Acute Kidney Injury in the ICU: Medication Dosing

Q:  As a hospitalist, I often see patients in our ICU develop AKI. Our pharmacist helps us with medication dosing, but sometimes I feel as if we're pulling a dose out of the air. Are there any studies or guidelines we can refer to?
Standard medication dosing adjustments for patients with impaired renal function are generally based on estimated glomerular filtration rate (eGFR). Because SCr is a lagging indicator of AKI, all methods of deriving eGFR from SCr are valid only when the patient is in a steady state.¹⁰

SCr has yet to be replaced by a real-time biomarker for AKI; this has left clinicians in the ICU setting with no simple or concise method for real-time assessment of renal function. In response to this common clinical conundrum, the RIFLE criteria,⁸ mentioned above, incorporates urinary output and relative increase in SCr as assessment criteria (see table for definitions).

This revised classification system may help the clinician define the severity of AKI in the acute setting. However, no medication dosing guidelines currently correspond with RIFLE staging. To further complicate the picture, there is evidence to suggest that AKI may affect drug metabolism through nonrenal pathways, such as hepatic clearance and transport functions.¹¹ Add to this the potential for impaired drug absorption, distribution, and/or clearance due to variance in intravascular volume status, hepatic hypoperfusion, hypoxia, decreased protein synthesis, and competitive inhibition from concomitant medications—in short, the variables become too complex for calculating therapeutic drug dosing to be possible.

In the absence of definitive guidelines, the clinician plays a critical role in medication dosing adjustment for the ICU patient with AKI. The clinician must use astute clinical judgment to assess and prioritize the unique constellation of factors in any given case. Some of the factors that should be carefully considered when estimating medication dose adjustments in this context include RIFLE staging, trend in SCr, baseline SCr, nephrotoxicity of the medication to be administered, the drug's volume of distribution, the metabolic pathways of drug excretion, and the patient's weight.

A serum drug level, when available, is generally the best guide for dosing adjustment.¹⁰ The RIFLE staging does offer some clinical pearls that may be helpful. Though not evidence-based recommendations, these guides are commonly used in the clinical environment.

When patients are in the Failure stage, for example (see specifics in the table), they are generally considered to have an eGFR of less than 15 mL/min for purposes of drug dose adjustment (personal communication, Gideon Kayanan, PharmD, February 2013). However, patients in this category are much more likely than others to be undergoing dialysis, in which case the pharmacokinetics and pharmacodynamics are further complicated. In some cases, it may be appropriate to order creatinine clearance studies with a 6- or 12-hour urine collection and extrapolate a 24-hour creatinine clearance from this value.

The dearth of literature addressing this topic (despite the prevalence of AKI in the acute care setting) is a clear indication of the complexity of creating guidelines to address such a dynamic, multivariate pharmacokinetic process. Review of the literature clearly demonstrates that medical science in this area is not yet sufficiently developed to produce a standardized, data-driven guideline for dose adjustment calculation in patients with AKI.¹⁰ Until biomarkers are detected that offer real-time assessment of renal function and that can be used in the clinical setting, there will continue to be a component of estimation, analysis of trends, and reliance on clinical judgment in adjusting medication doses for inpatients with AKI. —AC

References
1. National Institute of Diabetes and Digestive and Kidney Diseases, NIH. US Renal Data System, 2010 Annual Data Report. www.usrds.org/2010/view/default.asp. Accessed March 5, 2013.

2. National Institute of Diabetes and Digestive and Kidney Diseases, NIH. US Renal Data System, 2011 Annual Data Report. www.usrds.org/2011/view/v2_00_appx.asp. Accessed March 5, 2013.

3. Waikar SS, Liu KD, Chertow GM. Diagnosis, epidemiology and outcomes of acute kidney injury. Clin J Am Soc Nephrol. 2008;3:844-861.

4. Chertow GM, Burdick E, Honour M, et al. Acute kidney injury, mortality, length of stay, and costs in hospitalized patients. J Am Soc Nephrol. 2005;16:3365-3370.

