a3. pharmacists drug-induced kidney …. pharmacists drug-induced kidney injury 2:00 ......

FEBRUARY 7-9, 2014 | THE MEADOWS EVENTS & CONFERENCE CENTER | ALTOONA, IOWA

A3. PHARMACISTSDRUG-INDUCED KIDNEY INJURY

2:00 - 3:00PMACPE UAN: 107-000-14-027-L01-P 0.1 CEU/1.0 hrActivity Type: Application-Based

Learning Objectives for Pharmacists: Upon completion of this CPE activity participants should be able to:1. Describe the basic pathophysiology of drug induced kidney injury2. Identify risk factors for drug induced kidney injury3. Review drugs associated with renal disease, in particular to the mechanism of inducing injury and

clinical presentation4. Develop a systematic approach to determine the classifi cation of kidney injury & likely cause5. Describe preventive measures and outline a management plan in the setting of drug induced kidney

injury

Speaker: Brett Heintz, PharmD, BCPS-ID, AAHIVE, received his doctorate in pharmacy from the University of California, San Francisco and completed his residencies in pharmacy practice and infectious diseases at the University of California, Davis Medical Center in Sacramento, CA. He also is a board certifi ed pharmacotherapy specialist with added qualifi cations in infectious diseases and American Academy of HIV expert certifi ed.

Dr. Heintz, a Pharmacy Specialist in Internal Medicine and Infectious Diseases, joined the Iowa City VA Health Care System in September 2012. He also holds an academic position as Associate Clinical Professor at the University of Iowa College of Pharmacy and precepts pharmacy students, delivers didactic lectures and coordinates a pharmacotherapy course. Prior to joining the Iowa City VA and the University of Iowa he served as an Assistant Professor of Clinical Pharmacy at UC San Francisco School of Pharmacy with a clinical practice in Infectious Diseases and Internal Medicine at UC Davis Medical Center.

Dr. Heintz’s primary research and clinical interests include antimicrobial dosing in special populations, including renal failure, dialysis, hepatic failure and obesity; determination of predictors of resistance, treatment failure and toxicity of antistaphylococcal and antipseudomonal agents; and management of outpatient delivery of antimicrobial therapy.

Dr. Heintz has authored several articles and book chapters related to antimicrobial therapy and has presented his many of his research projects at local, state, national, and international level meetings. He is also the recipient of several teaching awards.

Speaker Disclosure: Brett Heintz reports no actual or potential confl icts of interest in relation to this CPE activity. Off-label use of medications will be discussed during this presentation.

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B r e t t H e i n t z , B S , P h a r m D , B C P S ( A Q - I D ) , A A H I V EA s s o c i a t e P r o f e s s o r ( C l i n i c a l )

U n i v e r s i t y O f I o w a C o l l e g e o f P h a r m a c yC l i n i c a l P h a r m a c y S p e c i a l i s t

I o w a C i t y V A H e a l t h C a r e S y s t e mM e d i c i n e / I n f e c t i o u s D i s e a s e s

Drug-Induced Kidney Injury

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General Reference: International Society of Nephrology: Acute Kidney Injury. Kidney International Supplements (2012) 2, 4; 1-141

Faculty Disclosure

No actual or potential conflicts of interest associated with this presentation

Off-label use of medications will be discussed during this presentation

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Learning Objectives

Upon completion of this activity, pharmacists should be able to:

1. Review drug induced kidney injury pathophysiology

2. Identify risk factors for drug induced kidney injury

3. Review drugs associated with kidney injury, mechanism of inducing injury & clinical presentation

4. Develop a systematic approach to determine the classification of kidney injury & likely cause

5. Provide preventative measures & management plan in the setting of drug induced kidney injury

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Drug Induced Kidney Disease: Epidemiology

5-10% of drug toxicities involve kidney injury Drug induced kidney disease is common in hospitals

Kidney at risk because: High exposure to toxins, high energy requirement

Intra-renal metabolism, autoregulation, etc.

Mechanisms of drug induced AKI:* Alterations in renal perfusion or filtration capacity

Direct Damage: vascular, tubular, glomerular, interstitial cells

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Taber SS, Mueller BA. Drug-associated renal dysfunction. Crit Care Clin 2006;22:357–74.

