Amphotericin B-Associated Nephrotoxicity in Bone Marrow
Study Objective: To characterize amphotericin B-associated nephrotoxicity and to determine the variables associated with it that can be used to identify, a priori, at-risk patients.
Design: Retrospective analysis.
Setting: University hospital.
Patients: A homogeneous population of 69 recipients of a bone marrow (BMT) or peripheral blood stem cell transplant (PBSCT) with multiple myeloma and who received at least two doses of amphotericin B deoxycholate from January 1, 1992-January 1, 1995.
Intervention: Data on demographics, prior and concomitant nephrotoxic drug therapy, daily laboratory values, and amphotericin B dosing were collected serially from medical and pharmacy records.
Measurements and Main Results: Forward stepwise logistic regression analysis was performed on the data from the first day of therapy to characterize and determine variables related to amphotericin B-associated nephrotoxicity. Nephrotoxicity occurred in 30 patients (43%) and developed rapidly. Patients who developed nephrotoxicity were similar to those who did not in many aspects associated with their treatment. However, baseline estimated creatinine clearance, cyclosporine therapy, nephrotoxic drug therapy within 30 days of starting amphotericin B, and the number of concomitant nephrotoxic drugs were significant predictors of amphotericin B-associated nephrotoxicity.
Conclusion: Recipients of a BMT or PBSCT who have multiple myeloma and are receiving cyclosporine or multiple nephrotoxic drugs at the start of amphotericin B therapy should be considered at high risk for developing amphotericin B-associated nephrotoxicity. Also, because amphotericin B-associated nephrotoxicity develops rapidly, clinicians should be aware of the rapid changes in serum creatinine and electrolyte levels that can occur.
Lipid-based amphotericin B formulations are less nephrotoxic than amphotericin B deoxycholate. Because the widespread administration of lipid-based amphotericin B formulations can be costly, many hospitals have developed guidelines regarding the use of these agents. The guidelines often resemble the criteria used to qualify patients for open-label emergency treatment studies conducted for product licensure. The criteria usually stipulate that lipid-based amphotericin B products be reserved for those intolerant of or with infections refractory to amphotericin B deoxycholate.
Such criteria are well suited for clinical trials, but they may not be applicable to all practice settings. In fact, some clinicians have suggested administering the lipid-based amphotericin B formulations earlier in high-risk populations, rather than delaying administration until amphotericin B deoxycholate-associated nephrotoxicity develops. Difficulty in identifying high-risk patients who would benefit from the nephrosparing effects of lipid-based amphotericin B formulations is the primary drawback to an early-treatment strategy. Recognizing such patients is difficult because the natural course of amphotericin B-associated nephrotoxicity is poorly characterized, and few studies have attempted to identify risk factors for this toxicity. Ideally, such studies should focus on a specific population that is at high risk for renal failure, and in whom choices for antifungal therapy are limited. However, to our knowledge, no data exist that characterize the risks of amphotericin B-associated nephrotoxicity in a homogeneous group of high-risk patients. Rather, existing studies have focused on heterogeneous populations that vary in degrees of severity of illness, risk for renal failure, and indications for receiving amphotericin B. In addition, existing studies have identified risks (e.g., total dose, length of therapy) that are unknown before starting amphotericin B therapy.
Investigators also have attempted to identify markers that could be used before or during therapy to more readily identify amphotericin B-associated nephrotoxicity. In a prospective trial, the authors studied a small (14 patients), heterogeneous population of patients with bone marrow transplants (BMTs) who were in the intensive care unit, to determine whether a relationship existed between serum lipoprotein cholesterol concentrations and the severity of amphotericin B-associated nephrotoxicity. Patients received 50 mg/day or less for 10 days without concomitant cyclosporine or aminoglycosides. No correlation between serum lipoprotein cholesterol concentrations and the severity of amphotericin B-associated nephrotoxicity was found, which may be the result of too few patients experiencing significant increases in serum creatinine levels from baseline.