5. Hsu RK, McCulloch CE, Dudley RA, et al. Temporal changes in incidence of dialysis-requiring AKI. J Am Soc Nephrol. 2012;24:37-42.

6. Wang HE, Muntner P, Chertow GM, Warnock DG. Acute kidney injury and mortality in hospitalized patients. Am J Nephrol. 2012;35:349-355.

7. Nisula S, Kaukonen KM, Vaara ST, et al. Incidence, risk factors and 90-day mortality of patients with acute kidney injury in Finnish intensive care units: the FINNAKI study. Intensive Care Med. 2013;39:420-428.

8. Hoste EA, Clermont G, Kersten A, et al. RIFLE criteria for acute kidney injury are associated with hospital mortality in critically ill patients: a cohort analysis. Crit Care. 2006;10:R73.

9. Coca SG, Yusuf B, Shlipak MG, et al. Long-term risk of mortality and other adverse outcomes after acute kidney injury: a systematic review and meta-analysis. Am J Kidney Dis. 2009;53:961-973.

10. Matzke GR, Aronoff GR, Atkinson AJ Jr, et al. Drug dosing consideration in patients with acute and chronic kidney disease: a clinical update from Kidney Disease: Improving Global Outcomes (KDIGO). Kidney Int. 2011;80:1122-1137.

11. Vilay AM, Churchwell MD, Mueller BA. Clinical review: drug metabolism and nonrenal clearance in acute kidney injury. Crit Care. 2008;12:235.

Q:  As a hospitalist, I often see patients in our ICU develop AKI. Our pharmacist helps us with medication dosing, but sometimes I feel as if we're pulling a dose out of the air. Are there any studies or guidelines we can refer to?
Standard medication dosing adjustments for patients with impaired renal function are generally based on estimated glomerular filtration rate (eGFR). Because SCr is a lagging indicator of AKI, all methods of deriving eGFR from SCr are valid only when the patient is in a steady state.¹⁰

SCr has yet to be replaced by a real-time biomarker for AKI; this has left clinicians in the ICU setting with no simple or concise method for real-time assessment of renal function. In response to this common clinical conundrum, the RIFLE criteria,⁸ mentioned above, incorporates urinary output and relative increase in SCr as assessment criteria (see table for definitions).

This revised classification system may help the clinician define the severity of AKI in the acute setting. However, no medication dosing guidelines currently correspond with RIFLE staging. To further complicate the picture, there is evidence to suggest that AKI may affect drug metabolism through nonrenal pathways, such as hepatic clearance and transport functions.¹¹ Add to this the potential for impaired drug absorption, distribution, and/or clearance due to variance in intravascular volume status, hepatic hypoperfusion, hypoxia, decreased protein synthesis, and competitive inhibition from concomitant medications—in short, the variables become too complex for calculating therapeutic drug dosing to be possible.

In the absence of definitive guidelines, the clinician plays a critical role in medication dosing adjustment for the ICU patient with AKI. The clinician must use astute clinical judgment to assess and prioritize the unique constellation of factors in any given case. Some of the factors that should be carefully considered when estimating medication dose adjustments in this context include RIFLE staging, trend in SCr, baseline SCr, nephrotoxicity of the medication to be administered, the drug's volume of distribution, the metabolic pathways of drug excretion, and the patient's weight.

A serum drug level, when available, is generally the best guide for dosing adjustment.¹⁰ The RIFLE staging does offer some clinical pearls that may be helpful. Though not evidence-based recommendations, these guides are commonly used in the clinical environment.

When patients are in the Failure stage, for example (see specifics in the table), they are generally considered to have an eGFR of less than 15 mL/min for purposes of drug dose adjustment (personal communication, Gideon Kayanan, PharmD, February 2013). However, patients in this category are much more likely than others to be undergoing dialysis, in which case the pharmacokinetics and pharmacodynamics are further complicated. In some cases, it may be appropriate to order creatinine clearance studies with a 6- or 12-hour urine collection and extrapolate a 24-hour creatinine clearance from this value.

