The Nephrotic Syndrome Associated with Neoplasia: An Unusual Paraneoplastic Syndrome Report of a Case and Review of the Literature
ROBERT G. GAGLIANO, M.D. JOHN J. COSTANZI,
M.D.
GERALD A. BEATHARD,
M.D., Ph.D.
HARRY E. SARLES, M.D. JOHN D. BELL, M.D. Galveston. Texas
The nephrotic syndrome complicating malignancy in the absence of renal vein thrombosis, amyloid or neoplastic infiltration of the kidney is an unusual occurrence. A case of diffuse, well differentiated, lymphocytic lymphoma and lipoid nephrosis documented by light microscopy, electron microscopy and immunofluorescent studies is reported. A review of the literature revealed 76 case reports in which the nephrotic syndrome was associated with neoplasia. The most frequently associated neoplasms are Hodgkin’s disease, various carcinomas, nonHodgkin’s lymphoma and leukemia In descending order. The most frequent renal lesion in patients with the nephrotlc syndrome associated with various carcinomas is membranous glomerulonephritis (61 per cent) as opposed to patients with lymphomas or leukemias who have predominantly lipoid nephrosis (60 per cent). The evidence is reviewed suggesting that the lesions In membranous nephropathy are immunologically mediated by tumor or viral antigen-antibody complexes and in lipold nephrosls perhaps by a defect in T-lymphocyte function. The nephrotic syndrome, which occurs in the absence of amyloidosis, renal vein thrombosis or neoplastic infiltration of the kidney, is a rare but recognized complication of malignancy [ 11. An association between the nephrotic syndrome and extrarenal malignancy was first described by Galloway ‘[2] in 1922. Cornig [3] reported the first case of nephrotic syndrome and Hodgkin’s disease in 1939. Since that time, a number of case reports have appeared in the literature linking the nephrotic syndrome with Hodgkin’s dis-
From The University of Texas Medical Branch Hospitals, The Department of Internal Medicine, Hematology-Oncology Division and Nephrology Division, Galveston, Texas. This study was supported by grant DHEW 2RlO CA 03096 18 and CA 17701. Requests for reprints should be addressed to Dr. Robert G. Gagliano, Division of Hematology-Oncology, Department of Internal Medicine, The University of Texas Medical Branch, Galveston, Texas 77550. Manuscript accepted October 22, 1975.
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ease [ 3,4,9-301, leukemia [ 7,18,31,32] and various carcinomas [ 1,33-451, but its association with nonHodgkin’s lymphoma is especially uncommon [4-81. Several clinical and immunologic observations support the hypothesis of a nonfortuitous relationship between the nephrotic syndrome and neoplasia. (1) The nephrotic syndrome often constitutes the prodomal stage of neoplastic disease [4]. (2) Removal [39] or irradiation [21] of the tumor is usually associated with dramatic diminution of the proteinuria whereas recurrence of the neoplasm is followed by increased proteinuria. (3) Tumor specific antigens and antibodies [41,44] and carcinoembryonic antigen [42] have been identified in the glomeruli of patients with the nephrotic syn-
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drome
and carcinoma.
kidney
in two cases
syndrome
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(4) Antibodies of carcinoma specifically
eluted
ET AL.
from the
and the nephrotic with
tumor
extract
1411. We describe a patient with well differentiated, diffuse, lymphocytic lymphoma presenting with the nephrotic syndrome and renal insufficiency. Six previous patients with nonHodgkin’s lymphoma associated with the nephrotic syndrome have been described
[4-81.
The literature
will
be reviewed
con-
cerning the association between the nephrotic syndrome and neoplasia in the absence of amyloidosis and renal vein thrombosis. CASE REPORT A 65 year old white man was admitted to the University of Texas Medical Branch Hospital on January 23, 1974, with a two-week history of peripheral edema and a 38 pound weight gain. Evaluation for a “flu-like” illness in August 1973 showed that he had a normal urinalysis, complete blood count, blood urea nitrogen and serum creatinine. Physical examination on this admission revealed bilateral cervical, supraclavicular and axillary lymphadenopathy, splenomegaly and anasarca. Laboratory evaluation revealed a total serum protein of 4.3 g/l00 ml, serum albumin 1.7 g/l00 ml, serum cholesterol 270 mg/lOO ml, blood urea nitrogen 72 mg/lOO ml, serum creatinine 3.9 mg/lOO ml, serum calcium 6.3 mg/ 100 ml and phosphorus 7.0 mg/lOO ml. A urinalysis revealed 4+ proteinuria, 0 to 4 white blood cells/hpf and 0 to 2 red blood cells/hpf with occasional broad granular casts. A 24-hour creatinine clearance and protein excretion was 19.6 ml/min and 13.6 g, respectively. Serum C3 was 82 mg/lOO ml and C4 was 73 mg/lOO ml. Serum protein immunoelectrophoresis revealed a nonspecific decrease in immunoglobulins, and serum protein electrophoresis showed no evidence of a monoclonal protein. Antistreptolysin 0 titer, antinuclear antibody, latex agglutination test and fluorescent treponemal antibody test were negative. An inferior venacavagram showed kidneys of normal size and position, and no evidence of renal vein thrombosis or compression. Additional laboratory studies included a hemoglobin level of 11.8 g, a hematocrit value of 35.8 per cent, a white blood count of 17,000/mm3 with 33 per cent polymorphonuclear leukocytes, 64 per cent lymphocytes and a platelet count of 209,000/mm3. Chest roentgenogram revealed hilar lymphadenopathy and a right pleural effusion. A bone marrow aspirate was hypercellular due predominantly to the presence of small, mature lymphocytes and prolymphocytes. A left supraclavicular lymph node biopsy specimen (Figure 1) revealed a diffuse, well differentiated, lymphocytic lymphoma. Combination chemotherapy was instituted with cyclophosphamide, adriamycin, vincristine and prednisone. Forty-five days later the patient showed no further evidence of proteinuria, and his creatinine clearance had increased to 68 ml/min. He experienced a complete remission of his malignant lymphoma within four months. He
Figure 1. Light microscopic appearance of lymph node. Obliteration of normal nodal architecture and invasion of capsule by small well differentiated lymphocytes. Hematoxylin and eosin stain; original magnification X 100, reduced by 50 per cent.
