ANNALS OF CLINICAL AND LABORATORY SCIENCE, Vol. 11, No. 5Copyright © 1981, Institute for Clinical Science, Inc.

Gold NephropathyTATIANA T. ANTONOVYCH, M.D.

Registry o f Nephropathology, American Registry o f Pathology,Armed Forces Institute o f Pathology,

and the Veterans Administration Special Reference Laboratory fo r Pathology,Washington, DC 20306

ABSTRACT

The early use of gold in medicine and dentistry dates back to the ancient Chinese and Egyptians. The discovery in 1890 that gold salts were toxic in vitro to tubercle bacilli led to the extensive treatment of tuberculosis with gold salts in the first three decades of this century. Eventually, gold therapy was extended to arthritis and lupus erythematosus, because of the belief that these diseases were forms of tuberculosis. Because of its beneficial effect particularly on active rheumatoid arthritis, chrysotherapy has remained one of the most widely used treatments of rheumatoid arthritis for the past half century. Toxicity of gold salts includes hypersensitivity reaction of skin and mucous membranes, bone marrow depression, and nephrotoxicity. The nephrotoxic clinical manifestations are renal insufficiency, proteinuria and hematuria, and the nephrotic syndrome. The pathologic changes are tubular degeneration, acute tubular necrosis or immune complex glomerulone­phritis. The justification that any of these possible changes are the result of gold therapy rests clinically upon the time relationship of gold therapy and the renal symptoms, and pathologically upon the presence of gold inclusions (aurosomes) in proximal tubular epithelial cells. Aurosomes can at times be visualized by light microscopy, are usually seen by electron microscopy, and can be identified by microprobe analysis. Their pathology will be illustrated and pathogenic mechanisms discussed.

Introduction

Chrysotherapy has been one of the most widely used medications in the manage­ment of patients with rheumatoid arthritis for the past 50 years, despite a rather high incidence of side effects. Untoward reac­tions may occur early or late in the course of therapy. The incidence of toxic reaction

is most probably related to the total body concentration of gold, since only 40 per­cent of gold is excreted each week on a standard weekly dose, leading to a pro­gressive increase in its body tissue stores. The most common toxic effects are those involving skin, mucous membranes, bone marrow, and the kidney. The nephrotoxic clinical and pathological manifestations

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GOLD NEPHROPATHY 387

have been well documented. Proteinuria, hematuria, the nephrotic syndrome, and renal insufficiency are well recognized complications of gold therapy. The renal lesions associated with chrysotherapy in­clude acute tubular necrosis, tubular de­generation , and im m une com plex glomerulonephritis. Similar lesions can be produced in experim ental animals with gold salts. The pathogenesis of the tubular lesions seem to be a direct drug “toxicity” of gold ions, while the immune complex glom erulonephritis is an im- munologically mediated drug toxicity.

The earliest use of gold in medicine and dentistry dates back to the ancient Egyp­tians and Chinese.21 The therapeutic use of gold in modem medicine was stimu­lated by the observation of Robert Koch of the adverse reaction of gold salts on the tubercle bacillus in 1890.8 Despite disap­pointing clinical results, gold was used in the treatment of tuberculosis, particularly in western Europe, until the late 1930’s. Eventually gold therapy was extended to the treatment of arthritis and lupus ery- thematosis because of the belief of some that these diseases were forms of tuber­culosis. The treatment of rheumatoid ar­th ritis w ith gold, how ever, was first popularized by Jaques Forestier in the early 1930’s.9 He reasoned that gold prob­ably stimulated the defense mechanism of the body in tuberculosis and might be­have similarly in rheumatoid arthritis.

Fifty years of use of gold in the man­agement of rheumatoid arthritis has had a mixed acceptance. Despite a rather high incidence of side effects, some prognosti- cally serious, chrysotherapy remains one of the most widely prescribed medica­tions in the management of patients with rheumatoid arthritis.

Gold exists in monovalent and trivalent forms. All significant preparations are au- reous (monovalent) salts in which gold is attached to sulfur. The strong affinity of monovalent gold for sulfur and the in­hibitory affects of certain gold salts on

peruvic dehydrogenase suggest that the therapeutic effects of gold salts are due to inhibition of sulfhydryl-related enzymes.

