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3/22/14
1
Hepatic and Renal Adverse Effects of Pharmacologic Agents
Mary Vilay, PharmD
Conflict of Interest ! None to declare
2
Learning Objectives ! Describe the pattern of kidney injury induced by
pharmacologic agents. ! Identify medications that commonly cause renal adverse
effects. ! Discuss the pattern of liver injury induced by
pharmacologic agents. ! Identify medications that commonly cause hepatic adverse
effects. ! Describe resources that may be used to learn more about
renal and hepatic adverse effects of pharmacologic agents.
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Drug Induced Nephrotoxicity
DIN
4
DIN ! Accounts for 20% of hospital admissions for acute kidney
injury ! 8-60% of hospital-acquired acute kidney injury related to
drugs ! ~20 of 100 most commonly used ICU drugs are known
nephrotoxins ! Kidneys susceptibility to DIN
! Receives 20-25% of cardiac output ! H20 reabsorption → ↑ concentration of solutes in tubules ! Renal tubular cells have high energy requirements
Alasy TA. Semin Dial 1996 Schetz M. Curr Opin Crit Care 2005
Taber SS. Crit Care Clin 2006 Wang Y. Renal Failure 2007 5
DIN First Principles ! More than one type of renal injury may be present ! Drugs can cause kidney damage by more than one
mechanism ! Pattern of injury can be reduced to 4 histological
components 1. Blood vessels 2. Glomerulus 3. Tubules 4. Interstitium
http://www.ratical.org/radiation/vzajic/8thchapter.html 6
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Major Types of DIN
Hemodynamically Mediated Renal Failure
Glomerulo-nephritis
Pseudo-Renal Failure
Acute Tubular Necrosis
Acute Allergic Interstitial Nephritis Chronic Interstitial Nephritis
Papillary Necrosis
Obstructive Nephropathy
http://kcfac.kilgore.cc.tx.us/mobleypageap1/images/nephron1.1web.jpg
Pseudo-Renal Failure ! Renal structure affected:
! None
! Pathogenesis: ! ↑production or ↓removal
of kidney function markers
! Clinical presentation: ! ↑SCr OR BUN without
actual ↓ in kidney function
! Examples: ! Competitively inhibit
secretion of creatinine SCr ! Trimethoprim, cimetidine
! Protein catabolism BUN ! Corticosteroids, tetracycline
! Outcome ! SCr/BUN returns to
baseline within days of drug being stopped
8
Hemodynamically Medicated Renal Failure
Renal structure affected: ! Glomerular blood vessels
Pathogenesis: ! ↓ blood flow through
glomerulus ! Afferent arteriole
vasoconstriction &/OR ! Efferent arteriole vasodilation
Presentation: ! ↑SCr & ↓GFR within days of
drug initiation
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Hemodynamically Medicated Renal Failure
Examples ! Afferent arteriole vasoconstriction
! NSAIDs ! Calcineurin inhibitors (cyclosporine, tacrolimus)
! Efferent arteriole vasodilation ! ACEI ! ARB
Outcome: ! Generally reversible if recognized early
10
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PGE 2 (Vasodilation) Afferent
Arteriole Efferent Arteriole Angiotensin II
(Vasoconstriction)
Intra-Glom pressure
maintained
GFR maintained
PGE 2 Afferent Arteriole
Efferent Arteriole
! Angiotensin II (Vasodilation)
Intra-Glom pressure decreased
GFR decreased
Physiologic response to ! blood flow
Effect of ACEIs / ARBs CAUTION with bilateral renal artery stenosis
**When initiating ACE/ARB if SCr " >50 % from baseline, DISCONTINUE**
Glomerulonephritis Renal structure affected:
! Damage & inflammation to glomerulus
Pathogenesis: ! immune-mediated >>
direct toxicity
Clinical Presentation: ! Proteinuria ± ↓GFR ! May be accompanied by
! Hematuria ! Hypertension
Examples: ! Minimal change disease:
! NSAIDs, ampicillin, lithium ! Focal segmental
glomerulosclerosis ! Chronic heroin abuse
! Membranous nephropathy ! Parenteral gold, NSAIDs
Outcome: ! Reversibility variable
! Cause ! Length of insult ! Degree of damage
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T.M., 19 y.o. male
! Started on tetracycline for acne
! What type of drug induced nephrotoxicity has been associated with tetracycline?
! If T.M. did experience this type of drug induced nephrotoxicity, what signs or symptoms would you expect to see?
