ANNALS O F CLIN ICAL AND LABORATORY SC IENCE, Vol. 6, No. 6

Copyright © 1976, Institute for Clinical Science

Acute Toxic Nephropathies: Clinical Pathologic Correlations- R O B E R T C. M U E H R C K E , M .D.,* F R E D E R IC K I. V O L IN I, M .D .,f

A R T H U R M. M O RRIS, M .D .,f JO S E P H B. M O L E S, M .D .,f an d A R TH U R G. L A W R E N C E , M .D .,f

*West Suburban Kidney Centerand

fWest Suburban Hospital, Oak Park, IL 60302

ABSTRACTM an’s e v e r in c reasing exp osu re to nu m ero us drugs an d chem icals, w h ich

are th e resu lts o f m ed ica l an d in d u s tria l progress, p ro d u ces a b y -p ro d u c t o f acu te toxic n ep h ro p a th ies . T h ese in c lu d e acu te toxic ren a l fa ilu re , drug- induced acute oliguric rena l failure, acute hem orrhagic glom erulonephritis, n ep h ro tic syndrom e, tu b u la r d is tu rban ces an d po tassiu m defic iency . In d e p th in fo rm ation is p ro v id ed for th e p rev iou sly m en tio n ed d iso rders.

In tro d u c tio nA c u te to x ic n e p h r o p a th y is a b y ­

p ro d u c t o f m an’s ev e r in creasing expo­sure to a vast array o f various chem icals an d drugs th a t re su lt from in d u stria l and m ed ica l p rog ress. T h e k id n ey , w ith its r ich b loo d supply , n u m ero us enzy m e sys­tem s an d su p e rio r excretory function , is e sp ec ia lly v u ln e rab le to th e ad v erse ef­fects of chem icals, bio logic products an d d r u g s .44,226 T h e k id n e y s c o m p rise 0.4 p e rc e n t o f th e to ta l bo dy w e ig h t an d re ­q u ire a h igh oxygen consum ption . T h e k id n e y ’s o x y g en r e q u i re d is s u p p l ie d th ro u g h approxim ately 20 to 25 p e rc e n t o f th e cardiac ou tpu t.

A lthough th e k idneys are o f re la tive ly sm all w e igh t, th ey have th e g rea te s t sur­face area of en d o th e lia l cells w h en com ­p a re d to o th e r organs. T he k idn eys w ith th e ir num erous enzy m e system are sec­o n d on ly to th e liv e r in com p lex ity o f m etab o lic function . F ina lly , th e k idneys

have ex trem ely vascu lar renal m ed u llae a n d re te m irab ile th a t fu n c tio n in th e final d ilu tio n an d co n cen tra tio n o f th e u rin e . T h is com plex m echan ism resu lts in hy perto n ic ity o f th e ren a l in te rs titiu m w ith con cen tra tion o f nephro tox ic ch em i­cals, b io logic p rod uc ts an d drugs.

In o u r ex p e rie n c e , ap p ro x im ate ly 25 p e rc e n t o f all p a tien ts w ith acu te o lig uria have rena l fa ilu re in d u c e d by drugs or c h e m ic a ls .188 T h e o th e r m a in c lin ic a l syndrom e o f toxic n ep h ro p a th y in c lu d e th e n ep h ro tic syn d rom e ,133,180,256 tu b u la r d i s o r d e r s ,96 a c u te h e m o r r h a g ic g lo m e ru lo n e p h r i t is a n d c h ro n ic re n a l failure.M echanism

N ep h ro to x ic ch em ica ls hav e e x e r te d th ese adv erse effects on th e k idn ey e ith e r s in g ly o r th ro u g h a c o m b in a t io n o f p a th o p h a rm aco lo g ic m ech an ism s . O n e m ech an ism is th e d ire c t a c tio n o f th e

4 7 8 M UEHRCKE, VOLINI, MORRIS, MOLES AND LAW RENCE

nephro tox ic su b stan ce as a p ro top lasm ic po iso n . T h e n e p h ro to x ic a g e n t p a sse s in to th e g lo m e ru la r f i l t r a t io n in a n a m o u n t p r o p o r t io n a te to th e f i l t e r e d p lasm a w a te r. As th e n ep h ro to x ic su b ­stance is a fo re ign com p oun d an d has no specific rena l tu b u la r tran sp o rt p rocess, it is p rog ressive ly co n cen tra ted w ith in th e tu b u la r lu m en . T h e co n cen tra tio n o f th e nephro tox ic ag en t is so g reat th a t it dam ­a g e s th e tu b u la r e p i th e l i a l c e l l s . M o reo v e r, o th e r n e p h ro to x ic s u b s ta n ­ce s204,228,238 m ay in crease in th e ir c o n cen ­tra tio n to reach toxic lev e ls w ith in th e m e d u lla ry in te rs tit iu m by th e osm otic con cen tra tio n o f flu ids. W hen su ffic ien t qu an tity is accu m u la ted , th e k id n ey in ­te rs titiu m is dam aged . C h ro n ic p h en ace- tin n e p h ritis is one exam p le o f su ch a co n d itio n .103,147,224

Som e nephrotoxic substances penetra te th e c e ll to in te ra c t w ith c e l lu la r c o n ­s titu en ts and , su b seq u en tly , po ison th e cell. O n e exam ple o f th is m echan ism is

TABLE I

Common Chemicals that Induce Acute Oliguric Renal Failure

Chemical

Mean Lethal Dosage (Approximately per 70 kg)

Anilin 10 gArsine gas (AsH-j) MAC* 30 ppmCamphor 2 gCarbon tetrachloride 4 ml (MAC* 25 ppm)Chlordane 8 gChloroform 25 mlCopper compounds 15 gCreosote 10 gEssential (volatile) oils 1 9Ethylene dischloride MAC* 100 ppmEthylene glycol 100 mlFormaldehyde (formalin) 30 mlGuaiacol 2 9 -aMercury compounds MAC* 0.1 mg/MJ

i gNaphthalene 5 gOxalates 5 gParadichlorobenzene 15 gPentachlorophenol i gphenol 10 gPhosphorus, yellow 0.05 g (MAC* 1 g/M3)Resorcinol 2 gTetrachloroethane. MAC* 5 ppmThymol 2 g

*MAC - maximum allowable concentration

th e n e p h ro to x ic e f fe c t o f m e ra l lu r id e (M e rc u h y d r in ) , w h ic h re a c ts w ith e n ­zym e system s o f th e su lfh ydry l g roups w ith in th e w all o f m ito cho nd ria . O th e r n ep h ro tox ins co u p le w ith enzy m es to in ­activate th em . Som e n ep hro tox ins affect enzym es w ith in th e m ito cho nd ria , w h ile o th e r toxins affect cy top lasm ic enzym es. T h is function a l in te rfe ren ce m ay re su lt in no ap p a ren t tu b u la r m orpho log ic abn or­m alitie s w h en th e tissu e is s tu d ie d b y lig h t or e lec tro n m icroscopy. O th e r p ro ­to p la sm ic to x in s , w h e n c o n c e n tra te d , m ay coagulate p ro te in an d m ay re su lt in e ith e r severe tu b u la r necrosis or d iffuse b ila te ra l ren a l cortical necrosis.

O th e r nep hro tox ic agen ts p ro d u ce th e ir adv erse effects th ro ug h an im m un olo g i­cal pathopharm aco log ic m echan ism . T he b e s t exam p le o f such a m od el is du ck egg a lb um in . T h e m orphologic site in vo lved is u su a lly th e large en d o th e lia l surface o f th e g lom eru la r cap illa ries , a rte rio les and arteries. T he duck egg a lbum in acts as an an tig en evok ing a p rod uc tion o f an tibody . Im m u n e com plexes fo rm ed in th e p re s ­en ce o f co m p lem en t p ro d u ce dam age to g lom eru lar cap illa ries.

A n o th er im p o rtan t ad d itio n a l s ite in ­v o lv ed b y h y p e rsen s itiv ity reac tio ns is th e re n a l in te rs tit iu m . T h is h y p e rs e n ­sitiv ity in te rs titia l reac tio n w as rep o rted m ore th an 75 years ago by C o u n c ilm an .60 K n o w n as “ C o u n c i lm a n ’s in te r s t i t ia l n ep h ritis ,” it is ch arac te rized by in te rs ti­tia l in filtra tes o f p lasm a ce lls , sm all lym ­phocy tes, and eosino ph ils . A few o f th e d ru g s th a t c a u se th is h y p e rs e n s it iv ity reac tio n are p h e n in d io n e , d ip h en y lh y - dan to in (D ilan tin ), m e th ic illin , p h e n y l­b u ta z o n e a n d m e ra llu r id e (M ercu h y d ­rin).

In gen era l, substances toxic to th e k id ­n ey in c lu d e chem icals, as p re se n te d in tab le I, in any physical sta te (liqu ids, sol­ids, an d gases); b io logic p ro d u c ts such as h o rse se ru m , fu n g i (m u sh ro o m s), a n d vaccines; an d drugs g iven o rally o r par­

ACUTE TOXIC NEPH R O PATH IES 479en te ra lly . D rug s p ro d u ce o th e r c lin ica l syndrom es o f ren a l d isease , in c lu d in g th e n ep h ro tic syndrom e, ch ro n ic ren a l fail­u r e , tu b u la r d i s tu r b a n c e s a n d a c u te h e m o r rh a g ic g lo m e r u lo n e p h r i t i s . I n som e situa tions, th e dam age is m ild and transitory . In o th e r s ituations, th e dam age is severe an d irrev e rs ib le le ad in g to th e p a tie n t’s dea th .

A cute (Toxic) R en a l F a ilu reT he m ore com m on nep hro tox ins pro­

d u c in g acute ren a l failu re are heavy m e t­als, o rgan ic so lven ts , g lycols, an a lin e , in ­sec tic id es , a rs in e , c reso l a n d a m isce l­laneous g ro u p o f chem icals. T h e y usu ally act d irec tly on th e tu b u la r cells to d is ru p t th e ir m etab o lic an d m orpho log ic in teg ­rity.

M e r c u r y C o m p o u n d s

T h e in o rgan ic sa lt b ich lo rid e o f m er­cury (m ercuric ch lo ride) is also know n as corrosive sub lim ate . M ercuric ch lo rid e is u su a lly in g es ted acc id en ta lly ,175 in su ic i­dal a ttem p ts ,34 o r fo llow ing its u se as an abortive agen t. T h e dose re q u ire d to in ­d u ce ren a l fa ilu re is d ifficu lt to assess .71 In m ost rep o rts th e p a tien ts w ith acu te renal fa ilu re h ad in g es ted tw o o r th ree tab le ts (0.5 g e a c h ).129 W hen m ore than fou r ta b le ts w e re tak en , a cu te o lig uric renal fa ilu re w as fatal. R enal lesions d e ­v e lo p ed w ith in th re e hours after in g es­tio n .47,245 E m e tic an d gastric lavage so­lu t io n s c a n b e m a d e fro m a g la ss o f sk im m ed m ilk w ith th re e to fo u r te a ­spoons o f tab le sugar, tw o tab lesp o o n s o f bak in g soda an d th re e eggs.

S ch re in e r an d M aher d e sc rib ed 11 p a ­t ie n ts w h o h a d m e rc u r ic c h lo r id e - in d u ced acu te o liguric renal fa ilu re .225,223 F ive p a tien ts w ho su rv ived w ere trea ted w ith in 48 hours after in g estin g m ercu ric ch lo ride ; hem o d ia lysis an d d im ercap ro l (BAL) in fu s io n w e re th e m e th o d s o f

t r e a tm e n t .138, 167,169 S ix p a t ie n ts w e re tre a te d a fte r u rem ia occu rred , an d on ly th re e o f th o se six su rv iv ed .168 BAL a p ­p ears to en h an ce th e rem oval o f m ercu ric ions by 7 to 11 p e rc e n t w ith th e u se o f h em o d ia ly s is .15

T h e c l in ic a l sy m p to m s o f in o rg a n ic m ercu ry po iso n in g b eg in w ith a lin g e rin g b i t te r an d m e ta llic ta s te in th e m ou th . T h e p a t ie n t ex p e rien ces a sen sa tio n o f th ro a t constric tion , suffocation, subster- n a l b u rn in g , g a s tritis , a b d o m in a l p a in and , finally , n au sea an d v o m iting .109 P e r­s i s t e n t v o m itin g le a d s to r e tc h in g o f b loo d . U lcera tion m ay b e n o ted in th e p a ­la te . T h e p a t ie n t goes in to c ircu la to ry fa ilu re ; th e p u ls e b e c o m e s w e a k a n d rap id . Syncope an d shock are fo llow ed b y a scanty u rin ary ou tp u t. F in a lly , a fatal an u ria develops. Jau n d ice occurs in a p ­prox im ately 35 p e rc e n t o f th e pa tien ts .

T h e k idn eys o f p a tien ts w ith in o rgan ic m ercu ry p o iso n in g are u su a lly en la rg ed an d w eig h up to 250 g each . T h e ren a l cortex is pa le an d th ick en ed . T h e ren a l m ed u llae are a s ligh tly darker b row n th an norm al. T h e m ost s trik ing m orpho log ic ab n o rm alitie s occu r in th e proxim al con­v o lu ted tu b u le s .97 T h e re is ex tensiv e ce l­lu la r necrosis an d th e lu m in a are filled w ith g ran u la r eo sin o p h ilic m ateria l b e ­lie v e d to b e d e riv ed from th e cytop lasm o f n ecro tic c e lls .61 L ess s trik ing ab n o r­m a l i t ie s a re fo u n d in th e a s c e n d in g lim bs, d ista l con vo lu ted tu b u le s a n d col­le c t in g tu b u le s . In ap p ro x im a te ly o n e w eek , th e lum inal necro tic d eb ris clears, p ro b ab ly b e c a u se o f d ig e s tio n by p la s ­m o ly tic enzym es. In ad d itio n , th e d eb ris is w ash ed dow n th e n ep h ro n lu m e n by th e g lo m e ru la r f i l t ra te . T h e p ro x im a l tu b u le app ears to be d ila ted an d lin e d by flat e p ith e lia l c e lls .181 P atchy calcification m ay occu r in severe ly dam ag ed tu b u les . I n t e r s t i t i a l e d e m a is n o te d e a r ly ; i f o lig uria is p ro lon ged , in te rs titia l fibrosis e n su e s . M ercu ria ls h av e p ro d u c e d th e n ep h ro tic syndrom e in som e p a tie n ts .17

4 8 0 MUEHRCKE, V OLINI, MORRIS, M OLES AND LAW RENCE

C a r b o n T e t r a c h l o r i d e

C arbon te trach lo rid e (C C 14) is w ide ly u sed as an in d u stria l so lven t, as a h o u se ­ho ld c lean in g agen t, as a co n s titu en t in ce rta in ty pes o f fire ex tin g u ish ers , in som e ha ir lo tions, as an an tih e lm in tic ag en t and as a v e rm ifu g e .2 I t is a vo latile , h eav ie r th an a ir liq u id th a t accounts for th e high in c id en ce o f exposu re in poorly v en tila ted areas. C arbo n te trach lo rid e is toxic in con­cen tra tion s g rea te r th an 100 p p m .86 I t is ab so rb ed th ro ug h th e lungs, th e sk in and th e gut. I t co n cen tra tes in fatty tissu e such as th e b ra in an d b o n e m arrow .

C a rb o n te t r a c h lo r id e is s o lu b le in e th an o l. T h e re fo re , th e d r in k in g o f a l­coholic bev erag es an d th e s im ultaneous exposu re to carbon te trach lo rid e te n d to in crease or en h an ce ca rbon te trach lo rid e ab so rp tio n an d s u b s e q u e n t toxicity . In v itro , carbon te trach lo rid e is ox id ized to p h o sg e n e an d la te r can c o n d en se w ith e th y l alcohol to form e th y l chloroform ate. T h e la t te r is an ex trem ely nephro tox ic substance . In th e ab sen ce o f e th y l alcohol, p h o sg e n e co n d e n se s w ith am m onia to form urea.

C a rb o n te t ra c h lo r id e a p p e a rs to b e m ore d an g ero u s in o b e se o r in u n d e r ­n o u rish ed ind iv id uals . In F ran ce , carbon te trach lo rid e was th e com m on est ch em i­cal p ro d u c in g acu te re n a l fa ilu re . T he c lin ica l features o f acu te p o iso n in g are variab le . M ales are m ore often afflicted th an fem ales by a ra tio o f 14 to 1. In h a la ­tion is th e m ost fre q u e n t rou te o f expo­sure. T oxicity cau sed by in g estio n carries a grave p rognosis. In itia lly , th e p a tie n t has surface or superfic ia l irrita tion to th e ex­p o sed sk in an d m ucous m em branes. L ater th e p a tie n t has head ach e , nau sea , vom it­ing, abd om in al p a in a n d m en ta l confusion le a d in g to c o n v u ls io n s a n d com a. A l­th o u g h liver dam age is a v ery strik ing fea­tu re o f carbon te trach lo rid e toxicity , acute ren a l fa ilu re is th e m ost f re q u e n t cause of d ea th .

