ANNALS OF CLINICAL AND LABORATORY SCIENCE, Vol. 6, No. 6 Copyright © 1976, Institute for Clinical Science

Acute Toxic Nephropathies: Clinical Pathologic Correlations - ROBERT C. MUEHRCKE, M.D.,* FREDERICK I. VOLINI, M.D.,f ARTHUR M. MORRIS, M.D.,f JOSEPH B. MOLES, M.D.,f and ARTHUR G. LAWRENCE, M.D.,f *West Suburban Kidney Center and fWest Suburban Hospital, Oak Park, IL 60302

ABSTRACT Man’s ever increasing exposure to numerous drugs and chemicals, which are the results of medical and industrial progress, produces a by-product of acute toxic nephropathies. These include acute toxic renal failure, drug- induced acute oliguric renal failure, acute hemorrhagic glomerulonephritis, nephrotic syndrome, tubular disturbances and potassium deficiency. In depth information is provided for the previously mentioned disorders.

Introduction have extremely vascular renal medullae Acute toxic nephropathy is a by­ and rete mirabile that function in the product of man’s ever increasing expo­ final dilution and concentration of the sure to a vast array of various chemicals urine. This complex mechanism results and drugs that result from industrial and in hypertonicity of the renal interstitium medical progress. The kidney, with its with concentration of nephrotoxic chemi­ rich blood supply, numerous enzyme sys­ cals, biologic products and drugs. tems and superior excretory function, is In our experience, approximately 25 especially vulnerable to the adverse ef­ percent of all patients with acute oliguria fects of chemicals, biologic products and have renal failure induced by drugs or drugs.44,226 The kidneys comprise 0.4 chem icals.188 The other main clinical percent of the total body weight and re­ syndrome of toxic nephropathy include quire a high oxygen consumption. The the nephrotic syndrome,133,180,256 tubular kidney’s oxygen required is supplied d iso rd ers,96 acute hemorrhagic through approximately 20 to 25 percent of glomerulonephritis and chronic renal the cardiac output. failure. Although the kidneys are of relatively small weight, they have the greatest sur­ M echanism face area of endothelial cells when com­ Nephrotoxic chemicals have exerted pared to other organs. The kidneys with these adverse effects on the kidney either their numerous enzyme system are sec­ singly or through a combination of ond only to the liver in complexity of pathopharmacologic mechanisms. One metabolic function. Finally, the kidneys mechanism is the direct action of the 4 7 8 MUEHRCKE, VOLINI, MORRIS, MOLES AND LAWRENCE nephrotoxic substance as a protoplasmic the nephrotoxic effect of meralluride poison. The nephrotoxic agent passes (Mercuhydrin), which reacts with en­ into the glomerular filtration in an zyme systems of the sulfhydryl groups amount proportionate to the filtered within the wall of mitochondria. Other plasma water. As the nephrotoxic sub­ nephrotoxins couple with enzymes to in­ stance is a foreign compound and has no activate them. Some nephrotoxins affect specific renal tubular transport process, it enzymes within the mitochondria, while is progressively concentrated within the other toxins affect cytoplasmic enzymes. tubular lumen. The concentration of the This functional interference may result in nephrotoxic agent is so great that it dam­ no apparent tubular morphologic abnor­ ages the tubular epithelial cells. malities when the tissue is studied by Moreover, other nephrotoxic substan­ light or electron microscopy. Other pro­ ces204,228,238 may increase in their concen­ toplasmic toxins, when concentrated, tration to reach toxic levels within the may coagulate protein and may result in medullary interstitium by the osmotic either severe tubular necrosis or diffuse concentration of fluids. When sufficient bilateral renal cortical necrosis. quantity is accumulated, the kidney in­ O ther nephrotoxic agents produce their terstitium is damaged. Chronic phenace- adverse effects through an immunologi­ tin nephritis is one example of such a cal pathopharmacologic mechanism. The condition.103,147,224 best example of such a model is duck egg Some nephrotoxic substances penetrate albumin. The morphologic site involved the cell to interact with cellular con­ is usually the large endothelial surface of stituents and, subsequently, poison the the glomerular capillaries, arterioles and cell. One example of this mechanism is arteries. The duck egg albumin acts as an antigen evoking a production of antibody. T A BLE I Immune complexes formed in the pres­ Common Chemicals that Induce ence of complement produce damage to Acute Oliguric Renal Failure glomerular capillaries. Mean Lethal Dosage Another important additional site in­ (Approximately Chemical per 70 kg) volved by hypersensitivity reactions is the renal interstitium. This hypersen­ Anilin 10 g sitivity interstitial reaction was reported Arsine gas (AsH-j) MAC* 30 ppm Camphor 2 g more than 75 years ago by Councilman.60 Carbon tetrachloride 4 ml (MAC* 25 ppm) Known as “Councilman’s interstitial Chlordane 8 g Chloroform 25 ml nephritis,” it is characterized by intersti­ Copper compounds 15 g tial infiltrates of plasma cells, small lym­ Creosote 10 g Essential (volatile) oils 1 9 phocytes, and eosinophils. A few of the Ethylene dischloride MAC* 100 ppm Ethylene glycol 100 ml drugs that cause this hypersensitivity Formaldehyde (formalin) 30 ml reaction are phenindione, diphenylhy- Guaiacol 2 9 -a Mercury compounds MAC* 0.1 mg/MJ dantoin (Dilantin), methicillin, phenyl­ i g butazone and meralluride (Mercuhyd­ Naphthalene 5 g Oxalates 5 g rin). Paradichlorobenzene 15 g Pentachlorophenol i g In general, substances toxic to the kid­ phenol 10 g Phosphorus, yellow 0.05 g (MAC* 1 g/M3) ney include chemicals, as presented in Resorcinol 2 g table I, in any physical state (liquids, sol­ Tetrachloroethane. MAC* 5 ppm ids, and gases); biologic products such as Thymol 2 g horse serum, fungi (mushrooms), and *MAC - maximum allowable concentration vaccines; and drugs given orally or par­ ACUTE TOXIC NEPHROPATHIES 479 enterally. Drugs produce other clinical treatm ent.138, 167,169 Six patients were syndromes of renal disease, including the treated after uremia occurred, and only nephrotic syndrome, chronic renal fail­ three of those six survived.168 BAL ap­ ure, tubular disturbances and acute pears to enhance the removal of mercuric hemorrhagic glomerulonephritis. In ions by 7 to 11 percent with the use of some situations, the damage is mild and hemodialysis.15 transitory. In other situations, the damage The clinical symptoms of inorganic is severe and irreversible leading to the mercury poisoning begin with a lingering patient’s death. bitter and metallic taste in the mouth. The patient experiences a sensation of throat constriction, suffocation, subster- Acute (Toxic) Renal Failure nal burning, gastritis, abdominal pain The more common nephrotoxins pro­ and, finally, nausea and vomiting.109 Per­ ducing acute renal failure are heavy met­ sistent vomiting leads to retching of als, organic solvents, glycols, analine, in­ blood. Ulceration may be noted in the pa­ secticides, arsine, cresol and a miscel­ late. The patient goes into circulatory laneous group of chemicals. They usually failure; the pulse becomes weak and act directly on the tubular cells to disrupt rapid. Syncope and shock are followed by their metabolic and morphologic integ­ a scanty urinary output. Finally, a fatal rity. anuria develops. Jaundice occurs in ap­ proximately 35 percent of the patients. M e r c u r y C o m p o u n d s The kidneys of patients with inorganic mercury poisoning are usually enlarged The inorganic salt bichloride of mer­ and weigh up to 250 g each. The renal cury (mercuric chloride) is also known as cortex is pale and thickened. The renal corrosive sublimate. Mercuric chloride is medullae are a slightly darker brown than usually ingested accidentally,175 in suici­ normal. The most striking morphologic dal attempts,34 or following its use as an abnormalities occur in the proximal con­ abortive agent. The dose required to in­ voluted tubules.97 There is extensive cel­ duce renal failure is difficult to assess.71 lular necrosis and the lumina are filled In most reports the patients with acute with granular eosinophilic material be­ renal failure had ingested two or three lieved to be derived from the cytoplasm tablets (0.5 g each).129 When more than of necrotic cells.61 Less striking abnor­ four tablets were taken, acute oliguric malities are found in the ascending renal failure was fatal. Renal lesions de­ limbs, distal convoluted tubules and col­ veloped within three hours after inges­ lecting tubules. In approximately one tion.47,245 Emetic and gastric lavage so­ week, the luminal necrotic debris clears, lutions can be made from a glass of probably because of digestion by plas­ skimmed milk with three to four tea­ mo lytic enzymes. In addition, the debris spoons of table sugar, two tablespoons is washed down the nephron lumen by of baking soda and three eggs. the glomerular filtrate. The proximal Schreiner and Maher described 11 pa­ tubule appears to be dilated and lined by tients who had mercuric chloride- flat epithelial cells.181 Patchy calcification induced acute oliguric renal failure.225,223 may occur in severely damaged tubules. Five patients who survived were treated Interstitial edema is noted early; if within 48 hours after ingesting mercuric oliguria is prolonged, interstitial fibrosis chloride; hemodialysis and dimercaprol ensues. Mercurials have produced the (BAL) infusion were the methods of nephrotic syndrome in some patients.17 4 8 0 MUEHRCKE, VOLINI, MORRIS, MOLES AND LAWRENCE

C a r b o n T etrachloride The onset of oliguria is prolonged and Carbon tetrachloride (CC14) is widely may occur seven to ten days after expo­ used as an industrial solvent, as a house­ sure. Some patients may have forgotten hold cleaning agent, as a constituent in their exposure to this solvent. Absolute certain types of fire extinguishers, in some anuria may last from one day to several hair lotions, as an antihelmintic agent and weeks. One patient had carbon as a vermifuge.2 It is a volatile, heavier tetrachloride-induced oliguria for 67 days. than air liquid that accounts for the high In the present author s experience, pa­ incidence of exposure in poorly ventilated tients with acute renal failure caused by areas. Carbon tetrachloride is toxic in con­ carbon tetrachloride were usually “do-it- centrations greater than 100 ppm .86 It is yourselfers.” They usually worked in­ absorbed through the lungs, the skin and doors, generally in the basement during the gut. It concentrates in fatty tissue such the winter months. This meant that the as the brain and bone marrow. windows were closed and there was no source of ventilation. They usually drank Carbon tetrachloride is soluble in several cans of beer while they refinished ethanol. Therefore, the drinking of al­ furniture or cleaned outboard motors or coholic beverages and the simultaneous clothes, — usually neckties. exposure to carbon tetrachloride tend to Morphologic abnorm alities occur in the increase or enhance carbon tetrachloride cortical convolutions and Henle’s loops. absorption and subsequent toxicity. In Tubular necrosis is most prominent in the vitro, carbon tetrachloride is oxidized to outmost cortical portion. Acute tubular phosgene and later can condense with necrosis may be severe with tubular ethyl alcohol to form ethyl chloroformate. coagulation and degranulation.236 Ultra- The latter is an extremely nephrotoxic structural study of the glomeruli reveals substance. In the absence of ethyl alcohol, them to be normal. Initially interstitial phosgene condenses with ammonia to edema is common; later, interstitial fi­ form urea. brosis occurs.233 Carbon tetrachloride appears to be more dangerous in obese or in under­ T etrachloroethylene nourished individuals. In France, carbon Tetrachloroethylene is a colorless tetrachloride was the commonest chemi­ liquid with an ethereal odor. It is soluble cal producing acute renal failure. The in organic solvents. Tetrachloroethylene clinical features of acute poisoning are has replaced carbon tetrachloride in the variable. Males are more often afflicted treatment of hookworm infestation. It is than females by a ratio of 14 to 1. Inhala­ placed in soft gelatin capsules of either tion is the most frequent route of expo­ 0.2, 1.0 or 2.5 ml. Tetrachloroethylene pro­ sure. Toxicity caused by ingestion carries duces inebriation, giddiness and liver a grave prognosis. Initially, the patient has damage. It is less nephrotoxic than carbon surface or superficial irritation to the ex­ tetrachloride but has produced acute posed skin and mucous membranes. Later oliguric renal failure from acute tubular the patient has headache, nausea, vomit­ necrosis. ing, abdominal pain and mental confusion leading to convulsions and coma. Al­ G l y c o l T o x ic it y though liver damage is a very striking fea­ Glycols, as presented in table II, are ture of carbon tetrachloride toxicity, acute found in automobile antifreeze, solvents renal failure is the most frequent cause of for plastics, paints (especially lacquers, death. textiles, and cosmetics) and flavoring ACUTE TOXIC NEPHROPATHIES 4 8 1

