Kidney Involvement in Multicentric Castleman Disease

KIDNEY BIOPSY TEACHING CASE Kidney Involvement in Multicentric Castleman Disease Sumeet Suneja, MD,1 Mala Chidambaram, MD,1 Andrew M. Herzenberg, MD,2 and Joanne M. Bargman, MD1 INDEX WORDS: Castleman disease; thrombotic microangiopathy; immunosuppressive therapy; interleukin 6.

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astleman disease, also known as angiofollicular lymphoid hyperplasia, is an atypical lymphoproliferative disorder that has been linked to the human immunodeficiency virus (HIV) and human herpes virus 8 (HHV-8 or Kaposi sarcoma–associated herpes virus).1 It has been associated with such malignancies as Kaposi sarcoma, non-Hodgkin lymphoma, and Hodgkin disease, as well as polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes (POEMS) syndrome. Clinically, Castleman disease can be divided into 2 subtypes that differ in disease course and prognosis: unicentric and multicentric. Unicentric Castleman disease most often is an isolated benign lymphoproliferative disorder of young adults, usually unassociated with HHV-8 infection and generally curable with surgical resection. Multicentric Castleman disease is a multisystem illness characterized by fever, generalized lymphadenopathy, and hypergammaglobulinemia.2 The association of kidney disease with Castleman disease is uncommon; however, glomerulonephritis, amyloidosis, and interstitial nephritis have been reported.3-5 In this report, we describe a patient with multicentric Castleman disease who presented with proteinuric kidney disease that proved to be the result of From the Departments of 1Medicine and 2Pathology, University Health Network, University of Toronto, Canada. Received March 13, 2008. Accepted in revised form August 14, 2008. Originally published online as doi: 10.1053/j.ajkd.2008.08.026 on November 7, 2008. Address correspondence to Joanne M. Bargman, MD, Toronto General Hospital, 200 Elizabeth St, 8N-840, Toronto, Ontario M5G 2C4, Canada. E-mail: joanne.bargman@uhn. on.ca © 2009 by the National Kidney Foundation, Inc. 0272-6386/09/5303-0024$36.00/0 doi:10.1053/j.ajkd.2008.08.026 550

thrombotic microangiopathy. There are limited reports in the literature describing the association between thrombotic microangiopathy and Castleman disease. Dysregulated production of interleukin 6 (IL-6) has been implicated in the pathogenesis of Castleman disease6 and may have contributed to the renal lesions seen. Unlike previous reports, our patient received treatment with cyclophosphamide and prednisone, resulting in successful reversal of kidney impairment.

CASE REPORT Clinical History A 48-year-old man from Ghana was found to have proteinuria on routine urine dipstick testing in 1997. Investigations showed evidence of Bence-Jones proteinuria. The patient did not describe constitutional symptoms or bony pain. Bone marrow aspirate and biopsy showed mild plasmacytosis (4% to 5% plasma cells). Serum immunoelectrophoresis showed a monoclonal immunoglobulin A (IgA) ␭ protein (4.54 g/L [454 mg/dL]; normal, 0.6 to 3.2 g/L [60 to 320 mg/dL]). Skeletal survey results were normal, and serum creatinine level was 100 ␮mol/L (1.13 mg/dL), corresponding to an estimated glomerular filtration rate (eGFR) of 89 mL/min/ 1.73 m2 (1.48 mL/s/1.73 m2).7 At evaluation 2 years later, the patient remained asymptomatic. His only medication at the time was an angiotensinconverting enzyme inhibitor for hypertension. Physical examination findings were normal, and blood pressure was 140/90 mm Hg. Laboratory investigations showed normal hemoglobin level and white blood cell count; however, platelet count was increased at 538 ⫻ 109/L (538 ⫻ 103/␮L; normal, 150 to 400 ⫻ 109/L [150 to 400 ⫻ 103/␮L]). Electrolyte, liver enzyme, calcium, albumin, and lactate dehydrogenase levels were normal. Erythrocyte sedimentation rate was increased at 37 mm/first hour (normal, 0 to 20 mm/first hour). Serum creatinine level was now increased at 112 ␮mol/L (1.27 mg/dL), corresponding to an eGFR of 78 mL/min/1.73 m2 (1.30 mL/s/1.73 m2). Urinalysis showed 3⫹ albumin on dipstick and microscopy showed hyaline casts. A 24-hour urine collection showed 1.25 g of protein (mostly albumin), and now there was no evidence of BenceJones proteinuria. Serum immunoelectrophoresis again showed a monoclonal IgA ␭ protein (4.82 g/L [482 mg/dL]; normal range, 0.6 to 3.2 g/L [60 to 320 mg/dL]), unchanged

