Renal effects of AA

[Ref:SH4:p69]

Generic effects

• All AAs produce similar dose-related:
  * Decrease in renal blood
  * Decrease in GFR
  * Decrease in urine output
• Prevented or lessened by preoperative hydration
• Due to effects of AA on BP and cardiac output

Fluoride-induced nephrotoxicity

• First recognised with methoxyflurane
  * Extensive metabolism (70%)
  * No renal effect when [F-]< 40microm/L
  * Subclinical when [F-] = 50-80
  * Clinical toxicity when [F-] > 80
• Fluoride level alone is not an indicator for fluoride-induced nephrotoxicity
  * Lack of toxicity when [F-] >50 with ENF and SEVO
• Fluoride interferes with enzymes in both proximal and distal tubules
• Risk factor for enflurane nephrotoxicity (??? also true for other fluoride-induced nephrotoxicity)
  * Enzyme induction
  * Obesity
  * Preexisting renal dysfunction

S&S of fluoride-induced nephrotoxicity

• Polyuria
  * High output failure
  * (???) ADH resistant
• Hypernatremia
• Hyperosmolarity
• Increased plasma creatinine
• Inability to concentrate urine

Sevoflurane

Has not been shown to cause renal impairment
* Despite peak plasma fluoride consistently higher than enflurane

Possible explanation

• Intrarenal production of inorganic fluoride is more important for nephrotoxicity than hepatic metabolism
• Plasma fluoride level is related to hepatic metabolism
• Methoxyflurane and enflurane undergoes greater intrarenal metabolism

Vinyl halide nephrotoxicity

(i.e. compound A nephrotoxicity)

SEVO reacts with carbon dioxide absorbents containing KHO and NaOH
--> F+ and H+ removed

A few degradation products produced
* Highest level is compound A (fluoromethyl-2,2-difluro-1-(trifluoromethyl) vinyl ether)

Compound A

Compound A is a dose-dependent nephrotoxin in rats
--> Causes proximal tubular injury at 50 to 100ppm
* LD50 in rats is 400pm for 3 hours

Production of compound A is higher when Baralyme is used
* Probably due to higher absorbent temperature than soda lime

So far, it has not been demonstrated that compound A causes in human impairment of urine concentrating ability and plasma creatinine level.

Concentration of compound A in the circuit

• At 1L/min, 19.7 ppm
• At 3L/min, 8.1 ppm
• At 6L/min, 2.1 ppm

Fresh gas flow of 2L/min is supposed to limit the concentration of compound A in the circuit

Probenecid

Selective inhibitor of organic anion transport

Prevents compound A-induced renal injury in rats

Mechanism of renal injury

Metabolism of compound A to a reactive thiol
* Via the beta-lyse pathway

Human has less than 1/10 of the enzymatic activity in this pathway than rats

Halothane

Halothane also react with CO2 absorbent to form degradation products that are nephrotoxic to rats

But the product is les nephrotoxic than compound A