T h e o n se t o f o lig u ria is p ro lo n g ed and m ay occu r sev en to te n days after expo­sure . Som e p a tien ts m ay have forgotten th e ir exp osu re to th is so lven t. A bsolute an u ria m ay la s t from one day to several w e e k s . O n e p a t ie n t h a d c a rb o n te trach lo rid e -in d u ced o liguria for 67 days. In th e p re se n t au th o r s ex p erien ce , pa­tien ts w ith acu te ren a l failu re cau sed by carbon te trach lo rid e w ere u su ally “ do-it- y o u rse lfe rs .” T h e y u su a lly w o rk ed in ­doors, gen e ra lly in th e b a sem en t d u ring th e w in te r m on ths. T h is m ean t th a t th e w indow s w ere c lo sed an d th e re w as no source o f v en tila tio n . T h ey usu ally drank several cans o f b e e r w h ile th ey re fin ish ed fu rn itu re o r c lean ed ou tb oard m otors or c lo thes, — usu a lly neck ties.

M orpho log ic abn orm alities occur in th e cortical convo lu tions and H e n le ’s loops. T u b u la r necrosis is m ost p ro m in en t in th e ou tm ost co rtica l po rtion . A cute tu b u la r n e c ro s is m ay b e s e v e re w ith tu b u la r coagu lation an d deg ran u la tio n .236 U ltra- s truc tu ra l stu dy o f th e g lom eru li reveals th em to b e norm al. In itia lly in te rs titia l ed em a is com m on; la ter, in te rs titia l fi­b rosis occu rs .233T e t r a c h l o r o e t h y l e n e

T e tr a c h lo r o e th y le n e is a c o lo r le s s liq u id w ith an e th e re a l odor. I t is so lub le in organ ic so lven ts. T e trach lo ro e th y len e has rep laced carbon te trach lo rid e in the tre a tm e n t o f hookw orm in festation . I t is p laced in soft ge la tin capsu les o f e ith e r 0.2, 1.0 or 2.5 ml. T etrachloroethylene pro­d u ces in e b r ia tio n , g id d in e ss an d liv e r dam age. I t is less nephro tox ic th an carbon te t ra c h lo r id e b u t h as p ro d u c e d acu te oliguric renal fa ilu re from acu te tu b u la r necrosis.G l y c o l T o x i c i t y

G lycols, as p re se n te d in tab le II, are found in au tom ob ile an tifreeze , so lvents for p lastics, pa in ts (especia lly lacquers, te x tile s , an d co sm etic s ) an d flav o rin g

TABLE IX

The Toxic Glycols

ACUTE TOXIC NEPH RO PATH IES 4 8 1

G1ycol

Ethylene glycol (antifreeze)Ethylene glycol diacetate Propylene glycol Diethylene glycol (diglycol)Ethyl diethylene glycol (carbitol)Methyl diethylene glycol (methyl carbitol) Butyl diethylene glycol (butyl carbitol)

Diethylene dioxide (dioxane)

Dipropylene glycol

h o «c h 2c h 2 *o hc h 3c o *o *c h 2 *CH2 *0 *C0 *c h 3h o -c h 2 -c h -o h -c h 3H O •CH 2 * CH 9 * 0• CH ? * CH ?•OHC2H5 •0•CH2 •CH2 •0•CH2 •CH2 •OH CH3 * O •CH2 * CH2 * O •CH2 ■CH2 ‘OH C4H9*0*CH2 *CH2 *0«CH2 *CH2 'OH

CHo «CHo.

1 2 2

CH,-OH-CH-CH,-0-CH0-CH-0H-CH,

ex tracts. A llen has c la ss if ie d th e toxic g lyco ls .5 T h e m ore im p o rtan t nephro tox ic g lyco ls a re e th y le n e g lyco l a n d d ie th ­y len e glycol. E th y le n e glycol d in itrite , a yellow liq u id u se d in th e exp losive in d u s­try, p ro d u ces sym ptom s re se m b lin g th ose o f n itro g ly c e ro l to x ic ity . M eth em o g lo - b in u ria a n d a c u te tu b u la r n ec ro sis a re th e p ro m in en t ren a l fea tu res. P ro p y len e glycol p ro d u ces h em o g lo b in u ria an d p ro ­lo n g ed o lig u ria w ith o u t c rysta ls in th e tu b u la r lu m en . E th y le n e d ich lo rid e m ay p ro d u c e shock , p u lm o n a ry e d e m a an d tu b u la r necrosis.

E th y le n e g lyco l. E th y le n e glycol is th e m ain su b stan ce in an tifreeze an d w as m ade p o p u la r d u rin g W orld W ar I. I t is a co lorless odorless liq u id an d is in g es ted b y m is ta k e d u r in g “ a lc o h o lic b o u ts .” Som e d esc rib e its taste as u n p lea san t and waxy; o thers d e sc rib e it as sw e e t .164 W h en it is m ixed w ith w a te r an d is sw allow ed, it im parts a fee lin g o f w arm th to th e m ucous m em branes an d p ro d u ces acu te in eb ria ­tion . E th y le n e glycol is co n v erted to th e m o re n e p h r o to x ic in te r m e d ia r ie s , — g lyeo la ld ehy de , glyco lic acid an d oxalic a c id .137,206 E ach o f th e in te rm ed ia ry com ­po u n d s is a p recu rso r o f oxalate.

A lthough calc ium oxalate crystals are found w ith in th e renal tu b u le s an d o th e r organs, acu te o lig uric failu re does no t re­su lt from th e s im p le ob struc tive effects o f

oxalate. I t is th e d irec t nephro tox ic effects o f e th y le n e g lyco l o r o n e o f its in te r ­m e d ia ry p ro d u c ts th a t in d u c e s a c u te o lig u ric re n a l fa ilu re . T h e m o st lik e ly nep hro tox ic p ro d u c t is oxalic acid. T h e le th a l dose o f e th y le n e glycol (100 m l) w o u ld b e co n v erted to th re e to 10 g o f oxalic acid . As sm all a dose o f oxalic acid as tw o g w o u ld b e fa ta l.95 G astric lavage an d sod iu m b icarb on a te in fusion are tw o im p o rtan t aspects o f in itia l therapy .

W h e n la rg e q u a n t i t i e s o f e th y le n e glycol are in gested , th e c lin ical fea tu res are d o m in a ted by th re e d is tin c t s tag es .145 T h e first ex tend s from 30 m in to 12 hrs a fte r in g es tio n an d is ch a ra c te r iz e d by cen tra l n ervo us system sym ptom s w ith in ­itia l h y perac tiv ity p rog ressing to com a. I f th e p a tie n t survives th e in itia l com plica­tion , h e en te rs th e secon d stage w h ich is ch a rac te rized by card iac an d p u lm o n ary fe a tu re s w ith ta c h y p n e a , cyan osis an d p u lm o n a ry e d e m a . T h e th ird s ta g e is c au sed by d ep o s itio n o f calcium oxalate c ry s ta ls w ith in th e k id n e y , a n d a c u te o ligu ric ren a l fa ilu re occurs. In th e early stage o f ren a l affliction th e u rin e m ay con­ta in oxalate crystals an d p ro te in .

T rea tm en t in c lu d es th e in itia l gastric lavage w ith a 5 p e rc e n t so lu tion o f sod ium b icarb on a te . In te rm e d ia te d ia ly sis is im ­po rtan t to rem ove th e g lyco l.200 In trav en ­ous e th an o l is he lp fu l in com p etin g w ith

482 M UEHRCKE, VOLINI, MORRIS, MOLES AND LAW RENCE

liv er enzym es (e.g., deh yd ro gen ase ) th a t m etab o lize e th y le n e glycol. M orphologic abn orm alities o f e p ith e lia l ce ll d e s tru c ­tion w ith in tac t b a se m e n t m em brane are com m on. T u b u le s are filled w ith m asses o f calcium oxalate crystals th a t are b ire- frin gen t u n d e r po la rized ligh t. In tra ren a l h y d ro n e p h ro s is is n o te d . I n te r s t i t i a l e d e m a a n d focal c e llu la r in f i ltra te s o f m o n o n u c lear cells are p re sen t. In a d d i­tion , oxala te c ry s ta ls a re fo u n d w ith in o th e r organs such as th e b ra in , th e h ea rt an d th e lungs.

D ie th y len e g lycol. D ie th y len e glycol is a colorless liq u id w h ich was u sed w ith catastrophic resu lts as a m ed ic ina l v eh ic le in an e lix ir o f su lfan ilam ide. D u rin g S ep ­te m b e r an d O ctob er o f 1937, at leas t 76 p a tien ts d ied w ith in a few days a fte r tak­ing th e e lix ir w h ich co n ta in ed 72 p e rcen t d ie th y len e glycol an d a 10 p e rc e n t so lu­tion o f su lfan ilam ide. T h is d ru g -in d u ced d isa s te r o c c u rre d in an e ra b e fo re th e U n ited States F o o d a n d D ru g A dm inistra­tion h ad its d ru g eva lua tion program in effect. T h e recom m endatio n o f G eilin g and C an n o n in a rep o rt on th e toxicity o f th e su lfan ilam id e e lix ir c an b e u se d as an ex ce llen t g u id e lin e for th e p h a rm aceu ti­cal eva lua tion o f d ru g s .105 T h e ir rep o rt is reco m m en d ed to in d iv id u a ls w ho have any doub ts o f th e necess ity for d ru g tox­icity evaluation .

G rossly , th e k id n ey w as pa le , flabby an d sw ollen . M icroscopically , th e re was severe hydropic tu b u la r degeneration sim i­lar to th a t seen in th e proxim al tu b u le s o f p o tass iu m -d ep le ted p a tien ts . T h e e p ith e ­lial cells w ere sw o llen an d th e ir lum ina w e re p a te n t . S p o k e - l ik e d e e p ly basoph ilic crystals w ere seen in the d istal con vo lu ted tu b u les . B ilateral renal co rti­cal necrosis w as seen in a large group o f in d iv id ua ls fo llow ing su lfan ilam ide e lix ir ingestion .A n i l i n e

A niline an d its deriv a tiv e , ph eny lhy d- roxylam ine, have low m o lecu la r w eigh ts

(93 a n d 109, re sp e c tiv e ly ) . T h e y pass th ro ug h th e sem ip erm eab le m em brane o f th e h em o d ia ly s is un it. A cute p o iso n in g by p u re an ilin is ra re .118 H ow ever, p o iso n in g does occu r in in d u stria l w orkers an d in c h i ld re n e x p o sed to in ks, co lo red wax c ra y o n s a n d sh o e p o l i s h e s . D ia p e r s fresh ly s tam p ed w ith an ilin e m ark ing ink have re su lte d in fatal m eth em o g lob inu ria an d acu te ren a l fa ilu re in infants.

A n iline po iso n in g has b e e n cau sed by th e p e rc u ta n e o u s a b so rp tio n o f an ilin e from f re s h ly d y e d sh o es o r b la n k e ts . A n il in e a n d its d e r iv a t iv e p ro d u c e hem olysis, m eth em o g lo b in u ria ,53 shock, cyanosis, d y sp n ea , h ead ach e , d izz in ess and b lu rr in g o f m en ta l functions. I f th e an ilin e po iso n in g is severe , th e m an ifesta­tions are shock, cyanosis, com a, anem ia and , finally , fatal an u ria .259

T h e d ia g n o s is is m a d e w h e n m e th em o g lo b in u ria is found. T h is is d e ­tec ted as a w e ll-d e fin ed abso rp tion ban d at 630 w av e len g th s an d im m ed ia te ly d is­appears a fte r th e a dd ition o fa few drops o f 5 p e rc e n t po tassium cyan id e (KCN) solu­tion . D iazo -reac ting com pounds can be found in th e b lood , u rin e , and hem odialy- sate. C o m parisons o f th e d iazo-reacting com pounds in b lood, u rin e and dia lysate are u sed to o b ta in an op tim al c lin ica l en d p o in t for d ialysis.

T rea tm en t for th e p o iso n in g is th e re ­m oval o f an ilin e b y gastric lavage, p u rges, an d hem odialysis . T his rem oval perm its th e re d u c in g enzy m e system o f th e e ry th ­ro cy te to re c o n v e r t m e th e m o g lo b in to h e m o g lo b in rap id ly . In tra v e n o u s ly in ­je c te d m e th y len e b lu e in doses o f 1.0 to2 .0 m g p e r kg bo dy w e ig h t sh o u ld be g iven over a p e rio d o f several m inutes. T h is d o s e v e ry r a p id ly r e c o n v e r ts m eth em o g lo b in to hem oglobin . I t m ay be n ecessary to re p e a t m e th y len e b lu e in jec­t io n s a t h o u r ly in te r v a ls . T h e b lo o d p ressu re sh o u ld b e su p p o rted by w hole b lo o d transfusio ns, vaso p ressive agen ts an d h e m o d ia ly s is . D ia ly sis sh o u ld b e

ACUTE TOXIC NEPH RO PATH IES 483m ain ta in ed for lo n g e r p e rio d s th a n are usu al for tre a tin g acu te ren a l failu re. S uch trea tm en t w ill rem ove th e toxic deriv a tiv e m o b ilized as a l ip id so lu b le m ateria l from b o dy tissues. A cute tu b u la r necrosis is th e com m on m orp h o lo g ic ch an g e fo u n d in an ilin e po ison ing .I n s e c t i c i d e s

T h e tw o m ain groups o f nephro tox ic in ­sec tic ides are th e ch lo rin a ted h y drocar­b o ns an d th e o rg an o p h o sp h a te s . A cute tu b u la r n e c ro s is is th e co m m o n m o r­phologic fin d in g in p a tien ts w ith acu te o liguric ren a l fa ilu re .

C h lo rd a n e . T h e c h lo r in a te d h y d ro ­carbon in sec tic id es are s tim u lan ts o f th e cen tra l nervous system . T h e y kill in sec ts by o v e rs tim u la tio n an d m ay cau se th e d ea th o f m an th ro u g h th e sam e m echa­nism . T h e c h lo rin a ted hy drocarbo n in sec ­tic ides p e n e tra te th e sk in o f m an or are in h a led w h en th e in sec tic id e is in a fine aerosol spray.

C h lo rdan e , o n e exam ple o f th is group has p ro d u c e d fatal a n u ria .66 T h e in itia l c lin ica l sym ptom s a re d izz in ess, nausea, head ache an d ataxia. S u d d en u n ex p ec ted convu lsions s im ila r to gran m al ep ilep sy o c c u r a n d le a d to s tu p o r a n d co m a . P u lm o n ary e d e m a m ay occu r b e tw e e n ep isod es o f re p e a te d convu lsions. Shock m ay occur an d m ay b e fo llow ed by acute o ligu ria an d d ea th in urem ia.

P a r a th io n . P a ra th io n is a n or- gan op ho sp ha te ty pe o f in sec tic ide . M ann an d associates o b se rv ed th a t renal tu b u la r m alfunction occu rred in in d iv id ua ls d u r­in g occupational exposu re to para th ion . T he chron ic exp osu re to p es tic id es con­ta in in g para th io n p ro d u ces a ch ron ic irre ­versib le renal tu b u la r dysfunction th a t in ­creases w ith du ra tio n o f exposure.H e x o l

H exol is a m ix ture o f a s team -d istilled p in e oil d e riv a tiv e (70 p e rcen t) an d n e u t­ral soap (30 p ercen t). T h e p in e oil d e riv a­tive is a m ix ture o f te rp in alcohol, p re ­

do m in a te ly te rp in eo l, w ith 5 to 10 p e rc e n t each o f te rp e n e , b o rn eo l an d te re p e n e e th ers . H exol is u sed in th e U n ited S tates as a h o u seh o ld d isin fec tan t.

T h e com m on toxic effects o f p in e oil d is tilla te s are local irrita tion on th e sk in o r b u rn in g p a in in th e m o u th .177 T h ey p ro ­d u ce cen tra l nervo us system exc ita tion and , la te r, d ep re ss io n . H exol p ro d u c e s head ach es , g id d in ess , ataxia, s tu p o r an d d ea th in resp ira to ry fa ilu re c au sed b y c e n ­tra l n ervo us system d ep ression .

