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April 27, 2015
Medications, Mechanisms of Injury, and Management
Drug-Induced Acute Kidney Injury
Cam Roessner
Review mechanisms of nephrotoxicity and common medications implicated in acute kidney injury (AKI)
Differentiate between the different forms of renal injury based on pathogenesis, clinical presentation, and risk factors
Outline strategies used to prevent and manage drug-induced acute kidney injury
Learning Objectives
Epidemiology of Drug-Induced AKI
1. Hemodynamically Mediated Kidney InjuryACE InhibitorsNSAIDsCalcineurin Inhibitors
2. Tubuloepithelial Injury & Tubulointerstitial NephritisAcute Tubular Necrosis (ATN)Acute Interstitial Nephritis (AIN)
3. Crystal NephropathyDirect Intratubular Obstruction & Nephrolithiasis Indirect Intratubular Obstruction
Outline
Up to 20% of hospital admissions due to acute kidney injury are thought to be drug related
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
While the etiology of AKI tends to be multifactorial, drugs have been implicated in up to 60% of in hospital AKI cases and 19-25% of cases of severe acute renal failure
Epidemiology
Prerenal Injury
Hemodynamically Mediated Kidney Injury
“Prerenal” injury related to reduced renal blood flow (i.e. hypovolemia, CHF, sepsis)
Injury results from a decrease in intraglomurular pressure and filtration and therefore decreased tissue perfusion
Normally, 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
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
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↑ weight/edema, BUN, Scr, K+, blood pressureurine sodium < 20mmol/L and FeNa < 1%
Risk Factors: age > 60 years, CKD, heart failure, concurrent nephrotoxic medications, and hepatic disease with ascites
NSAIDs
Prevention:Use alternative analgesicsUse 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
Up to 20-25% of patients with heart failure will develop renal dysfunction
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 reasonableDetrimental: ↑ Scr > 30% within 1-2 weeks of initiation
Risk Factors: renal artery stenosis, volume depletion, heart failure, CKD including diabetic nephropathy
Angiotensin Converting Enzyme Inhibitors & Angiotensin Receptor Blockers
Prevention:Recognize patients at highest risk (i.e. decompensated HF) Initiate at very low doses (i.e. ramipril 1.25mg)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 replete or at a
point where the diuretic dose can be decreased)Manage hyperkalemia accordinglyBaseline function is usually restored several days after
discontinuation
Angiotensin Converting Enzyme Inhibitors & Angiotensin Receptor Blockers
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 → ↓ GFR
Clinical Presentation:↓ creatinine clearance, urine output, Mg2+
↑ Scr, blood pressure, K+Sodium retention, renal tubular acidosis
Calcineurin Inhibitors
Risk Factors: age > 65 yrs, high dose, concurrent nephrotoxic drugs (diuretics, NSAIDs), interactions ↑ calcineurin inhibitor concentrations (CYP 3A4 inhibitors), salt depletion, older kidney allograft age
Prevention: Therapeutic drug monitoring of cyclosporine/tacrolimus Calcium channel blockers are thought to oppose renal vasoconstriction
Mostly studied in post-kidney transplant recipients with conflicting results Decreased dose (balance nephrotoxicity with risk of graft rejection) Appropriate monitoring (Scr, BUN, etc.)
