DESCRIPTION OF THE NEPHROLOGY-HYPERTENSIONTRAINING PROGRAM AT THE UNIVERSITY

OF CALIFORNIA SAN DIEGO,SCHOOL OF MEDICINE

UCSD offers a 2- or 3-yr program in clinical nephrology-hypertension and research training in nephrology-hyperten-sion. This program prepares physicians for careers in both academic and clinical nephrology. There are opportunities

for research experience without clinical training for both MDs and PhDs. and approximately 20 fellows are in the currentnephrology-hypertension program. These programs are sponsored by a faculty of 21 members. headed by RolandBlantz. MD. The program offers a balance between clinical training in a very active clinical teaching program and avariety of research opportunities and disciplines. Clinical rotations are supervised by faculty members at two UCSDMedical Center hospitals-the San Diego Veterans Affairs Medical Center and the San Diego Naval Regional MedicalCenter. There are four clinical rotations, which include a rotation on the UCSD Transplant and Pheresis Program.Approximately 120 transplants are performed each year, and several hundred renal transplants are monitored. TheNephrology-Hypertension Consultation Service exposes each fellow to consult experiences in pancreas. liver. lung, andheart transplants as appropriate for these disciplines. There is also an active, vigorous medical intensive care unitexposure during all of the rotations. The fellow has primary responsibility for the care of transplant patients during theacute phase of treatment, and there exists a strong working relationship with the Transplant Surgery Division. More than100 acute hemodialyses are performed each month at UCSD Medical Center. After clinical training, fellows areexposed to a broad range of laboratory experiences in a unique School of Medicine setting. With the exception ofpharmacology. there are no basic science departments at the UCSD School of Medicine. and there is a vigorousinteraction among basic scientists and clinical investigators. Within the division, there are laboratories actively engagedIn the study of renal physiology and pathophysiology. biochemistry. cellular physiology and molecular medicine. renaland molecular cellular immunology. research and treatment modalities for acute and chronic renal failure, andprograms on the clinical mechanisms of systemic hypertension as well as the genetics of hypertension. The School ofMedicine provides extensive training in laboratory methods in research for all research fellows, and there are extensive

opportunities for collaboration with Cellular and Molecular Medicine, the Department of Pharmacology Salk Institute,and The Scripps Research Institute. There are also extended research opportunities through two institutional Physician/Scientist Training Grant Programs. Most of the faculty in the Division of Nephrology-Hypertension are actively involvedin clinical and basic research activities that span programs beyond the Division of Nephrology-Hypertension. Each of

these laboratories is characterized by a high degree of fellow and facutty interaction. The University of California. SanDiego. offers a broad. balanced program directed toward the preparation of individuals for academic careers and theprovision of a broad base of scientific techniques that will prepare them for the decades ahead.

EDITORIAL COMMITTEE

48 Volume 6 . Number 1 . 1995

Tomas Berl, EditorDenver, CO

William HenrichToledo, OH

Mark PallerMinneapolis, MN

Fred SilvaOklahoma City, OK

Acute Renal Failure due to Acetaminophen Ingestion:A Case Report and Review of the Literature1Patricia BIakeIy2 and Brian R. McDonald

P. Blakely, Division of Nephrology and Hypertension,UCSD Medical Center, San Diego, CABR. McDonald, Department of Internal Medicine (Ne-�rology Division), Naval Medical Center, San Diego,

(J. Am. Soc. Nephrol. 1995; 6:48-53)

� Recetved April 15, 1994. Accepted October 3, 1994.2 correspondence to Dr. P. Blakely, Division of Nephrology and Hypertension,

UCSD School of Medicine, 9500 Gilman Drive, La Jolla, CA 920930623.

