CL.INICAL.
IMMUNOLOGY
AND
IMMUNOPATHOLOGY
6, 341-346
(1976)
Thyroid Antigen-Antibody SEAN
O’REGAN,~
JEAN-PIERRE
Nephritis’
JACK S. C. FONG,* BERNARD S. KAPLAN,~ DE CHADAR~IAN,~ NORMAND LAPOINTE,~ AND
N.
KEITH
DRUMMOND~
The 2Department of Nephrology and 3Department of Pathology, Montreal Children’s Hospital, and the ‘Department of Immunology, Ste. Justine Hospital. Montreal, Canada Received A patient cence. and
with autoimmune electron microscopic
epimembranous onstrable
nephropathy. in her
glomeruli
February
thyroiditis developed examination of Thyroglobulin
by
2, 1976
indirect
and
nephrosis. renal biopsy
thyroid
Light, tissue
microsomal
immunofluorescence
immunofluoresdemonstrated
antigen
were
dem-
microscopy.
INTRODUCTION
In many animal species specific antigens bound to antibody have been identified in the glomeruli by immunofluorescence microscopy. However, although immunoglobulin deposition has been detected in many human glomerular diseases, there has been only limited success in identifying specific antigens in conditions where immune complex injury is suspected. Those that have been identified are mainly bacterial (1,2), viral (3), or fungal (4) in origin. In this report a patient is presented who had Hashimoto’s thyroiditis and the nephrotic syndrome; thyroglobulin and thyroid microsomal antigens were detected in her glomeruli by indirect immunofluorescence microscopy. CASE HISTORY
A 15year-old white girl presented in 1970 with clinical and laboratory features of thyrotoxicosis. She was treated with propylthiouracil and thyroid extract. Enlargement of the thyroid gland was initially present, and by 1974 the gland had increased in size sufficiently to cause symptomatic laryngeal compression. In May 1974 a partial thyroidectomy was done and propylithiouracil therapy was stopped. Pathologic examination of the gland confirmed the diagnosis of Hashimoto’s thyroiditis. Since that time she has remained euthyroid on 0.2 mg L-thyroxine daily. In June 1975 she presented herself to her physician with ankle swelling and proteinuria. Physical examination revealed only pedal edema. She was normotensive. Her weight at that time was 65 kg. Laboratory studies were as follows: Hgb 13 g/dl, PBI 4 &dl, creatinine clearance 89 mYmin/m2/24 hr, serum Na,K,Cl, and BUN were normal, serum calcium 8.2 mg/dl and phosphate 4.1 mg/dl, serum albumin 1.3 to 4.1 g/dl, serum globulin 1.4-2.4 g/dl, 24hr urine protein excretion 2-5 g/24 hr, serum cholesterol 470-566 mg/dl, serum C3 105 mg/dl. Urine cultures were negative. Intravenous urogram was normal. A diagnosis of the nephrotic syndrome was made and she was treated with prednisone in a dose of 20 mg ’ Supported
in part
by
Medical
Research
Council
of Canada
341 Copyright @ 1976 by Academic Press. Inc. All rights of reproduction in any form reserved
Grant
MA-1579.
