Drug induced AKF

Tauhid Ahmed Bhuiyan, PharmD
PGY-1 Resident
King Faisal Specialist Hospital & Research Center
Drug-Induced Acute Kidney Injury:
A Contemporary Overview and Prevention Strategies
King Faisal Specialist Hospital and Research Center (KFSHRC) is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing
pharmacy education. (UAN# 0833-0000-14-006-L01-P, 0833-0000-14-006-L01-T)
A Knowledge Based Activity

You have a heart murmur
and I’m starting to hear
your liver and kidneys
complain, too

Objectives
 Familiarize with the background, epidemiology, and general
overview of acute kidney injury (AKI)
 Recognize diagnostic criteria and laboratory parameters of AKI
 Review pathogenic mechanisms and practical prevention
strategies of drug-induced AKI (DI-AKI)
 Evaluate implications of computerized Clinical Decision Support
System (CDSS) for medication dosing in patients with renal
insufficiency
I do not have financial relationship and no actual or potential conflict of interest in relation to this activity

Renal System
Blood flow to
the glomeruli
Formation and processing
of ultrafiltrate
Excretion
Basic physiology:
Plasma filtration: 120
mL/min
http://patients.uroweb.org/kidney-ureteral-stones/symptoms

Epidemiology
 In US, the reported incidence of AKI in all hospital admission:
 1% (community-acquired)
 7.1% (hospital-acquired)
 About 5-20% of critically ill patients experience an episode of AKI
during the course of their illness
 AKI receiving renal replacement therapy (RRT) has been reported in
4.9% of all admission to intensive-care unit (ICU)
 Prognosis:
 Mortality range ≈10%-80% depending on patient population
Lewington A., et al. Clinical practice guideline 2010; www.renal.org/guidelines

Definition
 Clinical characterization:
Abrupt decrease in renal function
Accumulation of nitrogenous waste
products (azotemia)
Inability to maintain and regulate
fluid, electrolytes, and acid-base
balance

Clinical Course
 Three distinct phases:
• Generally occurs over 1 to 2 days
• Characterized by progressive decrease in urine production
(UO <400mL/day)
• Lasts from days to weeks
• Worse prognosis than nonoliguric patients
• Strict fluid and electrolyte monitoring and management are
required
Oliguric
• Period of increased urine production over several days
immediately after oliguric phase
• Signals the initial repair of the kidney insult
• Patients may remain markedly azotemic for several days
Diuretic
• Occurs over several weeks to months depending on the
severity
• Signals the return to the patient’s baseline kidney function,
normalization of urine production
Recovery

Pathogenesis
 Acute Kidney Failure (AKF)
Classification Causes
Prerenal azotemia
 Intravascular volume depletion
 Decreased effective circulating volume
 Hypotension, shock syndrome
 Increased renal vascular occlusion or constriction
Functional
 Afferent arteriole vasoconstrictors
 Efferent arteriole vasodilators
Intrinsic
 Glomerular disorders
 Acute tubular necrosis (ATN)
 Acute interstitial nephritis (AIN)
Postrenal  Ureter obstruction
Donald FB. Acute Renal Failure. Applied Therapeutics: The Clinical Use Of Drugs. 2009;30:1-11

Risk Factors
 Age >75
 Sepsis
 Heart failure
 Diabetes mellitus
 Liver disease
 Use of nephrotoxic agents/medications
 Urinary tract obstruction

Objectives
 Familiarize with the background, epidemiology, and general
overview of acute kidney injury (AKI)
 Recognize diagnostic criteria and laboratory parameters of AKI
 Review pathogenic mechanisms and practical prevention
strategies of drug-induced AKI (DI-AKI)
 Evaluate implications of computerized Clinical Decision Support
System (CDSS) for medication dosing in patients with renal
insufficiency

Diagnosis
 Clinical assessment
 Comprehensive history and physical examination
 Volume status
 AKI risk factors
 Assessment of kidney function
 RIFLE vs. AKIN ?
 Laboratory findings