was then placed on maintenance chemotherapy with cyclophosphamide, vincristine and prednisone; and he has remained in complete remission for 13 months with normal renal function and no evidence of proteinuria. METHODS AND MATERIALS Light Microscopy. A left percutaneous renal biopsy specimen was obtained and was immediately divided into three portions for light, immunofluorescent and electron microscopic study. The material for light microscopy was fixed overnight in 4 per cent paraformaldehyde buffered with O.lM cacadylate, embedded in parafin and sectioned at 2 ~1.Alternating sections were stained with hematoxylin and eosin, periodic acid methanamine and Gomori’s trichrome. Electron Microscopy. Material for electron microscopy was fixed in O.lM S-collidine buffered 1 per cent osmium tetroxide, dehydrated in graded alcohols and embedded in Spur. Sections 800 to 900 A in thickness were cut, stained with uranyl acetate and lead citrate, and examined using a Phillips 200 electron microscope. lmmunofluorescent Studies. Material for immunoflourescent studies was snap frozen in an isopentanedry ice preparation. Cryostat sections were cut at 4 to 5 p and stained with monospecific fluoresceniated antiserums raised commercially in rabbits (Meloy Laboratories). The biopsy specimen was stained for human :,nmunoglobulins G (IgG), A (IgA), M (IgM), D (IgD), E (IgE), C3 and fibrinogen. Classic controls for direct immunofluorescence were used. The stained sections were examined using a vertical illuminator and an interference filter system for incident light excitation (Leitz). RESULTS Light Microscopy. Examination of the renal biopsy specimen by light microscopy showed moderate focal interstitial fibrosis, mild focal tubular atrophy
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Figure 2. Electron microscopic appearance of glomerulus. Epithelial cell foot processes are completely fused. The glomerular capillary basement membrane is of normal thickness. There is some wrinkling and contraction of the basement membrane adjacent to mesangial areas. No deposits are present. Original magnification X 4,000, reduced by 50 per cent.
and a mild degree of localized mesangial sclerosis. Glomerular capillary basement membranes were of normal thickness, and no increased cellularity or exudative changes were present. Electron Microscopy. Examination of the renal biopsy specimen by electron microscopy revealed complete epithelial cell foot process fusion. The glomerular capillary basement membrane was of normal thickness, and no perimembranous deposits were noted. A moderate degree of mesangial sclerosis was evident, but no mesangial deposits were present. (Figure 2) lmmunofluorescent lmmunofluorescent Studies. staining of the renal biopsy specimen for IgG, IGA, IgM, IgD, IgE, C3 and fibrinogen was negative. COMMENTS The nephrotic syndrome which occurs in the absence of renal vein thrombosis and amyloid or neo-
TABLE I
Freauencv Distribution
Disease NonHodgkin’s Hodgkin’s Leukemia Carcinoma
of Renal Lesions in Nephrotic Syndrome Associated with Neoplasia
No. Biop sied LM and/or No. No. EM lmmuno Cases 7 37 5 28
6 24 3 21
plastic infiltration of the kidneys is an unusual but recognized paraneoplastic syndrome. The most frequently reported associated neoplasm has been Hodgkin’s disease, with 37 cases reported: 28 cases of various carcinomas, six cases of nonHodgkin’s lymphomas and five cases of leukemia have also been associated with the nephrotic syndrome. A single case of nephrotic syndrome secondary to immunologically mediated glomerulonephritis has recently been described in Waldenstrom’s macroglobulinemia [46]. This represents the first description of the association of diffuse, well differentiated, lymphocytic lymphoma and lipoid nephrosis. The true incidence of the nephrotic syndrome associated with malignancy is unknown. Lee et al. [l] found 11 cases of carcinoma among 104 cases of the nephrotic syndrome (13.5 per cent). Plager et al. [21] reviewed 600 cases of Hodgkin’s disease and found four cases associated with the nephrotic syndrome (0.65 per cent). The frequency of the association has probably been underestimated. Subclinical immune complex nephritis has been detected in nine of 94 (9.5 per cent) postmortem kidneys obtained from patients with lymphoma or leukemia [47] and in six of 45 (13.3 per cent) kidneys (23 postmortem) obtained from patients with Hodgkin’s disease [48]. Table I summarizes the type and distribution of renal lesions in relation to the type of malignancy. A striking difference between the distribution of glomerular lesions in patients with carcinoma (81 per cent membranous glomerulonephritis, 4.7 per cent lipoid nephrosis) and the patients with lymphomaleukemia (60 per cent lipoid nephrosis, 15.1 per cent membranous glomerulonephritis and 12.1 per cent membranoproliferative glomerulonephritis) is apparent. These differences in distribution suggest different pathogenetic mechanisms. The similarities between immunopathologic features of membranous glomerulonephritis in man and experimentally induced immune complex nephritis in
4 6 1 7
PerCent Distribution MC
MGN
2/6(33.4) 16/24(66.6)
2/6(33.4) 4/24(16.6) l/3(33.4) 17/21(81.0)
O(O) l/21 (4.7)
MPGN 2/6(33.4) l/24(4.2) l/3(33.4) O(O)
Other* O(O) 3/24(12.5) l/3(33.4) 2/21(9.5)
Immunopositive 2/4(50) 2/6(33.3) l/l (100) 7/7(100)
I‘JOTE: MPGN = membranoproliferative glomerulonephritis; MGN = membranous glomerulonephritis; MC = minimal changes; lmmunopositive = granular deposits of IgG and B,C globulin. LM = light microscopy; EM = electron microscopy; lmmuno = immun’ofluorescent study. Figures in parentheses indicate per cent. *Includes unclassified glomerulonephritis, lobular glomerulonephritis and focal proliferative glomerulonephritis.
