Medications, Mechanisms of Injury, and Management - PowerPoint Presentation

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Medications, Mechanisms of Injury, and Management

Drug-Induced Acute Kidney Injury

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Review common

medications implicated in acute kidney injury (AKI

) and their mechanisms of nephrotoxicityDifferentiate between clinical presentations and risk factors of drug-induced AKIOutline strategies used to prevent and manage drug-induced AKI

Learning Objectives

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AKI is reported to occur in up to 7% of hospitalized patients and 20-30% of critically ill patients, with 6% eventually requiring renal replacement therapy

Drugs

have been implicated in up to 60% of in-hospital AKI cases and 19-25% of cases of severe acute renal failureEpidemiology3

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Hemodynamically

-Mediated Kidney Injury

ACE InhibitorsNSAIDsCalcineurin InhibitorsTubuloepithelial Injury & Tubulointerstitial NephritisAcute Tubular Necrosis (ATN)Acute Interstitial Nephritis (AIN)Crystal NephropathyDirect Intratubular Obstruction & Nephrolithiasis

Indirect Intratubular Obstruction

Drug-Induced AKI: Classification

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Prerenal Injury

Hemodynamically

-Mediated Kidney Injury5

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“Prerenal” injury related to reduced renal blood flow (i.e. hypovolemia,

CHF, bleeding, sepsis, ascites)

Injury results from decreased tissue perfusion and decrease in GFRNormally, the kidney attempts to maintain the GFR by altering renal blood flow via prostaglandins (afferent) and angiotensin II (efferent arteriole)The insult is exacerbated when this response is inhibited by medications (i.e. ACEIs/ARBs and NSAIDs)

Hemodynamically Mediated Kidney Injury

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Prostaglandins are primarily involved in vasodilation of the afferent or “incoming” arteriole while angiotensin II is involved in vasoconstriction of the efferent or “outgoing” arteriole

Hemodynamically Mediated Kidney Injury

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Unlikely to affect renal function in the absence of diminished renal

perfusion

Mechanism: ↓ prostaglandin synthesis → afferent arteriole vasoconstriction → ↓ glomerular pressure → ↓ GFR Clinical Presentation:↓ urine output↑ edema, BUN, Scr, K+, blood pressureFractional excretion Na < 1%Risk Factors:

age > 60 years, CKD, heart failure, concurrent nephrotoxic medications, and hepatic disease with ascites

NSAIDs

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Prevention:

Use alternative analgesics

Use low-dose/short duration treatmentAvoid potent NSAIDs (i.e. indomethacin)Avoid ACEIs/ARBs and diuretics in high-risk or dehydrated patientsAppropriate monitoring (Scr, BUN, etc.)Management:Discontinue NSAIDRecovery is rapid and baseline function is usually restored

NSAIDs

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Mechanism:

↓

angiotensin II production/action → efferent arteriole vasodilation → ↓ glomerular pressure → ↓ GFR Clinical Presentation:Moderate vs. detrimental rise in serum creatinineModerate: ↑ Scr ≤ 30% within 3-5 days of initiation with stabilization in 1-2 weeks is expected and reasonable

Detrimental: ↑ Scr > 30% within 1-2 weeks of initiationRisk Factors:

renal artery stenosis, volume depletion, heart failure, CKD including diabetic nephropathy

Angiotensin Converting Enzyme Inhibitors & Angiotensin Receptor Blockers

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Prevention:Recognize patients at highest risk

Initiate

at very low doses Titrate every 2-4 weeks as opposed to every 3-5 daysAvoid NSAIDs and diuretics in high-risk or dehydrated patientsAppropriate monitoring (Scr, K+, etc

.)Management:

Discontinue ACEI/ARB (reinitiate once volume

is corrected

or at a point where the diuretic dose can be decreased)

Manage hyperkalemia accordingly

Baseline function is usually restored several days after discontinuation

Angiotensin Converting Enzyme Inhibitors & Angiotensin Receptor Blockers

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The nephrotoxic potential of cyclosporine and tacrolimus complicates their use, as they are the most common immunosuppressive agents used in kidney transplantation

Mechanism: ↑

renal vasoconstriction (thromboxane A2, endothelin, RAAS) + ↓ renal vasodilation (prostaglandins) → afferent vasoconstriction → ↓ glomerular pressure → ↓ GFRClinical Presentation:↓ urine output↑ Scr, blood pressure, K+

Sodium retention

Calcineurin Inhibitors

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Risk Factors: age > 65 yrs,

high dose

, concurrent nephrotoxic drugs (diuretics, NSAIDs), interactions that ↑ calcineurin inhibitor concentrations (CYP 3A4 inhibitors) Prevention:Therapeutic drug monitoring of cyclosporine/tacrolimusDecreased dose (balance nephrotoxicity with risk of graft rejection)Appropriate monitoring (Scr, BUN, etc.)Management:

