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