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animals strongly suggests a common mechanism due to the glomerular deposition of circulating antigen-antibody complexes [49,50]. Tumor associated and carcino-fetal antigens have been demonstrated in many human tumors [5 l-54]. Circulating antibody to carcinoembryonic antigen [55] and a variety of tumor specific antigens [56] have been demonstrated in man. Moreover, circulating antigen-antibody complexes have been tentatively identified in the serums of cancer patients [57]. Tumor specific antibodies have been eluted from the kidneys of two patients with bronchial carcinoma and the nephrotic syndrome [41,45], and tumor specific antigen from the glomeruli of one patient with colonic carcinoma and the nephrotic syndrome [44]. Carcinoembryonic antigen-antibody complexes have been identified in the glomeruli of a similar patient [42]. The source of the antigen-antibody complexes may derive from oncogenic viruses. Evidence exists in several animal models that oncogenic viruses induce immune complex formation with deposition of these complexes in the glomeruli. Glomerular immune complexes containing a type-specific antigen related to murine leukemia virus-like particles have been demonstrated in NZB mice [ 581. Murine leukemia viruses have been implicated in the pathogenesis of glomerulonephritis in the AKR mice which are infected with wild-type Gross leukemia viruses [59]. Hirsch et al. [60] have shown that in BALBX mice infected with Moloney leukemia virus glomerulonephritis develops. Circulating Moloney leukemia virus antibodies, as well as Moloney virus immune complexes are noted in the kidneys. These findings are strengthened by the recent report of Sutherland et al. [47] who demonstrated the presence of a mammalian oncornavirusrelated antigen in the kidneys of two patients with acute myeloblastic leukemia and immune complex disease. Furthermore, a number of reports have suggested a viral etiology for several human malignancies including Hodgkin’s disease [6 11, nonHodgkin’s lymphomas [62], leukemia [63], sarcomas [64],
and carcinoma of the cervix [65], nasopharynx 1661 and breast [ 671. The pathogenesis of lipoid nephrosis in various malignancies is unknown; however, recent studies suggest that it may also be immunologically mediated. Shalhoub [68] has postulated that lipoid nephrosis may be a disorder of T-cell function. Lymphocytotoxins have been found in the serums of patients with lipoid nephrosis and diffuse proliferative glomerulonephritis [69]. A lymphokine-type factor which enhanced vascular permeability has been isolated from cultured peripheral blood lymphocytes of patients with the nephrotic syndrome [70]. Giangiacomo et al. [71] have suggested that the primary defect in the idiopathic nephrotic syndrome may be a deficiency in T-cell function that mediates conversion of IgM synthesis to IgG synthesis. In addition, serum IgE levels have been found to be elevated in untreated idiopathic nephrotic syndrome [72]. The response of idiopathic nephrotic syndrome to immunosuppressive therapy with prednisone [33,35] and cyclophosphamide [73] is further suggestive evidence that immunologic mechanisms may be involved. The occurrence of lipoid nephrosis in lymphomas and leukemias may relate to defects in Tlymphocyte function known to occur in these disorders [74,75]. The nephrotic syndrome may be a prodromal manifestation of malignancy [4]. Several reports describe resolution of the nephrotic syndrome in patients with various neoplasms following treatment or removal of the tumor [3,4,9,11,13,15,18,21,38,39] and recurrence of proteinuria at the time of relapse [3,15,21]. In most cases the exact nature of the renal lesion and its etiologic relationship to the tumor are not well defined. Even though the association is infrequent, it would seem clinically reasonable to screen all older patients with the nephrotic syndrome for underlying malignancy and conversely to obtain a 24-hour urine protein excretion in all patients with malignancies.
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Lee JC, Yamauchi H, Hopper J: The association of cancer and the nephrotic syndrome. Ann Intern Med 64: 41, 1966. Galloway J: Remarks on Hodgkin’s disease. Br Med J 2: 1201,1922. Cornig HJ: Une forme nouvelle de la maladie de Hodgkin: lymphogranulomatose maligne a type de nephrose lipoidique. These de Paris 1939, no. 517, cited by Tapie, J, Laporte J, Ricalen S: Syndrome nephrotique au tours de la maladie de Hodgkin-Sternberg. Presse Med 65: 287, 1957. Ghosh L, Muehrcke RC: The nephrotic syndrome: a prodrome to lymphoma. Ann Intern Med 72: 379, 1970. Muggia FM: Glomerulonephritis or nephrotic syndrome in
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malignant lymphoma, reticulum-cell type. Lancet 1:805, 1971. Hyman LR, Burkholder PM, Joo PA, Segar WE: Malignant lymphoma and nephrotic syndrome. J Pediat 82: 207, 1973. Gluck MC, Gallow G, Lowenstein J, Baldwin DS: Membranous glomerulonephritis: evolution of clinical and pathological features. Ann Intern Med 78: 1, 1973. Rabkin R, Thatcher GN. Diamond LH, Eales L: The nephrotic syndrome, malignancy and immunosuppression. South Afr Med J 47: 605, 1973. Rohmer P, Sacrez R: Un cas de nephrose lipoidique au tour dune maladie de Hodgkin. Strasbourg Med 108: 45, 1948.
