Nephrotoxic Drug

Aka: Nephrotoxic Drug, Nephrotoxin, Drug-induced Nephrotoxicity, Medication Causes of Acute Kidney Injury, Medication Causes of Acute Tubular Necrosis, Medication Causes of Interstitial Nephritis, Medication Causes of Glomerulonephritis, Medication Causes of Prerenal Failure, Medication Causes of Postrenal Failure, Toxic Nephropathy, Drug-Induced Renal Disease, Renal Toxin

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II. Risk Factors: Nephrotoxicity

  1. See Nephrotoxicity Risk
  2. Concurrent medications that interfere with GFR autoregulation or renal blood supply
    1. Angiotensin-converting enzyme inhibitors (ACE Inhibitors)
    2. Angiotensin Receptor Blockers (ARBs)
    3. Cycosporine
    4. Non-Steroidal Antiinflammatory drugs (NSAIDs)
    5. Tacrolimus

III. Evaluation: Criteria to consider stopping agent due to nephrotoxicity

  1. Relative Serum Creatinine increase 50% over baseline
  2. Absolute Serum Creatinine increase
    1. Serum Creatinine baseline <2 mg/dl: Creatinine increase 0.5 mg/dl over baseline
    2. Serum Creatinine baseline >2 mg/dl: Creatinine increase 1.0 mg/dl over baseline

IV. Causes: Medication mediated injury by renal site

  1. Prerenal Failure Causes (primarily intra-renal Vasoconstriction)
    1. See Acute Prerenal Failure
    2. Duretics (volume depletion)
    3. Tacrolimus
    4. Cyclosporine
    5. NSAIDs inhibit cyclooxygenase
      1. Depletes renal vasodilatory Eicosanoids
      2. Exacerbates Vasoconstriction afferent arterioles
        1. Volume depletion
        2. Elderly
        3. Edema
    6. ACE Inhibitors (and Angiotensin Receptor Blockers) lower renal perfusion
      1. Result in dilated efferent arterioles
      2. Decrease Glomerular Filtration Rate
  2. Intrinsic Renal Failure - Interstitial causes (onset 2 weeks after medication started; analogous to renal Allergic Reaction )
    1. See Acute Interstitial Nephritis
    2. Penicillins and Cephalosporins
      1. Hypersensitivity (fever, rash, Arthralgia)
    3. Sulfonamides
      1. Vasculitis reaction
    4. NSAIDs
      1. Nephrotic Syndrome type reaction
    5. Acyclovir (Zovirax)
    6. Rifampin
    7. Diuretics (Thiazides and Lasix)
    8. Allopurinol
    9. Cimetidine
    10. Ciprofloxacin
    11. Phenytoin (Dilantin)
    12. Interferon
    13. Proton Pump Inhibitors (e.g. Omeprazole)
      1. Increasing Incidence, especially in older patients
    14. Other medications have caused AIN to a lesser extent
  3. Intrinsic Renal Failure - Tubular Injury causes (Acute Tubular Necrosis causes)
    1. Aminoglycosides (e.g. Tobramycin, Gentamycin)
    2. Amphotericin B
    3. Cidofovir
    4. Cisplatin
    5. Ethylene Glycol
    6. Foscarnet
    7. Hetastarch (Hydroxyethyl Starch)
    8. Intravenous Contrast Related Acute Renal Failure
    9. Intravenous Immunoglobulin (esp. with sucrose)
    10. Mannitol
    11. Methotrexate
    12. Pentamidine
    13. Synthetic Cannabinoids (e.g. K2)
    14. Tenofovir
    15. Vancomycin
  4. Intrinsic Renal Failure - Glomerular injury
    1. See Glomerulonephritis Causes (especially RPGN)
    2. Penicillamine
    3. Hydralazine
    4. Allopurinol
    5. Rifampin
  5. Postrenal causes (intrarenal obstruction at distal tubules)
    1. Uric Acid crystals (Hyperuricemia, Gout)
      1. Methotrexate
      2. Acyclovir
      3. Protease Inhibitors (e.g. Indinavir or Crixivan)

