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  • Review Article
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What nephrologists need to know about hemophagocytic syndrome

Nature Reviews Nephrology volume 5, pages 329–336 (2009)Cite this article

Abstract

Hemophagocytic syndrome (HPS) is a rare but distinct condition caused by inappropriate and dysregulated activation of the immune system. HPS is characterized by febrile hepatosplenomegaly, pancytopenia, hypofibrinemia and liver dysfunction; these changes are associated with the infiltration of bone marrow and organs by nonmalignant macrophages that phagocytose blood cells. Primary HPS is linked to inherited immune dysregulation, whereas secondary HPS tends to be triggered by an infectious or neoplastic disease. Multiorgan failure can complicate this life-threatening condition and renal involvement has frequently been reported; however, precise descriptions of the renal manifestations of HPS are lacking. Acute kidney injury due to tubular necrosis is the most common renal presentation, but nephrotic syndrome can also occur. HPS can be observed in immunocompromised patients and nephrologists must be aware that this condition can occur in renal transplant recipients. Mortality in patients with HPS can be as high as 50%. Despite considerable advances in the treatment of familial HPS, no specific therapy has demonstrated a consistent capacity to control reactive HPS when combined with suppression of the triggering factor. This Review summarizes the presentation, causes, pathophysiology and renal features of HPS for the benefit of the practicing nephrologist.

Key Points

  • Hemophagocytic syndrome (HPS) is characterized by proliferation of and organ infiltration with benign activated macrophages, which results in febrile cytopenia and a dysregulated inflammatory response that can lead to multiorgan failure

  • Primary HPS occurs in children with inherited dysfunction of the immune response, whereas secondary HPS is triggered by factors such as infectious agents, autoimmune disease and neoplasia

  • Acute kidney injury due to tubular necrosis is the most frequent type of kidney involvement in HPS

  • Nephrotic syndrome can be observed in the acute phase of HPS; the associated renal pathology is usually minimal-change disease or collapsing glomerulopathy, although thrombotic microangiopathy has also been described

  • Patients who receive immunosuppressive treatment after organ transplantation or for autoimmune disease are at increased risk of HPS

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Figure 1: Bone marrow aspiration smear from a patient with hemophagocytic syndrome, showing a large activated macrophage that contains phagocytosed red blood cells (R) and granulocytes (G; May–Grünwald–Giemsa stain, original magnification ×1,600).
Figure 2: Pathogenesis of hemophagocytic syndrome.
Figure 3

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References

  1. Risdall, R. J. et al. Virus-associated hemophagocytic syndrome: a benign histiocytic proliferation distinct from malignant histiocytosis. Cancer 44, 993–1002 (1979).

    Article  CAS  Google Scholar 

  2. Wong, K. & Chan, J. K. Reactive hemophagocytic syndrome: a clinicopathologic study of 40 patients in an Oriental population. Am. J. Med. 93, 177–180 (1992).

    Article  CAS  Google Scholar 

  3. Reiner, A. & Spivak, J. L. Hemophagocytic histiocytosis: a report of 23 new patients and a review of the literature. Medicine (Baltimore) 67, 369–388 (1988).

    Article  CAS  Google Scholar 

  4. Tsuda, H. Hemophagocytic syndrome in children and adults. Int. J. Hematol. 65, 215–226 (1997).

    Article  CAS  Google Scholar 

  5. Kaito, K. et al. Prognostic factors of hemophagocytic syndrome in adults: analysis of 34 cases. Eur. J. Haematol. 59, 247–253 (1997).

    Article  CAS  Google Scholar 

  6. Scott, R. B. et al. Histiocytic medullary reticulocytosis. Lancet 2, 194–198 (1939).

    Article  Google Scholar 

  7. Farquhar, J. W. et al. Familial hemophagocytic reticulocytosis. Arch. Dis. Child. 27, 519–525 (1952).

    Article  CAS  Google Scholar 

  8. Gauvin, F., Toledano, B., Champagne, J. & Lacroix, J. Reactive hemophagocytic syndrome presenting as a component of multiple organ dysfunction syndrome. Crit. Care Med. 28, 3341–3345 (2000).

    Article  CAS  Google Scholar 

  9. Ohga, S. Inflammatory cytokines in virus-associated hemophagocytic syndrome. Am. J. Pediatr. Hematol. Oncol. 15, 291–298 (1993).

