Kidney Toxicity

Question 1

Why is the kidney exposed to high levels of drugs and toxicants? (2)

Answer 1

1. By virtue of the concentrating effect of the glomerular filtrate in the LoH and CD.
2. The kidney itself has the capacity to conduct drug metabolism, which can lead to the activation of pro-toxicants

Question 2

What is the result of numerous toxicants and drugs on the kidney?

Answer 2

They can cause mitochondrial dysfunction via compromised ETC activity or ATP production, leading to apoptosis or necrosis

Question 3

What is acute kidney injury (AKI) characterized by?

Answer 3

Abrupt decline in GFR with resulting azotemia (increased nitrogen wastes in the blood)

Question 4

Are all renal injuries the same?

Answer 4

No, they span a spectrum from minimal elevation in serum creatinine to anuric renal failure

Question 5

Function of the renal tubules is highly dependent on what?

Answer 5

total epithelial cell integrity

Question 6

When drugs compromise total epithelial integrity of the renal tubule, what two things can happen?

Answer 6

1. Diminished GFR: epithelial compromise→ opportunity for back leaking of renal filtrate→reduced GFR
2. Tubular Obstruction: compromise→ detached cells can aggregate in tubule or adhere to other epithelial cells downstream→tubular obstruction

Question 7

Inflammatory cells are attracted to what? Under what conditions? What does this result in?

Answer 7

Where there is low O2 tension, inflammatory cells are attracted by the release of numerous chemokines→creates pro-inflammatory situation with neutrophil adhesion to underlying tubular structures

Question 8

After exposure to a toxicant , one or more of what possible mechanisms may contribute to reduced GFR?

Answer 8

1. Renal Vasoconstriction→ leading to pre-renal azotemia and obstruction due to precipitation of a drug or endogenous compound w/in the kidney
2. Intarenal factors include: direct tubular obstruction and dysfunction→tubular back-leak and increased tubular pressure
3. Alterations in the levels of various vasoactive mediators→decreased renal perfusion pressure or afferent arteriolar tone and increased efferent arteriole(??make sure eff and aff are right??) tone→decreased glomerular hydrostatic pressure

Question 9

After an acute injury, what happens to damaged kidney cells? What happens to the rest of the tissue?

Answer 9

They are repaired or undergo apoptosis, if unviable.
The remaining tissue undergoes a compensatory hypertrophy and proliferation to reconstruct the functional integrity of the glomerulus and nephron

Question 10

Pre-renal AKI?

Answer 10

reduced blood supply to the kidney; GFR falls as a consequence

Question 11

Crystalluria?

Answer 11

precipitation in tubules causing obstruction

Question 12

Tubular Toxicity?

Answer 12

damage to and loss of integrity of tubules

Question 13

Endothelial KI’s?

Answer 13

endothelial pro-inflammatory condition with detachment, release of chemotactic factors, and reduced NO (vasodilator) production

Question 14

Glomerulopathy?

Answer 14

damage to the glomerulus leading to loss of integrity and abrupt onset of hematuria, proteinuria, edema, and hypertension

Question 15

Interstitial nephritis?

Answer 15

inflammation of the spaces between the renal tubules

Question 16

What types of test can be done to assess the adverse effects of drugs on renal function? (3)

Answer 16

determination of GFR, Serial serum creatinine/BUN, Urine osmolality examination

Question 17

How can you directly determine GFR?

Answer 17

By measurement of inulin or creatinine clearance (both freely filtered and not secreted or reabsorbed)

Question 18

What are indirect measures of renal function?

Answer 18

serial serum creatinine or BUN can indicate an accumulation trend

Question 19

What can examination of urine osmolality and contents disclose? (2)

Answer 19

it can disclose impaired concentrating ability and identification of components that should no be there are indicative area-specific damage

Question 20

What are two examples of components in the urine that indicate damage to a particular area of the kidney?

Answer 20

1. High MW protein like albumin→ glomerular damage

2. LMW protein like B2-microglobulin→ proximal tubular damage

Question 21

Chronic renal toxicity:

Long-term exposure to a number of drugs can produce what?

Answer 21

Maladaption of the damaged areas with development of glomerulosclerosis, tubular atrophy, and interstitial fibrosis.

Question 22

In chronic renal toxicity, how does the remaining viable tissue respond? What does this lead to?

Answer 22

The remaining viable tissue increases glomerular pressure and flow, which over time, lead to mechanical damage and altered permeability of the capillaries.

Question 23

What is the result of acetaminophen toxicity on the kidney?

Answer 23

Proximal tubule necrosis. Increased BUN and Serum Creatinine, reduced GFR.

Question 24

What two things possible play a role in acetaminophen’s toxicity on the kidney?

Answer 24

CYP activation and glutathione conjugates

Question 25

What are three mechanisms of NSAID toxicity on the kidneys?

Answer 25

1. Inhibition of PG synthesis→ vasoconstriction → decreased RBF and ischemia 2. Chronic consumption→Analgesic Nephropathy (see next slide) 3. Interstitial nephritis is a more rare form of toxicity

Question 26

What two drugs can cause Analgesic Nephropathy? What is it characterized by? How does it happen?

Answer 26

Chronic use of NSAIDs and acetaminophen; it's characterized by chronic interstitial nephritis and papillary necrosis; Under hypoxic conditions, the generation of a reactive intermediate is thought to bind to cellular macromolecules

Question 27

How do aminoglycosides harm the kidneys?

Answer 27

These antibiotics cause an increase in number and size of lysosomes, which contain phospholipid, due to drug-induced inhibition of Sphingomyelinase and phospholipases, both important lysosome hydrolases→lysosomes rupture→cytoplasm is exposed to toxic contents

Question 28

What is the mechanism of Amphotericin B toxicity to the kidneys?

Answer 28

it impairs the functional integrity of the glomerulus, PT, and DT→reduced RBF and reduced GFR

Question 29

What does cyclosporine cause?

Answer 29

acute reversible renal dysfunction and acute vasculopathy

Question 30

How is this cyclosporine dysfunction and vasculopathy mediated?

Answer 30

May be mediated by thromboxane-induced vasoconstriction, reduced vasodilatory PGs, ANG-II, endothelium PAF, or reduced endothelium-dependent relaxation factors

Question 31

How does cisplatin cause renal toxicity?

Answer 31

thru its anti-tumor mechanism of action→inhibition of DNA synthesis and transport functions

Question 32

How does cisplatin affect the nephron and glomerulus?

Answer 32

Glomerulus is unaffected; focal necrotic lesions arise in the nephron

Question 33

What is the total effect on renal function of patients treated with cisplatin?

Answer 33

Patients treated with this drug permanently lose 10-30% of their renal function

Question 34

What agents are among the nephrotoxic substances a patient might receive?

Answer 34

Iodinated radio-contrast agents used for imaging

Question 35

What causes a patient to have an increased risk of nephrotoxicity when given radio-contrast?

Answer 35

if they have pre-existing renal conditions or are taking other nephrotoxic drugs

Question 36

Where does the nephrotoxicity associated with radiocontrast arise from? (2)

Answer 36

from both acute vasoconstrictive response, and from the cellular generation of ROS

Question 37

What is the incidence of nephrotoxicity in patients given radiocontrast agents such as IOTROL or IOPAMIDOL?

Answer 37

incidence of 0-10% in pts with normal renal function; 12-50% in pts with various risk factors