Acute and Chronic Toxic Nephropathies

Transcription

1 ANNALS O F CLINICAL AND LABORATORY SCIEN CE, Vol. 19, No. 3 Copyright 1989, Institute for Clinical Science, Inc. Acute and Chronic Toxic Nephropathies M. M ELINDA SANDERS, M.D. and ANNE P. M ARSHALL, M.D. Department o f Pathology, University of Arkansas for Medical Sciences, Little Rock, AR ABSTRACT Toxic nephropathies manifest morphologically as glomerulonephritides, vasculitides, tubular necrosis, and acute or chronic tubulointerstitial disease. The most common toxicity is acute interstitial nephritis owing to hypersensitivity. However, focal segm ental glomerulosclerosis and necrotizing angiitis secondary to heroin abuse, m embranous glomerulopathy owing to gold, penicillamine and captopril, throm botic microangiopathy associated with mitomycin and tubular necrosis owing to cyclosporine A, cisplatin, aminoglycosides, and cephalosporins are also review ed. The mechanisms of toxicity are poorly understood in most cases, but hypotheses related to cyclosporine A, cisplatin, gold, aminoglycosides, cephalosporins, intravenous narcotics, sulfonamides, and m ethotrexate are sum marized. Toxic N ephropathies The spectrum of toxic nephropathies ran g es from g lo m e ru lo n e p h ritis to chronic tubulointerstitial disease and involves a list of drugs from antibiotics to drugs of abuse. This review will cover the major morphologic patterns of injury and will highlight some of the purported mechanisms of injury. Glomerular injury is most commonly seen with drugs of abuse. Virtually all types of glom erulonephritis have been r e p o r t e d, b u t h e r o in a s s o c ia te d nephropathy is usually characterized by focal, segm ental glom erulosclerosis. Both IgM and C 3 are frequently identified within the abnormal segments; foot process fusion is p resen t by electron microscopic evaluation. 13 M ost patients p resen t w ith the nephrotic syndrom e and exhibit a relentless course. 11 At least two m echanism s of injury have been postulated: (1) the narcotic serves as a hapten to stim ulate im m une complex formation on a chronic basis, or (2 ) the narcotic causes increased glom erular capillary p erm eab ility w hich in tu rn causes the focal lesions.8 It is interesting that the m ost common renal lesion in AIDS patients is also focal segm ental g lo m eru lo sclero sis. T he d ifferen ces betw een these two glomeruloscleroses are subtle. 2 M em branous glom erulonephritis is seen w ith gold, penicillam ine, and captopril (figure 1). The m orphologic findings are sim ilar to those of idiopathic m em branous glom erulonephritis, but the renal dysfunction resolves upon w ith d ra w a l of th e d ru g. A lth o u g h /89/ $00.90 Institute for Clinical Science, Inc.

2 217 TOXIC NEPHROPATHIES jf v«tv # '#? *** w* * h * 'il «-4 * %.%<r W $& #1 A ; jt, * IP^CM '#*$? j r 1$' *. ## & **, *» 1 i" F ig u r e 1. T h e g lo m e r u l u s e x h i b i t s ty p ic a l fe a tu re s o f m e m b ra n o u s g lo m e ru lo n e p h ritis w h ic h m a y b e a s s o c i a t e d w i th g o ld, p e n ic illa m in e, a n d c a p to p r il. (H & E m ag 25 x ) F ig u r e 2. Tubular n e c ro s is a c c o m p a n ie d b y d e n s e in te rs titia l ly m p h o c y tic in filtra te s c h a r a c te r iz e s c y c lo s p o rin e to x ic ity (H & E m ag 5 0 x ).

