Nephrotoxicity Flashcards
What do the kidneys do?
Concentrate bloodborne waste for elimination, produce concentrated urine, save water, excrete wastes.
Where is the kidney located?
Upper quadrant, retroperitoneum (behind the liver/pancreas).
What is the input to the kidney?
Blood from the descending aorta.
What is the output from the kidney?
Vein joins the ascending inferior vena cava; excreted waste is transported to the bladder for storage and elimination.
What are the functional subunits of the kidney?
Nephrons; integrated blood vessel and tubule networks form ‘pyramids’.
What is the outer region of the kidney?
Cortex.
What are the two inner regions of the kidney?
Outer and inner medulla.
Where are nephrons located?
Within the pyramids, spanning all three regions of the kidney.
What is the blood flow through the kidneys?
90% of blood flows through the cortex, 6-10% to the medulla, 1-2% to papilla.
What are the main exchanging compartments of the kidney?
The nephron.
What do excretory mechanisms do?
Concentrate poisons in tubules, which might reach dangerous levels.
What drives high [poison] in the tubule?
Diffusion into cells lining tubules (tubular epithelial cells).
What can cause the precipitation of poisons?
High concentrations and removal of water, leading to concentration of chemicals and induction of damaging cascades.
What can active renal transport and metabolism do?
Uptake and transform chemicals into poisons.
What occurs in the proximal tubule?
Water is reabsorbed isosmotically; transport of K+, HCO3-, Cl-, PO43-, Ca2+, Mg2+, amino acids, glucose, citric acid cycle substrates, and low MW proteins by endocytosis.
What does GFR require?
Hydrostatic pressure and oncotic (protein related) draw.
What are the three main cell types of the nephron?
Endothelial, epithelial (focus on tubular epithelial cells), podocytes.
What do podocytes do?
Produce little holes through which filtrate flows.
What can indicate the location of kidney toxicity?
Changes in urine production.
What is non-oliguric renal failure?
Inability to concentrate urine; indicates proximal tubule damage.
What is oliguria?
Reduced urine flow; indicates glomerulus damage.
What is polyuria?
Excessive urine flow; indicates loop of Henle, distal tubule, or collecting ducts damage.
What is anuria?
No urine flow; indicates post-renal blockages or precipitates.
What is a post-renal blockage?
Occurs downstream/outside the kidney (nephron).
What do precipitates cause?
Shedding of epithelial cells, which move into filtrate and cause precipitates in collecting duct.
What may changes in urine chemistry indicate?
Location of kidney toxicity.
What is proteinuria?
Excess protein in the urine.
How does the size of protein in proteinuria indicate location of damage?
High MW = glomeruli; low MW = proximal tubule reabsorption.
What does lactate dehydrogenase indicate?
General cell damage.
What do alkaline phosphatases or gamma-glutamyl transferase indicate?
Tubule brush border damage (apical membrane of tubular epithelium).
What does hematuria indicate?
Sign of glomerular damage; blood is toxic to the renal tubules.
What does glucosuria indicate?
Proximal tubule damage.
What is a sign of kidney toxicity?
Decline of function.
What is the most common symptom of kidney damage?
Acute kidney injury (AKI).
What does an abrupt decline in GFR reflect?
Azotemia (high blood urea nitrogen) due to less hydrostatic pressure and oncotic draw, leading to decreased urine output.
What can poisons damage?
Tubular integrity; damaged cells release basement membrane causing gaps in lining, leading to tubular obstructions and blockages.
What is pre-renal AKI?
Incoming chemicals (upstream of the kidney), impaired arterial perfusion.
What does dark urine indicate?
Big pre-renal problems.
What is an example of pre-renal problems?
Muscle breakdown (rhabdomyolysis) after extreme exercise or statin-induced rhabdomyolysis.
What is renal AKI?
Anything that affects functional components: vascular, glomerular, tubulo-interstitial.
What is post-renal AKI?
Obstruction of urine flow from renal pelvis, collecting ducts, bladder, urethra.
What are the hallmarks of renal AKI?
- Acute tubular necrosis (ATN). 2. Sloughed off cells are called a cast, forced through tubules/ducts into urine. 3. Blockage causes abrupt decrease in GFR, blockage of lumen by casts and cellular debris. 4. Muddy brown urine.
What is ATN?
Acute tubular necrosis; characterized by patchy brown necrosis of tubular epithelium.
What percentage of ATN is direct toxicity on renal cells?
35%; the rest is pre-renal.
What are direct measurements that gauge kidney function?
Creatinine and inulin levels.
What does clearance of creatinine or inulin equal?
GFR (because it is not secreted nor reabsorbed).
What is creatinine?
Nitrogenous waste excreted in the urine; an endogenous molecule generated in metabolism.
What is inulin?
A polysaccharide completely excreted by the kidney; used to measure kidney function (not endogenous).
What happens to creatinine and inulin levels once they enter the filtrate?
Their levels do not change.
What is the usual inulin clearance rate?
