- Email: [email protected]
Splenectomy may improve the glomerulopathy of type ii mixed cryoglobulinemia
CASE REPORTS
Splenectomy May Improve the Glomerulopathy of Type II Mixed Cryoglobulinemia Yoshifumi Ubara, MD, Shigeko Hara, MD, Hideyuki Katori, MD, Tetsuo Tagami, MD, Akiko Kitamura, MD, Masafumi Yokota, MD, Yoshio Matsushita, MD, Fumi Takemoto, MD, Akira Yamada, MD, Kiyotaka Nagahama, MD, Mituru Hara, MD, and Kazuaki Chayama, MD ● Many patients with type II mixed cryoglobulinemia have been shown to be infected with hapatitis C virus (HCV). Therefore, interferon-alfa has become the first choice of treatment for patients with HCV-associated cryoglobulinemia. However, the disease often relapses after the discontinuation of interferon therapy. The long-term effect of interferon therapy is controversial. Therefore, a more effective therapy needs to be developed. A 62-year-old Japanese woman was admitted to our hospital for the examination of abnormal liver function tests, severe edema, and purpura in her lower extremities. Glomerulopathy secondary to HCV-related cryoglobulinemia was suspected. Her serum creatinine was increased to 2.1 mg/dL. Interferon therapy was considered initially. However, because of pancytopenia caused by liver cirrhosis and splenomegaly, splenectomy was performed in February 1997, before the start of interferon therapy. Renal biopsy specimen taken at the time of the splenectomy showed typical cryoglobulinemic glomerulonephritis. Gradually, after surgery, the patient’s thrombocytopenia and anemia improved, her proteinuria and hematuria were decreased, her cryocrit dropped from 15% to 5%, the Ccr increased from 21.1 mL/min to 48.8 mL/min, and the purpura in her lower extremities disappeared. A repeat renal biopsy performed in May 1998 showed marked histological improvement. Splenectomy is not widely accepted as a treatment for cryoglobulinemia. Our case suggests the possibility that the monoclonal-IgM component of the type II cryoglobulin may be formed in the spleen. In conclusion, splenectomy may be an effective therapy for cryoglobulinemia in patients with HCV-positive liver cirrhosis and pancytopenia secondary to splenomegaly. 娀 2000 by the National Kidney Foundation, Inc. INDEX WORDS: Cryoglobulinemic glomerulopathy; splenectomy; hepatitis C virus (HCV); type II mixed cryoglobulinemia; liver cirrhosis.
U
NTIL 1990, STEROIDS, immunosuppressives, and plasmapheresis were the main therapies for type II mixed cryoglobulinemia without secondary causes such as lymphoproliferative disorder, autoimmune diseases, and infection. Since 1990, when the hepatitis C virus (HCV) was first detected in these patients, most patients with mixed cryoglobulinemia have been shown to be infected with HCV.1,2 Therefore, interferonalfa has been expected to become the therapy of choice for patients with HCV-associated cryoglobulinemia.3-6 However, once interferon therapy is discontinued, the disease relapses.4 The long-term effectiveness of this therapy is controversial.7 In addition, the effectiveness of interferon has been reported to
From the Nephrology Center, Department of Pathology and Department of Gastroenterology, Toranomon Hospital, Tokyo, Japan. Received August 23, 1999; accepted in revised form November 19, 1999. Address reprint requests to Yoshifumi Ubara, MD, Nephrology Center, Toranomon Hospital, 2-2-2, Toranomon, Minatoku, Tokyo 105-8470, Japan. E-mail: [email protected]
娀 2000 by the National Kidney Foundation, Inc. 0272-6386/00/3506-0023$3.00/0 doi:10.1053/ajkd.2000.7489 1186
differ according to the serotype of HCV.7,8 Accordingly, interferon is not necessarily the best therapy,7 and a more effective therapy needs to be developed. We experienced a patient of cryoglobulinemia with HCV-positive liver cirrhosis who showed both clinical and histological improvement after a splenectomy was performed. We investigated whether a splenectomy is useful therapy for patients with HCVrelated type II cryoglobulinemia. CASE REPORT We report a 62-year-old Japanese woman with cryoglobulinemic glomerulonephritis complicated with HCV-positive liver cirrhosis. She was transfused with more than 10 units of red blood cells after an ectopic pregnancy in 1963. Elevated liver function tests were first noted in 1966, which was left untreated. In 1986, a right nephrectomy was performed because of renal tumor, which was diagnosed as a renal cell carcinoma histologically, and no abnormal finding was noted in a nontumor site. Starting in 1993, retiform exanthemas began to appear on her lower extremities. In October 1996, abnormal liver function tests were detected on a health check, and she was admitted for more extensive studies. On admission, she was 159 cm tall and weighed 78 kg. Her blood pressure was 172/88 mm Hg. Her abdomen was distended, and there was severe edema and purpura in her lower extremities (Fig 1).
American Journal of Kidney Diseases, Vol 35, No 6 (June), 2000: pp 1186-1192
SPLENECTOMY AND CRYOGLOBULINEMIA
Fig 1. Photography of the patient before splenectomy. Severe edema and purpura were shown in the lower extremities.