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Solsona-Conillera J: Linfogranulomatosis maligna: forma monogaglionary nephrosica. Med Clin 20: 37, 1953. 11. Tapie T. Laporte J, Richalens S: Syndrome nephrotique au tours de la maladie de Hodgkin-Sternberg. Presse Med 65: 287, 1957. 12. Hardin JG, Coker AS, Blantin JH: Medical grand rounds. South Med J 62: 1111, 1963. L: Nerczyca lipidowa w przebiegu 13. Perlinska-Schneider choroby Hodgkina. Proba wyjosnienia patogenezy zespolu nerczycowego. Pol Tyg Lek 20: 132, 1965. 14. Miller DG: The association of immune disease and malignant lymphoma. Ann Intern Med 66: 507, 1967. 15. Mehta SR, Kumar KK, Gupta ML: Hodgkin’s disease with nephrotic syndrome and erythema multiforme. J Indian Med Assoc 48: 279, 1967. 16. Paslawska-Udolf E: Przypadek nerczycy kipoidowej w przebiegu ziarnicy zlosliwej u dziecka 2-letniego. Pediat Pol 42: 591, 1967. 17. Kiy Y: Sindrome nefrotica associada a doenca de Hodgkin. Rev Hosp Clin Fat Med Sao Paulo 22: 186, 1967. 16. Brodovsky HS, Samuels ML, Migliore PJ, Howe CD: Chronic lymphocytic leukemia, Hodgin’s disease, and the nephrotic syndrome. Arch Intern Med 121: 71, 1968. 19. Hamburger J, Richet G. Crosnier J, Funck-Brentano F, Antoine B, Ducrot H, Mery JP, deMontera H, Nephrology, vol 1, Philadelphia, W. B. Saunders Company, 1968, p 226. 20. Kiely JM, Wagoner RD. Holley KE: Renal complication of lymphoma. Ann Intern Med 71: 1159, 1969. 21. Plager J, Stutzman L: Acute nephrotic syndrome as a manifestation of active Hodgkin’s disease: report of four cases and review of the literature. Am J Med 50: 56, 1971. 22. Bichel J, Jensen KB: Nephrotic syndrome and Hodgkin’s disease. Lancet 2: 1425, 1971. 23. Jackson RH, 00 M: Nephrotic syndrome with Hodgkin’s disease. Lancet 2: 821, 1971. Aach Ft. Kissane J: Hodgkin’s disease complicated by 24. thrombocytopenia and nephrotic syndrome. Clinicopathologic Conference. Am J Med 51: 109, 1971. 25. Lowny WS, Munzenrider JE, Lynch GA: Nephrotic syndrome in Hodgkin’s disease. Lancet 1: 1127, 1971. 26. Hansen HE, Skov PE, Askjaer SA, Albertsen K: Hodgkin’s disease associated with the nephrotic syndrome without kidney lesion. Acta Med Stand 191: 307, 1972. Froom DW, Franklin WA, Hano JE, Potter EV: Immune de27. posits in Hodgkin’s disease with nephrotic syndrome. Arch Pathol 94: 547, 1972. Sherman RL, Susin M, Weksler ME, Becker EL: Lipoid ne28. phrosis in Hodgkin’s disease. Am J Med 52: 699, 1972. 29. Lokich JJ. Galvanek EG, Moloney WC: Nephrosis of Hodgkin’s disease. Arch Intern Med 132: 597, 1973. Castleman B, Scully RE, McNeely BU: Case records of the 30. Massachusetts General Hospital. Case 49-1973. N Engl J Med 289: 1241, 1973. Scott, RB: Chronic lymphocytic leukemia. Lancet 1: 1162, 31. 1957. Dathan JRE, Heyworth MF, Maciver AG: Nephrotic syn32. drome in chronic lymphocytic leukemia. Br Med J 3: 655, 1974. 33. Johnson JR, Reader R: Prognosis in the nephrotic syndrome; a study with particular reference to the adult and older child. Aust Ann Med 8: 200, 1959. Castleman B, Kibbee BU: Case records by the Massachu34. setts General Hospital. Case 29-1963. N Engl J Med 268: 943, 1963. Nesson HR, Sproul LE, Relman AS, Schwartz WB: Adrenal 35. steroids in the treatment of idiopathic nephrotic syndrome in adults. Ann Intern Med 58: 268, 1963. Zunin C. Soave F: Association of nephrotic syndrome and 36.