Treat contributing illness and/or remove interacting drugSwitch immunosuppressant if nephrotoxicity is progressive/severe

Calcineurin Inhibitors

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Intrarenal Injury

Tubuloepithelial Injury & Tubulointerstitial

Nephritis14

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“Intrarenal” injury involving ischemia or cellular injury due

endogenous

toxins (i.e. myoglobin), or exogenous toxins (i.e. aminoglycosides)Direct cellular toxicity or ischemia leads to cellular degeneration and sloughing from the proximal and/or distal tubules → inability to reabsorb electrolytes, ↓ GFR, tubular obstructionUrine contains cellular debris/cast and will appear muddy-brown often without evidence of hematuriaOliguric phase (2-3 weeks) is often followed by tubular regeneration or a recovery phase (2-3 weeks)

Acute Tubular Necrosis (ATN)

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Damaged cells with Na

+

/K+/ATPase pumps unable to resorb Na+ leads to increased Na+ sensed at the macula densa. Negative feedback then leads to afferent vasoconstriction and ↓ GFRAcute Tubular Necrosis (ATN)

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Gentamicin, Tobramycin, Neomycin, AmikacinNephrotoxicity occurs in up to 10-25% of patients undergoing a therapeutic course

Aminoglycosides are non-protein bound medications primarily excreted by glomerular filtration

Toxicity is a result of their cationic charge, facilitating their binding to negatively charged tubular epithelium phospholipids and intracellular lysosomal transportMost cationic (and therefore toxic) → least cationicNeomycin > tobramycin, gentamicin, amikacin > streptomycinAminoglycosides

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Mechanism:

uptaken

by proximal tubule → ↑ reactive oxygen species → mitochondrial injury → cellular necrosisClinical Presentation: Within 5-10 days of initiation↑ Scr, BUN, urine electrolytes Typically non-oliguric (urine > 500mL/d)Mild

proteinuria (< 1g/d)Risk Factors:

↑ dose/duration/trough concentration, concurrent nephrotoxic drugs (i.e. cyclosporine, diuretics, NSAIDs, vancomycin), patient related factors (↑ age, diabetes, CKD, dehydration, shock, liver disease)

Aminoglycosides

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Prevention:

Alternate antibiotics if

possibleLimit total aminoglycoside dose and duration (< 7 days if possible)Extended interval dosing (once daily) associated with less nephrotoxicity than traditional dosing (TID) – 0-5% vs. 17%Renal tubule accumulation is saturated during peak concentrationsAvoid volume depletionAvoid concurrent nephrotoxic drugsManagement:Discontinue aminoglycoside or alter regimen

Discontinue other nephrotoxic drugs if possibleMaintain adequate hydration

Kidney injury is generally reversible after discontinuation

Aminoglycosides

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Nephrotoxicity related to amphotericin B is associated with the cumulative dose administered

It is estimated that approximately 80% of patients treated with amphotericin B will develop some renal dysfunction

Toxicity is related to a combination of direct proximal tubular cell toxicity and afferent arteriole vasoconstrictionLiposomal formulations are able to reduce direct amphotericin B interaction with tubular epithelial cell membranesAmphotericin B

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Clinical Presentation:

↑

Scr, BUN, urine electrolytesTypically non-oliguric (urine > 500mL/d)Impaired urinary concentrating abilityRisk Factors: large cumulative doses, pre-existing kidney disease, volume depletion, ↑ age, concurrent use of diuretics or nephrotoxic drugs (i.e. cyclosporine)

Amphotericin B

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Prevention:

Use the liposomal formulation in high risk patients or an alternative antifungal agent if possible (i.e. voriconazole, micafungin)

Normal saline 10-15mL/kg prior to each doseConsider longer infusion timesAppropriate monitoring (Scr, serum electrolytes)Management:Discontinuation of amphotericin B and substitution with alternative antifungal therapy if possibleKidney injury may be reversible or irreversible after discontinuation

Amphotericin B

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Contrast media-induced nephrotoxicity (CIN) can

occur in up to 50% of patients with pre-existing CKD or diabetes mellitus

Nephrotoxicity results from acute renal ischemia and direct cellular toxicity due to increased exposure to contrast media following reduced blood flow Kidney injury may be irreversible, especially in those with pre-existing kidney diseaseRadiographic Contrast Media

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Clinical Presentation

:

↑ Scr, BUNNon-oliguric or irreversible oliguria (urine < 500mL/d) in high-risk patientsgranular casts on urinalysis (not always)Fractional excretion of sodium <1%Risk

Factors: CKD (GFR <60mL/min), volume depletion, heart failure, hypotension, diabetic nephropathy, large volumes/doses, concurrent nephrotoxic drugs

Radiographic Contrast Media

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Prevention:Use alternative diagnostic procedures if possible