TABLE IX

The Toxic Glycols

G1ycol

Ethylene glycol (antifreeze) h o «c h 2 c h 2 *o h Ethylene glycol diacetate c h 3 c o *o *c h 2 *C H 2 *0 *C0 *c h 3 Propylene glycol h o -c h 2 -c h -o h -c h 3 Diethylene glycol (diglycol) H O •C H 2* CH 9 * 0• C H ? * CH ?• OH Ethyl diethylene glycol (carbitol) C 2H 5 •0•CH2 •CH2 •0•CH2 •CH2 •OH Methyl diethylene glycol (methyl carbitol) CH3 * O•CH2 * CH2 * O•CH2 ■CH2 ‘OH Butyl diethylene glycol (butyl carbitol) C 4H9*0*CH2 *CH2 *0«CH2 *CH2 'OH CHo «CHo.

Diethylene dioxide (dioxane)

12 2 Dipropylene glycol CH,-OH-CH-CH,-0-CH0-CH-0H-CH, extracts. Allen has classified the toxic oxalate. It is the direct nephrotoxic effects glycols.5 The more important nephrotoxic of ethylene glycol or one of its inter­ glycols are ethylene glycol and dieth­ mediary products that induces acute ylene glycol. Ethylene glycol dinitrite, a oliguric renal failure. The most likely yellow liquid used in the explosive indus­ nephrotoxic product is oxalic acid. The try, produces symptoms resembling those lethal dose of ethylene glycol (100 ml) of nitroglycerol toxicity. Methemoglo- would be converted to three to 10 g of binuria and acute tubular necrosis are oxalic acid. As small a dose of oxalic acid the prominent renal features. Propylene as two g would be fatal.95 Gastric lavage glycol produces hemoglobinuria and pro­ and sodium bicarbonate infusion are two longed oliguria without crystals in the important aspects of initial therapy. tubular lumen. Ethylene dichloride may When large quantities of ethylene produce shock, pulmonary edema and glycol are ingested, the clinical features tubular necrosis. are dominated by three distinct stages.145 Ethylene glycol. Ethylene glycol is The first extends from 30 min to 12 hrs the main substance in antifreeze and was after ingestion and is characterized by made popular during World War I. It is a central nervous system symptoms with in­ colorless odorless liquid and is ingested itial hyperactivity progressing to coma. If by mistake during “alcoholic bouts.” the patient survives the initial complica­ Some describe its taste as unpleasant and tion, he enters the second stage which is waxy; others describe it as sweet.164 W hen characterized by cardiac and pulmonary it is mixed with water and is swallowed, it features with tachypnea, cyanosis and imparts a feeling of warmth to the mucous pulmonary edema. The third stage is membranes and produces acute inebria­ caused by deposition of calcium oxalate tion. Ethylene glycol is converted to the crystals within the kidney, and acute more nephrotoxic intermediaries, — oliguric renal failure occurs. In the early glyeolaldehyde, glycolic acid and oxalic stage of renal affliction the urine may con­ acid.137,206 Each of the intermediary com­ tain oxalate crystals and protein. pounds is a precursor of oxalate. Treatment includes the initial gastric Although calcium oxalate crystals are lavage with a 5 percent solution of sodium found within the renal tubules and other bicarbonate. Intermediate dialysis is im­ organs, acute oliguric failure does not re­ portant to remove the glycol.200 Intraven­ sult from the simple obstructive effects of ous ethanol is helpful in competing with 482 MUEHRCKE, VOLINI, MORRIS, MOLES AND LAWRENCE liver enzymes (e.g., dehydrogenase) that (93 and 109, respectively). They pass metabolize ethylene glycol. Morphologic through the semipermeable membrane of abnormalities of epithelial cell destruc­ the hemodialysis unit. Acute poisoning by tion with intact basement membrane are pure anilin is rare.118 However, poisoning common. Tubules are filled with masses does occur in industrial workers and in of calcium oxalate crystals that are bire- children exposed to inks, colored wax fringent under polarized light. Intrarenal crayons and shoe polishes. Diapers hydronephrosis is noted. Interstitial freshly stamped with aniline marking ink edema and focal cellular infiltrates of have resulted in fatal methemoglobinuria mononuclear cells are present. In addi­ and acute renal failure in infants. tion, oxalate crystals are found within Aniline poisoning has been caused by other organs such as the brain, the heart the percutaneous absorption of aniline and the lungs. from freshly dyed shoes or blankets. Diethylene glycol. Diethylene glycol Aniline and its derivative produce is a colorless liquid which was used with hemolysis, methemoglobinuria,53 shock, catastrophic results as a m edicinal vehicle cyanosis, dyspnea, headache, dizziness in an elixir of sulfanilamide. During Sep­ and blurring of mental functions. If the tember and October of 1937, at least 76 aniline poisoning is severe, the manifesta­ patients died within a few days after tak­ tions are shock, cyanosis, coma, anemia ing the elixir which contained 72 percent and, finally, fatal anuria.259 diethylene glycol and a 10 percent solu­ tion of sulfanilamide. This drug-induced The diagnosis is made when disaster occurred in an era before the methemoglobinuria is found. This is de­ United States Food and Drug Administra­ tected as a well-defined absorption band tion had its drug evaluation program in at 630 wavelengths and immediately dis­ effect. The recommendation of Geiling appears after the addition ofa few drops of and Cannon in a report on the toxicity of 5 percent potassium cyanide (KCN) solu­ the sulfanilamide elixir can be used as an tion. Diazo-reacting compounds can be excellent guideline for the pharmaceuti­ found in the blood, urine, and hemodialy- cal evaluation of drugs.105 Their report is sate. Comparisons of the diazo-reacting recommended to individuals who have compounds in blood, urine and dialysate any doubts of the necessity for drug tox­ are used to obtain an optimal clinical end icity evaluation. point for dialysis. Grossly, the kidney was pale, flabby Treatment for the poisoning is the re­ and swollen. Microscopically, there was moval of aniline by gastric lavage, purges, severe hydropic tubular degeneration simi­ and hemodialysis. This removal permits lar to that seen in the proximal tubules of the reducing enzyme system of the eryth­ potassium-depleted patients. The epithe­ rocyte to reconvert methemoglobin to lial cells were swollen and their lumina hemoglobin rapidly. Intravenously in­ were patent. Spoke-like deeply jected methylene blue in doses of 1.0 to basophilic crystals were seen in the distal 2.0 mg per kg body weight should be convoluted tubules. Bilateral renal corti­ given over a period of several minutes. cal necrosis was seen in a large group of This dose very rapidly reconverts individuals following sulfanilamide elixir methemoglobin to hemoglobin. It may be ingestion. necessary to repeat methylene blue injec­ tions at hourly intervals. The blood A n il in e pressure should be supported by whole Aniline and its derivative, phenylhyd- blood transfusions, vasopressive agents roxylamine, have low molecular weights and hemodialysis. Dialysis should be ACUTE TOXIC NEPHROPATHIES 483 maintained for longer periods than are dominately terpineol, with 5 to 10 percent usual for treating acute renal failure. Such each of terpene, borneol and terepene treatment will remove the toxic derivative ethers. Hexol is used in the United States mobilized as a lipid soluble material from as a household disinfectant. body tissues. Acute tubular necrosis is the The common toxic effects of pine oil common morphologic change found in distillates are local irritation on the skin or aniline poisoning. burning pain in the mouth.177 They pro­ duce central nervous system excitation I nsecticides and, later, depression. Hexol produces The two main groups of nephrotoxic in­ headaches, giddiness, ataxia, stupor and secticides are the chlorinated hydrocar­ death in respiratory failure caused by cen­ bons and the organophosphates. Acute tral nervous system depression. tubular necrosis is the common mor­ phologic finding in patients with acute The pine oil distillates have produced oliguric renal failure. dysuria, hematuria, proteinuria, and C hlordane. The chlorinated hydro­ glycosuria.55,132 In general, renal damage carbon insecticides are stimulants of the is transient and completely reversible. central nervous system. They kill insects Gomel and Goldman reported a 31 year by overstimulation and may cause the old woman who had hexol-induced acute death of man through the same mecha­ oliguric renal failure.111 She used a nism. The chlorinated hydrocarbon insec­ syringe and catheter to instill into her ticides penetrate the skin of man or are uterus three to six ounces of 2:1 m ixture of inhaled when the insecticide is in a fine hexol and water. The following day she aerosol spray. had anuria, which lasted four days and a Chlordane, one example of this group diuresis followed. Eleven months later has produced fatal anuria.66 The initial her creatinine clearance was 47 ml per clinical symptoms are dizziness, nausea, min. Two renal biopsy studies were done, headache and ataxia. Sudden unexpected the first at six weeks and the second at five convulsions similar to gran mal epilepsy months after anuria. The prominent find­ occur and lead to stupor and coma. ings were a completely healed renal tubu­ Pulmonary edema may occur between lar lesion, atrophied tubules and intersti­ episodes of repeated convulsions. Shock tial fibrosis. may occur and may be followed by acute oliguria and death in uremia. A r s in e P arathion. Parathion is an or- Arsine-induced renal failure was dis­ ganophosphate type of insecticide. Mann cussed previously. It usually occurs as an and associates observed that renal tubular occupational hazard.67,74 When anuria oc­ malfunction occurred in individuals dur­ curs the prognosis is grave.33 A rsine ing occupational exposure to parathion. (AsH3) is inhaled and readily combines The chronic exposure to pesticides con­ with the hemoglobin within the erythro­ taining parathion produces a chronic irre­ cyte to form an arsine-oxyhemoglobin versible renal tubular dysfunction that in­ com plex.151 This is initially oxidized to creases with duration of exposure. AsH2-hemoglobin. As the oxidation proc­ ess continues an arsenic-hemoglobin- H e x o l bound product occurs. Intravascular Hexol is a mixture of a steam-distilled hemolysis occurs and results in pine oil derivative (70 percent) and neut­ methemoglobinuria and massive hemo­ ral soap (30 percent). The pine oil deriva­ globinuria. Hemoglobin and erythrocyte tive is a mixture of terpin alcohol, pre­ casts fill the tubular lumen.173 A number of 4 8 4 MUEHRCKE, VOLINI, MORRIS, MOLES AND LAWRENCE simultaneous conditions occur. The is­ solution used after Toni permanent wave chemia caused by anemia, the presence of or Coldwave. Dunsky reported a 17 hemoglobin, methemoglobin, and eryth­ month old infant who had fatal acute rocyte casts and the direct tissue anoxia of oliguric renal failure following ingestion arsine on the respiratory enzymes of the of the neutralizing solution.78 nephron all, either singly or in combina­ At autopsy the patient had generalized tion, produce acute tubular necrosis.194 edema and acute tubular necrosis. War­ Cresol ren and Gross reported a two year old in­ Cresol shares the generalized nephro­ fant who was accidentally fed Toni neut- toxicity of carbolic acid, naphtol, ralizer.250 After 38 days of anuria and guaiacol, creosote and other phenols. oliguria, the child gradually recovered. Lysol (cresol) has been taken for suicide C h l o r a t e C o m p o u n d s purposes or in excessive concentrated so­ Sodium chlorate and potassium chlo­ lutions via vaginal douches to induce rate are used in the manufacture of abortion.92 Cresol is lethal in a dose of 50 matches, explosives, toothpaste and to 100 ml. It produces mucous membrane synthetic pigments. They are also used as necrosis, but the patient is not aware of weedkillers. Potassium chlorate is used the toxic effect. The clinical features are as an oxidizing agent in lozenges and nausea, vomiting, dizziness, ataxia, ab­ gargles. dominal pain and shock. Severe intravas- If the patient develops acute renal fail­ cular hemolysis occurs and is followed by ure, the onset stage varies from 3 to 15 hemoglobinuria, proteinuria, hematuria, hours. The clinical features are fever, acute cystitis and acute oliguria caused hypotension, jaundice, abdominal pain, by acute tubular necrosis. The penetrat­ nausea, vomiting, diarrhea, extreme ing smell of cresol makes the diagnosis fatigue, nervousness and headache. The easier. The mucous membrane of the skin and mucous membranes are deeply mouth and tongue may be burned and cyanosed with a brownish-gray color. may appear to be dull white with phenol The patient has massive hemolysis with and darker brown with cresol. hemoglobinuria. Acute tubular necrosis Treatment includes lavage of the is the common morphologic lesion.69 stomach with sodium bicarbonate, fol­ A clinical test can make the diagnosis lowed by a purge of magnesium sulfate (6 of chlorate poisoning. Ten grams of kid­ g in 100 ml). Skin burns should be ney obtained at autopsy are minced in 16 thoroughly washed with soap and copi­ ml of warm distilled water and an equal ous amounts of water. This should be fol­ volume of acetone is added. The mixture lowed by a wash with a 10 percent solu­ is centrifuged, the acetone is evaporated tion of alcohol. The skin should be and the mixture is filtered. The aqueous dressed with gauze soaked in a sterile filtrate is decolorized by a few drops of a solution of sodium bicarbonate (0.5 per­ dilute solution of indigo sulfate followed cent). Tracheobronchial secretions should by a few drops of sulfurous acid. Silver be aspirated to prevent pulmonary infec­ nitrate is added followed by sulfurous tion. The patient may require dialysis. acid. Silver chloride forms a white pre­ cipitate and is used for a quantitative es­ P o t a s s iu m B r o m a t e timate of the chlorates. Accidental poisoning with potassium bromate occurs in infants and children. M iscellaneous C h e m ic a l s Potassium bromate was the primary Acute oliguric renal failure has fol­ chemical constituent of the neutralizing lowed exposure to a wide variety of ACUTE TOXIC NEPHROPATHIES 485 common chemicals.27 Listed in table I are should be directed toward correction of these common chemicals, their maximum the hypotensive state and interuptions of allowable concentration (MAC) and their the hypersensitivity reaction. Patients mean lethal dosage (MLD). Some of the with severe, acute anaphylactic reactions listed chemicals produce acute renal fail­ should be given epinephrine subcutane- ure, but such a case is rare.108 These in­ ously (0.5 ml to 1 ml of a 0.001 percent clude methyl chloride,45, 143 arsenic, solution). An adrenocortical steroid such phenols, copper sulfate,219 paracetamol,154 as hydrocortisone (100 mg) should be polyvinyl alcohol,117 formalin, pyrogallol, administered intravenously and, if nec­ dischromate,10 tartaric acid, phos­ essary, in multiple dosage. phorus113 and sodium tetrathionate. A parenteral antihistaminic should be B io l o g ic P r o d u c t s given. If the anaphylactic reaction is se­ Acute renal failure can result from vere, vasopressive agents and adrenocor­ biologic products of acute reactions such tical steroids should be given by intraven­ as anaphylactic allergic reactions, from ous infusion. If a reduction of urinary out­ delayed reactions to horse serum and put occurs, 25 g of mannitol in a 20 percent vaccines or from a biologic toxin such as solution must be given. If mannitol proves that found in mushrooms230 ineffective, ethacrynic acid (50 mg) should Anaphylactic Allergic Reactions. Acute be given intravenously. If this is unsuc­ oliguric renal failure has resulted from cessful in producing diuresis, then the anaphylactic shock caused by horse usual methods of treating acute oliguric serum, penicillin, streptomycin and other renal failure must be employed. antibiotics. They produce sudden and Horse Serum-induced Fatal Glomerulo­ prolonged hypotensive states resulting nephritis. In 1962, De LaPava and col­ in acute tubular necrosis. Penicillin leagues reported three patients who had most often produces anaphylactic shock malignant tumors and were treated with on a hypersensitivity basis. The manage­ horse anti-human cancer serum .65 All de­ ment of patients with anaphylactic shock veloped a fatal acute renal failure. At au­