Management: Treat contributing illness and/or remove interacting drug Switch immunosuppressant if nephrotoxicity is progressive/severe
Calcineurin Inhibitors
Intrarenal Injury
Tubuloepithelial Injury & Tubulointerstitial Nephritis
“Intrarenal” injury involving ischemia or cellular injury due to hypotension/vasoconstriction, 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 concentrate urine, ↓ electrolyte resorption, tubular obstruction, and reduced GFR
Urine contains cellular debris/cast and will appear muddy-brown often without evidence of hematuria
Oliguric phase (2-3 weeks) is often followed by tubular regeneration or a recovery phase (2-3 weeks) with marked diuresis, although if injury is severe regeneration may not occur
Acute Tubular Necrosis (ATN)
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 ↓ GFR
Acute Tubular Necrosis (ATN)
Gentamicin, Tobramycin, Neomycin, Amikacin
Nephrotoxicity 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 transport
Most cationic (and therefore toxic) → least cationicNeomycin > tobramycin, gentamicin, amikacin > streptomycin
Aminoglycosides
Mechanism: ↑ proximal tubule uptake → ↑ reactive oxygen species → mitochondrial injury → cellular necrosis
Clinical Presentation: Within 5-10 days of initiation↓ creatinine clearance, serum calcium/magnesium (sometimes)↑ Scr, BUN, urine electrolytes (early: Ca2+/Mg2+, late: Na+/K+)
Typically non-oliguric (urine > 500mL/d)Microscopic hematuria and 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
Prevention: Alternate antibiotics if possible (i.e. fluoroquinolones, 3rd/4th gen
cephalosporins) based on cultures and sensitivity Limit 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 concentrations
Traditional dosing trough concentrations <1mcg/mL Avoid volume depletion Avoid concurrent nephrotoxic drugs
Management: Discontinue aminoglycoside or alter regimen Discontinue other nephrotoxic drugs if possible Maintain adequate hydration Kidney injury is generally reversible after discontinuation
Aminoglycosides
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 vasoconstriction
Liposomal formulations are able to reduce direct amphotericin B interaction with tubular epithelial cell membranes and therefore reduce the risk of nephrotoxicity
Amphotericin B
Mechanism: afferent vasoconstriction + tubular epithelial cell damage (via ergosterol) → ↑ tubular cell permeability → Na+/K+/Mg2+ wasting → proximal tubular call necrosis
Clinical Presentation: Dose-dependent nephrotoxicity is usually seen after 1-2 weeks and cumulative doses of 2-3g ↓ creatinine clearance, serum K+/Mg2+ (may need replacement) ↑ Scr, BUN, urine electrolytes (Mg2+, Na+, K+)
Typically non-oliguric (urine > 500mL/d) Impaired urinary concentrating ability and renal tubular acidosis
Risk Factors: large cumulative doses, pre-existing kidney disease, volume depletion, hypokalemia, ↑ age, concurrent use of diuretics or nephrotoxic drugs (i.e. cyclosporine)
Amphotericin B
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 possibleMonitor and correct serum magnesium, potassium, and calciumKidney injury may be reversible or irreversible after discontinuation
Amphotericin B
Rates of contrast media-induced nephrotoxicity (CIN) can range from 3-7% in those with no risk factors but can occur in up to 50% of patients with pre-existing CKD or diabetes mellitus
Patients who develop CIN have a 5.5-fold increased risk of death when compared to patients who do not develop CIN
Nephrotoxicity results from acute renal ischemia and direct cellular toxicity due to increased exposure to contrast media following reduced blood flow and clearance
Kidney injury may be irreversible, especially in those with pre-existing kidney disease
Radiographic Contrast Media
Mechanism: ↓ prostaglandins → renal vasoconstriction + ↓ renal blood flow → ↓ renal oxygenation + ↑ tubular epithelial cell exposure to contrast media → ischemia + direct cellular toxicity
Clinical Presentation: ↓ GFR within 24-48h of administration, peak Scr in 3-5 days and a return to baseline within 7-10 days ↓ creatinine clearance, urine sodium concentration ↑ Scr, BUN Non-oliguric or irreversible oliguria (urine < 500mL/d) in high-risk patients Hyaline and granular 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, low- and high-osmolar contrast agents, intra-arterial administration, concurrent nephrotoxic drugs
Radiographic Contrast Media
Prevention: Use alternative diagnostic procedures if possible Avoid volume depletion and nephrotoxic drugs (i.e. NSAIDs) Use lowest volumes of contrast agents possible (nephrotoxicity is likely
with a volume ≥ 3.7 times baseline CrCl) Low-osmolar agents are less toxic than high-osmolar compounds Iso-osmolar non-ionic contrast agents (i.e. iodoxanol) have the lowest risk
of CIN in patients with CKD and diabetes Volume expansion – isotonic saline or isotonic sodium bicarbonate prior
to and continued for several hours after contrast exposure Data is conflicting as to the benefits of oral acetylcysteine given prior to
and following exposure, yet it is cheap and considered safe
Management: Supportive (monitoring, renal replacement therapy if irreversible damage
occurs)
Radiographic Contrast Media
The incidence of AIN is unclear but it is estimated to account for approximately 3-15% of all drug-induced acute kidney injury
Generally, it occurs 7-14 days after exposure to a drug but can manifest sooner in a previously sensitized individual
It consists of an acute idiosyncratic reaction involving inflammatory infiltration and edema of the intersititium leading to patchy necrotic lesions of adjacent tubules
