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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
Major Pathway .f.�SULFATE
IP4COCII,
34% 6 -�21 % � 5 %
1”__Unchiged P-iso MixedFunction Oxidase
t
Postulated [ i�o � coal,
,Y OilToxicIntermediates
,�coai,Minor Pathway
GlutathIo�e
w�cocn,
� ���Glutathlone
(\%��_,� Merc!pturicAcid
Nucleophilic Cell&,M�acromolecules
HNCOCII,
Cell
ft Macromolecules
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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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