Fig 2. First renal biopsy taken in February 1997 at the time of the splenectomy. Light microscopic examination showed a marked increase in the mesangial matrix with extensive proliferation of the mesangial cells and leukocytes, including monocytes and macrophages, resulting in lobular accentuation of the glomerular tuft. Thrombi also were seen in the glomerular capillaries (periodic acid-Schiff’s reagent staining; original magnification ⴛ 320).
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Laboratory findings were as follows: erythrocyte count was 2.39 ⫻ 106/µL, hemoglobin concentration was 7.6 g/dL, hematocrit was 22.7%, leukocyte count was 2,200/µL, and thrombocyte count was 5.1 ⫻ 104/µL. Total protein concentration was 5.1 g/dL, albumin was 3.0 g/dL, urea nitrogen was 12 mg/dL, creatinine was 1.2 mg/dL, and uric acid was 8.3 mg/dL. Sodium was 147 mmol/L, potassium was 3.6 mEq/L, chloride was 108 mmol/L, and total cholesterol was 136 mg/dL. Total bilirubin was 1.5 mg/dL, aspartate aminotransferase (AST) was 27 (IU/L), alanine aminotransferase (ALT) was 10 (IU/L), an indocyanine green test (R15) was 12%, C-reactive protein was 0.4 mg/dL, and the erythrocyte sedimentation rate was 48 mm/h. Serum immunoglobulin G (IgG) concentration was 1,573 mg/dL, IgA was 224 mg/dL, and IgM was 281 mg/dL. The CH50 was 2 U, C3 concentration was 31.6 mg/dL, and C4 was 6.5 mg/dL. IgM-rheumatoid factor was 52 U/mL. A serum cryoglobulin was positive, and the patient was diagnosed as having type II cryoglobulinemia consisting of a monoclonal IgM combined with polyclonal IgG. Cryocrit was 15%. On viral examination, serum was positive for HCV antibody, and HCV-serotype was I. Serum HCV-RNA level was 1.1 mEq/mL by branched HCV-probe assay (Quantiplex, Chiron, Emeryvilly, CA). Serum was negative for hepatitis B surface antigen. The urine pH was 7.0, negative for glucose, 3⫹ for protein and occult blood. The urine sediment contained many erythrocytes per high-power field (HPF). The urine was negative for Bence-Jones protein. Twenty-four-hour urine contained 8.73 g protein and 5,200 µg 2-microglobulin. Creatinine clearance was 21.1 mL/min. Computed tomographic and ultrasonographic studies showed liver cirrhosis with splenomegaly, compensatory left renal hypertrophy after a right nephrectomy, and massive ascites. A chest radiograph showed bilateral pleural effusions. A laparoscopy showed liver cirrhosis with nodular lesions. A skin biopsy showed mild perivascular lymphocytic infiltration and granular deposits of IgG, IgM, C3, C9, and fibrinogen along the capillaries of the papillary layer.
Fig 3. First renal biopsy. Immunofluorescent examination showed significant staining for (A) IgG, (B) IgM, and (C) C3 along the capillary walls and mesangium (original magnification ⴛ 320).
SPLENECTOMY AND CRYOGLOBULINEMIA
Type II cryoglobulinemia was diagnosed, and nephroticrange proteinuria secondary to cryoglobulinemia was suspected. The fluid retention was supposed to be related to the liver cirrhosis and the glomerulopathy of cryoglobulinemia. In December 1996, her serum creatinine increased to 2.1 mg/dL, and her serum urea nitogen was 23 mg/dL. Interferon therapy was considered initially for the cryoglobulinemia and HCV infection. However, she had pancytopenia caused by liver cirrhosis and splenomegaly. Therefore, a splenectomy was performed before the start of interferon therapy. In February 1997, a renal biopsy was performed at the time of the splenectomy.
First Renal Biopsy Light microscopic examination of a renal specimen containing 33 glomeruli showed a marked increase in the mesangial matrix with extensive proliferation of the mesangial cells and leukocytes, including monocytes and macrophages, resulting in lobular accentuation of the glomerular
Fig 4. First renal biopsy. Electron microscopic examination showed huge subendothelial deposits as well as mesangial deposits. The subendothelial deposits appeared as granular structures and uniform thick-walled mirotubules at high magnification (original magnification ⴛ 40,000).
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tuft (Fig 2). Thrombi also were seen in the glomerular capillaries. The capillary walls showed circumferential mesangial interposition with double contours. A mild lymphoid cell infiltration and fibrosis were observed in the interstitium. The interlobular arteries were normal, and mild hyaline sclerosis was detected in the arterioles. Congo red staining was negative. Immunofluorescent examination showed significant staining with IgG, IgM, and C3 along capillary walls and mesangium (Fig 3). Electron microscopic examination showed huge subendothelial deposits as well as mesangial deposits. The subendothelial deposits had granular structures, and uniform thick-walled microtubules could be seen at higher magnification (Fig 4). The epithelial foot processes were partially effaced. The removed spleen was markedly enlarged because of portal hypertension, and the histology showed no lymphoproliferative disorders such as lymphoma. The liver biopsy at the time of surgery indicated multimonolobular cirrhosis with thin septa. After surgery, her urinary protein and occult blood gradually decreased, and the purpura in her lower extremities faded.
