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Hypogammaglobulinemia in a Renal Transplant Recipient With Antiglomerular Basement Membrane Disease
Hypogammaglobulinemia in a Renal Transplant Recipient With Antiglomerular Basement Membrane Disease Matthew R. Smolin, MD, William Rickman, PhD, and James Hasbargen, MD • A thirty-six-year-old woman developed antiglomerular basement membrane disease, necessitating bilateral nephrectomies. Subsequent to cadaveric renal transplant and 8 years of immunosuppressive treatment with prednisone and azathioprine, the patient developed multiple life-threatening infections. Quantitative immunoglobulins revealed IgG = 9, IgA < 6.7, and IgM = 33. Lymphocyte population studies revealed absence of a-lymphocytes. It is suspected that prednisone or azathioprine may have caused a defect in a cell differentiation. In patients who are taking immunosuppressive medications and develop multiple infections, it is indicated to evaluate immunoglobulin and/or B lymphocyte status. © 1988 by the National Kidney Foundation, Inc. INDEX WORDS: Hypogammaglobulinemia; renal transplant; prednisone; azathioprine; antiglomerular basement membrane disease.
ACQUIRED inununoglobulin deficiency has been ftbeen reported in a variety of autoimmune diseases to include rheumatoid arthritis, systemic lupus erythematosis, idiopathic thrombocytopenic purpura, pernicious anemia, and hemolytic anemia. In addition, several case reports have linked panhypogammaglobulinemia with prednisone and azathioprine.v? We report an unusual case of severe panhypogammaglobulinemia secondary to a defect in B lymphocyte differentiation in a patient with antiglomerular basement membrane disease receiving prednisone and azathioprine following renal transplantation. CASE REPORT A 36-year-old woman develped renal failure (RF) and hemoptysis, typical of Goodpasture's Syndrome, in 1975. The patient had persistent pulmonary hemorrhage in spite of highdose steroid therapy, and consequently required emergent bilateral nephrectomies. Light microscopy revealed crescentic glomerulonephritis, and immunofluorescent studies of the kidney revealed 4 + linear IgG deposits, diagnostic of antiglomerular basement membrane disease. The patient was maintained on hemodialysis until she received a cadaveric renal transplant in 1977. The patient was subsequently placed on long-term immunosuppressive therapy. Dosages of prednisone varied from 50 mg daily to 15 mg every other day, and azathioprine (75 to 150 mg daily). Except for a minor rejection episode I month after the transplant, graft function has been excellent . The patient's course was complicated by cataracts, osteoporosis, Cushingoid body habitus, hypertension, and multiple infections. The patient had several episodes of sinusitis from May 1982 to May 1983. In July 1983 the patient developed Herpes simplex stomatitis and underwent surgical drainage of both maxillary sinuses. Postoperatively, the patient developed cerebrospinal fluid rhinorrhea complicated by Hemophilus influenza meningitis. This was followed by Pseudomonas fluorescens meningitis. Following successful antibiotic therapy of these infections, the patient developed a right upper
lobe Candida albicans pneumonitis that responded well to Amphotericin B. The patient also suffered a Hickman catheter abscess with Staphylococcus aureus, and a cellulitis that was caused by Escherichia coli and S aureus . The patient was hospitalized for pneumococcal pneumonia in May 1985. In July 1985, while receiving azathioprine , 100 mg daily and prednisone, 15 mg every other day, the patient was again hospitalized for a polymicrobial right middle lobe pneumonia. Concurrently, she developed Herpes stomatitis and an inflammatory lesion of the right lower extremity. The creatinine was normal and there was no proteinuria. Skin testing revealed anergy to candida, tetanus, trichophyton , and mumps antigens. A serum protein electropheresis was obtained that revealed profoundly decreased gammaglobulin. Quantitative immunoglobulins revealed that IgG = 9 mg /mL (normal 639 to 1,349); IgM = 33 mg /mL (normal 56 to 352); and IgA < 6.7 mg /mL (normal 70 to 312). Further evaluation included flow cytometric quantification of the patient's lymphocyte populations that demonstrated absence of B-lymphocytes . Responses to Pokeweed mitogen and Phytohemagglutinin A were diminished (Table I) . Chest and abdominal computerized tomography showed no evidence of thymoma or lymphoma. Biopsy of the lesion on the right leg demonstrated " lymphohistiocytic infiltrate with evidence of vasculitis." The patient's treatment with azathioprine was tapered off and cyclosporine , 60 mg twice daily, was started in August 1985. She has continued to receive prednisone , 12.5 mg every other day. Intravenous (IV) immunoglobulin therapy consisting of 12 g every 3 weeks was started in August 1985 and continues . The
From the Departments of Medicine and Clinical Investigation, Fitzsimons Army Medical Center, Aurora, CO. The opinions or assertions contained herein are those of the authors and are not to be construed as official or as reflecting the views of the Department of Defense or the Department of the Arm)! Address reprint requests to James Hasbargen , MD, Department of Medicine , Fitzsimons Army Medical Center, Aurora , CO 80045. © 1988 by the National Kidney Foundation , Inc. 0272-6386/88/1103-0012$3.00/0
American Journal of Kidney Diseases, Vol XI, No 3 (March), 1988: pp 267-269
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268
SMOLIN , RICKMAN, AND HASBARGEN Table 1.