*AKI = acute kidney injury: ≥ 1.5-fold increase in baseline SCr OR UOP < 0.5mL/kg/hr x 6 hours

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Drug Induced Kidney Disease: Risk Factors

Demographics Age > 70 years

Gender: female

Race: African American

Pre-existing kidney dz

Other comorbidities Diabetes

Heart Failure & cirrhosis Cardiorenal / Hepatorenal

Allergies

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Pharmacogenomics Renal Transporters

Cyp P450 enzyme

Volume depletion Sepsis/Shock

Surgery

Dehydration

Acid/base disorder

Other nephrotoxins Exposure: dose/duration


Drug Induced Kidney Disease: Manifestations

Acid-base abnormalities

Electrolyte abnormalities

Increase in blood urea nitrogen (BUN)

Increase in serum creatinine (SCr)

Urinalysis (UA) abnormalities Urine sediment abnormalities

Proteinuria (protein in urine)

Pyuria (pus or white blood cells in urine)

Hematuria (blood in urine)

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Classifications of Acute Kidney Injury

Acute Kidney Injury

Prerenal Intrinsic / Intrarenal Postrenal

renal artery

Arterioles

Glomeruli

Tubules kidney pelvis

Ureter

Include any condition that reduces blood flow to kidney (ischemia)

Result from obstruction of urine flow from the kidney to the ureters & bladder

Glomerulovascular or tubulointerstitial

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Bladder

Urinary Indices in AKI (Reference)

Normal range Prerenal Intra-renal Post-renal

Naurine (mEq/L) 20 – 40 < 20 (low) >20 (usually high) >40 (high)

FENa (%) ~1 <1 (low) >1 (high) Variable

FEUrea 40-50% < 35% >50% Variable

BUN:SCr ratio 10:1 >20:1 (high) 15:1 15:1

Ucr:SCr ratio 20-40 >40:1 (high) <20:1 (low) <20:1 (low)

Urine osmolality(mOsm/kg)

300 – 500 > 500 (high) < 300 (low) < 300 (low)

Specific gravity 1.010 – 1.020 High Low Variable

Urine sediment None Normal, may havehyaline casts

Granular casts, epithelial cells, debris

urate/phosphate crystals, myoglobin, may be normal

WBC and RBC Negative Negative Positive Variable

Protein Negative Negative Positive Negative

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Etiology

Pre-renal ischemia

Intrinsic renal diseaseAcute Interstitial Nephritis

Acute Tubular Necrosis

Post-renal obstruction

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Pre-Renal Ischemia

The healthy kidney receives 25% of cardiac output Oxygen extracted for secretion and reabsorptive functions

Kidney susceptible to reduced blood flow (ischemia) Vasoconstriction of afferent arterioles: ↓ intraglomerular pressure

Vasodilation of efferent arterioles: ↓ renal perfusion

Occurs more often in patients who can’t compensate for alterations in afferent/efferent blood flow Elderly & volume depleted

Heart failure (cardiorenal)

Liver failure (hepatorenal)

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Devarajan P. Update on Mechanisms of Ischemic Acute Kidney Injury. J Am Soc Nephrol 12006; 7: 1503–1520

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Causes of Decreased Oxygen Delivery

Volume depletion Absolute (dehydration) vs. functional (ascites, CHF)

Vasoconstriction of the medulla Endothelin, AT-II

Disruption in Tubuloglomerular Feedback (TGF)

Thrombosis Decreased blood flow

Pre-existing kidney disease

Medullary workload Active transport primary determinant of O2 consumption

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Offending Agents & Risk Factors12

Offending Agents Constrict Afferent

NSAIDs / COX 2-Inhib.

Calcineurin inhibitors

Cyclosporine

Tacrolimus

Radiocontrast Media

Dilate Efferent ACEI, ARB, hydralazine

Calcium channel blockers

Diuretics

Risk Factors Volume depletion

Dehydration

Diuretic overuse

Functional (CHF, ascites)

Sepsis (blood shunting)

Vomiting / Diarrhea

Renal-artery stenosis

Polycystic kidney disease


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NSAIDs / Calineurin-I & ACE-Inhibitors Induced Kidney Injury

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NSAIDs/COX-2-I Prostaglandin Inhibition

Results in vasoconstriction of the afferent arteriole

Other offending agents cyclosporine, tacrolimus

Radiocontrast dye

ACE-I / ARB Angiotensin Inhibition

Results in vasodilation of the efferent arteriole

Other offending agents CCBs, hydralazine

Diuretics

Afferent Arteriole

Efferent Arteriole

Glomerulus

Urine

Choudhury D, Ziauddin A. Drug-associated renal dysfunction and injury. Nature Clinical Practice: Nephrology 2006;2(2):80-82.

