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Hepatic and Renal Adverse Effects of Pharmacologic Agents

Mary Vilay, PharmD

Conflict of Interest !  None to declare

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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

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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

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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

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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?

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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

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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

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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?

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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

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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

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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

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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

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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:

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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

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!  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

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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

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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

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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