The dearth of literature addressing this topic (despite the prevalence of AKI in the acute care setting) is a clear indication of the complexity of creating guidelines to address such a dynamic, multivariate pharmacokinetic process. Review of the literature clearly demonstrates that medical science in this area is not yet sufficiently developed to produce a standardized, data-driven guideline for dose adjustment calculation in patients with AKI.¹⁰ Until biomarkers are detected that offer real-time assessment of renal function and that can be used in the clinical setting, there will continue to be a component of estimation, analysis of trends, and reliance on clinical judgment in adjusting medication doses for inpatients with AKI. —AC

References
1. National Institute of Diabetes and Digestive and Kidney Diseases, NIH. US Renal Data System, 2010 Annual Data Report. www.usrds.org/2010/view/default.asp. Accessed March 5, 2013.

2. National Institute of Diabetes and Digestive and Kidney Diseases, NIH. US Renal Data System, 2011 Annual Data Report. www.usrds.org/2011/view/v2_00_appx.asp. Accessed March 5, 2013.

3. Waikar SS, Liu KD, Chertow GM. Diagnosis, epidemiology and outcomes of acute kidney injury. Clin J Am Soc Nephrol. 2008;3:844-861.

4. Chertow GM, Burdick E, Honour M, et al. Acute kidney injury, mortality, length of stay, and costs in hospitalized patients. J Am Soc Nephrol. 2005;16:3365-3370.

5. Hsu RK, McCulloch CE, Dudley RA, et al. Temporal changes in incidence of dialysis-requiring AKI. J Am Soc Nephrol. 2012;24:37-42.

6. Wang HE, Muntner P, Chertow GM, Warnock DG. Acute kidney injury and mortality in hospitalized patients. Am J Nephrol. 2012;35:349-355.

7. Nisula S, Kaukonen KM, Vaara ST, et al. Incidence, risk factors and 90-day mortality of patients with acute kidney injury in Finnish intensive care units: the FINNAKI study. Intensive Care Med. 2013;39:420-428.

8. Hoste EA, Clermont G, Kersten A, et al. RIFLE criteria for acute kidney injury are associated with hospital mortality in critically ill patients: a cohort analysis. Crit Care. 2006;10:R73.

9. Coca SG, Yusuf B, Shlipak MG, et al. Long-term risk of mortality and other adverse outcomes after acute kidney injury: a systematic review and meta-analysis. Am J Kidney Dis. 2009;53:961-973.

10. Matzke GR, Aronoff GR, Atkinson AJ Jr, et al. Drug dosing consideration in patients with acute and chronic kidney disease: a clinical update from Kidney Disease: Improving Global Outcomes (KDIGO). Kidney Int. 2011;80:1122-1137.

11. Vilay AM, Churchwell MD, Mueller BA. Clinical review: drug metabolism and nonrenal clearance in acute kidney injury. Crit Care. 2008;12:235.

Q:  As a hospitalist, I often see patients in our ICU develop AKI. Our pharmacist helps us with medication dosing, but sometimes I feel as if we're pulling a dose out of the air. Are there any studies or guidelines we can refer to?
Standard medication dosing adjustments for patients with impaired renal function are generally based on estimated glomerular filtration rate (eGFR). Because SCr is a lagging indicator of AKI, all methods of deriving eGFR from SCr are valid only when the patient is in a steady state.¹⁰

SCr has yet to be replaced by a real-time biomarker for AKI; this has left clinicians in the ICU setting with no simple or concise method for real-time assessment of renal function. In response to this common clinical conundrum, the RIFLE criteria,⁸ mentioned above, incorporates urinary output and relative increase in SCr as assessment criteria (see table for definitions).

This revised classification system may help the clinician define the severity of AKI in the acute setting. However, no medication dosing guidelines currently correspond with RIFLE staging. To further complicate the picture, there is evidence to suggest that AKI may affect drug metabolism through nonrenal pathways, such as hepatic clearance and transport functions.¹¹ Add to this the potential for impaired drug absorption, distribution, and/or clearance due to variance in intravascular volume status, hepatic hypoperfusion, hypoxia, decreased protein synthesis, and competitive inhibition from concomitant medications—in short, the variables become too complex for calculating therapeutic drug dosing to be possible.