    CAS  PubMed  Google Scholar 

  10. De Kerguenec, C. et al. Hepatic manifestations of hemophagocytic syndrome: a study of 30 cases. Am. J. Gastroenterol. 96, 852–857 (2001).

    Article  CAS  Google Scholar 

  11. Esumi, N. Ikushima, S., Todo, S. & Imashuku, S. Hyperferritinemia in malignant histiocytosis and virus-associated hemophagocytic syndrome. N. Engl. J. Med. 316, 346–347 (1987).

    Article  CAS  Google Scholar 

  12. Henter, J. I. et al. Treatment of hemophagocytic lymphohistiocytosis with HLH-94 immunotherapy and bone marrow transplantation. Blood 100, 2367–2373 (2002).

    Article  CAS  Google Scholar 

  13. Strauss R. et al. Multifactorial risk analysis of bone marrow histiocytic hyperplasia with hemophagocytosis in critically ill medical patient: a postmortem clinicopathologic analysis. Crit. Care Med. 32, 1316–1321 (2004).

    Article  Google Scholar 

  14. Janka, G. E. Hemophagocytic syndromes. Blood Rev. 21, 245–253 (2007).

    Article  CAS  Google Scholar 

  15. Aricó, M. et al. Pathogenesis of haemophagocytic lymphohistiocytosis. Br. J. Haematol. 114, 761–769 (2001).

    Article  Google Scholar 

  16. Stepp, S. E. et al. Perforin gene defects in familial hemophagocytic lymphohistiocytosis. Science 286, 1957–1959 (1999).

    Article  CAS  Google Scholar 

  17. Feldmann, J. et al. Munc13-4 is essential for cytolytic granules fusion and is mutated in a form of familial hemophagocytic lymphohistiocytosis (FHL3). Cell 115, 461–473 (2003).

    Article  CAS  Google Scholar 

  18. Zur Stadt, U. et al. Linkage of familial hemophagocytic lymphohistiocytosis (FHL) type-4 to chromosome 6q24 and identification of mutations in syntaxin 11. Hum. Mol. Genet. 14, 827–834 (2005).

    Article  CAS  Google Scholar 

  19. Certain, S. et al. Protein truncation test of LYST reveals heterogeneous mutations in patients with Chediak–Higashi syndrome. Blood 95, 979–983 (2000).

    CAS  PubMed  Google Scholar 

  20. Menasché, G. et al. Mutations in RAB27A cause Griscelli syndrome associated with haemophagocytic syndrome. Nat. Genet. 25, 173–176 (2000).

    Article  Google Scholar 

  21. Arico, M. et al. Hemophagocytic lymphohistiocytosis due to germline mutations in SH2D1A, the X-linked lymphoproliferative disease gene. Blood 97, 1131–1133 (2001).

    Article  CAS  Google Scholar 

  22. Fisman, D. N. Hemophagocytic syndromes and infection. Emerg. Infect. Dis. 6, 601–608 (2000).

    Article  CAS  Google Scholar 

  23. Rouphael, N. G. et al. Infections associated with haemophagocytic syndrome. Lancet Infect. Dis. 7, 814–822 (2007).

    Article  Google Scholar 

  24. Han, A. R. et al. Lymphoma-associated hemophagocytic syndrome: clinical features and treatment outcome. Ann. Hematol. 86, 493–498 (2007).

    Article  Google Scholar 

  25. Fardet, L. et al. HHV-8 associated hemophagocytic lymphohistiocytosis in HIV-infected patients. Clin. Infect. Dis. 37, 285–291 (2003).

    Article  CAS  Google Scholar 

  26. Chuang, H. C. et al. EBV latent membrane protein-1 down-regulates TNF-α receptor-1 and confers resistance to TNF-α-induced apoptosis in T cells: implication for the progression to T-cell lymphoma in EBV-associated hemophagocytic syndrome. Am. J. Pathol. 170, 1607–1617 (2007).

    Article  CAS  Google Scholar 

  27. Karras, A. et al. Syndrome d'activation macrophagique/hemophagocytic syndrome [French]. Rev. Med. Interne. 23, 768–778 (2002).

    Article  CAS  Google Scholar 

  28. Dhote, R. et al. Reactive hemophagocytic syndrome in adult systemic disease: report of twenty-six cases and literature review. Arthritis Rheum. 49, 633–639 (2003).