1046.6673/0601.0048$03.00/OJournal of the American Society of Nephrologycopytight C 1995 by the American Society of Nephrology

ABSTRACTAcetaminophen is the most commonly reported drugoverdose in the United States. Acute renal failureoccurs in less than 2% of all acetaminophen poison-ings and 10% of severely poisoned patients. At thera-peutic dosages, acetaminophen can be toxic to thekidneys in patients who are glutathione depleted

(chronic alcohol ingestion, starvation, or fasting) orwho take drugs that stimulate the P-450 microsomaloxidase enzymes (anticonvulsants). Acute renal fail-

ure due to acetaminophen manifests as acute tubu-lar necrosis (ATN). ATN can occur alone or in combi-

Blakely and McDonald

Journal of the American Society of Nephrology 49

nation with hepatic necrosis. The azotemia ofacetaminophen toxicity is typically reversible, al-though it may worsen over 7 to 10 days before therecovery of renal function occurs. In severe over-

doses, renal failure coincides with hepatic encepha-lopathy and dialysis may be required. Recognition ofacetaminophen nephropathy requires the following:( 1) a thorough drug history, including over-the-counter medications such as Tylenol� or Nyquil�; (2)knowledge of the risk factors that lessen Its margin ofsafety at therapeutic ingestions, i.e., alcoholism; and(3) consideration of acetaminophen in the differen-tial diagnosis of patients who present with combinedhepatic dysfunction and ATN.

Key Words: Acetaminophen. acute renal failure. acute tubu-

lar necrosis. drug overdose

A cetaminophen is contained in a wide variety ofover-the-counter preparations In the United

States ( 1 ). Acetaminophen is the most commonly re-ported drug overdose in the United States (personal

communication, San Diego Poison Center), with80,000 cases in 1992. In toxIc amounts, acetamino-phen can result in hepatic necrosis and acute tubularnecrosis (2-5). At therapeutic dosages, acetamino-

phen can be toxic in patients who consume alcohol or

who take drugs that stimulate the P-450 microsomal

oxidase enzymes (6-9). The overall incidence of acute

renal failure in patients with acetaminophen poison-ing is hess than 2%, and renal failure occurs in about

1 0% of severely poisoned patients (2). Acute renal

failure secondary to acetaminophen poisoning occursalone ( 1 0) or in combination with hepatic necrosis(3,4, 1 1 , 1 2). The following case provides a forum for

discussing acute renal failure after acetaminophen

ingestion.

CASE PRESENTATION

A 39-yr-old white woman presented to the emer-

gency room complaining of nausea. vomiting. diar-

TABLE � . Laboratory data for case presentation

rhea, abdominal pain, and a decrease in urine output.Four days before admission. she developed a sore

throat and cough and began medicating herself withNyquih� (Proctor and Gamble Pharmaceuticals. Inc.,Cincinnati, OH; 167 mg of acetaminophen per 5 mL)and Extra-Strength Tylenoh@ (McNeil Consumer Prod-ucts Company. Fort Washington. PA: 500 mg of acet-

aminophen per tablet). She was seen at an outsideclinic 2 days later for nausea and vomiting and re-

ceived amoxicilhin, gualfenesin, belladonna and phe-

nobarbital, and pseudoephedrine hydrochloride for a

viral syndrome. Worsening symptoms precipitated heremergency room visit.

In the emergency room, she appeared ill, with a

blood pressure of 150/98 mm Hg, a pulse rate of 107beats/mm, and an oral temperature of 37.4#{176}C(99.4#{176}F). Her examination was remarkable for perior-

bital edema and ecchymosis, scheral icterus. and an

enlarged. tender liver. There was no evidence of he-

patic encephalopathy. Routine laboratory tests re-

vealed the following values: sodium, 12 1 mmol/L;

blood urea nitrogen (BUN). 16.4 mmol/L; creatinine,486 �moh/L; total bilirubin, 94 �mol/L; serum glu-

tamic oxalacetic transaminase (SGOT), 2,2 16 IU / L;serum glutamic pyruvic transaminase (SGPT). 2.732IU/L; prothrombin time, 15.7 s; and partial thrombo-

phastin time, 27.4 s (Table 1 ). A urinalysis had a

specific gravity of less than 1 .005, 1 + protein, traceblood and positive bilirubin by dipstick. three to fourwhite blood cells per high-power field, and six to eight

red blood cells per high-power field. No casts werereported by the laboratory. On admission, the frac-tional excretion of sodium was 2.9% and her urinesodium was 20 mmol/L. The hatter quickly rose to 147

mmol/L by hospital day 3. Urine osmolahity and se-rum osmolality were 146 m#{216}sm/L and 269 m#{216}sm/L.