Drug Induced Pre-Renal Ischemia: Presentation: Urinalysis

Diagnosis Urinalysis (UA) BUN/

SCr

Urine to

Plasma

Osmolality

UNa Fractional

excretion

of Na^

Prerenal Normal, ± hyaline casts >20 >1 <20 <1

Interstitial nephritis + eosinophils, RBC, WBC,

± granular casts

≤15 1 >20 >1

Acute tubular

necrosis

Granular/renal casts,

epithelial cells, necrotic cells

≤15 1 >20 > > 1

Glomerulonephritis RBC, RBC casts, proteinuria ≤15 >1 <20 <1

Vascular disorders Normal or RBC, proteinuria ≤15 >1 <20 <1

Postrenal Normal or RBC, WBC, crystal ≤15 <1 >40 variable

^ FENa (%) = Urine Na * Plasma Cr * 100 FENa=Fractional Excretion of Na; Na=Sodium; Cr= Creatinine

Urine Cr * Plasma Na FE Urea <35% is better predictor of pre-renal if receiving diuretics

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Management

Discontinue offending agent Use safer alternatives

Hydration Crystalloids (0.9% normal saline) vs. colloids (albumin)

SAFE (Saline vs. Albumin for Fluid Evaluation) study

Cost Albumin 20x more expensive than 0.9% normal saline

Outcome Albumin Saline RRR (95% CI)

NNT

All cause mortality

20.9% 21.1% 1% (-9 to 9) Notsignificant

The SAFE Study Investigators. A Comparison of Albumin & Saline for Fluid Resuscitation in the ICU. N Engl J Med 2004; 350:2247-56.

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Etiology

Pre-renal ischemia

Intrinsic renal disease

Acute Interstitial Nephritis

Acute Tubular Necrosis

Post-renal obstruction

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Acute Interstitial Nephritis (AIN)17

Kodner CM, et al. Diagnosis and Management of Acute Interstitial Nephritis. American Family Physician 2003;67(12):2527-2534.

Drug Induced AIN: Pathophysiology

Inflammation of kidney interstitium & tubules Infiltration of the interstitial compartment by

inflammatory/immune cells T-cells, monocytes, plasma cells, eosinophils

Immune complex reaction or cell mediated response to offending drugs

Diagnosis made by renal biopsy


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Drug Induced AIN: Offending Agents

Allopurinol

NSAIDs

Phenytoin

Azathioprine

Chinese Herbs stephania tetrandra,

magnolia officinalis, aristolochia fangchi

Cimetidine (H2As)

Omeprazole (PPIs)

Diuretics (thiazides, loops)

Gold

Antibiotics Semisynthetic penicillins

nafcillin, oxacillin, piperacillin

Sulfonamides

Vancomycin

Quinolones

Rifamycins

Macrolides


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Drug Induced AIN:Presentation (Signs & Symptoms)

Onset is variable (days to weeks) Generally subacute picture (> 7-10 days)

Acute kidney injury with or without oliguria Generally mild increase in SCr and mild reduction in UOP

Urinalysis RBCs, WBCs, ± WBC casts, ± proteinuria (see next slide)

+ Eosinophils (peripheral eosinophila as well)

Tubular dysfunction polyuria, vol. depletion, hyperkalemia, metabolic acidosis

Other uticarial rash, fever, myalgias, evidence on renal biopsy

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Drug Induced AIN: Presentation: Urinalysis*


SCr

Urine to

Plasma

Osmolality

UNa Fractional

excretion

of Na



± granular casts

≤15 1 >20 >1

Acute tubular

necrosis


epithelial cells, necrotic cells

≤15 1 >20 > > 1




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* Specificity high (>75%): if + can rule-in AIN, however sensitivity is poor (<50%): if ‒ can not rule-out AIN


AIN: Prognosis & Treatment

Usually reversible after discontinuation of the offending agent

Use of corticosteroids are controversial No clear benefit in literature

Possible benefit in the setting of prolonged oliguria Prednisone 1mg/kg/day for ≥ 3 days then consider taper

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AIN: Treatment (Supplemental)

Patient with renal insufficiency, AIN suspected (subacute, mild oliguria, eosinophils)

Withdraw potential agent

Improved renal function No clinical improvement

Observe, supportive care Renal Biopsy or alternative study (callium 67 scan, ultrasound)

Positive Negative

Evaluate for other causes of renal failure

Evidence of severe fibrosis?