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In May 1998, her laboratory findings were as follows: Total serum protein was 7.9 g/dL; albumin, 4.3 g/dL; urea nitogen, 15 mg/dL; serum creatinine, decreased to 1.1 mg/ dL; and Ccr, 65 mL/min. Erythrocyte count was 3.37 ⫻ 106/µL; hematocrit had improved to 36.3%; leukocytes, 4,500/µL; and thrombocyte count, 19.8 ⫻ 104/µL. Cryocrit had decreased to 5%. The urinary sediment of erythrocyte contained less than 1 cell/HPF, and she had only 0.06 g protein in her 24-hour urine. However, AST had increased to 45 (IU/L); ALT was 50 (IU/L); and her serum HCV-RNA level was 2.3 mEq/mL by branched HCV-probe assay. Serum IgG concentration had increased to 2,153 mg/dL; IgA, 286 mg/dL; and IgM, 251 mg/dL. The CH50 was 2 U, C3 concentration was 58 mg/dL, and C4 was 15 mg/dL. IgMrheumatoid factor was 58 U/mL. In May 1998, 15 months after the splenectomy, a repeat renal biopsy was performed with the informed consent of the patient, because her serum cryoglobulin remained positive with 5% of cryocrit, despite the improvement of urinary abnormalities.
Second Renal Biopsy Light microscopic examination of a specimen containing four glomeruli showed a slight increase in the mesangial matrix with slight mesangial cell proliferation. The diffuse thickening of the capillary walls with double contours seen in the first biopsy specimen had disappeared (Fig 5). Immunofluorescent studies showed only a slight staining for IgG, IgM, C3, and kappa light chain. On electron microscopic examination, the subendothelial electron-dense deposits had decreased, and electron-lucent areas appeared (Fig 6). The renal biopsy findings and the patient’s clinical features showed marked improvement. In October 1999, 16 months after the second renal biopsy, her serum creatinine remains in the normal range, and her proteinuria is negative, although her HCV-RNA is positive, with 5% of cryocrit.
UBARA ET AL
DISCUSSION
Type II mixed cryoglobulinemia not secondary to lymphoproliferative disorder, autoimmune diseases, or infection has been regarded as a disease of unknown cause and had been called ‘‘essential’’ until 1990. However, since Pascual et al1 suggested the possibility of an association between HCV and type II cryoglobulinemia in 1990,1 many patients with ‘‘essential’’ type II mixed cryoglobulinemia have been found to be infected with HCV. Agnello et al2 suggested a role of HCV in the pathogenesis of type II cryoglobulinemia, because HCV-RNA was detected in 16 of 19 patients with type II cryoglobulinemia. It may be inappropriate to designate cryoglobulinemia secondary to HCV as ‘‘essential.’’ Johnson et al3 have reported that chronic HCV infection is associated with both cryoglobulinemia and membranoproliferative glomerulonephritis. Four of their patients who had chronic HCV infection and cryoglobulinemia with membranoproliferative glomerulonephritis had improvement of their renal diseases, as well as HCV viremia and liver diseases, after treatment with interferon-alfa.3 Misiani et al4 have reported that 15 of 25 patients with HCV-associated type II cryoglobulinemia had a significant improvement after treatment with interferon alfa-2a.4 However, the cryoglobulinemia recurred after the interferon was discontinued. It was concluded that the antiviral effect of interferon parallels its
Fig 5. Second renal biopsy finding performed in May 1998, 15 months after splenectomy. Light microscopic examination showed a mild increase in mesangial matrix with mild mesangial cell proliferation. Diffuse thicking of capillary wall with double contours seen in the first biopsy disappeared (periodic acid-Schiff’s reagent staining; original magnification ⴛ 400).
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Fig 6. Second renal biopsy. On electron microscopic examination, the subendothelial electron dense deposits had decreased and electron lucent areas appeared (original magnification ⴛ 30,000).
effects on the cryoglobulinemia and therefore that the virus must in some way precipitate the cryoglobulinemia. The histological improvement in the kidneys of patients with cryoglobulinemia was reported subsequently, in addition to clinical and serological improvement with interferon-alfa therapy.5,6 Interferon was expected to become a main therapy for cryoglobulinemia secondary to HCV. However, Mazzaro et al7 have reported that only 4 of 20 patients maintained a complete response a few months after therapy was stopped, whereas the remaining 16 patients either suffered relapse or were nonresponders. Alfa-interferon therapy has not proved effective for all patients with HCV-related cryoglobulinemia. The HCV serotype has been hypothesized to be a predictive factor for the response to antiviral therapy by
interferon.7,8 Patients with HCV serotype II have been reported to have the poorest response to interferon.8 Tarantino et al9 studied 105 essential mixed cryoglobulinemia (EMC) patients with renal involvement, and patient survival was only 49% at 10 years after renal biopsy regardless of the type of treatments, including interferon, and type II mixed cryoglobulinemia had a poor prognosis. D’Amico reported that interferon-alfa is not effective for cryoglobulinemic patients with acute nephrotic syndrome and rapidly progressive renal insufficiency. They proposed that interferon should be combined with steroids (including high-dose methylprednisolone), plasmapheresis, or cyclophosphamide.10-12 Our patient had liver cirrhosis as an unfavorable complication. Because the side effects of interferon-alfa include thrombocytopenia and