Assessment of Kidney Function
Acute Kidney Injury Network
Stage Serum Creatinine (Scr)
Urine Output
(UO)
1
Scr increase 1.5 to 2 fold OR ≥26.5 µmol/L
from baseline
<0.5 mL/kg/h ≥6 hours
2 Scr increase >2 to 3 fold from baseline
<0.5 mL/kg/h ≥12
hours
3
Scr increase >3 fold from baseline OR
≥354 µmol/L with an acute rise of at least
>44 µmol/L OR on RRT
<0.3 mL/kg/h ≥24
hours OR anuria ≥12
hours
This staging system is accepted by Kidney Disease Improving Global Outcome
(KDIGO) clinical practice guideline of AKI
−Diagnosis
Kellum JA., et al. Kidney International Supplements 2012; 2:124-138

Assessment of Kidney Function
Risk, Injury, Failure, Loss, and ESRD
Serum Creatinine (Scr) Urine Output (UO)
R
Scr increase 1.5 fold OR GFR
decrease >25%
I
Scr increase 2 fold OR GFR
decrease >50%
F
Scr increase 3 fold OR GFR
decrease >75%; Scr >354 µmol/L
with an acute rise >44 µmol/L
<0.3 mL/kg/h ≥24 hours OR
anuria ≥12 hours
L
Persistent acute renal failure =
complete loss of kidney function
>4 weeks
E ESRD >3 months
−Diagnosis
Kellum JA., et al. Kidney International Supplements 2012; 2:124-138

Laboratory Evaluation
 Quantitative measurements
 Urine output: direct evaluation of kidney function
 Measured over 24hrs as I/O’s
 Glomerular Filtration Rate (GFR)
 Cockcroft-Gault vs. MDRD (Modification of Diet in Renal Disease)
 Qualitative measurements
 Urinanalysis (UA): GOLD standard
 Specific to differentiating AKF
−Diagnosis

Laboratory Evaluation Cont.
 UA
Component
Prerenal
Azotemia
Acute Tubular
Necrosis
Postrenal
Obstruction
Urine
Na+(mEq/l)
<20 >40 >40
FENa+ <1% >2% >1%
Urine/plasma
creatinine
>40 <20 <20
Specific gravity >1.010 <1.010 Variable
Urine
osmolality
(mOsm/kg)
Up to 1200 <300 <300
[Urinary indices in acute kidney failure]
Donald FB. Acute Renal Failure. Applied Therapeutics: The Clinical Use Of Drugs. 2009;30:1-11

DRUG-INDUCED ACUTE
KIDNEY INJURY (DI-AKI)

Epidemiology
 Drug-induced kidney injury causes
 7% of all drug toxicities
 18%—20% of AKI in hospitals
 1%—5% of nonsteroidal anti-inflammatory drugs (NSAIDs) users in
community
 Most implicated medications
Aminoglycosides (AG) Amphotericin B (Amp B) Radiocontrast media
Angiotensin Converting
Enzyme Inhibitor (ACEI)
Angiotensin Receptor
Blockers (ARBs)
NSAIDs
Howell HR., et al. US Pharm 2007;32(3): 45-50
Lewington A., et al. Clinical practice guideline 2010; www.renal.org/guidelines

Pathogenic Mechanisms
 Altered intraglomerular hemodynamics
 Acute Tubular Necrosis (ATN) or tubular cell toxicity
 Acute Interstitial Nephritis (AIN)
 Crystal nephropathy

Altered Intraglomerular
Hemodynamics
 Pathogenesis is via reducing the
volume OR pressure OR both
of blood delivered to the kidney
 Common medications
 NSAIDs
 ACEI, ARBs
 Calcineurin inhibitors (e.g.
cyclosporine, tacrolimus)
Prostaglandins (PGs) Angiotensin II
Vasodilation Vasoconstriction
http://biologigonz.blogspot.com/2010/02/mengenal-ginjal.html
−Functional

 In most circumstances, do not pose significant risk to patients with
normal renal function
 In patients with decreased renal perfusion
 Inhibition of PGs vasoconstrictions ↓ blood flow & ischemic injury
 Indomethacin poses the highest risk
Hemodynamics−NSAIDs
Pannu N., et al. Crit Care Med. 2008;36(4):216-22

 Frequent cause of AKI in patient with
 Severe renal artery stenosis
 Chronic kidney disease (CKD)
 Congestive heart failure
 “Double-edged sword”
 Exerts a predictable dose-related reduction in GFR
 Nephrotoxicity is due to vasoconstrictive effect on efferent arteriole in
the absence of “absolute” or “effective” circulatory volume
Hemodynamics−ACEI/ARBs

