Nephrotic syndrome in Hodgkin's disease

Nephrotic Syndrome in Hodgkin’s Disease Evidence for Pathogenesis Alternative

A. VISHNU MOORTHY,

M.D.*

STEPHEN W. ZIMMERMAN,

M.D.

PETER M. BURKHOLDER, M.D. Madison, Wisconsin

From the Nephrology Program, Departments of Medicine and Pathology, University of Wisconsin Center for Health Sciences, Madison, Wisconsin. This study was supported in part by Research Grant AM 15159 from the National Institutes of Health, Bethesda, Maryland. Requests for reprints should be addressed to Dr. A. Vishnu Moorthy, Nephrology Section, Department of Medicine, University Hospitals, 1300 University Avenue, Madison, Wisconsin 53706. Manuscript accepted January 23, 1976. * Recipient of a joint fellowship from the National Kidney Foundation and the Kidney Foundation of Wisconsin.

to immune Complex Deposition

The nephrotfc syndrome has been reported to occur in patients with Hodgkin’s disease even in the absence of amyloidosis, tumor infiltration or renal vein thrombosis. Three patients are presented with Hodgkin’s disease and the nephrotic syndrome whose renal biopsy specimens studied with light, immunofluorescence and electron microscopy were compatible with “lipoid nephrosis” (minimal change disease). A review of the literature reveals 35 patients with Hodgkin’s disease and the nephrotic syndrome. Renal tissue was available for examination in only 27 patients. The majottty of patients apparently had glomerular alterations consistent with lipoid nephrosis. The nephrotic syndrome in most of these patients remitted with a variety of methods of therapy (including excision, irradiation, prednisone and cyclophosphamide) and tended to relapse with a recurrence of Hodgkin’s disease. In three-fourths of the patients with Hodgkin’s disease and the nephrotic syndrome, the Hodgkin’s disease was of a mixed cellularity type. The etiology of lipoid nephrosis, although.unclear, may be a consequence of altered lymphocyte function. Hodgkin’s disease is a malignancy involving T lymphocytes, and the nephrotic syndrome occurring in the course of Hodgkin’s disease may be a result of an adverse effect on glomeruli by products of tumor lymphocytes rather than of glomerular deposition of immune complexes. Renal complications in the course of Hodgkin’s disease due to a variety of mechanisms such as ureteral obstruction, tumor infiltration of the kidneys, amyloidosis and renal vein thrombosis have been reported. Since 1939 the occurrence of the nephrotic syndrome in patients with Hodgkin’s disease in the absence of any of the symptoms listed has been reported on many occasions [l-23]. In the majority of these patients, renal tissue has usually revealed no specific abnormalities. Findings similar to those seen in lipoid nephrosis have been noted, although an occasional patient has shown more extensive glomerular changes. This is in contrast to the nephrotic syndrome associated with carcinoma of the lung and colon in which renal biopsy specimens have revealed membranous glomerulonephropathy [24], and tumor antigen has been eluted from immune complexes deposited along gfomerular capillary wails [25]. We describe here three patients with the nephrotic syndrome and Hodgkin’s disease in whom the findings on renal biopsy were compatible with lipoid nephrosis, and review the data on 32 other patients described in the literature.

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MATERIAL AND METHODS Biochemical and hematologic analyses were made. in the clinical laboratories. Surgically removed lymph nodes were examined by hematoxylin and eosin stained sections. Renal tissue obtained by percutaneous needle biopsy was processed for light microscopy by fixation in formalin. Two micron paraffin sections were stained with hematoxylin and eosin, periodic acid-Schiff and periodic acid silver metherramine Masson stain as described elsewhere [26]. A portion of renal tissue for immunofluorescence study was frozen in aqueous gelatin and 4 fl sections were stained with fluorescein-conjugated immunoglobulin fractions of antiserum to human immunoglobulins G (IgG), M (IgM), A (IgA), third component of complement (C3) and fibrinogen. A third portion of each renal biopsy specimen was processed for electron microscopy and examined as previously described [26]. Serum was assayed for macrophage migration inhibition activity against guinea pig peritoneal macrophages harvested four days after giving the guinea pigs an intraperitoneal injection of light mineral oil. A 50 per cent dilution of the patient’s serum with tissue culture medium (medium 199) was used in Sykes-Moore chambers containing capillary tubes filled with guinea pig macrophages, and the areas of migration after 24 hours’ incubation at 37% in 5 per cent carbon dioxide were drawn and measured with a planimeter as described elsewhere [27]. The experiment was carried out in triplicate, using normal human serum as control. Migration inhibition was considered to be present when the area of nfigration decreased to less than 60 per cent of normal control migration.

