What is New in Augmented Renal Clearance in Septic Patients?

When a patient is critically ill, kidney function can be significantly altered, leading to profound physiological and clinical alterations. Clinicians used to focus on acute renal injury; however, concentrating solely on one end of the range of renal function can limit our understanding and hinder a comprehensive analysis. Augmented renal clearance (ARC) remains an underappreciated clinical condition, and strategies for managing it are still being developed. ARC can potentially decrease the plasma concentrations of renally eliminated drugs. This has been extensively demonstrated with antibiotics, but also with other drugs, such as enoxaparin [1], metformin [2], and levetiracetam [3‐5].

Antibiotics are one of the touchstones of the treatment of sepsis, and their early and appropriate administration improves clinical outcome. Clinicians are used to adjusting antibiotics to decreased renal performance; however, the reverse is quite rare. Dosing adaptation in critically ill patients is crucial due to the complex interplay of physiological changes, altered drug pharmacokinetics, and multiple co-existing medical conditions. Consequently, standard dosing regimens may not achieve the desired therapeutic effect or could lead to adverse drug reactions. Particularly, the critically ill frequently shows ARC, and this condition shows a robust association with under-therapeutic serum concentrations of several antibiotics. ARC impact has been increasingly described in intensive care units (ICU) around the world and has become included in recent guidelines and recommendations [6‐11].

A literature search was conducted on PubMed/MEDLINE between January 2018 and July 2023 to focus on publications within the last 5 years. All references that reported information on definition, identification, epidemiology, pathophysiology, and clinical relevance in sepsis of ARC were included. The search was limited to adult humans and articles published in English.

Although its recognition is not recent [12], the concept of ARC was first proposed in 2010 by Udy et al. and defined as an “increased elimination of circulating solutes compared with an expected baseline, involving changes in glomerular filtration and renal tubular function” [13]. There is still no standard definition for ARC, but there is a broad consensus that a creatinine clearance (CL_CR) ≥ 130 ml/min/1.73 m² seems to be an acceptable and clinically important cut-off value to define ARC: it is clearly supra-physiological, and it is the most used value in investigation and is undoubtedly associated with underexposure to antibiotics. By definition, the critically ill patient is often in unstable condition, and renal function varies quite substantially during the ICU stay. For that reason, augmented renal function should be interpreted more as a continuum and less as a dichotomic factor (presence/absence of ARC), as there is a linear correlation between renal function and elimination of most hydrophilic antibiotics.

Variations of glomerular filtration rate (GFR) are poorly reflected by daily changes in serum creatinine concentrations in critically ill patients. For that reason, creatinine-based equations are flawed in the critically ill and will tend to significantly underestimate renal function in patients with ARC [14, 15]. Despite the overwhelming medical evidence demonstrating the insensitivity of these methods, clinicians and investigators persist in assessing renal function this way. These considerations are strengthened in several recently published studies in ICU settings, including studies where a significant percentage of patients exhibited ARC.

In a study by Troisi et al., adult critically ill patients who underwent therapeutic drug monitoring (TDM) for meropenem and for whom a 24 h urine collection for measuring CL_CR (24 h-CL_CR) was performed were retrospectively included [16]. One quart of the studied cohort had at least one episode of ARC. The authors evaluated the performance of Cockcroft-Gault (CG), Modification of Diet in Renal Disease (MDRD) study, and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations. They concluded that these mathematical formulas were not adequate for calculating the doses of meropenem necessary to achieve a therapeutic level and that renal function should be measured rather than estimated, especially for those displaying ARC. In a retrospective, single-center study, among 74 patients admitted to a neurocritical ICU, Monteiro et al. showed a weak statistical correlation between measured and estimated methods, with underestimation of ARC, and concluded that these discrepancies were not clinically acceptable [17•].

