Drug-Induced Kidney Disease

Question 1

Reasons Kidneys are Susceptible to Drug Toxicity

Answer 1

Drug Exposure

• Kidneys get 20-25% cardiac
• Water reabsorption increases solute concentration in tubules

High Energy Requirements of Renal Tubular Cells

• Metabolic enzymes in kidneys
• Transporters in tubule cells

Question 2

Drug-Induced Kidney Disease

Answer 2

• > 1 type of renal injury may be present
• Drugs can cause damage by more than one mechanism
• 4 main histological components

Question 3

4 Histological Components

Answer 3

1. Blood Vessels
2. Glomerulus
3. Tubules
4. Interstitium

Question 4

Types of Drug-Induced Kidney Disease

Answer 4

1. Hemodynamically Mediated Renal Failure
2. Glomerulonephritis
3. Acute Tubular Necrosis
4. Acute Allergic Interstitial Nephritis
5. Chronic Interstitial Nephritis
6. Obstructive Nephropathy
7. Acute Phosphate Nephropathy
8. Pseudo-Renal Failure

Question 5

Pseudo-Renal Failure

Answer 5

• NO renal structures affects
• Patho: increased production or decreased clearance of renal function markers
• Presentation: Increased SCr OR BUN from baseline without actual decreases in GFR/kidney function
• Outcome: SCr and BUN return to baseline when drug is stopped

Question 6

Pseudo-Renal Failure Examples

Answer 6

1. Increased protein catabolism - increases BUN (corticosteroid, tetracycline)
2. Competitively inhibits renal tubule secretion of Cr which increases SCr (trimethoprim, fenofibrate)

Question 7

Hemodynamically Mediated Renal Failure

Answer 7

• Glomerulus blood vessels affected
• Patho: decreased blood flo though glomerulus via AFFerent arteriole constriction OR EFFerent arteriole vasodilation
• Presentation: Increased SCr and decreased GFR within days of drug initiation

Question 8

NSAIDs & SGLT2i

Answer 8

Causes afferent arteriole vasoconstriction

Question 9

ACEIs & ARBs

Answer 9

• Causes efferent arteriole vasodilation

- Discontinue if SCr increases >50% or GFR decreases by >50% from baseline

Question 10

Other Factors that Predispose ACEI Patients to DNI/AKI

Answer 10

1. Na/H2O depletion: dehydration, poor fluid intake, low sodium diet
2. ACEI dramatically decreases systemic blood pressure such that renal perfusion cannot be sustained
3. Concomitant administration with drugs that cause affection afferent arteriole vasoconstriction

Question 11

GN

Answer 11

• Glomerulonephritis
• Damage/inflammation to glomerular filtration surface
• Patho: immune-mediated patho more common than direct toxicity
• Presentation: proteinuria +/- decreased GFR, also dysmorphic RBCs in urine
• EX: NSAIDs, ampicillin
• Outcome: reversible depending on cause/length of insult

Question 12

ATN

Answer 12

• Acute Tubular Necrosis
• Tubular epithelium damaged
• Patho: caused by renally eliminated drugs, dose related partly, drugs/metabolites directly toxic or cause ischemia, cells die and slough off
• Presentation: granular and epithelial casts (muddy and brown) with free epithelial cells in urine; also increased urinary sodium
• Outcome: reversible if identified early; depends on drug/exposure/damage, PROLONGED recovery

Question 13

ATN Examples

Answer 13

1. Aminoglycoside
2. Radiographic contrast dye
3. Amphotericin B

Question 14

Aminoglycoside-Induced Nephropathy - Patho

Answer 14

Patho: accumulates aminoglycoside in renal tubular cells => dysfunction and death

• Dose dependent risk
• Increased risk with prolonged therapy, large total cumulative doses, high trough concentrations
• Presentation: increased SCr and decreased CrCl after 5-10 days of therapy, also cause hypo-osmolar, nonoliguria (>500 mL/day)
• Outcome: usually reversible if caught early
• Preventable: alternative agent, extend drug interval (once a day), monitor drug levels and kidney function