T h e p in e oil d is tilla tes have p ro d u ced d y s u r ia , h e m a tu r ia , p r o te in u r i a , a n d g lyco su ria .55,132 In gen era l, ren a l dam age is tra n s ie n t an d c o m p le te ly re v e rs ib le . G o m e l an d G o ldm an rep o rted a 31 year o ld w om an w ho h ad h ex o l-in d u ced acu te o l ig u r ic r e n a l f a i lu r e .111 S h e u s e d a sy rin ge an d c a th e te r to in still in to h e r u te ru s th re e to six ounces o f 2:1 m ix tu re o f hexol an d w ater. T h e fo llow ing day she h ad anu ria , w h ich la s ted four days an d a d iu re s is fo llow ed. E le v e n m on ths la te r h e r c rea tin in e c learance w as 47 m l p e r m in . T w o ren a l b iop sy s tu d ies w ere do n e , th e first a t six w eek s a n d th e secon d a t five m on ths a fte r anu ria . T h e p ro m in e n t fin d ­ings w ere a com p le te ly h e a le d ren a l tu b u ­la r lesion , a tro p h ie d tu b u le s an d in te rs ti­tia l fibrosis.A r s i n e

A rsin e-in d u ced ren a l fa ilu re w as d is­cu ssed p rev iously . I t u su a lly occurs as an occu pation al h aza rd .67,74 W h en an u ria oc­c u rs th e p ro g n o s is is g ra v e .33 A rs in e (A sH 3) is in h a le d an d read ily com b ines w ith th e hem o g lo b in w ith in th e e ry th ro ­cy te to form an a rs in e -o x y h e m o g lo b in co m p lex .151 T h is is in itia lly ox id ized to A sH 2-hem og lob in . As th e ox idation p roc­ess c o n tin u e s an a rse n ic -h e m o g lo b in - b o u n d p r o d u c t o c c u rs . I n t r a v a s c u la r h e m o ly s is o c c u rs a n d r e s u l t s in m eth em o g lo b in u ria an d m assive h em o ­g lob inu ria . H em o g lo b in an d e ry th ro cy te casts fill th e tu b u la r lu m e n .173 A n u m b e r o f

4 8 4 M UEHRCKE, VOLINI, MORRIS, M OLES AND LAW RENCE

s im u ltan eous co n d itio n s occur. T h e is ­ch em ia cau sed b y anem ia , th e p re sen ce of hem o glo b in , m eth em o g lo b in , an d e ry th ­rocyte casts and th e d ire c t tissue anoxia o f a rsine on th e resp ira to ry enzy m es o f th e n ep h ro n all, e ith e r sing ly or in com b ina­tion , p ro d u ce acu te tu b u la r n ec ro s is .194Cresol

C reso l shares th e g en e ra liz ed n e p h ro ­to x ic i ty o f c a r b o l ic a c id , n a p h to l , g u a iaco l, c re o so te a n d o th e r p h e n o ls . Lysol (cresol) has b e e n tak en for su ic ide p u rp o ses o r in excessive co n cen tra ted so­lu tio n s v ia v ag in a l d o u c h e s to in d u c e ab o rtio n .92 C reso l is le th a l in a dose o f 50 to 100 m l. I t p ro d u ces m ucous m em brane necrosis, b u t th e p a tie n t is n o t aw are o f th e toxic effect. T h e c lin ica l fea tu res are n au sea , vom iting , d izz in ess, ataxia, a b ­dom inal p a in an d shock. S evere intravas- cu la r hem olysis occurs an d is fo llow ed b y hem o g lo b inu ria , p ro te in u ria , hem aturia , acu te cystitis an d acu te o lig u ria cau sed by acu te tu b u la r necrosis. T h e p e n e tra t­ing sm ell o f c reso l m akes th e d iagnosis e a s ie r . T h e m u co u s m e m b ra n e o f th e m ou th and to n g u e m ay b e b u rn e d and m ay ap p ea r to b e d u ll w h ite w ith p h en o l an d d a rk e r b row n w ith cresol.

T r e a tm e n t in c lu d e s la v a g e o f th e sto m ach w ith sod iu m b ic a rb o n a te , fo l­lo w ed by a p u rg e o f m agn esium sulfate (6 g in 100 m l). S k in b u rn s s h o u ld b e th o rou gh ly w ash ed w ith soap and cop i­ous am ounts o f w ater. T h is sh o u ld b e fol­lo w ed by a w ash w ith a 10 p e rc e n t so lu­t io n o f a lc o h o l. T h e sk in s h o u ld b e d re sse d w ith gauze soak ed in a s te rile so lu tion o f sod ium b icarb o n a te (0.5 p e r­cent). T racheobronchial secretions should b e a sp ira ted to p re v e n t pu lm on ary in fec­tion . T h e p a tie n t m ay re q u ire d ialysis.P o t a s s i u m B r o m a t e

A cciden ta l p o iso n in g w ith po tassium b rom ate occurs in in fan ts an d ch ild ren . P o ta s s iu m b ro m a te w a s th e p r im a ry chem ical co n s titu en t o f th e n eu tra liz in g

so lu tio n u se d a fte r T on i p e rm a n e n t w ave o r C o ld w a v e . D u n s k y r e p o r te d a 17 m o n th o ld in fa n t w h o h a d fa ta l a c u te o lig uric ren a l fa ilu re fo llow ing in gestion o f th e n eu tra liz in g so lu tio n .78

At au top sy th e p a tie n t h ad g en e ra lized ed em a an d acu te tu b u la r necrosis. W ar­ren an d G ross re p o rte d a tw o year o ld in ­fan t w ho w as acc id en ta lly fed T on i neu t- r a l iz e r .250 A fter 38 day s o f a n u ria a n d o liguria , th e ch ild gradually recovered .C h l o r a t e C o m p o u n d s

Sodium ch lo ra te an d po tassiu m ch lo ­ra te a re u s e d in th e m a n u fa c tu re o f m a tc h e s , e x p lo s iv e s , to o th p a s te a n d syn th e tic p igm en ts . T h ey a re also u se d as w eed k ille rs . P o tassium ch lo ra te is u sed as a n o x id iz in g a g e n t in lo zen g es an d gargles.

I f th e p a tie n t d ev elo ps acu te ren a l fail­u re , th e o n se t stage varies from 3 to 15 h o u rs . T h e c lin ic a l fea tu res are fever, h y p o ten sio n , jau n d ice , abdom inal pa in , n a u s e a , v o m it in g , d ia r r h e a , e x tre m e fatigue, ne rv o u sn ess an d head ache . T h e skin an d m ucous m em branes are d eep ly c y a n o se d w ith a b ro w n ish -g ra y co lo r. T h e p a tie n t has m assive hem olysis w ith h em o g lo b inu ria . A cute tu b u la r necrosis is th e com m on m orphologic le s io n .69

A clin ica l te s t can m ake th e d iagnosis o f ch lo ra te po ison ing . T en gram s o f k id ­n ey o b ta in ed a t au topsy are m in ced in 16 m l o f w arm d is tilled w ater an d an equ al vo lu m e o f a ce to n e is add ed . T h e m ix ture is cen trifu ged , th e ace tone is evap ora ted an d th e m ix tu re is filtered . T h e aqu eou s filtra te is d eco lo rized by a few drops o f a d ilu te so lu tion o f ind igo sulfate fo llow ed by a few drops o f su lfurous acid . S ilver n itra te is a d d e d fo llo w ed b y su lfu rous acid . S ilver ch lo rid e form s a w h ite p re ­c ip ita te an d is u sed for a q u an tita tiv e e s ­tim ate o f th e ch lorates.M i s c e l l a n e o u s C h e m i c a l s

A cu te o lig u ric re n a l fa ilu re h as fo l­lo w e d e x p o s u re to a w id e v a r ie ty o f

ACUTE TOXIC N EPHROPATHIES 485com m on ch em ica ls .27 L is ted in tab le I are th e se com m on chem icals, th e ir m axim um allow able con cen tra tion (MAC) and th e ir m ean le th a l dosage (M LD ). Som e o f th e lis ted chem ica ls p ro d u ce acu te rena l fail­u re , b u t such a case is ra re .108 T h ese in ­c lu d e m e th y l c h lo r id e ,45, 143 a r s e n ic , p h en o ls , co p p e r su lfa te ,219 p a race tam o l,154 p o lyv iny l a lco ho l,117 form alin , pyrogallo l, d i s c h r o m a te ,10 ta r ta r ic a c id , p h o s ­p h o ru s113 an d sod ium te tra th io na te .B i o l o g i c P r o d u c t s

A cu te r e n a l fa ilu re c a n r e s u l t from bio log ic p rod ucts o f acu te reac tio ns such as an ap h y lac tic a lle rg ic reac tio ns, from d e la y e d re a c tio n s to h o rse se ru m an d vacc ines o r from a b io log ic toxin such as th a t foun d in m u sh ro o m s230

A na ph ylac tic A llergic Reactions. A cute o lig uric renal fa ilu re has re su lte d from a n a p h y la c t ic sh o c k c a u s e d b y h o rs e serum , p en ic illin , s trep tom ycin an d o th e r a n tib io tic s . T h e y p ro d u c e su d d e n an d p ro lo n g e d h y p o te n s iv e s ta tes re su ltin g in a c u te tu b u la r n e c ro s is . P e n ic i l l in m ost o ften p rod uces anap hy lac tic shock on a h y p ersen sitiv ity basis. T h e m anag e­m e n t o f p a tien ts w ith anap hy lac tic shock

sh o u ld be d ire c te d tow ard co rrec tio n o f th e h y p o ten siv e sta te an d in te ru p tio n s o f th e h y p e rse n s it iv ity reac tio n . P a tie n ts w ith severe , acu te anap hy lac tic reactions sh o u ld b e g iven e p in e p h r in e sub cu tane- ously (0.5 m l to 1 m l o f a 0.001 p e rc e n t solution). An ad reno cortica l ste ro id such as h y d ro c o rtiso n e (10 0 m g) sh o u ld b e a d m in is te red in traven ously and , i f n ec ­essary , in m u ltip le dosage.

A p a ren te ra l an tih is tam in ic sh o u ld be g iven. I f th e anaphy lactic reac tio n is se­vere , vaso p ressive a g e n ts an d ad ren o co r­tical s te ro ids sh o u ld b e g iven by in trav en ­ous infusion . I f a red u c tio n o f u rin ary o u t­p u t occurs, 25 g o f m ann ito l in a 20 p e rc e n t so lu tion m u st b e g iven . I f m ann ito l p roves ineffec tive , e th acry n ic ac id (50 m g) sho u ld b e g iven in travenously . I f th is is u n su c ­cessfu l in p ro d u c in g d iu res is , th e n th e usual m eth ods o f trea tin g acu te o liguric ren a l failu re m ust b e em ployed .

H orse S eru m -in d u ced F a ta l G lo m eru lo ­n ep h ritis . In 1962, D e L aP ava an d co l­leag ues rep o rted th ree p a tien ts w ho had m a lig n an t tum ors and w ere tre a ted w ith ho rse an ti-hum an cancer se ru m .65 A ll d e ­v e lo p ed a fatal acu te renal failu re. A t au ­

TABLE III

Clinical and Morphological Data Four Patients with Drug Induced Immune Complex Glomerulonephritis and Acute Renal Failure

Patient Sex & Age Drug

Microscopic Study

Light ElectronFluores­

centBeta 1C

Complement

Tritiated Thymidine Uptake by Lymphocytes

Other Organs Involved

Responseto

Prednisone

36/F Bunamiodyl(OrabilexR)

Proliferativeglomerulo­nephritis

Immunecomplexglomerulo­nephritis

IgG - - - Excellent

40/F Dextran Proliferativeglomerulo­nephritis

Immunecomplexglomerulo­nephritis

IgG Angiitis Excellent

41/F Methoxyflurane

(PenthraneR)

Proliferativeglomerulo­nephritis

Immunecomplexglomerulo­nephritis

IgG, C3 Decreased Positive Hepatitis Excellent

58/M Polyvalentfluvaccine

Proliferativeglomerulo­nephritis

Immunecomplexglomerulo­nephritis

igG, c3 Decreased Positive Requiredadditionalnitrogenmustard

4 8 6 M UEHRCKE, VOLINI, MORRIS, M OLES AND LAW RENCE

topsy, a p ro life ra tive g lo m eru lo n ep h ritis w ith e p i th e lia l c re sc e n ts w as p re s e n t . T h e k id n e y w as s tu d ied by e lec tro n m i­c ro sc o p y . E p i th e l i a l h u m p s o n th e g lo m e ru la r la m in a d e n sa w e re fo u n d . T h ey w e re sim ilar to hu m ps o f an tig en- a n t ib o d y c o m p le x s e e n in p o s t s t r e p ­to c o c c a l g lo m e ru lo n e p h r i t is , d e x tra n - in d u c e d g lo m e ru lo n e p h ritis an d re n a l d isease cau sed by syph ilis . T h e u se o f large dosages o f ad reno cortica l stero ids has b e e n m o st b e n e fic ia l in re so lv in g th e se lesions o f d ru g -in d u ced d iseases.

A ho rse se ru m -in d u ced d isease w as first o b se rv ed by R ackem ann, L ongcope and P e te rs .208 T h ey n o te d w a te r re ten tio n , d e ­c reased u rin ary o u tp u t an d re te n tio n o f ch lo ride . T h ey w e re th e firs t to p o in t ou t th a t th e m e c h a n ism s o f h o rse se ru m - in d u c e d ren a l fa ilu re w ere im m unologi- c a lly b a s e d . L a te r , th e s p e c i f ic im ­m u n o lo g ic r e a c t io n w as b o u n d to b e cau sed by so lub le an tig en -an tibo dy com ­p lexes in th e p re sen ce o f excessive an ti­gen.

T h e au thors hav e s tu d ied four p a tien ts w i th d r u g - in d u c e d im m u n e c o m p le x g lo m eru lo n ep h ritis an d acu te rena l fail­u re as show n in tab le I II . T h e c lin ica l p re se n ta tio n w as a seru m sick ness-lik e reac tio n lead in g to acu te o liguric rena l failure.P A T IE N T S.B.

A 58 year o ld w hite m ale rece ived 0.5 m l o f a po lyvalen t in fluenza vaccine con tain ing duck egg album in . Six days la te r h e dev e lo p ed hem aturia. On the e igh th day he h ad oliguria. T he p a tien t was ad­m itted to a hosp ita l an d found to have an e levated blood u rea n itrogen level. A retrograde pyelogram was norm al. T he p a tien t was referred to th e p resen t authors for treatm en t. H is clin ical course an d b lood u rea n itrogen leve l are p lo tted on th e curve (figure 1).

H is B eta 1C g lobu lin was norm al at 115 m g p e r d l . An a r te r io v e n o u s s h u n t w as in s e r te d ; hem odialysis was sta rted and was co n tinu ed fre­quen tly . F ive renal b iopsies w ere perfo rm ed w ith th e fifth one done th ree m onths after d ischarge from th e hospital. T h e first renal b iopsy study revealed , on lig h t m icroscopy , p ro life ra tiv e g lo m eru lo n e ­phritis (figure 2). By electrom icroscopy, electron

d e n se im m u n e c o m p le x e s w ere n o te d on th e glom eru lar b asem en t m em brane (figure 3). IgG and Beta 1C g lobu lin w ere found by im m unofluores­cence in im m une com plexes. U nfortunately , the first ren a l b io p sy tissu e w as lo st to fu r th e r im- m u n o co m p lex es s tu d y u s in g f lu o re scen t tagged an tiduck egg album in . A second biopsy was per­form ed 16 days la ter w ith the hope o f s tudying the tissue w ith fluorescen t tagged an tiduck egg albu­m in . To th e p re se n t au th o rs ’ su rp rise , im m une com plexes w ere no longer p re sen t (figure 4). T he th ird an d fo u rth re n a l b io p sy s tu d ie s sh o w ed g ra d u a l reco v e ry o f p ro l ife ra tiv e g lo m e ru lo n e ­phritis (figures 5 and 6). T h e b e ta 1C g lobulin was norm al initially , was low on th e 20 th and 34th days and re tu rned to norm al leve l after recovery from renal failure. In th e acu te stage, p red n iso n e therapy was sta rted and n itrogen m u sta rd was g iven in ­travenously in four d iv id ed doses. T he p a tien t m ade a gradual recovery an d was d ischarged from hosp i­tal. A fifth ren a l b io p sy study , p erfo rm ed th ree m o n th s la te r , w as n o rm a l. T h is p a t i e n t ’s im ­m unological data are p re sen ted in (figure 7).C O M M EN T

N ote the sim ilarity o f th e im m unological data of pa tien t S.B. to the data o f D ixon’s serum sickness m odel. O ur p a tien t rece iv ed duck egg a lbum in as th e an tigen in th e flu vaccine. Initially , th e b e ta 1C g lobulin was norm al. O n th e 20 th day and 34th day, it was red u ced an d la ter re tu rn e d to norm al after renal dam age recovered . Renal dam age as ind icated by hem aturia started on th e sixth day and subsided at th e h e ig h t o f d iuresis . Im m une com plex deposits w ere found in th e g lom eru lar b asem en t m em brane by electron m icroscopic study o f th e renal biopsy, IgG a n d b e ta 1C g lo b u lin s w e re fo u n d in th e im m une com plexes by im m u n o flu o re scen t te ch ­n ique. In addition , th e p a tien t’s in cu b a ted lym pho­cytes reac ted positively to duck egg album in . T he im m une m echanism o f action in this patient paralelled the D ixon m odel of serum sickness.

P ertussis V accine. A cute o liguric renal fa ilu re c a u se d by p e r tu ss is v acc in e is ra re .30 F a ta l re n a l fa ilu re has fo llow ed e ig h t in jections o f p e rtu ss is vacc ine over a six -w eek p e rio d . O n e w eek a fte r th e e ig h th in jection , th e p a tie n t dev e lo p ed fev e r, a r th ra lg ia , a d e n o p a th y an d p ro ­g ressive renal failu re. O n th e e ig h th day h e w as com atose, h ad m ild hy p erten sio n , an d h ad a B U N o f 201 m g p e r d l . A dif­fuse h ea lin g vascu litis w as found to be in vo lv ing th e m ed iu m an d sm all a rte ries , a rte rio les an d veins. T h e patho log ic find­ings in th e k id n ey w ere m u ltip le infarc­tion in th e cortex a n d m ed u lla . T h e re w ere n u m ero us an tem o rtem th ro m b i and ex tensiv e pap illa ry necrosis.

