Nephrol Dial Transplant (1992) 7: 357-359 £ 1992 European Dialysis and Transplant Association-European Renal Association
Nephrology Dialysis Transplantation
Case Report
Thymoma and minimal-change glomerulonephritis P. McDonald, P. A. Kalra and R. A. Coward Renal Unit, Royal Preston Hospital, Preston, UK
Key words: minimal-change , glomerulonephritis; nephrotic syndrome; thymoma
Introduction The association of minimal-change glomerulonephritis with lymphoproliferative processes is well recognised [1], and there have been three reported cases in patients having had a thymoma [2-4]. In addition thymoma has been described in association with nephrotic syndrome that resulted from membranous glomerulonephritis [5]. We report a further case of minimal-change disease associated with thymoma, the nephrotic presentation occurring some 15 months after thymectomy, at which time there was no overt evidence of recurrence of the tumour. The case lends more support to the theory that Tcell mediated processes are implicit in the pathogenesis of minimal-change glomerulonephritis [6], and the literature is reviewed.
Case report A 70-year-old man presented in January 1989 with fatigue and left-sided chest pain. Clinical examination was normal but chest radiography revealed a large mediastina! mass. The patient had no features which would suggest myasthenia gravis and there was no clinical or serologica! evidence for other autoimmune Corrvspundinte und tttjprint rtyutsts try. R. A. Cov.ard. Rer.al L'r.i!, Royal Preston Hospital, Sharoe Green Lane, Fulwood, Preston PR2 4BR, UK.
disease. The mass was fully resected in March 1989, and histology showed lymphocytes and spindleshaped epithelial cells with areas of myxoid change, features that were consistent with a diagnosis of malignant thymoma. Postoperatively the patient received a 3-week course of radiotherapy (4000 centigray in 15 fractions) to the anterior mediastinum, and subsequent clinical progress was satisfactory with no evidence of recurrence of the tumour. In May of 1990 the patient was referred with nephrotic syndrome. Previous routine urinalysis had been normal. He was normotensive, with no evidence of lymphadenopathy. Investigations showed a 24 h urinary protein excretion of 8.8 g (selectivity not measured), serum albumin 19 g/1, cholesterol 15.2mmol/l, blood urea 14.1 mmol/1, creatinine 308 umol/1, and ESR 120mm/h; other liver function tests and haematological parameters were normal. Immunology showed a markedly raised IgM at 17 g/1 (0.66-3.52) with a low IgG of 2.1 g/1 (6-15); IgA was 2.54 g/1 (1.0-4.5). No monoclonal bands were found in serum or urine and immune complexes were not detected. Anti-DNA IgG antibody at a titre of 1: 1280 and anti-DNA IgM of 1:80 were also present. Chest X-ray and CT scan of the thorax and abdomen yielded no evidence of recurrent thymoma or of mediastinal and para-aortic lymphadenopathy, and there was no vena caval obstruction. Renal biopsy showed normal glomerular architecture or. light microscopy, immunofluorescence was negative, and electron-microscopy demonstrated non-specific fusion of glomerular epithelial cell foot-processes, all of these being features compatible with the diagnosis of minimal-change disease. The patient was treated with diuretics and plasma
358
protein infusion and he received pulsed methylprednisolone ( I g / d a y x 3 ) followed by oral prednisolone, initially at 80 mg/day. After 2 months a response to therapy was evidenced by his serum albumin increasing to 34 g/1 and 24 h urinary protein excretion declining to 4.5 g, with an improvement in serum creatinine to 112umol/l. Cyclosporin 300 mg/day was introduced and this was coincident with complete remission of his nephrotic state. Five months after the commencement of treatment his 24 h urinary protein excretion was 0.09 g, serum albumin 37 g/1, and serum creatinine 115umol/l. Serum IgM had fallen to 5.04 g/1 and anti DNA IgG was negative. The patient has since remained in remission with a maintenance regime of prednisolone 20 mg and cyclosporin 300 mg/day.