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nephroblastoma in siblings. Ann Pediat 203: 29, 1964. Chassagnon C, Robillard J: Syndrome nephrotique revelateur d’un cancer bronchique. Lyon Med 213: 1063, 1965. Lumeng J, Moran JF: Carotid body tumor associated with mild membranous glomerulonephritis. Ann Intern Med 65: 1266, 1966. Cantrell EG: Nephrotic syndrome cured by removal of gastric carcinoma. Br Med J 2: 739, 1969. Loughridge LW, Lewis MG: Nephrotic syndrome in malignant disease of non-renal origin. Lancet 1: 256, 1971. Lewis MG, Loughridge LW, Phillips TM: Immunological studies in nephrotic syndrome associated with extrarenal malignant disease. Lancet 2: 134, 1971. Costanza ME. Pinn V, Schwartz RS, Nathanson L: Carcinoembryonic antigen-antibody complexes in a patient with colonic carcinoma and nephrotic syndrome. N Engl. J Med 269: 520. 1973. Higgins MR, Randall RE, Still WJS: Nephrotic syndrome with oat-cell carcinoma. Br Med J 3: 450, 1974. Couser WG, Wagonfeld JB, Spargo BH, Lewis EJ: Glomerular deposition of tumor antigen in membranous nephropathy associated with colonic carcinoma. Am J Med 57: 962, 1974. Mendes Da Costa CR, DuPont E, Hamers R, Hoogue R, Dupuis F, Potvliege R: Nephrotic syndrome in bronchogenic carcinoma: report of two cases with immunochemical studies. Clin Nephrol 2: 245, 1974. Martelo OJ, Schultz DR, Pardo V, Perez-Stable E: Immunologically-mediated renal disease in Waldenstrom’s macroglobuinemia. Am J Med 58: 587, 1975. Sutherland JC, Mardiney MR Jr: Immune complex disease in the kidneys of lymphoma-leukemia patients: the presence of an oncornavirus-related antigen. J Natl Cancer lnst 50: 633, 1973. Sutherland JC, Markham RV Jr, Ramsey HE, Mardiney MR Jr: Subclinical immune complex nephritis in patients with Hodgkin’s disease. Cancer Res 34: 1179, 1974. Edgington TS, Glassock RJ, Dixon FJ: Autologous immune complex pathogenesis of experimental allergic glomerulonephritis. Science 155: 1432, 1967. Dixon FJ, Feldman JD, Vazquez JJ: Experimental glomerulonephritis. The pathogenesis of a laboratory model resembling the spectrum of human glomerulonephritis. J Exp Med 113: 899, 1961. Gold P, Freedman SO: Demonstration of tumor-specific antigens in human colonia carcinomata by immunological tolerance and absorption techniques. J Exp Med 121: 439, 1965. Order SE, Porter MP, Hellman S: Hodgkin’s disease: evidence for a tumor-associated antigen. N Engl J Med 285: 471,197l. Halterman RH, Leventhal BG, Mann DL: An acute-leukemia antigen: correlation with clinical status. N Engl J Med 287: 1272, 1972. Edynak EM, Old LF, Vrana M, Lardis MP: A fetal antigen associated with human neoplasia. N Engl J Med 286: 1178, 1972. Gold P: Circulatory antibodies against carcinoembryonic antigens of the human digestive system. Cancer 20: 1603, 1967. Aprel SC, Southam CM: Cytotoxicity of sera from healthy persons and cancer patients. lntl J Cancer 4: 548, 1969. Sjbgren HO, Helstrbm I, Bansal SC, Hellstrom KE: Suggestive evidence that “blocking” antibodies of tumor-bearing individuals may be antigen-antibody complexes. Proc Natl Acad Sci 68: 1372, 1971. Mellors RC: Wild-type gross leukemia virus and heritable autoimmune disease of New Zealand mice. Am J Clin Pathol 56: 270, 197 1.
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Gross L: Recent studies on the mouse leukemia virus. Perspect Virol 4: 226, 1965. Hirsch MS, Allison AC, Harvey JJ: immune complexes in mice infected neonatally with Mofoney leukaemogenic and murine sarcoma viruses. Nature (Lond) 223: 739, 1969. Esinger M, Fox SM, DeHarven E, Biedler JL, Sanders FK: Virus-like agents from patients with Hodgkin’s disease. Nature (Lond) 233: 104, 197 1. Henle W: Evidence for viruses in acute leukemia and Burkitt’s tumor. Cancer 21: 580, 1968. Gallo RC, Tang SS. Ting RC: RNA dependent DNA polymerase of human acute leukaemia cells. Nature (Lond) 228: 927. 1970. Wood WC, Morton DL: Host immune response to a common cell-surface antigen in human sarcomas. N Engl J Med 284: 569, 1971. Rawls WE, Tompkins WAF, Melnick JL: The association of herpesvirus type 2 and carcinoma of the uterine cervix. Am J Epidemiol 89: 547, 1969. Henle W, Henle G: Epstein-Barr virus and human malignancies. Cancer 34: 1368, 1974. Dmochowski L, Seman G, Gallager HS: Viruses as possible etiologic factors in human breast cancer. Cancer 24:
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1241, 1969. Shalhoub RJ: Pathogenesis of lipoid nephrosis: a disorder of T-cell function. Lancet 2: 556, 1974. Ooi BS. Orlina AR, Masaitis L: Lymphocytotoxins in primary renal disease. Lancet 2: 1348, 1974. Lagrue G. Xheneumont S, Branellec A, Weil B: Lymphokines and nephrotic syndrome. Lancet 1: 217, 1975. Giagiacomo J. Cleary TG, Cole BR. Hoffsten P, Robson AM: Serum immunoglobulins in the nephrotic syndrome: a possible cause of minimal-change nephrotic syndrome. N Engl J Med 293: 8, 1975. Groshong T, Mendelson L, Mendoza S, Bazaral M, Hamburger R, Tune B: Serum IgE in patients with minimalchange nephrotic syndrome. J Pediatr 83: 767, 1973. Barratt TM Osofsky SG, Bercowsky A, Soothill JF: Cyclophosphamide treatment in steroid-sensitive nephrotic syndrome of childhood. Lancet 1: 55, 1975. Levy R. Kaplan HS: Impaired lymphocyte function in untreated Hodgkin’s disease. N Engl J Med 290: 181, 1974. Hersh EM, Gutterman JU, Mavligit GM. McCredie KB, Burgess MA, Matthews A, Freireich EJ: Serial studies of immunocompetence of patients undergoing chemotherapy for acute leukemia. J Clin Invest 54: 40 1, 1974.
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ROBERT G. GAGLIANO, M.D. JOHN J. COSTANZI,
M.D.