    Article  Google Scholar 

  29. Stéphan, J. L. et al. Reactive haemophagocytic syndrome in children with inflammatory disorders: a retrospective study of 24 patients. Rheumatology (Oxford) 40, 1285–1292 (2001).

    Article  Google Scholar 

  30. Lambotte, O. et al. Characteristics and long-term outcome of 15 episodes of systemic lupus erythematosus-associated hemophagocytic syndrome. Medicine (Baltimore) 85, 169–182 (2006).

    Article  Google Scholar 

  31. Arlet, J. B. et al. Reactive haemophagocytic syndrome in adult-onset Still's disease: a report of six patients and a review of the literature. Ann. Rheum. Dis. 65, 1596–1601 (2006).

    Article  Google Scholar 

  32. Lee, S. M. et al. Characterization of diverse PRF1 mutations leading to decreased natural killer cell activity in North American families with hemophagocytic lymphohistiocytosis. J. Med. Genet. 41, 137–144 (2004).

    Article  CAS  Google Scholar 

  33. Osugi, Y. et al. Cytokine production regulating TH1 and TH2 cytokines in hemophagocytic lymphohistiocytosis. Blood 89, 4100–4103 (1997).

    CAS  PubMed  Google Scholar 

  34. Akashi, K. et al. Involvement of interferon-γ and macrophage colony-stimulating factor in pathogenesis of haemophagocytic lymphohistiocytosis in adults. Br. J. Haematol. 87, 243–250 (1994).

    Article  CAS  Google Scholar 

  35. Ueda, I. et al. Late-onset cases of familial hemophagocytic lymphohistiocytosis with missense perforin gene mutations. Am. J. Hematol. 82, 427–432 (2007).

    Article  CAS  Google Scholar 

  36. Hazen, M. M. et al. Mutations of the hemophagocytic lymphohistiocytosis-associated gene UNC13D in a patient with systemic juvenile idiopathic arthritis. Arthritis Rheum. 58, 567–570 (2008).

    Article  CAS  Google Scholar 

  37. Nahum, E. et al. Hemophagocytic lymphohistiocytic syndrome: unrecognized cause of multiple organ failure. Pediatr. Crit. Care Med. 1, 51–54 (2000).

    Article  CAS  Google Scholar 

  38. Sawhney, S., Woo, P. & Murray, K. J. Macrophage activation syndrome: a potentially fatal complication of rheumatic disorders. Arch. Dis. Child. 85, 421–426 (2001).

    Article  CAS  Google Scholar 

  39. Fitzgerald, N. E. & MacClain, K. L. Imaging charcteristics of hemophagocytic lymphohistiocytosis. Pediatr. Radiol. 33, 392–401 (2003).

    Article  Google Scholar 

  40. Wan, L., Bellomo, R., Di Giantomasso, D. & Ronco, C. The pathogenesis of septic acute renal failure. Curr. Opin. Crit. Care 9, 496–502 (2003).

    Article  Google Scholar 

  41. Thaunat, O. et al. Nephrotic syndrome associated with hemophagocytic syndrome. Kidney Int. 69, 1892–1898 (2006).

    Article  CAS  Google Scholar 

  42. Karras, A. et al. Hemophagocytic syndrome in renal transplant recipients: report of 17 cases and review of literature. Transplantation 77, 238–243 (2004).

    Article  Google Scholar 

  43. Ponzoni, M. et al. Definition, diagnosis and management of intravascular large B-cell lymphoma: proposals and perspectives from an international consensus meeting. J. Clin. Oncol. 25, 3168–3173 (2007).

    Article  Google Scholar 

  44. Braun, M. C., Cohn, R. A. & Kletzel, M. Nephrotic syndrome accompanying familial hemophagocytic syndrome. J. Pediatr. Hematol. Oncol. 18, 195–197 (1996).

    Article  CAS  Google Scholar 

  45. Chiang, W. C. et al. Thrombotic microangiopathy in hemophagocytic syndrome: a case report. J. Formos. Med. Assoc. 101, 362–367 (2002).

    PubMed  Google Scholar 

  46. McCarthy, E. T. et al. TNF-α increases albumin permeability of isolated rat glomeruli through the generation of superoxide. J. Am. Soc. Nephrol. 9, 433–438 (1998).

