- Email: [email protected]
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QUIZ Acute Kidney Injury and Pancytopenia 5 Months After Kidney Transplantation 9%; eosinophils, 1%; and basophils, 1%); hemoglobin level, 7.7 g/dL; platelets, 65 3 103/ mL; mean corpuscular volume, 88 fL; reticulocyte count, 0.6%; haptoglobin level, 206 mg/ dL; lactate dehydrogenase level, 403 IU/L; ferritin level, 15,605 ng/mL; and triglyceride level, 210 mg/dL. Coombs test was negative, and peripheral smear showed few ovalocytes with normal platelet and leukocyte morphology. Urinalysis revealed a spot protein-creatinine ratio of 15.5 g/g; measurement of protein excretion using a 24-hour urine collection (which may differ in the setting of acute kidney injury) was not performed. CMV viral load was 2.8 million copies/mL. A kidney biopsy was performed (Fig 1). What are the causes of pancytopenia following kidney transplantation? What does the biopsy specimen show? What is the diagnosis? What are the causes of this clinical picture?
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CLINICAL PRESENTATION A 31-year-old African American man with endstage renal disease of unknown cause was admitted 5 months after deceased donor kidney transplantation with 1 week of high-grade fever and diarrhea. He had received induction with alemtuzumab therapy and was maintained on tacrolimus, mycophenolate mofetil, and prednisone immunosuppression with a nadir creatinine level of 2.4 mg/dL (corresponding to estimated glomerular filtration rate [eGFR] of 38 mL/min/1.73 m2 as calculated by the 4variable MDRD [Modification of Diet in Renal Disease] Study equation). Donor cytomegalovirus (CMV) serostatus was positive, and recipient CMV serostatus was negative. The patient received 6 months of CMV prophylaxis with valganciclovir therapy. Physical examination findings were unremarkable except for splenomegaly. Blood tests showed creatinine level of 4.9 mg/dL (eGFR, 17 mL/min/ 1.73 m2); white cell count, 1.7 3 103/mL (neutrophils, 86%; lymphocytes, 3%; monocytes,
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Figure 1. Kidney biopsy specimen. (A) Hematoxylin and eosin stain (original magnification, 3400). (B) Silver stain (original magnification, 3400). (C) Electron microscopy (original magnification, 3 25,625; scale length, 25 mm).
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DISCUSSION What are the causes of pancytopenia following kidney transplantation? Pancytopenia is common following kidney transplantation and occurs due to infectious, drug-related, immune-mediated, and inflammatory causes (Table 1).1 What does the biopsy specimen show? The kidney transplant biopsy specimen shows acute CMV glomerulopathy. Light microscopy reveals characteristic CMV inclusion bodies with enlarged glassy nuclei within glomerular endothelial cells (Fig 1A and B, arrow) and positive immunohistochemistry for CMV. Electron microscopy shows the absence of immune
complex deposits and diffuse foot-process effacement (Fig 1C). What is the diagnosis? We diagnosed CMV-induced hemophagocytic syndrome. Hemophagocytic syndrome, also known as macrophage activating syndrome or hemophagocytic lymphohistiocytosis, is a disorder of the mononuclear phagocytic system characterized by non-neoplastic proliferation of histocytes and macrophages exhibiting phagocytosis of erythrocytes, leukocytes, platelets, and precursors.2 Hemophagocytic syndrome is a life-threatening complication of kidney transplantation with an estimated prevalence of 0.4% and carries a high mortality rate of 47%.3 Five of 8 criteria should be met to diagnose
Table 1. Common Causes of Pancytopenia Following Kidney Transplantation
QUIZ
Cause
Mechanism
Infections Parvovirus B19 Cytomegalovirus Human herpes virus 6 and 8 Epstein-Barr virus Leishmania
Hypoproliferative marrow: Infection mediated
Medications Immunosuppressive drugs Mycophenolate mofetil Alemtuzumab Antithymocyte globulin Antibiotics Linezolid Chloramphenicol Antivirals Valganciclovir Ganciclovir Chemotherapy
Hypoproliferative marrow: Drug mediated
Immune-mediated mechanisms Graft-vs-host disease Posttransplant lymphoproliferative disorder Inflammation Hemophagocytic syndrome