342
O’REGAN
ET AL
q.i.d. She appeared to respond to this therapy initially. Urine protein excretion fell to 100-200 mg/24 hr on 3 consecutive determinations. The serum albumin rose to 4.1 g/d1 and she lost 7 kg in weight. This improvement was shortlived and she again developed massive proteinuria, edema, and hypoalbuminemia within 6 weeks. After 1 month of daily therapy she was put on 80 mg of prednisone on alternate days. She was referred to the Montreal Children’s Hospital for further evaluation in July 1975. On examination her weight was 69 kg; she had mild cushingoid facies with acne, and abdominal striae. There was mild pitting edema at her ankles. The right lobe of her thyroid gland was readily palpable. The serum albumin was 2.3 g/d1 and the urine protein excretion was 2.8 g/24 hr. Serum cholesterol was 400 mg/dl and triglycerides 290 mg/dl. Red cells, red cell casts, and some granular casts were present in the urinary sediment. Urine cultures were negative. LABORATORY
STUDIES
One week after termination of steroid therapy, studies of her immune status were done (Table 1) and a renal biopsy was performed. Renal tissue was examined under light, immunofluorescence, and electron microscopy. Tissue for light microscopy was fixed in 2% glutaraldehyde and embedded in paraffin. Four micra sections were stained with hemalum phloxine saffron, periodic acid-Schiff (PAS), Masson trichrome and other selected stains. Tissue was also snap-frozen in isopentane chilled in dry ice. Three micrasections were cut on a cryostat at -20°C. After washing in phosphate-buffered saline pH 7.2, sections were stained with fluorescein isothiocyanate (FITC) labeled rab-
TABLE LABORATORY
Serologic tests Antinuclear factor Rheumatoid factor Clq, Cl esterase inhibitor c3 c4 Antithyroid antibody” thyroglobulin microsomal Serum IgG W W Endocrine test+’ TSH( 10 pU/ml) T4(4- 12.8 &dl) T3(100-230 ng/dl) LATS
1 DATA
Negative Negative Normal 115 mg% (normal) 25 mg% (normal) 1/102,400 1125,600 160 mg/dl (decreased) 225 mg/dl 56 mg/dl July 8, 1975
Aug. 19-21. 1975
21 7.0 53
50 6.5 6.6 Negative
D Other antibodies sought against adrenal, smooth muscle and gastric parietal cells were not detected. b Normal values given in parentheses.
THYROID
ANTIGEN-ANTIBODY
NEPHRITIS
343
bit antisera to human IgG,IgA,IgM,IgE,C4,C3 and fibrin.5 They were then washed again in PBS prior to mounting. Sections were also incubated with purified rabbit antisera to either human thyroglobulin or to human thyroid microsomal antigen: washed three times in PBS, and stained with an FITC labeled goat antiserum to rabbit IgG.7 Renal biopsy sections from other patients with and without glomerular immunoglobulin and complement deposition (minimal lesion nephrosis, hypocomplementemic glomerulonephritis, lupus nephritis, idiopathic epimembranous nephropathy, poststreptococcal glomerulonephritis) were stained in a similar manner. Although the antithyroglobulin antiserum was monospecific the antimicrosomal antigen antiserum (titer 1:500,000) contained a titer of 1: 100 of antithyroglobulin. Therefore, tissue was stained with a 1:200 dilution of this antiserum to eliminate possible staining with the antithyroglobulin. Electron microscopy. Tissue for electron microscopy study was sliced into 0.5- 1 mm cubes, fixed in 2% glutaraldehyde, and postfixed in osmium tetroxide (1%). The tissue was washed in phosphate buffer and dehydrated in graded alcohols (70%, 90%, and absolute), was further treated with propylene oxide, and left in a 50/50 mixture of propylene oxide and Epon overnight. The specimens were embedded in Epon. Ultrathin sections were cut on an ultramicrotome, doubly stained with uranyl acetate and lead citrate, and examined using a Philips EM-201 electron microscope. RESULTS Light microscopy. Tissue from both cortex and medulla was obtained. The interstitial tissue was essentially normal; proteinaceous casts were present in the lumina of some of the cortical and medullary tubules. Seven glomeruli were present. The most striking change was a moderate diffuse thickening of the glomerular basement membrane of each of the glomeruli as seen with hematoxylin-eosin and PAS staining. With periodic acid silver methenamine staining the basement membrane proper was of normal thickness in some areas and moderately thickened in others. In many loops a regular series of saw tooth projections of the basement membrane was present along the epithelial aspect. These findings are characteristic of early membranous glomerulopathy (membranous glomerulonephritis). Some of the capillary loops were moderately ectatic; there was swelling of the nuclei and cytoplasm of some of the visceral epithelial cells. There was focal segmental increase in mesangial matrix of mild degree, and in several glomeruli this was associated with a slight increase in the number of mesangial cells. Review of the thyroid tissue obtained at the initial partial thyroidectomy s FITC conjugated rabbit antisera to human IgM, IgG, IgA, C4, C3, and fibrin were obtained from Meloy Laboratories Inc., Biological Products Division, Springfield, Va. 22151. 8 Purified rabbit antisera to human thyroglobulin and human thyroid microsomal antigen were kindly provided by Dr. Joseph P. Kriss, Director, Department of Nuclear Medicine, Stanford University School of Medicine, Stanford, Calif. ’ FITC conjugated goat anti-rabbit IgG was obtained from Meloy Laboratories Inc., Biological Products Division, Springfield, Va. 22151.
