Augmented renal clearance: when supranormal renal function may cause harm

What is augmented renal clearance? 

Augmented renal clearance (ARC) is the phenomenon of enhanced renal function in critically ill patients. ARC is characterized by a higher than predicted increase in the renal elimination of solutes. It occurs due to an increase in glomerular filtration and altered renal tubular function, usually manifest as an increase in the creatinine clearance. ARC leads to increased clearance of drugs excreted through the kidneys resulting in suboptimal concentrations of important medications, including antibiotics, and may lead to treatment failure. This phenomenon was first described more than 40 years ago in burns patients who were observed to have higher than normal creatinine clearance, leading to a reduction in the half-life of intravenously administered tobramycin.¹

Definition

Currently, ARC is defined as an increase in creatinine clearance above 130 ml/min/1.73 cm². It is considered clinically significant at a level of more than 150 ml/min/1.73 m² in female and more than 160 ml/min/1.73m² in male subjects.² ARC may occur in 20–65% of critically ill patients.³

Risk factors, pathophysiological mechanisms

The systemic inflammatory reaction that occurs in critically ill patients, secondary to major trauma, burns, sepsis, and following major surgery could play an important role in triggering ARC. The release of inflammatory mediators lead to systemic vasodilatation, with a reduction in the systemic vascular resistance, leading to an increase in the cardiac output; an increase in the renal blood flow and the glomerular filtration rate (GFR) ensues. Fluid resuscitation and the use of vasopressor medication may also increase the GFR, leading to ARC.⁴ Another factor that may play an important role in ARC is the functional reserve of the kidney, which enables an increase in the GFR in response to critical illness. The functional reserve is higher in younger subjects, who have a greater propensity to the development of ARC.⁵ ARC is frequently observed in neurocritical care, including patients with traumatic brain injury and subarachnoid haemorrhage; contributing factors may be the use of osmotherapy for raised intracranial pressure and vasopressors to maintain the cerebral perfusion pressure. Younger age group (34–50 y), polytrauma, and lower severity of illness are common risk factors for ARC.³      

How do you diagnose ARC? 

The commonly used equations for the calculation of GFR, including the Cockcroft–Gault and the Modification of Diet in Renal Disease equations are inaccurate in estimating GFR, and may under or overestimate measured values of creatinine clearance (CrCl).^6,7 Hence, measurement of urinary CrCl is more appropriate in the diagnosis of ARC. Although an 8–24 h urine collection is conventionally followed, a 2 h urine collection may be adequate in most circumstances. 

CrCl = urinary creatinine (mg/dl)x collected urinary volume (ml) x 1.73/serum creatinine x collection time in min xbody surface area

Body surface area = square root of [height (cm) x weight (kg)/3600]

Scoring systems to identify risk factors ARC 

Various scoring systems have been proposed for the early recognition of ARC. The ARC scoring system is based on age < 50 years, presence of trauma, and a SOFA score ≤ 4 as predictive criteria.⁵ It has been shown to have 100% sensitivity and 71% specificity for identifying patients with ARC, based on pharmacokinetic data after piperacillin/tazobactam administration in critically ill patients.⁸ The ARCTIC scoring system, that does not include the SOFA score, has been developed to identify ARC in trauma patients, and shown to have a sensitivity of 84% and specificity of 68% in identifying ARC.⁹ (Table. 1)

Table 1. Scoring systems for the early identification of ARC 

	ARC scoring system	ARCTIC scoring system
Criteria	Age 50 or less: 6 pointsTrauma: 3 pointsSOFA < 4: 1 point	S. creat 0.7 mg/dl: 3 pointsMale gender: 2 pointsAge <56: 4 pointsAge 56–75: 3 points
Risk for ARC	0–6 points: low risk 7–10 points: high risk	<6 points: low risk>6 points: high risk

What is the impact of ARC on drug clearance in critically ill patients? 

Enhanced renal elimination leads to a reduction in the half-life and reduced effectiveness of several antibiotics in common use among critically ill patients. ARC may lead to increased elimination of beta-lactam antibiotics, including penicillins and cephalosporins. Beta-lactams exhibit time-dependent killing, with their efficacy contingent on the duration for which the serum level of the drug is above the minimum inhibitory concentration. There may be a strong rationale for the administration of beta-lactams as a continuous infusion is patients with ARC.¹⁰ Continuous administration may be particularly relevant as therapeutic drug level monitoring of beta-lactams is rarely carried out in clinical practice.  

