Drug Induced Nephrotoxicity

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Drug Induced Nephrotoxicity
2011-02-13 00:04:46
Drug Induced Nephrotoxicity

Drug Induced Nephrotoxicity
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  1. what is the definition of acute renal failure?
    • Serum creatinine increase of 0.5mg/dL from baseline
    • or
    • a value >1.5mg/dL
  2. What is MOST IMPORTANT in prevention and management of ARF?
  3. Which two drugs cause BUN rise but not SCr rise? What is the mechanism?
    • corticosteroid use
    • tetracycline therapy
    • can cause protein catabolism and increase ureagenesis and BUN as a result of tissue breakdown.
    • GFR is unchanged.
  4. What kind of renal failure can tetracycline cause? why? What would be the lab change?
    • pseudo renal failure
    • can cause protein catabolism and increase ureagenesis and BUN as a result of tissue breakdown.
    • BUN increase but SCr remain the same
  5. What kind of renal failure can corticosteroid therapy cause? What would be the lab change?
    • pseudo renal failure can cause protein catabolism and increase ureagenesis and BUN as a result of tissue breakdown.
    • BUN increase but SCr remains the same
  6. Which two drugs cause SCr rise but not BUN? What is the mechanism?
    • trimethoprim
    • cimetidine
    • competitively inhibit secretion of creatinine into proximal tubular lumen, therefore increase SCr
  7. What kind of renal failure can cimetidine cause? What would be the lab change?
    • pseudo renal failure
    • competitively inhibit secretion of creatinine into proximal tubular lumen, therefore increase SCr
    • SCr increase but BUN remains the same
  8. What kind of renal failure can tetracycline cause? What would be the lab change?
    • pseudo renal failure
    • competitively inhibit secretion of creatinine into proximal tubular lumen, therefore increase SCr
    • SCr increase but BUN remains the same
  9. What is pre-renal failure?
    • diminshed renal blood flow as a result of intravascular depletion, decreased effective circulating volume to the kidneys, agents that impair renal blood flow
    • before the kidneys
  10. What is intrinsic (renal) failure?
    • damage to the renal parenchyma
    • tubular disease, glomerular disease, vascular disease and interstitial disease
  11. what is obstructive (post renal) failure?
    • urinary tract obstruction
    • prostatic hypertrophy
    • prostate cancer
    • cervical cancer
    • retroperitoneal disorders
  12. What are implicated drugs for pre-renal failure?
    • diuretics
    • NSAIDs
    • ACE-i
    • radiocontrast media
    • cyclosporine
    • tacrolimus
  13. What are the lab findings for pre-renal failure?
    • low urine volume
    • low sodium excretion
    • low/high osmolality and specific gravity (not realy good subjective findings)
  14. What is a treatment option for pre-renal failure?
    d/c the offending agent
  15. What are examples of intrinsic renal failure?
    • acute tubular necrosis
    • acute and chronic interstitial nephritis
    • thrombotic microangiopathy
  16. What kind of renal failure is acute tubular necrosis?
    what are implicated drugs?
    what are the findings?
    • intrinsic renal failure
    • aminoglycosides, amphotericin B, cisplatin, radiocontrast media, cocaine, IV immunoglobulin
    • finding: oliguria, abnormal urinary casts
  17. what is the clinical presentation of aminoglycoside nephrotoxicity?
    • gradual increase of SCr (and decrease of CrCl) after 6-10 days of therapy
    • non-oliguric: maintain urine volume >500 ml/d (patient is still urinating, no decrease volume of urine)
    • potential renal Mg and K wasting (high Mg and K in urinalysis)
  18. What is the pathogenesis of AG nephrotox?
    • cellular dysfunction and death due to release of lysosomal enzymes, reactive oxygen species, altered cellular metabolism, altered cell fluidity
    • Proximal tubular epithelial cell damage leads to obstruction of the tubular lumen & backleak of the glomerular filtrate across the damaged tubular epithelium
    • Catatonic charge: facilitates binding of filtered aminoglycoside to renal tubular epithelial cell membranes
  19. What are the risk factors of AG nephrotox?
    • dosing: large dose, prolong therapy, trough >2mg/L, recent past therapy with AG
    • synergistic toxicity: cyclosporine, amphotericin B, vancomycin, diuretic
    • predisposing conditions: preexisting renal insufficiency, increased age, poor nutrition, shock, gram negative bacteria, liver disease, hypoalbuminemia, obstructive jaundice, dehydration and K or Mg deficiencies
  20. How do you prevent AG nephrotox?
    • avoid use if possible
    • QD dosing when possible
    • avoid volume depletion
    • limit total AG used
    • avoid concomitant thearpy with other nephrotox drugs (i.e. vanco)
    • administer agent that decreases binding to phospholipids in kidney: polyaspartic acid, daptomycin, antioxidant
  21. what are agents that may help dcrease binding to phospholipids in kidney?