344
O’KEGAN
ET AL
showed massive lymphocytic and plasmocytic infiltration of the gland. Many prominent lymphoid follicles with active germinal centers were present. Most thyroid follicles were undergoing active destruction and occasional giant cells were noted in the vicinity of disrupted follicles. There was focal oxyphilic alteration of the lining epithelial cells. Immunofluorescent microscopy. There was granular deposition of IgG, C3, and C4 along all capillary loops; there was no IgM, IgA, or fibrin deposition. There was marked fluorescence with both the rabbit antihuman thyroglobulin (Fig. 1) and rabbit antihuman microsomal antigen, even in a dilution of I:200 (Fig. 21, in the same pattern as that of the IgG and C3. Sections from the other patients with various glomerulopathies showed no fluorescence when stained for thyroglobulin and thyroid microsomal antigen. Electron microscopy. Ultrastructural study of one glomerulus confirmed the findings noted by light microscopy. Numerous finely granular relatively discrete electron dense deposits were seen on the epithelial side of the basement membrane of the glomerular capillary wall. Projections of the basement membrane separated the deposits and tended to encircle and incorporate them within the capillary wall. Moderate epithelial and endothelial cell swelhng was noted. Occa-
FIG.
I. Glomerular
distribution
of thyroglobulin
by immunofluorescence
microscopy
THYROID
FIG. 2. Glomerular
sional polymorphs conspicuous.
distribution
ANTIGEN
-ANTIBODY
345
NEPHRITIS
of thyroid microsomal antigen by immunofluorescence
were seen within capillary lumina.
Mesangial
mickoscopy.
changes were not
DISCUSSION
This patient developed the nephrotic syndrome due to epimembranous glomerulopathy during the course of chronic thyroiditis. The finding of a palpable thyroid gland while her renal disease was active raises the possibility that thyroid tissue may have served as a continuous source of antigen for the formation of circulating immune complexes consisting of thyroid constituents and antibody. The evidence that circulating complexes are formed during the course of Hashimoto’s thyroiditis is, although circumstantial, very strong. Anticomplementary activity is present in the sera of the majority of patients with Hashimoto’s thyroiditis (5). Immune complex deposition in the thyroid follicular basement membrane has also been observed in this disease (6). Autoimmune thyroiditis and nephritis due to glomerular deposition of immunoglobulin, complement, and thyroglobulin has been produced in rabbits who had high circulating titers of antithyroglobulin antibody (7,s). A surprising aspect of our patient’s disease was the finding of positive glomerular staining for both thyroglobulin and thyroid microsomal antigen. Similar deposition of two different antigens bound to specific antibody has been observed in (NZB/NZW) F, hybrid mice who have both DNA-antiDNA complexes and Gross viral antigen-anti-Gross-viral antigen complexes in their glomeruli (9). Since thyroglobulin-antithyroglobulin antibody complexes do not readily fix complement (lo), the complement observed in her glomeruli is more likely to have fixed to complexes containing antibody to the microsomal antigen.
346
O’REGAN
ETAL.