ACUTE TOXIC NEPHROPATHIES 4 8 7

FIGURE 1. Im m u n e- Im m une-com plex G lom eru lonephritis fo llo w ing Poly Valent Flu Vaccine

Complex Glom eruloneph­ritis Following Polyvalent Flu Vaccine. T he clinical course of patient S.B., aged 58 years, is plotted. He de­veloped gross hem aturia and oliguria following an injection of a polyvalent flu vaccin e co n ta in in g duc- kegg album in (DEA). The blood urea nitrogen is plot­ted in the broken line. The daily urinary volum e is the shaded grey area. H e was treated by hem odialysis.Four renal biopsy studies w ere done. An im m une-com plex g lom erulonephritis was found and adrenal corticosteroids w ere given (bar graph at bottom o f figure).

T yp h o id Vaccine. F ou r p a tien ts g iven ty ph o id vaccine in travenously for tw o to th re e d a y s d ie d in sh o ck a n d a c u te o liguric renal failu re. O ne p a tien t d ied in acu te renal failu re four days after rece iv ­in g th e v a c c in e . A n o th e r p a t ie n t d e ­v e lo p ed th e hepato renal syndrom e. T he th ird p a tien t d ied six hours follow ing in ­

jec tio n o f th e vaccine. A cute tu b u la r n e ­crosis and acute necrosis o f the liver w ere noted .

T he fourth pa tien t, a seven m on th old boy w ho had h e re d ita ry ag am m ag lo b ­u lin e m ia , d e v e lo p e d c o m p le te a n u ria follow ing one in jection o f th y p h o id vac­c ine . At autopsy, acute renal cortical ne-

FlGURE 2. Light Micro­scop ic S tudy A ntigen- A n tibody G lo m eru lo n e­phritis was found on renal biopsy study of S.B., a 58 year old laborer. A poly­valent flu vaccine contain­ing duckegg albumin was given 15 days before. Note the proliferative lesions in the g lom eru li associated with interstitial edema. (H & E x 400).

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!..........»Vf*.F i g u r e 3. Im m une Com plex G lom erulonephritis. T he first renal biopsy study taken 15 days after injec­

tion of duckegg album in revealed proliferative g lom erulonephritis. E lectronm icroscopic study revealed im m une-com plex (arrows) on the glom erular capillary basem ent m em brane (BM). P roteinaceous m aterial is seen in the capillary lum en (CL) and in the u rinary space (U S), (x 900).crosis w as found. In add ition , th e re was d iffu se th ro m b o s is o f th e g lo m e ru la r capillaries. T his p a tien t m ay have h ad an in creased suscep tib ility to th e th yp ho id vaccine in v iew o f an in ad eq u a te or u n ­d e rd e v e lo p e d r e tic u lo e n d o th e lia l sys­tem .

M ushroom -induced A cute Oliguria. T he term s “ m ushroom ” and “ to adstoo l” hav e no sp e c if ic id e n tify in g m e a n in g and are u sed in te rch an g eab ly by som e m yco log ists . T h e re are a p p ro x im a te ly2,000 spec ies o f m ushroom s, o f w h ich about 30 are poisonous. Some m ushroom s are toxic if ea ten (1) in excessive q u an ­tities, (2) d u ring certa in seasons, (3) at sp e c if ic s tag es o f g ro w th o r (4) by a s u s c e p tib le in d iv id u a l .43 In E n g la n d and W ales, th e re w ere 38 fatal cases of m ushroom po isoning b e tw een 1921 and

1949. In th e U n ited States, th e overall m ortality rate is d ifficu lt to estim ate . T he c o m m o n p o is o n m u sh ro o m is th e Am anita p h a llo id es. I t c an b e d is t in ­gu ish ed from th e com m on fie ld m ush ­room (Agaricus cam pestris) by n o tin g th e p resen ce o f th e volva on the p h a l­lo ides. I t is strongly recom m ended that “ m ush room a m a teu rs” p u rch ase m u sh ­ro o m s from c o m m e rc ia l so u rc e s an d n e ith e r pick them no r accep t th em from a neighbor.

Pro longed anu ria m ay resu lt from the m ycetous toxins o f Amanita phalloides.187 A cute tu b u la r n ecro sis is th e com m on m orph o lo g ic le s io n an d in v o lv es b o th proxim al and d istal con vo lu ted tu bu les. T he g lom eru li are usually no t affected. F o l lo w in g re c o v e ry fro m p ro lo n g e d a n u ria , d iffu se in te r s ti t ia l fib rosis d e ­

ACUTE TOXIC NEPHROPATHIES 489

F i g u r e 4. C learing o f Im m une Com plexes. A second renal biopsy study was done on the 32nd day after a polyvalent flu vaccine injection . No im m une com plexes w ere seen by electronm icroscopic study. T he glom erular basem en t m em brane (BM) appeared norm al. N um erous polym orphonucleocytes (WBC) w ere noted in the capillary lum en (CL), (x 14,350).

velops and is associated with thickening of the cortical convoluted tubular base­ment membrane. The creatinine clear­ance remains reduced for several months until diffuse interstitial fibrosis becomes more focal in its renal distribution. The creatinine clearance may then approach normal values.

Treatment is directed toward sustain­ing life by the use of conservative mea­sures and dialysis. Peritoneal dialysis is the method of choice, especially if albu­min is added to the peritoneal fluid to remove mycetous toxins. If toxicity is in­duced by Amanita muscaria, atropine is effective in neutralizing the muscarine effects of poisonous mushrooms.D r u g s

In general, drugs induce renal damage through any one of or a combination of

many pathopharmacologic mechanisms. Of these, the nephrotoxicity mechanism is the most common and is dose-related. In general, excessively large doses are used. Drugs such as methicillin, penicil­lin, phenylbutazone,172 sulfonamide,93-163 diphenylhydantoin (Dilantin),123 phenin- d io n e 11 and m era l lu r id e (M ercuhy- drin)189 produce acute oliguric renal fail­ure w hen adm in is te red in e i th e r the usual dosages or in very small amounts. Hypersensitivity to these drugs can pro­duce acute renal failure. There are also metabolic,75 mechanical and secondary mechanisms that produce the disease; the latter are usually caused by drug- induced hemolytic anemia.

The tetracyclines may produce pre- renal azo tem ia th ro u g h a m e tabo lic mechanism, such as their antianabolic ac­

490 MUEHRCKE, VOLINI, MORRIS, MOLES AND LAWRENCE

W M m & -

F i g u r e 5 . R esolution o f Im m une-C om plex G lom erulonephritis. Renal biopsy study was done on the 34th day after injection of polyvalent flu vaccine. T he g lom eru lar capillary lum en (CL) was paten t. E rythro­cytes (RBC) w ere no ted in th e lum en. N um erous polym orphonuclear leukocytes (WBC) w ere noted, (x 3,300).

tion on the proximal tubules.87,100 This is reflected by proteinuria, amino-aciduria, p h o sp h a tu r ia , h y p o k a le m ia ," a low plasma urate and acidosis. Tetracycline may undergo spontaneous degradation during storage, especially under warm and moist conditions. Anhydrotetracy- cline and epianhydrotetracycline are the nephrotoxic degradation products that produce the Fanconi syndrome.114158

In addition to classification according to the pathopharmacologic mechanism, nephrotoxic drugs can be classified ac­cording to the site of morphologic dam­age. Finally, drug-induced acute renal failure can be classified therapeutically, e.g., antibiotics and chemotherapeutic agents, diuretic agents, radiologic con­trast media and others. In this section,

nephrotoxic drugs will be reviewed by therapeutic classification and will em ­phasize the morphologic site of drug in­teraction.

Drugs interact at specific morphologic sites within the kidney to produce acute renal failure. On a structural basis drugs interact at all four major components: the vessels, the glomeruli, the tubules and the interstitium. Arteritis has resulted from arsen ic , b ism uth , d ip h en y l- hydan to in (D ilan tin ) ,190 gold sa lts ,112 horse serum, iodides, penicillin, propyl­thiouracil, chlorathizides148 and sulfona­mides. Glomerulonephritis has followed hydralazine,3,4 bunamiodyl (Orabilex), pheny lbu tazone77 and sulfonamides.72 Acute tubular necrosis has followed a large variety of drugs. These include am-

ACUTE TOXIC NEPHROPATHIES 491

F IG U R E 6. Recovery period. Renal biopsy study was done th ree m onths after d ischarge from hospital (145 days after exposure to duckegg album in). T he glom erular capillary lum en (CL) w ere patent and con­ta in ed erythrocytes (RBC). A lthough renal function was recovered, the g lom erular basem ent m em brane was th ick en ed on the endo the lia l side (arrows), (x 4,400).

photeric ine B,21,49 aristolochic acid,191 bacitracin, colistin,83 ferrous sulfate,136 kanamycin,25 meralluride (Mercuhydrin), n e o m y c in ,79 bunam io d y l (Orabilex), para-aminosalicylic acid,174 penicillin , p h e n y lb u ta z o n e ,165 q u in in e sulfate , salicylates and sodium acetrizoate (Uro- kon).

Acute interstitial nephritis and sub­sequent acute renal failure have followed treatment with meralluride (Mercuhyd­rin),56 m eth ic il l in ,88 n itrofuran to in ,203 penicillin, phenacetin,7 phenindione,38 polymyxin B,20 sulfonamides,98 diphenyl- h y d an to in (D ilan t in )211 and p h e n y l ­butazone.

Drug-induced Acute Oliguric Renal FailureR a d i o l o g i c C o n t r a s t M e d i a

The essential ingredient in all absorb­able radiologic contrast media is iodine. Individuals sensitive to iodine in any form may have mild to severe hypersen­sitivity reactions to contrast media. When inorganic iod in e was used , such as sodium iodide in a concentration of 80 to 100 percent, numerous hypersensitivity reactions occurred. These varied from iodine mumps, dermatologic lesions and anaphylactic shock to fatal acute oliguric renal failure.28 Although contrast media

492 M UEHRCKE, VOLINI, MORRIS, MOLES AND LAW RENCE

Im munologic C ourse of D rug-induced G lom erulonephritis 58 yrs, W.,M.

Flu vaccine (DEA)

F IG U R E 7. Im m u n o lo g ica l C o u rse o f D ru g - In d u ced G lom eru lonephritis. T he figure illustra tes th e c lin ical course o f S.B., a 58 year o ld w hite m ale. H e rece ived a po lyvalen t flu vaccine con tain ing an an tigen (Ag) duckegg a lbum in (DEA). Six days la ter renal d isease was ev id en t by gross hem atu ria fol­low ed by oliguria. T h e serum Beta ,c g lobu lin was norm al on th e 12th day b u t red u ced on the 18th and 32nd day. T he th ird com ponent of com plem ent was norm al on th e 48 th day. T h e first renal b iopsy study on the 15th day rev ea led an tigen -an tibody com ­plexes w ith a p rolifera tive g lom eru lonephritis. T he second renal b io p sy study on th e 32nd day revea led no an tigen-an tibody com plexes. T he a lp h a2 globu­lins w ere e lev a ted on th e 35th day. T he p a tien t’s course is sim ilar to th e D ixon’s anim al m odel o f an tigen-an tibody g lom eru lonephritis.

con ta in in g organ ic iod ides are safer th an th o se co n ta in in g inorgan ic io d ides, th e form er have b e e n im p lica ted in a steady f lo w o f r e p o r ts o f s e v e r e n e p h r o ­tox ic ity .130

P hy sic ian s d e p e n d on rad io log ic co n ­trast m ed ia for d iagnosis o f b ilia ry d is­e a se s , vascu lar d iseases as w ell as d is­eases o f th e k idn eys an d gen itourin ary tract. T h ese agen ts are u su a lly ad m in is­te re d orally to eva lua te th e b iliary tract, in traven ously to eva lua te th e a rte ria l c ir­cu la tio n an d th e k id n e y s , and by re tro ­grade in jections in to th e ren a l pelv is to e v a lu a te th e u p p e r g e n i to u r in a ry trac t .6-26- 32

A n t i b i o t i c s a n d C h e m o t h e r a p e u t i c A g e n t s

A n tib io t ic s a n d c h e m o th e r a p e u t ic agen ts hav e beco m e in d isp en sab le in th e tr e a tm e n t o f u r in a ry tra c t in fe c tio n as w ell as in th e tre a tm en t o f system ic and local in fec tions. As th e se agen ts becom e m ore ex ten siv e ly u sed , th e ir adv erse side effects an d nephro tox ic ity beco m e m ore a p p a re n t .102,237 In th e p re sen ce o f u n d e r ­ly in g re n a l d isease , it m ay be d ifficu lt to re c o g n iz e n e p h ro to x ic ity o f a sp ec ific a n tib io tic .149 M oreover, w h en an tib io tics are u se d in com bination w ith o th e r an ­tib io tics o r w ith ch em o th e rap eu tic agen ts th e ir exact nep hro toxic effect as w ell as th e specific ag en t o f th e adverse reac tio n m ay b e im p o ssib le to d e te rm in e .14 N ep h ­rotoxicity cau sed by ch lo ram phen ico l or e ry th ro m y cin has no t b e e n o b se rv ed by th e p re se n t authors.

Su lfona m ides . D am age to th e k idn ey is th e m ost serious and fre q u e n t com p li­ca tion o f su lfonam ide tre a tm e n t .40,243,246 S u lfo n a m id e s w e re th e f irs t e f fe c tiv e ch em o th e rap eu tic agents to have n e p h ro ­toxic p ro p e r t ie s .110,254 T h e in c id en ce o f re n a l ab n o rm a litie s varies co n s id e rab ly an d d e p e n d s in a g reat p a rt on th e so lu­b ility o f su lfo n am id es .59,76 A cute o liguric ren a l fa ilu re has b e e n in d u ced by su lfon­a m id e t r e a tm e n t o f p a re n c h y m a l le s io n s179,192 a n d o f o b struc tive u rop ath y cau sed by su lfonam ide c ry sta lliza tio n 142 of th e u n ch an g ed d rug or o f its acety l d e r­ivative w ith in th e renal p e lv is .23,122 T he m e th o d o f p re v e n tio n o f su lfo n a m id e ob struc tive u rop ath y is th e p re fe ren tia l u s e o f a m o re s o lu b le s u lfo n a m id e , ad eq u a te hy d ra tio n , and alk a lin iza tion o f th e u r in e w ith so d iu m b ic a rb o n a te . O b stru c tiv e u rop ath y cau sed by th e low so lu b ility o f su lfo nam id es is m ore fre ­q u e n t ly o b s e rv e d th a n a re th e p a re n ­chym al lesion o f tu b u la r necrosi s, focal- g ranu lom atous in te rstitia l lesions, d iffu se in te r s t i t ia l n e p h r i t i s , h y p e rs e n s it iv ity g lo m eru lo n ep h ritis an d acu te h y p e rse n ­sitiv ity arteritis .

ACUTE TOXIC N EPHROPATHIES 493S ev era l h u n d re d p a tie n ts hav e b e e n

re p o r te d w ith re n a l fa ilu re c a u se d by su lfonam ide c ry sta lliza tio n .205 T h e m ost f re q u e n t su lfo nam id es im p lica ted w ere s u l f a p y r id in e , s u l f a th ia z o le a n d s u l ­f a d ia z in e .35 T h e so lu b il i ty o f su lfo n a ­m id es d e p en d s on a n u m b e r o f factors th a t in c lu d e th e d ru g con cen tra tion , state o f d e h y d ra t io n , u r in a ry p H a n d re n a l f u n c t io n .217 S u l fa d ia z in e is th e m o s t d a n g e r o u s .258 S u lfa d im id in e a n d su l- fisoxazole form m ore so lu b le crystals and are less h aza rd o u s .170,260 T h e fin d in g o f su lfo nam id e crystals in th e u rin e leads th e ph ysic ian to su sp ec t acu te su lfona­m id e c rysta lliza tion w ith in th e ren a l p e l­vis. T h e m e th o d o f tre a tm e n t is re tro ­grade ca th e te riza tio n o f th e u re te rs an d lavage o f th e ren a l p e lv is w ith w arm al- k a lin ized so lu tion (10 p e rc e n t N a H C 0 3).

A cute tu b u la r necrosis can occu r w ith o r w ith o u t su lfo n am id e c ry s ta lliza tio n . T h e tu b u la r lu m in a a re p lu g g e d w ith a m o rp h o u s d e b r is c o n ta in in g e ry th ro ­cytes, leukocy tes, h em o g lo b in casts and c ry sta ls . W h en su lfo n a m id e s in d u c e a h y p ersen s itiv ity ren a l lesion , one o f th re e sites is invo lved . In som e h y p e rsen s itiv ­ity reactions, th e in tra ren a l a rte ries w ere in v o lv e d w ith an g iitis o r w ith p o ly a r­te ritis nodosa. In a secon d ty pe o f hy ­p e r s e n s i t iv i ty re a c tio n , th e g lo m e ru li w e re in v o lv e d w i th h y p e r s e n s i t iv i ty g lo m eru lo n ep h ritis .264 T h e th ird site for su lfo n a m id e - in d u c e d h y p e rs e n s i t iv i ty reac tio n w as th e ren a l in te rs titiu m . A cute in te rs titia l n ep h ritis w as th e m ore com ­m on in te rs titia l le s ion an d w as sim ilar to a C o un c ilm an acu te in te rs titia l n e p h r i­t is .182 A focal in te rs titia l granu lom atous in te rs titia l n ep h ritis w as a less com m on in te rs titia l lesion .