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anemia, it may not be suitable for patients with liver cirrhosis and pancytopenia. A splenectomy was performed first, with the expectation that her thrombocytes and erythrocytes would increase before the initiation of interferon therapy. However, we found that not only her thrombocytopenia and anemia, but also her proteinuria, renal function, purpura, and cryocrit, improved after splenectomy. Because splenectomy is not widely recognized as a treatment for cryoglobulinemia, we performed a literature search. We found only a single case report, by Mathison et al13 in 1971. Although the investigators initially instituted prednisolone therapy for IgM-IgG cryoglobulinemia with purpura and arthralgias, it was ineffective. Cyclophosphamide was administered next, but it was discontinued because of pancytopenia. Finally, a splenectomy was performed to improve the pancytopenia. After the splenectomy, the cryocrit, skin lesions, and pancytopenia resolved. It was suggested that because IgMcontaining plasma cells were observed in the spleen, lymphoid cells in the spleen may have produced much of the abnormal cryoglobulin protein. They proposed that a splenectomy is effective for cryoglobulinemia. However, after this report, a splenectomy for cryoglobulinemia has not been widely performed, even though another report discussed the importance of the spleen for IgM production.14 Ron et al14 have shown that, after a splenectomy, there are fewer mature B cells in the peripheral blood, and they proposed, based on experiments with mice, that the spleen may play an important role in B-cell differentiation, including IgM formation. The pathogenesis of type II cryoglobulin remains unknown. However, our patient’s clinical course and the report by Ron et al14 suggest the possibility that the IgM-monoclonal component of type II cryoglobulin may be formed in the spleen. In summary, since interferon therapy was first introduced for patients with HCV-related cryoglobulinemia, many studies have confirmed the effectiveness of this therapy. However, these studies also have shown that there are many nonresponders to interferon and that many relapse after the discontinuation of interferon. It also is not effective for patients with liver cirrhosis. Our patient’s clinical course suggests that a splenectomy may be considered for cryoglobulinemic patients with HCV-liver cirrhosis, spleno-
UBARA ET AL
megaly, and pancytopenia who do not respond to interferon. REFERENCES 1. Pascual M, Perrin L, Giostra E, et al: Hepatitis C virus in patients with cryoglobulinemia type II. J Infect Dis 162:569-570, 1990 2. Agnello V, Chung RT, Kaplan LM: A role for hepatitis C virus infection in type II cryoglobulinemia. N Engl J Med 327:1490-1495, 1992 3. Johnson RJ, Gretch DR, Yamabe H, Hart J, Bacchi CE, Hartwell P, Couser WG, Corey L, Wener MH, Alpers CE, Willson R: Membranoproliferative glomerulonephritis associated with hepatitis C virus infection. N Engl J Med 328:465-470, 1993 4. Misiani R, Bellavita P, Fenili D, Vicari O, Marchesi D, Sironi PL, Zilio P, Vernocchi A, Massazza M, Vendramin G, Tanzi E, Zanetti A: Interferon alfa-2a therapy in cryoglobulinemia associated with hepatitis C virus. N Engl J Med 330:751-756, 1994 5. Yamabe H, Johnson RJ, Gretch DR, Osawa H, Inuma H, Sasaki T, Kaizuka M, Tamura N, Tsunoda S, Fujita Y, Sato A, Onodera K: Membranoproliferative glomerulonephritis associated with hepatitis C virus infection responsive to interferon-alfa. Am J Kidney Dis 25:67-69, 1995 6. Morosetti M, Sciarra G, Meloni C, Palmieri G, Palombo M, Gallucci MT, Casciani CU: Membranoproliferative glomerulonephritis and hepatitis C: Effects of interferonalfa therapy on clinical outcome and histological pattern. Nephrol Dial Transplant 11:532-534, 1996 7. Mazzaro C, Franzin F, Tulissi P, Pussini E, Crovatto M, Carniello GS, Efremov DG, Burrone O, Santini G, Pozzato G: Regression of monoclonal B-cell expansion in patients affected by mixed cryoglobulinemia responsive to alfainterferon therapy. Cancer 77:2604-2613, 1996 8. Kanai K, Kato M, Okamoto H: HCV genotypes in chronic hepatitis C and response to interferon. Lancet 339: 1543, 1992 9. Tarantino A, Campise M, Banfi G, Confalonieri R, Bucci A, Montoli A, Colasanti G, Damilano I, D’Amico G, Minetti L, Ponticelli C: Long-term predictors of survival in essential mixed cryoglobulinemic glomerulonephritis. Kidney Int 47:618-623, 1995 10. Quigg RJ, Brathwaite M, Gardner DF, Gretch DR, Ruddy S: Successful cyclophosphamide treatment of cryoglobulinemic membranoproliferative glomerulonephritis associated with hepatitis C virus infection. Am J Kidney Dis 25:798-800, 1995 11. D’Amico G, Fornasieri A: Cryoglobulinemic glomerulonephritis: A membranoproliferative glomerulonephritis induced hepatitis C virus. Am J Kidney Dis 25:361-369, 1995 12. D’Amico G: Renal involvement in hepatitis C infection: Cryoglobulinemic glomerulonephritis. Kidney Int 54: 650-671, 1998 13. Mathison DA, Condemi JJ, Leddy JP, Callerame ML, Panner BJ, Vaughan JH: Purpura, arthralgia, and IgM-IgG cryoglobulinemia with rheumatoid factor activity. Ann Intern Med 74:383-390, 1971 14. Ron Y, Baetselier PD, Segal S: Involvement of the spleen in murine B cell differentiation. Eur J Immunol 11:94-99, 1981