in six weeks. He has been followed for a year and has been given monthly injections of 5 mg vinblastine sulfate; during this time his urine has remained protein free.

CASE REPORTS

Case 2. A 26 year old, mentally handicapped white woman presented in January 1966 with cervical lymphadenopathy. A lymph node biopsy specimen showed Hodgkin’s disease of mixed cellularity type. It was staged I-A after lymphangiography and hepatic and splenic scans, and the patient was treated with upper mantle irradiation over three weeks for a total dose of 4,000 rads. Over the next five years she had three further courses of irradiation (to a total dose of 6,000 rads) for right submandibular, left cervical and iliac recurrences of Hodgkin’s disease. The kidneys were shielded during irradiation. Urinalysis was negative for protein during this period. In September 1972 she presented with pedal edema. There was no lymphadenopathy. Blood pressure was 1 lo/70 mm Hg. Urinalysis revealed 3-t protein with Maltese crosses, hyaline casts and a few white blood cells in the sediment. The 24-hour urine protein excretion was 5 g. Urine protein was highly selective being 90 per cent albumin on electrophoresis. Serum albumin was 2.0 g/dl. The creatinine clearance was 110 ml/min. Abdominal lymphangiogram, hepatic and splenic scans, bone marrow biopsy, renal venogram and rectal biopsy for amyloid disclosed no abnormalities. Serum antinuclear antibodies were negative and serum C3 was 110 mg/dl. A renal biopsy was performed. She was treated with vinblastine, 7 mg intravenously, twice monthly with disappearance of proteinuria in three months. Vinblastine therapy has been continued, 10 mg given intravenously monthly, and she has remained protein free.

Case 1. In a 14 year old Caucasian boy, poison ivy dermatitis developed on his legs in October 1973 and responded completely to local and systemic steroid therapy. Two weeks later he was hospitalized with ankle edema and ascites. On admission to the hospital he had discrete lower cervical lymphadenopathy; three lymph nodes measured about 5 cm by 2 cm. No other lymph nodes were enlarged, and neither the spleen nor liver was palpable. His blood pressure was 100/70 mm Hg. Roentgenographic examination of the chest was within normal limits. Urinalysis revealed 4-F protein with a rare red blood cell and an occasional hyaline cast in the sediment. The daily urinary protein excretion was 5.6 g. Serum albumin was 3.0 g/d& blood urea nitrogen 20 mg/dl and cholesterol 300 mg/dl. Antinuclear antibodies were negative and serum C3 was 108 mg/dl (normal 80 to 150 mg/dl). A renal biopsy was performed, and therapy with prednisone, 40 mglday, was initiated. As the cervical lymphadenopathy became more prominent, a lymph node was obtained surgically and interpreted as showing Hodgkin’s disease of the mixed cellularity type. The disease was considered to be at stage I-B after abdominal lymphangiography and hepatic and splenic scan. The patient was then treated with cervical irradiation, to a total dose of 3,000 rads in three weeks: therapy was continued with prednisone, 40 mglday, to which was added cyclophosphamide, at a dose of I .5 mg/kg and vincristine, 1 mg daily. Proteinuria decreased and disappeared