Signs of renal injury include oliguria, sterile pyuria, eosinophiluria (frequently absent), acidosis, hyperkalemia, salt wasting, and concentrating defects
Systemic signs and symptoms include fever, rash, arthralgia and eosinophilia More common in antibiotic-associated AIN than NSAID-associated
AIN is a hypersensitivity reaction and is expected to recur with re-challenge
Acute/Allergic Interstitial Nephritis (AIN)
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 initiation
General: fever (27-80%), maculopapular rash (15-25%), eosinophilia (23-80%) arthralgia (45%), oliguria (50%)
Possible: anemia, leukocytosis, and ↑ IgE levels, hyperkalemiaNSAIDs – Average onset of 6 months from initiation
Fever, 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
Prevention:No specific preventative measuresAppropriate monitoring so that prompt discontinuation can
improve the chances of complete renal recovery
Management:Discontinue offending drugHigh-dose oral prednisone (1mg/kg/d or 40-60mg/d) for 8-14
weeks in total (including a stepwise taper)Monitor 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
Ciprofloxacin
Omeprazole, lansoprazole
Cimetidine, ranitidine
Loop diuretics
Allopurinol
Sulfonamides
Rifampin
5-aminosalicylates
Acute Interstitial Nephritis
Chemotherapy Cisplatin, carboplatin, cytarabine, 5-
fluoruracil, ifosfamide, plycamicin
Tenofovir, cidofovir, adefovir
Foscarnet
Zoledronate
Vancomycin
Pentamidine
IVIG
Acute Tubular Necrosis
Other drugs Associated with ATN and AIN
Postrenal Injury
Crystal Nephropathy
Direct Intratubular ObstructionAcute kidney injury is a result of intratubular obstruction and direct
injury via drug precipitation (crystallization)Volume depletion and the resulting production of concentrated,
acidic urine can precipitate drugs unable to remain in solution at ↓ pH
NephrolithiasisAbnormal crystal precipitation in the renal collecting system
leading to pain, hematuria, infection, or urinary tract obstructionDrug-induced nephrolithiasis is estimated to be 1%
Indirect Intratubular ObstructionDrugs may indirectly produce large amounts of endogenous toxins
(i.e. uric acid, myoglobin) leading to intratubular obstruction and direct cellular damage
Crystal Nephropathy
Indinavir, a protease inhibitor, can lead to crystalluria in 2/3 of treated patients and crystal nephropathy, dysuria, urinary frequency, back and flank pain, or nephrolithiasis in approximately 8% of treated patients
Crystal Nephropathy
Mechanism: Insolubility of drug in either alkaline or acidic urine + low urine volume → precipitation of drug → crystalluria → obstruction of tubulePoor alkaline solubility: IndinavirPoor acidic solubility: Acyclovir,
triamterene, sulfadiazine, methotrexate
Medications: Acyclovir IndinavirTenofovirAtazanavirFoscarnetMethotrexate
(IV)SulfadiazineTriamtereneCiprofloxacin
Direct Intratubular Obstruction & Nephrolithiasis
Clinical Presentation: May have asymptomatic crystalluria↓ urine output↑ Scr, hematuria, pyuria, and crystalluriaAcyclovir: Hematuria, pyuria, and/or flank pain within 24-48hrs Indinavir: Dysuria, back/flank pain, or gross hematuriaSulfadiazine: Stone formation, back/flank pain, or hematuriaTriamterene: Stone formation, crystalline and brown castsMethotrexate: Non-oliguric, Scr peak within first week and
return to baseline in 1-3 weeks
Direct Intratubular Obstruction & Nephrolithiasis
Risk Factors: Volume depletion (fluid loss or sequestration), pre-existing kidney disease, high IV doses (acyclovir), concurrent NSAIDs (triamterene) and ACEIs (ciprofloxacin)
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)
Appropriate dose reduction in CKD and hepatic disease (indinavir) Appropriate monitoring (Scr, BUN, etc.) Urinary alkalinisation for drugs with poor acidic solubility
Potassium citrate or sodium bicarbonate
Management: Discontinue drug (kidney injury is usually reversible) Volume resuscitation Hemodialysis in select cases
Direct Intratubular Obstruction & Nephrolithiasis
Statin-induced rhabdomyolysis is rare (1 in 1000) but the risk is increased with drug interactions ↑ statin exposure
Tubular precipitation of myoglobin (among other mechanisms) results in AKI and production of red-brown urine
Treatment includes hydration/volume expansion and potentially, urinary alkalinisation
Rhabdomyolysis
Antineoplastic agents increase circulating by-products of tumor breakdown
Acute oliguric or anuric kidney injury is a result of uric acid crystal obstruction
Urine uric acid to creatinine ratio is usually >1
Treatment includes hydration, allopurinol or rasburicase, and urinary alkalinisation
Tumor Lysis Syndrome
Indirect Tubular Obstruction
Glomerular Disease
Renal Vasculitis and Thrombosis
Cholesterol Emboli
Chronic Interstitial Nephritis
Papillary Necrosis
• Gold• Lithium• Pamidronate• NSAIDs• Interferon
Vasculitis• Hydralazine• PTU• Allopurinol• Penicillamine• AdalimumabThrombosis• Cyclosporine• Clopidogrel• Quinine• Gemcitabine• Mitomycin C• Bevacizumab
• Warfarin• Thrombolytic
agents
• Cyclosporine• Lithium• Carmustine• Aristocholic
acid (herbs)
• NSAIDs• Aspirin• Caffeine
analgesics
Miscellaneous Causes of Drug-Induced AKI
Drug-induced acute kidney injury can be caused by a variety of medications and is mediated by several direct and indirect mechanisms
Many risk factors for nephrotoxicity exist however, volume depletion and the combined use of nephrotoxic medications are a common theme
Prevention and management strategies involve close monitoring, safe dosing, awareness of patient and drug-specific risk factors, and prompt discontinuation of the offending drug/use of a less nephrotoxic alternative
Summary
Questions?