Circulating Lymphocyte Populations and Response to Mitogens
Total lymphs Total T cells (Leu-1) Helper T cells (Leu-3) Suppressor T cells (Leu-2) Total B cells (Leu-12) NK cells (Leu-11) SRBC receptor T cells (Leu-5) la Receptor (HLNDR) PHA SI (Control) PWM SI (Control)
Aug 1985 (%)
Oct 1985 (%)
April 1986 (%)
Normal (%)
16.0 77.5 71.5 10.0 0 0.8 81.0 2.2 29.2 (376.0) 13.1 (100.0)
46.0 88.0 50.0 36.0 0 1.0 95.0 2.0 2311.0 (742.0) 251 (148.0)
24.0 NA 46.7 12.7 0 3.2 80.6 5.1 NA
18-44 66-81 36-53 20-30 5-16 3-17 62-91 0-17
NA
Abbreviations: PHA SI, Phy10hemagglutinin A Stimulation Index; PWM SI, Pokeweed Mitogen Stimulation Index; SRBC, Sheep Red Blood Cell; NA, not available ; HLNDR, Human Leukocyte Antigen . right leg vasculitis resolved within a month of the start of the immunoglobulin replacement, and the patient has remained free of serious infection. For the last 17 months, the patient has remained hypogammaglobulinemic despite manipulation of her immunosuppressive therapy, with IgA < 6.7, IgM = 38, and IgG = 439. The patient continues to have an absence of Blymphocytes. Due to problems with hirsutism and hypertension, the cyclosporine was discontinued, and azathioprine was restarted in May 1986.
COMMENT
The patient study reported here appears to be the first case of acquired panhypogammaglobulinemia cited in either a patient with antiglomerular basement membrane disease or in a renal transplant reo cipient on immunosuppressive therapy. The panhypogammaglobulinemia in the patient reported may be a consequence of long-term treatment with azathioprine and prednisone . Alternatively, hypogammaglobulinemia may be part of the spectrum of immune dysfunction in antiglomerular basement membrane disease. Significant depression of antibody production has been reported in several patients receiving a combination of prednisone and azathioprine or prednisone alone. Sussman et al reported on four patients with immunoglobulin deficiency, all of whom had systemic lupus erythematosis (SLE). Two of these patients were taking prednisone and azathioprine , whereas two were treated with prednisone alone. 1 Epstein et al reported on a patient with SLE and panhypogammaglobulinemia that was temporally related to treatment with azathioprine.? Though SLE has rarely been associated with panhypogammaglobulinemia, in these patients the relation of the institution of therapy to onset of immunoglobulin deficiency and cessation
of treatment to recovery of antibody production suggests that the medications may be responsible for the hypogammaglobulinemia. Recently, cyclophosphamide (being given concurrently with prednisone), has been associated with the development of hypogammaglobulinemia in a patient with SLE. 3In addition, Lee and Fay implicated prednisone as the causative factor in a patient who developed hypogammaglobulinemia while being treated for asthma. 4 There are several possible mechanisms for prednisone or azathioprine-induced hypogammaglobulinem ia. Hypogammaglobulinemia may result from impaired B-Iymphocyte maturation, excess T cell suppressor activity, or defective immunoglobulin synthesis. B cells have been shown by Dimitriu and Fauci to be sensitive to azathioprine in vitro. 5 A variety of autoimmune diseases have been associated with hypogammaglobulinemia, including rheumatoid arthritis , polymyositi s , SLE , idiopathic thrombocytopenic purpura , thyroiditis, and diabetes. Antiglomerular basement membrane disease is presumably a B-Iymphocyte mediated disorder, and it is possible that hypogammaglobulinemia is part of the natural evolution of the disease. In this case, the patient is known to have had immunoglobulins present initially from immunofluorescence of the kidney biopsy. The onset of chronic sinopulmonary infections in 1982 suggests that immunoglobulin production ceased at about that time. Regrettably, quantitative immunoglobulins were not obtained until 1985. The gammaglobulin deficiency thus appears to be acquired . The absence of B cells suggests impaired B cell dif-