Case 3. A 57 year old Caucasian man, a retired construction worker, presented to his local physician in May 1974 with cervical lymph node swelling of three weeks’ duration. A lymph node biopsy specimen showed Hodgkin’s disease of mixed cellularity type. He was transferred to the VA Hospital in Madison, Wisconsin, as he had increasing edema and a weight gain of 27 pounds over the next three weeks. His past medical history included thrombophlebitis in the legs with recurrent pulmonary emboli necessitating inferior venacaval ligation in October 1967. He had been receiving Coumadine for 14 months prior to this. He had a history of treated pulmonary tuberculosis 14 years earlier and an uncomplicated myocardial infarction three years earlier. Physical examination on admission revealed a middle-aged man with gross edema of the legs, sacrum and forearms. He had multiple enlarged cervical lymph nodes on both sides. There was no hepatosplenomegaly. Blood pressure was 150190 mm Hg. Urinalysis revealed 4-l- protein with occasional red blood cells in the sediment. The 24-hour urinary protein excretion was 7.1 g. The creatinine clearance was 91 ml/min. Serum albumin was 1.8 g/d1 and cholesterol 486 mg/dl. Renal venogram, abdominal lymphangiogram, hepatic and splenic scans disclosed no abnormalities. The serum was negative for antinuclear antibodies and serum C3 was 88 mg/dl. A renal biopsy was performed. The patient was treated

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IN HODGKIN’S DISEASE-MOORTHY

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Figure 1. Electron micrograph of a glomerulus showing normal looking basement membrane with extensive effacement of epithelial cell foot processes. Original magnification X 4,700, reduced by 45 per cent.

with upper mantle irradiation for a total of 4,000 rads over six weeks and prednisone, 60 mg/day. The proteinuria decreased to 2.0 g/day in two weeks and disappeared in eight weeks. He has remained protein-free during follow-up for a year, without therapy. RESULTS . Case 1. The renal biopsy specimen contained 7 glomeruli, all of which were essentially normal on light microscopy apart from showing a minimal increase in mesangial matrix material. The cells of the proximal and distal tubules were rich in lipid, and occasional tubules were filled with proteinaceous material. The blood vessels appeared normal. lmmunofluorescence microscopy for immunoglobulins G, M and A, C3 and fibrin were negative. Four glomeruli were studied by electron microscopy. In all these glomeruli the basement membrane was of normal thickness without any electron-dense deposits, but there was widespread and complete effacement of the foot processes of epithelial cells (Figure 1). Case 2. The renal biopsy specimen contained 11 glomeruli. Most glomeruli were normal on light microscopy, although in an occasional glomerulus minimal

endocapillary hypercellularity was noted. Moderate hyalinization was seen in afferent arterioles. Stains for amyloid were negative. lmmunofluorescence microscopy revealed IgM, C3 and fibrinogen in limited segmental streaks in a few glomeruli, but electron microscopic study of 5 glomeruli revealed uniformly thin, normal-appearing glomerular capillary basement membranes without electrondense deposits. Epithelial cell foot processes were effaced in all the glomeruli (Figure 2). Case 3. The renal biopsy specimen contained 8 glomeruli, one of which was sclerosed. The other glomeruli were essentially normal without any increase in cellularity and with occasional increase in mesangial matrix. lmmunofluorescence microscopy was negative for immunoglobulins G, M and A, C3 and fibrin. Electron microscopic study of 3 glomeruli revealed normal basement membranes with no dense deposits. Epithelial foof processes were effaced in all glomeruli. The patient’s serum showed the presence of macrophage migration inhibition activity as tested on guinea pig peritoneal macrophages. The area of macrophage migration was only 48 per cent of a normal human serum control.

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Figure 2. Electron micrograph of a glomerulus with complete effacement of epithelial cell foot processes. The basement membrane is free of deposits. Original magnification X 6,600, reduced by 40 per cent. BM = basement membrane. EP = epitheliai cells.