13
Acute Allergic Interstitial Nephritis (AIN) Renal structures affected:
! Inflammation of tubules and interstitium
Pathogenesis: ! Immune-mediated ! Idiosyncratic ! Not dose related
Clinical Presentation: ! Onset ~2 wk, as short as 3-5
days with re-exposure ! Systemic symptoms
common: fever, rash ! Eosinophilia and/or
eosinophiluria ! White cell casts in urine
Examples: ! β-lactams, sulfonamides,
ciprofloxacin ! Proton pump inhibitors ! NSAIDs (non-typical
presentation) Outcome:
! Usually reversible once drug is stopped
! Corticosteroids may increase rate and extent of renal recovery ! Variable doses used ! Prednisone/prednisolone 1 mg/
kg daily then taper over 3-4 weeks
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Acute Tubular Necrosis (ATN) Renal structure effected:
! Damage to tubular epithelium
Pathogenesis ! Typically caused by renally
eliminated drugs ! Usually dose related ! Drugs/metabolites directly
toxic or cause ischemia ! Cells die and slough off
Clinical Presentation: ! GRANULAR and epithelial
cell casts with free epithelial cells in urine (aka Muddy Brown Casts)
! ↑ urinary Na
Examples: ! Aminoglycosides ! Contrast dye ! Amphotericin B
Outcome: ! Can be reversible if identified
early ! Degree of reversibility
dependent on drug, exposure, and degree of damage
! Prolonged recovery
http://www.irvingcrowley.com/cls/castform.htm 15
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Chronic Interstitial Nephritis Renal structure affected:
! Tubular atrophy and interstitial fibrosis
Pathogenesis: ! Not typically immune
mediated ! May potentially be dose
related Clinical Presentation:
! Slow, indolent progression
Examples: ! Lithium ! Cyclosporine, tacrolimus
Outcome ! Depends on underlying
cause and severity of damage
! Damage usually permanent
! Can lead to overt renal failure
16
Obstructive Nephropathy Renal structure affected:
! Any structure after glomerulus can be affected
Pathogenesis: ! Physical obstruction due to:
! Crystallization of drugs in tubules
! Tissue degradation products
Drug/metabolite Crystallization Clinical Presentation:
! Lower back or flank pain ! Hematuria
Examples: ! Acyclovir, indinavir,
sulfonamides
Outcome: ! Usually reversible
Gagnon, R. F. et. al. Ann Intern Med 1998;128:321 http://www.irvingcrowley.com/cls/urin.htm 17
Obstructive Nephropathy (2) Tissue degradation products
Clinical Presentation: ! Oliguria/anuria
Examples: ! Papillary necrosis, acute
tubular necrosis ! Drug-induced rhabdomyolysis
# Precipitation of myoglobin ! Tumor-lysis syndrome
# Chemotherapy → massive tumor cell destruction
# ↑Uric acid levels → precipitates in tubules
Outcome: ! Dependent on underlying
cause
Prevention: ! Proper hydration ! Alter urine pH
! Alkalinization: uric acid nephropathy, rhabdomyolysis
! Tumor lysis syndrome: ! HYDRATION, allopurinol,
rasburicase
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Papillary Necrosis ! Renal structure affected:
! Renal papilla ! Form of chronic interstitial
nephritis ! Tubule and interstitium inflammation
and scarring ! Can result in obstructive
nephropathy ! Pathogenesis
! Analgesics most common cause (Analgesic Nephropathy) ! Chronic (≥5 years) daily abuse
! Clinical Presentation ! Evolves insidiously over years ! Few symptoms early on ! Recurrent UTI/pyelonephritis
common ! Computed tomography
! Decreased renal mass bilaterally + bumpy contours or papillary calcifications
! Examples ! Acetaminophen, ASA, NSAIDs ! More common with combination
than single entity products ! Acetaminophen (alone) still
analgesic of choice in patients with renal disease
! Outcome ! Damage irreversible
19
G.B., 53 y.o., white female ! PMHx:
! Hypertension ! Coronary artery disease ! Peripheral vascular disease ! Diabetes mellitus
! Meds: ! Hydrochlorothiazide 25 mg
PO daily ! Atorvastatin 10 mg PO
daily ! ASA 81 mg PO daily ! NPH 30 U SC qam & 15 U
q evening
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G.B. Case ! Last weeks clinic visit:
! Two consecutive BP readings measured 20 min apart were 187/96 and 193/95 mmHg
! Hydrochlorthiazide discontinued ! Lisinopril 5mg PO daily started
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G.B. Case ! G.B returns to clinic today for her 1-wk follow-up
appointment complaining of dizziness, very little urine production over the past week, and swelling in her ankles.
! BP 98/43 mmHg. ! STAT blood work:
! BUN 62 mg/dL (5-20) ! SCr 6.2 mg/dL (0.5-1.2) [Patient’s baseline is 2.1 mg/dL]
! What is your assessment of the situation?