Yes No

Consider steroid trial (prednisone 1mg/kg/d)

Continue supportive care and consider trial of (alternative) immunosuppressive therapy

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Contraindication to corticosteroid

No

Yes


Etiology

►Pre-renal ischemia►Intrinsic renal disease►Acute Interstitial Nephritis►Acute Tubular Necrosis

►Post-renal obstruction

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Acute Tubular Necrosis (ATN)

Esson ML, et al. Diagnosis and Treatment of Acute Tubular Necrosis. Annals of Internal Medicine 2002; 137(9): 744-752.

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Drug Induced ATN: Pathophysiology

Direct renal tubular toxicity / acidosis

Disruption of mitochondrial respiration deranged cellular energy production

free radical injury: reactive oxygen species formation

Cytosolic calcium overload

Osmolar changes with vacuolization injury

Damage correlated to total exposure: dose, duration

Mechanism of toxicity is unique to each agent

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Esson ML, et al. Diagnosis and Treatment of Acute Tubular Necrosis. Annals of Internal Medicine 2002; 137(9): 744-752.

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Drug Induced ATN: Offending Agents

Contrast

Aminoglycosides

Amphotericin B

Colistin

Cisplatin, carboplatin

Cyclophosphamide, Ifosfamide

Pentamidine

Vancomycin (?)

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Esson ML, et al. Diagnosis and Treatment of Acute Tubular Necrosis . Annals of Internal Medicine 2002; 137(9): 744-752.

Drug Induced ATN:Presentation (Signs & Symptoms)

Onset is rapid (days) Generally considered to be acute onset (≤ 7-10 days)

Acute kidney injury with or without oliguria Generally rapid increase in SCr & decrease in UOP

Rise in SCr correlated with trough drug concentrations

Urinalysis Renal/granular casts, epithelial cells, necrotic cells

Tubular dysfunction / Electrolyte abnormalities hyperkalemia, hyperphosphatemia, metabolic acidosis

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Drug Induced ATN: Presentation: Urinalysis*


SCr

Urine to

Plasma

Osmolality

UNa Fractional

excretion

of Na^



± granular casts

≤15 1 >20 >1

Acute tubular

necrosis


epithelial/necrotic cells

≤15 1 >20 > > 1




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* Contrast nephropathy presents as pre-renal, then progresses to an intra-renal like presentation

Contrast Induced Nephrotoxicity30

Contrast media utilized to optimize visualization of blood flow Varying osmolality in

relation to plasma Iohexal

higher osmolar agent

Iodixanol

lower osmolar agent

Lower osmolar agents & dose reduce risk for AKI

Effects on kidneys Reactive oxygen species &

high osmotic load Direct tubular toxicity

Systemic hypotension, volume depletion, vasoconstriction (↓ nitric oxide)

↓ kidney blood flow

Blocks autoregulation of medullary blood flow

Walsh SR, et al. Contrast-Induced Nephropathy. Journal of Endovascular Therapy: 2007;14(1): 92-100.

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Pre-renal picture with superimposed intra-renal injury Transient osmotic diuresis, then direct tubular toxicity (ATN)

Abrupt increase in SCr SCr rises/peaks in 2-5 days

Marked reduction in UOP 50% patients develop oliguria (UOP < 400mL/24h)

Urinalysis findings (see Tables) Early: consistent with pre-renal injury

Late: consistent with intra-renal injury

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Contrast Induced Nephrotoxicity: Presentation


Contrast Induced Nephrotoxicity: Prognosis & Treatment

Prognosis Due to abrupt nature of damage & susceptibility of cells

to ischemic death, the damage is often irreversible

Higher mortality than inflammatory damage or direct toxin damage: multiple mechanisms

Treatment Withdraw offending agent (may be temporary)

Fluid replacement if volume depleted

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Intervention Recommendation Gradea

Contrast Minimize contrast volume/dose

Use noniodinated contrast studies

Use low-osmolar contrast agent (iodixanol)

A-1

A-2

A-2

Medications Avoid concurrent nephrotoxins A-2

Hydration (NS) 1mL/kg/h 6-12 hours pre and post exposure A-1

Sodium Bicarbonate 150 mEq/L D5W

3mL/kg/h 1 hour prior to contrast exposure, then 1mL/kg/h for 6 hours post contrast exposure