Therapeutic drug levels may be poorly achieved with carbapenems in the presence of ARC. Extended infusions of 2 g over 3 h after an initial loading dose of 2 g over 30 min may facilitate the attainment of appropriate serum levels of meropenem. Vancomycin is a hydrophilic drug, and 80­–90% is excreted unchanged by the kidneys. Target trough levels of vancomycin are difficult to achieve with conventional dosing in the presence of ARC.¹¹ An initial loading dose of 25–30 mg/kg followed by 45 mg/kg/day in three divided doses or as a continuous infusion along with therapeutic drug level monitoring is recommended. Aminoglycosides and fluoroquinolones are also primarily eliminated by the kidneys and need adjustment of dosing in the presence of ARC. Apart from antibiotics, levetiracetam clearance is higher among the neurocritical care patient population. Besides, patients with ARC may have a shorter duration of action of enoxaparin. Table 2 summarizes recommended dosing for drugs significantly impacted by ARC.¹²    

Table 2. Suggested intravenous dosing for drugs that are significantly impacted by ARC¹²

Drug	Suggested IV dose
Meropenem	Bolus: 2 g over 30 min, followed by 2 g/8 h, administered over 3 h
Vancomycin	Loading dose: 25–30 mg/kg; maintenance: 45 mg/kg/d, as continuous infusion or divided into 3 doses. Therapeutic drug level monitoring recommended. Maintain level 10–20 mg/l
Piperacillin/tazobactam	4.5 g/6h, as extended infusion over 4 h
Levofloxacin	750–1000 mg 24 hourly
Levetiracetam	1000 mg 8 hourly

The bottom line 

• ARC is characterized by an enhanced rate of drug elimination by the kidneys and may result in suboptimal drug levels and treatment failure, particularly during antibiotic administration.
• ARC is commonly seen in young patients with relatively low severity of illness. It is associated with sepsis, trauma, burns, and after major surgery. 
• Estimation of the glomerular filtration rate based on standard equations may be imprecise in the critical care setting and fail to identify patients with ARC. Measurement of urinary creatinine clearance is more appropriate. 
• Adjustment of dose to compensate for enhanced renal elimination is required with many antibiotics commonly used in the critically ill. Therapeutic drug monitoring should be carried out if feasible. 

References

1.         Loirat P, Rohan J, Baillet A, Beaufils F, David R, Chapman A. Increased glomerular filtration rate in patients with major burns and its effect on the pharmacokinetics of tobramycin. N Engl J Med. 1978;299(17):915-919. doi:10.1056/NEJM197810262991703

2.        Udy AA, Roberts JA, Boots RJ, Paterson DL, Lipman J. Augmented renal clearance: implications for antibacterial dosing in the critically ill. Clin Pharmacokinet. 2010;49(1):1-16. doi:10.2165/11318140-000000000-00000

3.        Bilbao-Meseguer I, Rodríguez-Gascón A, Barrasa H, Isla A, Solinís MÁ. Augmented Renal Clearance in Critically Ill Patients: A Systematic Review. Clin Pharmacokinet. 2018;57(9):1107-1121. doi:10.1007/s40262-018-0636-7

4.        Udy AA, Jarrett P, Lassig-Smith M, et al. Augmented Renal Clearance in Traumatic Brain Injury: A Single-Center Observational Study of Atrial Natriuretic Peptide, Cardiac Output, and Creatinine Clearance. J Neurotrauma. 2017;34(1):137-144. doi:10.1089/neu.2015.4328

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 Lond Engl. 2013;17(1):R35. doi:10.1186/cc12544

6.        Baptista JP, Udy AA, Sousa E, et al. A comparison of estimates of glomerular filtration in critically ill patients with augmented renal clearance. Crit Care Lond Engl. 2011;15(3):R139. doi:10.1186/cc10262

7.        Grootaert V, Willems L, Debaveye Y, Meyfroidt G, Spriet I. Augmented renal clearance in the critically ill: how to assess kidney function. Ann Pharmacother. 2012;46(7-8):952-959. doi:10.1345/aph.1Q708

8.        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

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

10.      Roberts JA, Lipman J. Optimal doripenem dosing simulations in critically ill nosocomial pneumonia patients with obesity, augmented renal clearance, and decreased bacterial susceptibility. Crit Care Med. 2013;41(2):489-495. doi:10.1097/CCM.0b013e31826ab4c4

11.      Campassi ML, Gonzalez MC, Masevicius FD, et al. [Augmented renal clearance in critically ill patients: incidence, associated factors and effects on vancomycin treatment]. Rev Bras Ter Intensiva. 2014;26(1):13-20.

12.      Mahmoud S, Shen C. Augmented Renal Clearance in Critical Illness: An Important Consideration in Drug Dosing. Pharmaceutics. 2017;9(4):36. doi:10.3390/pharmaceutics9030036