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Kidney Involvement in Multicentric Castleman Disease

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Figure 1. Kidney biopsy specimen shows pathological changes of thrombotic microangiopathy. (A) Glomerular capillary microaneurysm (double arrow), mesangiolysis, and segmental capillary wall double contouring (single arrow) (Jones stain; original magnification ⫻400). (B) Subendothelial widening (arrow) and mesangial-capillary interpositioning (electron microscopy; original magnification ⫻2,500). (C) Glomerular endothelial cell swelling (arrows) (Jones stain; original magnification ⫻600). (D) Glomerular capillary fibrin-platelet thrombus (arrow) (HematoxylinPhloxin-Saffron stain; original magnification ⫻600).

from previous results. The patient declined a kidney biopsy. Blood pressure was optimized with an increase in the dose of the angiotensin-converting enzyme inhibitor and addition of a thiazide diuretic. During the next year, the patient developed myalgias, arthralgias, drenching night sweats, and a 30-pound weight loss. Serum creatinine level increased to 130 ␮mol/L (1.47 mg/dL) with an eGFR of 66 mL/min/1.73 m2 (1.10 mL/s/ 1.73 m2), and 24-hour urine collection for protein persisted at 1 g/d. Repeated bone marrow biopsy showed 10% to 15% plasma cells, and an excess of ␭ light chains was reported. There was no evidence of tuberculosis, fungal infection, lymphoma, or amyloid or granulomatous disease. A complete workup for autoantibodies and complements was negative. Serological test results for hepatitis A, B, and C; HIV; parvovirus B19; Venereal Disease Research Laboratories; Schistosoma haematobium, leishmania; malaria; and tuberculin skin testing were negative. Urine and stool culture results were negative for parasites. The potential contribution of a genetic thrombophilia is unknown in this patient because it was assumed to be a result of his inflammatory syndrome. The patient agreed to proceed with kidney biopsy.

Kidney Biopsy The specimen contained 22 glomeruli, none of which was globally sclerosed. One glomerulus showed segmental sclerosis. The remaining glomeruli showed focal and segmental mesangial and occasional endocapillary hypercellularity. There were several foci of mesangiolysis and capillary microaneurysms. Glomerular capillaries contained swollen endothelial cells. Glomerular basement membranes showed segmental double contouring (Fig 1A). Atypical lymphocytes were noted in glomeruli and peritubular capillaries. Mild interstitial fibrosis and tubular atrophy were present.

There was no evidence of myeloma cast nephropathy, light or heavy chain deposition disease, or amyloid. No glomerular or arteriolar thrombi were identified. Immunofluorescence showed weak granular mesangial staining for IgM and C3. There was no staining for IgG, IgA, ␬ and ␭ light chains, or fibrin. Electron microscopy showed the presence of mesangial expansion with mildly increased cellularity. There was extensive mesangial-capillary interpositioning. Several capillary loops showed widening of the lamina rara interna by subendothelial electron-lucent granular material (Fig 1B).

Diagnosis: Thrombotic Microangiopathy Because of the presence of atypical lymphocytes in glomeruli and peritubular capillaries, flow cytometry was performed on peripheral blood and showed no evidence of a monoclonal population or T-cell lymphoma. After consideration of the laboratory investigations and pathological findings, a diagnosis of thrombotic microangiopathy was made.