Avoid volume depletion and nephrotoxic drugs (i.e. NSAIDs)

Use lowest volumes of contrast agents possibleVolume expansion – normal saline prior to and continued for several hours after contrast exposureOral N-acetylcysteine given prior to and following exposure

Management:Supportive (monitoring, renal replacement therapy if irreversible damage occurs)

Radiographic Contrast Media

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It consists of an acute idiosyncratic reaction involving inflammatory infiltration and edema of the

intersititium

Signs of renal injury include oliguria, sterile pyuria, eosinophiluria (frequently absent)Systemic signs and symptoms include fever, rash, arthralgia and eosinophiliaMore common in antibiotic-associated AIN than NSAID-associatedAIN is a hypersensitivity

reaction and is expected to recur with re-challenge

Acute/Allergic Interstitial Nephritis (AIN)

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Mechanism: Allergic hypersensitivity response via an antibody- or cell-mediated (commonly a T-cell interstitial infiltrate) immune mechanism

Clinical Presentation:

β-lactams – Average onset of 2 weeks from initiationFever (27-80%), maculopapular rash (15-25%), eosinophilia (23-80%) arthralgia (45%), oliguria (50%)NSAIDs – Average onset of 6 months from initiationFever, rash, and eosinophilia occur in <10% while nephrotic syndrome (proteinuria >3.5g/d) occurs in

>70% or patients

Risk Factors:

None identified

β

-lactams (including cephalosporins) & NSAIDs

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Prevention:No specific preventative measures

Appropriate monitoring so that prompt discontinuation can improve the chances of complete renal recovery

Management:Discontinue offending drugHigh-dose oral prednisoneMonitor renal function (Scr, BUN, etc.) for signs of improvementDocument the reaction to avoid re-exposureKidney injury may be reversible or irreversible

β-lactams (including cephalosporins) & NSAIDs

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CiprofloxacinOmeprazole, lansoprazole

Cimetidine, ranitidine

Loop diureticsAllopurinolSulfonamidesRifampin5-aminosalicylatesAcute Interstitial Nephritis

ChemotherapyCisplatin, carboplatin, cytarabine, 5-fluoruracil, ifosfamide

,

Tenofovir, cidofovir,

adefovir

Zoledronate

Vancomycin

IVIGAcute Tubular Necrosis

Other drugs Associated with ATN and AIN

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Postrenal Injury

Crystal

Nephropathy30

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Direct Intratubular

Obstruction & Nephrolithiasis

via drug precipitation (crystallization)Volume depletion and the resulting production of concentrated, acidic urine can precipitate drugs unable to remain in solution at ↓ pH Abnormal crystal precipitation in the renal collecting system leading to pain, hematuria, infection, or urinary tract obstructionIndirect Intratubular Obstruction

Drugs may indirectly produce large amounts of endogenous toxins (i.e. uric acid, myoglobin) leading to intratubular obstruction and direct cellular damage

Crystal Nephropathy

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Indinavir, a protease inhibitor, can lead to

crystalluria

Dysuria, urinary frequency, back and flank pain, or nephrolithiasis in approximately 8% of treated patients

Crystal Nephropathy

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Mechanism: Insolubility of drug in either alkaline or acidic urine + low urine volume → precipitation of drug → crystalluria → obstruction of

tubule

Poor alkaline solubility: IndinavirPoor acidic solubility: Acyclovir, triamterene, sulfadiazine, methotrexateMedications:

AcyclovirIndinavirTenofovir

Atazanavir

Methotrexate (IV)

Sulfadiazine

Triamterene

Ciprofloxacin

Direct Intratubular Obstruction & Nephrolithiasis

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Clinical Presentation: May have asymptomatic

crystalluria

↓ urine output↑ Scr, hematuria, pyuria, pain and crystalluriaDirect Intratubular Obstruction & Nephrolithiasis

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Risk Factors:

Volume depletion (fluid loss or sequestration)

Prevention:Hydration and prevention of volume depletion (crystal precipitation can be prevented in 75% of indinavir treated patients if they consume 2-3L of fluid per day)Urinary alkalinisation for drugs with poor acidic solubilityPotassium citrate or sodium bicarbonateManagement

:Discontinue drug (kidney injury is usually reversible)Volume resuscitation

Direct Intratubular Obstruction & Nephrolithiasis

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Statin-induced rhabdomyolysis is rare (1 in 1000) but the risk is increased with drug interactions

Tubular precipitation of myoglobin results in AKI and production of red-brown urine

Treatment includes hydration/volume expansion and potentially, urinary alkalinisationRhabdomyolysisAntineoplastic agents increase circulating by-products of tumor breakdown

Acute oliguric or anuric kidney injury is a result of uric acid crystal obstructionTreatment

includes hydration, allopurinol and urinary alkalinisation

Tumor Lysis Syndrome

Indirect Tubular Obstruction

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