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Peripheral destruction: Antibody mediated Infiltrative neoplasia
Peripheral destruction: Mononuclear phagocytic system mediated
Box 1. Diagnostic Criteria for Hemophagocytic Syndrome (5 of 8 criteria should be met) Pyrexia Cytopenia affecting at least 2 blood cell types Elevated ferritin ($500 mg/dL) Elevated triglycerides ($3 mmol/L) and/or low fibrinogen (,1.5 g/L) Splenomegaly Elevated sIL-2RA ($2,400 U/mL) NK cell activity is reduced or undetectable Hemophagocytosis in the bone marrow, lymph nodes, or cerebrospinal fluid Abbreviations: NK, natural killer; sIL2RA, soluble interleukin 2 receptor alpha chain. Based on Janka and Schneider.4
hemophagocytic (Box 1).4
syndrome
What are the causes of this clinical picture? Hemophagocytic syndrome is divided into familial (primary) forms, which mainly affect young children with a genetic mutation in perforin, and reactive (secondary) forms, which may occur at any age.2 Reactive hemophagocytic syndrome is commonly associated with viral infections (eg, CMV, Epstein-Barr virus, or herpes viridae group), tuberculosis, Escherichia coli, protozoan infections, lymphoid malignancies, and autoimmune diseases (eg, rheumatoid arthritis or systemic lupus erythematous). Viral infections provoke a highly stimulated but ineffective multisystem inflammatory response resulting in proliferation of macrophages producing proinflammatory cytokines; subsequent tissue infiltration by these proliferating macrophages leads to pancytopenia.5
Am J Kidney Dis. 2017;69(2):xiv-xvii
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The optimal management of hemophagocytic syndrome is not well defined, and targeted treatment of the triggering factor is of utmost importance. Steroids are given to the patient to reduce the macrophage activation, and the patient’s immunosuppression is reduced. Anti–tumor necrosis factor a antibody, interleukin 1 (IL-1) receptor antagonist, or polyvalent intravenous immunoglobulin may be beneficial in some cases.3,6 Our patient remained refractory to treatment of hemophagocytic syndrome with ganciclovir, reduction of immunosuppression, and pulse dose steroids. He then received anikinra, a recombinant IL-1 receptor antagonist, with clinical improvement. At the 9month follow-up, kidney function and pancytopenia had improved, with a creatinine level of 3 mg/dL (eGFR, 30 mL/min/1.73 m2), white cell count of 4.2 3 103/mL, hemoglobin level of 11.4 g/dL, platelet count of 117 3 103/mL, and spot urine protein-creatinine ratio of 0.61 g/g.
FINAL DIAGNOSIS Cytomegalovirus-induced hemophagocytic syndrome in a kidney transplant recipient.
6. Schulert GS, Grom AA. Pathogenesis of macrophage activation syndrome and potential for cytokinedirected therapies. Annu Rev Med. 2015;66:145-159.
REFERENCES 1. Yang Y, Yu B, Chen Y. Blood disorders typically associated with renal transplantation. Front Cell Dev Biol. 2015;3:1-12. 2. Ponticelli C, Alberighi OD. Haemophagocytic syndrome–a life-threatening complication of renal transplantation. Nephrol Dial Transplant. 2009;24(9):2623-2627. 3. Karras A, Thervet E, Legendre C. Hemophagocytic syndrome in renal transplant recipients: report of 17 cases and review of literature. Transplantation. 2004;77(2):238-243. 4. Janka GE, Schneider EM. Modern management of children with haemophagocytic lymphohistiocytosis. Br J Haematol. 2004;124(1): 4-14. 5. Risdall RJ, McKenna RW, Nesbit ME, et al. Virus-associated hemophagocytic syndrome: a benign histiocytic proliferation distinct from malignant histiocytosis. Cancer. 1979;44(3):993-1002.
CASE PROVIDED AND AUTHORED BY Silvi Shah, MD,1 Todd M. Stevens, MD,2 and Gaurav Agarwal, MD,1 Departments of 1 Nephrology and 2Pathology, University of Alabama at Birmingham, Birmingham, AL. Address correspondence to Silvi Shah, MD, Division of Nephrology, University of Cincinnati, 231 Albert Sabin Way, Rm 6214 MSB, Cincinnati, OH 45267. E-mail: [email protected] Ó 2016 by the National Kidney Foundation, Inc.
http://dx.doi.org/10.1053/j.ajkd.2016. 07.038 SUPPORT: None. FINANCIAL DISCLOSURE: The authors declare that they have no relevant financial interests. PEER REVIEW: Evaluated by a pathologist, Education Editor Gilbert, and Editor-in-Chief Levey.