    CAS  PubMed  Google Scholar 

  47. Koukouritaki, S. B. et al. TNF-α induces actin cytoskeleton reorganization in glomerular epithelial cells involving tyrosine phosphorylation of paxillin and focal adhesion kinase. Mol. Med. 5, 382–392 (1999).

    Article  CAS  Google Scholar 

  48. Nakabayashi, M., Adachi, T., Izuchi, S. & Sugisaki, A. Association of hypercytokinemia in the development of severe preeclampsia in a case of hemophagocytic syndrome. Semin. Thromb. Hemost. 25, 467–471 (1999).

    Article  CAS  Google Scholar 

  49. Pérard, L. et al. Hemophagocytic syndrome in a pregnant patient with systemic lupus erythematosus, complicated with preeclampsia and cerebral hemorrhage. Ann. Hematol. 86, 541–544 (2007).

    Article  Google Scholar 

  50. Fischer, A. et al. Treatment of four patients with erythrophagocytic lymphohistiocytosis by a combination of epipodophyllotoxin, steroids, intrathecal methotrexate and cranial irradiation. Pediatrics 76, 263–268 (1985).

    CAS  PubMed  Google Scholar 

  51. Tsuda, H. & Shirono, K. Successful treatment of virus-associated haemophagocytic syndrome in adults by cyclosporin A supported by G-CSF. Br. J. Haematol. 93, 572–575 (1996).

    Article  CAS  Google Scholar 

  52. Gill, D. S., Spencer, A. & Cobcroft, R. G. High-dose γ-globulin therapy in the reactive haemophagocytic syndrome. Br. J. Haematol. 88, 204–206 (1994).

    Article  CAS  Google Scholar 

  53. Henzan, T. et al. Success with infliximab in treating refractory hemophagocytic lymphohistiocytosis. Am. J. Hematol. 81, 59–61 (2006).

    Article  Google Scholar 

  54. Takahashi, N., Naniwa, T. & Banno, S. Successful use of etanercept in the treatment of acute lupus hemophagocytic syndrome. Mod. Rheumatol. 18, 72–75 (2008).

    Article  Google Scholar 

  55. Olin, R. L. et al. Successful use of the anti-CD25 antibody daclizumab in an adult patient with hemophagocytic lymphohistiocytosis. Am. J. Hematol. 83, 747–749 (2008).

    Article  CAS  Google Scholar 

  56. Balamuth, N. J., Nichols, K. E., Paessler, M. & Teachey, D. T. Use of rituximab in conjunction with immunosuppressive chemotherapy as a novel therapy for Epstein–Barr virus-associated hemophagocytic lymphohistiocytosis. J. Pediatr. Hematol. Oncol. 29, 569–573 (2007).

    Article  Google Scholar 

  57. Behrens, E. M., Kreiger, P. A., Cherian, S. & Cron, R. Q. Interleukin 1 receptor antagonist to treat cytophagic histiocytic panniculitis with secondary hemophagocytic lymphohistiocytosis. J. Rheumatol. 33, 2081–2084 (2006).

    PubMed  Google Scholar 

  58. Rostaing, L., Fillola, G., Baron, E., Cisterne, J. M. & Durand, D. Course of hemophagocytic syndrome in renal transplant patients. Transplantation 60, 506–509 (1995).

    Article  CAS  Google Scholar 

  59. Kürsat, S. et al. Haemophagocytic–histiocytic syndrome in renal transplantation. Nephrol. Dial. Transplant. 12, 1058–1060 (1997).

    Article  Google Scholar 

  60. Asci, G. et al. High-dose immunoglobulin therapy in renal transplant recipients with hemophagocytic histiocytic syndrome. J. Nephrol. 19, 322–326 (2006).

    CAS  PubMed  Google Scholar 

  61. Henter, J. I. et al. HLH-2004: diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr. Blood Cancer. 48, 124–131 (2007).

    Article  Google Scholar 

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  1. A. Karras, Service de Néphrologie, Hôpital Européen Georges Pompidou, Assistance Publique—Hôpitaux de Paris, 20 rue Leblanc, 75015 Paris, France alexandre.karras@egp.aphp.fr

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    Alexandre Karras

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Karras, A. What nephrologists need to know about hemophagocytic syndrome. Nat Rev Nephrol 5, 329–336 (2009). https://doi.org/10.1038/nrneph.2009.73

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