respectively. Serum creatine kinase was normal with a

urine negative for myoglobin. Viral hepatitis serologies

(A. B, C) were negative. A disseminated intravascular

coagulation (DIC) screen was positive (fibrin split

products >40; D-dimer >8), and the platelet count

Serum ParameterDay

2 3 4 5 6 7

Sodium (mmol/L) 121 123 12� 120 �34 134 �31

Potassium (mmol/L) 3.8 3.7 3.5 3.9 4.4 4.5 4.8Chloride (mmol/L) 86 84 83 90 95 93 90Co2 (mmol/L) 2� 21 23 21 24 24 23

BUN (mmol/L) 16.4 17.5 18.6 20 18.6 16.4 12.9Creatinine (�mol/L) 486 537 575 645 557 415 336AlkalmnePhosphatase (lU/L) 105 131 212 276 170SGOT (lU/I) 2,216 2,060 555 244 149 68

SGPT (lU/L) 2,732 3,226 2,169 1,635 1,044 518Total Bilirubin (�mol/L) 94 80 67 38 26Direct Bilirubin (�mol/L) 63 62 43 17 9Glucose (mmol/L) 5.6 5.3 5.3 5.8 5.6 5.9

was low at 103,000. A renal ultrasound was normal.No acetaminophen was detected on the serum drawn

ic�coai

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Cell Necrosis

Acute Renal Failure due to Acetaminophen

50 Volume 6 . Number 1 . 1995

in the emergency room.

On further questioning, the patient related consum-

ing two oz of Nyquil 4 days before admission and

taking one to two tablets of Extra-Strength Tylenolabout every 6 h over the 4 days before admission. She

drank approximately two glasses of wine a day withoccasional heavier intake. She denied intentionaloverdosing on any medication, Illicit drug use, orsuicidal ideation. We estimated that she ingestedapproximately 15 g of acetaminophen over 3.5 days.

The patient’s BUN and creatinine continued to riseover the next few days, reaching a peak of 20 mmob/Land 645 �tmol/L, respectively. on the fourth hospitalday (Table 1 ). Her transaminases fell gradually. and

her DIC parameters normalized. She remained nono-

higuric throughout her hospital stay. With conserva-

tive management and fluid restriction, her urine out-

put increased. No dialytic support was needed. Shewas discharged on hospital day 7 with a BUN of 12.9

mmol/L and a creatinine of 336 �tmoh/L. She did not

come to her follow-up clinic appointments.

OVERVIEW OF ACETAMINOPHENPHARMACOLOGY

Acetaminophen is rapidly absorbed from the gastro-intestinal tract, with peak drug bevels In the plasma

within 30 to 60 mm of ingestion. The drug is metabo-

lized in the liver in three ways: glucuronide conjuga-tion, sulfate conjugation, and microsomal oxidation

(13) (Figure 1). Studies have shown that adults form

primarily glucuronide conjugation (major pathway). Incontrast to neonates and children (aged 3 to 9 yr). who

use sulfate conjugation ( 14). These metabolites areexcreted In the urine. Under normal circumstances, a

small fraction ofacetaminophen (<5%) is converted by

the microsomal P-450 system into an active metabo-

lite that binds glutathione and is then excreted as a

mercapturic acid. Approximately 1% of the drug is

excreted unchanged (1).When barge doses of acetaminophen are consumed,

the limited hepatic stores of glucuronide and sulfate

are quickly depleted. This results in increased forma-

tion of an active metabolite via the minor pathway.

which if not bound by glutathione. binds to cytosol

Figure 1 . Metabolic pathway of acetaminophen. Under normal circumstances, acetaminophen is excreted in the kidney asglucuronide (63%) and sulfate (34%) conjugates (major pathway). Less than 5% of acetaminophen goes through the P-450system (minor pathway) and is then excreted as mercapturic acid. One percent of acetaminophen is excreted unchanged.When large doses of acetaminophen or therapeutic doses are taken in concert with drugs that stimulate the P-450(anticonvulsants) or deplete glufathione (alcohol), the minor pathway predominates. Nucleophilic cell macromoleculesformed via the P-450 system are thought to damage both the liver and kidney.

