5.2 Nephrotoxicity

Nephrotoxicity is a critical concern in toxicology, affecting kidney function and overall health. This topic explores how various substances can damage the kidneys, from common medications to environmental toxins. Understanding these mechanisms is key to preventing and managing kidney injury.

The kidneys play a vital role in filtering blood and maintaining bodily balance. This section delves into kidney structure, function, and the ways toxins can disrupt these processes. It covers risk factors, diagnosis, and strategies for preventing nephrotoxicity in clinical settings.

Kidney structure and function

• The kidneys are vital organs responsible for maintaining homeostasis by filtering blood, regulating electrolyte balance, and excreting waste products
• Understanding the structure and function of the kidneys is essential for comprehending the mechanisms and consequences of nephrotoxicity

Nephron anatomy and physiology

Top images from around the web for Nephron anatomy and physiology

• 

  Nephron - Wikipedia View original

  Is this image relevant?

• 

  16.4 Kidneys – Human Biology View original

  Is this image relevant?

• 

  The Kidneys and Osmoregulatory Organs | OpenStax Biology 2e View original

  Is this image relevant?

• 

  Nephron - Wikipedia View original

  Is this image relevant?

• 

  16.4 Kidneys – Human Biology View original

  Is this image relevant?

1 of 3

Top images from around the web for Nephron anatomy and physiology

• 

  Nephron - Wikipedia View original

  Is this image relevant?

• 

  16.4 Kidneys – Human Biology View original

  Is this image relevant?

• 

  The Kidneys and Osmoregulatory Organs | OpenStax Biology 2e View original

  Is this image relevant?

• 

  Nephron - Wikipedia View original

  Is this image relevant?

• 

  16.4 Kidneys – Human Biology View original

  Is this image relevant?

1 of 3

• The nephron is the functional unit of the kidney, consisting of the glomerulus, proximal tubule, loop of Henle, distal tubule, and collecting duct
• Each kidney contains approximately 1 million nephrons that work together to filter blood and produce urine
• The different segments of the nephron have specialized functions for filtration, reabsorption, and secretion of solutes and water
• The glomerulus is a network of capillaries surrounded by Bowman's capsule where initial filtration occurs (ultrafiltrate)
• The tubular system modifies the ultrafiltrate by selectively reabsorbing essential nutrients and secreting waste products

Glomerular filtration

• Glomerular filtration is the first step in urine formation, driven by Starling forces across the glomerular capillary wall
• The glomerular filtration rate (GFR) is a measure of kidney function, representing the volume of fluid filtered per unit time
• Factors affecting GFR include afferent and efferent arteriolar tone, plasma oncotic pressure, and glomerular capillary permeability
• Damage to the glomerular filtration barrier can lead to proteinuria and hematuria

Tubular secretion and reabsorption

• Tubular secretion involves the active transport of solutes from the peritubular capillaries into the tubular lumen (organic acids, drugs)
• Tubular reabsorption is the passive or active transport of solutes and water from the tubular lumen back into the bloodstream
• The proximal tubule is responsible for the majority of reabsorption, including glucose, amino acids, and electrolytes (sodium, potassium, chloride)
• The loop of Henle creates a concentration gradient in the medulla, allowing for the production of concentrated urine
• The distal tubule and collecting duct fine-tune the composition of urine under the influence of hormones (aldosterone, antidiuretic hormone)

Mechanisms of nephrotoxicity

• Nephrotoxicity can occur through various mechanisms that disrupt the normal structure and function of the kidneys
• Understanding these mechanisms is crucial for identifying potential nephrotoxic agents and developing preventive and therapeutic strategies

Direct cellular toxicity

• Some nephrotoxic agents can directly damage renal cells by disrupting cell membranes, mitochondria, or other organelles
• Examples of direct cellular toxicity include:
  • Aminoglycoside antibiotics (gentamicin) cause oxidative damage to proximal tubular cells
  • Cisplatin induces apoptosis in renal tubular epithelial cells
• Direct cellular toxicity can lead to acute tubular necrosis and acute kidney injury