TABLE III

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

Microscopic Study Tritiated Patient Thymidine Other Response Sex & Fluores­ Beta 1C Uptake by Organs to Age Drug Light Electron cent Complement Lymphocytes Involved Prednisone

36/F Bunamiodyl Proliferative Immune IgG - - - Excellent (OrabilexR) glomerulo­ complex nephritis glomerulo­ nephritis 40/F Dextran Proliferative Immune IgG Angiitis Excellent glomerulo­ complex nephritis glomerulo­ nephritis 41/F Methoxy Proliferative Immune IgG, C3 Decreased Positive Hepatitis Excellent flurane glomerulo­ complex (PenthraneR) nephritis glomerulo­ nephritis 58/M Polyvalent Proliferative Immune igG, c3 Decreased Positive Required flu glomerulo­ complex additional vaccine nephritis glomerulo­ nitrogen nephritis mustard 4 8 6 MUEHRCKE, VOLINI, MORRIS, MOLES AND LAWRENCE topsy, a proliferative glomerulonephritis dense immune complexes were noted on the glomerular basement membrane (figure 3). IgG and with epithelial crescents was present. Beta 1C globulin were found by immunofluores­ The kidney was studied by electron mi­ cence in immune complexes. Unfortunately, the croscopy. Epithelial humps on the first renal biopsy tissue was lost to further im- munocomplexes study using fluorescent tagged glomerular lamina densa were found. antiduck egg albumin. A second biopsy was per­ They were similar to humps of antigen- formed 16 days later with the hope of studying the antibody complex seen in poststrep­ tissue with fluorescent tagged antiduck egg albu­ min. To the present authors’ surprise, immune tococcal glomerulonephritis, dextran- complexes were no longer present (figure 4). The induced glomerulonephritis and renal third and fourth renal biopsy studies showed disease caused by syphilis. The use of gradual recovery of proliferative glomerulone­ phritis (figures 5 and 6). The beta 1C globulin was large dosages of adrenocortical steroids normal initially, was low on the 20th and 34th days has been most beneficial in resolving and returned to normal level after recovery from these lesions of drug-induced diseases. renal failure. In the acute stage, prednisone therapy was started and nitrogen mustard was given in­ A horse serum-induced disease was first travenously in four divided doses. The patient made a gradual recovery and was discharged from hospi­ observed by Rackemann, Longcope and tal. A fifth renal biopsy study, performed three Peters.208 They noted water retention, de­ months later, was normal. This patient’s im­ creased urinary output and retention of munological data are presented in (figure 7). chloride. They were the first to point out COMMENT that the mechanisms of horse serum- Note the similarity of the immunological data of induced renal failure were immunologi- patient S.B. to the data of Dixon’s serum sickness model. Our patient received duck egg albumin as cally based. Later, the specific im­ the antigen in the flu vaccine. Initially, the beta 1C munologic reaction was bound to be globulin was normal. On the 20th day and 34th day, caused by soluble antigen-antibody com­ it was reduced and later returned to normal after renal damage recovered. Renal damage as indicated plexes in the presence of excessive anti­ by hematuria started on the sixth day and subsided gen. at the height of diuresis. Immune complex deposits were found in the glomerular basement membrane The authors have studied four patients by electron microscopic study of the renal biopsy, with drug-induced immune complex IgG and beta 1C globulins were found in the glomerulonephritis and acute renal fail­ immune complexes by immunofluorescent tech­ nique. In addition, the patient’s incubated lympho­ ure as shown in table III. The clinical cytes reacted positively to duck egg albumin. The presentation was a serum sickness-like immune mechanism of action in this patient paralelled reaction leading to acute oliguric renal the Dixon model of serum sickness. failure. Pertussis Vaccine. Acute oliguric renal failure caused by pertussis vaccine is PATIENT S.B. rare.30 Fatal renal failure has followed A 58 year old white male received 0.5 ml of a eight injections of pertussis vaccine over polyvalent influenza vaccine containing duck egg albumin. Six days later he developed hematuria. On a six-week period. One week after the the eighth day he had oliguria. The patient was ad­ eighth injection, the patient developed mitted to a hospital and found to have an elevated fever, arthralgia, adenopathy and pro­ blood urea nitrogen level. A retrograde pyelogram was normal. The patient was referred to the present gressive renal failure. On the eighth day authors for treatment. His clinical course and blood he was comatose, had mild hypertension, urea nitrogen level are plotted on the curve (figure and had a BUN of 201 mg per dl. A dif­ 1). fuse healing vasculitis was found to be His Beta 1C globulin was normal at 115 mg per involving the medium and small arteries, dl. An arteriovenous shunt was inserted; hemodialysis was started and was continued fre­ arterioles and veins. The pathologic find­ quently. Five renal biopsies were performed with ings in the kidney were multiple infarc­ the fifth one done three months after discharge from the hospital. The first renal biopsy study revealed, tion in the cortex and medulla. There on light microscopy, proliferative glomerulone­ were numerous antemortem thrombi and phritis (figure 2). By electromicroscopy, electron extensive papillary necrosis. ACUTE TOXIC NEPHROPATHIES 4 8 7

FIGURE 1. Immune- Immune-complex Glomerulonephritis following Poly Valent Flu Vaccine Complex Glomeruloneph­ ritis Following Polyvalent Flu Vaccine. The clinical course of patient S.B., aged 58 years, is plotted. He de­ veloped gross hematuria and oliguria following an injection of a polyvalent flu vaccine containing duc- kegg albumin (DEA). The blood urea nitrogen is plot­ ted in the broken line. The daily urinary volume is the shaded grey area. He was treated by hemodialysis. Four renal biopsy studies were done. An immune- complex glomerulonephritis was found and adrenal corticosteroids were given (bar graph at bottom of figure). Typhoid Vaccine. Four patients given jection of the vaccine. Acute tubular ne­ typhoid vaccine intravenously for two to crosis and acute necrosis of the liver were three days died in shock and acute noted. oliguric renal failure. One patient died in The fourth patient, a seven month old acute renal failure four days after receiv­ boy who had hereditary agammaglob­ ing the vaccine. Another patient de­ ulinemia, developed complete anuria veloped the hepatorenal syndrome. The following one injection of thyphoid vac­ third patient died six hours following in­ cine. At autopsy, acute renal cortical ne-

FlGURE 2. Light Micro­ scopic Study Antigen- Antibody Glomerulone­ phritis was found on renal biopsy study of S.B., a 58 year old laborer. A poly­ * % * * *\ valent flu vaccine contain­ ing duckegg albumin was given 15 days before. Note the proliferative lesions in the glomeruli associated with interstitial edema. (H & E x 400). t o * 4 8 8 MUEHRCKE, VOLIMI, MORRIS, MOLES AND LAWRENCE