COMMENTS

The relationship of the nephrotic syndrome to Hodgkin’s disease is not clearly understood. Nephrotic syndrome occurring in the course of bronchogenic carcinoma, gastric carcinoma or carcinoma of the colon has been associated with membranous glomerulonephropathy [24]. However, the nephrotic syndrome associated with Hodgkin’s disease has seldom been observed to be secondary to membranous glomerulonephropathy. A review of the data on 35 patients with Hodgkin’s disease and nephrotic syndrome described in the literature is presented in Table I. Eight patients did not undergo renal biopsy; of the remaining 27, only light microscopic findings in the renal biopsy specimen are available in 13 patients. Eleven of these biopsy specimens were interpreted as showing lipoid nephrosis. In Case 19, the condition was said to be “proliferative glomerulonephritis” and in Case 20, there was minimal cellular proliferation and minimal thickening of basement membranes.

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In only 14 patients with Hodgkin’s disease and the nephrotic syndrome was the renal biopsy specimen examined by light, electron and/or immunofluorescence microscopy. In 12 of these patients the initial renal alterations could be classified as lipoid nephrosis. In one (Case 29) the first renal biopsy specimen was initially read as membranous glomerulonephropathy on light microscopic study only, but upon subsequent review was revised to lipoid nephrosis. A repeat renal biopsy specimen showed no abnormalities by light and immunofluorescence microscopy, and electron microscopy showed, in addition to extensive loss of epithelial foot processes, only one subepithelial deposit. In the three patients we describe here, renal biopsy specimens were interpreted as lipoid nephrosis. Immunofluorescence was negative for glomerular localization of immunoglobulins and complement except in one patient (Case 2) in whom faint, isolated streaks of IgM, C3 and fibrinogen were noted. We have noted similar streaks of IgM in the glomeruli in 17 of 31 other

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TABLE I Case No.

Nephrotic Syndrome in Patients with Hodgkin’s Disease Renal Pathology

Type of Hodgkin’s Disease

Clinical Course

Reference

Year

[II [21

1939

Unknown

No renal biopsy

Remission with radiotherapy

Unknown Unknown Unknown

No renal biopsy

Remission with radiotherapy

[31 (41

1948 1953 1957

No renal biopsy No renal biopsy

5

[51

1967

Unknown

LM: lipoid nephrosis

6 7 8 9 10 11 12

[6l

[IO1 [lOI [I1 I

1967 1967 1967 1968 1968 1968 1969

Unknown Unknown Unknown Unknown Unknown Unknown Lymphocyte

13 14

[I21 [I31

1969 1970

Unknown Granuloma

No renal biopsy No renal biopsy LM: lipoid nephrosis LM: lipoid nephrosis LM: lipoid nephrosis LM: lipoid nephrosis LM: membranous nephropathy EM: subepithelial deposits LM: lipoid nephrosis LM, EM: lipoid nephrosis

Resistant to radiotherapy Remission with cervical node excision Remission with nitrogen mustard and radiotherapy Remission with nitrogen mustard Remission with prednisone Remission with prednisone Remission with radiotherapy Remission with radiotherapy Remission with radiotherapy No information

15

[141

1971

Mixed cellularity

LM: lipoid nephrosis

16 17

[141 [I41

1971 1971

Mixed cellularity Nodular sclerosis

LM: lipoid nephrosis LM: lipoid nephrosis

18 19

[141 [151

1971 1971

Lymphocyte Unknown

20

[I51

1971

Unknown

21

[I61

1972

Mixed cellularity

No renal biopsy LM: proliferative glomerulonephritis LM: Minimal proliferation and basement membrane thickening Biopsy 1. LM: proliferative with crescents; EM: subepithelial deposits. Biopsy 2. LM: membranous; EM: subepithelial deposits; Immune.-positive for

22 23 24.

[I71 (171 I171

1972 1972 1972

Granulomatous thymoma Mixed cellularity Mixed cellularity

25

[181

1972

Mixed cellularity

lgG. P,C LM, EM: lipoi,d nephrosis LM: lipoid nephrosis LM, EM: Immuno.: lipoid nephrosis LM, EM: lipoid nephrosis

26

[I81

1972

Mixed cellularity

LM, EM: lipoid nephrosis

27

[191

1973

Mixed cellularity

LM: focal proliferative; Immuno.: IgG and IgA-fine granular pattern; EM: subepi-

-

1 2 3 4

28

29

[71

[81 [91

[201

[Zll

1973

1973

depletion

depletion

Mixed cellularity

Nodular

sclerosis

30 31 32

[221 [221 [231

1971 1971 1974

Unknown Unknown Unknown

33

Present report Present report Present report

1975

Mixed cellularity

1975

Mixed cellularity

1975

Mixed cellularity

34 35

NOTE:

