The American Journal of PATHOLOGY August 1978 * Volume 92, Number 2
Characterization of Feline Glomerulonephritis Associated With Viral-Induced Hematopoietic Neoplasms Alan D. Glick, MD, Robert G. Horn, MD, and Myron Holscher, DVM, PhD
Light, electron, and immunofluorescence microscopy on tissues from 63 domestic cats revealed that glomerulonephritis occurred in almost one third of cats with hematopoietic neoplasms of the type linked with feline leukemia virus (FeLV). Glomerular lesions were of the immune complex type with subepithelial, subendothelial, and mesangial dense deposits and reticular aggregates, similar to the nephropathy associated with systemic lupus erythematosus in humans. Evidence that the glomerular lesions may be viral-induced raises the possibility of similar pathogenetic mechanisms in human disease. (Am J Pathol 92:321-332. 1978)
SPONT.A-NEOUS GLOMERULONEPHRITIS in domestic cats is unusual. -3 However, a number of reports have indicated a high percentage of cases of feline glomerulonephritis to be associated with feline leukemia virus (FeLV) infection 4 and especially with hematopoietic neoplasms induced by feline leukemia virus.5'6 Glomerulonephritis has also been show n to be associated with experimentally produced feline leukemia.7 Feline hematopoietic disorders of various types, especially malignant lvmphomas, are relatively common in the cat,8 and these neoplasms are definitely linked with the FeLV, an RNA oncornavirus similar to other RNA tumor viruses. The pathogenesis of glomerulonephritis associated Xwith feline malignant lvmphoma or leukemia max involve the deposition of immune complexes of viral, or viral-induced, antigen and host antibody; viral antigen-antibody complexes have been found in the glomeruli of some cats infected wvith feline leukemia virus.9 The FeLV is known to From the Department of Pathology. Vanderbilt University School of Medicine, and the \eterans Xdministration Hospital. Nashville. Tennessee Xccepted for publication \March 2.3. 197,8 Address reprint requests to Alan D Glick. MD. Department of Pathology. School of Medicine. Vanderbilt University. Nashsille, TN 37232 321 0002-9440/78/081 0-0321$01 .00
322
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American Journal of Pathology
infect cells of other species, including man, as well as to be transmitted horizontally among cats.7 The possibility exists that this virus may be responsible for some cases of idiopathic glomerulonephritis in man. Although some of the glomerulonephritis cases associated with FeLV have been characterized as membranous,5 the lesions have been incompletely described. The present study was undertaken to determine the incidence and pathologic characteristics of immune complex glomerulonephritis occurring among a large series of cats with hematopoietic neoplasms. Materials and Methods Tissues from 63 domestic cats suspected of having hematopoietic neoplasms were obtained from local veterinary sources. Complete autopsies were performed on most cats to determine the extent of involvement by the neoplasms. For light microscopy, representative tissues from all major organs and all gross lesions were fixed in formalin and surveyed with hematoxylin and eosin (H&E) stained sections. Tissues from bone marrow, lvmph nodes, and spleen were fixed in B5 or Zenker's fixativ es, and sections were stained with periodic acid-Schiff (PAS) stains. Kidnev sections were examined by H&E, PAS, and the periodate methenamine silver (PANIS) stain, according to Jones' method.'0 For electron microscopy, specimens were prepared by methods previously described." Representative glomeruli from all kidney specimens and samples of all neoplasms were examined by electron microscopy. In selected cases, renal tissues were examined for deposits of immunogiobulin by the direct staining of cryostat sections of unfixed renal cortex with fluoresceinated anticat IgG obtained from Nlicrobiological Associates (Bethesda, Md.).
