1. Drug-Induced Acute Kidney Injury
Medications, Mechanisms of Injury, and Management

2. Learning Objectives
Review common medications implicated in acute kidney injury (AKI) and their mechanisms of nephrotoxicity
Differentiate between clinical presentations and risk factors of drug-induced AKI
Outline strategies used to prevent and manage drug-induced AKI

3. Epidemiology
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 failure

4. Drug-Induced AKI: Classification
Hemodynamically-Mediated Kidney Injury
ACE Inhibitors
NSAIDs
Calcineurin Inhibitors
Tubuloepithelial Injury & Tubulointerstitial Nephritis
Acute Tubular Necrosis (ATN)
Acute Interstitial Nephritis (AIN)
Crystal Nephropathy
Direct Intratubular Obstruction & Nephrolithiasis
Indirect Intratubular Obstruction

5. Hemodynamically-Mediated Kidney Injury
Prerenal Injury

6. Hemodynamically Mediated Kidney Injury
“Prerenal” injury related to reduced renal blood flow (i.e. hypovolemia, CHF, bleeding, sepsis, ascites)
Injury results from decreased tissue perfusion and decrease in GFR
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)

7. 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

8. NSAIDs
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 pressure
Fractional excretion Na < 1%
Risk Factors: age > 60 years, CKD, heart failure, concurrent nephrotoxic medications, and hepatic disease with ascites

9. NSAIDs Prevention: Use alternative analgesics
Use low-dose/short duration treatment
Avoid potent NSAIDs (i.e. indomethacin)
Avoid ACEIs/ARBs and diuretics in high-risk or dehydrated patients
Appropriate monitoring (Scr, BUN, etc.)
Management:
Discontinue NSAID
Recovery is rapid and baseline function is usually restored

10. Angiotensin Converting Enzyme Inhibitors & Angiotensin Receptor Blockers
Mechanism: ↓ angiotensin II production/action → efferent arteriole vasodilation → ↓ glomerular pressure → ↓ GFR
Clinical Presentation:
Moderate vs. detrimental rise in serum creatinine
Moderate: ↑ 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 initiation
Risk Factors: renal artery stenosis, volume depletion, heart failure, CKD including diabetic nephropathy

11. Angiotensin Converting Enzyme Inhibitors & Angiotensin Receptor Blockers
Prevention:
Recognize patients at highest risk
Initiate at very low doses
Titrate every 2-4 weeks as opposed to every 3-5 days
Avoid NSAIDs and diuretics in high-risk or dehydrated patients
Appropriate 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

12. Calcineurin Inhibitors
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:
↓ urine output
↑ Scr, blood pressure, K+
Sodium retention

13. Calcineurin Inhibitors
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/tacrolimus
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

14. Tubuloepithelial Injury & Tubulointerstitial Nephritis
Intrarenal Injury

15. Acute Tubular Necrosis (ATN)
“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 obstruction
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)

16. 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

17. Aminoglycosides 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 cationic
Neomycin > tobramycin, gentamicin, amikacin > streptomycin

18. Aminoglycosides
Mechanism: uptaken by proximal tubule → ↑ reactive oxygen species → mitochondrial injury → cellular necrosis
Clinical 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)

19. Aminoglycosides Prevention: Alternate antibiotics if possible
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
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

20. Amphotericin B
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

21. Amphotericin B Clinical Presentation: ↑ Scr, BUN, urine electrolytes
Typically non-oliguric (urine > 500mL/d)
Impaired urinary concentrating ability
Risk Factors: large cumulative doses, pre-existing kidney disease, volume depletion, ↑ age, concurrent use of diuretics or nephrotoxic drugs (i.e. cyclosporine)

22. 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 dose
Consider longer infusion times
Appropriate monitoring (Scr, serum electrolytes)
Management:
Discontinuation of amphotericin B and substitution with alternative antifungal therapy if possible
Kidney injury may be reversible or irreversible after discontinuation

23. Radiographic Contrast Media
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 disease

24. Radiographic Contrast Media
Clinical Presentation:
↑ Scr, BUN
Non-oliguric or irreversible oliguria (urine < 500mL/d) in high-risk patients
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, concurrent nephrotoxic drugs

25. 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
Volume expansion – normal saline prior to and continued for several hours after contrast exposure
Oral N-acetylcysteine given prior to and following exposure
Management:
Supportive (monitoring, renal replacement therapy if irreversible damage occurs)

26. Acute/Allergic Interstitial Nephritis (AIN)
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 eosinophilia
More common in antibiotic-associated AIN than NSAID-associated
AIN is a hypersensitivity reaction and is expected to recur with re- challenge

27. β-lactams (including cephalosporins) & NSAIDs
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
Fever (27-80%), maculopapular rash (15-25%), eosinophilia (23- 80%) arthralgia (45%), oliguria (50%)
NSAIDs – 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

28. β-lactams (including cephalosporins) & NSAIDs
Prevention:
No specific preventative measures
Appropriate monitoring so that prompt discontinuation can improve the chances of complete renal recovery
Management:
Discontinue offending drug
High-dose oral prednisone
Monitor renal function (Scr, BUN, etc.) for signs of improvement
Document the reaction to avoid re-exposure
Kidney injury may be reversible or irreversible

29. Other drugs Associated with ATN and AIN
Acute Tubular Necrosis
Acute Interstitial Nephritis
Chemotherapy
Cisplatin, carboplatin, cytarabine, 5-fluoruracil, ifosfamide,
Tenofovir, cidofovir, adefovir
Zoledronate
Vancomycin
IVIG
Ciprofloxacin
Omeprazole, lansoprazole
Cimetidine, ranitidine
Loop diuretics
Allopurinol
Sulfonamides
Rifampin
5-aminosalicylates

30. Crystal Nephropathy
Postrenal Injury

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

32. Crystal Nephropathy
Indinavir, a protease inhibitor, can lead to crystalluria
Dysuria, urinary frequency, back and flank pain, or nephrolithiasis in approximately 8% of treated patients

33. Direct Intratubular Obstruction & Nephrolithiasis
Medications:
Acyclovir
Indinavir
Tenofovir
Atazanavir
Methotrexate (IV)
Sulfadiazine
Triamterene
Ciprofloxacin
Mechanism: Insolubility of drug in either alkaline or acidic urine + low urine volume → precipitation of drug → crystalluria → obstruction of tubule
Poor alkaline solubility: Indinavir
Poor acidic solubility: Acyclovir, triamterene, sulfadiazine, methotrexate

34. Direct Intratubular Obstruction & Nephrolithiasis
Clinical Presentation:
May have asymptomatic crystalluria
↓ urine output
↑ Scr, hematuria, pyuria, pain and crystalluria

35. Direct Intratubular Obstruction & Nephrolithiasis
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 solubility
Potassium citrate or sodium bicarbonate
Management:
Discontinue drug (kidney injury is usually reversible)
Volume resuscitation

36. Indirect Tubular Obstruction
Tumor Lysis Syndrome
Rhabdomyolysis
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 alkalinisation
Antineoplastic agents increase circulating by- products of tumor breakdown
Acute oliguric or anuric kidney injury is a result of uric acid crystal obstruction
Treatment includes hydration, allopurinol and urinary alkalinisation