Clinical Follow-up During the next year, the patient continued to experience constitutional symptoms. In 2002, repeated computed tomographic imaging of the thorax, abdomen, and pelvis showed massive splenomegaly and a new focal lesion in the center of the spleen measuring 1.5 cm. The patient was referred for exploratory laparotomy. In early 2003, the patient underwent splenectomy and mediastinal node biopsy. Lymph node pathological examination results were consistent with reactive lymphocytosis, with no evidence of monoclonal B- or T-cell populations. Pathological examination of the spleen and splenic hilar nodes showed multicentric Castleman disease. Polymerase chain reaction analyses of splenic tissue were negative for Epstein-Barr virus and HHV-8. Peripheral-

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blood polymerase chain reaction analysis for HHV-8 was also negative. The patient was initiated on an immunosuppressive regimen using prednisone and daily oral cyclophosphamide. After several months of treatment, there was dramatic improvement in the patient’s constitutional symptoms and kidney function. At the last available follow-up, serum creatinine level was 84 ␮mol/L (0.95 mg/dL), corresponding to an eGFR of 108 mL/min/1.73 m2 (1.80 mL/s/1.73 m2), and urinalysis showed 1 g/L of protein on dipstick with bland urinary sediment.

DISCUSSION Castleman disease is a rare lymphoproliferative disorder that was described almost half a century ago by Benjamin Castleman et al8 as a localized mediastinal mass in otherwise usually asymptomatic patients. Traditionally, histological features of Castleman disease have been divided into the hyaline-vascular and plasmacell types. Hyaline-vascular Castleman disease (HV-CD) is most common, representing greater than 90% of cases, and is characterized by a benign clinical course. The plasma-cell subtype is far less common, comprising less than 10% of cases; is associated with a more aggressive clinical course2; and often is multicentric. Unlike patients with HV-CD, these patients often present with constitutional symptoms, and 50% to 90% show hematologic disorders, including anemia and leukocytosis, with many having hypergammaglobulinemia and hypoalbuminemia.9 In contrast to HV-CD, the plasma-cell variant is associated with HHV-810 and has abnormal IL-6 expression by cells in the germinal centers of lymph nodes, which is considered very important in the pathogenesis of this disease.11,12 As with HV-CD, surgical excision leads to resolution of systemic signs and symptoms.13,14 Renal complications from Castleman disease are uncommon. These have included renal amyloidosis, membranous glomerulonephritis, membranoproliferative glomerulonephritis, crescentic glomerulonephritis, and interstitial nephritis.3,4,15-17 Thrombotic microangiopathy, although rare, has been described in 3 previous reports of patients with Castleman disease and acute renal failure. The first reported case of thrombotic microangiopathy was clinically diagnosed in a patient with HV-CD and acute renal failure. However, kidney biopsy was not performed.18 Lajoie et al19 reported 2 pa-

tients who presented with generalized lymphadenopathy, constitutional symptoms, and acute renal failure. Multicentric Castleman disease eventually was diagnosed, and kidney biopsy showed thrombotic microangiopathy. Both patients also showed clinical and serological evidence of autoimmune disease, and antiphospholipid antibodies were found in 1 patient. The investigators proposed that production of antiphospholipid antibodies in patients with Castleman disease might have contributed to the development of renal thrombotic microangiopathy.19 Soon afterward, Jones and Will20 described a patient with HV-CD and acute renal failure, and kidney biopsy showed histological features consistent with hemolytic uremic syndrome (HUS). Antiphospholipid antibodies were not measured in this patient.20 In our patient, multicentric Castleman disease ultimately was diagnosed from pathological examination of the spleen in the setting of proteinuric kidney disease that proved to be thrombotic microangiopathy on kidney biopsy. Thrombotic microangiopathy can be associated with a number of diseases, including HUS and thrombotic thrombocytopenic purpura (TTP), malignant hypertension, preeclampsia, drug toxicity, solid-organ and bone marrow transplantation, malignancy, and autoimmune disease.21 In our patient, results of investigation for autoimmune disease, including antiphospholipid antibody, and other diseases characterized by thrombotic microangiopathy were negative. Furthermore, polymerase chain reaction analysis for HHV-8 and HIV were negative. Treatment with immunosuppressive agents resulted in successful reversal of the patient’s renal impairment. The presence of a paraprotein in this case is reflective of the plasma cell disorder that underlies the development of Castleman disease. There are multiple reports in the coagulation literature describing the interference of paraproteins with various steps in the coagulation pathways,21 and it is conceivable that this could result in thrombi in glomeruli and arterioles as a consequence of endothelial cell injury, similar to that in patients with chronic thrombotic microangiopathies. Such a possible relationship between paraproteinemia and thrombotic microangiopathy has been described in association with POEMS syndrome. Fukatsu et al22 described a patient with POEMS

