et al. Thymoglobulin-induced severe cardiovascular reaction and acute renal failure in a patient scheduled for orthotopic liver transplantation. Minerva Anestesiol 2006; 72: 243. Thymoglobulin (Anti-thymocyte Globulin [Rabbit]) Product Monograph. Sanofi-aventis Canada Inc. 2905 Place Louis-R.-Renaud Laval, Quebec H7V 0A3. Version 1.0 dated May 6, 2013.
A Case of Thrombotic Microangiopathy Associated With Antiphospholipid Antibody Syndrome Successfully Treated With Eculizumab
A
case of thrombotic microangiopathy (TMA) associated with antiphospholipid antibody syndrome (APS) successfully treated with eculizumab.
Antiphospholipid antibody syndrome is a multisystem disorder characterized
by vascular thrombosis and presence of circulating autoantibodies. The presence of APS can predispose to macrovascular thrombotic events, such as allograft thrombosis after kidney transplantation as well as microvascular thrombotic
renal disease (1) and is associated with a poor functional outcome in the first posttransplant year (2). Recent data have demonstrated the involvement of complement pathway in the pathogenesis of TMA because of APS nephropathy (3)
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
e18
www.transplantjournal.com
and prevention (4) with a complement C5 inhibitor has been found to be effective. We describe a case of TMA secondary to APS successfully treated with eculizumab. A 26-year-old man was admitted with abdominal discomfort, vomiting, and black stools lasting 3 days. His medical history was significant for class V lupus nephritis with a living related kidney transplant 3 years prior and LibmanSacks endocarditis status post mitral valve replacement. His immunosuppression comprised of thymoglobulin induction and maintenance with tacrolimus, mycophenolate, and prednisone. Physical examination was only remarkable for epigastric tenderness. Two days after admission, there was a fall in hemoglobin and platelets with simultaneous elevation in creatinine and significant evidence of intravascular hemolysis. A renal biopsy showed diffusely congested glomeruli containing fibrin thrombi with extension of thrombi into hilar arterioles and the interstitium contained patchy acute inflammation and hemorrhage with mild to moderate interstitial fibrosis (Fig. 1A). Tubular epithelial cells showed no evidence of viral cytopathic effect, and there was no evidence of vasculitis or peritubular capillaritis. Immunofluorescence microscopy showed no glomerular or vascular staining, but highlighted focal (G10%) peritubular C4d staining. Subsequent serologies showed elevated anticardiolipin and antiA-2 glycoprotein 1 antibodies as well as lupus anticoagulant titers. Heparin-PF4
Transplantation
antibody, serotonin release assay, C3/4, anti-nuclear antibody, anti-dsDNA antibodies, donor specific anti-HLA, and quantitative serologies for polyoma BK virus and cytomegalovirus were negative. A subtherapeutic tacrolimus level made tacrolimus-related TMA unlikely. Treatment with plasma exchange failed to resolve the features of TMA. Eculizumab was subsequently started with improved renal function and normalization of hemoglobin and platelets. A repeat biopsy performed after twice monthly dosing of eculizumab for 7 months demonstrated no evidence of TMA (Fig. 1B) and creatinine stabilized between 2.0 and 2.4 mg/dL. A repeat serological work-up showed no hemolysis or thrombocytopenia, normal levels of anticardiolipin, A-2microglobulin, and lupus anticoagulant. Atypical HUS panel showed no diseasecausing gene variants. This case illustrates a number of clinically important contributions to the literature. Thrombotic microangiopathy occurred de novo 3 years after transplantation in a lupus patient with APS syndrome as opposed to nearly all reported cases occurring within 6 months (3). Additionally, our patient’s favorable prognosis is in keeping with observations by Ponticelli and Banfi (5) who showed a less severe prognosis when TMA occurred later in the posttransplant course or affected recipients of living-donors. As has been demonstrated, APS occurred independent of positive serologies for anti-dsDNA and antinuclear antibodies.
FIGURE 1. (A) Glomerulus with endothelial injury and several fibrin thrombi (arrows). Jones silver 400. (B) Glomerulus without evidence of microthrombi. Jones silver 400.
& Volume 98, Number 3, August 15, 2014 As we progress to unravel the pathophysiology of APS-associated TMA, it is thus sensible to consider Eculizumab as an effective treatment first line or in cases which are resistant to plasmapheresis. Omid Bakhtar1 Bijin Thajudeen1 Beth L. Braunhut2 Sarah E. Yost3 Erika R. Bracamonte2 Amy N. Sussman1 Bruce Kaplan4 1 Division of Nephrology University of Arizona Health Sciences Center Tucson, AZ 2 Department of Pathology University of Arizona Health Sciences Center Tucson, AZ 3 Department of Pharmacy University of Arizona Health Sciences Center Tucson, AZ 4 Center for Transplantation University of Kansas Medical Center Kansas City, KS
The authors declare no funding or conflicts of interest. Address correspondence to: Bruce Kaplan, University of Kansas Medical Center, Center for Transplantation, 3901 Rainbow Boulevard, Kansas City, KS 66160. E-mail: [email protected] Received 18 April 2014. Accepted 24 April 2014. Copyright * 2014 by Lippincott Williams & Wilkins ISSN: 0041-1337/14/9803-00 DOI: 10.1097/TP.0000000000000267
REFERENCES 1.
Moroni G, Ventura D, Riva P, et al. Antiphospholipid antibodies are associated with an increased risk for chronic renal insufficiency in patients with lupus nephritis. Am J Kidney Dis 2004; 43: 28.
2.
Canaud G, Bienaime´ F, Noe¨l LH, et al. Severe vascular lesions and poor functional outcome in kidney transplant recipients with lupus anticoagulant antibodies. Am J Transplant 2010; 10: 2051.
3.
Pierangeli SS, Girardi G, Vega-Ostertag M, et al. Requirement of activation of complement C3 and C5 for antiphospholipid antibody-mediated thrombophilia. Arthritis Rheum 2005; 52: 2120.
4.
Lonze BE, Zachary AA, Magro CM, et al. Eculizumab prevents recurrent antiphospholipid antibody syndrome and enables successful renal transplantation. Am J Transplant 2014; 14: 459.
5.
Ponticelli C, Banfi G. Thrombotic microangiopathy after kidney transplantation. Transpl Int 2006; 19: 789.
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
