Risk factors for vancomycin nephrotoxicity

Onset / Magnitude

The onset of vancomycin nephrotoxicity typically ranges from three to eight days from the start of therapy. The degree of vancomycin-induced renal dysfunction is usually modest, with a typical decrease of 35-45% in creatinine clearance from baseline. However, severe renal toxicity has been associated with vancomcyin.

The histology of most cases of vancomycin-induced nephrotoxicity is unknown, but it is has traditionally been associated with interstitial nephritis.^{20, 21, 22} However, there are published case reports of biopsy-proven acute tubular necrosis associated with vancomycin.^{17, 18, 19}

Concomitant nephrotoxins

The use of concomitant nephrotoxins is a significant risk factor for development of nephrotoxicity with vancomycin. Common drugs include:

• ACE inhibitors^d
• Acyclovir^a
• Allopurinol^a
• Aminoglycosides^c
• Amphotericin B^c
• Antiretrovirals^c
• Beta-lactams^a,b
• Cisplatin^c
• Contrast dye^c
• Lithium^b
• Loop diuretics^a,e
• NSAIDs^a,b,d
• Proton-pump inhibitors^a
• Quinolones^a
• Sulfonamides^a

Mechanism of nephrotoxicity:

1. Acute interstitial nephritis
2. Glomerulonephritis
3. Tubular cell toxicity
4. Altered intraglomerular hemodynamics
5. Loop diuretics may also cause dehydration, which further increases the risk of developing nephrotoxicity. One study showed that a loop diuretic was present in 63% of adult patients who had nephrotoxicity during vancomycin therapy as compared with 44% with no renal toxicity.

Piperacillin-tazobactam

Piperacillin-tazobactam is increasingly being recognized as a contributor to vancomycin nephrotoxicity. In a single center retrospective study of 735 patients nephrotoxicity was reported in 4.9% of vancomycin alone and 11.1% of pip-taz alone, compared with 18.6% in combination of vancomycin and pip-taz.²⁸ A second single center study observed a cumulative incidence of nephrotoxicity of 40.5% with combination vancomycin and pip-taz compared with 9.0% in the vancomycin alone group among 140 surgical intensive care patients.²⁹ In a single center, retrospective, cohort study of 68 patients, nephrotoxicity occurred in 19.4% of patients in the vancomycin and pip-taz combination group compared with 6.3% in the control group.³⁰

Obesity

Obesity was seen to be a significant predictor for occurrence and time of development of nephrotoxicity. It is postulated that the volume of distribution in the central compartment does not increase proportionally with weight and thus accounts for the higher trough values observed among obese patients.

High dose

Nephrotoxicity occurred in 9-40% of patients on high-dose therapy compared with 2% in patients on standard-dose therapy in the absence of concomitant risk factors for nephrotoxicity. Doses greater than 4 g/day are associated with both an increased incidence and a more rapid onset of nephrotoxicity.⁵

Duration of therapy

A recent two-phase retrospective analysis identified vancomycin serum trough concentrations >= 14 mcg/ml, duration of vancomycin therapy >= 7 days, and baseline SCR levels >= 1.7 mg/dl as independent predictors of nephrotoxicity.¹⁰

Prabaker et al. observed that the rate of nephrotoxicity increased from 12 to 22% beyond ten days of therapy. Jeffres et al. observed an odds ratio of 2.55 for nephrotoxicity after >= 14 days of treatment. ⁷ In another study, Hidayat et al. found that the risk appeared to increase incrementally as the treatment was prolonged in patients who achieved high trough levels (15 to 20 mcg/ml): 6% for >=7 days, 21% for 8 to 14 days and 30% for >14 days.³

ICU patients

A high APACHE II score, ICU stay, and receipt of vasopressor agents appear to be significant risk factors for the development of nephrotoxicity.

Lodise et al. observed that ICU patients have a higher baseline risk for development of nephrotoxicity than non-ICU patients at a lower trough concentration threshold: >20% probability of nephrotoxicity at a trough >10 mcg/ml in ICU patients versus trough >20 mcg/ml in non-ICU patients.¹⁴

Long term outcome

Acute vancomycin nephrotoxicity may rarely lead to chronic kidney damage. Biopsy proven tubular necrosis has been reported.

Conclusion

The 2009 Vancomycin therapeutic guidelines advocating much higher vancomycin doses carry a substantial risk for nephrotoxicity. The risk is incremental with higher trough levels and longer duration of therapy. Patients with multiple risk factors are particularly at risk for vancomycin induced nephrotoxicity.

References

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