Nephrotoxicity: Risk Factors and Clinical Presentation

• Nephrotoxicity is kidney toxicity resulting from the harmful effects of chemicals and medications on renal function.
• Drug-induced nephrotoxicity is a common source of acute kidney injury, especially in specific clinical situations or for certain patients.

Risk Factors

• Patient-related risk factors include age, sex, race, pre-existing renal disease, specific diseases like diabetes mellitus, multiple myeloma, proteinuric conditions, sodium-retaining states (cirrhosis, heart failure, nephrosis), dehydration, and volume depletion.
• Further risk factors are acidosis, potassium and magnesium depletion, hyperuricemia, hyperuricosuria, sepsis, shock, and renal transplantation.
• Drug-related risk factors include inherent nephrotoxic potential, dose, duration, frequency, form of administration, and repeated exposure.
• Drug interactions, such as the combined use of diagnostic or therapeutic agents with nephrotoxic potential, raise the risk.

Clinical Presentation

• The most common general manifestation of nephrotoxicity is a decline in glomerular filtration, leading to increased serum creatinine and blood urea nitrogen levels.
• Symptoms include malaise, anorexia, vomiting, shortness of breath, or edema; all leading to a rise in Scr and BUN.
• A sign of nephrotoxicity is decreased urine output, especially with radiographic contrast media, NSAIDs, and ACEIs; progression can lead to volume overload and hypertension.

Pathogenic Mechanisms

• Drugs can cause nephrotoxicity through mechanisms like altered intraglomerular hemodynamics, tubular cell toxicity, inflammation, crystal nephropathy, rhabdomyolysis, and thrombotic microangiopathy.
• Knowledge of specific pathogenic mechanisms is crucial for preventing drug-induced renal impairment.

Pathogenic Mechanisms By Drug Class

• Analgesics such as acetaminophen and aspirin causes chronic interstitial nephritis.
• Nonsteroidal anti-inflammatory drugs causes acute interstitial nephritis, altered intraglomerular hemodynamics, chronic interstitial nephritis, and glomerulonephritis.
• Amitriptyline, doxepin, and fluoxetine (antidepressants/mood stabilizers) induce rhabdomyolysis.
• Lithium causes chronic interstitial nephritis, glomerulonephritis, and rhabdomyolysis.
• Antihistamines like diphenhydramine and doxylamine lead to rhabdomyolysis, acute interstitial nephritis, and crystal nephropathy.
• Antimicrobials such as acyclovir and aminoglycosides causes tubular cell toxicity.
• Cardiovascular agents like ACEIs and ARBs alter intraglomerular hemodynamics.
• Clopidogrel causes thrombotic microangiopathy.
• Statins result in rhabdomyolysis.
• Drugs of abuse like cocaine, fentanyl, and ketamine causes rhabdomyolysis.
• PPIs such as omeprazole, lansoprazole, and pantoprazole cause acute interstitial nephritis.

Tubular Cell Toxicity

• Drug accumulation in tubular cells due to drugs like aminoglycosides (gentamicin) and cisplatin being actively taken up by proximal tubular cells through specific transporters causes high intracellular concentrations, leading to toxicity.
• Drugs like amphotericin B, cisplatin, and vancomycin induce oxidative stress by generating reactive oxygen species (ROS), causing lipid peroxidation, protein damage, and DNA fragmentation, leading to cell death.
• Cisplatin and other nephrotoxic drugs impair mitochondrial respiratory chains, leading to decreased ATP production and triggering apoptosis.
• Drugs such as calcineurin inhibitors (cyclosporine, tacrolimus) increase intracellular calcium levels, activating destructive enzymatic pathways, causing cytotoxicity and cell death.
• Apoptotic pathways are activated via caspase enzymes in response to cellular stress induced by nephrotoxic drugs like cisplatin; excessive damage leads to necrotic cell death and tubular dysfunction.
• Amphotericin B interacts with cell membranes by binding to ergosterol-like components, leading to pore formation and ion leakage.
• NSAIDs and cisplatin promote inflammation by triggering cytokine release (e.g., IL-6, TNF-alpha), which can lead to tubular cell injury and acute interstitial nephritis.
• Accumulation of misfolded proteins in tubular cells, induced by drugs like cisplatin, leads to ER stress and activation of apoptosis pathways.
• NSAIDs inhibit prostaglandin synthesis, reducing renal blood flow and causing ischemic damage to tubular cells.
• Calcineurin inhibitors cause afferent arteriole vasoconstriction, reducing oxygen delivery to the renal tubules.
• Nephrotoxic mechanisms lead to tubular injury and compromised kidney function.
• Preventative strategies include dose adjustments, adequate hydration, therapeutic monitoring, and avoiding concomitant use of nephrotoxic agents.

Mechanisms Causing Drug-Induced Rhabdomyolysis

• Rhabdomyolysis involves the breakdown of skeletal muscle fibers, releasing intracellular contents like myoglobin, creatine kinase (CK), and electrolytes into the bloodstream.
• Direct muscle toxicity stems from drugs damaging muscle cell membranes directly, such as statins and daptomycin.
• Mitochondrial dysfunction results in impaired ATP production, leading to energy depletion and muscle breakdown from statins and zidovudine.
• Hyperthermia and muscle rigidity damage muscle cells due to excessive heat and sustained muscle contractions from anesthetics (succinylcholine) and SSRIs (serotonin syndrome).
• Excessive physical activity due to drug-induced hyperactivity or agitation overexerts muscles (cocaine and amphetamines).
• Reduced blood flow caused by ischemia leads to muscle injury (cocaine, ergot alkaloids)
• Conditions like hypokalemia and hypophosphatemia electrolyte imbalances impair muscle function (diuretics).
• Autoimmune reactions triggered by drugs cause immune-mediated myopathy and damage muscle tissue (statins in rare cases).
• Sedatives or narcotics cause prolonged immobility and ischemic injury due to prolonged compression (opioids, benzodiazepines).

Reducing Drug-Induced Nephrotoxicity

• Assess patient risk factors, ensure adequate renal function monitoring and evaluate baseline functions.
• Use the lowest effective dose for the shortest duration, with dose adjustments based on renal function.
• Maintain adequate hydration through oral intake or intravenous fluids.
• Substitute nephrotoxic drugs with safer options and avoid harmful drug combinations.
• Monitor kidney function, electrolyte balance, and drug serum levels for agents with narrow therapeutic indices.
• Implement urine alkalinization, antioxidant therapy (e.g., N-acetylcysteine for contrast agents), and educate patients on recognizing early signs of kidney injury.