! How would you manage this patient?
22
DIN Risk Factors ! Patient Factors
! Older age ! Pre-existing renal disease
! Diabetes
! Volume depletion/decreased effective blood volume ! Heart failure ! Sepsis
! Drug Factors ! Consider:
! Dose ! Length of exposure ! Drug specific prophylaxis
measures
! Multiple nephrotoxins
23
Prevention of Drug-Induced Nephropathy
! Adjust medication dosage based on patient’s renal function
! Avoid nephrotoxic combinations ! Correct risk factors for nephrotoxicity before initiation of
drug therapy ! Ensure adequate hydration before and during therapy ! Use equally effective non-nephrotoxic drugs when
possible
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Recognition and Early Intervention ! Most episodes of DIN are reversible
! Early recognition ! Offending agent is discontinued
! Monitoring ! Clinical signs: ! Laboratory signs
! ↑ SCr # 50% rise from baseline # If SCr < 2 mg/dL increase 0.5 mg/dL # If SCr > 2 mg/dL increase 1 mg/dL
! Acid/base, electrolytes, urinalysis
25
Prednisone could be considered to treat which of the following drug induced nephropathies?
A. Acute tubular necrosis
B. Acute interstitial nephritis
C. Chronic interstitial nephritis
D. Contrast induced nephropathy
26
Which of the following drugs will most likely cause papillary necrosis?
A. Anacin
B. Aspirin
C. Enalapril
D. Excedrin
E. Tylenol
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Drug Induced Liver Injury
DILI
28
Drug Induced Liver Injury (DILI) ! Over 1000 medications and herbals implicated ! Most common cause of acute liver failure in U.S. (>50%) ! Accounts for 10% of all cases of acute hepatitis
! Annual incidence 10-15 per 10,000 to 100,000 ! Risk for individual drug 1 in 10,000 to 100,000
! US most common drug implicated: ! Followed by antibiotics
! Worldwide, common drug implicated:
29
DILI First Principles ! The same drug can cause different patterns of liver injury ! Liver biochemical pattern at time of initial presentation
should be considered to define the pattern of hepatitis ! Hepatitis pattern is not static and may evolve over time ! Adaptation/Tolerance
! Phenomena where liver tests normalize while continuing the drug
! Occurs with 20% of medications
! Acute = Liver tests abnormal for <3 mo ! Chronic = Liver tests abnormal for >3 mo
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DILI Classification Type of Classification Examples
Clinical laboratory
Hepatocellular
Cholestatic
Mix hepatocellular/cholestatic
Mechanism of hepatotoxicity
Direct hepatotoxicity
Idiosyncratic Immune-mediated Metabolic
Histologic findings
Cellular necrosis or apoptosis
Cholestasis
Steatosis
Fibrosis
Phospholipidosis
Granulomatous
Sinusoidal obstruction syndrome 31
Liver Injury Pattern Based on Labs Hepatocellular Mixed Cholestatic
General description ↑ ALT ↑ ALT + ↑ Alk Phos ↑ Alk Phos + ↑ Total Bili
Lab Thresholds ALT 3 x ULN ALT >3 x ULN Alk Phos >2 x ULN
Alk Phos ≥ 2 x ULN
R=( ALT∕ULN) /( Alk Phos∕ULN) R ≥ 5 R 2-5 R ≤ 2
57% 20% 23%
Mortality 7% 2% 14%**
• Small risk of becoming chronic
• Small risk for protracted course
• Small risk of becoming chronic
Examples Acetaminophen Valproic Acid
Carbamazepine TMP/SMX
Amox-clavulanic Estrogens
32 Devarbhavi H. J Clin Exp Hepatol 2012;2:247-259
Case: 40 y.o. male
33
! Approximately 11 wks after starting lovastatin 20 mg daily, developed fatigue, dark urine, jaundice and itching
! No history of liver disease, drank little alcohol ! PMH: kidney stones, hyperlipidemia, hypertension ! Meds: allopurinol, hydrochlorothiazide, amiloride ! Patient comes to your office 17 week after starting
therapy. His labs are as follows:
Time after starting
Time after stopping
ALT
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Case: 40 y.o. male
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! His labs are as follows:
! Calculate “R”
! Based on what you calculated, how would you classify the liver injury pattern? (Hepatocellular, Mixed, Cholestatic)
Time after starting
ALT (U/L)
Alk P (U/L)
Bilirubin (mg/dL)
Other
0 25 77 Lovastatin started
7 weeks 38 64
17 weeks 381 277
Normal Values <35 <130 <1.2
Mechanism of Hepatotoxicity Experimental Reproduc-ability
Dose Related
Human incidence
Latency period
Drugs
Direct Hepatotoxicity
Yes Yes High Usually short (days)
Acetaminophen
Idiosyncratic (Unpredictable)
Lacking Usually no
Low Few days to months
(see below)
Latency Period
Dose Related
Skin rashes, fever, enlarged lymph node, eosinophilia
Rechallenge? Drug
Hypersensitivity (Immune Mediated)
1-6 wk No Yes No Phenytoin Carbamazepine Lamotrigine
Metabolic 1-52 wk, variable
Possibly No Yes (usually not advised)
Isoniazid Pyrazinamide
35 Zimmerman HJ. Hepatotoxicity: the adverse effects of drugs and other chemicals on the liver. 2nd ed. Philadelphia, PA: Lippincott Williams and Wilkins; 1999.