Kidney Involvement in Multicentric Castleman Disease

syndrome who developed decreased kidney function that proved to be thrombotic microangiopathy on kidney biopsy. Serum IL-6 level was increased, and immunofluorescence of the kidney biopsy specimen showed diffuse expression of IL-6 in areas other than mesangial cells, where IL-6 is normally detectable. The investigators speculated that the initial endothelial damage that occurs in patients with microangiopathic disease results in overproduction of IL-6, leading to further endothelial cell injury and an increase in vascular permeability.22 The cause of Castleman disease currently is unknown, but several explanations for its development include infection, autoimmunity, and cytokine dysregulation.23 Various cytokines and growth factors are implicated in the pathogenesis of Castleman disease. IL-6 is a pleiotropic proinflammatory cytokine secreted by lymphoid and nonlymphoid cells. In addition to Castleman disease, increased IL-6 production has been implicated in the pathogenesis of other diseases, such as multiple myeloma and rheumatoid arthritis.6,24 Furthermore, a significant decrease in IL-6 levels has been found after surgical lymph node excision in patients with Castleman disease.25 In animal models, retroviral transduction of the gene coding for IL-6 has resulted in a syndrome similar to multicentric Castleman disease, leading to the development of peripheral lymphadenopathy, massive splenomegaly, and diffuse hypergammaglobulinemia.26 Increased serum levels of IL-6 and other cytokines have been shown in patients with a number of diseases characterized by renal thrombotic microangiopathy, including HUS, TTP, preeclampsia, POEMS syndrome, and after solidorgan transplantation.22,27-30 Children with HUS related to verotoxin-producing Escherichia coli were found to have increased IL-6 levels compared with controls, and IL-6 levels were 10-fold greater in children with increased severity of renal dysfunction.28 In another study, patients with TTP were found to have significantly increased levels of tumor necrosis factor, IL-1, and IL-6 at the onset of disease, and levels decreased with disease remission. Plasma IL-6 levels correlated with disease prognosis, emphasizing the role of abnormal activation of inflammatory mediators in the pathogenesis of TTP.29 A number of studies of patients with preeclampsia showed

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that plasma IL-6 concentrations are dramatically increased, and it was suggested that increased cytokine concentrations contribute to the endothelial dysfunction characteristic of this disease.30 In addition to its effects on inflammatory cells and endothelium, IL-6 stimulates platelet production. When IL-6 is present in high levels, platelets are easily activated by thrombin and show an increased tendency toward the development of thrombus. IL-6 appears to directly stimulate platelet activation, as well as stimulate production of platelets with a more prothrombotic phenotype.31 Il-6 also increases vascular endothelial growth factor secretion, causing angiogenesis, proliferation of vascular smooth muscle cells, and capillary proliferation with endothelial hyperplasia. It also is responsible for polarization of T lymphocytes to a type 2 cytokine profile leading to an autoimmune pathological state.32,33 Furthermore, IL-6 modulates the release and cleavage of endothelial cell–derived ultralarge von Willebrand factor multimers.34 Deficiency of ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13), a metalloprotease that cleaves ultralarge von Willebrand factor to smaller and less active forms, has been implicated in the pathogenesis of TTP.35 These findings suggest a relationship between inflammation and thrombosis in general and IL-6 and thrombotic microangiopathy in particular. It therefore is plausible that increased serum IL-6 levels in patients with Castleman disease create a prothrombotic state that may result in the development of thrombotic microangiopathy. Renal thrombotic microangiopathy should be added to the differential diagnosis of renal complications from multicentric Castleman disease, and conversely, Castleman disease should be considered in a patient with constitutional symptoms and renal thrombotic microangiopathy. Immunosuppressive therapy may improve the kidney impairment that can occur in patients with this unusual disease.

