Augmented renal clearance: when supranormal renal function may cause harm

Introduction

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 manifesting 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 ARC has been the focus of extensive research in recent times; however, the pathophysiology is complex, and several unanswered questions remain. 

Definition

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 The duration of ARC has also been proposed as an important consideration. A substantial number of patients develop increased renal solute clearance over the first week of ICU stay, which may remain undetected.4  In a prospective observational study from a mixed medical-surgical ICU, ARC was identified in 51.6% of patients. Therapeutic failure was defined as an impaired clinical response to the antibiotics administered with the need for alternate therapy. Patients who had transient ARC (only for 1 day) were less likely to experience therapeutic failure (17.4%) compared to those who experienced ARC throughout the study period (33.3%).5

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 leads 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. Local release of nitric oxide and prostaglandins have also been implicated in the increase in renal blood flow.6 Fluid resuscitation and the use of vasopressor medication may also increase the GFR, leading to ARC.7 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 of the kidneys is higher in younger subjects, who have a greater propensity for the development of ARC.8 ARC is frequently observed in neurocritical care, including in patients with traumatic brain injury (TBI) and subarachnoid hemorrhage; contributing factors may be the use of osmotherapy for raised intracranial pressure and vasopressors to maintain the cerebral perfusion pressure. ARC may be mediated by an increase in the atrial natriuretic peptide (ANP) levels resulting from increased sympathetic activity seen in TBI. A rise in ANP levels leads to vasodilatation of the afferent arteriole, with an increase in the renal blood flow and the GFR.9 Younger age group (34–50 y), polytrauma, and lower severity of illness are common risk factors for ARC.3      

How do you diagnose ARC? 

There is ongoing debate regarding the methodology that may be appropriate to diagnose augmented renal clearance.

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).10,11 Hence, measurement of urinary CrCl is more appropriate in the diagnosis of ARC. Although an 8–24 hour urine collection is conventionally followed, a 2-hour 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 x body 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.8 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.12 The ARCTIC scoring system, which does not include the SOFA score, has been developed to identify ARC in trauma patients and was shown to have a sensitivity of 84% and specificity of 68% in identifying ARC.13 (Table. 1)

Table 1. Scoring systems for the early identification of ARC 

 ARC scoring system7ARCTIC scoring system11
Criteria Age 50 or less: 6 pointsTrauma: 3 pointsSOFA < 4: 1 pointS. creatinine <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 in patients with ARC.14 A 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.15 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. Therapeutic drug level monitoring may be an important facet of care in patients presenting with ARC. Therapeutic drug level monitoring in infected body fluids may also be an option, e.g., cerebrospinal fluid in meningitis. This may be important in situations with nonuniform antimicrobial distribution and poor correlation between levels in the plasma and infected tissues.16 Table 2 summarizes recommended dosing for drugs significantly impacted by ARC.17    

Table 2. Suggested intravenous dosing for drugs that are significantly impacted by ARC17

Drug Suggested IV dose 
Meropenem Bolus: 2 g over 30 min, followed by 2 g/8 h, administered over 3 h
VancomycinLoading 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 at 10–20 mg/l 
Piperacillin/tazobactam4.5 g/6h, as extended infusion over 4 h
Levofloxacin 750–1000 mg 24 hourly
Levetiracetam 1000 mg 8 hourly

ARC and the newer antibiotics 

Ceftazidime-avibactam is a newer beta-lactam and beta-lactamase combination that is effective in gram-negative infections including strains that produce Klebsiella pneumoniae carbapenemase (KPC) and Enterobacteriaceae spp. oxacillinase (OXA-48). Ceftazidime-avibactam is predominantly excreted by the kidneys and dose adjustment is required based on the renal function. In the REPROVE study, the ceftazidime-avibactam combination was compared with meropenem in patients with nosocomial pneumonia. In patients with ARC, the standard dose of ceftazidime 2 g and avibactam 500 mg as a 2-hour infusion, administered 8 hourly, attained a target drug concentration above the minimum inhibitory concentration (f T > MIC) for 50% of the time with 95% probability.18 Population pharmacokinetic models including five phase III trials also suggest that the dose of ceftazidime-avibactam may not require adjustments in patients with ARC.19 No information is available on dose adjustment of the meropenem-vaborbactam combination in the presence of ARC. Imipenem–relebactam is a new carbapenem-beta-lactamase inhibitor combination. It has enhanced activity against multidrug-resistant strains of P. aeruginosa and other carbapenemases-producing Klebsiella and Enterobacteriaceae. The packet insert warns about insufficient drug levels if the creatinine clearance exceeds 150 ml/min; however, no recommendations are made for dose adjustment.20