The influence of drugs on the thyroid gland is of great interest. Nephro& with thyroid enlargement has been observed after cessation of D-penicillamine therapy for rheumatoid arthritis (11). Penicillamine is known to cause membranous nephropathy (12) probably by acting as a haptene against which antiies are produced with resultant immune complex production. Propylthiouracil may induce a lupus-like syndrome with associated renal disease (13). In our patient no propylthiouracil had been taken for more than 1 year prior to the onset of her renal disease. The management of patients such as this presents a dilemma. Several courses of action may be considered. One could await cessation of the thyroiditis, which may last many years, and hope that no deterioration occurs in renal function; alternatively one may remove all remaining thyroid tissue with a view to eliminating the antigen source and, thus, terminating formation of the nephritogenic immune complexes. ADDENDUM Further clinical course. A total thyroidectomy was done. It was hoped that this would result in cessation of production of nephritogenic complexes. However 3 months after operation the patient still has marked proteinuria. Comment. The failure to date of this course of action raises important questions regarding the association of nephrosis and immune complex deposition in membranous nephropathy. Couser et al. (14) have reported the failure of resolution of nephrosis with a tumor-associated membranous nephropathy after removal of the source of antigen and resolution of glomerular immune complex deposition. Both states are associated with an altered immunological state. REFERENCES 1. Kaufman, D. B., and McIntosh, R., Amer. J. Med. 50, 262, 1971. 2. Bolton, W. K., Sande, M. A., Normansell, D. E., Sturgill, B. C., and Westervelt. F. B,. Jr.. Amer. J. Med. 59, 417, 1975. 3. Dayan, A. D., and Stokes, M. I., Brir. Med. J. 2, 375, 1972. 4. Chesney, R. W., O’Regan, S., Guyda, H. J., and Drummond, K, N., Cl& Nephrol. 5,232, 1976. 5. Calder, E. A., Penhale, W. J., Barnes, E. W., and Irvine, W. J.. &it. Med. J. 2, 30, 1974. 6. Kalderon, A. E., Bogaars, H. A., and Diamond, I., Amer. J. Med. 55, 485, 1973. 7. Weigle, W. O., and High, G. J., J. Zmmunol. 98, 1105, 1967. 8. Weigle, W. O., and Nakamura, R. M., Clin. Exp. Zmmunol. 4, 645, 1%9. 9. Dixon, F. J., Oldstone, M. B. A., and Tonietti, G.. J. Exp, med. 134, 65s, 1971. IO. Hay, F. C.. and Torrigani, G., Clin. Exp. Zmmunol. 16, 5’17, 1974. I I. Henningsen, B., Maintz, J., Basedown, M.. und Harder& H., Dtsch. Med. Wochenschr. 98, 1768, 1973. 12. Haas, Von P.. und Wendt, H., Wien. Med. Wochenschr. 124, 333, 1974. 13. Amrhein, J. A., Kenny, F. M., and Ross, D., J. Pediatr. 76, 54, 1970. 14. Couser, W. G., Wagonfeld, J. B., Spargo, B. H., and Lewis, E. J., Amer. J. Med. 57,962, 1974.
IMMUNOLOGY
AND
IMMUNOPATHOLOGY
6, 341-346
(1976)
Thyroid Antigen-Antibody SEAN
O’REGAN,~
JEAN-PIERRE
Nephritis’
JACK S. C. FONG,* BERNARD S. KAPLAN,~ DE CHADAR~IAN,~ NORMAND LAPOINTE,~ AND
N.
KEITH
DRUMMOND~
The 2Department of Nephrology and 3Department of Pathology, Montreal Children’s Hospital, and the ‘Department of Immunology, Ste. Justine Hospital. Montreal, Canada Received A patient cence. and
with autoimmune electron microscopic
epimembranous onstrable
nephropathy. in her
glomeruli
February
thyroiditis developed examination of Thyroglobulin
by
2, 1976
indirect
and
nephrosis. renal biopsy
thyroid
Light, tissue
microsomal
immunofluorescence
immunofluoresdemonstrated
antigen
were
dem-
microscopy.
INTRODUCTION
In many animal species specific antigens bound to antibody have been identified in the glomeruli by immunofluorescence microscopy. However, although immunoglobulin deposition has been detected in many human glomerular diseases, there has been only limited success in identifying specific antigens in conditions where immune complex injury is suspected. Those that have been identified are mainly bacterial (1,2), viral (3), or fungal (4) in origin. In this report a patient is presented who had Hashimoto’s thyroiditis and the nephrotic syndrome; thyroglobulin and thyroid microsomal antigens were detected in her glomeruli by indirect immunofluorescence microscopy. CASE HISTORY
A 15year-old white girl presented in 1970 with clinical and laboratory features of thyrotoxicosis. She was treated with propylthiouracil and thyroid extract. Enlargement of the thyroid gland was initially present, and by 1974 the gland had increased in size sufficiently to cause symptomatic laryngeal compression. In May 1974 a partial thyroidectomy was done and propylithiouracil therapy was stopped. Pathologic examination of the gland confirmed the diagnosis of Hashimoto’s thyroiditis. Since that time she has remained euthyroid on 0.2 mg L-thyroxine daily. In June 1975 she presented herself to her physician with ankle swelling and proteinuria. Physical examination revealed only pedal edema. She was normotensive. Her weight at that time was 65 kg. Laboratory studies were as follows: Hgb 13 g/dl, PBI 4 &dl, creatinine clearance 89 mYmin/m2/24 hr, serum Na,K,Cl, and BUN were normal, serum calcium 8.2 mg/dl and phosphate 4.1 mg/dl, serum albumin 1.3 to 4.1 g/dl, serum globulin 1.4-2.4 g/dl, 24hr urine protein excretion 2-5 g/24 hr, serum cholesterol 470-566 mg/dl, serum C3 105 mg/dl. Urine cultures were negative. Intravenous urogram was normal. A diagnosis of the nephrotic syndrome was made and she was treated with prednisone in a dose of 20 mg ’ Supported
in part
by
Medical
Research
Council
of Canada
341 Copyright @ 1976 by Academic Press. Inc. All rights of reproduction in any form reserved
Grant
MA-1579.