RENAL TRANSPLANT AND HYPOGAMMAGLOBULINEMIA
ferentiation. The initially depressed number of Tsuppressor cells and the generally appropriate ratio of helper to suppressor cells argues against excess T-suppressor activity as a contributory factor. Responsiveness to mitogens is consistent with adequate T-helper activity. In an attempt to restore normal B-cell differentiation, azathioprine was discontinued and replaced with cyclosporine . It was hoped that this modification would remove the toxic effect of azathioprine while maintaining suppression of cell-mediated immunity and preservation of graft function. This has resulted in the resolution of the lymphopenia and restoration of lymphocyte populations to normal levels with the exception of the B-Iymphocytes. The transplanted kidney continues to perform well. Unfortunately, there has not been an increase in native production of immunoglobins, and the patient continues to have absent peripheral B-Iymphocytes. The increased but still
269
subnormal IgM and IgG levels are likely the result of the IV immunoglobulin therapy. Infection is one of the most common causes of death in transplant recipients. This case serves as a reminder that vulnerability.to infection may be a consequence of immunoglobulin deficiency that may coexist with impaired cell-mediated immunity. There is a need for a prospective study of the natural history of immunoglobulin levels in transplant recipients. In patients receiving immunosuppressive therapy who develop recurrent infections, an evaluation for hypogammaglobulinemia and/or lymphocyte populations is indicated. ACKNOWLEDGMENT We thank Drs David Petros, Bryan Larson, Wheaton Williams, and William Dolan for their assistance in managing this patient. We also thank Joe Lima for assistance with flow cytometry.
REFERENCES 1. Sussman GL, Rivera VJ, Kohler PF: Transition from systemic lupus erythematosis to common variable hypogammaglobulinernia. Ann Intern Med 99:32-35, 1983 2. Epstein RG, Ogler RF, Gatenby PA: Lupus erythematosis and panhypogammaglobulinemia. Ann Intern Med 100: 162163, 1984 (letter) 3. Tsokos GC, Smith PL, Balow JE : Development of hypo-
gammaglobulinemia in a patient with systemic lupus erythematosis. Am J Med 81:1081-1084,1986 4. Lee RJE, Fay AC: Hypogammaglobulinemia associated with long-term , low dose steroid therapy. Postgrad Med J 61:523-524, 1985 5. Dimitriu A, Fauci AS: Differential sensitivity of human lymphocyte subpopulations to azathiopr ine. Transplant Proc 11:878-881, 1979
ACQUIRED inununoglobulin deficiency has been ftbeen reported in a variety of autoimmune diseases to include rheumatoid arthritis, systemic lupus erythematosis, idiopathic thrombocytopenic purpura, pernicious anemia, and hemolytic anemia. In addition, several case reports have linked panhypogammaglobulinemia with prednisone and azathioprine.v? We report an unusual case of severe panhypogammaglobulinemia secondary to a defect in B lymphocyte differentiation in a patient with antiglomerular basement membrane disease receiving prednisone and azathioprine following renal transplantation. CASE REPORT A 36-year-old woman develped renal failure (RF) and hemoptysis, typical of Goodpasture's Syndrome, in 1975. The patient had persistent pulmonary hemorrhage in spite of highdose steroid therapy, and consequently required emergent bilateral nephrectomies. Light microscopy revealed crescentic glomerulonephritis, and immunofluorescent studies of the kidney revealed 4 + linear IgG deposits, diagnostic of antiglomerular basement membrane disease. The patient was maintained on hemodialysis until she received a cadaveric renal transplant in 1977. The patient was subsequently placed on long-term immunosuppressive therapy. Dosages of prednisone varied from 50 mg daily to 15 mg every other day, and azathioprine (75 to 150 mg daily). Except for a minor rejection episode I month after the transplant, graft function has been excellent . The patient's course was complicated by cataracts, osteoporosis, Cushingoid body habitus, hypertension, and multiple infections. The patient had several episodes of sinusitis from May 1982 to May 1983. In July 1983 the patient developed Herpes simplex stomatitis and underwent surgical drainage of both maxillary sinuses. Postoperatively, the patient developed cerebrospinal fluid rhinorrhea complicated by Hemophilus influenza meningitis. This was followed by Pseudomonas fluorescens meningitis. Following successful antibiotic therapy of these infections, the patient developed a right upper