B-2 (JAMA 2004)

Acetylcysteine(Mucomyst®)

600mg PO twice daily x 4 doses (day before and day of radiocontrast study)

B-1

Ascorbic Acid (Vit C) 3g prior to procedure, 2g post & 2g next day C-2 (2013)

Contrast Induced Nephrotoxicity: Prevention

a. Strength of Recommendation: A, B, C (Good, Moderate, Poor)

Quality of Evidence: 1(Randomized controlled), 2 (Randomized, Cohort), 3 (Expert opinion)

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Barrett B, Parfrey PS. NEJM. 2006;354:379-386; Venkataraman R. CCM 2008;36(4) S166-171;Sterling KA . Curr Opin Neph 2008;17:616-23

Contrast Induced Nephrotoxicity

Saline vs. Sodium

bicarbonate

Zoungas et al. Systematic Review: Sodium Bicarbonate Treatment for the Prevention of Contrast-Induced Nephropathy. Ann Intern Med 2009; 151(9): 631

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Aminoglycoside Induced ATN

Pathophysiology (several hypotheses) Intracellular accumulation within lysosomes interferes

with cellular functions and leads to cell death

AGs stimulate calcium-sensing receptor on apical membrane which causes cell signaling / cell death

Balakumar P, et al. Gentamicin: Induced Nephrotoxicity: Therapeutic approaches to blunt it. Pharmacological Research 62 (2010) 179–186

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Aminoglycoside Induced ATN

Recommendations / Prevention Consider extended interval dosing (q24h), if appropriate

Increase efficacy Concentration dependent kill, Post antibiotic effect

Decreased toxicity Minimizes exposure of nephrons (t ½ = 2h) as uptake is saturable

Diligent monitoring (SCr, urine output, electrolytes, levels)

Use appropriate dose for shortest duration possible

Explore alternative antimicrobials, if possible

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Balakumar P, et al. Gentamicin: Induced Nephrotoxicity: Therapeutic approaches to blunt it. Pharmacological Research 62 (2010) 179–186

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Afferent arteriole

Efferent arteriole

Proximaltubule Distal

tubule

Glomerulus

Direct damage of distal tubular membranes leading to wasting of Na+, K+, and Mg++

Constriction of the afferent arterioles leading to decreasedglomerular filtration

Tubular-glomerular feedback:Further constriction of arterioles

Amphotericin B Induced ATN:Multifactorial Mechanism of Toxicity

Wingard JF, et al. CID 1999 29:1402-7; White MH, et al. CID 1998 27:296-302; Luke RG, Boyle JA. AJKD 1998 31:780-5 Walsh TJ, et al. NEJM 1999 340:764-71

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Amphotericin B Induced ATN

Recommendations / Prevention Liposomal formulations are less nephrotoxic

Avoid concomitant nephrotoxins

Fluid/sodium loading: NS pre/post drug adminstration

Prolonged infusion rates – controversial

Consider alternative antifungal agents, if possible

Monitor kidney function / electrolytes (K+, Mg++)

Scheduled & sliding scale potassium & magnesium orders

Stop offending agent if evidence of kidney injury

Wingard JF, et al. CID 1999 29:1402-7; White MH, et al. CID 1998 27:296-302; Luke RG, Boyle JA. AJKD 1998 31:780-5 Walsh TJ, et al. NEJM 1999 340:764-71

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Etiology

►Pre-renal ischemia►Intrinsic renal disease►Acute Interstitial Nephritis►Acute Tubular Necrosis

►Post-renal obstruction

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Obstructive Nephropathy

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Obstructive Nephropathy

Pathophysiology Kidney tubular obstruction due to buildup of tissue

degradation products Drugs or other sediment precipitate within renal tubules crystal or stone

Examples Crystal induced nephropathy

Uric acid precipitation after tumor lysis

Myoglobin precipitation secondary to rhabdomyolysis

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Perazella MA. Drug-induced nephropathy: an Update. Expert Opin. Drug Saf. (2005) 4(4):689-706

Obstructive Nephropathy42

Offending Agents Cystalluria

Acyclovir

Allopurinol

Indinavir, Nelfinavir

Methotrexate

Sulfonamides

Triamterene

Rhabdomyolisis Statins

Quinolones

Daptomycin

Presentation Timing is variable

Mild ↑ SCr

Mild ↓ UOP

Urinalysis (next slide) Crystals or stones

± urinary sediment (RBC, WBC, granular casts)