    • polyaspartic acid
    • daptomycin
    • antioxidants
  22. How do you manage AG nephrotox?
    • d/c or revise dosing in Scr incrase of more than 0.5mg/dL
    • if possible, d/c other nephrotoxic drugs
    • adequate hydration and stabilize hemodynamics (electrolytes)
  23. Is renal failure due solely to AG reversible?
    Yes, usually!
  24. Radiographic contrast media
    what is the clinical presentation?
    range of toxicity?
    lab changes? when does this resolve?
    • toxicity ranges from transient to irreversible
    • Scr: Scr rises and peaks between 2-5 days (or as early as 24-72 hrs) after exposure. this resolves 4-10 days
    • oliguria: urine volume <500ml/d presents in 50% of cases
  25. radiographic contrast media mostly causes nephrotox in which patient population?
    most common in diabetic pts with pre-existent renal insufficiency
  26. what is pathogenesis of radiographic contrast media for nephrotox?
    • direct tubular toxicity (intrinsic way of nephrotox)
    • renal ischemia (compromised hemodynamics)
    • ----systemic hypotension assoc with contrast inj (overall, renal perfusion is DECREASED)
    • ----vasoconstriction
    • ----dehydration
    • ---- increased blood viscosity
  27. what are the risk factors of radiographic contrast media for nephrotox?
    • pre-existent renal insufficiency (i.e. diabetic nephropathy)
    • conditions associated with decreased blood flow: CHF, dehydration, miltiple myeloma
    • large doses: >300ml of 300mg/L
    • older agents: high osmolality is worse
  28. How do you prevent radiographic contrast media nephrotox? (also any meds to hold and how/when do you hold?)
    • assess for risk factors
    • use smallest adequate dose
    • correct dehydration
    • hydrate patient (before and after!): 0.45% NS at 100ml/hr, 4 hours prior and 8-12 hours after
    • hold/dc other nephrotox drugs (24-72 hrs before): ACEI, ARB, NSAID, diuretic
    • hold metformin 48h prior to CM: only reinitiate when renal fxn is normal
    • possible protective agent: dopamine, theophylline, fenoldopam, prostaglandin E, CCB (dihydro)
  29. how do you manage radiographic contrast media nephrotox?
    • no specific therapy
    • care is supportive (hydrate)
    • dialysis as needed
    • avoid infection and bleeding
  30. What is the clinical presentation of cisplatin and carboplatin?
    when does it manifest, lab changes etc?
    • manifest early
    • peak Scr occur at 10-12 days after initiation with recovery by 21 days
    • hypomagnesemia (may be severe)
    • hypocalcemia and hypokalemia
  31. When there is Mg, Ca and K imbalance how do you treat?
    treat Mg first and Ca and K usually follow
  32. What is the pathogenesis of cisplatin and carboplatin nephrotox?
    proximal tubular damage and necrosis
  33. Risk factors for cisplatin and carboplatin nephrotox?
    • high dose: 200mg/m2
    • older age
    • dehydration
    • renal irradiation
    • concurrent use with AG
    • alcohol abuse
  34. Which is more nephrotox? cisplatin vs carboplatin, and why?
    • cisplatin is more toxic
    • carboplatin is more soluble and chemically stable
  35. How do you prevent cisplatin and carboplatin nephrotox?
    reduce dose and frequency of use

    • aggressive saline hydration is important and should be administered to ALL patients
    • * 1-4L/24h for cisplatin
    • * hypertonic saline used to inc Cl level and dec conversion of cisplatin to reactive platinum species
    • * up to 3L/24h for carboplatin
    • * furosemide diuresis for volume homeostasis
    • * mannitol used to enhance drug dilution

    • Amifostine (renal-protective)
    • - prodrug and metabolized to sulfhydrol donor
    • - administer 15 min prior to cisplat use
  36. Is cisplatin and carboplatin nephrotox reversible?
    • yes, partially reversible with time and supportive care
    • however, progressive chronic RF by cumulative toxicity may not be reversible. some may need chronic dialysis support
  37. how do you manage cisplatin and carboplatin nephrotox?