Results General Features
Of the 63 cats examined, 45 (71.4%) were found to have hematopoietic neoplasms (Table 1); 38 of the 45 had malignant lymphoma, and 7 had myeloproliferative disorders. Eighteen of the 63 cats were found to have no evidence of hematologic malignancies, although 2 of them had positive fluorescent antibody tests for FeLV. Fifteen cases of glomerulonephritis were found (23.8% of the total). Twelve cases of glomerulonephritis were found in cats with malignant lymphoma, and 2 were found in cats with -myeloproliferative disorders; 1 of the cats without evidence of a neoplasm had glomerulonephritis, and this case was positive for FeLV. These results indicate that glomerulonephritis occurred in 32% of cats with FeLVinduced disease. Chaterizatiai of Hematopoic Neopbsam
The types of malignant lymphoma and myeloproliferative diseases are indicated in Table 2. Twenty-two cases of alimentary lymphosarcoma, 8 cases of thymic lymphosarcoma, and 4 cases of multicentric lymphosar-
Vol. 92, No. 2 August 1978
FELINE GLOMERULONEPHRITIS
323
Table 1-Feline Hematopoietic Neoplasms and Glomerulonephritis
Diagnosis
No. of cats
No. of cases of glomerulonephritis
38 7 2 16 63
12 2 1 0 15
Malignant lymphoma Myeloproliferative disorder Positive FA*; no neoplasm Negative for FeLV disease Totals
Fluorescent antibody test for FeLV group specific antigens in blood
coma were found. Four cases were incompletely classified due to inadequate tissue sampling. Light microscopy indicated that most thymic lymphomas were composed of small transformed lymphocytes (Iymphoblastic) and most alimentary lymphomas were composed of cleaved (prolvmphocytic) cells or transformed cells (Table 2). Three alimentary cases demonstrated follicular nodulation similar to cases of human follicular center cell lvmphoma.'2 Four cases, including one multicentric case, were composed principally of small, "well differentiated" lymphocytes. Myeloproliferative cases were composed of a mixture of granulocytes, erythroblasts, and monocytes without clear predominance of a single cell type. Electron microscopy of these neoplasms demonstrated that all lymphoid neoplasms were composed of lymphocytes. No neoplasms showed the features of a malignant histiocytosis. Abundant budding, C-type oncornaviruses were seen in 6 cases: 3 thymic lymphomas, 2 myeloproliferative disorders, and 1 multicentric large transformed cell neoplasm (Figure 1). Characterztion of Gbfmwubnephriis
Fifteen cases of glomerulonephritis were found, all of the immune complex tvpe (Table 3). On light microscopic examination the glomeruli in 13 cases were diffuselv involved and showed demonstrable diffuse Table 2-Types of Hematopoietic Neoplasms
Cell type Diagnosis
S
P
L
ST
Mixed
4 7 1
5 1 1
-
-
7
Alimentary lymphoma Thymic lymphoma
-
10
-
-
Multicentric lymphoma Unclassified lymphoma Myeloproliferative disorder
1 3
-
-
-
-
4
10
12
Totals
3 1 1 7 12
No. of cats 22 8 4 4 7 45
S, small lymphocyte; P, prolymphocyte, cleaved follicular center cell; L, tymphoblastic, small transformed lymphocyte; ST, stem cell, large transformed lymphocyte
324
American Joumal of PaHtology
GLICK ET AL
Table 3-Types of Glomerukxnephritis
Reticular Location of deposits
Immunofluorescent staining
Epithelial, endothelial, and
lgG in 3 cases; 1 c
mesangial Endothelial and mesangial
IG in 1 case
negative
aggregates
No. of cats
3 cases
12
-
3
proliferative changes, thickened basement membranes, and mesangial prominence (Figure 2). PAMS stains often demonstrated basement membrane spiking indicative of epithelial side basement membrane deposits (Figure 3). Two cases showed no light microscopic indications of glomerular disease. One case was found to contain glomerular deposits of amyloid on Congo red stain in addition to dense -deposits of the immune complex type. Immunofluorescence microscopy demonstrated deposition of IgG in the basement membrane region of 4 of 5 cases examined (Figure 4); 1 case showed no staining. Electron microscopy allowed better localization of the dense deposits within glomeruli. The great majority of cases (12) showed deposits in the subepithelial, subendothelial, and mesangial locations. Some cases showed numerous epithelial-side basement membrane deposits in individual capillary segments in a pattern similar to that seen in membranous nephropathy (Figure 5). However, no cases had confluent epithelial-side deposits. Endothelial and mesangial deposits were less marked but not uncommon (Figures 6 and 7). Three cases contained only endothelial and mesangially placed deposits without subepithelial deposits. One of these cases showed massive endothelial and mesangial deposits while 2 had scanty deposits which were not apparent on light microscopic examination. Three cases demonstrated "reticular aggregates'" in the endothelial cells of glomerular capillaries (Figure 8). Virus particles were not seen in any of the glomeruli examined by electron microscopy. The one case with Congo-red-positive foci demonstrated typical amyloid filaments on electron microscopy as well (Figure
9). The results of the present study indicate a strong association of immune complex glomerulonephritis with hematopoietic neoplasms in cats, in that approximately one third of cats with these tumors had glomerular lesions. No cases of glomerulonephritis were observed in the 16 cats without evidence of hematopoietic neoplasms or FeLV infection.