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F i g u r e 3. Immune Complex Glomerulonephritis. The first renal biopsy study taken 15 days after injec­ tion of duckegg albumin revealed proliferative glomerulonephritis. Electronmicroscopic study revealed immune-complex (arrows) on the glomerular capillary basement membrane (BM). Proteinaceous material is seen in the capillary lumen (CL) and in the urinary space (U S), (x 900). crosis was found. In addition, there was 1949. In the United States, the overall diffuse thrombosis of the glomerular mortality rate is difficult to estimate. The capillaries. This patient may have had an common poison mushroom is the increased susceptibility to the thyphoid Amanita phalloides. It can be distin­ vaccine in view of an inadequate or un­ guished from the common field mush­ derdeveloped reticuloendothelial sys­ room (Agaricus campestris) by noting tem. the presence of the volva on the phal­ Mushroom-induced Acute Oliguria. loides. It is strongly recommended that The terms “mushroom” and “toadstool” “mushroom amateurs” purchase mush­ have no specific identifying meaning rooms from commercial sources and and are used interchangeably by some neither pick them nor accept them from mycologists. There are approximately a neighbor. 2,000 species of mushrooms, of which Prolonged anuria may result from the about 30 are poisonous. Some mushrooms mycetous toxins of Amanita phalloides.187 are toxic if eaten (1) in excessive quan­ Acute tubular necrosis is the common tities, (2) during certain seasons, (3) at morphologic lesion and involves both specific stages of growth or (4) by a proximal and distal convoluted tubules. susceptible individual.43 In England The glomeruli are usually not affected. and Wales, there were 38 fatal cases of Following recovery from prolonged mushroom poisoning between 1921 and anuria, diffuse interstitial fibrosis de­ ACUTE TOXIC NEPHROPATHIES 489

F ig u r e 4. Clearing of Immune Complexes. A second renal biopsy study was done on the 32nd day after a polyvalent flu vaccine injection. No immune complexes were seen by electronmicroscopic study. The glomerular basement membrane (BM) appeared normal. Numerous polymorphonucleocytes (WBC) were noted in the capillary lumen (CL), (x 14,350). velops and is associated with thickening many pathopharmacologic mechanisms. of the cortical convoluted tubular base­ Of these, the nephrotoxicity mechanism ment membrane. The creatinine clear­ is the most common and is dose-related. ance remains reduced for several months In general, excessively large doses are until diffuse interstitial fibrosis becomes used. Drugs such as methicillin, penicil­ more focal in its renal distribution. The lin, phenylbutazone,172 sulfonamide,93-163 creatinine clearance may then approach diphenylhydantoin (Dilantin),123 phenin- normal values. dione11 and meralluride (Mercuhy- Treatment is directed toward sustain­ drin)189 produce acute oliguric renal fail­ ing life by the use of conservative mea­ ure when administered in either the sures and dialysis. Peritoneal dialysis is usual dosages or in very small amounts. the method of choice, especially if albu­ Hypersensitivity to these drugs can pro­ min is added to the peritoneal fluid to duce acute renal failure. There are also remove mycetous toxins. If toxicity is in­ metabolic,75 mechanical and secondary duced by Amanita muscaria, atropine is mechanisms that produce the disease; effective in neutralizing the muscarine the latter are usually caused by drug- effects of poisonous mushrooms. induced hemolytic anemia. D r u g s The tetracyclines may produce pre- In general, drugs induce renal damage renal azotemia through a metabolic through any one of or a combination of mechanism, such as their antianabolic ac­ 490 MUEHRCKE, VOLINI, MORRIS, MOLES AND LAWRENCE

W M m & -

F ig u r e 5. Resolution of Immune-Complex Glomerulonephritis. Renal biopsy study was done on the 34th day after injection of polyvalent flu vaccine. The glomerular capillary lumen (CL) was patent. Erythro­ cytes (RBC) were noted in the lumen. Numerous polymorphonuclear leukocytes (WBC) were noted, (x 3,300). tion on the proximal tubules.87,100 This is nephrotoxic drugs will be reviewed by reflected by proteinuria, amino-aciduria, therapeutic classification and will em­ phosphaturia, hypokalemia," a low phasize the morphologic site of drug in­ plasma urate and acidosis. Tetracycline teraction. may undergo spontaneous degradation Drugs interact at specific morphologic during storage, especially under warm sites within the kidney to produce acute and moist conditions. Anhydrotetracy- renal failure. On a structural basis drugs cline and epianhydrotetracycline are the interact at all four major components: the nephrotoxic degradation products that vessels, the glomeruli, the tubules and produce the Fanconi syndrome.114158 the interstitium. Arteritis has resulted In addition to classification according from arsenic, bismuth, diphenyl- to the pathopharmacologic mechanism, hydantoin (Dilantin),190 gold salts,112 nephrotoxic drugs can be classified ac­ horse serum, iodides, penicillin, propyl­ cording to the site of morphologic dam­ thiouracil, chlorathizides148 and sulfona­ age. Finally, drug-induced acute renal mides. Glomerulonephritis has followed failure can be classified therapeutically, hydralazine,3,4 bunamiodyl (Orabilex), e.g., antibiotics and chemotherapeutic phenylbutazone77 and sulfonamides.72 agents, diuretic agents, radiologic con­ Acute tubular necrosis has followed a trast media and others. In this section, large variety of drugs. These include am- ACUTE TOXIC NEPHROPATHIES 491

F IG U R E 6. Recovery period. Renal biopsy study was done three months after discharge from hospital (145 days after exposure to duckegg albumin). The glomerular capillary lumen (CL) were patent and con­ tained erythrocytes (RBC). Although renal function was recovered, the glomerular basement membrane was thickened on the endothelial side (arrows), (x 4,400). photericine B,21,49 aristolochic acid,191 Drug-induced Acute Oliguric bacitracin, colistin,83 ferrous sulfate,136 Renal Failure kanamycin,25 meralluride (Mercuhydrin), neomycin,79 bunamiodyl (Orabilex), R a d i o l o g i c C o n t r a s t M e d ia para-aminosalicylic acid,174 penicillin, The essential ingredient in all absorb­ phenylbutazone,165 quinine sulfate, able radiologic contrast media is iodine. salicylates and sodium acetrizoate (Uro- Individuals sensitive to iodine in any kon). form may have mild to severe hypersen­ Acute interstitial nephritis and sub­ sitivity reactions to contrast media. When sequent acute renal failure have followed inorganic iodine was used, such as treatment with meralluride (Mercuhyd­ sodium iodide in a concentration of 80 to rin),56 methicillin,88 nitrofurantoin,203 100 percent, numerous hypersensitivity penicillin, phenacetin,7 phenindione,38 reactions occurred. These varied from polymyxin B,20 sulfonamides,98 diphenyl- iodine mumps, dermatologic lesions and hydantoin (Dilantin)211 and phenyl­ anaphylactic shock to fatal acute oliguric butazone. renal failure.28 Although contrast media 492 MUEHRCKE, VOLINI, MORRIS, MOLES AND LAWRENCE