lobe Candida albicans pneumonitis that responded well to Amphotericin B. The patient also suffered a Hickman catheter abscess with Staphylococcus aureus, and a cellulitis that was caused by Escherichia coli and S aureus . The patient was hospitalized for pneumococcal pneumonia in May 1985. In July 1985, while receiving azathioprine , 100 mg daily and prednisone, 15 mg every other day, the patient was again hospitalized for a polymicrobial right middle lobe pneumonia. Concurrently, she developed Herpes stomatitis and an inflammatory lesion of the right lower extremity. The creatinine was normal and there was no proteinuria. Skin testing revealed anergy to candida, tetanus, trichophyton , and mumps antigens. A serum protein electropheresis was obtained that revealed profoundly decreased gammaglobulin. Quantitative immunoglobulins revealed that IgG = 9 mg /mL (normal 639 to 1,349); IgM = 33 mg /mL (normal 56 to 352); and IgA < 6.7 mg /mL (normal 70 to 312). Further evaluation included flow cytometric quantification of the patient's lymphocyte populations that demonstrated absence of B-lymphocytes . Responses to Pokeweed mitogen and Phytohemagglutinin A were diminished (Table I) . Chest and abdominal computerized tomography showed no evidence of thymoma or lymphoma. Biopsy of the lesion on the right leg demonstrated " lymphohistiocytic infiltrate with evidence of vasculitis." The patient's treatment with azathioprine was tapered off and cyclosporine , 60 mg twice daily, was started in August 1985. She has continued to receive prednisone , 12.5 mg every other day. Intravenous (IV) immunoglobulin therapy consisting of 12 g every 3 weeks was started in August 1985 and continues . The
From the Departments of Medicine and Clinical Investigation, Fitzsimons Army Medical Center, Aurora, CO. The opinions or assertions contained herein are those of the authors and are not to be construed as official or as reflecting the views of the Department of Defense or the Department of the Arm)! Address reprint requests to James Hasbargen , MD, Department of Medicine , Fitzsimons Army Medical Center, Aurora , CO 80045. © 1988 by the National Kidney Foundation , Inc. 0272-6386/88/1103-0012$3.00/0
American Journal of Kidney Diseases, Vol XI, No 3 (March), 1988: pp 267-269
267
268
SMOLIN , RICKMAN, AND HASBARGEN Table 1.
Circulating Lymphocyte Populations and Response to Mitogens
Total lymphs Total T cells (Leu-1) Helper T cells (Leu-3) Suppressor T cells (Leu-2) Total B cells (Leu-12) NK cells (Leu-11) SRBC receptor T cells (Leu-5) la Receptor (HLNDR) PHA SI (Control) PWM SI (Control)
Aug 1985 (%)
Oct 1985 (%)
April 1986 (%)
Normal (%)
16.0 77.5 71.5 10.0 0 0.8 81.0 2.2 29.2 (376.0) 13.1 (100.0)
46.0 88.0 50.0 36.0 0 1.0 95.0 2.0 2311.0 (742.0) 251 (148.0)
24.0 NA 46.7 12.7 0 3.2 80.6 5.1 NA
18-44 66-81 36-53 20-30 5-16 3-17 62-91 0-17
NA
Abbreviations: PHA SI, Phy10hemagglutinin A Stimulation Index; PWM SI, Pokeweed Mitogen Stimulation Index; SRBC, Sheep Red Blood Cell; NA, not available ; HLNDR, Human Leukocyte Antigen . right leg vasculitis resolved within a month of the start of the immunoglobulin replacement, and the patient has remained free of serious infection. For the last 17 months, the patient has remained hypogammaglobulinemic despite manipulation of her immunosuppressive therapy, with IgA < 6.7, IgM = 38, and IgG = 439. The patient continues to have an absence of Blymphocytes. Due to problems with hirsutism and hypertension, the cyclosporine was discontinued, and azathioprine was restarted in May 1986.
