Are there any human case reports or evidence of compound A (a degradation product of sevoflurane) affecting renal function in patients with pre-existing renal conditions or risk factors for renal impairment?

Compound A and Renal Effects in Humans: Evidence from Case Reports and Clinical Studies

Yes, there is substantial human evidence demonstrating that Compound A (a degradation product of sevoflurane) can cause transient renal injury, particularly affecting glomeruli and proximal tubules, with injury severity correlating to exposure duration and concentration. 1, 2

Direct Human Evidence of Compound A Nephrotoxicity

Documented Renal Injury Patterns

The most compelling evidence comes from controlled volunteer studies showing dose-dependent renal injury from Compound A exposure:

• Glomerular injury manifested as albuminuria occurred after 8 hours of 1.25 MAC sevoflurane at 2 L/min flow (average Compound A concentration 40 ppm), with albumin excretion ranging from normal (<0.03 g) to severely elevated (4.4 g) on postanesthesia Day 3 2

• Proximal tubular injury demonstrated by glucosuria and increased urinary alpha-glutathione-S-transferase (alpha-GST) excretion occurred with the same exposure parameters 1, 2

• Distal tubular injury revealed by increased urinary pi-GST occurred after 8-hour sevoflurane exposure 2

Dose-Response Relationship

A clear threshold for renal injury exists between 80-168 ppm/h of Compound A exposure:

• 8-hour exposure (168 ppm/h): Significant glomerular and tubular injury 1, 2
• 4-hour exposure (168 ppm/h): Statistically significant but transient glomerular injury (slightly increased urinary albumin and serum creatinine) and proximal tubular injury (increased urinary alpha-GST) 1
• 2-hour exposure (80 ppm/h): No detectable injury 1

This dose-response pattern in humans approximates that previously found in rats 1

Evidence in Patients with Pre-existing Renal Impairment

Stable Renal Insufficiency Studies

Critically, patients with pre-existing stable renal insufficiency (serum creatinine ≥1.5 mg/dL) did not experience worsening of renal function after sevoflurane exposure, despite higher fluoride levels:

• In 21 patients with baseline creatinine >1.5 mg/dL receiving sevoflurane, laboratory measures of renal function remained stable throughout the 7-day postoperative period, with no permanent deterioration and no patients requiring dialysis 3

• Peak serum inorganic fluoride concentrations were significantly higher after sevoflurane (25.0 ± 2.2 μM) versus enflurane (13.3 ± 1.1 μM), yet renal function remained stable 3

• In 17 patients with moderate renal insufficiency receiving low-flow sevoflurane (1 L/min, Compound A exposure <130 ppm/h), there were no significant differences in blood urea nitrogen, serum creatinine, or creatinine clearance before and after anesthesia compared to isoflurane 4

Critical Distinction

The FDA label acknowledges this paradox: sevoflurane was evaluated in renally impaired patients with baseline serum creatinine >1.5 mg/dL, with creatinine levels increasing in only 7% of sevoflurane patients versus 8% with isoflurane and 10% with enflurane 5

However, the FDA recommends caution because the small number of patients studied means the safety profile has not been fully established in this population 5

Clinical Context: When Injury Occurs vs. When It Doesn't

Factors Associated with Detectable Injury

Renal injury from Compound A appears to require specific conditions:

• Prolonged exposure (≥4 hours at clinically relevant concentrations) 1
• Low fresh gas flow rates (≤2 L/min) generating higher Compound A concentrations 1, 2
• Fluid restriction (volunteers were fasted overnight, potentially concentrating nephrotoxic effects) 2
• Normal baseline renal function (paradoxically, injury was documented in healthy volunteers but not in patients with chronic renal insufficiency) 1, 3, 2

Protective Factors

Several factors appear protective against clinically significant injury:

• Higher fresh gas flow rates (≥2 L/min reduces Compound A formation) 5
• Shorter exposure duration (<2 hours) 1
• Adequate hydration 5
• Pre-existing stable renal insufficiency (possibly due to adaptive mechanisms or reduced metabolic capacity) 3, 4

Comparison with Other Anesthetic Agents

Desflurane and isoflurane do not produce Compound A and showed no renal injury markers in direct comparisons:

• Desflurane at identical exposure conditions (8 hours, 1.25 MAC, 2 L/min) produced no albuminuria, glucosuria, or increased urinary GST 1, 2
• Isoflurane at low flow (1 L/min) showed similar renal safety to sevoflurane in patients with moderate renal insufficiency 4, 6

Limitations of Standard Renal Function Tests

A critical finding is that conventional markers (serum creatinine, BUN) failed to detect the injury that more sensitive markers revealed:

• Neither sevoflurane nor desflurane affected serum creatinine or BUN despite documented tubular injury by urinary enzyme markers 2
• The kidney's ability to concentrate urine in response to vasopressin remained intact despite injury 2
• This explains why larger surgical studies using only creatinine and BUN found no differences between sevoflurane and other anesthetics 6

Practical Clinical Implications

For patients with pre-existing renal conditions or risk factors:

• The FDA-mandated minimum fresh gas flow of 2 L/min provides a safety margin, though transient subclinical injury can still occur at this flow rate with prolonged exposure 5, 1
• Patients with stable chronic renal insufficiency (creatinine >1.5 mg/dL) appear to tolerate sevoflurane without functional deterioration, even with low-flow techniques generating Compound A 3, 4
• However, sevoflurane should be used with caution in renal insufficiency because the safety database remains limited 5

The injury documented in healthy volunteers is transient and subclinical, resolving within days without permanent functional impairment, but the long-term implications of repeated exposures remain unknown 1, 2