Oxidative stress and inflammation

• Nephrotoxic agents can generate reactive oxygen species (ROS) and induce oxidative stress in renal cells
• Oxidative stress triggers inflammatory responses, leading to the release of cytokines and chemokines
• Inflammation attracts immune cells (macrophages, neutrophils) that further contribute to renal injury
• Examples of nephrotoxic agents causing oxidative stress and inflammation include:
  • Radiocontrast agents used in imaging studies
  • Environmental toxins (heavy metals, pesticides)

Hemodynamic alterations

• Some nephrotoxic agents can alter renal blood flow and glomerular hemodynamics, leading to reduced GFR and ischemic injury
• Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit prostaglandin synthesis, causing afferent arteriolar vasoconstriction and reduced glomerular perfusion
• Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) can cause efferent arteriolar vasodilation, leading to a drop in glomerular filtration pressure
• Hemodynamic alterations are particularly problematic in patients with pre-existing kidney disease or volume depletion

Crystal formation and obstruction

• Certain nephrotoxic agents can precipitate and form crystals within the tubular lumen, causing obstruction and injury
• Examples of crystal-forming nephrotoxic agents include:
  • Acyclovir, a antiviral drug, can form crystals in the distal tubules
  • Ethylene glycol, found in antifreeze, is metabolized to oxalate crystals that deposit in the tubules
• Crystal obstruction leads to increased intratubular pressure, reduced GFR, and tubular cell injury

Common nephrotoxic agents

• A wide range of drugs, environmental toxins, and endogenous compounds can cause nephrotoxicity
• Recognizing common nephrotoxic agents is essential for preventing and managing kidney injury in clinical practice

Drugs (NSAIDs, antibiotics, chemotherapy)

• Nonsteroidal anti-inflammatory drugs (NSAIDs) like ibuprofen and naproxen can cause acute interstitial nephritis and hemodynamic alterations
• Antibiotics, particularly aminoglycosides (gentamicin, tobramycin) and vancomycin, can cause acute tubular necrosis and crystal nephropathy
• Chemotherapeutic agents, such as cisplatin and ifosfamide, can induce oxidative stress and direct cellular toxicity in renal tubular cells
• Other nephrotoxic drugs include:
  • Calcineurin inhibitors (cyclosporine, tacrolimus) used in transplantation
  • Bisphosphonates used for osteoporosis treatment

Heavy metals (lead, cadmium, mercury)

• Heavy metal exposure can occur through occupational hazards, environmental contamination, or ingestion of contaminated food or water
• Lead nephrotoxicity is characterized by proximal tubular dysfunction, leading to Fanconi syndrome (glycosuria, aminoaciduria, phosphaturia)
• Cadmium accumulates in the proximal tubules, causing oxidative stress and inflammation, and increasing the risk of chronic kidney disease
• Mercury induces oxidative damage and mitochondrial dysfunction in renal cells, leading to acute tubular necrosis

Environmental toxins (pesticides, herbicides)

• Pesticides and herbicides can cause nephrotoxicity through various mechanisms, including oxidative stress, inflammation, and direct cellular toxicity
• Glyphosate, a widely used herbicide, has been associated with an increased risk of chronic kidney disease in agricultural workers
• Organochlorine pesticides (DDT, lindane) can accumulate in renal tissues and cause tubular damage
• Paraquat, a herbicide, generates reactive oxygen species and induces acute kidney injury

Endogenous compounds (myoglobin, hemoglobin)

• Endogenous compounds released during tissue injury or hemolysis can cause nephrotoxicity when they exceed the renal capacity for clearance
• Myoglobin, released from damaged muscle cells during rhabdomyolysis, can precipitate in the tubules and cause obstruction and oxidative stress
• Hemoglobin, released during intravascular hemolysis, can cause pigment nephropathy and acute tubular necrosis
• Uric acid, a product of purine metabolism, can form crystals in the tubules and cause acute urate nephropathy (tumor lysis syndrome)

Risk factors for nephrotoxicity

• Certain patient characteristics and clinical conditions can increase the susceptibility to nephrotoxicity
• Identifying risk factors is crucial for preventing and managing kidney injury in vulnerable populations

Age and gender

• Elderly patients are at higher risk of nephrotoxicity due to age-related changes in kidney function, reduced drug clearance, and polypharmacy
• Neonates and infants have immature renal function and are more susceptible to nephrotoxic agents
• Some studies suggest that women may be more vulnerable to certain nephrotoxic agents (NSAIDs, contrast media) due to hormonal factors and body composition