Study Objective: To characterize amphotericin B-associated nephrotoxicity and to determine the variables associated with it that can be used to identify, a priori, at-risk patients.
Design: Retrospective analysis.
Setting: University hospital.
Patients: A homogeneous population of 69 recipients of a bone marrow (BMT) or peripheral blood stem cell transplant (PBSCT) with multiple myeloma and who received at least two doses of amphotericin B deoxycholate from January 1, 1992-January 1, 1995.
Intervention: Data on demographics, prior and concomitant nephrotoxic drug therapy, daily laboratory values, and amphotericin B dosing were collected serially from medical and pharmacy records.
Measurements and Main Results: Forward stepwise logistic regression analysis was performed on the data from the first day of therapy to characterize and determine variables related to amphotericin B-associated nephrotoxicity. Nephrotoxicity occurred in 30 patients (43%) and developed rapidly. Patients who developed nephrotoxicity were similar to those who did not in many aspects associated with their treatment. However, baseline estimated creatinine clearance, cyclosporine therapy, nephrotoxic drug therapy within 30 days of starting amphotericin B, and the number of concomitant nephrotoxic drugs were significant predictors of amphotericin B-associated nephrotoxicity.
Conclusion: Recipients of a BMT or PBSCT who have multiple myeloma and are receiving cyclosporine or multiple nephrotoxic drugs at the start of amphotericin B therapy should be considered at high risk for developing amphotericin B-associated nephrotoxicity. Also, because amphotericin B-associated nephrotoxicity develops rapidly, clinicians should be aware of the rapid changes in serum creatinine and electrolyte levels that can occur.
Lipid-based amphotericin B formulations are less nephrotoxic than amphotericin B deoxycholate. Because the widespread administration of lipid-based amphotericin B formulations can be costly, many hospitals have developed guidelines regarding the use of these agents. The guidelines often resemble the criteria used to qualify patients for open-label emergency treatment studies conducted for product licensure. The criteria usually stipulate that lipid-based amphotericin B products be reserved for those intolerant of or with infections refractory to amphotericin B deoxycholate.
Such criteria are well suited for clinical trials, but they may not be applicable to all practice settings. In fact, some clinicians have suggested administering the lipid-based amphotericin B formulations earlier in high-risk populations, rather than delaying administration until amphotericin B deoxycholate-associated nephrotoxicity develops. Difficulty in identifying high-risk patients who would benefit from the nephrosparing effects of lipid-based amphotericin B formulations is the primary drawback to an early-treatment strategy. Recognizing such patients is difficult because the natural course of amphotericin B-associated nephrotoxicity is poorly characterized, and few studies have attempted to identify risk factors for this toxicity. Ideally, such studies should focus on a specific population that is at high risk for renal failure, and in whom choices for antifungal therapy are limited. However, to our knowledge, no data exist that characterize the risks of amphotericin B-associated nephrotoxicity in a homogeneous group of high-risk patients. Rather, existing studies have focused on heterogeneous populations that vary in degrees of severity of illness, risk for renal failure, and indications for receiving amphotericin B. In addition, existing studies have identified risks (e.g., total dose, length of therapy) that are unknown before starting amphotericin B therapy.
Investigators also have attempted to identify markers that could be used before or during therapy to more readily identify amphotericin B-associated nephrotoxicity. In a prospective trial, the authors studied a small (14 patients), heterogeneous population of patients with bone marrow transplants (BMTs) who were in the intensive care unit, to determine whether a relationship existed between serum lipoprotein cholesterol concentrations and the severity of amphotericin B-associated nephrotoxicity. Patients received 50 mg/day or less for 10 days without concomitant cyclosporine or aminoglycosides. No correlation between serum lipoprotein cholesterol concentrations and the severity of amphotericin B-associated nephrotoxicity was found, which may be the result of too few patients experiencing significant increases in serum creatinine levels from baseline.