ACKNOWLEDGEMENTS Support: None. Financial Disclosure: None.

REFERENCES 1. Hengge UR, Ruzicka T, Tyring SK, et al: Update on Kaposi’s sarcoma and other HHV8 associated diseases. Part

554 2: Pathogenesis, Castleman’s disease, and pleural effusion lymphoma. Lancet Infect Dis 2:344-352, 2002 2. Shahidi H, Myers JL, Kvale PA: Castleman’s disease. Mayo Clin Proc 70:969-977, 1995 3. Montoli A, Minola E, Stabile F, et al: End-stage\failure from renal amyloidosis of the AA type associated with giant lymph node hyperplasia (Castleman’s disease). Am J Nephrol 15:142-146, 1995 4. Ruggieri G, Barsotti P, Copppola G, et al: Membranous nephropathy associated with giant lymph node hyperplasia. Am J Nephrol 10:323-328, 1990 5. Seida A, Wada J, Morita Y, et al: Multicentric Castleman’s disease associated with glomerular microangiopathy and MPGN-like lesion: Does vascular endothelial cellderived growth factor play causative or protective roles in renal injury? Am J Kidney Dis 43:E3-E9, 2004 6. Naka T, Nishimoto N, Kishimoto T: The paradigm of IL-6: From basic science to medicine. Arthritis Res 4:S233S242, 2002 (suppl 3) 7. Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D: A more accurate method to estimate glomerular filtration rate from serum creatinine: A new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med 130:461-470, 1999 8. Castleman B, Iverson L, Menendez VP: Localized mediastinal lymph-node hyperplasia resembling thymoma. Cancer 9:822-830, 1956 9. Keller AR, Hochholzer L, Castleman B: Hyalinevascular and plasma-cell types of giant lymph node hyperplasia of the mediastinum and other locations. Cancer 29:670-683, 1972 10. Dupin N, Diss TL, Kellam P, et al: HHV-8 is associated with a plasmablastic variant of Castleman disease that is linked to HHV-8-positive plasmablastic lymphoma. Blood 95:1406-1412, 2000 11. Hsu SM, Waldron JA, Xie SS, et al: Expression of interleukin-6 in Castleman’s disease. Hum Pathol 24:833839, 1993 12. Chadburn A, Cesarman E, Nador RG, et al: Kaposi’s sarcoma-associated herpesvirus sequences in benign lymphoid proliferations not associated with human immunodeficiency virus. Cancer 80:788-797, 1997 13. McCarty MJ, Vukelja SJ, Banks PM, et al: Angiofollicular lymph node hyperplasia (Castleman’s disease). Cancer Treat Rev 21:291-310, 1995 14. Frizzera G: Castleman’s disease and related disorders. Semin Diagn Pathol 5:346-364, 1988 15. Chan T, Cheng IKP, Wong K, et al: Resolution of membranoproliferative glomerulonephritis complicating angiofollicular lymph node hyperplasia (Castleman’s disease). Nephron 65:628-632, 1993 16. Tsukamoto Y, Hanada N, Nomura Y, et al: Rapidly progressive renal failure associated with angiofollicular lymph node hyperplasia. Am J Nephrol 11:430-436, 1991 17. Summerfield GP, Taylor W, Bellingham AJ, et al: Hyaline-vascular variant of angiofollicular lymph node hyperplasia with systemic manifestation and response to corticosteroids. J Clin Pathol 36:1005-1011, 1983 18. Couch WD: Giant lymph node hyperplasia associated with thrombotic thrombocytopenic purpura. Am J Clin Pathol 74:340-344, 1980