Vol. 92, No.2 August 1978
FELINE GLOMERULONEPHRITIS
325
The types of hematopoietic neoplasms encountered were comparable to those previously described.13 The alimentary form of malignant lymphoma was the most common neoplasm. These tumors were usually composed of prolymphocytes or cells with nuclear irregularity and cleavage planes. These cells were very similar to those seen in follicular center cell lymphomas, the most common B-lymphocyte-derived tumor in humans. 4'15 Three alimentary cases demonstrated follicular nodules, definite evidence of follicular center cell lymphoma.u Thymic lymphomas were almost exclusively composed of small transformed lymphocytes (lymphoblasts). The same findings have been previously noted in these presumptive T lymphocytes.'3 The unclassified cases were predominantly composed of small "well differentiated" lymphocytes and could conceivably be a form of chronic lymphocytic leukemia in cats. Not enough information was available to categorize these cases further. Immunologic marking techniques would be of great interest if T- and B-cell markers for cats were available. The myeloproliferative disorders were so classified because of the lack of predominance of any one cell type. These proliferations appear to be composed of granulocytes, monocytes, and erythroblasts without the monomorphic appearance of an acute leukemia. All cases of glomerulonephritis were found to be of the immune complex type with dense deposits located on the subepithelial and subendothelial sides of the glomerular basement membrane, as well as in the mesangial regions in most cases. No cases were found to contain only confluent epithelial side deposits, characteristic of membranous nephropathy.'6 The pattern of location of the deposits in these cases is very similar to patterns encountered in systemic lupus erythematosus in humans.'7 The presence of "reticular aggregates" in three cases also corresponds to a characteristic feature of human lupus nephropathy."8 Glomerulonephritis associated with systemic lupus in humans is caused by deposition of immune complexes in which DNA is a significant antigen." A similar disease appears to occur in New Zealand mice, and there is evidence that leukemia virus antigen is also deposited in the glomerular basement membranes.20 Other animals with immune complex glomerulonephritis are known to have chronic viral infections, eg, dogs with canine adenovirus infections (infectious canine hepatitis) have been found to have viral antigens in the glomerular immune complex deposits.9 The glomerulonephritis in cats is apparently of a similar nature, with viral antigen reportedly demonstrable."92' Several published reports indicate a possible association of glomerulonephritis with neoplasms in man,'."3 and evidence of mammalian oncornavirus antigen has been found in some cases.24 Occult infection with
326
GLICK ET AL
American Journal of Pathology
the hepatitis B virus is associated with many human cases of disseminated arteritis I and in some cases of immune-complex-mediated glomerulonephritis." Two human patients with acute leukemia have been found to be positive for FeLV by immunofluorescent staining.24 FeLV is know to have the abilitv to infect human cells,7 and this fact raises the possibility that some cases of immune-complex-mediated glomerulonephritis and/or hematopoietic neoplasms in humans may be caused by the same pathogenetic mechanisms operative in cats. This study has not only documented the association of immune complex glomerulonephritis with hematopoietic neoplasms in cats but also leaves implications of a similar process in humans. Although no documentation is available, concem about transmission of FeLV to humans has been recognized.27"2' Further studies linking FeLV or other oncornaviruses to glomerulonephritis and hematopoietic neoplasms mav have important public health implications. References 1. Slauson DO, Russell SW, Schechter RD: Naturally occurring immune complex glomerulonephritis in the cat. J Pathol 103:131-133, 1971 2. Farrow BRH, Huxtable CR, McGovern VJ: Nephrotic syndrome in the cat due to diffuse membranous glomerulonephritis. Pathology 