Efficacy of combination therapy in ARC

Combination therapy has been investigated as a possible treatment strategy to overcome ARC using the hollow fiberinfection model (HFIM).21 HFIM is an in vitro system that enables high-andensity microbial cultures in an enclosed compartment.22 Ayeman et al., using the HFIM model, demonstrated the efficacy of the meropenem-ciprofloxacin combination compared to monotherapy with maximum daily doses under ARC conditions.23 Clinical studies are required to test the efficacy of combination compared to monotherapy among patients with ARC.

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. The ARC and the ARCTIC scoring systems enable early identification of ARC
  • 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
  • A strategy of combination therapy with antimicrobials may be one of the options to overcome ARC and ensure antibiotic efficacy 

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, Baptista JP, Lim NL, et al. Augmented renal clearance in the ICU: results of a multicenter observational study of renal function in critically ill patients with normal plasma creatinine concentrations*. Crit Care Med. 2014;42(3):520-527. doi:10.1097/CCM.0000000000000029

5.         Claus BOM, 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

6.         Sharma A, Mucino MJ, Ronco C. Renal functional reserve and renal recovery after acute kidney injury. Nephron Clin Pract. 2014;127(1-4):94-100. doi:10.1159/000363721

7.         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

8.         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

9.         Khalid F, Yang GL, McGuire JL, et al. Autonomic dysfunction following traumatic brain injury: translational insights. Neurosurg Focus. 2019;47(5):E8. doi:10.3171/2019.8.FOCUS19517

10.       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

11.       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

12.       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

13.       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

14.       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

15.       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.

16.       Abdul-Aziz MH, Alffenaar JWC, Bassetti M, et al. Antimicrobial therapeutic drug monitoring in critically ill adult patients: a Position Paper#. Intensive Care Med. 2020;46(6):1127-1153. doi:10.1007/s00134-020-06050-1

17.       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

18.       Torres A, Zhong N, Pachl J, et al. Ceftazidime-avibactam versus meropenem in nosocomial pneumonia, including ventilator-associated pneumonia (REPROVE): a randomised, double-blind, phase 3 non-inferiority trial. Lancet Infect Dis. 2018;18(3):285-295. doi:10.1016/S1473-3099(17)30747-8

19.       Li J, Lovern M, Green ML, et al. Ceftazidime-Avibactam Population Pharmacokinetic Modeling and Pharmacodynamic Target Attainment Across Adult Indications and Patient Subgroups. Clin Transl Sci. 2019;12(2):151-163. doi:10.1111/cts.12585

20.       Gorham J, Taccone FS, Hites M. Drug Regimens of Novel Antibiotics in Critically Ill Patients with Varying Renal Functions: A Rapid Review. Antibiotics. 2022;11(5):546. doi:10.3390/antibiotics11050546

21.       Yadav R, Bergen PJ, Rogers KE, et al. Meropenem-Tobramycin Combination Regimens Combat Carbapenem-Resistant Pseudomonas aeruginosa in the Hollow-Fiber Infection Model Simulating Augmented Renal Clearance in Critically Ill Patients. Antimicrob Agents Chemother. 2019;64(1):e01679-19. doi:10.1128/AAC.01679-19

22.       Sadouki Z, McHugh TD, Aarnoutse R, et al. Application of the hollow fibre infection model (HFIM) in antimicrobial development: a systematic review and recommendations of reporting. J Antimicrob Chemother. 2021;76(9):2252-2259. doi:10.1093/jac/dkab160

23.       Agyeman AA, Rogers KE, Tait JR, et al. Evaluation of Meropenem-Ciprofloxacin Combination Dosage Regimens for the Pharmacokinetics of Critically Ill Patients With Augmented Renal Clearance. Clin Pharmacol Ther. 2021;109(4):1104-1115. doi:10.1002/cpt.2191

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