342
O’REGAN
ET AL
q.i.d. She appeared to respond to this therapy initially. Urine protein excretion fell to 100-200 mg/24 hr on 3 consecutive determinations. The serum albumin rose to 4.1 g/d1 and she lost 7 kg in weight. This improvement was shortlived and she again developed massive proteinuria, edema, and hypoalbuminemia within 6 weeks. After 1 month of daily therapy she was put on 80 mg of prednisone on alternate days. She was referred to the Montreal Children’s Hospital for further evaluation in July 1975. On examination her weight was 69 kg; she had mild cushingoid facies with acne, and abdominal striae. There was mild pitting edema at her ankles. The right lobe of her thyroid gland was readily palpable. The serum albumin was 2.3 g/d1 and the urine protein excretion was 2.8 g/24 hr. Serum cholesterol was 400 mg/dl and triglycerides 290 mg/dl. Red cells, red cell casts, and some granular casts were present in the urinary sediment. Urine cultures were negative. LABORATORY
STUDIES
One week after termination of steroid therapy, studies of her immune status were done (Table 1) and a renal biopsy was performed. Renal tissue was examined under light, immunofluorescence, and electron microscopy. Tissue for light microscopy was fixed in 2% glutaraldehyde and embedded in paraffin. Four micra sections were stained with hemalum phloxine saffron, periodic acid-Schiff (PAS), Masson trichrome and other selected stains. Tissue was also snap-frozen in isopentane chilled in dry ice. Three micrasections were cut on a cryostat at -20°C. After washing in phosphate-buffered saline pH 7.2, sections were stained with fluorescein isothiocyanate (FITC) labeled rab-
TABLE LABORATORY
Serologic tests Antinuclear factor Rheumatoid factor Clq, Cl esterase inhibitor c3 c4 Antithyroid antibody” thyroglobulin microsomal Serum IgG W W Endocrine test+’ TSH( 10 pU/ml) T4(4- 12.8 &dl) T3(100-230 ng/dl) LATS
1 DATA
Negative Negative Normal 115 mg% (normal) 25 mg% (normal) 1/102,400 1125,600 160 mg/dl (decreased) 225 mg/dl 56 mg/dl July 8, 1975
Aug. 19-21. 1975
21 7.0 53
50 6.5 6.6 Negative
D Other antibodies sought against adrenal, smooth muscle and gastric parietal cells were not detected. b Normal values given in parentheses.