Hemodynamics−Calcineurin inhibitors
 Despite improved allograft half-life and patient survival
 Nephrotoxicity often limits the clinical use
 Severity
 Acute (reversible)
 Chronic (irreversible)
 Mechanism of nephrotoxicity has not been clearly established
 Experimental model
 Exerts preglomerular vasoconstriction significant reduction of renal plasma
flow and GFR tissue ischemia

Prevention Strategies
Drugs Practical Prevention
NSAIDs,
ACEIs/ARBs
 Use analgesics with lesser PG activity
(e.g. acetaminophen, aspirin)
 Avoid ACEIs/ARBs in patients with
hypovolemia or bilateral renal artery
stenosis
Calcineurin
inhibitors
 Use lowest effective dose
 For cyclosporine
 Use micronized form
 Avoid strong CYP3A4 inhibitors
 Calcium channel blockers may
ameliorate or provide early protection
Guo X., et al. CLEV CLIN J MED. 2002;69(4):289312

Acute Tubular Necrosis (ATN)
 Most common drug-induced kidney disease in the inpatient settings
 Proposed mechanisms of toxicity
 Impairing mitochondrial function
 Interfering with tubular transport
 Increase oxidative stress or forming free radicals
 Antibiotics: Amp B, AGs , Vancomycin
 Antivirals: Adefovir, Cidofovir, Tenofovir, Foscarnet
 Antineoplastics: Cisplatin
 Bisphosphonate: Zoledronate
 Radiocontrast media
Naughton CA., et al. Am Fam Physician. 2008;78(6)743-50
−Intrinsic

 Approximately 80% of patients experience some renal dysfunction with
amp B treatment (> 4g dose)
 Proposed pathogenic mechanisms
 Direct proximal and distal tubular toxicity
 Afferent arterial vasoconstriction
 Risk factors
 Pre-existing renal insufficiency
 Volume depletion
 Hypokalemia
 High average daily dose
 Diuretic use
 Concomitant nephrotoxin use
 Rapid infusion
Acute Tubular Necrosis−Amp B

 Variable incidence of nephrotoxicity
1.7%—58%
 Proposed pathogenic mechanisms
 Cationic charge binding and uptake
by tubular epithelial cells disrupt
normal cellular function cellular
death
 Stimulate calcium sensing receptor
on the apical membrane induction
of cellular signaling and cell death
 Risk factors
 Prolonged therapy
 Trough concentration >2 μg/mL
(except amikacin)
 Previous AG therapy (recent)
 Concurrent use of other
nephrotoxins
 Patient related factors
Acute Tubular Necrosis−AGs
 Relative toxicities (in descending order)
Neomycin > Gentamycin > Tobramicin > Amikacin > Streptomycin

 Mostly contributed to the early
formulations
 “Mississippi mud” (~70% pure)
 Variable incidence of
nephrotoxicity
 Monotherapy: 5-7%
 Concomitant aminoglycoside:
7-35%
 Proposed mechanisms
 Stimulates oxygen consumption
and ATP in proximal tubule
 Oxidative stress damages
glomeruli and proximal tubule
 Independent risk factors
 Concomitant nephrotoxins use
 Age
 Duration of therapy
 Trough >15 μg/mL
Informative reading: “Vancomycin nephrotoxicity: myths and facts”
Acute Tubular Necrosis−Vancomycin
Rybak M, et al. Am J Health‐Syst Pharm. 2009;82-98

 Third leading cause of inpatient AKI
 Associated with a high (34%) inpatient mortality rate
 Complex pathogenic mechanism
 Started with renal vasodilation and an osmotic diuresis to intense
vasoconstriction ischemia
 Risk factors
 Underlying diabetic nephropathy or chronic renal insufficiency
 Age >75 years
 Congestive heart failure
 Patient receiving aggressive diuretic regimens
Acute Tubular Necrosis−Radiocontrast
media
Donald, Brophy F. Acute Renal Failure. Applied Therapeutics: The Clinical Use of Drugs. 2009; 30-41