Blakely and McDonald

Journal of the American Society of Nephrology 51

proteins in tissue within 1 to 2 h, resulting in cellular

necrosis. Increased activity of the mixed-function oxi-dases leads to a higher proportion of formation of the

active metabolite. Drugs that induce the P-450 en-

zymes (anticonvubsants) or depletion of gbutathione(chronic alcohol ingestion. starvation, or fasting) seemto potentiate the hepatic injury in patients with acet-

aminophen overdose ( 13). In chronic alcoholics, the

toxic dose of acetaminophen may be as low as 4 g.Like the liver, the kidney is susceptible to acetamin-

ophen toxicity. In humans, the mechanism of acute

renal failure after toxic amounts of acetaminophenhas not been well defined. Strong evidence for a direct

nephrotoxic effect of large doses of acetaminophenhas come from animal models. Mitchell et al. using

Fischer rats and mice with high microsomal cyto-

chrome P-450 in their kidneys, induced acute necro-sis of the proximal convoluted tubules of the inner

cortex with a single, nonlethal dose of acetaminophen( 15). Pretreatment of these animals with 3-methyl-

chobanthrene, a hepatic sebective drug that increasesP-450 mixed-function oxidases, resulted in potentla-tion of hepatic necrosis alter the administration of

acetaminophen but had no effect on the renal lesion.Furthermore, when a toxic dose of tritium-labeledacetaminophen was given to rats pretreated with3-methylcholanthrene. the amount of covalent bind-ing of the tritlum-labebed drug in the kidney was

reduced. On the other hand, cobalt chloride, whichinhibits liver and kidney P-450 synthesis. resulted in

decreased hepatorenal necrosis. These studies sug-gest that a renal toxic metabohite of acetaminophen

was formed by in situ metabolic activation rather than

by a distant effect from hepatic injury.

The depletion of glutathione in the kidney results inthe potentlation of renal necrosis, whereas pretreat-ment with cysteine. a precursor of gbutathlone, de-

creased the severity of the acetaminophen-inducedkidney lesions. The kidney is thought to form a toxic

metabolite only when it is gbutathione depleted (15).Thus, the animal studies indicate that when the kid-

ney is overwhelmed with acetaminophen, the oxidiza-

tion of acetaminophen via the P-450 system results in

tubular damage.

REVIEW OF PATHOPHYSIOLOGY

After a toxic dose of acetaminophen. anorexia, nau-sea, and vomiting appear 12 to 24 h later. Clinical

evidence of hepatoxicity may not become apparentuntil 4 to 6 days after ingestion. when the level of

acetaminophen is no longer detectable. The charac-

teristic lesion in human liver Is necrosis around the

central vein. This region corresponds to the location ofthe enzymes responsible for the main metabolism of

the drug. The liver becomes enlarged and often tender.There is a rise in the level of transaminases (SGOT and

SGPT) that normalizes after 1 to 2 wk. Severe liver

damage is associated with transaminases levels over1 ,000 hUlL. Despite the hepatocelbular damage, the

bilirubin bevels are usually only moderately elevated

( 1 ). Hepatic synthesis of clotting factors is reduced,and prolongation of prothrombin time occurs. DIC in

conjunction with hepatic necrosis has been described

(16).

ATN associated with acetaminophen poisoning oc-

curs in combination with hepatic necrosis (3,4,11,12)

or alone ( 10). Patients have variable urine output.

Urinary findings may help to distinguish ATN from

hepatorenal syndrome (HRS) and prerenal azotemia.