    • aggressive hydration
    • dialysis
    • correct Mg concentration
    • (hypocalcemia and hypokalemia may be hard to reverse if hypomagnesemia is not corrected)
  38. what is clinical presention of amphotericin B nephrotox?
    • decrease in K, Na, Mg
    • impaired urine concentrating ability
    • distal renal tubular acidosis (increase aciditiy in kidney)
    • increase SrCr and BUN
  39. what is pathogenesis of amphotericin B nephrotox?
    • direct tubular epithelial cell toxicity with increased tubular permeability and necrosis
    • arterial vasoconstriction (kind of like pre-renal)
  40. what are risk factors for amphotericin B nephrotox?
    • baseline renal insufficiency
    • increase daily dose (>35mg, >7days)
    • diuretic use
    • volume depletion
    • concomitant administration of other nephrotoxin
    • rapid infusion
  41. how do you prevent amphotericin B nephrotox?
    • limit cumulative dose
    • adminsiter liposomal formulation (lipid based allow for increase dose for longer time with less toxicities)
    • avoid concomitant nephrotoxin
    • hydrate with high sodium diet and 1L IV 0.9% NaCl daily
    • pretreat with CCB may be useful (not clinically validated)
  42. how do you manage amphotericin B nephrotox?

    adminsiter liposomal formulation (lipid based allow for increase dose for longer time with less toxicities)
    • d/c therapy (and substitute with anther antifungal)
    • focus on prevention
  43. is amphotericin B nephrotox irreversible?
    some may improve gradually but some may be irreversible
  44. when is foscarnet used?
    for CMV
  45. what is the prevalence of nephrotox for foscarnet?
  46. what is the mechanism of foscarnet nephrotox?
    how do you treat?
    • complex of Ca+ and foscarnet forms and the crystals precipitate in renal glomeruli to cause crystalline glomerulonephritis.
    • this develops large pores and necrosis
    • may also precipitate in tubules and lead to tubular necrosis
    • administer appropriate dose after vigorously pre-hydrating the patient (IV)
  47. which agents cause osmotic nephrosis?
    • mannitol
    • dextran
    • IV immunoglobulin
  48. Why does renal function decrease in osmotic nephrosis?
    how do you prevent?
    • due to hypertonic and osmotically active nature of the agents (mannitol, dextran, IV Ig)
    • prevent: dilute solution, decrease infusion rate
    • hydroxyethylstarch (HES): plasma volume expander,
  49. what are risk factors for ACEi and ARB nephrotox?
    • severe artherosclerotic renal artery stenosis with SCr >1.6 mg/dL
    • patients with decreased renal blood flow (CHF, volume depleted from excess diuresis or GI fluid loss, hepatic cirrhosis, nephrotic syndrome)
    • primary renal disease (diabetic nephropathy, Scr >30mg/dL)
  50. what is a clinical presentation of ACEi and ARB nephrotox?
    increase in SCr
  51. what is pathogenesis of ACEi and ARB nephrotox?
    • dilates efferent arteriole and reduces glomerular capillary hydrostatic pressure
    • ultimately decreases glomerular ultrafiltration and GFR
  52. how do you prevent ACEi and ARB nephrotox?
    • inpatient: administer low doses of short acting ACEi (i.e. captopril TID) then gradually up-titrate the dose to convert to longer acting agent
    • outpatient: start on low dose of long acting ACEi with gradual dose titration
    • monitor SCr and K (hyperkalemia)
    • ensure hydration (avoid dehydration, hold/dec diuretic prior, counsel on drinking water, not juice etc.)
  53. how do you manage ACEi and ARB nephrotox?
    • if increase in SCr is <20%: continue
    • if increase in SCr is >30%: dec dose by 50% (hold dose in outpatient)
    • if patient is on lowest possiblel dose and SCr is increasing for >4wk then d/c
    • treat any K+ abnormality
    • correct volume depletion if necessary
    • hydralazine and nitrate combo to reduce afterload in CHF
  54. is damage due to ACEi and ARB nephrotox reversible?
    yes, given that flow was not impaired for too long.
  55. what is the clinical presentation of NSAIDs nephrotox? how fast does it occur? what is the prevalence?
    • renal failure within days of initiation (esp with short acting NSAIDs)
    • prevalence up to 40%
    • low urine volume
    • low sodium concentration in urine
    • granular casts may be present in urine
    • urine sediment is usually unchanged from baseline
  56. what is the first line for osteoarthritis?