Relatedly, in a post hoc analysis of an observational study in 80 neurocritical patients, 8 h-CL_CR seems to translate into the most appropriate assessment of renal function in patients with aneurysmatic subarachnoid hemorrhage, after comparison with 14 mathematical Eqs. (18). Another retrospective, single-center, study including 82 critically ill patients (43% with severe acute coronavirus 2 respiratory syndrome (SARS-CoV-2)) showed the low concordance between the GFR estimated by the CKD-EPI formula and the 24 h-CL_CR [19]. In a sub-study of an ICU multicenter randomized controlled trial, the performance of CG, MDRD, CKD-EPI, and Jelliffe equations was evaluated against measured urinary CL_CR in 237 critically ill patients with different degrees of kidney function (38.4% had ARC based on 24 h-CL_CR). The conclusion was that such equations had limited ability to adequately estimate 24 h-CL_CR [20]. Identical conclusions were reached in a prospective observational study, encompassing 100 patients consecutively admitted to a medical ICU in Taiwan [21]. Cucci et al. performed a larger multicenter, retrospective study (383 ICU-admitted patients were included, providing 1708 8 h- or 24 h-CL_CR paired measurements) and reported that among ARC patients, there was a low correlation (r = 0.24–0.28), a low to moderate accuracy (range 38–70%), and a high bias (range of − 58.5 to − 21.6) between CG and measured CL_CR [22•].

In a retrospective cohort study, investigators showed that there was 25% discordance in drug dosing depending on the use of either estimated (CG) or measured renal function. In addition, 69% of the estimated values deviated ± 20% from the reference value (CL_CR) [23•]. Similar conclusions were reached in a prospective cross-sectional study (145 ICU patients), showing that none of the used mathematical estimates accurately detects the ARC as accurately as 12 h-CL_CR [24], as well as in another recent study investigating a cohort of 68 burn patients, even after using the new 2021 updated CKD-EPI Eq. [25•]. In a prospective, observational cohort study of critically ill Indigenous Australian and non-Indigenous patients, Tsai et al. included a total of 131 patients, showing a prevalence of ARC of 32%. CG and CKD-EPI equations showed limited agreement with measured CL_CR [26]. A recent multicenter retrospective study investigated the agreement between 24 h-CL_CR and CG, CKD-EPI, and MDRD; a total of 51.604 ICU days were included, with an ARC prevalence of 20% [27•]. The authors concluded that all the studied estimates were flawed in the critically ill and showed a tendency to significantly under-evaluate renal function. Identical conclusions were reached in another multicentric study involving 561 critically ill patients, showing no concordance between the estimation of GFR by the CKD-EPI formula and 4 h-CL_CR [28•].

Recently, Huang et al., applying machine learning algorithms, developed and validated models for 1 day in advance daily prediction of CL_CR in ICU setting [29]. Among the ten most predictive variables of the three models, seven were related to 24 h-CL_CR on the previous day; however, unstable renal function incremented the attributable error. Taking into account the daily creatinine variation, a group of investigators studied the kinetic estimated GFR equation, based on two separated serum creatinine levels, in a cohort of 60 patients (180 paired samples with an ARC prevalence of 48%); they concluded that this “dynamic” formula is not a reliable alternative when compared to measured 24 h-CL_CR [30].

Of interest, in 232 adult non-critically ill surgery patients with a significant proportion displaying ARC, a remarkable disagreement and low precision were present between estimated and measured renal function (8 h-CL_CR), and studied equations underestimated renal function [31].

Mathematical equations for estimation of renal function are typically derived from non-ICU populations, such as patients with normal renal function or with mild dysfunction or normal individuals, and are not validated in the critically ill population. Therefore, in the ICU, any method of assessing kidney function that does not consider urine output should be considered unreliable. Of note, the 2020 Japanese Clinical Practice Guidelines for Management of Sepsis and Septic Shock warn readers about the potentially inadequate results related to the use of estimates of renal function in the critically ill [6]. Similarly, for the optimization of β-lactam treatment in critical care patients, the French Society of Pharmacology and Therapeutics (2018) suggests estimating GFR by calculating urinary creatinine clearance instead of equations. [8].