Splenectomy May Improve the Glomerulopathy of Type II Mixed Cryoglobulinemia Yoshifumi Ubara, MD, Shigeko Hara, MD, Hideyuki Katori, MD, Tetsuo Tagami, MD, Akiko Kitamura, MD, Masafumi Yokota, MD, Yoshio Matsushita, MD, Fumi Takemoto, MD, Akira Yamada, MD, Kiyotaka Nagahama, MD, Mituru Hara, MD, and Kazuaki Chayama, MD ● Many patients with type II mixed cryoglobulinemia have been shown to be infected with hapatitis C virus (HCV). Therefore, interferon-alfa has become the first choice of treatment for patients with HCV-associated cryoglobulinemia. However, the disease often relapses after the discontinuation of interferon therapy. The long-term effect of interferon therapy is controversial. Therefore, a more effective therapy needs to be developed. A 62-year-old Japanese woman was admitted to our hospital for the examination of abnormal liver function tests, severe edema, and purpura in her lower extremities. Glomerulopathy secondary to HCV-related cryoglobulinemia was suspected. Her serum creatinine was increased to 2.1 mg/dL. Interferon therapy was considered initially. However, because of pancytopenia caused by liver cirrhosis and splenomegaly, splenectomy was performed in February 1997, before the start of interferon therapy. Renal biopsy specimen taken at the time of the splenectomy showed typical cryoglobulinemic glomerulonephritis. Gradually, after surgery, the patient’s thrombocytopenia and anemia improved, her proteinuria and hematuria were decreased, her cryocrit dropped from 15% to 5%, the Ccr increased from 21.1 mL/min to 48.8 mL/min, and the purpura in her lower extremities disappeared. A repeat renal biopsy performed in May 1998 showed marked histological improvement. Splenectomy is not widely accepted as a treatment for cryoglobulinemia. Our case suggests the possibility that the monoclonal-IgM component of the type II cryoglobulin may be formed in the spleen. In conclusion, splenectomy may be an effective therapy for cryoglobulinemia in patients with HCV-positive liver cirrhosis and pancytopenia secondary to splenomegaly. 娀 2000 by the National Kidney Foundation, Inc. INDEX WORDS: Cryoglobulinemic glomerulopathy; splenectomy; hepatitis C virus (HCV); type II mixed cryoglobulinemia; liver cirrhosis.
U
NTIL 1990, STEROIDS, immunosuppressives, and plasmapheresis were the main therapies for type II mixed cryoglobulinemia without secondary causes such as lymphoproliferative disorder, autoimmune diseases, and infection. Since 1990, when the hepatitis C virus (HCV) was first detected in these patients, most patients with mixed cryoglobulinemia have been shown to be infected with HCV.1,2 Therefore, interferonalfa has been expected to become the therapy of choice for patients with HCV-associated cryoglobulinemia.3-6 However, once interferon therapy is discontinued, the disease relapses.4 The long-term effectiveness of this therapy is controversial.7 In addition, the effectiveness of interferon has been reported to
From the Nephrology Center, Department of Pathology and Department of Gastroenterology, Toranomon Hospital, Tokyo, Japan. Received August 23, 1999; accepted in revised form November 19, 1999. Address reprint requests to Yoshifumi Ubara, MD, Nephrology Center, Toranomon Hospital, 2-2-2, Toranomon, Minatoku, Tokyo 105-8470, Japan. E-mail: [email protected]
娀 2000 by the National Kidney Foundation, Inc. 0272-6386/00/3506-0023$3.00/0 doi:10.1053/ajkd.2000.7489 1186
differ according to the serotype of HCV.7,8 Accordingly, interferon is not necessarily the best therapy,7 and a more effective therapy needs to be developed. We experienced a patient of cryoglobulinemia with HCV-positive liver cirrhosis who showed both clinical and histological improvement after a splenectomy was performed. We investigated whether a splenectomy is useful therapy for patients with HCVrelated type II cryoglobulinemia. CASE REPORT We report a 62-year-old Japanese woman with cryoglobulinemic glomerulonephritis complicated with HCV-positive liver cirrhosis. She was transfused with more than 10 units of red blood cells after an ectopic pregnancy in 1963. Elevated liver function tests were first noted in 1966, which was left untreated. In 1986, a right nephrectomy was performed because of renal tumor, which was diagnosed as a renal cell carcinoma histologically, and no abnormal finding was noted in a nontumor site. Starting in 1993, retiform exanthemas began to appear on her lower extremities. In October 1996, abnormal liver function tests were detected on a health check, and she was admitted for more extensive studies. On admission, she was 159 cm tall and weighed 78 kg. Her blood pressure was 172/88 mm Hg. Her abdomen was distended, and there was severe edema and purpura in her lower extremities (Fig 1).
American Journal of Kidney Diseases, Vol 35, No 6 (June), 2000: pp 1186-1192
SPLENECTOMY AND CRYOGLOBULINEMIA
Fig 1. Photography of the patient before splenectomy. Severe edema and purpura were shown in the lower extremities.
Fig 2. First renal biopsy taken in February 1997 at the time of the splenectomy. Light microscopic examination showed a marked increase in the mesangial matrix with extensive proliferation of the mesangial cells and leukocytes, including monocytes and macrophages, resulting in lobular accentuation of the glomerular tuft. Thrombi also were seen in the glomerular capillaries (periodic acid-Schiff’s reagent staining; original magnification ⴛ 320).