P olym yx in B. T h e po lym yxins A, B, C, D and E a re a g rou p o f c lo se ly re la ted cyclic p o ly p ep tid es . P olym yxin B is an an tib io tic com p osed o f am ino acids an d a fatty acid . I t is active against a varie ty o f g ram -n eg a tiv e b a c i l l i .42 T h e s e in c lu d e

P seu d o m o n a s , E sc h e r ic h ia , K lebs ie l la , A e r o b a c te r , S a lm o n e l la , S h ig e l la a n d H e m o p h i lu s s p e c ie s .227 Po lym yxin B is an tib ac te ria lly m ore ac tive th an po lym y­xin E . N ep h ro to x ic ity o f p o ly m y x in is d o se -re la ted .186,262 F o llo w in g adm in istra ­tio n o f po lym yxin B su lfa te , p ro te in u ria , ep ith e lia l ce lls , an d casts ap p ea r in th e u r in e an d azo tem ia d e v e lo p s .134 In th e p re se n c e o f no rm al ren a l func tion , th e nephro tox ic ity is n eg lig ib le at 2 m g p e r kg b o d y w e ig h t p e r day.

B e im e an d co lleag u es re p o rte d a 44 y ear o ld m ale w ho d e v e lo p ed an acute o liguric ren a l fa ilu re cau sed by acu te in ­te rs titia l n e p h r itis .171 Polym yxin B sulfate seem ed th e m ost cap ab le o f several an te ­c e d e n t a g e n ts . T h e p a t i e n t h a d an e o s in o p h ilia o f 25 p e rc e n t b u t h ad no derm ato log ic lesion . T h e p a tie n t g rad u ­ally reco v e red w h e n po lym yxin B w as w ith d raw n . A ren a l b io p sy stu dy do n e on th e se c o n d d ay o f o lig u ria re v e a le d a C o u n c ilm a n ty p e o f a c u te in te r s t i t ia l nep h ritis .

C o lis t in m e th a n e su l fo n a te . C o lis tin , w h ich differs from po lym yxin B on ly by th e ab se n c e o f a s in g le am in o acid , is k n ow n to b e id e n tic a l w ith po lym yxin E .155 B ecause o f th is c lo se s truc tu ra l re la ­t io n s h ip , c o l is t in s h a re s so m e o f th e n ep h ro to x ic p o te n tia l o f p o ly m y x in B. C o lis tin is an an tib io tic p ro d u ced by th e soil b a c te r iu m B a c i l lu s p o ly m y x a var. g a ryp ha lus. Its a n tib a c te r ia l ac tiv ity is aga inst a n u m b e r o f g ram -negative bac­teria .

T oxicity s tu d ie s in anim als have d em ­o n stra ted th a t co lis tin p ro d u ces im p a ired renal func tion an d ren a l le s io n s .156 P artial to c o m p le te n e c ro s is o f th e p ro x im a l tu b u le s w as foun d on h isto log ic exam ina­tio n .141 T h e e ffect o f in tram u scu la r co lis tin on rena l function in m an is u n p red ic ta ­b le . H ea lth y in d iv id u a ls a n d p a tien ts w ith chron ic p y e lo n ep h ritis an d o th e r form s o f re n a l d is e a s e h a v e re c e iv e d th e d ru g w ith o u t s ig n ifican t chan ges in u rin a lysis

494 M UEHRCKE, VOLINI, MORRIS, M OLES AND LAW RENCE

o r B U N .128,202 I n o th e r p a t ie n ts w ith azo tem ia fu rth e r e lev a tio n o f BU N has occu rred . O lig u ria d e v e lo p e d in a five year o ld c h ild w h o rec e iv e d an acc id en ta l overdose o f co lis tin (37.7 m g p e r kg bo dy w e ig h t p e r day for tw o days and 9.4 m g p e r kg b o d y w e ig h t p e r day for th re e m ore days). W h en co lis tin w as d isco n ­tin u ed , rena l function re tu rn e d to norm al.

A lth o u g h th e m ech a n ism o f co lis tin nep hro tox ic ity is un kn ow n, it m ay b e re ­la ted to th e ab ility o f th e d rug to d is ru p t th e in teg rity o f ce rta in ce ll m em b ran es ,89 pro b ab ly b y ac ting as a cation ic d e te rg e n t th a t destroys th e ce llu la r osm otic b arrie r, com bines w ith po ly p h o sp h a tes an d th us allow s leak age o f sub stances e ssen tia l to ce ll function . S uch an action is th e ra p e u t­ically va lu ab le w h en lim ited to th e ce ll w all o f various b ac te ria b u t m ay b e harm ­ful i f h u m an ren a l tu b u la r cells exposed to h ig h con cen tra tion s o f th e d ru g share th is su scep tib ility . In th is resp ec t, co lis­tin n ep h ro tox ic ity m ay re se m b le th a t o f am p h o te ric in B; th e la tte r also d isru p ts cell m em b ran es , b u t does so b y b in d in g to stero ls ra th e r th an to po ly pho sph ates . M a m m a lia n c e l l m e m b ra n e s c o n ta in stero ls, a n d am p h o te ric in B 131 has b e e n show n to dam age b o th tissu e cells in cu l­tu re an d h u m an ren a l tu b u la r cells m ay b e d am ag ed in like m an n er by h ig h lu m ­inal co n cen tra tio n s o f th e drug.

S t r e p t o m y c i n . S tr e p to m y c in is an an tib io tic th a t w as d isco v e red in 1944 b y S c h a tz , B u g ie a n d W ak sm an in c u l tu re s o f th e a c tin o m y c e te S tre p to - m yces grieseus.220 S trep tom ycin , a carbo­h y d r a te d e r iv a t iv e , is N -m e th y l-L - g lu c o s a m in id o - s tr e p to -s id o s tre p tid in e and has a w id e spectru m o f an tib ac teria l a c tiv ity .126 S tre p to m y c in , v an co m y c in , kan am ycin a n d neo m ycin have severa l fea tu res in com m on. T h ey are re la tive ly strong o rgan ic bases th a t cross ce ll m em ­b ran es very slow ly; th ere fo re , th ey are poorly ab so rb ed from th e g u t.121 T h ey are a lm o st e n t ir e ly d is tr ib u te d in th e ex ­

trace llu la r flu id and are ex cre ted m ain ly in th e u r in e .253 In add ition , all fou r an ­tib io tic s hav e o to tox icity . T h e n e p h ro ­toxicity is in c reased in p a tien ts in w hom th e re is a red u c tio n o f g lom eru la r filtra­tion ra te . I f th e se an tib io tics are u se d in c o m b in a t io n th e i r n e p h r o to x ic i ty is g rea tly in c reased .

In in d iv id u a ls w ith norm al ren a l func­tio n , ap p ro x im a te ly 70 p e rc e n t o f par- e n te ra l ly in je c te d s tre p to m y c in is ex ­c re te d u n ch an g ed in th e u rin e w ith in 24 h o u rs . In p a t ie n ts w i th re n a l in s u f f i­c iency , less th an 2 p e rc e n t o f an in jec te d do se o f s trep tom ycin is ex c re ted in th e u r in e . V e s t ib u la r d a m a g e c a u s e d b y strep tom ycin is f re q u e n t in p a tien ts w ith sev ere ren a l fa ilu re . D ia ly sis has b e e n u se fu l in th e rem oval o f s trep tom ycin in th e tre a tm e n t o f n eu ro toxic ity an d n e p h ­rotoxicity .

D u rin g th e cou rse o f tre a tm e n t w ith s trep tom ycin , p ro te in u ria an d cy lin d u ria m ay occassionally occur. M cD erm o tt re ­p o rte d a p a tie n t w ith acu te o liguric renal fa ilu re cau sed by acu te tu b u la r necrosis fo llo w in g a d a ily d o sag e o f fo u r g o f s trep to m y c in .193

K a n a m y c in . T h e n e p h r o to x ic i ty o f kanam ycin has b e e n d e sc rib ed in n u m er­ous rep o rts w h e n e v e r its c lin ica l ap p lica ­t io n w as m e n t io n e d .153,261 K an am y c in n e p h ro to x ic ity w as r e la te d n e i th e r to do se lev e l n o r to du ra tion o f tre a tm en t b u t occu rred m ore freq u en tly in e ld e rly p a t ie n ts .24,255 K anam ycin n ep hro tox ic ity o ccu rred in doses o f 20 to 50 m g p e r kg b o dy w e ig h t p e r day and was c lin ica lly e v id e n t by m ild p ro te in u ria , n itro g en re ­ten tio n , m icroscop ic hem atu ria an d fine g ran u la r casts in th e u rin ary sed im en t. In a p p ro x im a te ly 10 p e r c e n t o f p a t ie n ts t r e a te d w i th k a n a m y c in , th e r e w e re azo tem ia . S ev ere tu b u la r n ec ro sis w as re p o rte d by K leem an and M axw ell.215 In g e n e ra l, n ep h ro to x ic ity w as re v e rs ib le w h e n k a n a m y c in a d m in is t r a t io n w as sto pp ed .

ACUTE TOXIC N EPH ROPATHIES 495K untz n o ted o lig u ria in e ig h t p a tien ts

o u t o f t e n r e c e iv in g k a n a m y c in .157 S c h r ie n e r a n d M a h e r o b s e rv e d a c u te tu b u la r n ecrosis in tw o p a tien ts fo llow ing trea tm en t o f kan am y cin .184 O n e o f th e se p a tien ts d ie d in urem ia.

O totoxicity is th e m ost com m on toxic effect of kanam ycin .222 I t is likely to occur in patien ts w ith renal insufficiency or d e ­hydration . W h en kanam ycin is g iven to p a tien ts w ith an u ria o r o lig uria o r to a d iab e tic p a tie n t w ith n ep h ro p a th y , it is im p era tive to red u ce th e do se b y careful ca lcu la tion o f it and to p re sc rib e kanam y­c in in “ sp re a d o u t” d o se s . (A re c o m ­m e n d e d kanam ycin dosage is 0.5 g every th re e o r four days.) A pproxim ately 29 to 63 p e r c e n t o f th e in je c te d d o se o f kanam ycin can b e rem oved by effective p e rito n e a l d ia lysis. In an anu ric p a tien t, app rox im ately 30 p e rc e n t o f kanam ycin can b e rem o v ed by hem odia lysis in an e ig h t h o u r perio d .

D u rin g p e r ito n e a l d ia ly sis , h o w ev er, 25 m g o f kanam ycin can be g iven safely daily . T h e m orphologic change ow ing to kanam ycin nep hro tox ic ity is alw ays seen in proxim al tu b u le s o f th e k idney . W hen acu te o liguric ren a l failu re occurs, it is th e re su lt o f acu te tu b u la r necrosis. W hen ad m in istra tion o f kanam ycin is sto pp ed , d iu re s is fo llo w s w ith in five days an d renal function u su a lly re tu rn s to norm al w ith in tw o m onths.

Bacitracin. B acitracin is a p o ly p ep tid e an tib io tic p ro d u ced by th e T racy 1 stra in o f B a c i l lu s s u b t i l i s .229 B ac itra c in h as proved to be highly effective against gram- po sitive cocci an d organism s th a t cause gas g an grene . Its chem ical u se is lim ited to topical app lica tio n an d local in filtra­tion . T ransito ry u rin ary abnorm alities or p ro te in u ria , cy lin du ria , azo tem ia and oc­casional o lig u ria w ere n o ted in n early all r e p o r te d p a t ie n ts . B a c itra c in is v e ry nephro tox ic an d p rod uces b o th proxim al an d d ista l tu b u la r necrosis.

G en k ins, U h r an d B ryer re p o rte d a 57 y e a r o ld h o u se w ife w ith p r io r n o rm al renal fu n c tio n .107 She d ev e lo p e d a fatal acu te o liguric renal fa ilu re fo llow ing five d iv id e d d o ses o f 50 ,000 u n its d a ily o f bac itrac in . O n th e th ird day o f bac itrac in t re a tm e n t , sh e d e v e lo p e d p ro te in u r ia , o lig u ria an d azotem ia. T h e p a tie n t d ie d on th e te n th d ay a f te r in t r a m u s c u la r b ac itrac in trea tm en t. A cute tu b u la r n e ­crosis w as found at autopsy.

N eom ycin . N eom ycin is an an tib io tic d is c o v e re d b y W ak sm an a n d L e c h e - v a lie r. I t is d e r iv e d from th e m etab o lic p r o d u c ts o f S t r e p t o m y c e s f r a d i a e . N eom ycin is p rim arily a top ica l an tib io tic an d is u se d for its local an tib ac te ria l ac­

tio n w ith in th e lu m en o f th e gu t .140,249 I t is ex trem ely nep hro toxic and dam ages th e e ig h th c ran ia l n e rv e .196,207 A lthough th e d ru g is poorly abso rb ed , it crosses th e p e r i to n e a l c a v ity m u c h m o re re a d ily . T h ere fo re , renal dam age can occur w h en n e o m y c in is a d m in is t e r e d in to th e p e rito n e a l cavity.

E m m erso n an d P ry se -D av ies84 fo u n d n eo m ycin to b e very nephro tox ic a n d to cause severe proxim al tu b u la r n ec ro s is .91 R andall rep o rted four pa tien ts w ho suf­fe red ad v erse effects from in jections o f 4, 6 , 8 an d 72 g o f neom ycin , re sp ec tiv e ly .209 T w o p a tie n ts d e v e lo p e d d ea fn ess , o n e p a t ie n t d e v e lo p e d acu te o lig u ric ren a l fa ilu re and one su b seq u en tly h ad p e rm a­n e n t ren a l in su ffic iency . H em o d ia ly s is a n d p e r ito n e a l d ia ly sis re m o v e d la rg e am ounts o f neom ycin , an d m ann ito l p re ­v e n te d acute renal fa ilu re in tw o pa tien ts . H e m o d ia ly s is r a p id ly r e d u c e d se ru m neo m ycin con cen tra tion in tw o o th e r p a ­tien ts , w h ile m ann ito l d iu resis rem o ved s ig n i f ic a n t a m o u n ts in a n o th e r . P e rito n ea l d ialysis was th e leas t effective o f all m ethods.

Penicillin. P en ic illin in d u ces acu te o li­gu ria th ro ug h a h y p ersen sitiv ity m echa­n ism .19 D eh y d ra tio n w as a p o ssib le co n ­tr ib u tin g factor in tw o in fan ts w ith ab­

496 MUEHRCKE, VOLINI, MORRIS, MOLES AND LAW RENCE

norm al ren a l function . W h en acu te o lig u ­ria occurs, it is u su a lly associa ted w ith derm ato log ic lesions an d eo s in o p h ilia .265

R andall re p o rte d acu te o liguric renal failu re cau sed by h y p ersen s itiv ity m an­ifesta tions o f am p ic illin , ox acillin , oral p e n ic illin an d in tra m u sc u la r p e n ic illin G .152 T w o p a tien ts d ied , o n e o f w hom was a 24 year o ld s tu d en t w ho rece iv ed oral p e n ic i l l in . H e d e v e lo p e d c lin ic a l fea ­tu res o f th e hem o ly tic u rem ic syndrom e an d nec ro tiz in g a rte rio litis w as foun d at autopsy. T h e o th e r p a tie n t h a d a m arked acu te in te rs titia l n ep h ritis ch a rac te rized b y in t e r s t i t i a l c e l l u la r in f i l t r a te s o f p lasm a cells. P en ic illin a se m ay b e h e lp ­ful in tre a tm e n t o f a cu te re n a l in su ffi­c ien cy c a u se d b y p e n ic i l l in h y p e rs e n ­s itiv ity .244

M eth ic i l l in . M e th ic ill in (S tap h c illin ) does n o t d iffer in its sen sitiz in g po ten tia l from o th e r p e n ic i l l i n s .46 T h e c lin ic a l h y p e rse n s itiv ity fea tu res o f m e th ic illin are d e rm a to lo g ic le s io n s , n e p h ro p a th y an d eo s in o p h ilia . D u rin g th e p a s t few years, m e th ic illin -in d u c e d n e p h ro p a th y has b e e n re p o rte d by severa l in d iv id ua ls . T h e c lin ica l m an ifesta tions o f ren a l d is­ease w ere p ro te in u ria , h em atu ria , dysuria a n d azo tem ia w ith o r w ith o u t oliguria. N ep h ro p a th y usu a lly a p p e a re d b e tw e e n 7 and 21 days a fte r tre a tm en t w as beg un . In m ost in stances, it su b s id ed w ith in 24 to 48 hours a fte r cessa tion o f tre a tm en t w ith m eth ic illin .