1. Deray, G. (2002). Amphotericin B nephrotoxicity. The Journal of Antimicrobial Chemotherapy, 49 Suppl 1, 37-41.
2. Kuypers, D. R., Neumayer, H. H., Fritsche, L., Budde, K., Rodicio, J. L., Vanrenterghem, Y., et al. (2004). Calcium channel blockade and preservation of renal graft function in cyclosporine-treated recipients: A prospective randomized placebo-controlled 2-year study.Transplantation, 78(8), 1204-1211.
3. Naughton, C. A. (2008). Drug-induced nephrotoxicity. American Family Physician, 78(6), 743-750.
4. Nolin, T. D., & Himmelfarb, J. (2011). Drug-Induced Kidney Disease. In J. T. Dipiro, R. L. Talbert, G. C. Yee, G. R. Matzke, B. G. Wells, & L. M. Posey, Pharamcotherapy, A Pathiophysiologic Approach (pp. 819-836). New York: McGraw-Hill
5. Pannu, N., & Nadim, M. K. (2008). An overview of drug-induced acute kidney injury. Critical Care Medicine, 36(4 Suppl), S216-23. doi:10.1097/CCM.0b013e318168e375; 10.1097/CCM.0b013e318168e375
6. Schreiber, D. H., & Anderson, T. R. (2006). Statin-induced rhabdomyolysis. The Journal of Emergency Medicine, 31(2), 177-180.
References
7. Sharfuddin, A. A., Weisbord, S. D., Palevsky, P. M., & Molitoris, B. A. (2012). Acute Kidney Injury. In M. W. Taal, G. M. Chertow, P. A. Marsden, K. Skorecki, A. S. Yu, & B. M. Brenner, Brenner and Rector's the Kidney (pp. 1044-1099). Philadelphia: Elsevier
8. Shilliday, I. R., & Sherif, M. (2007). Calcium channel blockers for preventing acute tubular necrosis in kidney transplant recipients. The Cochrane Database of Systematic Reviews, (4)(4), CD003421. doi:10.1002/14651858.CD003421.pub4
9. Steddon, S., & Ashman, N. (2014). Oxford Handbook of Nephrology and Hypertension. Oxford: Oxford University Press
10. Wargo, K. A., & Edwards, J. D. (2014). Aminoglycoside-induced nephrotoxicity. Journal of Pharmacy Practice, 27(6), 573-577. doi:10.1177/0897190014546836; 10.1177/0897190014546836
11. Wingard, J. R., White, M. H., Anaissie, E., Raffalli, J., Goodman, J., Arrieta, A., et al. (2000). A randomized, double-blind comparative trial evaluating the safety of liposomal amphotericin B versus amphotericin B lipid complex in the empirical treatment of febrile neutropenia. L Amph/ABLC collaborative study group. Clinical Infectious Diseases : An Official Publication of the Infectious Diseases Society of America, 31(5), 1155-1163. doi:10.1086/317451
12. Yarlagadda, S. G., & Perazella, M. A. (2008). Drug-induced crystal nephropathy: An update. Expert Opinion on Drug Safety, 7(2), 147-158. doi:10.1517/14740338.7.2.147; 10.1517/14740338.7.2.147
References