125 mL/min.
Why do creatinine measurements vary?
Due to different levels of normal in different people.
What are indirect markers of kidney function?
BUN and serum [creatinine] (relative).
What does BUN stand for?
Blood urea nitrogen.
What does GFR vs [creatinine] and BUN show?
Diagnosis can be difficult until GFR drops 50-70%, making it hard to catch before it becomes full renal damage.
Why can kidney damage lay hidden?
Other glomeruli can subsume workload to compensate for damaged glomeruli.
What can happen even when parts of the kidney are failing?
The GFR can look normal.
What part of the nephron works harder during kidney damage?
Proximal tubules work harder to reabsorb solutes and water.
What masks failure until the kidneys are overwhelmed?
Compensation.
What happens to sick tubular epithelial cells during kidney damage?
They detach, which can cause a blockage.
What does a urine cast sample contain?
Tubule cells and debris, protein, lipid, white and red blood cells.
What type of MRI can visualize kidney function?
BOLD (blood oxygenation level dependent); increase in signal = increase in blood (O2) supply.
What can causes of toxic effects be traced to?
Different cell types, outside or within a kidney.
Why are causes of kidney damage hard to discern?
Because they can be multifactorial.
What is an example of kidney damage?
NSAIDs can decrease blood flow to the kidney (pre-renal) but also induce ATN.
What color of urine is ATN characterized by?
Brown urine.
What is pre-renal AKI urine usually like?
Normal (no cast).
What is the main site of active excretion and reabsorption in the kidney?
Proximal tubule.
What is the effect of transporters in the proximal tubule?
Xenobiotics end up in the urine by active secretion, enter cells via SLCs (passive), concentrated in tubule or blood via ABCs (active), some poisons get reabsorbed.
What are two of the main transporters in the kidney (nephron)?
- MATE1 (multidrug and toxin extrusion).
- URAT (uric acid transporter).
What is an example of transporter use in the kidney?
Methylmercury uptake for excretion via OAT1; with OAT1, mercury causes bloating and dilation of tubule, indicating toxicity.
What percentages of solutes and water are reabsorbed in the proximal tubule?
60-80%.
How can we demonstrate the critical role of a protein in toxicity?
Animal knockouts.
What are animal knockouts?
Eliminate expression of a specific protein in a specific cell-type(s) of a tissue(s).
What does mercury exposure cause?
Dilation of tubule cell.
When does mercury exposure not cause dilation of tubule cell?
When there is no OAT1 expression (OAT1 KO); mercury is not toxic to tubular epithelial cells.
What organelle powers the proximal tubule epithelium?
Basolateral mitochondria.
What are proximal tubules susceptible to damage by?
ATP and/or O2 depletion.
Where is the most site of injury due to high expression of transporters for reabsorption?
Proximal tubule.
What does ATP and/or O2 damage lead to?
High chemical concentrations in proximal tubule cells using ATP and O2 dependent mechanisms.
What cells are more sensitive to ischemia?
Proximal cells.
What enzymes are primarily exposed on the proximal tubules and can activate chemicals?
Cytochrome P450 and beta-lyase.
What molecules are directly toxic?
Aminoglycoside antibiotics and mercury.
What agents can cause ischemia and tubular damage?
Radiocontrast agents.
What is chloroform nephrotoxicity?
- Industrial solvent, water contaminant.
- Rapidly absorbed by inhalation, ingestion.
- Toxic to brain, liver, kidney (necrosis of tubular epithelium-proteinuria, glucosuria, increased BUN).
How is chloroform activated?
By P450 to phosgene in the kidney, same pathway as in the liver.
What does highly reactive phosgene electrophile do?
Covalently modifies proteins, leading to stress and necrosis likely via direct mitochondrial stress.
What can aminoglycoside antibiotics cause?
Severe kidney damage in some individuals.
What is gentamicin?
Aminoglycoside, non-oliguric kidney failure, reduced GFR, increased serum creatinine, BUN; first sign is polyuria followed by proteinuria, glucosuria.
What is the mechanism of action of aminoglycosides?
Thought to inhibit sphingomyelinase and phospholipase in lysosomes, resulting in increased size and number of lysosomes, leading to phospholipidosis.
What may aminoglycosides involve in kidney toxicity?
Rupture and release of lysosomal enzymes and toxicants, which damage and kill cells.
What is the interaction of aminoglycosides with the kidney tubule?
Dose-dependent.
How are aminoglycosides allowed to enter the cell?
Via pinocytosis; positive charge absorbs these drugs onto brush borders of tubule cells leading to pinocytic entry.
What happens to aminoglycosides inside the cell?
They are contained within vesicles which are either exocytosed into the blood or ruptured and released back into the tubule cell.
What happens with lysosomal phospholipidosis above threshold?
Lysosomal swelling, disruption, or leakage.
What happens with lysosomal phospholipidosis below threshold?
Exocytosis shuttle.
What is N-acetylcysteine?
An antioxidant.