V. Causes: Antibiotics

  1. Aminoglycosides (10-15% Incidence of Acute Tubular Necrosis)
    1. Occurs in 10-20% patients on 7 day course
    2. Results in non-oliguric increased Creatinine
    3. A single dose early in septic course is usually safe
  2. Sulfonamides
  3. Amphotericin B
    1. Incidence 80-90%, esp. with deoxycholic acid formulation
    2. Causes Acute Tubular Necrosis
  4. Foscarnet
  5. Quinolones (e.g. Ciprofloxacin, Levofloxacin)
  6. Rifampin
  7. Tetracycline
  8. Acyclovir (only nephrotoxic in intravenous form)
    1. Causes Acute Interstitial Nephritis and crystal nephropathy
  9. Pentamidine
  10. Vancomycin
  11. Piperacillin/Tazobactam (Zosyn) with Vancomycin
    1. Associated with greater Incidence of Acute Kidney Injury
    2. (2017) Clin Infect Dis 64(5): 666-74 [PubMed]

VI. Causes: Chemotherapy and Immunosuppressants

  1. Cisplatin
  2. Methotrexate
  3. Mitomycin
  4. Cyclosporine
  5. Ifosphamide (Causes Fanconi's Syndrome)
  6. Zoledronic Acid (Zometa)

VII. Causes: Heavy Metals

  1. Mercury Poisoning
  2. Lead Poisoning
  3. Arsenic Poisoning
  4. Bismuth
  5. Lithium related Kidney disorders
    1. Polydipsia and Nephrogenic Diabetes Insipidus
    2. Acute Renal Failure
      1. Dialysis indications: Creatinine >2.5 or Seizures, ALOC, Rhabdomyolysis
    3. Chronic Kidney Disease with fibrosis

VIII. Causes: AntiHyperlipidemics

  1. Statin Drugs (Rhabdomyolysis)
  2. Gemfibrozil
    1. Associated with Acute Renal Failure due to Rhabdomyolysis

IX. Causes: Miscellaneous Drugs

  1. Chronic Stimulant Laxative use
    1. Resulting chronic volume depletion and Hypokalemia causes nephropathy
    2. For Bowel Preparation, use Polyethylene Glycol (PEG) instead of phosphate or Magnesium prep
  2. Radiographic contrast
    1. See Intravenous Contrast Related Acute Renal Failure
  3. ACE Inhibitors
    1. Expect an increase of Serum Creatinine in Chronic Kidney Disease
    2. See ACE Inhibitors for guidelines on Serum Creatinine rise that warrants stopping medication
  4. NSAIDs
    1. See Nephrotoxicity due to NSAIDs
  5. Aspirin
    1. Low dose Aspirin reduces Renal Function in elderly
      1. Decreased Creatinine Clearance after 2 weeks of use
      2. Changes persisted for at least 3 weeks off Aspirin
      3. Segal (2003) Am J Med 115:462-6 [PubMed]
  6. Mesalamine (Asacol, Pentasa)
    1. Mesalamine is an NSAID analog and has systemic absorption from the bowel
    2. See Nephrotoxicity due to NSAIDs
  7. Chinese Herbals containing aristocholic acid

X. Causes: Drugs of Abuse

  1. Cocaine
  2. Heroin
  3. Methamphetamine
  4. Methadone

XI. Causes: Reversible Serum Creatinine increase without significant effect on GFR

  1. Cimetidine
  2. Fenofibrate (Tricor)
  3. Trimethoprim

XII. References

  1. Endbruegger (2019) Etiology and Diagnosis of Prerenal Disease, UpToDate, accessed 12/3/2019
  2. Mercado (2019) Am Fam Physician 100(11): 687-94 [PubMed]
  3. Naughton (2008) Am Fam Physician 78(6): 743-50 [PubMed]
  4. Thatte (1996) Postgrad Med 100(6):83-100 [PubMed]

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