LM = light microscopy;

EM = electron

microscopy;

Remission with radiotherapy and chemotherapy Resistant to prednisone; remission with radiotherapy

Biopsy 1. LM: lipoid nephrosis. Biopsy 2. LM, Immuno.: lipoid nephrosis; EM: one subepithelial deposit in 4 glomeruli LM: lipoid nephrosis No biopsy LM: lipoid nephrosis; Immuno.: granular IgG, plC deposits; EM: subendothelial granular and radiolucent material LM, EM, Immuno.: lipoid nephrosis LM, EM, Immuno.: lipoid nephrosis LM, EM, Immune.: lipoid nephrosis = immunofluorescence

Remission after two courses of radiotherapy

Remission with surgery Remission with radiotherapy Resistant to radiotherapy

thelial electron-dense deposits and electron-lucent areas Biopsy 1. LM, Immuno., EM: lipoid nephrosis. Biopsy 2. mesangial proliferation; Immuno.: IgG, IgM-positive

Immuno.

Remission with prednisone Remission with combination chemotherapy Remission with combination chemotherapy and radiotherapy Remission with chemotherapy Remission with chemotherapy and radiotherapy Remission with chemotherapy Remission with cyclophosphamide Remission with chemotherapy and radiotherapy

Remission with combination chemotherapy

Remission with radiotherapy Remission with cyclophosphamide Spontaneous

remrssron

Initial response to prednisone Remission with prednisone No information

microscopy

Remission with chemotherapy and radiotherapy Remission with chemotherapy Remission with radiotherapy and prednisone

NEPHROTIC SYNDROME IN HODGKIN’S DISEASE-MOORTHY

TABLE II

ET AL.

Course of Nephrotic Syndrome in 35 Patients with Hodgkin’s Disease* No. of Cases

Therapy

Remissionin Nephrotic Syndrome

Surgical excision Radiotherapy only

2 9

Prednisone only Chemotherapy only

5 7

Combination. prednisone therapy

radiotherapy, and chemo-

9

Cases 5, 15, 17, 20, 25, 26,28,33, 35

Spontanews

remission

1

Case 29

*Details

merular epithelial cells. Additional evidence for a circulatina lymphokine is provided by the finding of inhi-

Cases 4, 22 Cases 1, 2, 9, 10, 11, 21, 23 (resistant’in Cases 3 and 24) Cases 7, 8, 13, 30, 31 Cases 6, 14, 16, 18, 19, 27,34

unclear in Cases 12 and 32.

patients with lipoid nephrosis. Electron microscopic study of glomeruli did not reveal any electron-dense deposits. Only three patients have been described in the literature with initial renal biopsy changes other than minimal changes (Cases 12,2 1 and 27). Review of reported renal alterations associated with the nephrotic syndrome seen in Hodgkin’s disease reveals that the lesion noted most frequently was lipoid nephrosis. Membranous glomerulopathy in this situation seemingly occurs rarely. Response of the nephrotic syndrome to therapy of the Hodgkin’s lymphoma is reported in Tables I and II. The course of the nephrotic syndrome has usually paralleled the course of Hodgkin’s disease, but occasionally the nephrotic syndrome has persisted in the absence of detectable activity of Hodgkin’s disease (Cases 24 and 34). Recurrence of Hodgkin’s disease seems to cause a relapse of the nephrotic syndrome, and this can happen repeatedly [ 141. Disappearance of proteinuria in response to therapy has been rapid. Urine protein selectivity when studied (Cases 22 and 34) has been highly selective. The etiology of idiopathic minimal change nephrotic syndrome itself is unclear. The response of the nephrotic syndrome to therapy with agents like prednisone and cyclophosphamide, the remission induced during measles-virus infection and the increased incidence of pneumococcal peritonitis in patients with the nephrotic syndrome all suggest an abnormality in T lymphocytes that might result in production of a “lymphokine” injurious to glomeruli [28]. Hodgkin’s disease is considered a malignant tumor involving T lymphocytes. Cell-mediated immunity is often suppressed in Hodgkin’s disease [29], possibly as a consequence in part of recently recognized hyperactivity of suppressor T lymphocytes [30]. It is possible that an occasional clone of T lymphocytes might produce a lymphokine injurious to glomerular basement membrane or toxic to glo-