No eosinophils


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Drug Induced Obstructive Nephropathy: Presentation: Urinalysis*


SCr

Urine to

Plasma

Osmolality

UNa Fractional

excretion

of Na^



± granular casts

≤15 1 >20 >1

Acute tubular

necrosis



≤15 1 >20 > > 1



Postrenal Normal or RBC, WBC,

sediment: crystal, stones…

≤15 <1 >40 variable

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Obstructive Nephropathy: Prognosis & Treatment

Usually reversible after reducing the dose or discontinuation of offending agent

Hydration Hydration Hydration Alkaline diuresis or acidify urine depending on

the characteristics of the drug Alkaline: Na bicarbonate, polycitra (Na/K citrate)

Acidify: acetazolamide

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Other: Glomerular disease

Pathophysiology / Definitions Glomerulonephritis: inflammation of the glomerulus

Glomerulosclerosis: scarring of kidney blood vessels

Causes include diabetes, lupus, medications

Causative drugs NSAIDs, heroin, hydralazine, procainamide

Urinalysis (see next slide) Proteinuria is hallmark sign, ± RBC & RBC casts

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Choudhury D, Ziauddin A. Nature Clinical Practice: Nephrology 2006;2(2):80-82; Rubin RL. Toxicology 2005;135–147 .

Glomerulonephritis Presentation: Urinalysis*


SCr

Urine to

Plasma

Osmolality

UNa Fractional

excretion

of Na^



± granular casts

≤15 1 >20 >1

Acute tubular

necrosis



≤15 1 >20 > > 1



Postrenal Normal or RBC, WBC,

sediment: crystal, stones…

≤15 <1 >40 variable

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Choudhury D, Ziauddin A. Nature Clinical Practice: Nephrology 2006;2(2):80-82; Rubin RL. Toxicology 2005;135–147 .

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Other: Fanconi’s Syndrome47

Pathophysiology Direct damage to the proximal tubules of the kidney

glucose, proteins, uric acid, phosphate, bicarbonate are secreted in urine instead of being reabsorbed

Causative drugs Tenofovir, adefovir, didanosine, tetracyclines

Presentation and Urinalysis Chronic (months), polyuria, polydipsia, dehydration

Proteinuria, glycosuria, hypophosph, hypoK, acidosis

Izzedine H, et al. Drug-Induced Fanconi’s Syndrome. American Journal of Kidney Diseases, 2003; 41(2): 292-309

Pseudo-drug-induced nephropathy

Drugs that inhibit SCr excretion (“pseudoazotemia”) Trimethoprim; cimetidine; probenicid; cobicistat

K-sparing diuretics: amiloride, triamterene spironolactone Note: expect 10-30% increase in SCr from baseline

Drugs that increase BUN (hypercatabolic effect) Corticosteroids; tetracycline

Drugs that interfere with SCr assay Cefoxitin; levo/methyldopa; flucytosine; ascorbic acid

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Nephrotoxins

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Patient Assessment

Kidney Hypoperfusion

Patient Assessment

Clinical History Age, Size, Allergies, Sex IBW vs. ABW for obese

Renal function

Urinalysis

Medical Conditions Baseline kidney disease

Autoimmune diseases

Infection, sepsis, N/V/D

Cardiac / liver disease

Medication History Concurrent medications Cyclosporine, tacrolimus

ACE-I, ARB with NSAIDs

Diuretics

Aminoglycosides

Nephrotoxin History Dose & frequency

Duration of therapy

Time course

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Pre-Renal (↓ Blood delivery)

AIN ATN CrystalNephropathy

Amphotericin B Allopurinol Aminoglycosides Acyclovir

ACE-I / ARB Azathioprine Amphotericin B Allopurinol

NSAIDS / COX-II inhibitors β-lactams (nafcillin, pip) Colistin Indinavir

Cyclosporine / Tacrolimus Chinese herbs Cisplatin Nelfinavir

Calcium channel blockers Diuretics (thiazide, loops) Carboplatin Methotrexate

Hydralazine Gold Cyclophosphamide Fluoroquinolines

Lithium Fluoroquinolones Ifosfaide Sulfonamides

Radiocantrast Media H2As (cimetidine) Pentamidine Triamterene

Vasopressors Macrolides, Rifamycins Radiocontrast

NSAIDs Vancomycin?