Pre-existing kidney disease

• Patients with chronic kidney disease (CKD) have reduced renal reserve and are more sensitive to nephrotoxic insults
• Nephrotoxic agents can accelerate the progression of CKD and lead to end-stage renal disease (ESRD)
• Dose adjustment and careful monitoring are essential when using potentially nephrotoxic drugs in CKD patients

Polypharmacy and drug interactions

• Polypharmacy, the concurrent use of multiple medications, increases the risk of nephrotoxicity due to drug interactions and cumulative toxicity
• Some drug combinations can potentiate nephrotoxicity, such as:
  • NSAIDs and ACE inhibitors/ARBs, which can cause acute kidney injury
  • Aminoglycosides and loop diuretics, which can enhance ototoxicity and nephrotoxicity
• Regular medication review and deprescribing can help minimize the risk of nephrotoxicity in patients with polypharmacy

Dehydration and electrolyte imbalances

• Dehydration reduces renal perfusion and increases the concentration of nephrotoxic agents in the tubular lumen, enhancing their toxic effects
• Electrolyte imbalances, such as hypokalemia and hypomagnesemia, can potentiate the nephrotoxicity of certain drugs (aminoglycosides, cisplatin)
• Ensuring adequate hydration and correcting electrolyte abnormalities can help prevent nephrotoxicity in at-risk patients

Clinical manifestations of nephrotoxicity

• Nephrotoxicity can present with a range of clinical manifestations, depending on the site and mechanism of injury
• Recognizing the signs and symptoms of nephrotoxicity is essential for prompt diagnosis and management

Acute kidney injury (AKI)

• AKI is a sudden decline in kidney function, characterized by an increase in serum creatinine and/or a decrease in urine output
• Nephrotoxic agents can cause AKI through various mechanisms, such as acute tubular necrosis, acute interstitial nephritis, or glomerular injury
• Clinical features of AKI include:
  • Oliguria or anuria (reduced or absent urine output)
  • Fluid retention and edema
  • Electrolyte and acid-base disturbances (hyperkalemia, metabolic acidosis)

Chronic kidney disease (CKD)

• CKD is a progressive loss of kidney function over months or years, often resulting from repeated or prolonged exposure to nephrotoxic agents
• Nephrotoxicity can contribute to the development and progression of CKD by causing chronic tubular injury, interstitial fibrosis, and glomerulosclerosis
• Clinical manifestations of CKD include:
  • Hypertension
  • Anemia
  • Bone mineral disorders (secondary hyperparathyroidism, renal osteodystrophy)
  • Uremic symptoms (fatigue, nausea, pruritus)

Proteinuria and hematuria

• Proteinuria, the presence of excess protein in the urine, can be a sign of glomerular or tubular injury caused by nephrotoxic agents
• Hematuria, the presence of blood in the urine, can indicate glomerular damage or hemorrhagic cystitis (cyclophosphamide)
• Persistent proteinuria and hematuria may be early markers of nephrotoxicity and should prompt further evaluation

Electrolyte and acid-base disorders

• Nephrotoxic agents can disrupt the renal handling of electrolytes and the maintenance of acid-base balance
• Common electrolyte disorders associated with nephrotoxicity include:
  • Hyperkalemia, due to reduced potassium excretion (ACE inhibitors, NSAIDs)
  • Hypomagnesemia, due to enhanced magnesium wasting (aminoglycosides, cisplatin)
  • Hypophosphatemia, due to proximal tubular dysfunction (tenofovir, ifosfamide)
• Metabolic acidosis can occur due to impaired renal acid excretion or loss of bicarbonate (proximal renal tubular acidosis)

Diagnosis of nephrotoxicity

• The diagnosis of nephrotoxicity involves a combination of clinical assessment, laboratory tests, imaging studies, and sometimes renal biopsy
• Early detection and accurate diagnosis are crucial for preventing further kidney damage and initiating appropriate management