THYROID
ANTIGEN-ANTIBODY
NEPHRITIS
343
bit antisera to human IgG,IgA,IgM,IgE,C4,C3 and fibrin.5 They were then washed again in PBS prior to mounting. Sections were also incubated with purified rabbit antisera to either human thyroglobulin or to human thyroid microsomal antigen: washed three times in PBS, and stained with an FITC labeled goat antiserum to rabbit IgG.7 Renal biopsy sections from other patients with and without glomerular immunoglobulin and complement deposition (minimal lesion nephrosis, hypocomplementemic glomerulonephritis, lupus nephritis, idiopathic epimembranous nephropathy, poststreptococcal glomerulonephritis) were stained in a similar manner. Although the antithyroglobulin antiserum was monospecific the antimicrosomal antigen antiserum (titer 1:500,000) contained a titer of 1: 100 of antithyroglobulin. Therefore, tissue was stained with a 1:200 dilution of this antiserum to eliminate possible staining with the antithyroglobulin. Electron microscopy. Tissue for electron microscopy study was sliced into 0.5- 1 mm cubes, fixed in 2% glutaraldehyde, and postfixed in osmium tetroxide (1%). The tissue was washed in phosphate buffer and dehydrated in graded alcohols (70%, 90%, and absolute), was further treated with propylene oxide, and left in a 50/50 mixture of propylene oxide and Epon overnight. The specimens were embedded in Epon. Ultrathin sections were cut on an ultramicrotome, doubly stained with uranyl acetate and lead citrate, and examined using a Philips EM-201 electron microscope. RESULTS Light microscopy. Tissue from both cortex and medulla was obtained. The interstitial tissue was essentially normal; proteinaceous casts were present in the lumina of some of the cortical and medullary tubules. Seven glomeruli were present. The most striking change was a moderate diffuse thickening of the glomerular basement membrane of each of the glomeruli as seen with hematoxylin-eosin and PAS staining. With periodic acid silver methenamine staining the basement membrane proper was of normal thickness in some areas and moderately thickened in others. In many loops a regular series of saw tooth projections of the basement membrane was present along the epithelial aspect. These findings are characteristic of early membranous glomerulopathy (membranous glomerulonephritis). Some of the capillary loops were moderately ectatic; there was swelling of the nuclei and cytoplasm of some of the visceral epithelial cells. There was focal segmental increase in mesangial matrix of mild degree, and in several glomeruli this was associated with a slight increase in the number of mesangial cells. Review of the thyroid tissue obtained at the initial partial thyroidectomy s FITC conjugated rabbit antisera to human IgM, IgG, IgA, C4, C3, and fibrin were obtained from Meloy Laboratories Inc., Biological Products Division, Springfield, Va. 22151. 8 Purified rabbit antisera to human thyroglobulin and human thyroid microsomal antigen were kindly provided by Dr. Joseph P. Kriss, Director, Department of Nuclear Medicine, Stanford University School of Medicine, Stanford, Calif. ’ FITC conjugated goat anti-rabbit IgG was obtained from Meloy Laboratories Inc., Biological Products Division, Springfield, Va. 22151.
344
O’KEGAN
ET AL
showed massive lymphocytic and plasmocytic infiltration of the gland. Many prominent lymphoid follicles with active germinal centers were present. Most thyroid follicles were undergoing active destruction and occasional giant cells were noted in the vicinity of disrupted follicles. There was focal oxyphilic alteration of the lining epithelial cells. Immunofluorescent microscopy. There was granular deposition of IgG, C3, and C4 along all capillary loops; there was no IgM, IgA, or fibrin deposition. There was marked fluorescence with both the rabbit antihuman thyroglobulin (Fig. 1) and rabbit antihuman microsomal antigen, even in a dilution of I:200 (Fig. 21, in the same pattern as that of the IgG and C3. Sections from the other patients with various glomerulopathies showed no fluorescence when stained for thyroglobulin and thyroid microsomal antigen. Electron microscopy. Ultrastructural study of one glomerulus confirmed the findings noted by light microscopy. Numerous finely granular relatively discrete electron dense deposits were seen on the epithelial side of the basement membrane of the glomerular capillary wall. Projections of the basement membrane separated the deposits and tended to encircle and incorporate them within the capillary wall. Moderate epithelial and endothelial cell swelhng was noted. Occa-
FIG.
I. Glomerular
distribution
of thyroglobulin
by immunofluorescence
microscopy
THYROID
FIG. 2. Glomerular
sional polymorphs conspicuous.
distribution
ANTIGEN
-ANTIBODY
345
NEPHRITIS
of thyroid microsomal antigen by immunofluorescence
were seen within capillary lumina.