COMMENT
The patient study reported here appears to be the first case of acquired panhypogammaglobulinemia cited in either a patient with antiglomerular basement membrane disease or in a renal transplant reo cipient on immunosuppressive therapy. The panhypogammaglobulinemia in the patient reported may be a consequence of long-term treatment with azathioprine and prednisone . Alternatively, hypogammaglobulinemia may be part of the spectrum of immune dysfunction in antiglomerular basement membrane disease. Significant depression of antibody production has been reported in several patients receiving a combination of prednisone and azathioprine or prednisone alone. Sussman et al reported on four patients with immunoglobulin deficiency, all of whom had systemic lupus erythematosis (SLE). Two of these patients were taking prednisone and azathioprine , whereas two were treated with prednisone alone. 1 Epstein et al reported on a patient with SLE and panhypogammaglobulinemia that was temporally related to treatment with azathioprine.? Though SLE has rarely been associated with panhypogammaglobulinemia, in these patients the relation of the institution of therapy to onset of immunoglobulin deficiency and cessation
of treatment to recovery of antibody production suggests that the medications may be responsible for the hypogammaglobulinemia. Recently, cyclophosphamide (being given concurrently with prednisone), has been associated with the development of hypogammaglobulinemia in a patient with SLE. 3In addition, Lee and Fay implicated prednisone as the causative factor in a patient who developed hypogammaglobulinemia while being treated for asthma. 4 There are several possible mechanisms for prednisone or azathioprine-induced hypogammaglobulinem ia. Hypogammaglobulinemia may result from impaired B-Iymphocyte maturation, excess T cell suppressor activity, or defective immunoglobulin synthesis. B cells have been shown by Dimitriu and Fauci to be sensitive to azathioprine in vitro. 5 A variety of autoimmune diseases have been associated with hypogammaglobulinemia, including rheumatoid arthritis , polymyositi s , SLE , idiopathic thrombocytopenic purpura , thyroiditis, and diabetes. Antiglomerular basement membrane disease is presumably a B-Iymphocyte mediated disorder, and it is possible that hypogammaglobulinemia is part of the natural evolution of the disease. In this case, the patient is known to have had immunoglobulins present initially from immunofluorescence of the kidney biopsy. The onset of chronic sinopulmonary infections in 1982 suggests that immunoglobulin production ceased at about that time. Regrettably, quantitative immunoglobulins were not obtained until 1985. The gammaglobulin deficiency thus appears to be acquired . The absence of B cells suggests impaired B cell dif-
RENAL TRANSPLANT AND HYPOGAMMAGLOBULINEMIA
ferentiation. The initially depressed number of Tsuppressor cells and the generally appropriate ratio of helper to suppressor cells argues against excess T-suppressor activity as a contributory factor. Responsiveness to mitogens is consistent with adequate T-helper activity. In an attempt to restore normal B-cell differentiation, azathioprine was discontinued and replaced with cyclosporine . It was hoped that this modification would remove the toxic effect of azathioprine while maintaining suppression of cell-mediated immunity and preservation of graft function. This has resulted in the resolution of the lymphopenia and restoration of lymphocyte populations to normal levels with the exception of the B-Iymphocytes. The transplanted kidney continues to perform well. Unfortunately, there has not been an increase in native production of immunoglobins, and the patient continues to have absent peripheral B-Iymphocytes. The increased but still
269
subnormal IgM and IgG levels are likely the result of the IV immunoglobulin therapy. Infection is one of the most common causes of death in transplant recipients. This case serves as a reminder that vulnerability.to infection may be a consequence of immunoglobulin deficiency that may coexist with impaired cell-mediated immunity. There is a need for a prospective study of the natural history of immunoglobulin levels in transplant recipients. In patients receiving immunosuppressive therapy who develop recurrent infections, an evaluation for hypogammaglobulinemia and/or lymphocyte populations is indicated. ACKNOWLEDGMENT We thank Drs David Petros, Bryan Larson, Wheaton Williams, and William Dolan for their assistance in managing this patient. We also thank Joe Lima for assistance with flow cytometry.
REFERENCES 1. Sussman GL, Rivera VJ, Kohler PF: Transition from systemic lupus erythematosis to common variable hypogammaglobulinernia. Ann Intern Med 99:32-35, 1983 2. Epstein RG, Ogler RF, Gatenby PA: Lupus erythematosis and panhypogammaglobulinemia. Ann Intern Med 100: 162163, 1984 (letter) 3. Tsokos GC, Smith PL, Balow JE : Development of hypo-
gammaglobulinemia in a patient with systemic lupus erythematosis. Am J Med 81:1081-1084,1986 4. Lee RJE, Fay AC: Hypogammaglobulinemia associated with long-term , low dose steroid therapy. Postgrad Med J 61:523-524, 1985 5. Dimitriu A, Fauci AS: Differential sensitivity of human lymphocyte subpopulations to azathiopr ine. Transplant Proc 11:878-881, 1979