GERALD A. BEATHARD,
M.D., Ph.D.
HARRY E. SARLES, M.D. JOHN D. BELL, M.D. Galveston. Texas
The nephrotic syndrome complicating malignancy in the absence of renal vein thrombosis, amyloid or neoplastic infiltration of the kidney is an unusual occurrence. A case of diffuse, well differentiated, lymphocytic lymphoma and lipoid nephrosis documented by light microscopy, electron microscopy and immunofluorescent studies is reported. A review of the literature revealed 76 case reports in which the nephrotic syndrome was associated with neoplasia. The most frequently associated neoplasms are Hodgkin’s disease, various carcinomas, nonHodgkin’s lymphoma and leukemia In descending order. The most frequent renal lesion in patients with the nephrotlc syndrome associated with various carcinomas is membranous glomerulonephritis (61 per cent) as opposed to patients with lymphomas or leukemias who have predominantly lipoid nephrosis (60 per cent). The evidence is reviewed suggesting that the lesions In membranous nephropathy are immunologically mediated by tumor or viral antigen-antibody complexes and in lipold nephrosls perhaps by a defect in T-lymphocyte function. The nephrotic syndrome, which occurs in the absence of amyloidosis, renal vein thrombosis or neoplastic infiltration of the kidney, is a rare but recognized complication of malignancy [ 11. An association between the nephrotic syndrome and extrarenal malignancy was first described by Galloway ‘[2] in 1922. Cornig [3] reported the first case of nephrotic syndrome and Hodgkin’s disease in 1939. Since that time, a number of case reports have appeared in the literature linking the nephrotic syndrome with Hodgkin’s dis-
From The University of Texas Medical Branch Hospitals, The Department of Internal Medicine, Hematology-Oncology Division and Nephrology Division, Galveston, Texas. This study was supported by grant DHEW 2RlO CA 03096 18 and CA 17701. Requests for reprints should be addressed to Dr. Robert G. Gagliano, Division of Hematology-Oncology, Department of Internal Medicine, The University of Texas Medical Branch, Galveston, Texas 77550. Manuscript accepted October 22, 1975.
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ease [ 3,4,9-301, leukemia [ 7,18,31,32] and various carcinomas [ 1,33-451, but its association with nonHodgkin’s lymphoma is especially uncommon [4-81. Several clinical and immunologic observations support the hypothesis of a nonfortuitous relationship between the nephrotic syndrome and neoplasia. (1) The nephrotic syndrome often constitutes the prodomal stage of neoplastic disease [4]. (2) Removal [39] or irradiation [21] of the tumor is usually associated with dramatic diminution of the proteinuria whereas recurrence of the neoplasm is followed by increased proteinuria. (3) Tumor specific antigens and antibodies [41,44] and carcinoembryonic antigen [42] have been identified in the glomeruli of patients with the nephrotic syn-
The American Journal of Medicine
Volume 60
THE NEPHROTIC SYNDROME WITH NEOPLASIA-GAGLIANO
drome
and carcinoma.
kidney
in two cases
syndrome
reacted
(4) Antibodies of carcinoma specifically
eluted
ET AL.
from the
and the nephrotic with
tumor
extract
1411. We describe a patient with well differentiated, diffuse, lymphocytic lymphoma presenting with the nephrotic syndrome and renal insufficiency. Six previous patients with nonHodgkin’s lymphoma associated with the nephrotic syndrome have been described
[4-81.
The literature
will
be reviewed
con-
cerning the association between the nephrotic syndrome and neoplasia in the absence of amyloidosis and renal vein thrombosis. CASE REPORT A 65 year old white man was admitted to the University of Texas Medical Branch Hospital on January 23, 1974, with a two-week history of peripheral edema and a 38 pound weight gain. Evaluation for a “flu-like” illness in August 1973 showed that he had a normal urinalysis, complete blood count, blood urea nitrogen and serum creatinine. Physical examination on this admission revealed bilateral cervical, supraclavicular and axillary lymphadenopathy, splenomegaly and anasarca. Laboratory evaluation revealed a total serum protein of 4.3 g/l00 ml, serum albumin 1.7 g/l00 ml, serum cholesterol 270 mg/lOO ml, blood urea nitrogen 72 mg/lOO ml, serum creatinine 3.9 mg/lOO ml, serum calcium 6.3 mg/ 100 ml and phosphorus 7.0 mg/lOO ml. A urinalysis revealed 4+ proteinuria, 0 to 4 white blood cells/hpf and 0 to 2 red blood cells/hpf with occasional broad granular casts. A 24-hour creatinine clearance and protein excretion was 19.6 ml/min and 13.6 g, respectively. Serum C3 was 82 mg/lOO ml and C4 was 73 mg/lOO ml. Serum protein immunoelectrophoresis revealed a nonspecific decrease in immunoglobulins, and serum protein electrophoresis showed no evidence of a monoclonal protein. Antistreptolysin 0 titer, antinuclear antibody, latex agglutination test and fluorescent treponemal antibody test were negative. An inferior venacavagram showed kidneys of normal size and position, and no evidence of renal vein thrombosis or compression. Additional laboratory studies included a hemoglobin level of 11.8 g, a hematocrit value of 35.8 per cent, a white blood count of 17,000/mm3 with 33 per cent polymorphonuclear leukocytes, 64 per cent lymphocytes and a platelet count of 209,000/mm3. Chest roentgenogram revealed hilar lymphadenopathy and a right pleural effusion. A bone marrow aspirate was hypercellular due predominantly to the presence of small, mature lymphocytes and prolymphocytes. A left supraclavicular lymph node biopsy specimen (Figure 1) revealed a diffuse, well differentiated, lymphocytic lymphoma. Combination chemotherapy was instituted with cyclophosphamide, adriamycin, vincristine and prednisone. Forty-five days later the patient showed no further evidence of proteinuria, and his creatinine clearance had increased to 68 ml/min. He experienced a complete remission of his malignant lymphoma within four months. He
Figure 1. Light microscopic appearance of lymph node. Obliteration of normal nodal architecture and invasion of capsule by small well differentiated lymphocytes. Hematoxylin and eosin stain; original magnification X 100, reduced by 50 per cent.