1:67-72, 1969 3. Lucke VNM: Renal disease in the domestic cat. J Pathol Bacteriol 95:67-91, 1968 4. Hardy WD, McClelland AJ: Feline leukemia virus: Its related disease and control. Vet Clin North Am 7:93-103, 1977 5. Anderson LJ, Jarrett WFH: NMembranous glomerulonephritis associated with leukemia in cats. Res Vet Sci 12:179-180, 1971 6. Ward JM, Sodikoff CH, Schalm DW: Mveloproliferative disease and abnormal erythrogenesis in the cat. J Am Vet Med Assoc 155:879-8, 1969 7. Jarrett WFH: Feline leukemia. Int Rev Exp Pathol 10:243-263, 1971 8. Jarrett 0: Virology and host range of feline leukemia virus. J Am Vet Med Assoc 158:1032-1036, 1971 9. Osborne CA: Glomerulopathv and the nephrotic syndrome. Current Veterinary Therapy. Philadelphia, W. B. Saunders Co., 1977, p 1125 10. Jones DB: Nephrotic glomerulonephritis. Am J Pathol 33:313-329, 1957 11. Glick AD, Leech JH, Waldron JA, Flexner J\M, Hom RG, Collins RD: Malignant lvmphomas of follicular center cell origin. II. Ultrastructural and cytochemical studies. J Natl Cancer Inst 54:23-36, 1975 12. Collins RD, Leech JH, Waldron JA, Flexner JM, Glick AD: Diagnosis of hematopoietic, mononuclear, and lvmphoid cell neoplasms. Manual of Clinical Immunology. Edited by NR Rose, H Friedman. American Society for Microbiology, 1976, p 723 13. Mackey LJ, Jarrett WFH: Pathogenesis of lymphoid neoplasia in cats and its relationship to immunologic cell pathways. I. Morphologic aspects. J Natl Cancer Inst 49:853-865, 1972 14. Lukes RJ, Collins RD: Immunologic characterization of human malignant lymphomas. Cancer 34:1488-1503, 1974 15. Leech JH, Glick AD, Waldron JA, Flexner JM, Horn RG, Collins RD: Malignant Ivmphomas of follicular center cell origin. I. Immunologic studies. J Natl Cancer Inst 54:11-21, 1975
Vol. 92, No. 2 August 1978
FELINE GLOMERULONEPHRITIS
327
16. Rosen S: Membranous glomerulonephritis: Current status. Hum Pathol 2:209-231. 1971 17. Dujovne I, Pollak VE, Pirani CL, Dillard MG: The distribution and character of glomerular deposits in systemic lupus ervthematosus. Kidney Int 2:22-50, 1972 18. Tisher CC, Kelso HB, Robinson RR, Gunnells JC, Burkholder PM: Intraendothelial inclusions in kidneys of patients with systemic lupus erythematosus. Ann Intem NMed 75:537-547, 1971 19. Cochrane CG, Koffler D: Immune complex disease in experimental animals and man. Adv Immunol 16:185-264, 1973 20. Imamura M, Mellors RC, Strand M, August JT: Murine type C viral envelope glycoprotein GP 69/71 and lupus-like glomerulonephritis of New Zealand mice: An immunoperoxidase study. Am J Pathol 86:375-W3, 1977 21. Hardy WD: Immunology of oncomaviruses. VJet Clin N Am 4:133-146, 1974 22. Lee, JC, Yamauchi H, Hopper J Jr: The association of cancer and the nephrotic svndrome. Ann Intem Med 64:41-51, 1966 23. Hopper J Jr: Tumor related renal lesions. Ann Intern Med 81:550, 1974 24. Sutherland JC, Mardiney MR: Immune complex disease in the kidneys of l-mphoma-leukemia patients: The presence of an oncomavirus-related antigen. J Natl Cancer Inst 50:633-644, 1973 25. Gocke DJ, Morgan C, Lockshin M, Hsu K, Bonbardieri S, Christian SL: Association between polvarteritis and Australia antigen. Lancet 1:1149-1153, 1970 26. Combes B, Shorev J, Barrera A, Stastny P, Eigenbrodt EH, Hull AR, Carter NW': Glomerulonephritis with deposition of Australian antigen-antibody complexes in glomerular basement membrane. Lancet 1:234-237, 1971 27. Heath CW: Sick pets and human leukemia. Ann Intemn Med 78:605, 1973 28. Levy SB: Cat leukemia: A threat to man? N Engl J Med 290:513-514, 1974
328
GLICK ET AL
American Joumal
of Pathobgy
[Iugstruons follow]
2
'V
p
0
0
1
1 i.
-0
41b
*A
rn ;ye
*..
-_ S W a-~-- x
Fiue 1-Re resentative budding viral particles from cases of feline malignant lymphoma. (x Fgure 2-Feline glomerulus with diffuse proliferative change. (PAS, x 223) 78,000)
3
Fgure 3-Feline glomerulus with basement membrane spiking (arrows). (PAMS, 4-Feline glomerulus stained wfth anticat IgG. (x 600)
x 563)
FW
Figure 5-Subepithelial basement membrane deposits in feline gomerulus (asterisk). (x 17,100)
Figur 6-Subendothelial
basemnt membrane deposits in feline glomerulus (asterisk). (x 17,100)
I
L.