PPIs (omeprazole)

Sulfonamides

Vancomycin

Review:Drug Induced Kidney Injury

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Supplemental Slide:Site-specific Drug Induced Kidney Injury

Proximal tubules

ABX: Aminoglycoside, Colistin, AmphotericinAntivirals: Foscarnet, Cidofivir, Adefovir, TdFIS: Cyclosporine, Tacrolimus (FK), Cisplatin

Renal vessel

NSAIDs (afferent) ACE–I (efferent)Cyclosporine (CSA)

Pappillae

PhenacetinInterstitium

Penicillins, CephalosporinsCadmiumNSAIDs

Glomeruli

Interferon-αGoldDoxorubicinPenicillaminePamidronate

Distal Tubules

Amphotericin BIS: FK, CSA, sulfadiazineLithium

Collecting Duct

Amphotericin BAcyclovirLithium

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Pre-Renal Acute Tubular Necrosis (ATN)

Acute Interstitial Nephritis (AIN)

Crystal-InducedNephropathy

Mechanism Ischemia Direct cellular toxicity or renal blood flow impairment

Immune reaction after binding to endogenous nephrotogenic antigen

Precipitation within the renal tubules (crystal or stones)

Timing Acute (≤ 7 d) Acute (≤ 7 days) Subacute (> 7 days) Anytime

SCr, Urine output ↑↑↑, ↓↓↓ ↑↑↑, ↓↓↓ ↑, ↓ ↔ ↑, ↓

Electrolyte changes Variable HyperPhos / kalemia --- ---

Urinalysis/other:BUN/SCr, osmolality UNa, FENA

Normal↑ (> 20, > 1)↓ (< 20, < 1)

Casts, epithelial cells↓ (≤ 15, ≤ 1) ↑ (> 20, > 2)

Eosinophils,f ever/rash↓ (≤ 15, ≤1) ↑ (> 20, 1-2)

Crystals ↓ (≤ 15, < 1) ↑ (> 40, variable)

Common Antimicrobials

--- AGs, colistin, AmB, cidofovir, foscarnet

β-lactams, sulfa, FQs, vancomycin, macrolide

Acyclovir, sulfonamides

Other drugs ACE-I, NSAID, Contrast, CSA

Thiazides, tacrolimus,cyclosporine, contrast

NSAIDs, allopurinol, cimetidine, diuretics

NSAIDs, thiazides, PI, PHT, allopurinol

Risk Factors Age, underlying kidney disease, volume depletion (CHF, ascites, etc.)

β-lactam / sulfa allergy Rapid , high dose(IV), vol. depletion

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Systematic Review:Drug Induced Kidney Injury


Conclusions

Kidney injury has many implications in regards to drugs Many drugs can result in kidney injury

Altered kidney function can affect excretion of many drugs

Drug-induced kidney injury can be (sub)acute or chronic, and of prerenal, intrarenal,* or postrenal mechanisms

Renal injury caused by drugs can be minimized if detected early & preventative measures are utilized Minimize dehydration and hypotension

Appropriate monitoring & dose adjustments needed

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* vascular, tubular, glomerular, interstitial

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Key References

1. Dager WE, Halilovic J. Chapter 51. Acute renal failure. In: Pharmacotherapy. 7th ed. New York, NY: McGraw-Hill; 2010. 741-766.

2. Nolin TD, Chapter 55. Drug Induced Kidney Disease: Pharmacotherapy. 7th ed. New York, NY: McGraw-Hill; 2010. 819-836.

3. Uchino S. The epidemiology of acute renal failure in the world. Curr Opin Crit Care. 2006;12:538-543.

4. Hilton R. Acute renal failure. BMJ. 2006;333:786-790.

5. Hoste E, Kellum JA. Acute kidney injury: epidemiology and diagnostic criteria. Curr Opin Crit Care. 2006;12:531-537.

6. Bellomo R. The epidemiology of acute renal failure: 1975 versus 2005. Curr Opin Crit Care. 2006;12:557-560.

7. Uchino S, Kellum JA, Bellomo R, et al. Acute renal failure in critically ill patients: a multinational, multicenter study. JAMA. 2005;294:813-818.

8. Schetz M, Dasta J, Goldstein S, Golper T. Drug-induced acute kidney injury. Curr Opin Crit Care. 2005;11:555-565.

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11. Guo X. How to prevent, recognize, and treat drug-induced nephrotoxicity. Cleve Clin J Med. 2002;69:289-290,293-294,296-297.