Immunologic Course of Drug-induced Glomerulonephritis A n t ib io t ic s a n d C hemotherapeutic 58 yrs, W.,M. A g e n t s Antibiotics and chemotherapeutic agents have become indispensable in the treatment of urinary tract infection as well as in the treatment of systemic and local infections. As these agents become more extensively used, their adverse side effects and nephrotoxicity become more apparent.102,237 In the presence of under­ lying renal disease, it may be difficult to recognize nephrotoxicity of a specific antibiotic.149 Moreover, when antibiotics are used in combination with other an­ Flu vaccine tibiotics or with chemotherapeutic agents (DEA) their exact nephrotoxic effect as well as F IG U R E 7. Immunological Course of Drug- the specific agent of the adverse reaction Induced Glomerulonephritis. The figure illustrates may be impossible to determine.14 N eph­ the clinical course of S.B., a 58 year old white male. rotoxicity caused by chloramphenicol or He received a polyvalent flu vaccine containing an antigen (Ag) duckegg albumin (DEA). Six days later erythromycin has not been observed by renal disease was evident by gross hematuria fol­ the present authors. lowed by oliguria. The serum Beta ,c globulin was Sulfonamides. Damage to the kidney normal on the 12th day but reduced on the 18th and 32nd day. The third component of complement was is the most serious and frequent compli­ normal on the 48th day. The first renal biopsy study cation of sulfonamide treatment.40,243,246 on the 15th day revealed antigen-antibody com­ Sulfonamides were the first effective plexes with a proliferative glomerulonephritis. The second renal biopsy study on the 32nd day revealed chemotherapeutic agents to have nephro­ no antigen-antibody complexes. The alpha2 globu­ toxic properties.110,254 The incidence of lins were elevated on the 35th day. The patient’s renal abnormalities varies considerably course is similar to the Dixon’s animal model of and depends in a great part on the solu­ antigen-antibody glomerulonephritis. bility of sulfonamides.59,76 Acute oliguric renal failure has been induced by sulfon­ amide treatment of parenchymal lesions179,192 and of obstructive uropathy containing organic iodides are safer than caused by sulfonamide crystallization142 those containing inorganic iodides, the of the unchanged drug or of its acetyl der­ former have been implicated in a steady ivative within the renal pelvis.23,122 The flow of reports of severe nephro­ method of prevention of sulfonamide toxicity.130 obstructive uropathy is the preferential Physicians depend on radiologic con­ use of a more soluble sulfonamide, trast media for diagnosis of biliary dis­ adequate hydration, and alkalinization of eases, vascular diseases as well as dis­ the urine with sodium bicarbonate. eases of the kidneys and genitourinary Obstructive uropathy caused by the low tract. These agents are usually adminis­ solubility of sulfonamides is more fre­ tered orally to evaluate the biliary tract, quently observed than are the paren­ intravenously to evaluate the arterial cir­ chymal lesion of tubular necrosi s, focal- culation and the kidneys, and by retro­ granulomatous interstitial lesions, diffuse grade injections into the renal pelvis to interstitial nephritis, hypersensitivity evaluate the upper genitourinary glomerulonephritis and acute hypersen­ tract.6-26- 32 sitivity arteritis. ACUTE TOXIC NEPHROPATHIES 493 Several hundred patients have been Pseudomonas, Escherichia, Klebsiella, reported with renal failure caused by Aerobacter, Salmonella, Shigella and sulfonamide crystallization.205 The most Hemophilus species.227 Polymyxin B is frequent sulfonamides implicated were antibacterially more active than polymy­ sulfapyridine, sulfathiazole and sul­ xin E. Nephrotoxicity of polymyxin is fadiazine.35 The solubility of sulfona­ dose-related.186,262 Following administra­ mides depends on a number of factors tion of polymyxin B sulfate, proteinuria, that include the drug concentration, state epithelial cells, and casts appear in the of dehydration, urinary pH and renal urine and azotemia develops.134 In the functio n .217 Sulfadiazine is the most presence of normal renal function, the dan gerou s.258 Sulfadimidine and sul- nephrotoxicity is negligible at 2 mg per fisoxazole form more soluble crystals and kg body weight per day. are less hazardous.170,260 The finding of Beime and colleagues reported a 44 sulfonamide crystals in the urine leads year old male who developed an acute the physician to suspect acute sulfona­ oliguric renal failure caused by acute in­ mide crystallization within the renal pel­ terstitial nephritis.171 Polymyxin B sulfate vis. The method of treatment is retro­ seemed the most capable of several ante­ grade catheterization of the ureters and cedent agents. The patient had an lavage of the renal pelvis with warm al- eosinophilia of 25 percent but had no kalinized solution (10 percent NaHC03). dermatologic lesion. The patient gradu­ Acute tubular necrosis can occur with ally recovered when polymyxin B was or without sulfonamide crystallization. withdrawn. A renal biopsy study done on The tubular lumina are plugged with the second day of oliguria revealed a amorphous debris containing erythro­ Councilman type of acute interstitial cytes, leukocytes, hemoglobin casts and nephritis. crystals. When sulfonamides induce a hypersensitivity renal lesion, one of three Colistin methane sulfonate. Colistin, sites is involved. In some hypersensitiv­ which differs from polymyxin B only by ity reactions, the intrarenal arteries were the absence of a single amino acid, is involved with angiitis or with polyar­ known to be identical with polymyxin teritis nodosa. In a second type of hy­ E .155 Because of this close structural rela­ persensitivity reaction, the glomeruli tionship, colistin shares some of the were involved with hypersensitivity nephrotoxic potential of polymyxin B. glomerulonephritis.264 The third site for Colistin is an antibiotic produced by the sulfonamide-induced hypersensitivity soil bacterium Bacillus polymyxa var. reaction was the renal interstitium. Acute garyphalus. Its antibacterial activity is interstitial nephritis was the more com­ against a number of gram-negative bac­ mon interstitial lesion and was similar to teria. a Councilman acute interstitial nephri­ Toxicity studies in animals have dem­ tis.182 A focal interstitial granulomatous onstrated that colistin produces impaired interstitial nephritis was a less common renal function and renal lesions.156 Partial interstitial lesion. to complete necrosis of the proximal tubules was found on histologic examina­ Polymyxin B. The polymyxins A, B, C, tion.141 The effect of intramuscular colistin D and E are a group of closely related on renal function in man is unpredicta­ cyclic polypeptides. Polymyxin B is an ble. Healthy individuals and patients with antibiotic composed of amino acids and a chronic pyelonephritis and other forms of fatty acid. It is active against a variety of renal disease have received the drug gram-negative bacilli.42 These include without significant changes in urinalysis 494 MUEHRCKE, VOLINI, MORRIS, MOLES AND LAWRENCE or BU N .128,202 In other patients with tracellular fluid and are excreted mainly azotemia further elevation of BUN has in the urine.253 In addition, all four an­ occurred. Oliguria developed in a five tibiotics have ototoxicity. The nephro­ year old child who received an accidental toxicity is increased in patients in whom overdose of colistin (37.7 mg per kg body there is a reduction of glomerular filtra­ weight per day for two days and 9.4 mg tion rate. If these antibiotics are used in per kg body weight per day for three combination their nephrotoxicity is more days). When colistin was discon­ greatly increased. tinued, renal function returned to normal. In individuals with normal renal func­ Although the mechanism of colistin tion, approximately 70 percent of par- nephrotoxicity is unknown, it may be re­ enterally injected streptomycin is ex­ lated to the ability of the drug to disrupt creted unchanged in the urine within 24 the integrity of certain cell membranes,89 hours. In patients with renal insuffi­ probably by acting as a cationic detergent ciency, less than 2 percent of an injected that destroys the cellular osmotic barrier, dose of streptomycin is excreted in the combines with polyphosphates and thus urine. Vestibular damage caused by allows leakage of substances essential to streptomycin is frequent in patients with cell function. Such an action is therapeut­ severe renal failure. Dialysis has been ically valuable when limited to the cell useful in the removal of streptomycin in wall of various bacteria but may be harm­ the treatment of neurotoxicity and neph­ ful if human renal tubular cells exposed rotoxicity. to high concentrations of the drug share During the course of treatment with this susceptibility. In this respect, colis­ streptomycin, proteinuria and cylinduria tin nephrotoxicity may resemble that of may occassionally occur. McDermott re­ amphotericin B; the latter also disrupts ported a patient with acute oliguric renal cell membranes, but does so by binding failure caused by acute tubular necrosis to sterols rather than to polyphosphates. following a daily dosage of four g of Mammalian cell membranes contain streptomycin.193 sterols, and amphotericin B131 has been Kanamycin. The nephrotoxicity of shown to damage both tissue cells in cul­ kanamycin has been described in numer­ ture and human renal tubular cells may ous reports whenever its clinical applica­ be damaged in like manner by high lum­ tion was mentioned.153,261 Kanamycin inal concentrations of the drug. nephrotoxicity was related neither to Streptomycin. Streptomycin is an dose level nor to duration of treatment antibiotic that was discovered in 1944 but occurred more frequently in elderly by Schatz, Bugie and Waksman in patients.24,255 Kanamycin nephrotoxicity cultures of the actinomycete Strepto- occurred in doses of 20 to 50 mg per kg myces grieseus.220 Streptomycin, a carbo­ body weight per day and was clinically hydrate derivative, is N-methyl-L- evident by mild proteinuria, nitrogen re­ glucosaminido-strepto-sidostreptidine tention, microscopic hematuria and fine and has a wide spectrum of antibacterial granular casts in the urinary sediment. In activity.126 Streptomycin, vancomycin, approximately 10 percent of patients kanamycin and neomycin have several treated with kanamycin, there were features in common. They are relatively azotemia. Severe tubular necrosis was strong organic bases that cross cell mem­ reported by Kleeman and Maxwell.215 In branes very slowly; therefore, they are general, nephrotoxicity was reversible poorly absorbed from the gut.121 They are when kanamycin administration was almost entirely distributed in the ex­ stopped. ACUTE TOXIC NEPHROPATHIES 495 Kuntz noted oliguria in eight patients Genkins, Uhr and Bryer reported a 57 out of ten receiving kanamycin.157 year old housewife with prior normal Schriener and Maher observed acute renal function.107 She developed a fatal tubular necrosis in two patients following acute oliguric renal failure following five treatment of kanamycin.184 One of these divided doses of 50,000 units daily of patients died in uremia. bacitracin. On the third day of bacitracin Ototoxicity is the most common toxic treatment, she developed proteinuria, effect of kanamycin.222 It is likely to occur oliguria and azotemia. The patient died in patients with renal insufficiency or de­ on the tenth day after intramuscular hydration. When kanamycin is given to bacitracin treatment. Acute tubular ne­ patients with anuria or oliguria or to a crosis was found at autopsy. diabetic patient with nephropathy, it is Neomycin. Neomycin is an antibiotic imperative to reduce the dose by careful discovered by Waksman and Leche- calculation of it and to prescribe kanamy­ valier. It is derived from the metabolic cin in “spread out” doses. (A recom­ products of Streptomyces fradiae. mended kanamycin dosage is 0.5 g every Neomycin is primarily a topical antibiotic three or four days.) Approximately 29 to and is used for its local antibacterial ac­ 63 percent of the injected dose of tion within the lumen of the gut.140,249 It is kanamycin can be removed by effective extremely nephrotoxic and damages the peritoneal dialysis. In an anuric patient, eighth cranial nerve.196,207 Although the approximately 30 percent of kanamycin drug is poorly absorbed, it crosses the can be removed by hemodialysis in an peritoneal cavity much more readily. eight hour period. Therefore, renal damage can occur when neomycin is administered into the During peritoneal dialysis, however, peritoneal cavity. 25 mg of kanamycin can be given safely Emmerson and Pryse-Davies84 found daily. The morphologic change owing to neomycin to be very nephrotoxic and to kanamycin nephrotoxicity is always seen cause severe proximal tubular necrosis.91 in proximal tubules of the kidney. When Randall reported four patients who suf­ acute oliguric renal failure occurs, it is fered adverse effects from injections of 4, the result of acute tubular necrosis. When 6, 8 and 72 g of neomycin, respectively.209 administration of kanamycin is stopped, Two patients developed deafness, one diuresis follows within five days and patient developed acute oliguric renal renal function usually returns to normal failure and one subsequently had perma­ within two months. nent renal insufficiency. Hemodialysis Bacitracin. Bacitracin is a polypeptide and peritoneal dialysis removed large antibiotic produced by the Tracy 1 strain amounts of neomycin, and mannitol pre­ of Bacillus subtilis.229 Bacitracin has vented acute renal failure in two patients. proved to be highly effective against gram- Hemodialysis rapidly reduced serum positive cocci and organisms that cause neomycin concentration in two other pa­ gas gangrene. Its chemical use is limited tients, while mannitol diuresis removed to topical application and local infiltra­ significant amounts in another. tion. Transitory urinary abnormalities or Peritoneal dialysis was the least effective proteinuria, cylinduria, azotemia and oc­ of all methods. casional oliguria were noted in nearly all Penicillin. Penicillin induces acute oli­ reported patients. Bacitracin is very guria through a hypersensitivity mecha­ nephrotoxic and produces both proximal nism .19 Dehydration was a possible con­ and distal tubular necrosis. tributing factor in two infants with ab­ 496 MUEHRCKE, VOLINI, MORRIS, MOLES AND LAWRENCE normal renal function. When acute oligu­ phologic renal changes is insufficient. ria occurs, it is usually associated with The complete reversibility of methicillin- dermatologic lesions and eosinophilia.265 induced nephropathy, together with Randall reported acute oliguric renal other allergic manifestations, suggests failure caused by hypersensitivity man­ that a pathopharmocologic mechanism ifestations of ampicillin, oxacillin, oral of hypersensitivity occurs. penicillin and intramuscular penicillin Histologic abnormalities of the kidney G.152 Two patients died, one of whom was include an acute interstitial nephritis a 24 year old student who received oral with or without tubular damage.146 This penicillin. He developed clinical fea­ interstitial nephritis is characterized by tures of the hemolytic uremic syndrome cellular infiltrates of eosinophils, plasma and necrotizing arteriolitis was found at cells and small lymphocytes. Adrenocor­ autopsy. The other patient had a marked tical steroids have been effective in re­ acute interstitial nephritis characterized solving this drug-induced lesion. by interstitial cellular infiltrates of Tetracycline. Tetracycline, a so-called plasma cells. Penicillinase may be help­ broad-spectrum antibiotic, is produced ful in treatment of acute renal insuffi­ by several Streptomyces species. The tet­ ciency caused by penicillin hypersen­ racyclines produce changes in nitrogen sitivity.244 m etabolism .251 The tetracyclines are not Methicillin. Methicillin (Staphcillin) usually nephrotoxic agents. However, if does not differ in its sensitizing potential storage degereration occurs they may from other penicillins.46 The clinical produce proximal tubular damage.63 hypersensitivity features of methicillin Chemical deterioration is more likely to are dermatologic lesions, nephropathy occur if the drug is improperly stored and eosinophilia. During the past few under moist or warm conditions. years, methicillin-induced nephropathy Anhydrotetracycline and epianhydro- has been reported by several individuals. tetracycline are the nephrotoxic products. The clinical manifestations of renal dis­ The formation of these products is ac­ ease were proteinuria, hematuria, dysuria complished by temperature elevation, and azotemia with or without oliguria. high humidity and reduced pH. They are Nephropathy usually appeared between especially likely to occur when citric acid 7 and 21 days after treatment was begun. is added to tetracycline. However, tet­ In most instances, it subsided within 24 racycline preparations containing lactose to 48 hours after cessation of treatment are less likely to degenerate into nephro­ with methicillin. toxic products. Patients with methicillin-induced ne­ The tetracyclines are concentrated in phropathy had additional manifestations the liver, teeth and bones and are ex­ of hypersensitivity,37 the most common of creted through the kidneys and bile. which was an eosinophilia. In some pa­ Death has resulted from severe hepatic tients thrombocytopenia was observed. and pancreatic damage with excessive in­ Hypersensitivity dermatologic lesions travenous doses of tetracycline. Aged or were noted. They included hemorrhagic degenerated tetracycline produces a re­ bullae, urticaria, maculopapular lesions, versible Fanconi syndrome99,232 as­ purpura with petechiae and exfoliative sociated with polyuria, proteinuria, renal dermatitis. None of these reported pa­ glycosuria, phosphaturia, aminoaci­ tients with methicillin-induced nephrop­ duria,39 acidosis, hypokalemia and a low athy had a renal biopsy study. In general, plasma urate. In general, tetracycline- knowledge regarding the overall mor­ induced Fanconi syndrome is slowly re­ ACUTE TOXIC NEPHROPATHIES 497 versible once the drug is discontinued.114 In general, they were minor