Discussion The occurrence of nephrotic syndrome with thymoma is uncommon—in a review of 960 cases heavy proteinuria was observed in two patients, one of whom had minimal-change disease [9]. In our patient the nephrotic syndrome occurred many months after thymectomy. This delayed association has been reported once before in the literature but in that patient, unlike in our own, there was evidence of recurrent thymoma [3]. In the two other reported cases associating thymoma with minimal-change disease, nephrotic syndrome was a terminal event in one patient in whom thymoma was discovered at postmortem [4]; the second case had extensive tumour which could not be adequately cleared by surgery and radiotherapy [2]. Despite the lack of overt evidence of recurrent thymoma there are several factors in our patient's clinical picture (positive antinuclear antibody serology, markedly raised IgM levels and a partial response to conventional treatment with steroids) which makes him atypical of idiopathic minimalchange disease and strongly suggest an association with a thymic tumour. An increase in antinuclear antibodies as seen in this case is present in up to 50% of patients with thymic neoplasia [10], whilst Tcell dysfunction is recognized in association with thymomas and is thought to be implicit in the expression of most of the parathymic syndromes that occur in 40-70% of patients, including pure red cell aplasia, hypogammaglobulinaemia, and most commonly myasthenia gravis [8,9]. Our case lends further support to the pathogenetic involvement of T cell dysfunction in minimal-change disease [6] and complements several clinical and experimental observations which imply an important
P. McDonald el at.
role of T cells in idiopathic minimal-change disease. In thymoma there may be an imbalance of helper and suppressor T cell functions, so depressing antibody production [11]. T cells are thought to participate in the conversion of IgM to IgG and IgA, and their dysfunction may well be partly responsible for the finding of extremely high circulating levels of IgM with low IgG and IgA which can occur in the nephrotic phase of minimal-change disease [12], and which was particularly marked in our case. In addition, modification of cell-mediated immunity, such as can occur coincident with measles infection, has been shown to result in remission of both minimal-change disease and in cases of Hodgkin's disease [13-15]. It is not surprising, therefore, that a strong association exists between both Hodgkin's disease (where depression of cell-mediated immunity is an early feature of the condition), other T cell lymphoproliferative neoplasias such as mycosis fungoides [16], and minimalchange glomerulonephritis. Further support for a lymphokine-mediated pathogenesis of minimal-change nephritis is indirectly provided by the response of the condition to corticosteroids, which are known to exert a profound effect upon T cell mediated lymphopoiesis as well as being able to block the action of lymphokines [17]. In steroid-resistant cases cyclophosphamide often induces a response, acting by inhibiting the proliferative response of lymphocytes, predominantly by acting upon T helper cells, so preventing lymphokine production and arresting the generation of cytotoxic T cells. Cyclosporin has an established role in minimal-change disease, thought to be due to its effect on depleting thymus-dependent areas of lymph nodes and so minimizing T and B cell effects [18]. It is noteworthy that the nephrotic syndrome occurring in association with Hodgkin's disease is frequently steroid resistant unless the lymphoma is adequately treated [19]. Such a pattern is very similar to the one we saw in our patient, with only partial response to steroids yet full remission when cyclosporin A was added to the treatment regime. This response would strongly indicate a proliferative neoplastic T cell clone perhaps originating from thymic tissue. As our case illustrates, the parathymic syndrome may not necessarily disappear with thymectomy— improvement in the clinical features of myasthenia gravis may only be fully apparent 10 years after surgery [8]. It is suspected that T cell clones may take years to be eradicated from lymphopoietic tissues and this might explain the delayed nephrotic presentation in our patient, as well as the response of the nephrosis to agents that modify T cell function. In conclusion, we feel that our patient illustrates that T cell dysfunction may well be of pathogenic importance in the development of minimal-change
Thymoma and minimal-change glomerulonephritis
359
disease. The late presentation of minimal-change disease following thymectomy for thymoma removal may represent longevity of the T cell clones implicit in the pathogenesis of the glomerulonephritis.
10.
Acknowledgements. We would like to thank Mrs Fiona Attwater for typing the manuscript.
11.
References
12.
1. Eagen JW, Lewis EJ. Glomerulopathies of neoplasia. Kidney Im 1977; 11:297-306 2. Varsano S, Bruderman I, Bernheim JL, Rathaus M, Griffel B. Minimal-change nephropathy and malignant thymoma Chest 1980; 77: 695-697 3. Scadding GK, Sweny P, Wilson SG, Harvard CWH, NewsomDavies J. Glomerulonephritis, thymoma and myasthenia gravis. QJ Med 1983; 206: 187-193 4. Hirokawa M, Moriya T, Manabe T. Minimal change renal disease associated with thymoma and pancreatic carcinoma. Ada PatholJpn 1986; 36 (7): 1075-1081 5. Posner MR, Prout MN, Berk S. Thymoma and the nephrotic syndrome. Cancer 1980; 45: 387-391 6. Shalhoub RJ. Pathogenesis of lipoid nephrosis: a disorder of T-cell function. Lancet 1974; 2: 556-560 7. Burnet M. Role of the thymus and related organs in immunity. Br MedJ 1962; 2: 807-811 8. Rosenow EC, Hurley BT. Disorders of the thymus: A review. Arch Intern Med 1984; 144: 763-770 9. Souadjian JV, Enriquez P, Silverstein MN, Pepin J. The
13. 14. 15.