Jr
Fe 7-Mesangial deposits in feline gkonerulus
(asterisk). M, mesangial cell. (x 17,100)
I
-
_S 5. :>
'
Characterization of Feline Glomerulonephritis Associated With Viral-Induced Hematopoietic Neoplasms Alan D. Glick, MD, Robert G. Horn, MD, and Myron Holscher, DVM, PhD
Light, electron, and immunofluorescence microscopy on tissues from 63 domestic cats revealed that glomerulonephritis occurred in almost one third of cats with hematopoietic neoplasms of the type linked with feline leukemia virus (FeLV). Glomerular lesions were of the immune complex type with subepithelial, subendothelial, and mesangial dense deposits and reticular aggregates, similar to the nephropathy associated with systemic lupus erythematosus in humans. Evidence that the glomerular lesions may be viral-induced raises the possibility of similar pathogenetic mechanisms in human disease. (Am J Pathol 92:321-332. 1978)
SPONT.A-NEOUS GLOMERULONEPHRITIS in domestic cats is unusual. -3 However, a number of reports have indicated a high percentage of cases of feline glomerulonephritis to be associated with feline leukemia virus (FeLV) infection 4 and especially with hematopoietic neoplasms induced by feline leukemia virus.5'6 Glomerulonephritis has also been show n to be associated with experimentally produced feline leukemia.7 Feline hematopoietic disorders of various types, especially malignant lvmphomas, are relatively common in the cat,8 and these neoplasms are definitely linked with the FeLV, an RNA oncornavirus similar to other RNA tumor viruses. The pathogenesis of glomerulonephritis associated Xwith feline malignant lvmphoma or leukemia max involve the deposition of immune complexes of viral, or viral-induced, antigen and host antibody; viral antigen-antibody complexes have been found in the glomeruli of some cats infected wvith feline leukemia virus.9 The FeLV is known to From the Department of Pathology. Vanderbilt University School of Medicine, and the \eterans Xdministration Hospital. Nashville. Tennessee Xccepted for publication \March 2.3. 197,8 Address reprint requests to Alan D Glick. MD. Department of Pathology. School of Medicine. Vanderbilt University. Nashsille, TN 37232 321 0002-9440/78/081 0-0321$01 .00
322
GLICK ET AL
American Journal of Pathology
infect cells of other species, including man, as well as to be transmitted horizontally among cats.7 The possibility exists that this virus may be responsible for some cases of idiopathic glomerulonephritis in man. Although some of the glomerulonephritis cases associated with FeLV have been characterized as membranous,5 the lesions have been incompletely described. The present study was undertaken to determine the incidence and pathologic characteristics of immune complex glomerulonephritis occurring among a large series of cats with hematopoietic neoplasms. Materials and Methods Tissues from 63 domestic cats suspected of having hematopoietic neoplasms were obtained from local veterinary sources. Complete autopsies were performed on most cats to determine the extent of involvement by the neoplasms. For light microscopy, representative tissues from all major organs and all gross lesions were fixed in formalin and surveyed with hematoxylin and eosin (H&E) stained sections. Tissues from bone marrow, lvmph nodes, and spleen were fixed in B5 or Zenker's fixativ es, and sections were stained with periodic acid-Schiff (PAS) stains. Kidnev sections were examined by H&E, PAS, and the periodate methenamine silver (PANIS) stain, according to Jones' method.'0 For electron microscopy, specimens were prepared by methods previously described." Representative glomeruli from all kidney specimens and samples of all neoplasms were examined by electron microscopy. In selected cases, renal tissues were examined for deposits of immunogiobulin by the direct staining of cryostat sections of unfixed renal cortex with fluoresceinated anticat IgG obtained from Nlicrobiological Associates (Bethesda, Md.).