was then placed on maintenance chemotherapy with cyclophosphamide, vincristine and prednisone; and he has remained in complete remission for 13 months with normal renal function and no evidence of proteinuria. METHODS AND MATERIALS Light Microscopy. A left percutaneous renal biopsy specimen was obtained and was immediately divided into three portions for light, immunofluorescent and electron microscopic study. The material for light microscopy was fixed overnight in 4 per cent paraformaldehyde buffered with O.lM cacadylate, embedded in parafin and sectioned at 2 ~1.Alternating sections were stained with hematoxylin and eosin, periodic acid methanamine and Gomori’s trichrome. Electron Microscopy. Material for electron microscopy was fixed in O.lM S-collidine buffered 1 per cent osmium tetroxide, dehydrated in graded alcohols and embedded in Spur. Sections 800 to 900 A in thickness were cut, stained with uranyl acetate and lead citrate, and examined using a Phillips 200 electron microscope. lmmunofluorescent Studies. Material for immunoflourescent studies was snap frozen in an isopentanedry ice preparation. Cryostat sections were cut at 4 to 5 p and stained with monospecific fluoresceniated antiserums raised commercially in rabbits (Meloy Laboratories). The biopsy specimen was stained for human :,nmunoglobulins G (IgG), A (IgA), M (IgM), D (IgD), E (IgE), C3 and fibrinogen. Classic controls for direct immunofluorescence were used. The stained sections were examined using a vertical illuminator and an interference filter system for incident light excitation (Leitz). RESULTS Light Microscopy. Examination of the renal biopsy specimen by light microscopy showed moderate focal interstitial fibrosis, mild focal tubular atrophy
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Figure 2. Electron microscopic appearance of glomerulus. Epithelial cell foot processes are completely fused. The glomerular capillary basement membrane is of normal thickness. There is some wrinkling and contraction of the basement membrane adjacent to mesangial areas. No deposits are present. Original magnification X 4,000, reduced by 50 per cent.
and a mild degree of localized mesangial sclerosis. Glomerular capillary basement membranes were of normal thickness, and no increased cellularity or exudative changes were present. Electron Microscopy. Examination of the renal biopsy specimen by electron microscopy revealed complete epithelial cell foot process fusion. The glomerular capillary basement membrane was of normal thickness, and no perimembranous deposits were noted. A moderate degree of mesangial sclerosis was evident, but no mesangial deposits were present. (Figure 2) lmmunofluorescent lmmunofluorescent Studies. staining of the renal biopsy specimen for IgG, IGA, IgM, IgD, IgE, C3 and fibrinogen was negative. COMMENTS The nephrotic syndrome which occurs in the absence of renal vein thrombosis and amyloid or neo-
TABLE I
Freauencv Distribution
Disease NonHodgkin’s Hodgkin’s Leukemia Carcinoma
of Renal Lesions in Nephrotic Syndrome Associated with Neoplasia
No. Biop sied LM and/or No. No. EM lmmuno Cases 7 37 5 28
6 24 3 21
plastic infiltration of the kidneys is an unusual but recognized paraneoplastic syndrome. The most frequently reported associated neoplasm has been Hodgkin’s disease, with 37 cases reported: 28 cases of various carcinomas, six cases of nonHodgkin’s lymphomas and five cases of leukemia have also been associated with the nephrotic syndrome. A single case of nephrotic syndrome secondary to immunologically mediated glomerulonephritis has recently been described in Waldenstrom’s macroglobulinemia [46]. This represents the first description of the association of diffuse, well differentiated, lymphocytic lymphoma and lipoid nephrosis. The true incidence of the nephrotic syndrome associated with malignancy is unknown. Lee et al. [l] found 11 cases of carcinoma among 104 cases of the nephrotic syndrome (13.5 per cent). Plager et al. [21] reviewed 600 cases of Hodgkin’s disease and found four cases associated with the nephrotic syndrome (0.65 per cent). The frequency of the association has probably been underestimated. Subclinical immune complex nephritis has been detected in nine of 94 (9.5 per cent) postmortem kidneys obtained from patients with lymphoma or leukemia [47] and in six of 45 (13.3 per cent) kidneys (23 postmortem) obtained from patients with Hodgkin’s disease [48]. Table I summarizes the type and distribution of renal lesions in relation to the type of malignancy. A striking difference between the distribution of glomerular lesions in patients with carcinoma (81 per cent membranous glomerulonephritis, 4.7 per cent lipoid nephrosis) and the patients with lymphomaleukemia (60 per cent lipoid nephrosis, 15.1 per cent membranous glomerulonephritis and 12.1 per cent membranoproliferative glomerulonephritis) is apparent. These differences in distribution suggest different pathogenetic mechanisms. The similarities between immunopathologic features of membranous glomerulonephritis in man and experimentally induced immune complex nephritis in
4 6 1 7
PerCent Distribution MC
MGN
2/6(33.4) 16/24(66.6)
2/6(33.4) 4/24(16.6) l/3(33.4) 17/21(81.0)
O(O) l/21 (4.7)
MPGN 2/6(33.4) l/24(4.2) l/3(33.4) O(O)
Other* O(O) 3/24(12.5) l/3(33.4) 2/21(9.5)
Immunopositive 2/4(50) 2/6(33.3) l/l (100) 7/7(100)
I‘JOTE: MPGN = membranoproliferative glomerulonephritis; MGN = membranous glomerulonephritis; MC = minimal changes; lmmunopositive = granular deposits of IgG and B,C globulin. LM = light microscopy; EM = electron microscopy; lmmuno = immun’ofluorescent study. Figures in parentheses indicate per cent. *Includes unclassified glomerulonephritis, lobular glomerulonephritis and focal proliferative glomerulonephritis.
