NEPH 07: Drug Induced Kidney Injuries

Learning Objective 1: Explains the pathogenesis and risk factors associated with the different types of drug-induced kidney injuries (KI)

Pathogenesis of Drug-Induced Kidney Injury (KI):

  • Kidney dysfunction occurs when there’s direct or indirect exposure to toxic substances, such as medications (prescribed, over-the-counter, or street drugs), natural health products, or agents used for diagnosis (e.g., contrast agents).

  • A rise in serum creatinine (sCr) by 44 μmol/L or doubling of sCr over 24 to 72 hours can indicate kidney injury after exposure to a nephrotoxic agent. This typically requires at least 24-48 hours of drug exposure.

Risk Factors:

  1. Kidney-Related Factors:

    • Kidneys have a high blood flow (20% of the heart’s stroke volume), which means drugs/toxins are delivered quickly to the kidneys, increasing the potential for injury.

    • CYP 450 enzymes and flavin-containing monooxygenase metabolize drugs into toxic metabolites, leading to oxidative stress, which can damage kidney cells. This happens because kidney cells are very active metabolically and can get damaged easily, especially in hypoxic conditions (low oxygen).

  2. Patient-Related Factors:

    • Women and older adults: Their bodies may have less lean mass and less water content, which can affect how drugs are processed, leading to higher drug doses in the bloodstream.

    • Pharmacogenetics: Some people’s bodies break down drugs in different ways (due to genes affecting enzymes, transporters, or immune response). This can increase the risk of kidney injury.

    • Comorbidities: Conditions like volume depletion (low body fluid levels) can reduce blood flow to the kidneys and worsen kidney damage.

  3. Drug-Related Factors:

    • Exposure level: The dose and duration of drug therapy play a major role in the risk of kidney injury.

    • Drug characteristics: Things like solubility, structure, and charge (e.g., aminoglycosides are positively charged and stick to the negatively charged membranes in kidney cells) can make a drug more likely to cause kidney damage.

    • Polypharmacy (using many drugs) can increase the risk of interactions that harm the kidneys.

Learning Objective 2: Identify drugs commonly associated with different types of kidney injuries

Types of Drug-Induced Kidney Injury (KI):

  1. Hemodynamically Mediated AKI (Pre-Renal AKI):

    • Kidneys need a constant blood flow to function properly. A drop in blood flow (due to dehydration, heart failure, etc.) can lead to pre-renal AKI.

    • Drugs that decrease blood flow to the kidneys:

      • Diuretics: These can cause dehydration, leading to decreased kidney blood flow.

      • NSAIDs: They reduce blood flow to the kidneys by blocking prostaglandins, which normally help dilate blood vessels.

      • SGLT-2 inhibitors and CNIs (Calcineurin inhibitors): These can cause vasoconstriction (narrowing of blood vessels), especially in the kidneys.

      • ACE inhibitors and ARBs: These cause vasodilation (widening of blood vessels), but if there’s already low blood flow to the kidneys, this can be harmful.

  2. Glomerulonephritis:

    • An autoimmune reaction (where the body’s immune system attacks its own tissues) can cause inflammation in the glomeruli (tiny filters in the kidneys).

    • Drugs linked to glomerulonephritis:

      • Lithium and pamidronate: Can cause FSGS (focal segmental glomerulosclerosis).

      • NSAIDs, hydralazine: Can cause membranous nephropathy.

      • Hydralazine, isoniazid, phenytoin: Can cause drug-induced lupus.

      • Cocaine, sulfasalazine: Can cause ANCA vasculitis.

  3. Acute Tubular Necrosis (ATN):

    • The most common cause of AKI (acute kidney injury), often caused by ischemia (lack of oxygen) or toxicity.

    • Drugs causing ATN:

      • Aminoglycosides: These antibiotics can build up in kidney cells and cause cell death.

      • Radiocontrast agents (e.g., used in imaging like CT scans): These can reduce blood flow and damage kidney cells.

  4. Acute Interstitial Nephritis (AIN):

    • AIN is an allergic reaction that causes inflammation in the kidney tissue (interstitium) and affects the tubules.

    • Drugs that cause AIN:

      • Antibiotics (e.g., penicillins, cephalosporins, sulfonamides).

      • NSAIDs and PPIs (proton pump inhibitors).

      • Immune-checkpoint inhibitors (used in cancer treatment).

  5. Obstructive Nephropathy (Post-Renal AKI):

    • This occurs when urine flow is blocked after the kidneys, causing kidney damage.

    • Drugs causing obstructive nephropathy:

      • Acyclovir and methotrexate: These drugs can precipitate in the kidneys and form crystals that block urine flow.

Learning Objective 3: Establish a therapeutic plan to prevent and manage the most common types of drug-induced kidney injuries

Therapeutic Plan:

  1. Prevention:

    • Drug history: Always check the patient’s medication list for any nephrotoxic drugs.

    • Low doses and short therapy duration: Only give the minimum effective dose of potentially nephrotoxic drugs, and use them for as short a time as necessary.

    • Hydration: Ensure patients are properly hydrated, especially if they’re taking drugs that affect kidney blood flow.

    • Monitoring kidney function: Regularly check kidney function (like sCr and urine output), especially for patients at high risk (e.g., those with CKD or those taking multiple drugs).

  2. Management:

    • Stop the offending drug: The first step in managing any drug-induced kidney injury is stopping the drug that’s causing it.

    • Maximize kidney perfusion: For ischemic injuries (like in ATN), ensure the kidneys are getting enough blood and oxygen. Fluid repletion may help.

    • Avoid nephrotoxic drugs: Stop using any other drugs that might worsen kidney injury.

  3. Specific Drug Management:

    • For Aminoglycosides: Use once-daily dosing instead of multiple daily doses, as this reduces the risk of kidney damage. Monitor trough levels of the drug to make sure it’s not accumulating.

    • For Radiocontrast-Induced Nephropathy: Ensure the patient is euvolemic (not dehydrated) before administering contrast and use newer, safer contrast agents.

    • For Acyclovir-Induced Nephropathy: Ensure the patient is hydrated to reduce the risk of kidney crystals forming.

Key Takeaways:

  • Drug-induced kidney injury can happen in many ways, but it’s often related to how the drug affects kidney blood flow, causes toxicity, or creates blockages.

  • Prevention is key: Use drugs at the lowest effective dose, monitor kidney function regularly, and make sure patients are well-hydrated.

  • Management usually involves stopping the offending drug and providing supportive care (like fluids) to help the kidneys recover