    • Tylenol
    • NOT NSAIDs because no inflammation
  57. what is the first line for rheumatoic arthritis?
    • NSAID
    • because all inflammation
  58. do you d/c NSAID if you have kidney stones?
    • Nope but you must monitor
    • you can give Vicodin
  59. what is pathogenesis of NSAIDs nephrotox?
    impair renal function by decreasing synthesis of vasodilatory prostaglandins from arachidonic acid so causes vasoconstriction
  60. what are risk factors of NSAIDs nephrotox?
    • pre-existing renal insufficiency
    • medical problems associated with high plasma renin activity
    • systemic lupus erythematosus
    • artherosclerotic CV disease
    • diuretic therapy
    • elderly (due to concomitant use of drugs)
    • increased doses and prolonged therapy
  61. how do you prevent NSAIDs nephrotox?
    • low dose and short term therapy (3-5 days)
    • recognize high risk patients
    • use analgesics with less prostaglandin inhibition (APAP, ASA, nabumetone)
    • MONITOR (K, Na, BUN, SCr): baseline and q 3-6mo
    • Sulindac may be assoc with less renal tox
  62. how do you manage NSAIDs nephrotox?
    • d/c therapy
    • supportive therapy (volume repletion, treat K abnormality)
  63. what do you ask patients using NSAID to prevent renal tox?
    • do you see physician often?
    • what other medicines do you use?
    • use Tylenol if it is possible
  64. what is the presentation of cyclosporine and tacrolimus nephrotox? when does it occur?
    • usually occurs within 6-12 mo of therapy
    • increase in SCr and BUN
    • HTN, hyperkalemia, sodium avidity, hypomagnesemia may occur
  65. what is the pathogenesis of cyclosporine and tacrolimus nephrotox?
    • vasoconstriction and injury to glomerular afferent arterioles
    • direct tubular toxicity
  66. what are risk factors for cyclosporine and tacrolimus nephrotox?
    • increased length of exposure
    • older age
    • high initial doses
    • renal graft rejection
    • hypotension
    • infection
    • concomitant nephrotox drugs
  67. how do you prevent cyclosporine and tacrolimus nephrotox?
    • this is really difficult
    • MONITORING: mostly renal function, not necessarily drug level (this is important because patient is usually on these drugs for a long time)
    • CCB may antagonize vasoconstrictor effect of cyclosporine
    • decreased doses
  68. how do you manage cyclosporine and tacrolimus nephrotox?
    • dose reduction or d/c
    • treat contributing illness
    • d/c interacting drugs
    • change of therapy if possible
  69. what is the main mechanism of acute interstitial nephritis based on? what kind of renal toxicity is this?
    • mainly allergic mechanism
    • intrinsic renal
  70. what are the implicated drugs for acute interstitial nephritis?
    • antibiotics: PCN, cephalo, sulfonamides, amphotericin B
    • cocaine
    • NSAIDs
    • diuretics
    • lithium
    • ranitidine
    • omeprazole
    • captopril
    • phenytoin, valproic acid
    • streptokinase
    • 5-ASA
    • allopurinol
    • rifampin
  71. what are the findings in acute interstitial nephritis?
    • fever, rash, arthralgia, abnormal urinary cast, WBC and RBC in urine, proteinuria, eosinophilia, eosinophiluria
    • (damage in kidneys so all these "uria")
  72. how do you treat acute interstitial nephritis?
    • d/c offending agent
    • if renal failure persists, steroid therapy may be beneficial
    • irreversible damage occurs if offending agent is used for >1mo, persistent ARF, delayed response to steroids and increased interstitial granulomas
  73. when does penicillin induced acute interstitial nephritis occur? what are symptoms?
    • 17 days after initiation
    • fever, maculopapular rash, eosinophilia, pyruia, hematuria, low level proteinuria, oliguria
  74. when does NSAIDs induced acute interstitial nephritis occur? what is the clinical presentation?
    • delayed onset (5.4 mo)
    • usually in older patients
    • common s&s of allergic reaction is uncommon
    • proteinuria >3.5 g/d (higher than PCN-induced)
  75. how do you prevent acute interstitial nephritis?
    • idiosyncratic in nature
    • no specific preventative means known
    • recognize s&s early
  76. how do you manage acute interstitial nephritis?