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Am J Kidney Dis. 2017;69(2):xiv-xvii
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CLINICAL PRESENTATION A 31-year-old African American man with endstage renal disease of unknown cause was admitted 5 months after deceased donor kidney transplantation with 1 week of high-grade fever and diarrhea. He had received induction with alemtuzumab therapy and was maintained on tacrolimus, mycophenolate mofetil, and prednisone immunosuppression with a nadir creatinine level of 2.4 mg/dL (corresponding to estimated glomerular filtration rate [eGFR] of 38 mL/min/1.73 m2 as calculated by the 4variable MDRD [Modification of Diet in Renal Disease] Study equation). Donor cytomegalovirus (CMV) serostatus was positive, and recipient CMV serostatus was negative. The patient received 6 months of CMV prophylaxis with valganciclovir therapy. Physical examination findings were unremarkable except for splenomegaly. Blood tests showed creatinine level of 4.9 mg/dL (eGFR, 17 mL/min/ 1.73 m2); white cell count, 1.7 3 103/mL (neutrophils, 86%; lymphocytes, 3%; monocytes,
xiv
Am J Kidney Dis. 2017;69(2):xiv-xvii
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Figure 1. Kidney biopsy specimen. (A) Hematoxylin and eosin stain (original magnification, 3400). (B) Silver stain (original magnification, 3400). (C) Electron microscopy (original magnification, 3 25,625; scale length, 25 mm).
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Am J Kidney Dis. 2017;69(2):xiv-xvii
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DISCUSSION What are the causes of pancytopenia following kidney transplantation? Pancytopenia is common following kidney transplantation and occurs due to infectious, drug-related, immune-mediated, and inflammatory causes (Table 1).1 What does the biopsy specimen show? The kidney transplant biopsy specimen shows acute CMV glomerulopathy. Light microscopy reveals characteristic CMV inclusion bodies with enlarged glassy nuclei within glomerular endothelial cells (Fig 1A and B, arrow) and positive immunohistochemistry for CMV. Electron microscopy shows the absence of immune
complex deposits and diffuse foot-process effacement (Fig 1C). What is the diagnosis? We diagnosed CMV-induced hemophagocytic syndrome. Hemophagocytic syndrome, also known as macrophage activating syndrome or hemophagocytic lymphohistiocytosis, is a disorder of the mononuclear phagocytic system characterized by non-neoplastic proliferation of histocytes and macrophages exhibiting phagocytosis of erythrocytes, leukocytes, platelets, and precursors.2 Hemophagocytic syndrome is a life-threatening complication of kidney transplantation with an estimated prevalence of 0.4% and carries a high mortality rate of 47%.3 Five of 8 criteria should be met to diagnose
Table 1. Common Causes of Pancytopenia Following Kidney Transplantation
QUIZ
Cause
Mechanism
Infections Parvovirus B19 Cytomegalovirus Human herpes virus 6 and 8 Epstein-Barr virus Leishmania
Hypoproliferative marrow: Infection mediated
Medications Immunosuppressive drugs Mycophenolate mofetil Alemtuzumab Antithymocyte globulin Antibiotics Linezolid Chloramphenicol Antivirals Valganciclovir Ganciclovir Chemotherapy
Hypoproliferative marrow: Drug mediated
Immune-mediated mechanisms Graft-vs-host disease Posttransplant lymphoproliferative disorder Inflammation Hemophagocytic syndrome
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Peripheral destruction: Antibody mediated Infiltrative neoplasia
Peripheral destruction: Mononuclear phagocytic system mediated
Box 1. Diagnostic Criteria for Hemophagocytic Syndrome (5 of 8 criteria should be met) Pyrexia Cytopenia affecting at least 2 blood cell types Elevated ferritin ($500 mg/dL) Elevated triglycerides ($3 mmol/L) and/or low fibrinogen (,1.5 g/L) Splenomegaly Elevated sIL-2RA ($2,400 U/mL) NK cell activity is reduced or undetectable Hemophagocytosis in the bone marrow, lymph nodes, or cerebrospinal fluid Abbreviations: NK, natural killer; sIL2RA, soluble interleukin 2 receptor alpha chain. Based on Janka and Schneider.4