The most commonly used gold com­pounds in the treatment of rheumatoid ar­thritis are aurothioglucose (Solganal) and gold sodium thiomalate (Myochrysin). Both compounds contain approximately 50 percen t gold. W ater soluble com­pounds are rapidly absorbed after in­tramuscular injection. Serum gold con­centration peaks within two to four hours, after which it declines gradually. Ninety- two percent of gold in the blood is protein bound, of which 95 percent is present in the albumin fraction.10 Gold is widely dis­tributed throughout the body.20 The high­est concentration of soluble compounds is found in the kidneys, while insoluble com pounds are recovered in larger amounts from the reticulo-endothelial system. Gold compounds are selectively concentrated within the inflamed syno­vial tissue of active rheumatoid arthritis. Soluble gold compounds are excreted mainly by the kidney, while insoluble compounds are excreted in the bile. How­ever, only 40 percent of administered gold is excreted each week during standard treatm ent; therefore, w ith weekly in­jections, the body stores increase progres­sively. Gold was found to persist in various tissues up to 23 years after chry­sotherapy was stopped. In the past, unduly large doses of gold compounds used in the treatm ent of tuberculosis and later of rheumatoid arthritis resulted in a high in­cidence of severe toxic reactions.3 Unto­ward reactions to gold may occur early or later in the course of therapy. The inci­dence of toxic reactions to gold is unre­lated to its plasma levels but is probably related to its total body concentration. The most common toxic effects of chryso­therapy are those involving the skin and the mucous membranes. Less common but more severe in their consequences are the hematologic and renal manifestations of gold toxicity.6' 13

388 ANTONOVYCH

R enal symptoms of gold toxicity range from renal pro teinuria and hem aturia and the nephro tic syndrom e13,14 to renal insuf­ficiency and even fatal anuric failure.3,11 T he renal lesions associated w ith chryso- th e ra p y have b e e n w ell d o cu m en ted . Large doses of gold salts produce acute tubu lar necrosis.3 T he m ain lesion is con­fined to the proxim al convoluted tubules. T he evolution of the tubu lar lesion was extensively stud ied in experim ental an i­m als.12,17,18

By ligh t m icroscopy, in hem atoxylin and eosin stained sections, the proxim al tu b u lar cells appear sw ollen and show areas of rarifaction or vacuolization in w hich at tim es small yellow ish-brow n, re- fractile, poorly defined granules can be recognized. T hese may be shown in light m icroscop ic sec tio n s to b e go ld by a p h o to c h e m ic a l m e th o d d e s c r ib e d by Gilg,7 or recognized by their distinct mor­phologic structure by electron microscopy or id en tified by elec tron probe m icro­analysis (figure 1).

Gold deposits (aurosom es) of soluble gold com pounds consist of electron dense g ranules, th e ir p ro jec ting rod like and linear structure giving them a feathery a p p e a ra n c e , w h e rea s au ro so m es p ro ­duced by colloidal gold are m ade up of aggregates of spherical e lec tron dense structures (figure 2).J2,17,18,20

T he prim ary site of gold deposition in the kidney is the m itochondria of the prox­imal convoluted tubules. T he dam age to the m itochondria is proportional to the am ount of gold injected. A ccum ulation of gold results in m itochondrial d isruption and consequen t degeneration and necro­sis of the lining cells. T he tubu lar base­m e n t m em b ra n e rem a in s in tac t. T h e distal tubules becom e filled w ith cast of c e l lu la r d e b r is a n d c lu m p s o f go ld deposits .12,17,18

T h e percen tag e o f p a tien ts rep o rted who develop pro teinuria or the nephro tic syndrom e du rin g ch ryso therapy varies from 0.2 to 10 percent. A lthough m ost pa­tients p resen ting w ith pro teinuria have

F ig u r e 1. Light micro­scopic section of proximal convoluted tubu le . The cytoplasm is vacuolated and shows poorly defined refractile granules. Hem­atoxylin and eosin x 630 (AFIP 80-10684).

G OLD N EPH RO PA TH Y 389

F ig u r e 2. E le c t r o ­m icrograph of a portion of proxim al co n v o lu ted tu ­b u le s , sh o w in g d e ­g en era tin g m itochondria a n d g o ld in c lu s io n s , x 10,800 (AFIP 80-10685).

received a substantial am ount of gold, pro­te inuria has b een reported after as little as10 mg of gold sodium thiom alate. T he glom eruli in renal biopsies of these pa­tients v iew ed by light m icroscopy may appear norm al, or show m inim al increase

in endocapillary cells, or show focal or diffuse th icken ing of capillary walls (fig­ure 3). T he th ickened capillary walls in m e th e n a m in e s ilv e r s ta in e d sec tio n s show basem ent m em brane spiking and, in trichrom e sta in ed sections, granular

F ig u r e 3. Light micro­scopic section of glomeru­lus showing focal thicken­ing of cap illa ry w alls . Hematoxylin and eosin x 280 (AFIP 80-10683).