Results General Features
Of the 63 cats examined, 45 (71.4%) were found to have hematopoietic neoplasms (Table 1); 38 of the 45 had malignant lymphoma, and 7 had myeloproliferative disorders. Eighteen of the 63 cats were found to have no evidence of hematologic malignancies, although 2 of them had positive fluorescent antibody tests for FeLV. Fifteen cases of glomerulonephritis were found (23.8% of the total). Twelve cases of glomerulonephritis were found in cats with malignant lymphoma, and 2 were found in cats with -myeloproliferative disorders; 1 of the cats without evidence of a neoplasm had glomerulonephritis, and this case was positive for FeLV. These results indicate that glomerulonephritis occurred in 32% of cats with FeLVinduced disease. Chaterizatiai of Hematopoic Neopbsam
The types of malignant lymphoma and myeloproliferative diseases are indicated in Table 2. Twenty-two cases of alimentary lymphosarcoma, 8 cases of thymic lymphosarcoma, and 4 cases of multicentric lymphosar-
Vol. 92, No. 2 August 1978
FELINE GLOMERULONEPHRITIS
323
Table 1-Feline Hematopoietic Neoplasms and Glomerulonephritis
Diagnosis
No. of cats
No. of cases of glomerulonephritis
38 7 2 16 63
12 2 1 0 15
Malignant lymphoma Myeloproliferative disorder Positive FA*; no neoplasm Negative for FeLV disease Totals
Fluorescent antibody test for FeLV group specific antigens in blood
coma were found. Four cases were incompletely classified due to inadequate tissue sampling. Light microscopy indicated that most thymic lymphomas were composed of small transformed lymphocytes (Iymphoblastic) and most alimentary lymphomas were composed of cleaved (prolvmphocytic) cells or transformed cells (Table 2). Three alimentary cases demonstrated follicular nodulation similar to cases of human follicular center cell lvmphoma.'2 Four cases, including one multicentric case, were composed principally of small, "well differentiated" lymphocytes. Myeloproliferative cases were composed of a mixture of granulocytes, erythroblasts, and monocytes without clear predominance of a single cell type. Electron microscopy of these neoplasms demonstrated that all lymphoid neoplasms were composed of lymphocytes. No neoplasms showed the features of a malignant histiocytosis. Abundant budding, C-type oncornaviruses were seen in 6 cases: 3 thymic lymphomas, 2 myeloproliferative disorders, and 1 multicentric large transformed cell neoplasm (Figure 1). Characterztion of Gbfmwubnephriis
Fifteen cases of glomerulonephritis were found, all of the immune complex tvpe (Table 3). On light microscopic examination the glomeruli in 13 cases were diffuselv involved and showed demonstrable diffuse Table 2-Types of Hematopoietic Neoplasms
Cell type Diagnosis
S
P
L
ST
Mixed
4 7 1
5 1 1
-
-
7
Alimentary lymphoma Thymic lymphoma
-
10
-
-
Multicentric lymphoma Unclassified lymphoma Myeloproliferative disorder
1 3
-
-
-
-
4
10
12
Totals
3 1 1 7 12
No. of cats 22 8 4 4 7 45
S, small lymphocyte; P, prolymphocyte, cleaved follicular center cell; L, tymphoblastic, small transformed lymphocyte; ST, stem cell, large transformed lymphocyte
324
American Joumal of PaHtology
GLICK ET AL
Table 3-Types of Glomerukxnephritis
Reticular Location of deposits
Immunofluorescent staining
Epithelial, endothelial, and
lgG in 3 cases; 1 c
mesangial Endothelial and mesangial
IG in 1 case
negative
aggregates
No. of cats
3 cases
12
-
3
proliferative changes, thickened basement membranes, and mesangial prominence (Figure 2). PAMS stains often demonstrated basement membrane spiking indicative of epithelial side basement membrane deposits (Figure 3). Two cases showed no light microscopic indications of glomerular disease. One case was found to contain glomerular deposits of amyloid on Congo red stain in addition to dense -deposits of the immune complex type. Immunofluorescence microscopy demonstrated deposition of IgG in the basement membrane region of 4 of 5 cases examined (Figure 4); 1 case showed no staining. Electron microscopy allowed better localization of the dense deposits within glomeruli. The great majority of cases (12) showed deposits in the subepithelial, subendothelial, and mesangial locations. Some cases showed numerous epithelial-side basement membrane deposits in individual capillary segments in a pattern similar to that seen in membranous nephropathy (Figure 5). However, no cases had confluent epithelial-side deposits. Endothelial and mesangial deposits were less marked but not uncommon (Figures 6 and 7). Three cases contained only endothelial and mesangially placed deposits without subepithelial deposits. One of these cases showed massive endothelial and mesangial deposits while 2 had scanty deposits which were not apparent on light microscopic examination. Three cases demonstrated "reticular aggregates'" in the endothelial cells of glomerular capillaries (Figure 8). Virus particles were not seen in any of the glomeruli examined by electron microscopy. The one case with Congo-red-positive foci demonstrated typical amyloid filaments on electron microscopy as well (Figure
9). The results of the present study indicate a strong association of immune complex glomerulonephritis with hematopoietic neoplasms in cats, in that approximately one third of cats with these tumors had glomerular lesions. No cases of glomerulonephritis were observed in the 16 cats without evidence of hematopoietic neoplasms or FeLV infection.