    • no prospective treatments known
    • prednisone 0.5-1mg/kg for 1-4 wk: this is allergic mediated so prednisone may work here unlike other renal toxicity
  77. what is lithium-induced chronic interstitial nephritis? when does it usually occur? what is the clinical presentation?
    • impaired ability to concentrate urine
    • occurs 10 years after treatment
    • polydipsia, polyuria
    • ATN is common
    • patient is usually asymptomatic (if the patient is on lithium, assess hydration during every visit as possible)
    • rise in BUN or SCr
    • hypertension
    • urinalysis (moderate proteinuria, few RBC and WBC, granular cast)
  78. what is the pathogenesis of chronic interstitial nephritis induced by lithium?
    • impaired ability to concentrate urine is the result of dose related decrease in collecting duct response to anti diuretic hormone
    • common during lithium toxicity
  79. Is chronic interstitial nephritis induced by lithium reversible?
    • irreversible in most cases bbecause takes 10 years to manifest
    • damage has already been done
  80. what are the risk factors for chronic interstitial nephritis induced by lithium?
    • elevated lithium concentration
    • dehydration
    • concomitant neuroleptics, ACEi
  81. how do you prevent chronic interstitial nephritis induced by lithium?
    • maintain therapeutic Li concentration
    • avoid dehydration
  82. how do you manage chronic interstitial nephritis induced by lithium?
    • treat symptoms
    • d/c lithium if possible (check with the psych)
    • hydrate
  83. renal tubular obstruction is what kind of renal toxicity?
    post renal
  84. what are the implicated drugs in post renal obstruction?
    acyclovir, sulfonamide, methotrexate, indinavir, triamterene, high dose vitamin C, methysergide
  85. what are the findings in post renal obstruction?
    urinary RBC, WBC and crystals
  86. how do you treat post renal obstruction?
    • d/c offending agent
    • volume replacement (IV fluids)
    • alkalinization of urine (increase elimination by IV sodium bicarbonate)
  87. what kind of renal toxicity is acute uric acid nephropathy?
    when does it occur?
    why does renal failure occur here?
    what is an important lab finding?
    how do you prevent?
    • post renal
    • after chemotherapy
    • RF occurs due to obstruction by tissue degradation products
    • urine uric acid to creatinine ratio is >1
    • pretreat with hydration, urine alkalinization (with sodium bicarbonate IV) and allopurinol may prevent uric acid precipitation
  88. what kind of renal toxicity is drug induced rhabdomyolysis?
    what does this lead to?
    can this lead to renal failure?
    what are the risk factors?
    • post-renal
    • leads to intratubular precipitation of myoglobin
    • if severe, this can cause acute RF.

    • statins (alone or in combo) with gemfibrozil, niacin, other CYP3A4 inhibitor
    • pressure necrosis (coma) so make sure to rotate patient
    • abuse of CNS stimulant
  89. how does extrarenal urinary tract obstruction occur?
    • calculi or retroperitoneal fibrosis can cause ureteral obstruction
    • bladder dysfunction with urinary outflow obstruction may result (BPH)
    • anticholinergics drugs may cause as well
  90. what is nephrolothiasis?
    how is GFR affected?
    what are the clinical presentation?
    what are the causative agents?
    • formation of kidney stones. abnormal crystal precipitation in renal collection system
    • GFR usually does not decrease
    • flank pain, hematuria, infection, urinary tract obstruction with renal insufficiency
    • triamterene, sulfadiazine, indinavir, allopurinol, magnesium trisilicate aluminum hydroxide, laxative abuse (all these meds require counseling "drink plenty of water")
  91. what are the implicated drugs for CRF?
    which ones are reversible and which irreversible?
    what are the findings of CRF?
    how do you treat?
    • reversible: 5-ASA, ifosfamide
    • irreversible: lithium, cyclosporine
    • also chronic analgesic abuse, cisplatin
    • slow and progressive elevation of SCr, electrolyte disturbance, proteinuria
    • d/c offending agent
  92. what are the implicated drugs for nephrotic syndrome?
    what are the findings?
    how do you treat?
    is this reversible?
    • NSAIDs, captopril, gold, penicillamine, interferon
    • edema, proteinuria, hypoalbuminuria
    • d/c offending agent
    • irreversible injury is common
  93. What are the most common nephrotoxic agents?
    I C 3A Clair

    • indinavir
    • cyclosporin
    • amphotericin B
    • aminoglycoside
    • acyclovir
    • cisplatin
    • lithium
    • ACEi
    • interleukin 2
    • IV radiocontrast media