drug induced akf

Tauhid Ahmed Bhuiyan, PharmDPGY-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

http://www.acpe-accredit.org/pdfwebtool/Common/images/logo/ACPE_489_469.jpg

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

ACUTE KIDNEY INJURY (AKI)

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





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

3Scr 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%


FScr 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

LPersistent 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

Objectives





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): 45-50Lewington 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

Altered Intraglomerular 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

Altered Intraglomerular Hemodynamics−ACEI/ARBs


Altered Intraglomerular 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

Pannu N., et al. Crit Care Med. 2008;36(4):216-22Guo X., et al. CLEV CLIN J MED. 2002;69(4):289312



Acute Tubular Necrosis (ATN) or tubular cell toxicity


Crystal nephropathy

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

Common medications Antibiotics: Amp B, AGs , Vancomycin Antivirals: Adefovir, Cidofovir, Tenofovir, Foscarnet Antineoplastics: Cisplatin Bisphosphonate: Zoledronate Radiocontrast media

Pannu N., et al. Crit Care Med. 2008;36(4):216-22Naughton 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

http://www.ncbi.nlm.nih.gov/pubmed/21978980

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 Volume depletion 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




Acute Tubular Necrosis (ATN) a.k.a tubular cell toxicity


Crystal nephropathy


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


Common medications 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

Naughton CA., et al. Am Fam Physician. 2008;78(6)743-50



Acute Tubular Necrosis (ATN) a.k.a tubular cell toxicity


Crystal nephropathy

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

Common medications Antibiotics: Ampicillin,

Ciprofloxacin, Sulfonamides Antivirals: Acyclovir, Foscarnet,

Ganciclovir, Indinavir, Methotrexate

Triamterene

Risk factors Volume depletion Underlying renal insufficiency Excessive dose Intravenous (IV) administration


−Postrenal


Drugs Practical PreventionAcyclovir, 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

Objectives





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

THANK YOU

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

Self Assessment Questions

Question 1

What is the CORRECT sequence of clinical course of AKI?

a) Recovery Diuretic Oliguricb) Diuretic Recovery Oliguricc) Oliguric Diuretic Recoveryd) 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) Furosemidec) Mannitold) 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 formulationc) Consider alternate day administration or continuous

infusion over 24hd) All of the above

drug induced akf

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