16.
17.
18. 19.
spectrum of disease associated with thymoma. Coincidence or syndrome? Arch Intern Med 1974; 134: 374-379 Oosterhuis HJGH, Felkamp TEW, Van Rossum AL, van den Berg-Loonen PM, Nijenhuis LE. HL-A antigens, autoantibcdy production, and associated diseases in thymoma patients, with and without myasthenia gravis. Ann .V Y Acad Sti 1975; 274: 468-574 Baker JP, Staskak WP, Amabaugh FD, Prescott B, Barth RF. Evidence for the existence of two functionally distinct type of cells which regulate the antibody response to type III pneumccoccal polysaccharide. J Immunol 1970; 105: 1581-1583 Giangiocomo J, Cleary TG, Cole BR, Hoffstein P, Robson A. Serum immunoglobulins in the nephrotic syndrome: a possible cause of minimal-change nephrotic syndrome. A' Engl J Med 1975; 293: 8-12 Mota CH. Infantile Hodgkin's disease: remission after measles. BrMedJ 1973; 2: 421 Michael AF, McLean RH, Roy LP et al. Immunological aspects of nephrotic syndrome. Kidney Im 1973; 3: 105-115 Elisabeth MS, Summer B. In vitro suppression of the lymphocyte response to tuberculin by live measles virus. Proc Soc Exp Biol Med 1966; 123: 276-278 Allen M, Campbell W, Sherif N, Bourke E, Stoute J, Guntupalli J. Minimal change glomerulonephropathy and interstitial infiltration with mycosis fungoides Am J Med 1988; 84: 756-759 Yu DTY, Clements PJ, Paulus HE, Peter JB, Levy J, Barrett EVJ. Human lymphocyte subpopulation effects of corticosteroids. / Clin Invest 1974; 53: 565-571 Winkelstein A. Differential effects of immunosuppression on lymphocyte function. / Clin Invest 1973; 52: 2293-2299 Sherman RL, Susin M, Weksler ME, Becker EL. Lipoid nephrosis in Hodgkin's disease. Am J Med 1972; 52: 699-706
Received for publication 3.4.91 Accepted in revised form 16.8.91
Nephrology Dialysis Transplantation
Case Report
Thymoma and minimal-change glomerulonephritis P. McDonald, P. A. Kalra and R. A. Coward Renal Unit, Royal Preston Hospital, Preston, UK
Key words: minimal-change , glomerulonephritis; nephrotic syndrome; thymoma
Introduction The association of minimal-change glomerulonephritis with lymphoproliferative processes is well recognised [1], and there have been three reported cases in patients having had a thymoma [2-4]. In addition thymoma has been described in association with nephrotic syndrome that resulted from membranous glomerulonephritis [5]. We report a further case of minimal-change disease associated with thymoma, the nephrotic presentation occurring some 15 months after thymectomy, at which time there was no overt evidence of recurrence of the tumour. The case lends more support to the theory that Tcell mediated processes are implicit in the pathogenesis of minimal-change glomerulonephritis [6], and the literature is reviewed.
Case report A 70-year-old man presented in January 1989 with fatigue and left-sided chest pain. Clinical examination was normal but chest radiography revealed a large mediastina! mass. The patient had no features which would suggest myasthenia gravis and there was no clinical or serologica! evidence for other autoimmune Corrvspundinte und tttjprint rtyutsts try. R. A. Cov.ard. Rer.al L'r.i!, Royal Preston Hospital, Sharoe Green Lane, Fulwood, Preston PR2 4BR, UK.