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bition of -m&ration of guinea pig peritoneal macrophages by serum from patients with Hodgkin’s disease

[311. A review of the histologic type of Hodgkin’s disease in cases in which information was available showed it to be of mixed cellularity type in 11, of nodular sclerosis in two and of the lymphocyte depletion variety in two; none was of the lymphocyte dominant type. The usual incidence of mixed cellularity type in Hodgkin’s disease is about 35 per cent [29], but in 75 per cent of the patients with the nephrotic syndrome, it is of this histologic type. Whether patients with this type of Hodgkin’s disease are immunologically unusual or distinctive is unknown. A possible difference is suggested in demonstrating that lymphocytes from patients with Hodgkin’s disease of the mixed cellularity and lymphocyte depletion types studied in mixed lymphocyte cultures stimulated subnormal responses with normal allogeneic lymphocytes more often than lymphocytes from patients with lymphocyte predominant or nodular sclerotic tumors [30]. Very few immunologic evaluations of patients with the nephrotic syndrome and Hodgkin’s disease have been performed. Sherman et al. [ 181 have shown diminished responsiveness of lymphocytes to phytohemagglutinin when incubated in patients’ serum. The serum of one of our patients had macrophage migration inhibitor activity. Further work along these lines is needed. It is likely that the nephrotic syndrome of Hodgkin’s disease is usually a variety of minimal glomerular change nephrotic syndrome related more to abnormalities of lymphocyte function, although in infrequent instances it could be related to immune complex deposition. ACKNOWLEDGMENT We wish to thank Ms. Kay Kirk and Mr. Kenneth Groehler for their able technical assistance. We also wish to thank Dr. Gregory Beirne of the Veterans Administration Hospital, Madison, Wisconsin, for allowing us to include one of his patients in this report. ADDENDUM Since preparation of this manuscript, five more cases of Hodgkin’s disease have come to our attention. Larson et al. [32], Perlin et al. [33] and Yum et al. [34] each described a patient with Hodgkin’s disease and lipoid nephrosis. Yum et al. [34] also described a second patient with Hodgkin’s disease and nephrotic syndrome with membranous glomerulonephropathy. Row et al. [35] described one ‘patient with Hodgkin’s disease and membranous glomerulonephropathy.

