Nephrotoxicity Flashcards
Functions of the kidney
- Filtration and excretion of metabolic waste products (urea and ammonium)
- Regulation of necessary electrolytes, fluid, and acid-base balance.
- Stimulation of red blood cell production.
-Regulation of blood pressure via the renin-angiotensin-aldosterone system, controlling reabsorption of water and maintaining intravascular volume. - Reabsorption of glucose and amino acids
- Hormonal functions via erythropoietin, calcitriol, and vitamin D activation.
Types of nephrotoxicity
Acute glomerulonephritis (GN)
Acute kidney injury (AKI) or Acute Renal Failure (ARF)
Acute tubular necrosis (ATN)
Chronic Kidney Disease
Markers of glomerular nephrotoxicity
Collagen IV
Cystatin C
Total protein
Markers of proximal tubular nephrotoxicity
Alpha- GST
Clusterin
Microalbumin
Osteopontin
Alpha 1 microglobulin
Markers of loop of Henle nephrotoxicity
NHE3
Osteopontin
Markers of collecting duct nephrotoxicity
Calbindin d28
RPA-1
3-part sequence of ATN - Acute Tubular Necrosis
Initiation
Maintenance
Recovery
Describe the initiation phase of ATN
Acute decrease in glomerular filtration rate (GFR) to very low levels, with a corresponding sudden increase in serum creatinine and blood urea nitrogen (BUN) concentrations.
Describe the maintenance phase of ATN
Sustained severe reduction in GFR that persists for a variable length of time, most commonly 1-2 weeks.
Describe the recovery phase of ATN
The recovery phase of ATN is characterized by regeneration of tubular epithelial cells.
Nephrotoxicants causing pre-renal damage
Diuretics
Angiotensin receptor agonists
Antihypertensive drugs
Nephrotoxicants causing vasoconstriction damage
NSAID
Cyclosporine
Tacrolimus
Amphoterin B
Nephrotoxicants causing tubular damage
- Aminoglycosides
- Cisplatin
- Pentamidine
- Radiocontrast agents
Nephrotoxicants causing endothelial damage
Cyclosporine
Mitomycin
Conjugated oestrogens
Nephrotoxicants causing interstitial nephritis
Antibiotics
NSAIDs
Diuretics
Nephrotoxic metals
Cadmium
Chromium
Mercury
Lead
Arsenic
Mechanism of action of nephrotoxicity
ACTTIR
Altered intraglomerular hemodynamics
Tubular cell toxicity
Inflammation
Crystal nephropathy
Rhabdomyolysis
Thrombotic microangiopathy
GFR depends on
4 factors:
(1) adequate blood fl ow to the glomerulus
(2) adequate glomerular capillary pressure
(3) glomerular permeability
(4) low intratubular pressure.
Ways through which GFR is reduced
(B), Afferent arteriolar constriction decreases GFR by reducing blood flow, resulting in diminished capillary pressure.
C), Obstruction of the tubular lumen by cast formation increases tubular pressure; when tubular pressure exceeds glomerular capillary pressure, filtration decreases or ceases.
(D) Back-leak occurs when the paracellular space between cells increases and the glomerular filtrate leaks into the extracellular space and bloodstream
Drugs that cause tubular cell toxicity do so by
impairing mitochondrial function, interfering with tubular transport, increasing oxidative stress, or forming free radicals
Examples of drugs that cause tubular cell toxicity
Hespera, cisplastin, tenofovir.
Examples of drugs that cause glomerulus inflammation
Medications such as gold therapy, hydralazine, NSAIDs have been reported.
Examples of drugs that cause crystal nephropathy
Antibiotics (e.g., ampicillin, ciprofloxacin, sulfonamides)
Antivirals (e.g., acyclovir, foscarnet, ganciclovir [Cytovene])
Examples of drugs that cause rhabdomyolysis
Cocaine
Heroin
Methamphetamine
Alcohol
Mechanisms of renal injury secondary to drug-induced thrombotic microangiopathy include
an immune-mediated reaction or direct endothelial toxicity.
Drugs most often associated with this thrombotic microangiopathy include
- antiplatelet agents (e.g., clopidogrel [Plavix]
- cyclosporine
- mitomycin-C
In vivo models to study renal function
Continuous micro perfusion
Stopped-flow micro perfusion
Free-flow micro puncture
Confocal microscopy
Ex vivo models to study renal function
Isolated perfused kidney
Isolated perfused tubules
In vitro models to study renal function
- Renal slices
- Glomerular cells
- Tubular epithelial cells
- Fibroblasts
Renal protective strategies
- Avoid routine use of clinically confirmed nephrotoxic drugs like NSAIDS, cyclosporine low-dose dopamine, diuretics
- Avoid routine use of high-volume doses of contrast media
- Avoid long periods of hypotension
How man takes in nephrotoxicants
Pesticide/Fertilizer Farmland Well Water Drinking Kidneys
Some are inhaled or absorbed through the skin forming glyphosate-metal complex within circulation. In the kidneys, the complex causes oxidative stress, apoptosis, necrosis leading to glomerular sclerosis and collapse, proximal tubular damage and interstitial damage. All these = CKD.
Nephrotoxicant drugs that cause crystalluria
Methotrexate
Sulfonamide