Vol. 92, No.2 August 1978
FELINE GLOMERULONEPHRITIS
325
The types of hematopoietic neoplasms encountered were comparable to those previously described.13 The alimentary form of malignant lymphoma was the most common neoplasm. These tumors were usually composed of prolymphocytes or cells with nuclear irregularity and cleavage planes. These cells were very similar to those seen in follicular center cell lymphomas, the most common B-lymphocyte-derived tumor in humans. 4'15 Three alimentary cases demonstrated follicular nodules, definite evidence of follicular center cell lymphoma.u Thymic lymphomas were almost exclusively composed of small transformed lymphocytes (lymphoblasts). The same findings have been previously noted in these presumptive T lymphocytes.'3 The unclassified cases were predominantly composed of small "well differentiated" lymphocytes and could conceivably be a form of chronic lymphocytic leukemia in cats. Not enough information was available to categorize these cases further. Immunologic marking techniques would be of great interest if T- and B-cell markers for cats were available. The myeloproliferative disorders were so classified because of the lack of predominance of any one cell type. These proliferations appear to be composed of granulocytes, monocytes, and erythroblasts without the monomorphic appearance of an acute leukemia. All cases of glomerulonephritis were found to be of the immune complex type with dense deposits located on the subepithelial and subendothelial sides of the glomerular basement membrane, as well as in the mesangial regions in most cases. No cases were found to contain only confluent epithelial side deposits, characteristic of membranous nephropathy.'6 The pattern of location of the deposits in these cases is very similar to patterns encountered in systemic lupus erythematosus in humans.'7 The presence of "reticular aggregates" in three cases also corresponds to a characteristic feature of human lupus nephropathy."8 Glomerulonephritis associated with systemic lupus in humans is caused by deposition of immune complexes in which DNA is a significant antigen." A similar disease appears to occur in New Zealand mice, and there is evidence that leukemia virus antigen is also deposited in the glomerular basement membranes.20 Other animals with immune complex glomerulonephritis are known to have chronic viral infections, eg, dogs with canine adenovirus infections (infectious canine hepatitis) have been found to have viral antigens in the glomerular immune complex deposits.9 The glomerulonephritis in cats is apparently of a similar nature, with viral antigen reportedly demonstrable."92' Several published reports indicate a possible association of glomerulonephritis with neoplasms in man,'."3 and evidence of mammalian oncornavirus antigen has been found in some cases.24 Occult infection with
326
GLICK ET AL
American Journal of Pathology
the hepatitis B virus is associated with many human cases of disseminated arteritis I and in some cases of immune-complex-mediated glomerulonephritis." Two human patients with acute leukemia have been found to be positive for FeLV by immunofluorescent staining.24 FeLV is know to have the abilitv to infect human cells,7 and this fact raises the possibility that some cases of immune-complex-mediated glomerulonephritis and/or hematopoietic neoplasms in humans may be caused by the same pathogenetic mechanisms operative in cats. This study has not only documented the association of immune complex glomerulonephritis with hematopoietic neoplasms in cats but also leaves implications of a similar process in humans. Although no documentation is available, concem about transmission of FeLV to humans has been recognized.27"2' Further studies linking FeLV or other oncornaviruses to glomerulonephritis and hematopoietic neoplasms mav have important public health implications. References 1. Slauson DO, Russell SW, Schechter RD: Naturally occurring immune complex glomerulonephritis in the cat. J Pathol 103:131-133, 1971 2. Farrow BRH, Huxtable CR, McGovern VJ: Nephrotic syndrome in the cat due to diffuse membranous glomerulonephritis. Pathology 1:67-72, 