Amp B
 Use sodium loading before and after therapy initiation
 Use lipid-based formulation
 Consider alternate day administration or continuous
infusion over 24h
 Consider alternative agents in high-risk patients with renal
impairment
AGs
 Avoid use if possible in high-risk population
 Limit prolonged therapy
 Use extended interval dosing
 Adjust dosage for renal function
 Maintain trough levels ≤ 1 μg/mL

Vancomycin
 Avoid concomitant nephrotoxins
 Monitor trough levels
Radiocontrast
media
 Consider hydration with normal saline and sodium
bicarbonate before and after procedure
 Administration of diuretics such as, mannitol and
furosemide should be avoided
 Monitor renal function 24-48 h post-procedure
 Consider N-acetylcysteine therapy before procedure

Pathogenic Mechanisms
 Altered intraglomerular hemodynamics
 Acute Tubular Necrosis (ATN) a.k.a tubular cell
toxicity
 Acute Interstitial Nephritis (AIN)
 Crystal nephropathy

Acute Interstitial Nephritis (AIN)
 Cause of up to 3% of all AKI cases
 Etiology
 Drugs (antibiotics responsible for one-third of these cases) – 75%
 Infections – 5%-10%
 Tubulointerstitial nephritis and uveitis (TINU) syndrome – 5%-
10%
 Autoimmune/Systemic disease (e.g. sarcoidosis, SLE) – 5%-10%
 Inflammatory changes
 Glomerulus, renal tubular cells, and the surrounding interstitium
 Fibrosis and renal scarring
−Intrinsic

Acute Interstitial Nephritis (AIN)
 NSAIDs
 Penicillin (methicillin) and cephalosporin
 Lithium
 Rifampin
 Quinolones
 Diuretics (loops, thiazides)
 Hydralazine
 Interferon-alfa
 May need kidney biopsy to confirm diagnosis

NSAIDs
 Avoid long term use, particularly of more than one analgesic
 Use alternate agents in patients with chronic pain
Lithium
 Avoid volume depletion
 Monitor drug levels

Crystal Nephropathy
 Renal impairment results from
drugs that produce crystals
that are insoluble in human
urine
 Pathogenic mechanism
 Precipitation of crystals in distal
tubular lumen obstruct urine
flow and elicit interstitial
reaction
 Antibiotics: Ampicillin,
Ciprofloxacin, Sulfonamides
 Antivirals: Acyclovir, Foscarnet,
Ganciclovir, Indinavir,
Methotrexate
 Triamterene
 Risk factors
 Underlying renal insufficiency
 Excessive dose
 Intravenous (IV) administration
−Postrenal

Acyclovir,
methotrexate, sulfa
antibiotics,
triamterene
 Discontinue or reduce dose
 Ensure adequate hydration
 Establish high urine flow
 Administer orally

 Goals
 Short term: stop the progression of kidney damage
 Long term: restore normal kidney function
 In general
 Stopping the offending agent
 Avoid concomitant nephrotoxins
 Maintain adequate hydration
 RRT
Management of DI-AKI

General Preventative Measures
 Assess baseline renal function using MDRD
 Dose adjustment based on renal function
 Correct modifiable risk factors of nephrotoxicity before
initiation of drug therapy
 Ensure adequate hydration before and during therapy with
potential nephrotoxins
 Use equally effective non-nephrotoxic drugs whenever possible

Clinical Decision Support System
(CDSS)
 First introduced in clinical practice in the 1970s
 Designed to improve clinical decision making at the point
of care
 Implementation provided
 Improved medication related clinical outcomes, and
 Reduced medication related errors and adverse events

Guided Medication Dosing for Inpatients
With Renal Insufficiency
 Study objective
 Incorporation of guided dosing algorithms for inpatients with renal
insufficiency into existing computerized physician order entry system
would result in:
 Larger proportion of appropriate dosing and frequency orders
 Shorter hospital length of stay (LOS)
 Lower cost
 Lower frequency of worsening renal function
 Study design
 Study population: all patients admitted to the medical, surgical, neurology,
and obstetrics and gynecology services at Brigham and Women’s Hospital
between September 1997 and April 1998
 Study periods: 4 alternating 8-weeks blocks of intervention and control
subperiods
Chertow GM., et al. JAMA. 2001;286(22):2839-44