In the absence of definitive guidelines, the clinician plays a critical role in medication dosing adjustment for the ICU patient with AKI. The clinician must use astute clinical judgment to assess and prioritize the unique constellation of factors in any given case. Some of the factors that should be carefully considered when estimating medication dose adjustments in this context include RIFLE staging, trend in SCr, baseline SCr, nephrotoxicity of the medication to be administered, the drug's volume of distribution, the metabolic pathways of drug excretion, and the patient's weight.

A serum drug level, when available, is generally the best guide for dosing adjustment.¹⁰ The RIFLE staging does offer some clinical pearls that may be helpful. Though not evidence-based recommendations, these guides are commonly used in the clinical environment.

When patients are in the Failure stage, for example (see specifics in the table), they are generally considered to have an eGFR of less than 15 mL/min for purposes of drug dose adjustment (personal communication, Gideon Kayanan, PharmD, February 2013). However, patients in this category are much more likely than others to be undergoing dialysis, in which case the pharmacokinetics and pharmacodynamics are further complicated. In some cases, it may be appropriate to order creatinine clearance studies with a 6- or 12-hour urine collection and extrapolate a 24-hour creatinine clearance from this value.

The dearth of literature addressing this topic (despite the prevalence of AKI in the acute care setting) is a clear indication of the complexity of creating guidelines to address such a dynamic, multivariate pharmacokinetic process. Review of the literature clearly demonstrates that medical science in this area is not yet sufficiently developed to produce a standardized, data-driven guideline for dose adjustment calculation in patients with AKI.¹⁰ Until biomarkers are detected that offer real-time assessment of renal function and that can be used in the clinical setting, there will continue to be a component of estimation, analysis of trends, and reliance on clinical judgment in adjusting medication doses for inpatients with AKI. —AC

References
1. National Institute of Diabetes and Digestive and Kidney Diseases, NIH. US Renal Data System, 2010 Annual Data Report. www.usrds.org/2010/view/default.asp. Accessed March 5, 2013.

2. National Institute of Diabetes and Digestive and Kidney Diseases, NIH. US Renal Data System, 2011 Annual Data Report. www.usrds.org/2011/view/v2_00_appx.asp. Accessed March 5, 2013.

3. Waikar SS, Liu KD, Chertow GM. Diagnosis, epidemiology and outcomes of acute kidney injury. Clin J Am Soc Nephrol. 2008;3:844-861.

4. Chertow GM, Burdick E, Honour M, et al. Acute kidney injury, mortality, length of stay, and costs in hospitalized patients. J Am Soc Nephrol. 2005;16:3365-3370.

5. Hsu RK, McCulloch CE, Dudley RA, et al. Temporal changes in incidence of dialysis-requiring AKI. J Am Soc Nephrol. 2012;24:37-42.

6. Wang HE, Muntner P, Chertow GM, Warnock DG. Acute kidney injury and mortality in hospitalized patients. Am J Nephrol. 2012;35:349-355.

7. Nisula S, Kaukonen KM, Vaara ST, et al. Incidence, risk factors and 90-day mortality of patients with acute kidney injury in Finnish intensive care units: the FINNAKI study. Intensive Care Med. 2013;39:420-428.

8. Hoste EA, Clermont G, Kersten A, et al. RIFLE criteria for acute kidney injury are associated with hospital mortality in critically ill patients: a cohort analysis. Crit Care. 2006;10:R73.

9. Coca SG, Yusuf B, Shlipak MG, et al. Long-term risk of mortality and other adverse outcomes after acute kidney injury: a systematic review and meta-analysis. Am J Kidney Dis. 2009;53:961-973.

10. Matzke GR, Aronoff GR, Atkinson AJ Jr, et al. Drug dosing consideration in patients with acute and chronic kidney disease: a clinical update from Kidney Disease: Improving Global Outcomes (KDIGO). Kidney Int. 2011;80:1122-1137.

11. Vilay AM, Churchwell MD, Mueller BA. Clinical review: drug metabolism and nonrenal clearance in acute kidney injury. Crit Care. 2008;12:235.