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Case 156

CC/HPI

CC: Dizziness

HPI: GL is a 84 y/o & 62kg female with AMS who was brought to the ED by her daughter from her skilled nursing facility. She was discharged from the hospital 1 week ago following treatment for a CHF exacerbation. The patient is unable to provide a history at this time. According to the daughter, GL initially felt less fatigued and short of breath, which she attributes to the increased dose of her “water pill” that GL has continued to take since her hospital discharge. Her daughter, has noticed that GL has become progressively more confused and lethargic over the last few days. Today, the patient became very dizzy and lightheaded when trying to stand up and her daughter decided to bring her to the ED. GL also complains of tachypnea, fever & pleuritic chest pain, and in the ED the patient was found to have evidence of pneumonia.

PMH Allergies

CHF, DM, HTN, osteoarthritis, CKD, diabetic gastroparesis None

Medications

PTA: Lisinopril 20 mg po qday (started 1/1/2014), furosemide 80 mg po bid (increased 1/14/ 2014), metformin 500 mg po bid, sitagliptin 100 mg/d, glyburide 20mg/d, ibuprofen 200-400 mg po qid prn for pain (ave. 1200mg/day), MVI po qday, metoclopramide 10 mg po qid

On admit: cefepime 1g IV q12h, vancomycin 1g IV q24h, famotidine 20mg q24h, heparin 5000 U SC bid

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Case 1 (cont)57

Urinalysis

Collection: clean catchClarity: cloudyColor: yellowSpecific gravity: 1.032Glucose: negProtein: 30 mg/dlWBC: negRBC: small

Bacteria: negHyaline casts: positiveGranular casts: negativeLeukocytes esterase: negativeNitrites: negUNa 15 mEq/LUcr 113 mg/dLUosm 614 mOsm/kg

Physical Exam Labs

GENERAL: elderly female in no apparent distressSKIN: dry, no rashesHEENT: PERRLACHEST + crackles R lung baseCV: RRRABD: no tenderness/distensionUOP: 300ml/24hours on day of admission

Na 137 mEq/LK 5.7 mEq/LCl 101 mEq/LHCO3 28 mEq/LBUN 63 mg/dLSCr 3.0 mg/dLGlu 72 mg/dLCa 8.6 mg/dL

Mg 2.1 mEq/LPhos 4.4 mg/dLHgb 13.9 g/dLHct 41.3%Plts 339KWBC 9.2KAlb 2.8 g/dL

Case 1 (cont)58

1) What risk factors does the patient have for her AKI?

2) What is the most likely etiology of her AKI? Pre-renal, intrinsic (AIN / ATN) or post-renal?

3) What agent(s) is/are likely contributing to AKI?

4) Are any agents contraindicated in AKI? Which agents should be used with caution in AKI?

5) Provide a management plan, including providing alternative therapy if needed for problematic agents.

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Post-Assessment Questions

1. Risk factors for drug induced acute kidney injury include:A. Advanced ageB. Pre-existing renal diseaseC. DiabetesD. All of the above

2. Which of the following statement(s) is/are consistent with drug-induced acute interstitial nephritis (AIN)? A. Timing consistent with acute onset (< 7 days)B. Fraction of excreted sodium (FENA) < 1%C. Evidence of eosinophils in the urinalysisD. ALL of the above

3. True or False. The MOST important treatment option when managing drug induced acute kidney injury is stopping the offending agent?

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Post-Assessment Questions

4. Which of the following statement(s) is/are consistent with drug-induced Acute Tubular Necrosis (ATN)? A. Timing consistent with acute onset (< 7 days)B. Fraction of excreted sodium (FENA) > 2%C. Evidence of renal casts in the urinalysisD. ALL of the above

5. JR is a 82 year old female with hypertension currently receiving lisinopril. JR’s PCP instructs JR to take ibuprofen to help manage some joint pain. True of False. The addition of an NSAID to a patient receiving an ACE-I may increase the risk for pre-renal ischemia and associated nephrotoxicity.

6. True or False. Use of acetylcysteine or sodium bicarbonate is the primary method to reduce the risk for post-renal (obstructive) nephropathy.

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Questions

a3. pharmacists drug-induced kidney …. pharmacists drug-induced kidney injury 2:00 ......

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