Augmented Renal Clearance in ICU

Dr Swapnil Pawar & Dr Jose Chacko

What is ARC?

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.

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

What is the pathophysiology? Why do critically ill patients have ARC?

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. Fluid resuscitation and the use of vasopressor medication may also increase the GFR, leading to ARC. 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 for the development of ARC. ARC is frequently observed in neurocritical care, including patients with traumatic brain injury and subarachnoid hemorrhage; 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

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. Hence, measurement of urinary creatinine clearance 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. 

There are scoring systems that can predict which patients in ICU will have ARC –

Second – We need to consider the limitations of creatinine clearance estimation in ICU.

A comparison of the various mathematical estimates suggests the Cockcroft Gault (CG) formula may be the best method of creatinine clearance estimation in the ARC population. Even if a CG estimate shows an estimated creatinine clearance within the normal reference range, there is still a high likelihood that ARC can be present in a patient. Therefore, in the setting of ICU, it would be prudent to assess a patient’s measured creatinine clearance at least once, to determine whether a patient is truly experiencing ARC, and to also gauge the level of bias in the estimated creatinine clearance for that patient. although serum creatinine used for the determination of creatinine clearance is a reliable marker within the general population, consideration must be made when applying this measurement in patients with lower muscle mass, immobility, children or other conditions in which muscle mass are altered. Due to the reduced production of creatinine in these patients, falsely low measures of serum creatinine may inaccurately identify ARC in those populations.

What is the significance of ARC to the intensivist?

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 upon 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. A continuous administration may be particularly relevant as therapeutic drug level monitoring of beta-lactams is rarely carried out in clinical practice.

I agree. In the ICU setting, pharmacokinetic changes to drug therapy in the presence of ARC may have drastic implications on patient outcomes. This is especially important to drugs that are renally cleared known to exhibit a direct correlation between their renal clearance and creatinine clearance such as aminoglycoside antimicrobials, vancomycin, and levetiracetam.

The bathtub analogy can explain this better. The bathtub outlet is nothing but renal clearance. If tub empties quickly due to enlarged outlet size, we need to pour more water to keep the bathtub filled.

Enhanced drug clearance will lead to shorter drug half-life (t½), lower maximum drug concertation (Cmax) and lower area under the concentration curve (AUC) which could have direct implications on drug pharmacodynamic effects leading to therapy failure.

Currently, antimicrobial monograms and various dosing guidelines have not acknowledged the need for alterations to drug dosing regimen in the ARC population.

Also, this is not a standard practice across the globe, which is surprising.

What’s the evidence in using ARC for dose adjustment of Antibiotics in critically ill patients?

In a study of critically ill patients who were treated with beta-lactams, piperacillin was the most commonly prescribed beta-lactam. In this cohort, 85% of patients were ventilated, and 25% were on vasopressors. The trough drug concentration greater than or equal to MIC in only 58% of measured levels. Drug levels four times or higher than the MIC was achieved in only 31%. They also found that the 8-h creatinine clearance values ≥ 130 mL/min/1.73 m2 were associated with trough concentrations less than MIC in 82% and less than four times MIC in 72%. This study clearly showed that augmented renal clearance results in less than optimal level of beta-lactams in critically ill patients.¹

In another study that evaluated vancomycin levels, 40% of 93 patients exhibited ARC; in these patients, the vancomycin trough concentrations were significantly lower than in patients with ARC. Only 10.8% of patients in the ARC group exhibited ‘therapeutic levels’ on day 1; this increased to only 51.6% on day 3 of therapy.² This suggests that patients with ARC exhibit lower vancomycin concentrations and may have subtherapeutic concentrations early in therapy when standard dosing strategies are applied. 

Thus, there is good evidence to support failure to attain therapeutic levels of antibiotics in the presence of ARC. However, the evidence is unclear regarding the incidence of therapeutic failure and other clinical outcomes. In a prospective observational analysis of a mixed medical and surgical ICU cohort of 128 patients, 51% developed ARC. ARC was significantly associated with treatment failure (27.3% vs. 12.9%).³ In contrast, other studies of sepsis in critically ill patients with and without ARC have demonstrated low beta-lactam concentrations, but no differences in clinical cure, ICU-free days, or mortality after adjusting for age, SOFA score, and the presence of ARC.

Besides problems with sub-therapeutic drug levels and treatment failure, continuous exposure of bacteria to sub-therapeutic levels may lead to increased resistance. 

What’s your current practice?

We have started doing 4 h urinary creatinine clearance estimation in patients who may be at risk to develop ARC, particularly in sepsis and TBI. We have seen a couple of patients with urinary creatinine clearance that would be classified as ARC. When we encounter such patients, we increase the dose of antibiotics appropriately. 

We have also seen that the urinary creatinine clearance may be significantly low even in the presence of a creatinine level within the normal range and normal urine output. Thus, it may be important to assess renal function using urinary creatinine clearance in critically ill patients. The AKIN or KDIGO criteria which depend only on creatinine levels and urine output may not be sensitive enough to diagnose early stages of renal dysfunction.  

I agree. I recently came across this article by Sherif Mahamoud and Chen Shen published in Pharmaceutics. 2017 Sep; 9(3): 36. who proposed this approach – 

With regards to antibiotic dosing,

I follow the following principles – 

I use the following doses if suspected ARC – 

Additional References –

1. Udy AA, Varghese JM, Altukroni M, et al. Subtherapeutic initial beta-lactam concentrations in select critically ill patients: Association between augmented renal clearance and low trough drug concentrations. Chest. 2012;142:30-39. 
2. Baptista JP, Sousa E, Martins PJ, et al. Augmented renal clearance in septic patients and implications for vancomycin optimisation. Int J Antimicrob Agents. 2012;39:420-3. 
3. Claus BO, Hoste EA, Colpaert K, et al. Augmented renal clearance is a common finding with worse clinical outcomes in critically ill patients receiving antimicrobial therapy. J Crit Care. 2013;28:695-700.