reactions and Acute nonoliguric renal failure has included allergic phenomena, phlebitis at been reported by Solomon, Galloway and infusion sites, transient leukopenia and Patterson235 who prescribed two g of tet­ gastrointestinal symptoms. More serious racycline daily and observed an increase reactions include acute renal failure, in BUN from 63 mg to 161 mg per 100 ml. Coombs positive hemolytic anemia, super Tetracycline toxicity is also directly re­ infections and anaphylaxis. For example, lated to existing renal insufficiency.241 cephaloridine produced anaphylaxis in a Large doses of oxytetracycline have pro­ nurse who prepared an injection of the duced azotemia. Prerenal azotemia may drug.90 be induced by a negative nitrogen bal­ Renal damage caused by cephaloridine ance that produces anorexia, nausea, appears to be a result of a nephrotoxic vomiting and death. Nephrogenic diabe­ mechanism. The drug has been localized tes insipidus has been induced by by autoradiographic studies to the re- dimethylchlorotetracycline.54 nomedullary interstitium and proximal Para-aminosalicylic acid. Para- tubular cells.62 Cephaloridine is ac­ aminosalicylic acid (PAS) is highly active cumulative and dose-related. In large in inhibiting the growth of tubercle doses it produces a severe nephropathy, bacilli in vitro. The most common hyper­ while in low doses it produces pro­ sensitivity complication of PAS treatment teinuria, hematuria and cylindruria.139 is hepatitis. A reactive hepatitis induced When the drug is discontinued, urinary by PAS has been associated with fever, abnormalities disappear. rash, pruritus, conjunctivitis, hemolytic Cephaloridine has produced hypersen­ anem ia210 and eosinophilia. Renal invol­ sitivity reactions such as urticaria, vem ent116 owing to PAS was uncommon eosinophilia, drug fever and Coombs pos­ and was usually confined to patients who itive hemolytic anemia. Antibiotics such had hepatitis.68 Inasmuch as PAS is an as ampicillin and polymyxin B have pro­ organic acid, it requires a fixed cation to duced a hypersensitivity acute interstitial accompany its excretion;166 therefore, nephritis. It is suggested by the present hypokalemia can occur as well as an aci­ authors that cephaloridine will also pro­ dosis in children.36 duce an acute (hypersensitivity) intersti­ Owen reported a 31 year old man with tial nephritis and subsequent acute pulmonary tuberculosis receiving treat­ oliguric renal failure. ment with calcium PAS for 83 days with­ out m ishap.199 After 35 days of sodium D iu r e t ic A g e n t s PAS treatment, he developed a fever, a In the majority of instances the kidney pink vesicular rash, massive proteinuria responds favorably to diuretic agents with and acute oliguria without hepatitis. The a prompt diuresis. However, the kidney BUN reached 245 mg per 100 ml and also becomes the target of untoward ef­ spontaneously fell to normal. The patient fects of diuretic agents. It is not unlikely made a rapid and complete recovery from that acute oliguric renal failure developed acute renal failure. in patients following treatment with Cephaloridine. Cephaloridine is a meralluride (Mercuhydrin), acetazol- semisynthetic derivative of cephalospo­ am ide,64 the thiazides and aristolochic rin C. Its antibacterial activity is against acid. many gram-positive and gram-negative Mercurial diuretic agent. C alom el bacteria. Adverse reactions of cephalo­ (mercurous chloride) was the active diure­ ridine occurred in 35 percent of 76 patients. tic in the famous “Guy’s Hospital Pill” 498 MUEHRCKE, VOLINI, MORRIS, MOLES AND LAWRENCE (calomel, digitalis and squill). The diure­ agents are potassium deficiency, aggrava­ tic effects of organic mercurial were first tion of preexisting diabetes mellitus, ag­ discovered as a side effect in patients gravation of gout and blood dyscrasias.231 receiving antisyphilitic treatment. The The latter include leukopenia, throm­ primary action of the mercurial diuretic bocytopenic purpura and aplastic anemia. agents is their ability to inhibit sulphydryl- Thiazide diuretic agents cause acute containing enzyme systems that normally oliguric renal failure in two ways. The first supply energy for sodium reabsorption. way is by chlorothiazide and hyd­ Immediate fatal reactions to mercurial rochlorothiazide producing acute renal diuretic agents are rare,120 and when they necrotizing angiitis, glomerulonephritis do occur, they are related to anaphylactic with interstitial nephritis and acute tubu­ shock. Hypersensitivity reactions induced lar necrosis.70 These lesions produce by mercurial diuretics include general­ acute renal parenchymal damage, which ized pruritus, urticaria, exfoliative derma­ causes acute oliguric renal failure. titis and asthma. Most organic mercurials Kjellbo observed a patient who had are rapidly excreted by active renal acute necrotizing angiitis simultaneously tubular secretion bound with cysteine.115 in the skin and kidney.201 His patient was a Mercurial diuretic agents produce acute 62 year old mildly hypertensive woman oliguric renal failure from acute tubular who developed fever, right kidney pain, necrosis.216,248 Schreiner and Maher be­ gross hematuria, proteinuria and lieve that organic mercurials are slowly azotemia. Renal biopsy study revealed in­ converted to inorganic mercury secondary terstitial granulomatous inflammatory to abdominal renal retention by the nodules enclosing necrotic arterioles. The kidneys.225 glomeruli appeared normal. The Meralluride-induced acute oliguric renal granulomas were composed of lympho­ failure has developed as the result of acute cytes, histiocytes, plasma cells and neut­ tubular necrosis.81 This is probably the re­ rophilic leukocytes. sult of a nephrotoxicity mechanism. Acute Fitzgerald reported a patient who had oliguric renal failure, exfoliative der­ fatal glomerulonephritis with interstitial matitis, fever and eosinophilia have some­ nephritis complicating “allergic purpura” times followed several injections of caused by chlorothiazide.94 Abry and meralluride. Adrenocortical steroids were Cavusoglu reported a patient with fatal used to reverse this condition. This acute oliguric renal failure caused by hypersensitivity reaction produces an acute tubular necrosis following acute interstitial nephritis. There have chlorothiazide treatment.1 Elwood en­ been a few reports of patients developing countered a patient with coexisting nephritis following meralluride treat­ thrombocytopenic purpura and acute m ent.48 The morphologic lesion was tubu­ oliguric renal failure following lar degeneration associated with intersti­ chlorothiazide treatment.8 tial nephritis. The second mechanism of acute Thiazide diuretic agents. The thiazides oliguric renal failure is the more common. were discovered as a by-product of a Thiazides induce acute oliguric renal search for diuretic agents similar in struc­ failure by a gradual and chronic reduction ture to acetazolamide. In 1958, in the effective circulating blood volume; chlorothiazide was introduced as a potent this reduction is associated with severe oral diuretic agent. In a short time numer­ hyponatremia.144 Treatment consists of ous other thiazides were found. The un­ fluid and sodium chloride replacement. toward effects of the thiazide diuretic The physician must be very careful so that ACUTE TOXIC NEPHROPATHIES 499 he does not excessively expand the blood Phenindione. Phenindione is known as volume and precipitate the primary ill­ phenylindanedion (P.I.D.), Danilone, ness, especially if the condition is conges­ Hedulin and Eridone. It has been used as tive heart failure. a short-acting anticoagulant since it is rapidly absorbed from the gut and is Aristolochic acid. Aristolochic acid has rapidly excreted by the kidney. Phenin­ been used experimentally as a diuretic dione interfers with the liver synthesis of agent and as an anticancer drug. It has prothrombin. Proteinuria is commonly produced renal damage in horses, rabbits, observed during the first day of phenin­ rats and mice. It can abolish the anti diure­ dione treatment. Heavy proteinuria has tic effect of vasopressin in rabbits and is resulted in the nephrotic syndrome.239 therefore thought to have diuretic proper­ Six patients with severe and significant ties. Peters and Hedwall intensively renal damage caused by phenindione studied the effects of aristolochic acid tox­ have been reported by Brooks and Cal­ icity in rats. They found that a single injec­ leja.38 Four patients developed acute tion of 30 mg per kg body weight of the oliguric renal failure, one had the nephro­ drug induces reversible renal failure as­ tic syndrome, and the sixth had a heavy sociated with a decrease in glomerular proteinuria.85,101 Other clinical features filtration rate as well as increases in BUN were fever, skin rash* jaundice and and creatinine. Maximum polyuria oc­ eosinophilia.12 The histologic renal ab­ curred on the eighth day. Their data re­ normality in the patients with oliguria was veal a decrease in the permeability of the an acute diffuse interstitial nephritis collecting ducts and proximal tubules to characterized by interstitial infiltrates of urea. plasma cells, eosinophils and small lym­ A nticoagulants phocytes. In addition, there were intersti­ Bishydroxycoumarin (Dicumarol) and tial fibrosis and intimal fibrosis of the in­ phenindione (Hedulin) have been impli­ terlobular artery. The glomeruli were cated as possible causes of acute oliguric usually normal. Adrenocortical steroids renal failure. were beneficial in reversing the acute in­ Bishydroxycoumarin. In 1941, Butt and terstitial nephritis caused by phenindione Allen50 at the Mayo Clinic and Meyer and hypersensitivity. associates at the University of Wisconsin introduced bishydroxycoumarin as an an­ C a l c iu m V e r s e n a t e ticoagulant into clinical medicine. Doses Calcium versenate is a synthetic, in the therapeutic range have produced water-soluble polyamino acid (calcium nausea, vomiting and diarrhea. In addi­ disodium ethylenediamine tetraacetic tion, excessive doses caused bleeding. acid). It is an organic chelating agent that Painless gross hematuria is usually the is used in the treatment of heavy metal first evidence of toxicity. This bleeding poisonings. may arise from the kidney and in some In 1957, Vogt and Cottier reported a 38 patients is followed by renal pain, ureteral year old man with chronic lead poison­ colic and gross hematuria. Ureteral ing.247 He was treated with 600 mg per kg obstruction has followed blood clots body weight of calcium versenate daily for within the ureters. four days (ten times the average dose). In one patient, retroperitoneal Acute anuria developed on the fifth day, hematoma dissected down around the and the patient died on the sixth day. urinary bladder to produce an external Acute tubular necrosis was found with di­ ureteral obstruction and acute oliguria.135 lated proximal tubular epithelial cells. 500 MUEHRCKE, VOLINI, MORRIS, MOLES AND LAWRENCE In 1957, Moeschlin described two pa­ was observed by Morgan and colleagues tients who were treated for lead intoxica­ in three hydrated patients with acute tion with calcium versenate.185 Both died oliguria following dextran infusion.183 in uremia caused by acute oliguric renal Renal biopsy studies were performed on failure. Acute tubular necrosis was found each patient and grossly swollen tubular at autopsy. cells were found crammed with a foamy In 1958, Weinig and Schwerd described material. Distended cells completely acute renal failure associated with a occluded the tubular lumen. Special bleeding tendency in a 59 year old factory stains revealed large quantities of dextran worker who received three g of calcium within tubules but none in the tubular versenate.252 Acute tubular necrosis and lumen. dilated proximal tubules were found at The second lesion occurred in dehy­ autopsy. drated patients given dextran.176 Acute In 1960, Reuber and Bradley reported a oliguric renal failure was associated with one year old girl who had lead intox­ the finding of dextran casts obstructing ication.213 The child was treated with cal­ the tubular lumen.197 Once within the cium versenate in a dose of one g (125 mg tubular lumen, the dextran becomes con­ per kg body weight) daily; the subcutane­ centrated and a highly viscous urine is ous dose was given for three days. She formed; this results from the proximal developed acute oliguric renal failure 12 tubular reabsorption of electrolytes and days after the first injection and died four water.9 The highly concentrated viscous days later. Acute tubular necrosis and di­ dextran urine forms tubular casts. The lated proximal tubules were found at au­ massive obstruction within nephrons re­ topsy. sults in no urine flow and subsequent acute oliguric renal failure. Mannitol in­ D e x t r a n fusions (20 percent solution) have been Low molecular weight dextran effective in initiating a diuresis.22 (Dextran-60, Gentran) has a molecular Ferrous sulfate. The ingestion by chil­ weight of 40,000.106 It passes through the dren of large doses of ferrous sulfate fre­ glomerular membrane and is used in clin­ quently produces iron poisoning. The ical medicine as a short-term flow im­ mortality rate in a large series of children prover in small blood vessels and as a with iron poisoning was approximately “plasma volume expander.” 29,82,178 The 50 percent. Acute oliguric renal failure high urinary concentration of dextran occurred as a result of acute tubular ne­ creates a urine of high viscosity.125 An in­ crosis.136 This renal lesion may be related crease in blood clotting time has occurred to gastrointestinal tract damage.234 in a substantial number of individuals re­ Aminopyrine. Aminopyrine is a closely ceiving dextran. Adverse reactions to related compound to antipyrine and to dextran originate as hypersensitivity and phenylbutazone. It is used clinically as include urticaria, angioneurotic edema, an analgesic and an antipyretic, is rapidly bronchospasm and severe anaphylactic and virtually completely absorbed from shock. Hypersensitivity glomerulo­ the gut and is demethylated in the liver. nephritis caused by Arthus’s phenome­ The toxic effect of aminopyrine is a se­ non and acute oliguric renal failure are vere and often fatal agranulocytosis. It two renal conditions induced by dex­ can cause herpes labialis and angio­ tran.150,242 neurotic edema in hypersensitive indi­ Acute oliguric renal failure induced by viduals. Eknoyan and Matson reported a low molecular weight dextran has pro­ 37 year old woman who developed acute duced two distinct renal lesions. The first oliguric renal failure.80 Although she did ACUTE TOXIC NEPHROPATHIES 501 manifest renal damage following a brief this treatment was followed by acute course of treatment with amphotericin B, anuria and jaundice.77 The patient re­ a marked decrease in renal function oc­ mained anuric until her death 30 days curred coincident with aminopyrine ad­ after the onset of her illness. A renal ministration. Recovery occurred after biopsy study performed during the third aminopyrine was discontinued. There week of her illness revealed TTP as­ was a dramatic decrease in renal function sociated with a hemolytic anemia. In coincident with a second course of vitro phenylbutazone was found to be the aminopyrine ingestion. The patient died antigen to produce a positive Coombs in uremia; regrettably, no autopsy was test; the Coombs test became negative done. after treatment with adrenocortical ste­ Phenylbutazone. Phenylbutazone (Buta- roids. zolidin) is a congener of aminopyrine and Bismuth compounds. Bismuth com­ can induce damage to the skin, lungs, pounds have induced nephrotoxicity heart, liver, bone marrow, adrenal glands through repeated intramuscular injec­ and gut.195 Phenylbutazone has produced tions, rectal suppositories, accidental in­ both acute nonoliguric renal failure and gestion and idiosyncrasies to heavy met­ acute oliguric renal failure.41,104,263 als. The proximal renal tubules are the organs most sensitive to injury. Richardson and Alderfer reported a 43 Although the large number of bismuth year old executive who developed acute compounds formerly available to physi­ nonoliguric renal failure after taking 2.2 g cians has been greatly reduced, bismuth of phenylbutazone for six days.214 The pa­ compounds have been used extensively tient had severe hyponatremia (sodium, in the treatment of syphilis,18 oral infec­ 96 mmol per 1) and acidosis (C02, 14 tions such as Vincent’s gingivostomatitis mmol per 1). After massive sodium reple­ and gastroenteritis. Although bismuth tion, the patient recovered. Approxi­ compounds have been used in the treat­ mately eight days after the onset of renal ment of verrucae, they have no known failure, findings from a renal biopsy study beneficial value when so used. were normal. The toxicity of bismuth compounds is Phenylbutazone-induced acute oli­ directly related to the rapidity of absorp­ guric renal failure results from three dis­ tion. Approximately 90 percent of the ab­ tinct morphologic lesions. These include sorbed dose of a soluble bismuth salt is acute tubular necrosis,221 acute interstitial excreted by the kidneys. Bismuth tends nephritis, and thrombotic thrombocyto­ to concentrate in renal tissue to amounts penic purpura (TTP). Lipsett and five times that in the liver. Therefore, Goldman reported a patient with reversi­ damage occurs to the kidney. Proximal ble acute oliguric renal failure following tubular necrosis and intranuclear inclu­ treatment with phenylbutazone.166 A sion bodies are frequently observed in renal biopsy study done on the fifth day bismuth nephropathy. In addition to kid­ of oliguria revealed acute tubular necro­ ney damage, these compounds have pro­ sis. Hermann, Hopefeld and Berning re­ duced gut, liver, and central nervous sys­ ported a patient with fatal acute oliguric tem damage. Acute oliguric renal failure renal failure caused by treatment with was the chief cause of death in patients phenylbutazone.124 An acute interstitial poisoned with bismuth. nephritis was found at autopsy. Dunea and colleagues reported a 44 year old A n e s t h e t ic A g e n t housewife who was treated with phenyl­ Methoxyflurane anesthesia can pro­ butazone, 600 mg daily for three days; duce renal tubular dysfunction and lead 502 MUEHRCKE, VOLINI, MORRIS, MOLES AND LAWRENCE