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Laboratory findings were as follows: erythrocyte count was 2.39 ⫻ 106/µL, hemoglobin concentration was 7.6 g/dL, hematocrit was 22.7%, leukocyte count was 2,200/µL, and thrombocyte count was 5.1 ⫻ 104/µL. Total protein concentration was 5.1 g/dL, albumin was 3.0 g/dL, urea nitrogen was 12 mg/dL, creatinine was 1.2 mg/dL, and uric acid was 8.3 mg/dL. Sodium was 147 mmol/L, potassium was 3.6 mEq/L, chloride was 108 mmol/L, and total cholesterol was 136 mg/dL. Total bilirubin was 1.5 mg/dL, aspartate aminotransferase (AST) was 27 (IU/L), alanine aminotransferase (ALT) was 10 (IU/L), an indocyanine green test (R15) was 12%, C-reactive protein was 0.4 mg/dL, and the erythrocyte sedimentation rate was 48 mm/h. Serum immunoglobulin G (IgG) concentration was 1,573 mg/dL, IgA was 224 mg/dL, and IgM was 281 mg/dL. The CH50 was 2 U, C3 concentration was 31.6 mg/dL, and C4 was 6.5 mg/dL. IgM-rheumatoid factor was 52 U/mL. A serum cryoglobulin was positive, and the patient was diagnosed as having type II cryoglobulinemia consisting of a monoclonal IgM combined with polyclonal IgG. Cryocrit was 15%. On viral examination, serum was positive for HCV antibody, and HCV-serotype was I. Serum HCV-RNA level was 1.1 mEq/mL by branched HCV-probe assay (Quantiplex, Chiron, Emeryvilly, CA). Serum was negative for hepatitis B surface antigen. The urine pH was 7.0, negative for glucose, 3⫹ for protein and occult blood. The urine sediment contained many erythrocytes per high-power field (HPF). The urine was negative for Bence-Jones protein. Twenty-four-hour urine contained 8.73 g protein and 5,200 µg 2-microglobulin. Creatinine clearance was 21.1 mL/min. Computed tomographic and ultrasonographic studies showed liver cirrhosis with splenomegaly, compensatory left renal hypertrophy after a right nephrectomy, and massive ascites. A chest radiograph showed bilateral pleural effusions. A laparoscopy showed liver cirrhosis with nodular lesions. A skin biopsy showed mild perivascular lymphocytic infiltration and granular deposits of IgG, IgM, C3, C9, and fibrinogen along the capillaries of the papillary layer.
Fig 3. First renal biopsy. Immunofluorescent examination showed significant staining for (A) IgG, (B) IgM, and (C) C3 along the capillary walls and mesangium (original magnification ⴛ 320).
SPLENECTOMY AND CRYOGLOBULINEMIA
Type II cryoglobulinemia was diagnosed, and nephroticrange proteinuria secondary to cryoglobulinemia was suspected. The fluid retention was supposed to be related to the liver cirrhosis and the glomerulopathy of cryoglobulinemia. In December 1996, her serum creatinine increased to 2.1 mg/dL, and her serum urea nitogen was 23 mg/dL. Interferon therapy was considered initially for the cryoglobulinemia and HCV infection. However, she had pancytopenia caused by liver cirrhosis and splenomegaly. Therefore, a splenectomy was performed before the start of interferon therapy. In February 1997, a renal biopsy was performed at the time of the splenectomy.
First Renal Biopsy Light microscopic examination of a renal specimen containing 33 glomeruli showed a marked increase in the mesangial matrix with extensive proliferation of the mesangial cells and leukocytes, including monocytes and macrophages, resulting in lobular accentuation of the glomerular
Fig 4. First renal biopsy. Electron microscopic examination showed huge subendothelial deposits as well as mesangial deposits. The subendothelial deposits appeared as granular structures and uniform thick-walled mirotubules at high magnification (original magnification ⴛ 40,000).
1189
tuft (Fig 2). Thrombi also were seen in the glomerular capillaries. The capillary walls showed circumferential mesangial interposition with double contours. A mild lymphoid cell infiltration and fibrosis were observed in the interstitium. The interlobular arteries were normal, and mild hyaline sclerosis was detected in the arterioles. Congo red staining was negative. Immunofluorescent examination showed significant staining with IgG, IgM, and C3 along capillary walls and mesangium (Fig 3). Electron microscopic examination showed huge subendothelial deposits as well as mesangial deposits. The subendothelial deposits had granular structures, and uniform thick-walled microtubules could be seen at higher magnification (Fig 4). The epithelial foot processes were partially effaced. The removed spleen was markedly enlarged because of portal hypertension, and the histology showed no lymphoproliferative disorders such as lymphoma. The liver biopsy at the time of surgery indicated multimonolobular cirrhosis with thin septa. After surgery, her urinary protein and occult blood gradually decreased, and the purpura in her lower extremities faded.