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REFERENCES Cornig HJ: Une forme nouvelle de la maladie de Hodgkin. Lymphogranulomatose maligne a type de nephrose lipoidique. These 547. Faculte de Medecine de Paris, 1939. 2. Rohmer P, Sacrez R: Un cas de nephrose lipoidique au tours dune maladie de Hodgkin. Strasbourg Med 108: 45, 1948. 3. Solsona-Conillera J: Linfogranulomatosis maligna. Forma monoganglionary nefrosica. Med Clin (Barcelona) 20: 37, 1953. 4. Tapie J, Laporte J, Richalens J: Syndrome nephrotique au tours de la maladie de Hodgkin-Sternberg. Presse f&d 65: 287, 1957. 5. Miller DG: The association of immune disease and malignant lymphoma. Ann Intern Med 66: 507, 1967. 6. Mehta SR, Kumar KK, Gupta ML: Hodgkin’s disease with nephrotic syndrome and erythema multiforme. J Indian Med Assoc 48: 279, 1967. 7. Paslawska-Udolf E: Przypadek nerczycy lipoidowej w przebiegu ziarnicy zlosliwej u dziecka 2-letniego. Pediatr Pol 42: 591, 1967. 8. Kiy Y: Sindrome nefrotjca associada a doenca de Hodgkin. Rev Hosp Clin Fat Med Sao Paul0 22: 186, 1967. 9. Brodovsky HS, Samuels ML, Migliore PJ, et al.: Chronic lymphocytic leukemia, Hodgkin’s disease and the nephrotic syndrome. Arch Intern Med 121: 71, 1968. 10. Hamburger J, Richet G, Crosnier J, et al.: Nephrology, vol 1, Philadelphia, W. B. Saunders Co., 1968, p 226. 11. Hardin JG Jr, Coker AS, Blanton JH: Medicine grand rounds. South Med J 62: 1111, 1969. 12. Kiely JM, Wagoner RD, Holley KE: Renal complications of lymphoma. Ann Intern Med 71: 1159, 1969. 13. Ghosh (Banerji) L, Muehrcke R: The nephrotic syndrome: a prodrome to lymphoma. Ann Intern Med 72: 379, 1970. 14. Plager J, Stutzman L: Acute nephrotic syndrome as a manifestation of active Hodgkin’s disease. Am J Med 50: 56, 1971. 15. Lowry WS, Munzenrider JE, Lynch GA: Nephrotic syndrome in Hodgkin’s disease. Lancet 1: 1127, 1971. 16. Froom DW, Franklin WA, Hano JE. et al.: Immune deposits in Hodgkin’s disease with nephrotic syndrome. Arch Pathol 94: 547, 1972. 17. Hansen HE, Skov PE, Askjaer SA, et al.: Hodgkin’s disease associated with nephrotic syndrome without kidney lesion. Acta Med Stand 191: 307, 1972.

18. 19. 20. 21. 22. 23.

24. 25.

26.

27.

28. 29.

30.

31.

32. 33.

34. 35.

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Sherman RL, Susin M, Weksler ME, et al.: Lipoid nephrosis in Hodgkin’s disease. Am J Med 52: 699, 1972. Lokich JJ. Galvenek EG, Moloney WC: Nephrosis of Hodgkin’s disease. Arch Intern Med 132: 597, 1973. Hyman LR, Burkholder PM, Joo PA, et al.: Malignant lymphoma and nephrotic syndrome. J Pediatr 82: 207, 1973. Case Records of the Massachusetts General Hospital. Case 49, 1973. N Engl J Med 289: 1241, 1973. Jackson RH, 00 M: Nephrotic syndrome with Hodgkin’s disease. Lancet 2: 821, 1971. Sharma HM, Hurtubise PE, Stevenson TD: The nephrotic syndrome in Hodgkin’s disease. Lab invest 30: 404, 1974. 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. Burkholder PM: Atlas of Human Glomerular Pathology. Hagerstown, Md., Hoeber Medical Division, Harper & Row, 1974. David JR, David R: In Vitro Methods in Cell Mediated Immunity. (Bloom BR, Glade PR, eds), New York, Academic Press, 1971, p 249. Shalhoub RJ: Pathogenesis of lipoid nephrosis: a disorder of T-cell function. Lancet 2: 556, 1974. O’Conor GT, Correa P, Christine B, et al.: International Symposium on Hodgkin’s Disease, NCI Monographs, No. 36, 1973, p 7. Twomey JJ, Laughter AH, Farrow S, et al.: Hodgkin’s disease: an immuno-depleting and immunosuppressive disorder. J Clin Invest 56: 467, 1975. Cohen S: Serum migration-inhibitory activity in patients with lymphoproliferative diseases. N Engl J Med 290: 882, 1974. Larson LS, Fritz RD: Nephrotic syndrome in association with Hodgkin’s disease. Wis Med J 75: Sl4, 1976. Perlin E, Powers JM, Dickson LG, et al.: The nephrotic syndrome in Hodgkin’s disease. Med Ann DC 41: 354, 1972. Yum MN, Edwards JL, Kleit S: Glomerular lesions in Hodgkin’s disease. Arch Pathol 99: 645, 1975. Row PG, Cameron JG, Turner DR. et al.: Membranous nephropathy: long-term follow-up and association with neoplasia. Q J Med 174; 207, 1975.

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