Augmented Renal Clearance and the Impact on Antimicrobial Therapy

Whether practicing pharmacy in the ambulatory or inpatient setting, professionals devote a substantial amount of energy and time to appropriate dosing of medications for renal impairment. This is appropriate, considering that about 14% of the general population is affected by chronic kidney disease, and those with this disease likely have more frequent exposure to the health care system.¹ However, considerably less attention has been focused on the opposite end of the spectrum, those patients who may exhibit a hyperdynamic state of renal clearance. This phenomenon is commonly referred to as augmented renal clearance (ARC), and only within the past decade has it begun to gain attention in the medical community.² The definition of ARC varies in the literature with respect to actual filtration rate, duration of hyperdynamic filtration, and cutoff creatinine clearance (CrCl) values. The most widely accepted definition of ARC is a CrCl greater than 130 mL/min/1.73 m2. However, there is no consensus on grading or stratification of severity with escalating CrCl values.²

Much remains unknown regarding the mechanism of ARC. However, available evidence suggests that multiple changes to nephron physiology may be at play.² One model proposes that systemic inflammation in critically ill patients results in vasodilation and reduction of systemic vascular resistance. This decrease in resistance, when coupled with the administration of intravenous fluids and increases in heart rate, leads to increased cardiac output, increasing renal preload. This hyperdynamic state results in the increased glomerular filtration rates seen in ARC.³ The incidence of ARC may be as high as 30% to 65% in critically ill patients with normal serum creatinine. The most consistent patient factors associated with ARC across multiple studies are an age of younger than 50 years and trauma.^3,4 Other associated factors include being a man, modified sequential organ failure assessment (SOFA) scores ≤4, and lower Acute Physiology and Chronic Health Evaluation or Simplified Acute Physiology scores.^2,4-6

In order to more effectively and rapidly identify patients with ARC, multiple groups have attempted to develop and validate scoring tools. The 2 most popular ones are the ARC scoring system and the Attitudes Related to Trauma- Informed Care (ARCTIC) scoring system. The ARC scoring system uses the criteria of age, a SOFA score, and trauma to assign patients an ARC score. Scores from 0 to 6 predict a low ARC risk, whereas scores of 7 to 10 are associated with a high risk of ARC.⁵ This tool was validated in a separate study that showed a sensitivity and specificity of 100% and 71%, respectively.⁷ The ARCTIC scoring system uses the criteria of age, gender, and serum creatinine and has an associated sensitivity of 84% and specificity of 68%.⁸ Despite the reductions in sensitivity and specificity, the ARCTIC scoring system is the more realistically feasible of the 2. This is largely because the use of the SOFA score within the ARC scoring system adds a layer of complexity and may make the calculation of an ARC score much more difficult in clinical practice. These scoring tools may help identify patients with suspected ARC. However, to confirm the presence and quantify the degree of ARC, a patient-specific CrCl is required. This should be performed using an 8-to-24-hour urine collection when possible, with subsequent CrCl calculation.

Given the importance of early goal-directed therapy in sepsis, coupled with the associated high mortality rate of patients presenting with sepsis, the impacts of ARC on the pharmacokinetics/pharmacodynamics (PK/PD) of antimicrobials may have a profound impact on patients admitted to intensive care units (ICUs).^9,10 Many available antibiotics are extensively cleared by the kidneys, which is worrisome when evaluated within the context of ARC. Antibiotic dosing regimens are usually determined from studies in healthy individuals during PK/PD phase 2 trials and rarely, if ever, do they include critically ill patients or those likely to be experiencing ARC.⁹ The increased rate of drug clearance seen in patients with ARC may be detrimental to the PK/ PD of antibiotics with time-dependent killing mechanisms by leading to suboptimal time that serum concentration of the drug remains above the organism’s minimum inhibitory concentration (MIC).⁹ In a study by Carlier et al, investigators began to quantify the changes imposed by ARC on the PK/PD properties of b-lactam antibiotics. The fraction of time during a 24-hour period that free concentrations of antibiotics remained above the target MIC (fT>MIC) for Pseudomonas aeruginosa was measured in 61 patients exposed to extended infusion meropenem or piperacillin/tazobactam. Of the 19 patients who did not achieve the PK/PD target of 50% fT>MIC, 7 displayed a CrCl >130 mL/min. This study included a limited number of subjects, but it does raise the question: Are patients with ARC receiving antibiotic dosing regimens that fail to meet optimal pharmacodynamic targets?¹¹ A slightly larger study by Claus et al evaluated a population of 128 patients with a total of 599 antimicrobial therapy days in the ICU. They examined therapeutic failure, defined as an impaired clinical response that required the need for alternative therapy.⁹ ARC was present for at least 1 antimicrobial therapy day in 66 patients.⁹ ARC patients experienced more therapeutic failure (27.3% vs 12.9%).⁹ Additionally, in those patients with ARC, 4 developed antibiotic resistance, as opposed to just 1 in the non-ARC patient group.⁹ Antibiotic failure in patients with ARC occurred only in those patients receiving time-dependent b-lactam antibiotics, including amoxicillin/clavulanic acid, cefuroxime, meropenem, and piperacillin/tazobactam.