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In May 1998, her laboratory findings were as follows: Total serum protein was 7.9 g/dL; albumin, 4.3 g/dL; urea nitogen, 15 mg/dL; serum creatinine, decreased to 1.1 mg/ dL; and Ccr, 65 mL/min. Erythrocyte count was 3.37 ⫻ 106/µL; hematocrit had improved to 36.3%; leukocytes, 4,500/µL; and thrombocyte count, 19.8 ⫻ 104/µL. Cryocrit had decreased to 5%. The urinary sediment of erythrocyte contained less than 1 cell/HPF, and she had only 0.06 g protein in her 24-hour urine. However, AST had increased to 45 (IU/L); ALT was 50 (IU/L); and her serum HCV-RNA level was 2.3 mEq/mL by branched HCV-probe assay. Serum IgG concentration had increased to 2,153 mg/dL; IgA, 286 mg/dL; and IgM, 251 mg/dL. The CH50 was 2 U, C3 concentration was 58 mg/dL, and C4 was 15 mg/dL. IgMrheumatoid factor was 58 U/mL. In May 1998, 15 months after the splenectomy, a repeat renal biopsy was performed with the informed consent of the patient, because her serum cryoglobulin remained positive with 5% of cryocrit, despite the improvement of urinary abnormalities.
Second Renal Biopsy Light microscopic examination of a specimen containing four glomeruli showed a slight increase in the mesangial matrix with slight mesangial cell proliferation. The diffuse thickening of the capillary walls with double contours seen in the first biopsy specimen had disappeared (Fig 5). Immunofluorescent studies showed only a slight staining for IgG, IgM, C3, and kappa light chain. On electron microscopic examination, the subendothelial electron-dense deposits had decreased, and electron-lucent areas appeared (Fig 6). The renal biopsy findings and the patient’s clinical features showed marked improvement. In October 1999, 16 months after the second renal biopsy, her serum creatinine remains in the normal range, and her proteinuria is negative, although her HCV-RNA is positive, with 5% of cryocrit.
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DISCUSSION
Type II mixed cryoglobulinemia not secondary to lymphoproliferative disorder, autoimmune diseases, or infection has been regarded as a disease of unknown cause and had been called ‘‘essential’’ until 1990. However, since Pascual et al1 suggested the possibility of an association between HCV and type II cryoglobulinemia in 1990,1 many patients with ‘‘essential’’ type II mixed cryoglobulinemia have been found to be infected with HCV. Agnello et al2 suggested a role of HCV in the pathogenesis of type II cryoglobulinemia, because HCV-RNA was detected in 16 of 19 patients with type II cryoglobulinemia. It may be inappropriate to designate cryoglobulinemia secondary to HCV as ‘‘essential.’’ Johnson et al3 have reported that chronic HCV infection is associated with both cryoglobulinemia and membranoproliferative glomerulonephritis. Four of their patients who had chronic HCV infection and cryoglobulinemia with membranoproliferative glomerulonephritis had improvement of their renal diseases, as well as HCV viremia and liver diseases, after treatment with interferon-alfa.3 Misiani et al4 have reported that 15 of 25 patients with HCV-associated type II cryoglobulinemia had a significant improvement after treatment with interferon alfa-2a.4 However, the cryoglobulinemia recurred after the interferon was discontinued. It was concluded that the antiviral effect of interferon parallels its
Fig 5. Second renal biopsy finding performed in May 1998, 15 months after splenectomy. Light microscopic examination showed a mild increase in mesangial matrix with mild mesangial cell proliferation. Diffuse thicking of capillary wall with double contours seen in the first biopsy disappeared (periodic acid-Schiff’s reagent staining; original magnification ⴛ 400).
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Fig 6. Second renal biopsy. On electron microscopic examination, the subendothelial electron dense deposits had decreased and electron lucent areas appeared (original magnification ⴛ 30,000).
effects on the cryoglobulinemia and therefore that the virus must in some way precipitate the cryoglobulinemia. The histological improvement in the kidneys of patients with cryoglobulinemia was reported subsequently, in addition to clinical and serological improvement with interferon-alfa therapy.5,6 Interferon was expected to become a main therapy for cryoglobulinemia secondary to HCV. However, Mazzaro et al7 have reported that only 4 of 20 patients maintained a complete response a few months after therapy was stopped, whereas the remaining 16 patients either suffered relapse or were nonresponders. Alfa-interferon therapy has not proved effective for all patients with HCV-related cryoglobulinemia. The HCV serotype has been hypothesized to be a predictive factor for the response to antiviral therapy by
interferon.7,8 Patients with HCV serotype II have been reported to have the poorest response to interferon.8 Tarantino et al9 studied 105 essential mixed cryoglobulinemia (EMC) patients with renal involvement, and patient survival was only 49% at 10 years after renal biopsy regardless of the type of treatments, including interferon, and type II mixed cryoglobulinemia had a poor prognosis. D’Amico reported that interferon-alfa is not effective for cryoglobulinemic patients with acute nephrotic syndrome and rapidly progressive renal insufficiency. They proposed that interferon should be combined with steroids (including high-dose methylprednisolone), plasmapheresis, or cyclophosphamide.10-12 Our patient had liver cirrhosis as an unfavorable complication. Because the side effects of interferon-alfa include thrombocytopenia and