Suneja et al 19. Lajoie G, Kumar S, Min K, et al: Renal thrombotic microangiopathy associated with multicentric Castleman’s disease. Am J Surg Pathol 19:1021-1028, 1995 20. Jones CH, Will EJ: Angiofollicular lymph node hyperplasia, accelerated hypertension, and acute renal failure: A case report. Nephrol Dial Transplant 11:352354, 1996 21. Coppo P, Veyradier A, Durey MA, et al: Pathophysiology of thrombotic microangiopathies: Current understanding. Ann Med Interne (Paris) 153:153-166, 2002 22. Fukatsu A, Ito Y, Yuzawa Y, et al: A case of POEMS syndrome showing elevated serum interleukin 6 and abnormal expression of interleukin 6 in the kidney. Nephron 62:47-51, 1992 23. Greiner T, Armitage JO, Gross TG: Atypical lymphoproliferative diseases. Hematology (Am Soc Hematol Educ Program) Jan 2000:133-146, 2000 24. Leger-Ravet MB, Peuchmaur M, Devergne O, et al: Interleukin-6 gene expression in Castleman’s disease. Blood 78:2923-2930, 1991 25. Yoshizaki K, Matsuda T, Nishimoto N, et al: Pathogenic significance of interleukin-6 (IL-6/BSF-2) in Castleman’s disease. Blood 74:1360-1367, 1989 26. Brandt SJ, Bodine DM, Dunbar CE, et al: Dysregulated interleukin 6 expression produces a syndrome resembling Castleman’s disease in mice. J Clin Invest 86:592-599, 1990 27. Burke GW, Ciancio G, Cirocco R, et al: Microangiopathy in kidney and simultaneous pancreas/kidney recipients treated with tacrolimus: Evidence of endothelin and cytokine involvement. Transplantation 68:1336-1342, 1999 28. Litalien C, Proulx F, Mariscalco MM, et al: Circulating inflammatory cytokine levels in hemolytic uremic syndrome. Pediatr Nephrol 13:840-845, 1999 29. Wada H, Kaneko T, Ohiwa M, et al: Plasma cytokine levels in thrombotic thrombocytopenic purpura. Am J Hematol 40:167-170, 1992 30. Greer IA, Lyall F, Perera T, et al: Increased concentrations of cytokines interleukin-6 and interleukin-1 receptor antagonist in plasma of women with preeclampsia: A mechanism for endothelial dysfunction? Obstet Gynecol 84:937940, 1994 31. Esmon CT: Possible involvement of cytokines in diffuse intravascular coagulation and thrombosis. Baillieres Best Pract Res Clin Haematol 12:343-359, 1999 32. Nishi J, Arimura K, Utsunomiya A, et al: Expression of vascular endothelial growth factor in sera and lymph nodes of the plasma cell type of Castleman’s disease. Br J Haematol 104:482-485, 1999 33. Nishi J, Maruyama I: Increased expression of vascular endothelial growth factor (VEGF) in Castleman’s disease: Proposed pathomechanism of vascular proliferation in the affected lymph node. Leuk Lymphoma 38:387-394, 2000 34. Bernardo A, Ball C, Nolasco L, et al: Effects of inflammatory cytokines on the release and cleavage of the endothelial cell–derived ultralarge von Willebrand factor multimers under flow. Blood 104:100-106, 2004 35. Shelat SG, Ai J, Zheng XL, et al: Molecular biology of ADAMTS13 and diagnostic utility of ADAMTS13 proteolytic activity and inhibitor assays. Semin Thromb Hemost 31:659-672, 2005