P atien ts w ith m e th ic illin -in d u ced n e ­p h ro p a th y h ad add ition a l m anifesta tions o f h y p e rsen s itiv ity ,37 th e m ost com m on of w h ich w as an eosino ph ilia . In som e pa­tien ts th ro m b o cy to p en ia w as ob serv ed . H y p e rs e n s it iv ity d e rm a to lo g ic le s io n s w ere n o ted . T h ey in c lu d e d hem orrhag ic b u llae , urticaria , m acu lo p ap u la r lesions, p u rp u ra w ith p e te c h ia e an d exfoliative d e rm atitis . N o ne o f th e se re p o r te d p a ­tien ts w ith m e th ic illin -in d u ced n e p h ro p ­a thy h ad a ren a l b iopsy study . In general, k n o w le d g e re g a rd in g th e o v e ra ll m or­

p h o lo g ic re n a l c h an g es is in su ffic ien t. T he com plete reversibility o f m ethicillin- in d u c e d n e p h r o p a th y , to g e th e r w i th o th e r a lle rg ic m an ife s ta tio n s , sug g ests th a t a p a th o p h a rm o co lo g ic m ech an ism o f h y p e rsen s itiv ity occurs.

H isto log ic ab n o rm alitie s o f th e k idn ey in c lu d e an a c u te in te r s t i t ia l n e p h r it is w ith o r w ith o u t tu b u la r d am ag e .146 T his in te rs titia l n ep h ritis is ch arac te rized by ce llu la r in filtra tes o f eosino ph ils , p lasm a cells an d sm all lym phocy tes. A drenocor­tical stero ids have b e e n effective in re ­so lv ing th is d ru g -in d u ced lesion.

Tetracycline. T e tracycline , a so-called b ro ad -sp ec tru m a n tib io tic , is p ro d u ced by several S tre p to m yce s spec ies. T h e te t­racyclines p ro d u ce chan ges in n itrogen m etab o lism .251 T h e te tracy c lin es are no t u su a lly nephro tox ic agents. H ow ever, if s to rag e d e g e re ra tio n occu rs th e y m ay p r o d u c e p ro x im a l tu b u la r d a m a g e .63 C h em ical d e te rio ra tio n is m ore like ly to o ccu r i f th e d ru g is im p ro p e rly s to red u n d e r m o is t o r w a rm c o n d i t io n s . A n h y d ro te t ra c y c lin e a n d e p ia n h y d ro - te tracy c lin e are th e nephro tox ic products. T h e fo rm ation o f th e se p rod uc ts is ac­c o m p lis h e d b y te m p e ra tu re e le v a tio n , h ig h h u m id ity an d re d u c e d pH . T h ey are esp ec ia lly like ly to occu r w h en citric acid is a d d e d to te tracy c lin e . H o w ev er, te t­racycline p repara tion s co n ta in in g lactose are less like ly to d eg en e ra te in to n ep h ro ­toxic p rod ucts.

T h e te tracy clin es are co n cen tra ted in th e liver, te e th a n d b o n es an d are ex­c re te d th ro u g h th e k id n e y s an d b i le . D ea th has re su lte d from severe h ep atic an d pan crea tic dam age w ith excessive in ­travenous doses o f te tracy clin e . A ged or d e g e n e ra te d te tracy c lin e p rod uces a re ­v e r s ib le F a n c o n i s y n d ro m e 99,232 a s ­soc ia ted w ith po lyuria , p ro te in u ria , renal g ly c o s u r ia , p h o s p h a tu r ia , a m in o a c i­d u ria ,39 acidosis, hypokalem ia an d a low p la sm a u ra te . In g e n e ra l, te tracy c lin e - in d u ced F anco n i syndrom e is slow ly re ­

ACUTE TOXIC NEPH RO PATH IES 497v ers ib le once th e d ru g is d isc o n tin u e d .114

A cu te n o n o lig u r ic r e n a l fa ilu re has b e e n re p o rte d by Solom on, G allow ay and P a tte rso n 235 w ho p re sc rib ed tw o g o f te t­racycline daily an d o b se rv ed an increase in BU N from 63 m g to 161 m g p e r 100 m l. T e tracyc line toxicity is also d irec tly re ­la te d to ex is tin g re n a l in su ffic ie n c y .241 L arge doses o f oxytetracycline have p ro ­d u c e d azotem ia. P re ren a l azo tem ia m ay b e in d u c e d by a negative n itro g en b a l­a n c e th a t p ro d u c e s a n o re x ia , n a u se a , vom iting an d d ea th . N ep h ro g en ic d iab e ­te s in s ip id u s h a s b e e n in d u c e d b y d im eth y lch lo ro te tracy c lin e .54

P a r a - a m in o s a l i c y l i c a c id . P a ra - am inosalicy lic acid (PAS) is h igh ly active in in h ib i t in g th e g ro w th o f tu b e r c le b ac illi in v i tro . T h e m ost com m on h y p e r­sen sitiv ity com p lica tion o f PAS trea tm en t is hep a titis . A reac tiv e hep a titis in d u ced b y PAS has b e e n associa ted w ith fever, rash , p ru ritu s , con ju nc tiv itis , hem oly tic an em ia210 an d eosino ph ilia . R enal invo l­v e m e n t116 ow ing to PAS w as uncom m on an d w as u su a lly con fined to p a tien ts w ho h ad h e p a titis .68 In asm u ch as PAS is an organic acid , it req u ire s a fixed cation to a c c o m p a n y its e x c re t io n ;166 th e re fo re , h y po ka lem ia can occur as w e ll as an aci­dosis in c h ild re n .36

O w en rep o rted a 31 year o ld m an w ith pu lm on ary tu b e rcu lo sis rece iv ing trea t­m e n t w ith ca lc ium PAS for 83 days w ith ­o u t m ish a p .199 A fter 35 days o f sod ium PAS trea tm en t, h e d ev e lo p ed a fever, a p ink v esicu la r rash , m assive p ro te in u ria an d acute o lig uria w ith o u t h ep a titis . T h e BU N re a c h e d 245 m g p e r 100 m l an d spo n taneou sly fell to norm al. T h e p a tien t m ade a rap id an d co m p le te recovery from acu te ren a l fa ilu re .

C e p h a lo r i d in e . C e p h a lo r id in e is a sem isyn th e tic deriv a tiv e o f ceph a lo spo­rin C. Its an tib ac te ria l activ ity is against m any g ram -p ositive an d gram -negative b ac te ria . A dverse reac tions o f c ep h a lo ­ridine occurred in 35 percen t o f 76 patients.

In gen era l, th ey w ere m in o r reac tions and in c lu d e d alle rg ic ph en o m en a , p h le b itis at in fu sion sites, tran s ien t leu k o p en ia and g astro in testin a l sym ptom s. M ore serious re a c tio n s in c lu d e a c u te re n a l fa ilu re , C oom bs positive hem o ly tic anem ia, su p e r in fec tion s an d anaphylax is. F o r exam ple, c ep h a lo rid in e p ro d u ced anaphylax is in a n u rse w ho p rep a red an in jec tion o f th e d ru g .90

R enal dam age caused by cep h a lo rid in e app ears to b e a re su lt o f a nep hro toxic m echan ism . T h e d ru g has b e e n lo ca lized b y au to rad io g rap h ic s tu d ie s to th e re- n o m ed u lla ry in te rs titiu m an d p rox im al t u b u la r c e l l s .62 C e p h a lo r id in e is a c ­c u m u la tiv e an d d o se -re la te d . In la rg e do ses it p rod uces a severe nep h ro p a th y , w h i le in lo w d o se s it p ro d u c e s p r o ­te in u r ia , h e m a tu r ia a n d c y l in d ru r ia .139 W h en th e d ru g is d isco n tin u ed , u rin ary abn orm alities d isappear.

C ep h a lo rid in e has p ro d u ced h y p e rse n ­s i t iv i ty r e a c t io n s s u c h as u r t i c a r ia , eosino ph ilia , d ru g fever an d Coom bs p o s­itive hem oly tic anem ia. A ntib io tics such as am p ic illin an d polym yxin B have p ro ­d u ced a h y p ersen sitiv ity acu te in te rs titia l n ep h ritis . I t is su g g ested by th e p re se n t au thors th a t c ep h a lo rid in e w ill also p ro ­d u ce an acu te (hypersensitiv ity ) in te rs ti­t i a l n e p h r i t i s a n d s u b s e q u e n t a c u te o liguric renal failu re.D i u r e t i c A g e n t s

In th e m ajority o f in stances th e k id n ey resp on ds favorably to d iu re tic agen ts w ith a p ro m p t d iu resis . H ow ever, th e k id n ey also beco m es th e ta rge t o f un to w ard ef­fects o f d iu re tic agen ts. I t is no t u n lik e ly th a t acu te o ligu ric renal fa ilu re d e v e lo p ed in p a t ie n ts fo llo w in g t r e a tm e n t w ith m e ra l lu r id e (M e rc u h y d r in ) , a c e ta z o l- a m id e ,64 th e th ia z id e s an d a ris to lo ch ic acid .

M e r c u r ia l d i u r e t i c a g e n t . C a lo m e l (m ercurous ch lo ride) w as th e active d iu re ­tic in th e fam ous “ G uy’s H ospita l P ill”

498 M UEHRCKE, VOLINI, MORRIS, MOLES AND LAW RENCE

(calom el, d ig ita lis an d squ ill). T h e d iu re ­tic effects o f o rgan ic m ercu ria l w ere first d isco v e red as a s id e e ffec t in p a tie n ts re ce iv in g a n tisy p h ilitic tre a tm e n t. T h e p rim ary action o f th e m ercu ria l d iu re tic agents is th e ir ability to in h ib it sulphydryl- con ta in in g enzy m e system s th a t n o rm ally su p p ly en e rg y for sod ium reabso rp tion . Im m ed ia te fatal reac tio n s to m ercu ria l d iu re tic agen ts are ra re ,120 an d w h e n th ey do occur, th ey are re la ted to anaphy lactic shock. H ypersensitiv ity reactions induced by m ercu ria l d iu re tics in c lu d e g en era l­ized p ru ritu s , u rticaria , exfoliative d erm a­titis an d asthm a. M ost o rgan ic m ercu ria ls a re r a p id ly e x c r e te d b y a c t iv e r e n a l tu b u la r sec re tio n b o u n d w ith c y s te in e .115 M ercuria l d iu re tic agen ts p ro d u ce acute o liguric ren a l failu re from acu te tu b u la r n ecro sis .216,248 S ch re in er an d M ah er b e ­liev e th a t organ ic m ercu ria ls a re slow ly co n v erted to inorgan ic m ercu ry secondary to a b d o m in a l r e n a l r e te n t io n b y th e k id n ey s .225

M eralluride-induced acute oliguric renal failure has developed as the resu lt o f acute tu b u la r n ec ro s is .81 T h is is p ro b ab ly th e re ­su lt o f a nep hro tox ic ity m echan ism . A cute o lig u ric re n a l fa ilu re , ex fo lia tiv e d e r ­m atitis, fever an d eo sin o p h ilia have som e­t im e s f o l lo w e d s e v e r a l in je c t io n s o f m era llu rid e . A drenocortical stero ids w ere u s e d to r e v e r s e th is c o n d i t io n . T h is h y p e rs e n s it iv ity re a c tio n p ro d u c e s an acu te in te rs titia l n ep h ritis . T h e re have b e e n a few reports o f p a tien ts d ev e lo p in g n e p h r i t is fo llo w in g m e ra l lu r id e t r e a t ­m e n t .48 T h e m orphologic le s io n w as tu b u ­lar d eg en era tio n associa ted w ith in te rs ti­tial nep hritis .

T hiazide d iure tic agents. T h e th iaz id es w e re d is c o v e re d as a b y -p ro d u c t o f a search for d iu re tic agents sim ilar in struc­tu r e to a c e ta z o la m id e . In 1958, ch lo ro th iaz ide w as in tro d u ced as a p o ten t oral d iu re tic agen t. In a sho rt tim e n u m er­ous o th e r th iaz id es w ere found. T h e u n ­to w ard e ffec ts o f th e th ia z id e d iu re tic

agen ts are po tassiu m d efic iency , aggrava­tio n o f p reex is tin g d iab e te s m ellitu s, ag ­gravation o f g o u t an d b loo d dyscrasias .231 T h e la t te r in c lu d e le u k o p e n ia , th ro m ­bo cy topen ic p u rp u ra an d ap lastic anem ia.

T h iaz id e d iu re tic ag en ts cause acu te o liguric ren a l fa ilu re in tw o w ays. T h e first w ay is b y c h lo r o th ia z id e a n d h y d ­ro ch lo ro th iaz id e p ro d u c in g acu te ren a l n ec ro tiz in g an g iitis , g lo m eru lo n ep h ritis w ith in te rs titia l n ep h ritis an d acu te tu b u ­la r n e c r o s is .70 T h e s e le s io n s p ro d u c e acu te ren a l p a ren ch y m al dam age, w h ich causes acu te o liguric ren a l failu re .

K jellbo o b se rv e d a p a t ie n t w h o h ad acu te n ecro tiz in g ang iitis s im ultan eously in th e skin an d k id n e y .201 H is p a tie n t w as a 62 year o ld m ild ly h y p e rten s iv e w om an w ho d ev e lo p e d fever, r ig h t k id n ey pa in , g ro ss h e m a tu r ia , p r o t e in u r i a a n d azotem ia. R enal b iop sy study rev ea led in ­te r s t i t ia l g ra n u lo m a to u s in fla m m a to ry n o d u les e n c lo sin g n ecro tic a rterio les. T he g lo m e ru l i a p p e a r e d n o rm a l. T h e granulom as w ere com p osed o f ly m pho­cytes, h is tio cy tes , p lasm a cells and n e u t­roph ilic leukocy tes.

F itzg e ra ld rep o rted a p a tie n t w ho had fatal g lo m eru lo n ep h ritis w ith in ters titia l n ep h ritis com p lica ting “ allerg ic p u rp u ra” c a u se d b y c h lo ro th ia z id e .94 A bry a n d C avusog lu re p o rte d a p a tie n t w ith fatal a c u te o lig u ric re n a l fa ilu re c a u se d by a c u te tu b u la r n e c ro s is fo llo w in g c h lo ro th ia z id e t r e a tm e n t .1 E lw o o d e n ­c o u n te r e d a p a t i e n t w i th c o e x is t in g th ro m b o c y to p e n ic p u rp u ra a n d a c u te o l ig u r ic r e n a l f a i lu re fo llo w in gch lo ro th iaz ide tre a tm e n t .8

T h e s e c o n d m e c h a n is m o f a c u te o liguric renal fa ilu re is th e m ore com m on. T h ia z id e s in d u c e a c u te o lig u ric re n a l fa ilu re by a g radual an d chron ic red u c tio n in th e e ffective c ircu la tin g b lood vo lum e; th is red u c tio n is associa ted w ith severe h y p o n a tre m ia .144 T re a tm e n t co n sis ts o f flu id an d sod ium ch lo rid e rep lacem en t. T h e ph ysic ian m u st b e v ery carefu l so th a t

ACUTE TOXIC NEPH RO PATH IES 499h e does n o t excessive ly ex p an d th e b loo d vo lu m e an d p rec ip ita te th e p rim ary ill­ness , e sp ec ia lly i f th e c o n d itio n is con ges­tive h e a rt failu re.

A ris to lo ch ic acid. A risto lochic acid has b e e n u se d ex p erim en ta lly as a d iu re tic a g en t an d as an an tican ce r drug . I t has p ro d u ced ren a l d am age in horses, rabb its , rats an d m ice. I t can abo lish th e an ti d iu re ­tic e ffec t o f vaso p ressin in rabb its and is th e re fo re th o u g h t to have d iu re tic p ro p e r­t ie s . P e te r s a n d H e d w a ll in te n s iv e ly s tu d ie d th e effects o f aristo loch ic ac id tox­icity in rats. T h e y found th a t a sing le in jec ­tion o f 30 m g p e r kg b o d y w e ig h t o f th e d ru g in d u ces rev e rsib le ren a l failu re as­socia ted w ith a d ec rease in g lom eru lar filtra tion ra te as w e ll as increases in BU N an d c re a tin in e . M axim um p o ly u ria oc­cu rred on th e e ig h th day. T h e ir da ta re ­veal a d ec rea se in th e p e rm eab ility o f th e co llec tin g du cts an d proxim al tu b u le s to urea.A n t i c o a g u l a n t s

B ishyd ro xy coum arin (D icum arol) and p h e n in d io n e (H edu lin ) have b e e n im p li­ca ted as p o ss ib le causes o f acu te o liguric ren a l failu re.

B ish ydroxyco um arin . In 1941, B u tt and A llen50 a t th e M ayo C lin ic an d M ey er and associates a t th e U n iv ersity o f W isconsin in tro d u ced b ishydroxycoum arin as an an­tico ag u lan t in to c lin ica l m ed ic ine . D oses in th e th e ra p e u tic range have p ro d u ced nau sea , vo m iting and d iarrhea . In ad d i­tion , ex cess iv e do ses cau sed b leed in g . P a in less gross h em atu ria is u su ally th e first e v id e n c e o f toxicity. T his b leed in g m ay arise from th e k id n ey an d in som e p a tien ts is fo llow ed by renal pa in , u re te ra l c o l ic a n d g ro ss h e m a tu r ia . U re te r a l o b s tru c t io n h a s fo llo w e d b lo o d c lo ts w ith in th e u re te rs .