Vancomycin, one of the most commonly prescribed antibiot- ics for patients with sepsis, was excluded in both of the above studies. This may be explainable, given that vancomycin trough levels are typically closely monitored in the hospital setting. Subtherapeutic vancomycin levels are commonly explained by patient-specific PK/PD characteristics that deviate from the expected population values, and regimens are adjusted when the values are found to be outside the target concentrations. In 2015, Chu et al aimed to evaluate whether some of the variance seen in vancomycin levels in inpatients was due to ARC. They retrospectively examined 148 patients who received 1000 mg every 12 hours. Not surprisingly, nearly 63% of patients with a CrCl >130 mL/min had trough concentrations <10 mcg/ mL.12 No patient with a CrCl <80 mL/min obtained a trough <10 mcg/mL, and just 27.8% of patients with a CrCl between 80 and <130 mL/min achieved such a trough.¹² The relationship is made stronger when looking at patients with supratherapeutic levels. Just 1 patient with a CrCl >130 mL/min had a trough of >20 mcg/mL, compared with 31.5% of patients with a CrCl <130 mL/min.¹²

Clinicians should carefully consider the impact that ARC may have on treatments being administered in the inpatient care setting. When patients may be demonstrating a hyperdynamic state of renal clearance, a tool such as the ARC or ARCTIC score may be useful to help determine those in whom an 8-to-24-hour urine creatinine collection may be appropriate.

Knowledge of the impact of ARC on antibiotic PK/PD and overall treatment success is relatively limited. Once identified, patients with ARC should have close attention paid to their antimicrobial dosing, particularly those receiving drugs that depend on either area under the concentration time curve: MIC ratio or fT>MIC pharmacodynamics or those receiving antimicrobials for which therapeutic drug monitoring is available. Dosing adjustments may be necessary to assure adequate pharmacodynamic target achievement.

Ryan W. Stevens, PharmD, BCPS, is an infectious diseases clinical specialist at Providence Alaska Medical Center in Anchorage.

Nicholas A. Smith, PharmD, is a PGY1 pharmacy practice resident at Providence Alaska Medical Center in Anchorage.

References

1. National Institute of Diabetes and Digestive and Kidney Diseases. Kidney disease statistics for the United States. niddk.nih.gov/health-information/health- statistics/kidney-disease. Accessed November 1, 2017.

2. Mahmoud SH, Shen C. Augmented renal clearance in critical illness: an important consideration in drug dosing. Pharmaceutics. 2017;9(3):36. doi: 10 .3390/pharmaceutics9030036.

3. Sime FB, Udy AA, Roberts JA. Augmented renal clearance in critically ill patients: etiology, definition, and implications for beta-lactam dose optimization. Curr Opin Pharmacol. 2015;24:1-6. doi: 10.1016/j.coph.2015.06.002.

4. Hobbs AL, Shea KM, Roberts KM, Daley MJ. Implications of augmented renal clearance on drug dosing in critically ill patients: a focus on antibiotics. Pharmacotherapy. 2015;35(11):1063-1075. doi: 10.1002/phar.1653.

5. Udy AA, Roberts JA, Shorr AF, Boots RJ, Lipman J. Augmented renal clearance in septic and traumatized patients with normal plasma creatinine concentrations: identifying at-risk patients. Crit Care. 2013;17(1):R35. doi: 10.1186/ cc12544.

6. Minville V, Asehnoune K, Ruiz S, et al. Increased creatinine clearance in polytrauma patients with normal serum creatinine: a retrospective observational study. Crit Care. 2011;15(1):R49. doi: 10.1186/cc10013.

7. Akers KS, Niece KL, Chung KK, Cannon JW, Cota JM, Murray CK. Modified augmented renal clearance score predicts rapid piperacillin and tazobactam clearance in critically ill surgery and trauma patients. J Trauma Acute Care Surg. 2014;77:(3)(suppl 2):S163-170. doi: 10.1097/TA.0000000000000191.

8. Barletta JF, Mangram AJ, Byrne M, et al. Identifying augmented renal clearance in trauma patients: validation of the augmented renal clearance in intensive care scoring system. J Trauma Acute Care Surg. 2017;82(4):665-671. doi: 10.1097/ TA.0000000000001387.

9. Claus BO, Hoste EA, Colpaert K, Robays H, Decruyenaere J, De Waele JJ. Augmented renal clearance is a common finding with worse clinical outcome in critically ill patients receiving antimicrobial therapy. J Crit Care. 2013;28(5):695- 700. doi: 10.1016/j.jcrc.2013.03.003.

10. Rivers E, Nguyen B, Havstad S, et al. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med. 2001;345(19):1368-1377. doi: 10.1056/NEJMoa010307.

11. Carlier M, Carrette S, Roberts JA, et al. Meropenem and piperacillin/tazobactam prescribing in critically ill patients: Does augmented renal clearance affect pharmacokinetic/pharmacodynamic target attainment when extended infusions are used? Crit Care. 2013;17(3):R84. doi: 10.1186/cc12705.

12. Chu Y, Luo Y, Qu L, Zhao C, Jiang M. Application of vancomycin in patients with varying renal function, especially those with augmented renal clearance. Pharm Biol. 2016;54(12):2802-2806. doi: 10.1080/13880209.2016.1183684.