5?t ir v *• > * :• ' * r

390 ANTONOVYCH

F ig u r e 4. E lec tro - micrograph of a portion o f g lom eru lu s. W idely spaced subepithelial de­posits w ith early b ase ­ment mem brane spiking is present. There is diffuse effacem ent o f epithelia l cell foot processes, x 3700 (AFIP 80-10686).

m agenta red deposits. By electron m icros­copy, electron dense deposits are seen on the ep ithelia l surface o f the glom erular capillary b asem en t m em branes (figure 4).2-4 D ep en d in g on the tim e interval b e ­tw een the first gold injection, the appear­ance of proteinuria , and the day of the kidney biopsy, the deposits may be few and the underly ing basem ent m em brane intact, or there m ay be basem ent m em ­brane spiking or finely incorporation of deposits into the th ickened rem odeled basem ent m em brane. Thus, all stages of m em branous glom erulonephritis may be seen in gold glom erulonephropathy ex­cept tha t in the latter, irrespective of the stage, the num ber of deposits varies and a num ber of loops may be totally free of deposits.16 If properly searched for, auro- somes w ill be found in proxim al tubular ep ithelium and rarely, visceral glom eru­lar e p ith e l ia l c e l l s .18,19 F lu o re sc e n c e microscopy shows the deposits to contain IgG and com plem ent in a granular pattern along the g lom erular capillary basem ent m em brane. I f go ld th e ra p y is d isco n ­tinued soon after the p ro teinuria appears, and the g lom erular lesions are early and

segm ental, the prognosis is good. F irst, th ere is progressive and, finally, com plete d isappearance of proteinuria , follow ed by lo ss o f d e p o s its an d re s to ra tio n o f glom erular capillary basem ent m em brane as revealed by repeated b iopsies.4

T he tubu lar dam age in the course of chrysotherapy is caused by the deposition of gold inside m itochondria, w hich appear to be the target organelles of injury.17,23 T he exact pathogenesis of m itochondrial injury is not known, bu t gold probably en ters th e m itochondria in ionic form, s in ce it can b e see n in m ito ch o n d ria w hich have an intact ou ter m em brane. It is possib le that they becom e overloaded by large num bers of gold ions, w hich in terfere w ith th e ir norm al functions of s e le c t iv e b in d in g an d u n b in d in g o f cations.

Several hypothesis have b een proposed concern ing the pathogenesis of the im ­m u n e com plex g lo m eru lo n ep h ritis re ­lated to gold therapy. It was originally suggested that gold acts as a hapten w hen com bined w ith tissue proteins; how ever, up to date it has n ev er b een d e tec ted w ith in the im m une deposits. It has b een

GOLD NEPHROPATHY 391

suggested that the deposits may be com­plexes of rheumatoid autoantibodies and that gold may facilitate the glomerular deposition.15 Another hypothesis, recently w idely supported , is tha t the gold- damaged tubules liberate autoantigens, which are then deposited with antibody in the glomeruli.11 Finally, there is growing evidence that immunologically mediated drug toxicity may be controlled by genes of the histocompatibility system. It is known that patients with rheumatoid ar­thritis may have HLA-88 or HLA-DRw3 antigens. It was recently reported that DRw3 positive patients with rheumatoid arthritis have a high titer of rheumatoid factor and treatment with aurothiomal- a te 1 resu lts in a high inc idence of proteinuria.22

The diagnosis of gold induced mem­branous glomerulonephritis is justified only when there is a relationship between gold therapy and renal symptoms, and au- rosomes are found in the proximal convo­luted tubules. At times they are difficult to detect in conventionally stained electron microscopic sections, but they are rela­tively easily visualised in unosmicated unstained sections.5

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BlNSWANGER, U.: Unusual incidence of mem­branous glom erulonephritis after gold therapy for rheum atoid arthritis. Kidney Internat. 15 - 5:584, 1979.

2. D a v ie s , D . J., D o w l in g , J., and Xip e l l , J. M.: Gold nephropathy. Pathology 9:281-288,1977.

3. D e r o t , M., Ka h n , J., Ma z a l t o n , A., and PEYRAFORT, J.: N ephrite anurique aigue mor- te lle apres traitem ent aurique chrysocyanose associee. Bull. Mem. Soc. Med. Hop. 70:244- 239, 1959.