hemophagocytic (Box 1).4
syndrome
What are the causes of this clinical picture? Hemophagocytic syndrome is divided into familial (primary) forms, which mainly affect young children with a genetic mutation in perforin, and reactive (secondary) forms, which may occur at any age.2 Reactive hemophagocytic syndrome is commonly associated with viral infections (eg, CMV, Epstein-Barr virus, or herpes viridae group), tuberculosis, Escherichia coli, protozoan infections, lymphoid malignancies, and autoimmune diseases (eg, rheumatoid arthritis or systemic lupus erythematous). Viral infections provoke a highly stimulated but ineffective multisystem inflammatory response resulting in proliferation of macrophages producing proinflammatory cytokines; subsequent tissue infiltration by these proliferating macrophages leads to pancytopenia.5
Am J Kidney Dis. 2017;69(2):xiv-xvii
Quiz
The optimal management of hemophagocytic syndrome is not well defined, and targeted treatment of the triggering factor is of utmost importance. Steroids are given to the patient to reduce the macrophage activation, and the patient’s immunosuppression is reduced. Anti–tumor necrosis factor a antibody, interleukin 1 (IL-1) receptor antagonist, or polyvalent intravenous immunoglobulin may be beneficial in some cases.3,6 Our patient remained refractory to treatment of hemophagocytic syndrome with ganciclovir, reduction of immunosuppression, and pulse dose steroids. He then received anikinra, a recombinant IL-1 receptor antagonist, with clinical improvement. At the 9month follow-up, kidney function and pancytopenia had improved, with a creatinine level of 3 mg/dL (eGFR, 30 mL/min/1.73 m2), white cell count of 4.2 3 103/mL, hemoglobin level of 11.4 g/dL, platelet count of 117 3 103/mL, and spot urine protein-creatinine ratio of 0.61 g/g.
FINAL DIAGNOSIS Cytomegalovirus-induced hemophagocytic syndrome in a kidney transplant recipient.
6. Schulert GS, Grom AA. Pathogenesis of macrophage activation syndrome and potential for cytokinedirected therapies. Annu Rev Med. 2015;66:145-159.
REFERENCES 1. Yang Y, Yu B, Chen Y. Blood disorders typically associated with renal transplantation. Front Cell Dev Biol. 2015;3:1-12. 2. Ponticelli C, Alberighi OD. Haemophagocytic syndrome–a life-threatening complication of renal transplantation. Nephrol Dial Transplant. 2009;24(9):2623-2627. 3. Karras A, Thervet E, Legendre C. Hemophagocytic syndrome in renal transplant recipients: report of 17 cases and review of literature. Transplantation. 2004;77(2):238-243. 4. Janka GE, Schneider EM. Modern management of children with haemophagocytic lymphohistiocytosis. Br J Haematol. 2004;124(1): 4-14. 5. Risdall RJ, McKenna RW, Nesbit ME, et al. Virus-associated hemophagocytic syndrome: a benign histiocytic proliferation distinct from malignant histiocytosis. Cancer. 1979;44(3):993-1002.
CASE PROVIDED AND AUTHORED BY Silvi Shah, MD,1 Todd M. Stevens, MD,2 and Gaurav Agarwal, MD,1 Departments of 1 Nephrology and 2Pathology, University of Alabama at Birmingham, Birmingham, AL. Address correspondence to Silvi Shah, MD, Division of Nephrology, University of Cincinnati, 231 Albert Sabin Way, Rm 6214 MSB, Cincinnati, OH 45267. E-mail: [email protected] Ó 2016 by the National Kidney Foundation, Inc.
http://dx.doi.org/10.1053/j.ajkd.2016. 07.038 SUPPORT: None. FINANCIAL DISCLOSURE: The authors declare that they have no relevant financial interests. PEER REVIEW: Evaluated by a pathologist, Education Editor Gilbert, and Editor-in-Chief Levey.
QUIZ
Am J Kidney Dis. 2017;69(2):xiv-xvii
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