3 218 SANDERS AND MARSHALL im m une complexes are identified along the glom erular basem ent m em brane, neither the drugs nor their m etabolites can be isolated from these complexes. G o ld can b e d e te c te d b y e le c tro n microscopy in the proximal convoluted tubules. In at least one experim ental m odel, circulating renal tubular antibodies have developed concomitantly with the morphologic occurrence of tubulointerstitial disease after gold injection. Renal tubular antigens can also be identified in mesangial and subendothelial deposits. Thus, gold and o th er drugs eliciting a m em branous glom erulonephritis may release antigens from the kidney or o th e r sites w hich provoke im m une com plex d e p o sitio n. 15 Focal proliferative and necrotizing glom erulonephritis may be provoked by penicillin, allopurinol, or thiazides. It is probably due to hypersensitivity. Two types of vascular lesions have been attributed to drug toxicity. Patients who abuse eith er hallucinogens or narcotics may develop severe necrotizing angiitis resem bling polyarteritis nodosa. 3 Throm botic m icroangiopathy w ith endothelial cell proliferation and fibrin deposition has been reported with the use of m itom ycin and cis-diam m inedichloroplatinum II (cis-platin). The mechanisms of injury are unknown although direct toxicity, and im m une complex m ediated effects have been postulated. 4 Tubular dam age is caused by am inoglycosides, cephalosporins, and heavy m eta ls in c lu d in g c is-p la tin, su lfo n amides, and methotrexate. These agents cause acute tubular necrosis (figure 2 ). The m echanism of aminoglycoside toxicity has been extensively studied. Aminoglycosides are low m olecular w eight, highly water soluble, polycations which bind to the brush border of the proximal convoluted tubular cells. The aminoglycosides undergo pinocytosis and fusion with lysosomes. In the acid ph of the lysosome the drug binds to phospholipids impairing the activity of phospholipases and resulting in the accumulation of m yeloid bodies, lysosomal rupture, and cell death. Nephrotoxicity is related to the degree of renal uptake of the drug and increases with the num ber of free amino groups. 14 Cephalosporins are absorbed into the proximal convoluted tubular cells from the antiluminal surface and diffuse across the cell to the lumen. The rate of diffusion affects the intracellular concentration and the toxicity. Cephaloridine is particularly toxic owing to the developm ent of high intracellular concentrations. O ne of th e recen tly proposed m echanism s of cellular injury by cephalosporins is that the drug undergoes a redox reaction to form superoxide radicals w hich react w ith lipids to form hydroperoxides. These in turn inhibit g lu c o n e o g e n e s is w ith s u b s e q u e n t im p airm en t of organic ion tra n sp o rt across th e cell m em brane eventually resulting in cell death.5 C isplatin, a highly effective chem o therapeutic agent in a variety of tum or types (figure 3) causes severe nephrotoxicity w ith necrosis in th e proximal convoluted tu b u le. 10 At least two m echanisms are implicated: (1) reduced renal blood flow and glomerular filtration rate perhaps owing to increased preglom erular vascular resistance, 16 and (2 ) free radical production within the proximal convoluted tubular epithelium. Platinum can be identified on x-ray analysis of ultrathin sections in the microbodies of tubular epithelium 7 and radical scaveng ers can a m e lio ra te th e n e c ro s is, 12 im plying a m echanism sim ilar to that invoked in cephalosporin toxicity. Roth sulfonamides and m ethotrexate9 may precipitate in renal tubules causing an o b s tru c tiv e u ro p ath y. A d e q u a te hydration and selection of the patient can prevent this toxicity.

4 TOXIC NEPHROPATHIES 219 F ig u r e 3. T h e s m a ll a r te rio le e x h ib its in filtra tio n b y ly m p h o c y te s a n d endothelial nuclear e n la rg e m e n t c o n s is te n t w ith th e v ascu litis s e e n in c is - p la tin to x ic ity (H & E m ag 50 X ). F ig ure 4. Acute in te rs titia l n e p h r itis is th e m o st c o m m o n fo rm o f n e p h ro to x ic ity (H & E m ag 50 x ).