Serum creatinine and eGFR

• Serum creatinine is a widely used marker of kidney function, reflecting glomerular filtration rate (GFR)
• An increase in serum creatinine from baseline suggests acute kidney injury or worsening of chronic kidney disease
• Estimated GFR (eGFR) is calculated from serum creatinine, age, sex, and race using standardized formulas (MDRD, CKD-EPI)
• Limitations of serum creatinine include its dependence on muscle mass, age, and diet, and its delayed rise after kidney injury

Urinalysis and biomarkers

• Urinalysis can provide valuable information about the site and nature of kidney injury caused by nephrotoxic agents
• Proteinuria, hematuria, and urinary casts (granular, muddy brown) suggest glomerular or tubular damage
• Urine microscopy can reveal crystals (calcium oxalate, uric acid) or eosinophils (acute interstitial nephritis)
• Novel biomarkers, such as neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule-1 (KIM-1), may allow earlier detection of nephrotoxicity

Imaging studies (ultrasound, CT, MRI)

• Imaging studies can help assess kidney size, structure, and obstruction, and rule out other causes of kidney injury
• Renal ultrasound is a non-invasive tool for evaluating kidney size, echogenicity, and hydronephrosis
• Computed tomography (CT) and magnetic resonance imaging (MRI) can provide more detailed information about renal anatomy and vascular supply
• Contrast-enhanced studies should be used cautiously in patients with kidney dysfunction due to the risk of contrast-induced nephropathy

Renal biopsy indications

• Renal biopsy may be necessary to establish the diagnosis and prognosis of nephrotoxicity when clinical and laboratory findings are inconclusive
• Indications for renal biopsy in suspected nephrotoxicity include:
  • Rapidly progressive kidney failure of unknown etiology
  • Persistent proteinuria or hematuria despite discontinuation of the offending agent
  • Suspected glomerular or vascular involvement
• Renal biopsy can provide information about the type and extent of kidney injury, guide treatment decisions, and estimate prognosis

Prevention and management of nephrotoxicity

• Preventing and managing nephrotoxicity requires a multifaceted approach, including avoiding nephrotoxic agents, adjusting doses, ensuring adequate hydration, and providing supportive care
• Collaboration between healthcare providers, patients, and caregivers is essential for minimizing the risk and impact of nephrotoxicity

Avoiding nephrotoxic agents

• Whenever possible, nephrotoxic agents should be avoided in patients at high risk for kidney injury, such as those with pre-existing kidney disease or multiple risk factors
• Alternative therapies with lower nephrotoxic potential should be considered, if available
• If nephrotoxic agents are necessary, the lowest effective dose should be used for the shortest duration possible
• Combinations of nephrotoxic agents should be avoided or used with caution and close monitoring

Dose adjustment for kidney function

• Many drugs, including nephrotoxic agents, require dose adjustment based on kidney function to prevent accumulation and toxicity
• Renal dosing guidelines are available for most commonly used medications, based on creatinine clearance or eGFR
• Regular monitoring of kidney function is essential when using nephrotoxic agents, with dose adjustments made as needed
• Pharmacists can play a key role in ensuring appropriate dosing and monitoring of nephrotoxic agents

Hydration and electrolyte management

• Maintaining adequate hydration is crucial for preventing and managing nephrotoxicity, as it helps flush out toxins and reduces the concentration of nephrotoxic agents in the tubular lumen
• Patients should be encouraged to drink plenty of fluids, unless contraindicated by other medical conditions (heart failure, hyponatremia)
• Intravenous hydration may be necessary before and after procedures involving nephrotoxic agents (contrast media, chemotherapy)
• Electrolyte abnormalities should be promptly corrected, as they can potentiate the nephrotoxicity of certain agents (hypokalemia, hypomagnesemia)

Dialysis and renal replacement therapy

• In severe cases of nephrotoxicity, dialysis or renal replacement therapy may be necessary to support kidney function and remove toxic substances
• Indications for dialysis in nephrotoxicity include:
  • Severe acute kidney injury with oliguria or anuria
  • Life-threatening electrolyte or acid-base disturbances (hyperkalemia, metabolic acidosis)
  • Uremic complications (pericarditis, encephalopathy, bleeding)
• The choice of dialysis modality (hemodialysis, peritoneal dialysis, continuous renal replacement therapy) depends on the patient's clinical status, comorbidities, and available resources
• Renal transplantation may