disease. The mass was fully resected in March 1989, and histology showed lymphocytes and spindleshaped epithelial cells with areas of myxoid change, features that were consistent with a diagnosis of malignant thymoma. Postoperatively the patient received a 3-week course of radiotherapy (4000 centigray in 15 fractions) to the anterior mediastinum, and subsequent clinical progress was satisfactory with no evidence of recurrence of the tumour. In May of 1990 the patient was referred with nephrotic syndrome. Previous routine urinalysis had been normal. He was normotensive, with no evidence of lymphadenopathy. Investigations showed a 24 h urinary protein excretion of 8.8 g (selectivity not measured), serum albumin 19 g/1, cholesterol 15.2mmol/l, blood urea 14.1 mmol/1, creatinine 308 umol/1, and ESR 120mm/h; other liver function tests and haematological parameters were normal. Immunology showed a markedly raised IgM at 17 g/1 (0.66-3.52) with a low IgG of 2.1 g/1 (6-15); IgA was 2.54 g/1 (1.0-4.5). No monoclonal bands were found in serum or urine and immune complexes were not detected. Anti-DNA IgG antibody at a titre of 1: 1280 and anti-DNA IgM of 1:80 were also present. Chest X-ray and CT scan of the thorax and abdomen yielded no evidence of recurrent thymoma or of mediastinal and para-aortic lymphadenopathy, and there was no vena caval obstruction. Renal biopsy showed normal glomerular architecture or. light microscopy, immunofluorescence was negative, and electron-microscopy demonstrated non-specific fusion of glomerular epithelial cell foot-processes, all of these being features compatible with the diagnosis of minimal-change disease. The patient was treated with diuretics and plasma
358
protein infusion and he received pulsed methylprednisolone ( I g / d a y x 3 ) followed by oral prednisolone, initially at 80 mg/day. After 2 months a response to therapy was evidenced by his serum albumin increasing to 34 g/1 and 24 h urinary protein excretion declining to 4.5 g, with an improvement in serum creatinine to 112umol/l. Cyclosporin 300 mg/day was introduced and this was coincident with complete remission of his nephrotic state. Five months after the commencement of treatment his 24 h urinary protein excretion was 0.09 g, serum albumin 37 g/1, and serum creatinine 115umol/l. Serum IgM had fallen to 5.04 g/1 and anti DNA IgG was negative. The patient has since remained in remission with a maintenance regime of prednisolone 20 mg and cyclosporin 300 mg/day.
Discussion The occurrence of nephrotic syndrome with thymoma is uncommon—in a review of 960 cases heavy proteinuria was observed in two patients, one of whom had minimal-change disease [9]. In our patient the nephrotic syndrome occurred many months after thymectomy. This delayed association has been reported once before in the literature but in that patient, unlike in our own, there was evidence of recurrent thymoma [3]. In the two other reported cases associating thymoma with minimal-change disease, nephrotic syndrome was a terminal event in one patient in whom thymoma was discovered at postmortem [4]; the second case had extensive tumour which could not be adequately cleared by surgery and radiotherapy [2]. Despite the lack of overt evidence of recurrent thymoma there are several factors in our patient's clinical picture (positive antinuclear antibody serology, markedly raised IgM levels and a partial response to conventional treatment with steroids) which makes him atypical of idiopathic minimalchange disease and strongly suggest an association with a thymic tumour. An increase in antinuclear antibodies as seen in this case is present in up to 50% of patients with thymic neoplasia [10], whilst Tcell dysfunction is recognized in association with thymomas and is thought to be implicit in the expression of most of the parathymic syndromes that occur in 40-70% of patients, including pure red cell aplasia, hypogammaglobulinaemia, and most commonly myasthenia gravis [8,9]. Our case lends further support to the pathogenetic involvement of T cell dysfunction in minimal-change disease [6] and complements several clinical and experimental observations which imply an important
P. McDonald el at.
role of T cells in idiopathic minimal-change disease. In thymoma there may be an imbalance of helper and suppressor T cell functions, so depressing antibody production [11]. T cells are thought to participate in the conversion of IgM to IgG and IgA, and their dysfunction may well be partly responsible for the finding of extremely high circulating levels of IgM with low IgG and IgA which can occur in the nephrotic phase of minimal-change disease [12], and which was particularly marked in our case. In addition, modification of cell-mediated immunity, such as can occur coincident with measles infection, has been shown to result in remission of both minimal-change disease and in cases of Hodgkin's disease [13-15]. It is not surprising, therefore, that a strong association exists between both Hodgkin's disease (where depression of cell-mediated immunity is an early feature of the condition), other T cell lymphoproliferative neoplasias such as mycosis fungoides [16], and minimalchange glomerulonephritis. Further support for a lymphokine-mediated pathogenesis of minimal-change nephritis is indirectly provided by the response of the condition to corticosteroids, which are known to exert a profound effect upon T cell mediated lymphopoiesis as well as being able to block the action of lymphokines [17]. In steroid-resistant cases cyclophosphamide often induces a response, acting by inhibiting the proliferative response of lymphocytes, predominantly by acting upon T helper cells, so preventing lymphokine production and arresting the generation of cytotoxic T cells. Cyclosporin has an established role in minimal-change disease, thought to be due to its effect on depleting thymus-dependent areas of lymph nodes and so minimizing T and B cell effects [18]. It is noteworthy that the nephrotic syndrome occurring in association with Hodgkin's disease is frequently steroid resistant unless the lymphoma is adequately treated [19]. Such a pattern is very similar to the one we saw in our patient, with only partial response to steroids yet full remission when cyclosporin A was added to the treatment regime. This response would strongly indicate a proliferative neoplastic T cell clone perhaps originating from thymic tissue. As our case illustrates, the parathymic syndrome may not necessarily disappear with thymectomy— improvement in the clinical features of myasthenia gravis may only be fully apparent 10 years after surgery [8]. It is suspected that T cell clones may take years to be eradicated from lymphopoietic tissues and this might explain the delayed nephrotic presentation in our patient, as well as the response of the nephrosis to agents that modify T cell function. In conclusion, we feel that our patient illustrates that T cell dysfunction may well be of pathogenic importance in the development of minimal-change
Thymoma and minimal-change glomerulonephritis
359
disease. The late presentation of minimal-change disease following thymectomy for thymoma removal may represent longevity of the T cell clones implicit in the pathogenesis of the glomerulonephritis.