5 220 SANDERS AND MARSHALL A cute tu b u lo in te rstitia l disease or acute interstitial nephritis is the most common drug toxicity reported in the literature (figure 4). The histologic picture is that of interstitial edem a and chronic inflammation involving areas of tubular d eg en eratio n or necrosis. N um erous drugs have been im plicated including penicillins, sulfonam ides, allopurinol, diuretics, and non-steroidal antiinflam m atory agents (NSAIDS). In the majority of these cases, hypersensitivity to the drug is invoked; the reaction is not doserelated and may recur with réintroduction of the drug. 1 Although the morphologic features of cyclosporine A toxicity also include an interstitial infiltrate of ly m p h o c y te s and tu b u la r n e c ro sis, hypersensitivity has not been proven as a mechanism of injury. Instead, attention has been paid to tubular injury owing to d ire c t toxicity, in te ra c tio n w ith the cytochrom e P450 system to generate a toxic m e ta b o lite, or hypoxia from decreased blood flow by intrarenal arteriolopathy or by hem odynam ic alterations involving the renin-angiotensinaldosterone or prostaglandin system s. 6 C hronic tubulointerstitial disease is m ost com m only caused by analgesic nephropathy with aspirin and phenacetin im p lic a te d to g e th e r. M e d u llary injury w ith papillary necrosis and sclerosis comprise the morphologic findings. 1 Nephrotoxicity owing to drugs is a heterogeneous group of lesions involving all portions of the kidney. Although acute tubulointerstitial disease, allergic interstitial nephritis, owing to hypersensitivity is the m ost common drug-induced renal lesion, acute tubular necrosis, vasculitis, and glom erulonephritides have all been linked to specific drugs through a wide variety of mechanisms. References 1. A N TONOVYCH, T. T.: D rug-induced nephropathies. Pathol. Annu. i9(pt. 2): , C h a n d e r, P., e t a l.: Renal u ltrastru ctu ral markers in AIDS-associated nephropathy. Am. J. Pathol. 126: , Citron, B. P., et al.: Necrotizing angiitis associated w ith drug abuse. New Engl. J. Med. 283: , D o l l, D. C., Rin g e n b e r g, Q. S., and Yarbro, J. W.: Vascular toxicity associated with antineoplastic agents. J. Clin. Oncol. 4 : , G o l d s t e i n, R. S., P a s i n o, D. A., H e w i t t, W. R., and H o o k, J. B.: Biochemical mechanisms of cephaloridine nephrotoxicity: Time and concentration dependence o f peroxidative injury. Tox. Appl. Pharm. 83: , KAHAN, B. D.: Cyclosporine nephrotoxicity: pathogenesis, prophylaxis, therapy and prognosis. Am. J. Kid. Dis. 8: , M a k i t a, T., H a k o i, K., and O h o k a w a, T.: X-ray microanalysis and electron microscopy of platinum complex in the epithelium of proximal renal tubules of the cisplatin administered rabbits. Cell Biol. Int. Rep. 20: , M a y, D. C., et al.: Chronic sclerosing glomerulopathy (heroin-associated nephropathy) in intravenous T s and blues abusers. Am. J. Kid. Dis. 8: , R i e s, F. and K l a s t e r s k y, J.: N ephrotoxicity induced by cancer chemotherapy with special emphasis on cisplatin toxicity. Am. J. Kid. Dis. 8: , S a f i r s t e i n, R. et al.: Cisplatin nephrotoxicity. Am. J. Kid. Dis. 8: , S t a c h u r a, I. : Renal lesions in drug addicts. Path. Annu. 20(Pt. 2):84-99, S u g h i h a r a, K. and G e m b a, M.: Modification of cisplatin toxicity by antioxidants. Jap. J. Pharm. 40: , T r e s e r, G., C h e n i b i s, C., L o n a g a r, E. T., et al.: Renal lesions in narcotic addicts. Am. J. Med. 57: , T u l k e n s, P. M.: E xperim ental studies on nephrotoxicity of aminoglycosides at low doses. Am. J. Med. 80(suppl 6B): , U e d a, S. et al.: Experimental gold nephropathy in guinea pigs: detection of autoantibodies to renal tubular antigens. Kid. Int. 29: , W i n s t o n, J. A. and S a f i r s t e i n, R.: Reduced renal blood flow in early cisplatin-induced acute re n a l fa ilu re in th e rat. Am. J. P hysiol. 249:f490-f496, 1985.