In o n e p a t ie n t , r e t r o p e r i to n e a l h em a to m a d is s e c te d d o w n a ro u n d th e u rin ary b la d d e r to p ro d u ce an ex ternal u re te ra l o b stru c tio n and acute o lig u ria .135

Phenind ione . P h en in d io n e is know n as p h e n y l in d a n e d io n (P .I .D .) , D a n ilo n e , H e d u lin and E rid o n e . I t has b e e n u se d as a sh o rt-ac tin g an tic o a g u la n t s in c e i t is r a p id ly a b s o rb e d from th e g u t a n d is rap id ly ex cre ted by th e k idney . P h e n in ­d io n e in terfers w ith th e liv e r sy n th esis o f p ro th ro m b in . P ro te in u r ia is com m on ly o b se rv ed d u rin g th e first day o f p h e n in ­d io n e trea tm en t. H eavy p ro te in u ria has re su lte d in th e n ep h ro tic sy n d ro m e .239

Six p a tie n ts w ith severe and sign ifican t re n a l d am ag e c a u se d b y p h e n in d io n e have b e e n re p o rte d by Brooks an d C al­le ja .38 F o u r p a t ie n ts d e v e lo p e d a c u te o ligu ric renal fa ilu re , one h ad th e n ep h ro ­tic syndrom e, an d th e six th h ad a heavy p ro te in u ria .85,101 O th e r c lin ica l fea tu res w e r e fe v e r , sk in rash* ja u n d ic e a n d e o s in o p h ilia .12 T h e h isto log ic ren a l ab ­no rm ality in th e p a tien ts w ith o lig uria w as an a c u te d if fu se in te r s t i t ia l n e p h r i t i s ch a rac te rized by in te rs titia l in filtra tes o f p lasm a cells , eo sino ph ils an d sm all lym ­ph ocy tes. In add ition , th e re w ere in te rs ti­tia l fibrosis an d in tim al fibrosis o f th e in ­te r lo b u la r a rte ry . T h e g lo m e ru li w e re u su a lly norm al. A drenocortical s te ro ids w e re b en efic ia l in rev e rsin g th e acu te in ­te rs titia l n ep h ritis caused by p h en in d io n e hy p ersen sitiv ity .

C a l c i u m V e r s e n a t eC a lc iu m v e r s e n a te is a s y n th e t ic ,

w a te r-so lu b le p o ly am ino ac id (calcium d iso d iu m e th y le n e d ia m in e te t ra a c e t ic acid). I t is an o rgan ic ch e la tin g ag en t th a t is u se d in th e tre a tm en t o f heavy m eta l po isonings.

In 1957, V ogt and C o ttie r re p o rte d a 38 y ea r o ld m an w ith ch ron ic lead po iso n ­in g .247 H e w as tre a ted w ith 600 m g p e r kg b o d y w e ig h t o f calcium v e rsen a te d aily for four days (ten tim es th e average dose). A cute an u ria d e v e lo p ed on th e fifth day, a n d th e p a tie n t d ie d on th e six th day. A cute tu b u la r n ecrosis w as found w ith d i­la ted proxim al tu b u la r ep ith e lia l cells.

500 M UEHRCKE, VOLINI, MORRIS, M OLES AND LAW RENCE

In 1957, M o esch lin d e sc r ib e d tw o pa­tien ts w ho w ere tre a ted for le ad in toxica­tion w ith ca lc ium v e rse n a te .185 B oth d ied in u rem ia cau sed by acu te o lig u ric renal fa ilu re . A cute tu b u la r necrosis w as found at autopsy.

In 1958, W ein ig an d S chw erd d e sc rib ed a c u te r e n a l f a i lu re a s s o c ia te d w ith a b le e d in g te n d e n c y in a 59 y ear o ld factory w orker w ho rece iv ed th re e g o f calcium v e rsen a te .252 A cute tu b u la r necrosis and d ila ted proxim al tu b u le s w ere found at autopsy.

In 1960, R eu b e r and B rad ley rep o rted a o n e y ea r o ld g irl w ho h ad le a d in to x ­ica tion .213 T he ch ild w as tre a te d w ith cal­cium v ersen a te in a dose o f one g (125 m g p e r kg b o dy w eigh t) daily ; th e su b cu tan e ­ous dose w as g iven for th re e days. She d e v e lo p ed acu te o liguric ren a l fa ilu re 12 days after th e first in jec tion and d ied four days la ter. A cute tu b u la r necrosis and d i­la ted proxim al tu b u le s w ere found at au ­topsy.

D e x t r a nL o w m o le c u la r w e ig h t d e x tra n

(D ex tran -60 , G en tran ) has a m o le c u la r w e ig h t o f 40,000.106 I t passes th ro u g h th e g lom eru lar m em b ran e an d is u se d in c lin ­ical m ed ic in e as a sho rt-te rm flow im ­p rov er in sm all b loo d vessels an d as a “p lasm a vo lu m e e x p a n d e r .” 29,82,178 T h e h ig h u r in a ry c o n c e n tra t io n o f d e x tra n crea te s a u r in e o f h ig h v isco sity .125 An in ­c rease in b loo d c lo tting tim e has occu rred in a sub stan tia l n u m b e r o f in d iv id u a ls re ­c e iv in g d e x tra n . A d v e rse re a c tio n s to dex tran o rig ina te as h y p ersen sitiv ity and in c lu d e u rticaria , an g io n eu ro tic ed em a, b ro n ch o sp asm an d sev e re an ap h y lac tic sh o c k . H y p e r s e n s i t iv i ty g lo m e ru lo ­n ep h ritis cau sed by A rthus’s p h en o m e­no n an d acu te o liguric ren a l fa ilu re are tw o re n a l c o n d itio n s in d u c e d by d ex ­tra n .150,242

A cute o liguric rena l fa ilu re in d u ced by low m o lecu la r w e ig h t dex tran has p ro ­d u ced tw o d is tin c t renal lesions. T h e first

w as o b se rv ed by M organ an d co lleagues in th re e h y d ra te d p a t ie n ts w ith acu te o lig u ria fo llo w in g d e x tra n in fu s io n .183 R enal b iop sy s tu d ie s w ere p erfo rm ed on each p a tie n t a n d grossly sw o llen tu b u la r cells w ere foun d cram m ed w ith a foam y m a te r ia l. D is te n d e d c e lls c o m p le te ly o c c lu d e d th e tu b u la r lu m e n . S p e c ia l stains rev ea led large q u an titie s o f dex tran w ith in tu b u le s b u t n o n e in th e tu b u la r lum en .

T h e secon d le s io n occu rred in d eh y ­d ra te d p a tie n ts g iv en d e x tra n .176 A cute oliguric ren a l fa ilu re w as associa ted w ith th e find ing o f dex tran casts o b struc ting th e tu b u la r lu m e n .197 O n ce w ith in th e tu b u la r lu m en , th e dex tran becom es con­cen tra ted an d a h ig h ly v iscous u rin e is form ed; th is re su lts from th e proxim al tu b u la r reab so rp tio n o f e lec tro ly tes an d w a te r .9 T h e h ig h ly co n cen tra ted viscous dex tran u r in e form s tu b u la r casts. T h e m assive o b struc tion w ith in nep h ron s re ­su lts in no u r in e flow an d su b se q u e n t acu te o liguric ren a l failu re. M annito l in ­fusions (20 p e rc e n t so lu tion) have b een effective in in itia tin g a d iu re s is .22

Ferrous sulfa te . T h e in g estio n by ch il­d ren o f large doses o f ferrous sulfate fre­q u e n tly p ro d u c e s iro n p o iso n in g . T h e m orta lity ra te in a large series o f ch ild ren w ith iron p o iso n in g w as app rox im ately 50 p ercen t. A cute o lig uric renal failu re occu rred as a re su lt o f acu te tu b u la r n e ­crosis .136 T h is ren a l le s ion m ay b e re la ted to gastro in testina l tra c t d am ag e .234

A m inop yr in e . A m inopyrine is a closely re la te d co m p o u n d to an tip y rin e an d to p h en y lb u tazo n e . I t is u sed c lin ica lly as an analgesic and an an tip y re tic , is rap id ly an d v irtua lly co m p le te ly ab so rb ed from th e gut and is d em e th y la ted in th e liver.

T h e toxic e ffect o f am in opy rine is a se­v e re an d o ften fatal agranu locytosis. I t c a n c a u se h e r p e s la b ia l i s a n d a n g io ­n eu ro tic e d em a in h y p e rsen s itiv e in d i­v iduals. E kn oy an an d M atson rep o rted a 37 year o ld w om an w ho d ev e lo p ed acu te o liguric rena l fa ilu re .80 A lthough she d id

ACUTE TOXIC NEPHROPATHIES 501m an ifes t ren a l dam age fo llow ing a b r ie f cou rse o f tre a tm e n t w ith am p h o te ric in B, a m ark ed d ec rea se in ren a l function oc­c u rre d co in c id en t w ith am in opy rine ad­m in is tra tio n . R ec o v e ry o c c u r re d a f te r a m in o p y rin e w as d is c o n tin u e d . T h e re w as a d ram atic d ec rease in ren a l function c o in c id e n t w i th a s e c o n d c o u rs e o f am in o p y rin e in gestion . T h e p a tie n t d ied in u rem ia ; reg re ttab ly , no au top sy w as done.

Phenylbutazone. Phenylbutazone (Buta- zo lid in ) is a c o n g en e r o f am in opy rine and can in d u c e dam ag e to th e skin , lu n g s , heart, liver, b o n e m arrow , ad ren a l g lands an d g u t .195 P h en y lb u tazo n e has p ro d u ced b o th acu te nono liguric ren a l fa ilu re an d acu te o liguric ren a l fa ilu re .41,104,263

R ichardson an d A lderfer rep o rted a 43 yea r o ld execu tive w ho d e v e lo p ed acu te no n o lig u ric ren a l fa ilu re a fte r tak in g 2.2 g o f p h en y lb u tazo n e for six d ay s .214 T h e pa­tie n t h a d severe hy po na trem ia (sodium , 96 m m ol p e r 1) an d ac id o sis ( C 0 2, 14 m m ol p e r 1). A fter m assive sod ium re p le ­tio n , th e p a t ie n t r e c o v e re d . A p p ro x i­m ate ly e ig h t days a fte r th e o n se t o f renal fa ilu re , find ings from a renal b iop sy study w e re norm al.

P h e n y lb u ta z o n e - in d u c e d a c u te o l i­guric ren a l failu re re su lts from th re e d is­tin c t m orpho log ic lesions. T h ese in c lu d e acu te tu b u la r n ecro sis ,221 acu te in te rs titia l n e p h ritis , an d th ro m b o tic th ro m b ocy to ­p e n ic p u r p u r a (T T P ). L ip s e t t a n d G o ld m an re p o rte d a p a tie n t w ith rev e rs i­b le acu te o liguric renal fa ilu re fo llow ing t r e a tm e n t w i th p h e n y lb u ta z o n e .166 A ren a l b io p sy stu dy d o n e on th e fifth day o f o lig u ria rev ea led acu te tu b u la r necro ­sis. H erm an n , H o p efe ld and B ern in g re ­p o rted a p a tie n t w ith fatal acu te o liguric ren a l fa ilu re cau sed by tre a tm e n t w ith p h e n y lb u ta z o n e .124 An acu te in te rs titia l n ep h ritis w as found at autopsy. D u n ea an d co lleag u es re p o r te d a 44 y ea r o ld housew ife w ho was tre a ted w ith p h e n y l­b u tazo n e , 600 m g daily for th re e days;

th is tr e a tm e n t w as fo llo w e d by a c u te an u ria a n d ja u n d ic e .77 T h e p a t ie n t re ­m a in ed an u ric u n til h e r d ea th 30 days a f te r th e o n se t o f h e r il ln e ss . A ren a l b iop sy stu dy perfo rm ed d u rin g th e th ird w e e k o f h e r il ln e s s re v e a le d T T P as­so c ia te d w ith a h e m o ly tic a n e m ia . In vitro p h en y lb u tazo n e w as found to b e th e an tig en to p ro d u ce a p o s itiv e C oom bs test; th e C oom bs te s t becam e neg ative a fte r tre a tm e n t w ith ad ren o co rtica l s te ­roids.

B is m u th c o m p o u n d s . B ism u th com ­p o u n d s h a v e in d u c e d n e p h ro to x ic i ty th ro u g h r e p e a te d in tra m u s c u la r in je c ­tions, recta l sup po sito rie s, acc id en ta l in ­gestion an d id io sy ncrasies to heav y m et­als. T h e prox im al renal tu b u le s are th e organs m ost sensitiv e to in jury.

A lthough th e large n u m b er o f b ism u th com pounds fo rm erly availab le to p h y si­cians has b e e n greatly re d u c e d , b ism u th com pounds have b e e n u se d ex tensiv e ly in th e tre a tm en t o f sy p h ilis ,18 oral in fec­tions such as V in cen t’s g ingivostom atitis a n d g a s tro e n te r it is . A lth o u g h b is m u th com pounds have b e e n u se d in th e tre a t­m e n t o f v errucae , th ey have no know n b en efic ia l value w h e n so used .

T h e toxicity o f b ism u th com pounds is d irec tly re la ted to th e rap id ity o f abso rp ­tion . A pproxim ately 90 p e rc e n t o f th e ab­so rbed dose o f a so lu b le b ism u th sa lt is excre ted by th e k idn eys. B ism u th ten ds to co n cen tra te in renal tissue to am ounts five tim es th a t in th e liver. T h e re fo re , dam age occurs to th e k idney . P roxim al tu b u la r necrosis an d in tran u c lea r in c lu ­sion bo d ies are freq u en tly o b serv ed in b ism u th nep h ro p a th y . In ad d itio n to k id ­ney dam age, th e se com pounds h av e p ro ­d u ced gut, liver, an d cen tra l nervous sys­tem dam age. A cute o lig u ric renal fa ilu re w as th e c h ie f cause o f d ea th in pa tien ts p o iso n ed w ith b ism uth .A n e s t h e t i c A g e n t

M eth o x y flu ran e a n e s th e s ia can p ro ­du ce renal tu b u la r dysfunction an d lead

502 M UEHRCKE, VOLINI, MORRIS, M OLES AND LAW RENCE

Im m une-com plex G lom erulonephritis following M ethoxyflu ranej~Prednisone, 60m g./doy|

R.A., 41 y r s , W , F 1 ------

Renalb io p s y

1

B e ta 1C

5 6 mg %

F i g u r e 8. Im m u n e - C o m p lex G lo m e ru lo n e ­p h ritis F o llo w in g M eth­oxyflu rane. T h e c lin ica l course o f R.A., a 41 year old w h ite fem ale, is p lo t­ted . O n h e r th ird expo­su re to m e th o x y flu ra n e ana lgesia she d eve loped ja u n d ic e , an e ry th e m ­a to u s ra sh , eo s in o - p h il ia , an d ac u te r e n a l failure. R epeat hem odial­y s is w as s ta r te d . T h e BUN is p lo tted in the dot­te d lin e . T h e SG O T is p lo tted by th e dark line. A renal b iopsy study on the 1 4 th d a y r e v e a le d an

im m une-com plex glom erulonephritis. P redn isone was started and th e p a tien t rap id ly im proved.

SGOT

M e t h o x y f l u r a n eA n a l g e s i a

-------------r10D a ys in H o s p i t a l

!20

4 0 0 0

33 0 0 0 3

1—

2 0 0 0oo

E3

1 0 0 0 0)<S>5 0 0

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to acu te “h ig h -o u tp u t” renal fa ilu re .57,160 C alcium oxalatic crystal d ep o sitio n oc­curs in renal tu b u les . T h e m echan ism o f nep h ro to x ic ity is th e effec t o f flu o rid e w h ich blocks th e con cen tra ting capacity o f th e d ista l nep hron .

In m an, m ethoxyflurane is m etab o lized w ith lib e ra tio n o f bo th organic fluoride and organic m etab o lites con ta in in g fluo­r id e s .127 F lu o rid e m ay b e sto red in body fat and slow ly b u t con tinually re leased for several days after an esth e tic exposure. T hus, a “ h ig h -o u tp u t” renal failu re is p ro ­longed.