Screen Displays

Results

Authors’ Conclusion
 “The application intervention led to a statistically
significant and clinically meaningful increase in the
proportion of prescriptions considered appropriate for
inpatients with renal insufficiency”

Pharmacist Role
 Vigilance
 Early intervention
 Identify patient and drug related risk factors
 Recommend specific dosing or safer alternatives
 Suggest and help implement CDSS

Summary
 AKI is an abrupt decrease in renal function that leads to azotemia, and
imbalance of fluid, acid-base, and electrolytes
 Almost all cases of AKI are hospital-acquired and drug related
etiologies are being the most common
 Diagnosis of AKI is based on clinical presentations, assessment of
kidney function, and laboratory findings especially UA
 Pathogenic mechanisms of DI-AKI include altered intraglomerular
hemodynamics, ATN, AIN, and crystal nephropathy

Summary Cont.
 Management of DI-AKI is common across all drugs:
 Correcting volume and electrolyte depletion
 Stopping the offending agents, and
 Maintaining adequate hydration
 Implementation of CDSS had shown to have clinically meaningful
appropriate dose and frequency of drug orders, and decrease length of
stay in patients with renal insufficiency

References
 Pannu N., Nadim MK. An overview of drug-induced acute kidney injury. Crit Care Med.
2008;36(4):216-223
 Donald FB. Acute Renal Failure. In: Koda-kimble MA., Young LY., Alldredge BK., et al., ed. Applied
Therapeutics: The Clinical Use Of Drugs. Baltimore, Lippincott Williams & Wilkins; 2009: 30(1-11)
 Guo X., Nzerue C. How to prevent, recognize, and treat drug-induced nephrotoxicity. Clev Clin J Med.
2002; 69(4):289-312
 Lewington A., Kanagasundaram S. Module 5 - acute kidney injury clinical practice guideline. UK renal
association. www.renal.org/guidelines. Published March 08, 2011. Accessed January 12, 2014
 Howell HR., Brundige ML. et al. Drug-Induced Acute Renal Failure. US Pharm. 2007;32(3):45-50
 Schetz M., Dasta J., et al. Drug-induced acute kidney injury. Curr Opin Crit Care. 2005;11:555-65
 Singh NP., Ganguli A., et al. Drug-induced Kidney Disease. JAPI. 2003; 51:970-79
 Rybak M, Lomaestro B, Rotschafer JC., et al. Therapeutic monitoring of vancomycin in adult patients:
A consensus review of the American Society of Health-System Pharmacists, the Infectious Disease
Society of America, and the Society of Infectious Disease Pharmacists. Am J Health-Syst Pharm. 2009;
66: 82-98
 Kellum JA., Aspelin P., Barsoum RS., et al. Clinical practice guideline for acute kidney injury. Kidney
International Supplements. 2012; 2:124-138
 Chertow GM., Lee J., Kuperman GJ., et al. Guided medication dosing for inpatients with renal
insufficiency. JAMA 2001;286(22):2839-44

Question 1
 What is the CORRECT sequence of clinical
course of AKI?
a) Recovery Diuretic Oliguric
b) Diuretic Recovery Oliguric
c) Oliguric Diuretic Recovery
d) None of the above

Question 2
 How do NSAIDs alter intraglomerular
hemodynamics?
a) Vasoconstriction of afferent arteriole by blocking PG
activity
b) Vasodilation of efferent arteriole by blocking
Angiotnesin II
c) Vasoconstriction of efferent arteriole by blocking
Angiotnesin II
d) Vasodilation of afferent arteriole by blocking PG
activity

Question 3
 Which of the following pharmacologic agents
has been shown to decrease radiocontrast media
induced AKI when given concurrently with other
fluid therapies?
a) N-acetylcysteine
b) Furosemide
c) Mannitol
d) Calcium channel blockers

Question 4
 Which of the following aminoglycosides have
relatively the highest risk of nephrotoxicity?
a) Neomycin
b) Gentamycin
c) Amikacin
d) Streptomycin

Question 5
 Prophylactic measures to reduce amphotericin B
induced nephrotoxicity include:
a) Ensure adequate hydration before and after therapy
initiation
b) Use lipid-based formulation
c) Consider alternate day administration or continuous
infusion over 24h
d) All of the above

Drug induced AKF

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Editor's Notes