In ATN (Table 2), the sediment often has granular

casts with or without hematuria or pyuria. Urine

osmobality tends to be similar to plasma osmolality,

whereas urine sodium concentration is >20 mmol/L.HRS and prerenal azotemla differ from ATN in that the

urinary sediment is normal, urinary sodium is low

(< 10 mmob/L), and the urine osmolality is muchgreater than the plasma osmolality ( 1 7). The azotemiaof acetaminophen toxicity may increase progressively

for 7 to 1 0 days before the recovery of renal functionoccurs, as was seen in our case. In severe overdoses,

renal failure coincides with hepatic encephalopathy

and dialysis may be required.

TABLE 2. Renal manifestations of acetaminophen toxicity: an ATN pattern

Urinary FindingsUrine sedimentUrine osmolalityUrine sodiumconcentrationUrinary volume

Clinical CourseHistopathology

Light microscopy

Fluorescent microscopy

Electron microscopy

Granular casts with or without red blood cells or white blood cellsSimilar to plasma osmolality>20 mmol/L

Variable

Deterioration followed by improved renal function

Normal glomeruli and vessels; Necrosis of tubules extending fromthe proximal convoluted to the collecting ducts; Necroticdebris, cells, and pigmented granular casts in tubular lumens;Breaks in the tubular basement membrane

Negative for deposition of immunoglobulins or complementcomponents

Normal glomeruli and vessels; Tubular swelling with loss of brushborder and linear basolateral mitochondrial organization

dysfunction and ATN

DrugsAcetaminophen

overdose

Viral hemorrhagic feversViral hepatitis

ShockCardiogenicHypovolemic

Septic

Miscellaneous DisordersAcute fatty liverReye’s syndromeYellow atrophy of

pregnancy

Acute Renal Failure due to Acetaminophen

52 Volume 6 . Number 1 ‘ 1995

DIFFERENTIAL DIAGNOSIS

The differential diagnosis of acute azotemia In a

patient with liver disease includes prerenal azotemia,

HRS. and acute renal failure due to tubular necrosis.

Prerenal azotemia can be secondary to volume con-

traction or cardiac pump failure. Fluid challenges or

correction of the cardiac dysfunction will reverse the

azotemia. HRS is renal failure that occurs in patients

with liver disease who are not volume depleted and is

recognized by avid tubular reabsorption of sodium

and water, oliguria. and normal renal pathology. ATN

occurs in patients with liver disease, and its causes

are multifactorial but include the categories of drugs,toxins, infectious agents, and shock (18) (Table 3).

DIAGNOSIS

A thorough drug history must be obtained. This

must include commonly purchased over-the-counter

medications that contain acetaminophen and other

medications that induce the P-450 system and may

potentiate acetaminophen’s toxicity (Table 4). Other

risk factors include starvation, fasting. and chronic

alcohol abuse. A single toxic dose of acetaminophen

that will result in adverse effects usually exceeds 1 5 g

in 80% of cases, although much less can be enough to

poison some ( 13). Alcoholics have a predisposition toboth the hepatotoxic and nephrotoxic effects of acet-aminophen. Ingestions within the manufacturer’s rec-

ommendation of 4 g/day can result in toxicity in

patients using alcohol regularly.

An acetaminophen level should be determined 4 to

1 2 h after ingestion. Levels obtained before 4 h may

not represent peak levels in plasma. and those drawn

days after the poisoning may not detect acetamino-

phen. Acetaminophen levels in plasma can be plottedon Prescott’s nomogram to determine the probability

of potential hepatotoxic reactions. Severe hepatic in-

jury occurs in patients with drug levels of 200 �tg/mL

TABLE 3. Differential diagnosis of hepatic

AspirinHalothaneMethoxyfluraneSulfonamides

Tetracycline

ToxinsAmanita phalloidesArsenicCarbon tetrachlorideChloroformChromiumCopper sulfate

Infectious AgentsBacterial sepsis

TABLE 4. Risk factors that enhance acetaminophennephrotoxicity

Drugs That Induce theP-450 System Clinical Settings

Carbamazepine Chronic alcohol ingestionPhenobarbital Starvation or fastingPhenytoin Low-protein dietsPrimidone