4. D it s c h e r l e in , G., Sc h n e id e r , W., Mu l l e r , V., Kr u m h a a r , I., and STORCH, W.: Long term o b se rv a tio n on m em branous g lo m eru lo ­n e p h ritis due to go ld and p e n ic illa m in e therapy. Internat. Acad. Path. 195, 1980.

5. G h a d ia l l y , F. N., T h o m a s , I., and L a l o n d e , J. M. A.: Comparative ultrastructural morphology of aurosomes produced by collodial gold and soluble gold salts. J. Path. 123:181-185, 1977.

6. G i h b o n s , R. B.: Complications of chryso- therapy. Arch. Intern. Med. 139:343-346,1979.

7. GlGL, E.: A photochemical method for micro­detection of gold in tissue sections. Acta Psychiat. Scand. 2 7 :43-46, 1952.

8. G o o d m a n , L. S. and G ilm a n , A.: The Phar­macological Basis of Therapeutics, 4th ed. Philadelphia, The MacMillan Company, 1970, pp. 969-974.

9. H E R S P E R G E R , W. G.: Gold therapy for rheumatoid arthritis: A current evaluation. Ann. Int. Med. 36:571-582, 1952.

10. I n t e r n a t i o n a l W o r k s h o p a n d S y m p o siu m o n G o l d T h e r a p y i n R h e u m a t i c D i s e a s e . J. Rheumat. Suppl. 5, 1979.

11. K a t z , A. and L i t t l e , A. H.: Gold nephropathy. Arch. Path. 96:133-136, 1973.

12. N a g i , A. H., A l e x a n d e r , F., and B a r a b a s , A. Z .: Gold nephropathy in rats—Light and elec­tron microscopic studies. Exp. Mol. Path. J5:354-362, 1971.

13. S a m u e ls , B., L e e , J. C., E n g le m a n , E . P., and H o p p e r , J.: Membranous nephropathy in pa­tients with rheumatoid arthritis. Relation to gold therapy. Medicine 57:319-327, 1977.

14. S i l v e r b e r g , D. S., K id d , E. G., S h n i t k a , T. K., and U l a n , R. A.: Gold nephropathy. Arthritis Rheum. 13:812-825, 1970.

15. S k r i f v a r s , B. V., T o r n r o t h , T . S ., and T a l l q v i s t , G. N.: Gold induced immune com­plex nephritis in seronegative rheumatoid ar­thritis. Ann. Rheum Dis. 36:549-556, 1977.

16. T o r n r o t h , T . and S k r i f v a r s , B.: Gold ne­phropathy prototype of membranous glomer­ulonephritis. Amer. J. Path. 75:573-584, 1974.

17. S t u v e , J. and G a l l e , P.: Role of mitochrondria in the handling of gold by the kidney. J. Cell. Biol. 44:667-676, 1970.

18. S t r u n k , S. W. and Z i f f , M.: Ultrastructural studies of the passage of gold thiomalate across the renal glomerular capillary wall. Arthritis Rheum. 13:39-52, 1970.

19. V a a m o n d e , C. A. and H u n t , F. R.: The ne­phrotic syndrome as a complication of gold therapy. Arthritis Rheum. 13:826-833, 1970.

20. V e r n o n - R o b e r t s , B., D o r e , J. L., J e s s o p , J.D., and H e n d e r s o n , W. J.: Selective concen­tration and localization of gold in macrophages of synovial and other tissues during and after chrysotherapy in rheumatoid patients. Ann. Rheum. Dis. 35:477-486, 1976.

21. W i l s o n , W . J.: Alchemy in China. Ciba Sym- pos. 2:594-623, 1940.

22. W o o l e y , P . H., G r i f f i n , J., P a n a y i , G . S., B a t c h e l o r , J. R., W e l s h , K. I., and G ib s o n , T. J.: HLA-DR antigens and toxic reaction to sodium aurothiomalate and D-penicillamine in patients with rheumatoid arthritis. New Eng. J. Med. 303:300-302, 1980.

23. Y a ro m , R., S t e i n , H ., P e t e r s , P . D., S l a v i n ,S., and H a l l , T. A.: Nephrotoxic effect of par­enteral and intraarticular gold. Arch. Path. 99:36-43, 1975.