T h e au thors ob serv ed one p a tie n t ex­po sed to m ethoxyflurane analgesia using a face m ask -inh aler. T h e p a tien t, a 41 year o ld lady was exposed to m ethoxy­flurane d u rin g each o f th ree p regn ancies at term . At th e second exposu re she d e ­v e lo p ed jau n d ice . At th e th ird exposure she d ev e lo p ed jau n d ice , an e ry them atous sk in ra sh a n d a n im m u n e -c o m p le x g lom eru lo nep hritis w ith acute rena l fail­u re . She re q u ired hem odialysis and ad ­rena l corticostero ids to recover (figure 8 ).A cute H em orrhag ic G lom eru lo nep hritis

In genera l, th e p a tien ts w ho dev elo p a c u te h e m o rrh a g ic n e p h r i t i s d e v e lo p th e c lin ica l syndrom e o f acute ren a l fail­u re . T h is is u s u a l ly o n th e b a s is o f

a n t ig e n -a n tib o d y c o m p lex g lo m e ru lo ­nep h ritis o r hy p ersen sitiv ity g lom eru lo­nep hritis . A variety o f th e rap eu tic agents u s e d in th e t r e a tm e n t o f in fe c t io n s , h y p e rte n s io n , co n v u ls io n s an d card iac d y srh y th m ia have b e e n kn ow n to p ro ­duce a d ru g -in d u ced system ic lupus ery­them atosus. U sually in p a tien ts w ith sys­tem ic lu pu s, th e drugs p rec ip ita te ou t a fu lm in a tin g a n d f lo rid reac tio n o f sys­tem ic lupus ery them atosus. T hu s, drugs p ro d u c in g lu p u s u su a lly do n o t cau se lupus nep hritis .

An an tih y p erten siv e ag en t such as hy­dralazine w as th e first o f a n u m b er o f drugs im p lica ted to p rod uce th e c lin ica l syn­drom e o f system ic lu p u s e ry th em ato su s .31 O th e r a g e n ts in c lu d e iso n ia z id e , sul- fa n a m id ie s , p e n ic i l l i n , t e t r a c y c l in e , strep tom ycin , p-am ino-salicy late , m ethyl and propyl th iourac il, re se rp in e , alpha- m eth y ld op a , guanoxam , p h en o b u tazo n e and g riseo fu lv in .52,58,73 T h e authors have ob serv ed florid lu pu s n ep h ritis p rod uced b y b o th th e a n t ic o n v u ls iv e a g e n t d ip h en y lh y d an to in an d oral co n tracep ­tive agen ts (figure 9). W hen lupus n e p ­h ritis w as p ro d u c e d by th e la t te r tw o agen ts, it was severe and florid in p ro d u c­in g r a p id ly p r o g re s s iv e g lo m e ru lo ­nep h ritis w ith azotem ia. T h erap y w as d i­rec ted to w ith draw al o f th e ag en t an d use

ACUTE TOXIC NEPHROPATHIES 503

F i g u r e 9. E le c tro n - m ic ro scop ic P h o tograph o f Renal Biopsy Study of Oral Contraceptive-Induce- Lupus Nephritis. A 34 year o ld h o u sew ife in g ested oral contraceptives for 20 days. She developed hema­turia, massive proteinuria, azo tem ia and m alignant hypertension. H er LE cell te s t was positive and her serum Betaic globulin was 47 mg p e r dl (normal 100 to 170 mg per dl).

A portion of a glom er­u la r ca p illa ry is n o ted . T he lum en (L) is small. N u m erou s po lym orpho- n u c leo cy te s a re p re se n t (straight arrows). E lectron dense im m unological d e ­p o s its a re n o ted b e lo w the glom erular basem ent m e m b ra n e (c u rv e d a r ­row s). U ran y l n itra te (x 4,000).

o f h ig h dosage ad ren o co rtica l stero ids. T h e serum B eta ic g lobu lin was an excel­len t “ yard-stick” to d e te rm in e th e control o f d rug -indu ced d isease activity.

T he N ephro tic Syndrom eT he nep hro tic syndrom e has follow ed

th e th e rap eu tic adm in istra tion o f a vari­e ty o f d rug s as n ep h ro to x ic ag en ts . A com p reh ensiv e list is g iven in tab le IV. F o l lo w in g th e th e r a p e u t ic u se o f a specific drug from a n u m b er o f u n re la ted drugs listed , pa tien ts have b e e n observed to d e v e lo p th e n e p h r o t ic s y n d ro m e . W h en s to p p in g th e o f fe n d in g d ru g a p rom pt rem ission usually occurs and is associated w ith th e d isapp earan ce o f pro­te inu ria . T h ese u n re la ted drugs in c lu de trox idone, param ethad ione , p rob enec id , pen ic illam in e , to lb u tam id e , perch lo rate , gold salts, b ism u th salts and o th e r heavy m e ta ls .13,16,57

D r u g sR enal b io p sy s tu d y o f p a tien ts w ith

d ru g -in d u ced n ep h ro tic syndrom e u su ­a lly r e v e a l no s p e c if ic g lo m e ru la r changes by ligh t m icroscopy; how ever,

TABLE IV

Nephrotic Syndrome Owing to Adverse Reactions to Drugs and to Hypersensitivity States

DrugsOrganic and inorganic mercurial compounds Trimethadione (Troxidone)Paramethadione Probenecid Penicillamine Tolbutamide Perchlorate Phenindione Aurothiomalate Bismuth salts Other heavy metals

Hypersensitivity toxins Pollen Bee stings Poison oak and ivy Serum sickness Smallpox vaccination"Sting" Portuguese man-of-war (sea nettle)

504 M UEHRCKE, VOLINI, MORRIS, MOLES AND LAW RENCE

by e lec tro nm icrosco py fusion o f v isceral e p i th e lia l foo t p ro cesse s are n o ted . In p a t ie n ts w ith d -p e n ic i l la m id e - in d u c e d n e p h r o t ic s y n d r o m e ,51 e le c t r o n ­m icroscopy stu d ies h av e rev e a le d d ep o ­sition o f e lec tro n d en se m ateria l on th e e p ith e lia l s id e o f th e g lo m eru la r b a s e ­m en t m em brane associa ted w ith fusion o f v is c e ra l e p i t h e l i a l fo o t p r o c e s s e s . Im m u n o p a th o lo g ic a l s tu d ie s o f d -p en ic illam id e -in d u ced n ep h ro tic syn­drom e sug gest th e se chan ges m ay re p re ­s e n t a n t ig e n -a n tib o d y c o m p le x e s a n d s u p p o r t th e im m u n o lo g ic a l b a s is fo r “p en ic illa m in e ” nephro tox ic ity .

In g e n e ra l, i t is b e l ie v e d th a t som e drugs p ro d u ce th e n ep h ro tic syndrom e as an id iosyncrasy . H o w ev er, th is m ay no t b e th e s itu a tio n in th e n e p h ro tic syn­d ro m e a s s o c ia te d w i th th e r a p y o f t r im e th a d io n e a n d p a r a m e th a d io n e . C h i ld r e n o r y o u n g a d u l ts g iv e n tr im e th ad io n e for severa l w eeks dev e lo p th e n ep h ro tic sy n d ro m e .240 A n u m b e r o f th e s e p a t ie n ts im p ro v e s p o n ta n e o u s ly after w ith d raw al o f th e drug . T h ey have also reco v ered d e sp ite c o n tin u in g trea t­m e n t a t a lo w er d o se . A n o th e r p a t ie n t im p ro v ed a fte r a sev e re illn e ss las tin g th re e m onths. An add ition a l p a tie n t was u n im p ro v ed fo llow ing d ru g stoppage and ste ro id th e rap y an d five p a tien ts d ied .

H eavy m etals ap p ea r to p ro d u ce drug- in d u c e d n ep h ro tic syndrom e. T h ese in ­c lu d e m ercu ry , go ld a n d b ism u th . T h e m ercu ria l toxicity arises w h en th e p a tien t is e x p o s e d c h ro n ic a l ly to a m e rc u ria l d iu re tic ag en t or to am m o n ia ted m ercu ry o in tm en t. In add ition , m ercu ry is an oc­cu p a tio n a l h aza rd in em p lo y ees o f th e d is in fe c ta n t in d u s try . T h e p a tie n ts ex ­po sed to th is toxicity hav e d ev e lo p e d se­vere p ro te in u ria an d th e n ep h ro tic syn­d ro m e .162

G old has p ro d u ced th e n ep h ro tic syn­drom e by p ro d u c in g g lo m eru la r lesions. T h e re is a fu sio n o f v iscera l ep ith e lia l foo t p ro c e s se s o f th e e p i th e l ia l c e lls .

M andem a an d co lleag ues hav e rep o rted sim ila r ab n o rm alitie s in p a tie n ts g iven m ercu ria l co m p o u n d s .161H y p e r s e n s i t i v i t y A g e n t

M a s s iv e p r o t e in u r i a a n d th e s u b ­se q u e n t d e v e lo p m e n t o f th e n e p h ro tic syndrom e has b e e n rep o rted to a varie ty o f h y p e rsen s itiv ity to x ins .119' 218 T h ese in ­c lu d e b e e stings, se ru m sickness, sen s i­tiv ity to specific p o llen an d o th e r in h a l­ants. In ad d itio n , a d e lay ed reac tio n to po ison ivy o r po iso n oak can p ro d u ce th e n ep h ro tic syn d rom e. A lthough p a tien ts w ith h y p ersen s itiv ity toxin con stitu te a re la tiv e ly sm all g rou p o f th e n ep h ro tic syndrom e, th e syndrom e do es occu r fol­low ing exp osu re to hy p ersen sitiv ity tox­in . O n exam ination o f th e renal b iop sy m ateria l, th e re w ere areas o f eosino ph ilic in filtra tion b o th in th e renal in te rs titiu m as w e ll as th ro u g h o u t th e g lo m e ru la r c a p i l la r ie s . A s tu d y b y e le c t r o n ­m icroscopy sh o w ed a co lle seen t o f th e v iscera l e p ith e lia l foot p rocesses. T h is is very sim ilar to th e so-called m in im al le ­sions o f g lo m e ru lo n e p h ritis . I t is very po ss ib le th a t a n u m b er o f p a tien ts w ith re c u rre n t n ep h ro tic syndrom e in w hom th e o ffe n d in g a g e n t has n o t b e e n d e ­lin e a te d m ay also fall in to th e category of a h y p ersen sitiv ity toxin.Tubular Disturbances

D rugs can d irec tly o r in d irec tly in d u ce tu b u la r d is tu rb an ces by th e ir toxic effect on specific s ites on th e n ep h ro n . T his in ­c lu d es proxim al, d is ta l co llec tin g tu b u les and lim bs o f H e n le . T h u s, th e c lin ica l syndrom es in d u c e d by d ru g toxicity af­fecting th e n ep h ro n are re la ted to th e site o f tu b u la r dam age. R enal tu b u la r acidosis an d th e F an co n i syn drom e re flec t prox i­m al tu b u la r d a m a g e . P o ta s s iu m d e f i­c ien cy p ro d u ces rev e rs ib le dam age to the proxim al tu b u les .

T h e F a n c o n i s y n d ro m e is c h a ra c ­te r iz e d b y a m in o a c id u r ia , g ly c o su ria , po tassium loss and a d e fec t in hydrogen

ACUTE TOXIC NEPH RO PATH IES 505ion transp ort. O u td a ted te tracy c lin e has in d u c e d tu b u la r d y sfu nc tion to p ro d u ce a F an co n i type sy n d ro m e .96

T e tra c y c lin e m ay d e g ra d e sp o n ta n e ­ou sly on sto rage to form toxic ep im ers w h ich have b e e n h e ld re sp o n sib le for the d ev e lo p m en t o f a rev e rs ib le ty p e o f F an ­coni type sy n d ro m e .114 A zo tem ia in p a ­tien ts w ith s ig n ifican t rena l im p airm en t has b e e n fu rth er ac tiva ted by th e u se of te tracy clin es. T h e exp lan atio n for th is is n o t c le a r an d c a n n o t b e re a d ily e lu c i­d a te d in th e p r e s e n c e o f p re -e x is t in g ren a l d isease . Som e b e lie v e th a t th is is re la ted to th e ca tabo lic effects o f te tra ­cy c lin e .99R e n a l T u b u l a r A c i d o s i s

T h e n e p h ro to x ic p r o p e r t ie s o f a m ­p h o te ric in B have b e e n w ell recogn ized . N ecrosis o f b o th th e proxim al and distal e p ith e liu m occurs re su ltin g in a n u m b er o f functional defects. T h ese defec ts are re la te d to im p a irm e n t o f co n cen tra tin g capacity and in h y d ro g en ion secretion . T hu s, th e syndrom e o f ren a l tu b u la r aci­dosis occurs. W h en th is becom es chronic, nep h rocalc ino sis m ay develop .

A m p ho teric in B can also in d u ce severe h y p o k a lem ia by excessive ren a l p o ta s­sium loss. T h e m orphological lesions as­s o c ia te d in th e p ro x im a l tu b u le s o f h y p o k a le m ia are re v e rs ib le on d isc o n ­tin u in g am p h o te r ic in an d re p le n ish in g po tassium .

T o lu en e in ha la tio n o r g lue sniffing are o th e r causes o f ren a l tu b u la r ac id o sis .198 In r e c e n t y ea rs y o u n g te e n a g e rs h av e b e e n rep o rted d ev e lo p in g eu p h o ria from sniffing g lue so lven ts. T h e in c id en ce of nephro tox ic effects is d irec tly associa ted w ith th e g lue sniffing pastim e. O n e m ay q u es tio n th e m u lti-d ru g ab u se o f te e n ­agers as re la te d to th e adv erse effects of g lue sniffing.D i s t a l T u b u l a r D i s f u n c t i o n s

D em eclocy c lin e has p ro d u ced a p rim ­ary d ista l tu b u la r defect. T h is d efec t re­

sults in in h ib itin g th e d istal tu b u le s to th e ab so rp tio n w ater. T h e d e fec t is ac­co m p an ied by a decrease in u rin ary cyc­lic ad en o s in e m on oph osp ha te (AMP) ef­fect. T h is e ffec t was th o u g h t to b e d u e to in te rfe ren ce o f cyclic A M P -m edita ted ac­t io n o f a d e n in e d e h y d ro p h o s p h a te (A D H ) on th e d is ta l tu b u le . T h is co n d i­tion is rev e rs ib le once D em eclocy c lin e is rem oved .P o tassium D efic ien cy

As a group, th e m od ern d iu re tic agen ts a re rem ark ab ly safe d ru g s . T h e y hav e p ro d u ced a varie ty o f m etabo lic d is tu r­b a n c e s ,159,212 b u t th e ir specific toxic effect has n o t b e e n serious. T h e use o f oral d iu ­re tic ag en ts can p ro d u ce sev ere p o tas­sium d efic iency by an excessive u rin ary loss o f p o tassium .

P o tassium d e p le tio n ow ing to u se o f oral d iu re tic agen ts can b e easily over­looked by th e physic ian . T h e sym ptom s o f fatigue an d m uscu la r w eakness m ay b e a t t r ib u te d to th e u n d e r ly in g d is e a s e ra th e r th an to th e trea tm en t. T h e seru m po tassium con cen tra tion is th e b e s t in d i­cator th a t d ep le tio n is p resen t. M easu re ­m en t o f th e 24 h o u r u rinary po tassium e x c re tio n m ay su b s ta n tia te p o ta s s iu m loss.

P ro lo n g e d p o ta ss iu m d e f ic ie n c y can lead to in te rs titia l fibrosis and s u b se q u e n t renal scarring . C h ro n ic in te rs titia l fibrosis dev e lo p s associa ted w ith azotem ia. S evere renal fa ilu re m ay dev e lo p and m ay req u ire th e p a t i e n t to b e p la c e d on c h ro n ic hem odia lysis .

Sum m aryA cute toxic n ep h ro p a th ie s are b y p ro d ­

ucts o f m an ’s ever in creasing exposure to a vast array o f toxic chem icals and drugs th a t re su lt from in d u stria l an d m ed ica l p rog ­ress. T h e k id n ey is ex trem ely su scep tib le to nephro tox ic agents. Its n u m ero us e n ­zym e system w ith in th e cytoplasm and m ito cho nd ria , its rich b loo d sup p ly , its

506 M UEHRCKE, VOLINI, MORRIS, MOLES AND LAW RENCE

com plex su p e rio r excre to ry function , its large en d o th e lia l surface , an d th e in te rex ­change o f sub stances in th e in te rs titiu m p red isp o se th e k id n ey to nephro tox ic ef­fects.

A cute nep hro tox ic ity can p ro d u ce sev­e ra l c lin ica l syn d rom es. T h e se in c lu d e acu te o liguric ren a l failu re; b o th o liguria an d h ig h o u tp u t. An exam p le o f th e la tte r is acu te toxicity o f m ethoxy lflu rane . O th e r c lin ica l syndrom es o f acu te nephro tox ic ity in c lu d e n e p h r o t ic s y n d ro m e , a c u te h e m o rrh a g ic g lo m e ru lo n e p h r i t is , a n d tu b u la r d is tu rban ces.

M an agem en t in c lu d es w ith d raw al from th e specific toxic agen t. E lec tro ly te d e ­fic iencies sh o u ld b e correc ted . In som e p a tien ts it is nece ssa ry to p ro lon g th e w ell b e in g and life o f th e p a tie n t by u se o f hem odialysis u n ti l th e n ephro tox ic effects u n d erg o re so lu tio n an d heal.

F in a lly , p h ysic ians w ho th in k th ey are do in g w ell by th e ir p a tien ts m ay su d d en ly e n co u n te r an ad v erse d ru g reaction . In som e situations th e d ru g reac tions is tran s­itory a n d co m p le te ly rev ersib le . In o thers it m ay lead to ch ron ic p rog ressive k id n ey fa ilu re w ith d e a th as a n u n u su a l com plica­tion o f nephro tox icity .

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