Rifampin

Sulfonylureas

TABLE 5. Therapeutic options for acetaminophenpoisoning

AcetaminophenLevel in Serum200 �tg/mL at 4h or 30 .�g/mL

Time FromIngestion

Therapeutic Option

at 15 h

Yes <4 h Charcoal +

N-acetylcysteineYes >4 or <24 h N-acetylcysteineYes >24 h N-Acetylcysteine

recommended by

some

No >24 h Supportive therapy

4 h after ingestion, whereas it usually does not occur

in those with values lower than 150 jtg/mL. Liver

function tests, routine urine and serum electrolytes.

and a test for myoglobin and creatine kinase, alongwith hematology and coagulation parameters, should

be obtained.A renal biopsy may be indicated in patients with an

unobtainable history or atypical presentation. His-

topathobogical examination of acetaminophen ne-

phropathy has some characteristic features (Table 2).

Light microscopic sections show normal glomerubi

and vessels but severe necrosis involving the proximal

convoluted tubules as well as the distal tubules (5, 1 1).

Breaks in the tubular basement membrane occur.

Casts can be seen in the tubular lumens. Fluorescent

microscopy is negative for the deposition of immuno-

globulins or complement components. Electron mi-

croscopy is remarkable for the boss of huminal brush

borders, mitochondrial disarray. multiplication of in-

tramitochondrial vesicles, and disruption of tubular

basement membrane (5).

REVIEW OF THERAPEUTIC APPROACH

The treatment of acetaminophen poisoning has

emerged over time (Table 5). Gastric aspiration and

havage are effective when performed within the first

few hours after the acetaminophen overdose. Acti-vated charcoal reduced acetaminophen absorption,

Blakely and McDonald

Journal of the American Society of Nephrology 53

but only when given within 30 min after ingestion. The

administration of sullhydryh compounds (e.g. . N-ace-

tybcysteine. cysteamine, or methionine) reduces the

extent of liver necrosis after acetaminophen overdose.

These drugs are proposed to protect the biver by

maintaining or restoring the glutathione levels or by

acting as an alternate substrate for conjugation with

the reactive metabolite ( 19). Oral N-acetybcysteine isthe current recommended treatment when hepato-

toxic levels are present (20). If initial acetaminophenbevels are in the toxic range (>200 �tg/mL at 4 h or 30

�g/mL at 15 h), the patient should receive an oral

loading dose of acetybcysteine (140 mg/kg). followed

by 17 doses of 70 mg/kg every 4 h. If therapy is

Initiated before knowing the acetaminophen level and

it is found to be bow, N-acetylcysteine can be discon-

tinued. The initiation of treatment 24 h after ingestion

is controversial (20). Cysteamine and methionine have

also been used as alternative treatments, but N-ace-

tylcysteine is considered to be more effective and has

fewer side effects (20,2 1).N-Acetylcysteine has not been shown to ameliorate

renal tubular damage secondary to acetaminophen

and is not recommended for isolated suspected neph-

rotoxicity. These observations suggest there are addi-tional unidentified factors that contribute to acet-

aminophen injury to the kidney.

PROGNOSIS

Patients are considered at risk for hepatic failure if

their acetaminophen bevel in plasma after ingestion is200 �g/mL at 4 h or 30 �tg/mL at 15 h (2). Treatment

with N-acetylcysteine ameliorates damage in thesecases. In general, ATN is reversible, with only a smallnumber requiring temporary dialytic support. There isno known effective treatment to Interrupt renal tubu-bar damage at this time.

CONCLUSION

Acute renal failure secondary to acetaminophen

poisoning occurs alone or In combination with hepaticnecrosis. The renal manifestations of acetaminophentoxicity are those of ATN. The margin of safety of

acetaminophen is bess in patients with such risk

factors as starvation, chronic ingestion of alcohol, or

medications that activate the P-450 system. Recogni-tion of acetaminophen nephropathy requires the phy-

siclan to have knowledge of these risk factors and to

obtain an adequate drug history. Including over-the-

counter medications.

ACKNOWLEDGMENTSThis was supported by NIH Program Physician Scientist Award

DKO14O8 (PB.).

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