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animals strongly suggests a common mechanism due to the glomerular deposition of circulating antigen-antibody complexes [49,50]. Tumor associated and carcino-fetal antigens have been demonstrated in many human tumors [5 l-54]. Circulating antibody to carcinoembryonic antigen [55] and a variety of tumor specific antigens [56] have been demonstrated in man. Moreover, circulating antigen-antibody complexes have been tentatively identified in the serums of cancer patients [57]. Tumor specific antibodies have been eluted from the kidneys of two patients with bronchial carcinoma and the nephrotic syndrome [41,45], and tumor specific antigen from the glomeruli of one patient with colonic carcinoma and the nephrotic syndrome [44]. Carcinoembryonic antigen-antibody complexes have been identified in the glomeruli of a similar patient [42]. The source of the antigen-antibody complexes may derive from oncogenic viruses. Evidence exists in several animal models that oncogenic viruses induce immune complex formation with deposition of these complexes in the glomeruli. Glomerular immune complexes containing a type-specific antigen related to murine leukemia virus-like particles have been demonstrated in NZB mice [ 581. Murine leukemia viruses have been implicated in the pathogenesis of glomerulonephritis in the AKR mice which are infected with wild-type Gross leukemia viruses [59]. Hirsch et al. [60] have shown that in BALBX mice infected with Moloney leukemia virus glomerulonephritis develops. Circulating Moloney leukemia virus antibodies, as well as Moloney virus immune complexes are noted in the kidneys. These findings are strengthened by the recent report of Sutherland et al. [47] who demonstrated the presence of a mammalian oncornavirusrelated antigen in the kidneys of two patients with acute myeloblastic leukemia and immune complex disease. Furthermore, a number of reports have suggested a viral etiology for several human malignancies including Hodgkin’s disease [6 11, nonHodgkin’s lymphomas [62], leukemia [63], sarcomas [64],
and carcinoma of the cervix [65], nasopharynx 1661 and breast [ 671. The pathogenesis of lipoid nephrosis in various malignancies is unknown; however, recent studies suggest that it may also be immunologically mediated. Shalhoub [68] has postulated that lipoid nephrosis may be a disorder of T-cell function. Lymphocytotoxins have been found in the serums of patients with lipoid nephrosis and diffuse proliferative glomerulonephritis [69]. A lymphokine-type factor which enhanced vascular permeability has been isolated from cultured peripheral blood lymphocytes of patients with the nephrotic syndrome [70]. Giangiacomo et al. [71] have suggested that the primary defect in the idiopathic nephrotic syndrome may be a deficiency in T-cell function that mediates conversion of IgM synthesis to IgG synthesis. In addition, serum IgE levels have been found to be elevated in untreated idiopathic nephrotic syndrome [72]. The response of idiopathic nephrotic syndrome to immunosuppressive therapy with prednisone [33,35] and cyclophosphamide [73] is further suggestive evidence that immunologic mechanisms may be involved. The occurrence of lipoid nephrosis in lymphomas and leukemias may relate to defects in Tlymphocyte function known to occur in these disorders [74,75]. The nephrotic syndrome may be a prodromal manifestation of malignancy [4]. Several reports describe resolution of the nephrotic syndrome in patients with various neoplasms following treatment or removal of the tumor [3,4,9,11,13,15,18,21,38,39] and recurrence of proteinuria at the time of relapse [3,15,21]. In most cases the exact nature of the renal lesion and its etiologic relationship to the tumor are not well defined. Even though the association is infrequent, it would seem clinically reasonable to screen all older patients with the nephrotic syndrome for underlying malignancy and conversely to obtain a 24-hour urine protein excretion in all patients with malignancies.
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1241, 1969. Shalhoub RJ: Pathogenesis of lipoid nephrosis: a disorder of T-cell function. Lancet 2: 556, 1974. Ooi BS. Orlina AR, Masaitis L: Lymphocytotoxins in primary renal disease. Lancet 2: 1348, 1974. Lagrue G. Xheneumont S, Branellec A, Weil B: Lymphokines and nephrotic syndrome. Lancet 1: 217, 1975. Giagiacomo J. Cleary TG, Cole BR. Hoffsten P, Robson AM: Serum immunoglobulins in the nephrotic syndrome: a possible cause of minimal-change nephrotic syndrome. N Engl J Med 293: 8, 1975. Groshong T, Mendelson L, Mendoza S, Bazaral M, Hamburger R, Tune B: Serum IgE in patients with minimalchange nephrotic syndrome. J Pediatr 83: 767, 1973. Barratt TM Osofsky SG, Bercowsky A, Soothill JF: Cyclophosphamide treatment in steroid-sensitive nephrotic syndrome of childhood. Lancet 1: 55, 1975. Levy R. Kaplan HS: Impaired lymphocyte function in untreated Hodgkin’s disease. N Engl J Med 290: 181, 1974. Hersh EM, Gutterman JU, Mavligit GM. McCredie KB, Burgess MA, Matthews A, Freireich EJ: Serial studies of immunocompetence of patients undergoing chemotherapy for acute leukemia. J Clin Invest 54: 40 1, 1974.
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