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anemia, it may not be suitable for patients with liver cirrhosis and pancytopenia. A splenectomy was performed first, with the expectation that her thrombocytes and erythrocytes would increase before the initiation of interferon therapy. However, we found that not only her thrombocytopenia and anemia, but also her proteinuria, renal function, purpura, and cryocrit, improved after splenectomy. Because splenectomy is not widely recognized as a treatment for cryoglobulinemia, we performed a literature search. We found only a single case report, by Mathison et al13 in 1971. Although the investigators initially instituted prednisolone therapy for IgM-IgG cryoglobulinemia with purpura and arthralgias, it was ineffective. Cyclophosphamide was administered next, but it was discontinued because of pancytopenia. Finally, a splenectomy was performed to improve the pancytopenia. After the splenectomy, the cryocrit, skin lesions, and pancytopenia resolved. It was suggested that because IgMcontaining plasma cells were observed in the spleen, lymphoid cells in the spleen may have produced much of the abnormal cryoglobulin protein. They proposed that a splenectomy is effective for cryoglobulinemia. However, after this report, a splenectomy for cryoglobulinemia has not been widely performed, even though another report discussed the importance of the spleen for IgM production.14 Ron et al14 have shown that, after a splenectomy, there are fewer mature B cells in the peripheral blood, and they proposed, based on experiments with mice, that the spleen may play an important role in B-cell differentiation, including IgM formation. The pathogenesis of type II cryoglobulin remains unknown. However, our patient’s clinical course and the report by Ron et al14 suggest the possibility that the IgM-monoclonal component of type II cryoglobulin may be formed in the spleen. In summary, since interferon therapy was first introduced for patients with HCV-related cryoglobulinemia, many studies have confirmed the effectiveness of this therapy. However, these studies also have shown that there are many nonresponders to interferon and that many relapse after the discontinuation of interferon. It also is not effective for patients with liver cirrhosis. Our patient’s clinical course suggests that a splenectomy may be considered for cryoglobulinemic patients with HCV-liver cirrhosis, spleno-
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megaly, and pancytopenia who do not respond to interferon. REFERENCES 1. Pascual M, Perrin L, Giostra E, et al: Hepatitis C virus in patients with cryoglobulinemia type II. J Infect Dis 162:569-570, 1990 2. Agnello V, Chung RT, Kaplan LM: A role for hepatitis C virus infection in type II cryoglobulinemia. N Engl J Med 327:1490-1495, 1992 3. Johnson RJ, Gretch DR, Yamabe H, Hart J, Bacchi CE, Hartwell P, Couser WG, Corey L, Wener MH, Alpers CE, Willson R: Membranoproliferative glomerulonephritis associated with hepatitis C virus infection. N Engl J Med 328:465-470, 1993 4. Misiani R, Bellavita P, Fenili D, Vicari O, Marchesi D, Sironi PL, Zilio P, Vernocchi A, Massazza M, Vendramin G, Tanzi E, Zanetti A: Interferon alfa-2a therapy in cryoglobulinemia associated with hepatitis C virus. N Engl J Med 330:751-756, 1994 5. Yamabe H, Johnson RJ, Gretch DR, Osawa H, Inuma H, Sasaki T, Kaizuka M, Tamura N, Tsunoda S, Fujita Y, Sato A, Onodera K: Membranoproliferative glomerulonephritis associated with hepatitis C virus infection responsive to interferon-alfa. Am J Kidney Dis 25:67-69, 1995 6. Morosetti M, Sciarra G, Meloni C, Palmieri G, Palombo M, Gallucci MT, Casciani CU: Membranoproliferative glomerulonephritis and hepatitis C: Effects of interferonalfa therapy on clinical outcome and histological pattern. Nephrol Dial Transplant 11:532-534, 1996 7. Mazzaro C, Franzin F, Tulissi P, Pussini E, Crovatto M, Carniello GS, Efremov DG, Burrone O, Santini G, Pozzato G: Regression of monoclonal B-cell expansion in patients affected by mixed cryoglobulinemia responsive to alfainterferon therapy. Cancer 77:2604-2613, 1996 8. Kanai K, Kato M, Okamoto H: HCV genotypes in chronic hepatitis C and response to interferon. Lancet 339: 1543, 1992 9. Tarantino A, Campise M, Banfi G, Confalonieri R, Bucci A, Montoli A, Colasanti G, Damilano I, D’Amico G, Minetti L, Ponticelli C: Long-term predictors of survival in essential mixed cryoglobulinemic glomerulonephritis. Kidney Int 47:618-623, 1995 10. Quigg RJ, Brathwaite M, Gardner DF, Gretch DR, Ruddy S: Successful cyclophosphamide treatment of cryoglobulinemic membranoproliferative glomerulonephritis associated with hepatitis C virus infection. Am J Kidney Dis 25:798-800, 1995 11. D’Amico G, Fornasieri A: Cryoglobulinemic glomerulonephritis: A membranoproliferative glomerulonephritis induced hepatitis C virus. Am J Kidney Dis 25:361-369, 1995 12. D’Amico G: Renal involvement in hepatitis C infection: Cryoglobulinemic glomerulonephritis. Kidney Int 54: 650-671, 1998 13. Mathison DA, Condemi JJ, Leddy JP, Callerame ML, Panner BJ, Vaughan JH: Purpura, arthralgia, and IgM-IgG cryoglobulinemia with rheumatoid factor activity. Ann Intern Med 74:383-390, 1971 14. Ron Y, Baetselier PD, Segal S: Involvement of the spleen in murine B cell differentiation. Eur J Immunol 11:94-99, 1981