Immune-complex Glomerulonephritis following Methoxyflurane F i g u r e 8. Immune- j~Prednisone, 60mg./doy| R.A., 41 y r s , Complex Glomerulone­ W , F phritis Following Meth­ 1 ------1 oxyflurane. The clinical Renal course of R.A., a 41 year biopsy 4 0 0 0 old white female, is plot­ Beta 1C ted. On her third expo­ 3 56 mg % sure to methoxyflurane 3000 3 analgesia she developed 1— o jaundice, an erythem­ 2 0 0 0 o atous rash, eosino- E 3 philia, and acute renal 1000 0) SGOT failure. Repeat hemodial­ 5 0 0 ysis was started. The ------r ! 0 BUN is plotted in the dot­ 10 20 ted line. The SGOT is Days in H o spita l plotted by the dark line. A Methoxyflurane renal biopsy study on the Analgesia 14th day revealed an immune-complex glomerulonephritis. Prednisone was started and the patient rapidly improved. to acute “high-output” renal failure.57,160 antigen-antibody complex glomerulo­ Calcium oxalatic crystal deposition oc­ nephritis or hypersensitivity glomerulo­ curs in renal tubules. The mechanism of nephritis. A variety of therapeutic agents nephrotoxicity is the effect of fluoride used in the treatment of infections, which blocks the concentrating capacity hypertension, convulsions and cardiac of the distal nephron. dysrhythmia have been known to pro­ In man, methoxyflurane is metabolized duce a drug-induced systemic lupus ery­ with liberation of both organic fluoride thematosus. Usually in patients with sys­ and organic metabolites containing fluo­ temic lupus, the drugs precipitate out a rides.127 Fluoride may be stored in body fulminating and florid reaction of sys­ fat and slowly but continually released temic lupus erythematosus. Thus, drugs for several days after anesthetic exposure. producing lupus usually do not cause Thus, a “high-output” renal failure is pro­ lupus nephritis. longed. An antihypertensive agent such as hy­ The authors observed one patient ex­ dralazine was the first of a number of drugs posed to methoxyflurane analgesia using implicated to produce the clinical syn­ a face mask-inhaler. The patient, a 41 drome of systemic lupus erythematosus.31 year old lady was exposed to methoxy­ Other agents include isoniazide, sul- flurane during each of three pregnancies fanamidies, penicillin, tetracycline, at term. At the second exposure she de­ streptomycin, p-amino-salicylate, methyl veloped jaundice. At the third exposure and propyl thiouracil, reserpine, alpha- she developed jaundice, an erythematous methyldopa, guanoxam, phenobutazone skin rash and an immune-complex and griseofulvin.52,58,73 The authors have glomerulonephritis with acute renal fail­ observed florid lupus nephritis produced ure. She required hemodialysis and ad­ by both the anticonvulsive agent renal corticosteroids to recover (figure 8). diphenylhydantoin and oral contracep­ tive agents (figure 9). When lupus nep­ Acute Hemorrhagic Glomerulonephritis hritis was produced by the latter two In general, the patients who develop agents, it was severe and florid in produc­ acute hemorrhagic nephritis develop ing rapidly progressive glomerulo­ the clinical syndrome of acute renal fail­ nephritis with azotemia. Therapy was di­ ure. This is usually on the basis of rected to withdrawal of the agent and use ACUTE TOXIC NEPHROPATHIES 503