DILI Symptoms ! Wide variation in presentation
! Many asymptomatic ! Symptoms: malaise, low-grade fever, anorexia, nausea, vomiting,
RUQ pain, jaundice, acholic stools, dark urine ! Patients with cholestasis may have pruritis ! Hepatomegaly ! Severe cases: coagulopathy and hepatic encephalopathy
(acute liver failure) ! Chronic DILI may develop significant fibrosis or cirrhosis, → may develop signs and symptoms of cirrhosis or hepatic decompensation: jaundice, palmar, erythema, ascites
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DILI - Assessing Causality ! Making diagnosis of DILI can be difficult ! Obtain careful drug history ! Rule out other potential causes of liver injury
! Biliary abnormality (obstruction) ! Viral hepatitis ! Autoimmune disease ! Alcoholic liver disease
! Ratio of AST to ALT >2:1
! Metabolic and Genetic disease ! Hemodynamic instability resulting in liver ischemia ! Possible drug-related hepatotoxicity
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Key elements for attributing liver injury to a drug:
! Drug exposure preceded the onset of liver injury (latent period highly variable)
! Underlying liver disease is excluded ! Stopping drug leads to improvement in liver injury ! Rapid and severe recurrence with repeated exposure
(rechallenge is not advised in most cases)
! DILI Risk Factors: ! Adults ! Women ! Alcohol abuse and malnutrition predispose to DILI in some
cases
38
Useful Resources ! LiverTox
! http://livertox.nih.gov
! Drug-Induced Liver Injury Network ! https://dilin.dcri.duke.edu
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DILI Management ! Primary treatment = withdrawal of offending agent ! Early recognition important to permit assessment of severity
and monitor for acute liver failure ! Few therapies beneficial except:
! N-acetylcysteine for acetaminophen toxicity ! L-carnitine for valproic acid overdose
! Glucocorticoics unproven benefit, may have role in patients with hypersensitivity/immune reactions
! Serial lab tests until liver test normal ! Hepatology consult if:
! Pt may be developing acute liver failure ie signs of hepatic encephalopathy or coagulopathy
! Signs of chronic liver disease ! Uncertain diagnosis
40
DILI Prognosis ! Majority of DILI will experience complete recovery once
offending medication stopped ! Factors associated with poorer prognosis with
hepatocellular injury: ! Hepatocellular injury + jaundice (Hy’s Law)
! bilirubin > 2 mg/dL and AST or ALT >3 x ULN ! Acute liver failure due to antiepileptics in children ! Acute liver failure due to acetaminophen requiring
hemodialysis ! Elevated SCr
! Prognosis for purely cholestatic injury better than for hepatocellular injury
41
DIN References ! Schetz M et al. Drug-induced acute kidney injury. Curr
Opinion Crit Care 2005;11:555-65. ! **Naughton CA. Drug-induced nephrotoxicity. Am Fam
Physician 2008;78:743-50. ! John R et al. Renal toxicity of therapeutic drugs. J Clin
Pathol 2009;92:505-15. ! Perazella MA et a. Drug-induced acute interstitial
nephritis. Nat Rev Nephrol 2010;6:461-70. ! Chapter 31. Drug-induced kidney disease. In: Dipiro JT et
al eds. Pharmacotherapy: A Pathophysiologic Approach, 9e. New York: McGraw-Hill; 2014.
42 ** Highly recommended
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DILI References ! Navarro VJ et al. Drug-related hepatotoxicity. N Engl J
Med 2006;354:731-9. ! Chalasani N et al. Causes, clinical features, and outcomes
from a prospective study of drug-induced liver injury in the United States. Gastroenterology 2008;135:1924-34.
! Thanavaro JL. An overview of drug-induced liver injury. J Nurse Pract 2007;7:819-26.
! **Devarbhavi H. An update on drug-induced liver injury. J Clin Exp Hepatol 2012;2:247-59.
43 ** Highly recommended