Question 15

Radiographic Contrast Dye Nephropathy

Answer 15

• Patho: direct tubular toxicity and/or renal ischemia
• Risk Factors: diabetes, CKD, decreased blood flow patients (CHF, dehydration)
• Risk increases as risk factors increase
• Presentation: injury evident within 24 hours, SCr peaks in 2-5 days
• Outcome: usually reversible, recovery after 4-10 days, irreversible oliguric kidney injury requiring dialysis reported in high-risk patients

Question 16

Radiographic Contrast Dye Nephropathy Prevention

Answer 16

• Use alternative imaging procedure that requires no contrast contrast agent
• Administer smallest dose possible
• Use low or iso-osmolar contrast dye
• Hydration with IV
• Avoid using with other nephrotoxic agents like aminoglycosides
• Hold metformin before contrast and for 48 hours afterwards

Question 17

AIN

Answer 17

• Acute Allergic Interstitial Nephritis
• Inflammed tubules and interstitium
• Patho: immune-mediated, idiosyncratic, not dose related
• Presentation: onset ~2 weeks or as short as 3-5 days with re-exposure, causes fever or rash commonly, also eosinophilia/eosinophiluria/pyuria (while cell casts)
• Outcome: usually reversible when drug is stopped, costicosteroids may increase rate/extent of renal recovery

Question 18

AIN Examples

Answer 18

• Antibiotics: B-lactams

- PPIs

Question 19

Chronic Interstitial Nephritis

Answer 19

• Tubular atrophy and interstitial fibrosis
• Patho: not immune mediated usually, and potentially dose related
• Presentation: slow, indolent progression to CKD
• EX: lithium, cyclosporine, tacrolimus
• Outcome: depends on underlying cause and severity of damage; usually permanent, leads to overt kidney failue

Question 20

Obstructive Nephropathy

Answer 20

-Any structure after glomerular filter can be affected
Patho: obstruction due to crystallization of drugs in tubules, leads to degradation products
-Clinical presentation: dependent on cause

Question 21

Precipitate of Drug/Metabolite

Answer 21

• Example of obstructive nephropathy
• Presentation: lower back/flank pain, hematuria
• Example: acyclovir, sulfonamides
• Outcome: usually reversible

Question 22

Tissue Degradation Products

Answer 22

• Example of obstructive nephropathy
• Presentation: oliguria/anuria
• EX: acute tubular necrosis or Tumor-lysis syndrome
• Outcome: dependent on underlying cause

Question 23

Acute Tubular Necrosis

Answer 23

• Precipitation of myoglobin released
• Drug induced rhabdomyolysis
• Prevention: hydration, alter pH. Alkalinization with sulfonamides, uric acid nephropathy, and rhabdomyolysis

Question 24

Tumer-Lysis Syndrome

Answer 24

• Chemo causes massive tumor cell destruction
• Leads to intracellular contents being released
• Causes metabolic abnormalities which increases uric acid levels
• Prevention: hydration, allopurinol, rasburicase

Question 25

Acute Phosphate Nephropathy

Answer 25

- Tubules and interstitium affected - Patho: calcium phosphate crystals in tubules/interstitium, related to transient hyperphosphatemia and volume depletion - Presentation: increased SCr in asymptomatic patients for days to months following oral sodium phosphate administration - EX: oral sodium phosphate - Outcome: develop long term CKD

Question 26

Acute Phosphate Nephropathy Prevention

Answer 26

- Avoid in higher risk patients - Higher risk patients: CKD, ACEIs, ARBs, old, drugs, female, comorbidities - Limit the number of oral doses

Question 27

Managing Drug-Induced Nephrotoxicity

Answer 27

1. Know which drugs are nephrotoxins 2. Identify at risk patients 3. Precautions to prevent: know baseline function, adjust doses, avoid exposure to multiple nephrotoxins, correct risk factors first OR use strategies to prevent DIN (like hydration) 4. Monitor for lab and clinical signs of renal dysfunction (increase SCr/BUN, changes in urine, pain in back/flank) 5. Resolve DIN if it occurs: stop nephrotoxic drugs, AKI will take time to heal