F i g u r e 9. Electron- microscopic Photograph of Renal Biopsy Study of Oral Contraceptive-Induce- Lupus Nephritis. A 34 year old housewife ingested oral contraceptives for 20 days. She developed hema­ turia, massive proteinuria, azotemia and malignant hypertension. Her LE cell test was positive and her serum Betaic globulin was 47 mg per dl (normal 100 to 170 mg per dl). A portion of a glomer­ ular capillary is noted. The lumen (L) is small. Numerous polymorpho- nucleocytes are present (straight arrows). Electron dense immunological de­ posits are noted below the glomerular basement membrane (curved ar­ rows). Uranyl nitrate (x 4,000).

of high dosage adrenocortical steroids. D r u g s The serum Betaic globulin was an excel­ Renal biopsy study of patients with lent “yard-stick” to determine the control drug-induced nephrotic syndrome usu­ of drug-induced disease activity. ally reveal no specific glomerular changes by light microscopy; however, The Nephrotic Syndrome The nephrotic syndrome has followed TABLE IV Nephrotic Syndrome Owing to Adverse Reactions the therapeutic administration of a vari­ to Drugs and to Hypersensitivity States ety of drugs as nephrotoxic agents. A comprehensive list is given in table IV. Drugs Organic and inorganic mercurial compounds Following the therapeutic use of a Trimethadione (Troxidone) specific drug from a number of unrelated Paramethadione Probenecid drugs listed, patients have been observed Penicillamine to develop the nephrotic syndrome. Tolbutamide Perchlorate When stopping the offending drug a Phenindione Aurothiomalate prompt remission usually occurs and is Bismuth salts associated with the disappearance of pro­ Other heavy metals Hypersensitivity toxins teinuria. These unrelated drugs include Pollen Bee stings troxidone, paramethadione, probenecid, Poison oak and ivy penicillamine, tolbutamide, perchlorate, Serum sickness gold salts, bismuth salts and other heavy Smallpox vaccination m etals.13,16,57 "Sting" Portuguese man-of-war (sea nettle) 504 MUEHRCKE, VOLINI, MORRIS, MOLES AND LAWRENCE by electronmicroscopy fusion of visceral Mandema and colleagues have reported epithelial foot processes are noted. In similar abnormalities in patients given patients with d-penicillamide-induced mercurial compounds.161 nephrotic syndrome,51 electro n ­ microscopy studies have revealed depo­ H ypersensitivity A g e n t sition of electron dense material on the Massive proteinuria and the sub­ epithelial side of the glomerular base­ sequent development of the nephrotic ment membrane associated with fusion of syndrome has been reported to a variety visceral epithelial foot processes. of hypersensitivity toxins.119'218 These in­ Immunopathological studies of clude bee stings, serum sickness, sensi­ d-penicillamide-induced nephrotic syn­ tivity to specific pollen and other inhal­ drome suggest these changes may repre­ ants. In addition, a delayed reaction to sent antigen-antibody complexes and poison ivy or poison oak can produce the support the immunological basis for nephrotic syndrome. Although patients “penicillamine” nephrotoxicity. with hypersensitivity toxin constitute a In general, it is believed that some relatively small group of the nephrotic drugs produce the nephrotic syndrome as syndrome, the syndrome does occur fol­ an idiosyncrasy. However, this may not lowing exposure to hypersensitivity tox­ be the situation in the nephrotic syn­ in. On examination of the renal biopsy drome associated with therapy of material, there were areas of eosinophilic trimethadione and paramethadione. infiltration both in the renal interstitium Children or young adults given as well as throughout the glomerular trimethadione for several weeks develop capillaries. A study by electron­ the nephrotic syndrome.240 A number of microscopy showed a colleseent of the these patients improve spontaneously visceral epithelial foot processes. This is after withdrawal of the drug. They have very similar to the so-called minimal le­ also recovered despite continuing treat­ sions of glomerulonephritis. It is very ment at a lower dose. Another patient possible that a number of patients with improved after a severe illness lasting recurrent nephrotic syndrome in whom three months. An additional patient was the offending agent has not been de­ unimproved following drug stoppage and lineated may also fall into the category of steroid therapy and five patients died. a hypersensitivity toxin. Heavy metals appear to produce drug- Tubular Disturbances induced nephrotic syndrome. These in­ Drugs can directly or indirectly induce clude mercury, gold and bismuth. The tubular disturbances by their toxic effect mercurial toxicity arises when the patient on specific sites on the nephron. This in­ is exposed chronically to a mercurial cludes proximal, distal collecting tubules diuretic agent or to ammoniated mercury and limbs of Henle. Thus, the clinical ointment. In addition, mercury is an oc­ syndromes induced by drug toxicity af­ cupational hazard in employees of the fecting the nephron are related to the site disinfectant industry. The patients ex­ of tubular damage. Renal tubular acidosis posed to this toxicity have developed se­ and the Fanconi syndrome reflect proxi­ vere proteinuria and the nephrotic syn­ mal tubular damage. Potassium defi­ drom e.162 ciency produces reversible damage to the Gold has produced the nephrotic syn­ proximal tubules. drome by producing glomerular lesions. The Fanconi syndrome is charac­ There is a fusion of visceral epithelial terized by aminoaciduria, glycosuria, foot processes of the epithelial cells. potassium loss and a defect in hydrogen ACUTE TOXIC NEPHROPATHIES 505 ion transport. Outdated tetracycline has sults in inhibiting the distal tubules to induced tubular dysfunction to produce a the absorption water. The defect is ac­ Fanconi type syndrome.96 companied by a decrease in urinary cyc­ Tetracycline may degrade spontane­ lic adenosine monophosphate (AMP) ef­ ously on storage to form toxic epimers fect. This effect was thought to be due to which have been held responsible for the interference of cyclic AMP-meditated ac­ development of a reversible type of Fan­ tion of adenine dehydrophosphate coni type syndrome.114 Azotemia in pa­ (ADH) on the distal tubule. This condi­ tients with significant renal impairment tion is reversible once Demeclocycline is has been further activated by the use of removed. tetracyclines. The explanation for this is not clear and cannot be readily eluci­ Potassium Deficiency dated in the presence of pre-existing As a group, the modern diuretic agents renal disease. Some believe that this is are remarkably safe drugs. They have related to the catabolic effects of tetra­ produced a variety of metabolic distur­ cycline.99 bances,159,212 but their specific toxic effect has not been serious. The use of oral diu­ R e n a l T u b u l a r A c id o s is retic agents can produce severe potas­ The nephrotoxic properties of am­ sium deficiency by an excessive urinary photericin B have been well recognized. loss of potassium. Necrosis of both the proximal and distal Potassium depletion owing to use of epithelium occurs resulting in a number oral diuretic agents can be easily over­ of functional defects. These defects are looked by the physician. The symptoms related to impairment of concentrating of fatigue and muscular weakness may be capacity and in hydrogen ion secretion. attributed to the underlying disease Thus, the syndrome of renal tubular aci­ rather than to the treatment. The serum dosis occurs. When this becomes chronic, potassium concentration is the best indi­ nephrocalcinosis may develop. cator that depletion is present. Measure­ Amphotericin B can also induce severe ment of the 24 hour urinary potassium hypokalemia by excessive renal potas­ excretion may substantiate potassium sium loss. The morphological lesions as­ loss. sociated in the proximal tubules of hypokalemia are reversible on discon­ Prolonged potassium deficiency can tinuing amphotericin and replenishing lead to interstitial fibrosis and subsequent potassium. renal scarring. Chronic interstitial fibrosis Toluene inhalation or glue sniffing are develops associated with azotemia. Severe other causes of renal tubular acidosis.198 renal failure may develop and may require In recent years young teenagers have the patient to be placed on chronic been reported developing euphoria from hemodialysis. sniffing glue solvents. The incidence of nephrotoxic effects is directly associated Summary with the glue sniffing pastime. One may Acute toxic nephropathies are byprod­ question the multi-drug abuse of teen­ ucts of man’s ever increasing exposure to a agers as related to the adverse effects of vast array of toxic chemicals and drugs that glue sniffing. result from industrial and medical prog­ ress. The kidney is extremely susceptible D is t a l T u b u l a r D isfunctions to nephrotoxic agents. Its numerous en­ Demeclocycline has produced a prim­ zyme system within the cytoplasm and ary distal tubular defect. This defect re­ mitochondria, its rich blood supply, its 506 MUEHRCKE, VOLINI, MORRIS, MOLES AND LAWRENCE complex superior excretory function, its 7. A n g e r v a l l , L., L e h m a n n , L., and L i n c o l n , K.: On the effect of phenacetin and NAPA (N- large endothelial surface, and the interex­ acetyl-p-aminophenol) on the development of change of substances in the interstitium bacterial interstitial nephritis in the rat. Acta predispose the kidney to nephrotoxic ef­ Path. Microbiol. Scand., Supplement 154:61, fects. 1962. 8. A n t e s , E. H.: Thrombotic thrombocytopenic Acute nephrotoxicity can produce sev­ purpura. A review of the literature with report eral clinical syndromes. These include of a case. Ann. Int. Med. 48:512, 1958. acute oliguric renal failure; both oliguria 9. A r t u r s o n , G., G r a n a t h , K., T h o r n , L., an d W a l l e n i u s , G.: Renal excretion of low- and high output. An example of the latter is molecular-weight Dextran. Acta. Clin. Scand. acute toxicity of methoxylflurane. Other 127:543, 1964. 10. B a i n e s , A. D.: Cell renewal following dichro- clinical syndromes of acute nephrotoxicity mate induced renal tubular necrosis. Amer. J. include nephrotic syndrome, acute Path. 47:851, 1965. hemorrhagic glomerulonephritis, and 11. B a k e r , S. B., D e , C., a n d W i l l i a m s , R. T.: tubular disturbances. Acute interstitial nephritis due to drug sensi­ tivity. Brit. Med. J. 2:1655, 1963. Management includes withdrawal from 12. B a l d w i n , D. S., L e v i n e ,B .B ., M c C l u s k e y ,R. the specific toxic agent. Electrolyte de­ T., and G a l l o , G. R.: Renal failure and intersti­ tial nephritis due to penicillin and methicillin. ficiencies should be corrected. In some New Eng. J. Med. 279:1245, 1968. patients it is necessary to prolong the well 13. B A R K E R , H.: Nephrotic syndrome due to am- being and life of the patient by use of moniated mercury. Brit. J. Derm. 80:288,1968. hemodialysis until the nephrotoxic effects 14. B a t e m a n , J. C., B a r b e r i o , J. R., G r i c e , P., K l o p p , C. T., and P i e r p o n t , H.: Fatal compli­ undergo resolution and heal. cations of intensive antibiotic therapy in pa­ Finally, physicians who think they are tients with neoplastic disease. Arch. Intern. doing well by their patients may suddenly Med. 90:763, 1952. 15. B a t s o n , R. and P e t e r s o n , J. C.: Acute mer­ encounter an adverse drug reaction. In cury poisoning: treatment with B.A.L., and in some situations the drug reactions is trans­ anuric states with continuous peritoneal lav­ itory and completely reversible. In others age. Ann. Intern. Med. 29:278, 1948. 16. B e c k e r , C. G., B e c k e r , E. L., M a h e r , J. F., it may lead to chronic progressive kidney and S c h r e i n e r , G. E.: Nephrotic syndrome failure with death as an unusual complica­ after contact with mercury. Arch Intern. Med. tion of nephrotoxicity. 110:178, 1962. 17. B e c k e r , C. G., B e c k e r , E. L., M a h e r , J. F., and SCHREINER, G. E.: Nephrotic syndrome References after contract with mercury: a report of five 1. A B R Y , J. and CAVUSOGLU, M.: Fatal tubular cases, three after the use of ammoniated mer­ necrosis during chlorothiazide administration cury ointment. Arch. Intern. Med. 110:178, N. Y. State J. Med. 60:1638, 1960. 1962. BEERMAN, H.: 2. A D D IS , T.: Glomerular Nephritis: Diagnosis 18. Fatalities due to bismuth in and Treatment. New York, The Macmillan treatment of syphillis. Arch. Derm. Symph. Company, 1949. 26:797, 1932. 3. Alarcon-Segovia, D., Wa hm , K. G., Worth­ 19. BEIDLEMAN, B.: Kidney damage from penicil­ in g to n , J. W., and WARD, L. E.: Clinical lin sensitivity. Med. Trial Tech. Quart. 10:39, experimental studies on the hydralazine syn­ 1964. drome and its relationship to systemic lupus 20. B e i r n e , G. J., H a s i n g , C. E., O c t a v i a n o , G. erythematosus. Medicine 46:1, 1967. N., and B U R N S, R. O. : Acute renal failure caused 4. Alarcon-Segovia, D., Worthington, J. W., by hypersensitivity to Polymyxin B Sulfate, W ard, L. E., and Wakim, K. G.: Lupus diath­ J.A.M.A. 202:62, 1967. esis and hydralazine syndrome, New Eng. J. 21. B e l l , N. H., A n d r i o l e , V. T., S a b e s i n , S. M., Med. 272:462, 1965. and U t z , J. P.: On the nephrotoxicity of am­ 5. Allen , A. C.: The Kidney: Medical and Surgi­ photericin Binman. Amer. J. Med. 33:64,1962. cal Diseases. New York, Grune & Stratton, Inc., 22. B e r g e n t z , S. E., F a l k h e d e n , T., and O l s o n , 1951. S.: Diuresis and urinary viscosity in dehy­ 6. Alw all, N., E rlandson, P., and Tornberg, drated patients: influence of dextran—40,000 A.: The clinical course of renal failure occurring with and without mannitol. Ann. Surg.161:582, after intravenous urography and/or retrograde 1965. pyelography: casuistics of 11 cases (including 7 23. BERGSTRAND, H.: Comparison between kid­ deaths), Acta. Med. 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