1969 3. Lucke VNM: Renal disease in the domestic cat. J Pathol Bacteriol 95:67-91, 1968 4. Hardy WD, McClelland AJ: Feline leukemia virus: Its related disease and control. Vet Clin North Am 7:93-103, 1977 5. Anderson LJ, Jarrett WFH: NMembranous glomerulonephritis associated with leukemia in cats. Res Vet Sci 12:179-180, 1971 6. Ward JM, Sodikoff CH, Schalm DW: Mveloproliferative disease and abnormal erythrogenesis in the cat. J Am Vet Med Assoc 155:879-8, 1969 7. Jarrett WFH: Feline leukemia. Int Rev Exp Pathol 10:243-263, 1971 8. Jarrett 0: Virology and host range of feline leukemia virus. J Am Vet Med Assoc 158:1032-1036, 1971 9. Osborne CA: Glomerulopathv and the nephrotic syndrome. Current Veterinary Therapy. Philadelphia, W. B. Saunders Co., 1977, p 1125 10. Jones DB: Nephrotic glomerulonephritis. Am J Pathol 33:313-329, 1957 11. Glick AD, Leech JH, Waldron JA, Flexner J\M, Hom RG, Collins RD: Malignant lvmphomas of follicular center cell origin. II. Ultrastructural and cytochemical studies. J Natl Cancer Inst 54:23-36, 1975 12. Collins RD, Leech JH, Waldron JA, Flexner JM, Glick AD: Diagnosis of hematopoietic, mononuclear, and lvmphoid cell neoplasms. Manual of Clinical Immunology. Edited by NR Rose, H Friedman. American Society for Microbiology, 1976, p 723 13. Mackey LJ, Jarrett WFH: Pathogenesis of lymphoid neoplasia in cats and its relationship to immunologic cell pathways. I. Morphologic aspects. J Natl Cancer Inst 49:853-865, 1972 14. Lukes RJ, Collins RD: Immunologic characterization of human malignant lymphomas. Cancer 34:1488-1503, 1974 15. Leech JH, Glick AD, Waldron JA, Flexner JM, Horn RG, Collins RD: Malignant Ivmphomas of follicular center cell origin. I. Immunologic studies. J Natl Cancer Inst 54:11-21, 1975
Vol. 92, No. 2 August 1978
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16. Rosen S: Membranous glomerulonephritis: Current status. Hum Pathol 2:209-231. 1971 17. Dujovne I, Pollak VE, Pirani CL, Dillard MG: The distribution and character of glomerular deposits in systemic lupus ervthematosus. Kidney Int 2:22-50, 1972 18. Tisher CC, Kelso HB, Robinson RR, Gunnells JC, Burkholder PM: Intraendothelial inclusions in kidneys of patients with systemic lupus erythematosus. Ann Intem NMed 75:537-547, 1971 19. Cochrane CG, Koffler D: Immune complex disease in experimental animals and man. Adv Immunol 16:185-264, 1973 20. Imamura M, Mellors RC, Strand M, August JT: Murine type C viral envelope glycoprotein GP 69/71 and lupus-like glomerulonephritis of New Zealand mice: An immunoperoxidase study. Am J Pathol 86:375-W3, 1977 21. Hardy WD: Immunology of oncomaviruses. VJet Clin N Am 4:133-146, 1974 22. Lee, JC, Yamauchi H, Hopper J Jr: The association of cancer and the nephrotic svndrome. Ann Intem Med 64:41-51, 1966 23. Hopper J Jr: Tumor related renal lesions. Ann Intern Med 81:550, 1974 24. Sutherland JC, Mardiney MR: Immune complex disease in the kidneys of l-mphoma-leukemia patients: The presence of an oncomavirus-related antigen. J Natl Cancer Inst 50:633-644, 1973 25. Gocke DJ, Morgan C, Lockshin M, Hsu K, Bonbardieri S, Christian SL: Association between polvarteritis and Australia antigen. Lancet 1:1149-1153, 1970 26. Combes B, Shorev J, Barrera A, Stastny P, Eigenbrodt EH, Hull AR, Carter NW': Glomerulonephritis with deposition of Australian antigen-antibody complexes in glomerular basement membrane. Lancet 1:234-237, 1971 27. Heath CW: Sick pets and human leukemia. Ann Intemn Med 78:605, 1973 28. Levy SB: Cat leukemia: A threat to man? N Engl J Med 290:513-514, 1974
328
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American Joumal
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Fiue 1-Re resentative budding viral particles from cases of feline malignant lymphoma. (x Fgure 2-Feline glomerulus with diffuse proliferative change. (PAS, x 223) 78,000)
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Figure 5-Subepithelial basement membrane deposits in feline gomerulus (asterisk). (x 17,100)
Figur 6-Subendothelial
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Fe 7-Mesangial deposits in feline gkonerulus
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