10.
Acknowledgements. We would like to thank Mrs Fiona Attwater for typing the manuscript.
11.
References
12.
1. Eagen JW, Lewis EJ. Glomerulopathies of neoplasia. Kidney Im 1977; 11:297-306 2. Varsano S, Bruderman I, Bernheim JL, Rathaus M, Griffel B. Minimal-change nephropathy and malignant thymoma Chest 1980; 77: 695-697 3. Scadding GK, Sweny P, Wilson SG, Harvard CWH, NewsomDavies J. Glomerulonephritis, thymoma and myasthenia gravis. QJ Med 1983; 206: 187-193 4. Hirokawa M, Moriya T, Manabe T. Minimal change renal disease associated with thymoma and pancreatic carcinoma. Ada PatholJpn 1986; 36 (7): 1075-1081 5. Posner MR, Prout MN, Berk S. Thymoma and the nephrotic syndrome. Cancer 1980; 45: 387-391 6. Shalhoub RJ. Pathogenesis of lipoid nephrosis: a disorder of T-cell function. Lancet 1974; 2: 556-560 7. Burnet M. Role of the thymus and related organs in immunity. Br MedJ 1962; 2: 807-811 8. Rosenow EC, Hurley BT. Disorders of the thymus: A review. Arch Intern Med 1984; 144: 763-770 9. Souadjian JV, Enriquez P, Silverstein MN, Pepin J. The
13. 14. 15.
16.
17.
18. 19.
spectrum of disease associated with thymoma. Coincidence or syndrome? Arch Intern Med 1974; 134: 374-379 Oosterhuis HJGH, Felkamp TEW, Van Rossum AL, van den Berg-Loonen PM, Nijenhuis LE. HL-A antigens, autoantibcdy production, and associated diseases in thymoma patients, with and without myasthenia gravis. Ann .V Y Acad Sti 1975; 274: 468-574 Baker JP, Staskak WP, Amabaugh FD, Prescott B, Barth RF. Evidence for the existence of two functionally distinct type of cells which regulate the antibody response to type III pneumccoccal polysaccharide. J Immunol 1970; 105: 1581-1583 Giangiocomo J, Cleary TG, Cole BR, Hoffstein P, Robson A. Serum immunoglobulins in the nephrotic syndrome: a possible cause of minimal-change nephrotic syndrome. A' Engl J Med 1975; 293: 8-12 Mota CH. Infantile Hodgkin's disease: remission after measles. BrMedJ 1973; 2: 421 Michael AF, McLean RH, Roy LP et al. Immunological aspects of nephrotic syndrome. Kidney Im 1973; 3: 105-115 Elisabeth MS, Summer B. In vitro suppression of the lymphocyte response to tuberculin by live measles virus. Proc Soc Exp Biol Med 1966; 123: 276-278 Allen M, Campbell W, Sherif N, Bourke E, Stoute J, Guntupalli J. Minimal change glomerulonephropathy and interstitial infiltration with mycosis fungoides Am J Med 1988; 84: 756-759 Yu DTY, Clements PJ, Paulus HE, Peter JB, Levy J, Barrett EVJ. Human lymphocyte subpopulation effects of corticosteroids. / Clin Invest 1974; 53: 565-571 Winkelstein A. Differential effects of immunosuppression on lymphocyte function. / Clin Invest 1973; 52: 2293-2299 Sherman RL, Susin M, Weksler ME, Becker EL. Lipoid nephrosis in Hodgkin's disease. Am J Med 1972; 52: 699-706
Received for publication 3.4.91 Accepted in revised form 16.8.91