Mesangial
mickoscopy.
changes were not
DISCUSSION
This patient developed the nephrotic syndrome due to epimembranous glomerulopathy during the course of chronic thyroiditis. The finding of a palpable thyroid gland while her renal disease was active raises the possibility that thyroid tissue may have served as a continuous source of antigen for the formation of circulating immune complexes consisting of thyroid constituents and antibody. The evidence that circulating complexes are formed during the course of Hashimoto’s thyroiditis is, although circumstantial, very strong. Anticomplementary activity is present in the sera of the majority of patients with Hashimoto’s thyroiditis (5). Immune complex deposition in the thyroid follicular basement membrane has also been observed in this disease (6). Autoimmune thyroiditis and nephritis due to glomerular deposition of immunoglobulin, complement, and thyroglobulin has been produced in rabbits who had high circulating titers of antithyroglobulin antibody (7,s). A surprising aspect of our patient’s disease was the finding of positive glomerular staining for both thyroglobulin and thyroid microsomal antigen. Similar deposition of two different antigens bound to specific antibody has been observed in (NZB/NZW) F, hybrid mice who have both DNA-antiDNA complexes and Gross viral antigen-anti-Gross-viral antigen complexes in their glomeruli (9). Since thyroglobulin-antithyroglobulin antibody complexes do not readily fix complement (lo), the complement observed in her glomeruli is more likely to have fixed to complexes containing antibody to the microsomal antigen.
346
O’REGAN
ETAL.
The influence of drugs on the thyroid gland is of great interest. Nephro& with thyroid enlargement has been observed after cessation of D-penicillamine therapy for rheumatoid arthritis (11). Penicillamine is known to cause membranous nephropathy (12) probably by acting as a haptene against which antiies are produced with resultant immune complex production. Propylthiouracil may induce a lupus-like syndrome with associated renal disease (13). In our patient no propylthiouracil had been taken for more than 1 year prior to the onset of her renal disease. The management of patients such as this presents a dilemma. Several courses of action may be considered. One could await cessation of the thyroiditis, which may last many years, and hope that no deterioration occurs in renal function; alternatively one may remove all remaining thyroid tissue with a view to eliminating the antigen source and, thus, terminating formation of the nephritogenic immune complexes. ADDENDUM Further clinical course. A total thyroidectomy was done. It was hoped that this would result in cessation of production of nephritogenic complexes. However 3 months after operation the patient still has marked proteinuria. Comment. The failure to date of this course of action raises important questions regarding the association of nephrosis and immune complex deposition in membranous nephropathy. Couser et al. (14) have reported the failure of resolution of nephrosis with a tumor-associated membranous nephropathy after removal of the source of antigen and resolution of glomerular immune complex deposition. Both states are associated with an altered immunological state. REFERENCES 1. Kaufman, D. B., and McIntosh, R., Amer. J. Med. 50, 262, 1971. 2. Bolton, W. K., Sande, M. A., Normansell, D. E., Sturgill, B. C., and Westervelt. F. B,. Jr.. Amer. J. Med. 59, 417, 1975. 3. Dayan, A. D., and Stokes, M. I., Brir. Med. J. 2, 375, 1972. 4. Chesney, R. W., O’Regan, S., Guyda, H. J., and Drummond, K, N., Cl& Nephrol. 5,232, 1976. 5. Calder, E. A., Penhale, W. J., Barnes, E. W., and Irvine, W. J.. &it. Med. J. 2, 30, 1974. 6. Kalderon, A. E., Bogaars, H. A., and Diamond, I., Amer. J. Med. 55, 485, 1973. 7. Weigle, W. O., and High, G. J., J. Zmmunol. 98, 1105, 1967. 8. Weigle, W. O., and Nakamura, R. M., Clin. Exp. Zmmunol. 4, 645, 1%9. 9. Dixon, F. J., Oldstone, M. B. A., and Tonietti, G.. J. Exp, med. 134, 65s, 1971. IO. Hay, F. C.. and Torrigani, G., Clin. Exp. Zmmunol. 16, 5’17, 1974. I I. Henningsen, B., Maintz, J., Basedown, M.. und Harder& H., Dtsch. Med. Wochenschr. 98, 1768, 1973. 12. Haas, Von P.. und Wendt, H., Wien. Med. Wochenschr. 124, 333, 1974. 13. Amrhein, J. A., Kenny, F. M., and Ross, D., J. Pediatr. 76, 54, 1970. 14. Couser, W. G., Wagonfeld, J. B., Spargo, B. H., and Lewis, E. J., Amer. J. Med. 57,962, 1974.