In light of this information, we can state with some certainty that urinary creatinine clearance remains the more reliable, cost-effective, replicable, and biologically precise alternative compared to mathematical calculations for evaluating renal function at bedside and adequately detecting ARC in critically ill patients, particularly for the purpose of renal adjustment of antibiotic dosing. Although any time interval used for calculation of CL_CR is adequate and informative, the nighttime evaluation within a time period of 8 h coinciding with nursing shifts can be the most pragmatic and probably associated with less workload. Furthermore, in our experience, it provides “fresh data” for decision-making involving pharmacokinetic issues during the morning medical round.

There are few reports on how ARC occurs, as the pathophysiology behind this entity is still largely unknown. Recent publications suggest that rather than a fixed chain of events where one single alteration gives way to another, it seems to result from various processes occurring simultaneously.

As a consequence of severe physiological stress related to sepsis or septic shock, the body appears to enter into an inflammatory hypermetabolic state in which pro-inflammatory mediators and cytokines are released [62, 63]. These compounds trigger profound metabolic and cellular changes that culminate into an increase in cardiac output and decrease in peripheral vascular resistance, which translates into increased renal blood flow and thus enhanced glomerular filtration. However, the increase in GFR seen in hyperinflammatory states may reflect a direct consequence of the inflammatory mediators as well, regardless of the hemodynamic changes they entail. In an experimental model of endotoxemia, after a lipopolysaccharide (LPS) derived from Escherichia coli was administered in healthy subjects, Beunders et al. [64] described an increased plasma concentration of pro-inflammatory cytokines, correlating with an increase in GFR (as measured by iohexol clearance). However, this increase in GFR did not appear to be dependent of perfusion pressure, as blood pressure was significantly lower compared to baseline during observation. In another recent study [65•], evaluating pathogenesis behind ARC at a transcriptional and metabolic level, the authors concluded that patients with ARC exhibited upregulation of L-arginine and L-glutamate, which indicated an increased consumption of arginine in critically ill patients with ARC. This in turn provides sufficient conditions for an increased production of nitric oxide (NO), ultimately increasing renal blood flow perfusion through NO-related inflammatory mediators. The authors also reported a direct regulation of GFR through N-methyl-D-aspartate receptor, which is regulated by glutamate. Finally, they concluded that the upregulation of cAMP leads to increased capillary permeability and extra-stromal precipitation.

Perhaps subjacent to the entire concept of ARC, closely linked to both the release of inflammatory mediators and a hypercatabolic state seen in sepsis, is the concept of renal functional reserve (RFR). RFR refers to the ability of the kidney to recruit previously dormant nephrons in times of biological stress, which results into increased renal blood flow and/or glomerular hyperfiltration. Although the exact mechanism behind the occurrence of RFR is yet unclear, recent studies reiterate the importance of protein loading and dilation of afferent glomerular arterioles after impaired renal auto-regulation, as well as complex interactions between tubuloglomerular feedback (TGF), the release of NO and vasodilator prostaglandins, and the metabolism of glucagon [66, 67].

Another mechanism behind ARC seems to be related to the severely catabolic state seen in these patients, which results into increased tissue destruction and excessive protein breakdown. Increased protein intake is thought to be associated with elicitation of RFR and thus enhanced GFR: an increase in the filtered load of amino acids reduces distal delivery of sodium chloride by increasing its tubular reabsorption, leading to inhibition of TGF, thus inducing afferent arteriolar vasodilation and consequently promoting hyperfiltration [66]. However, until recently, such a conclusion was derived from stable, healthy, and non-critical patients. In a recent retrospective single-center ICU study with around half of the cohort in sepsis [58], ARC was prevalent in approximately half of the patients admitted, who demonstrated marked protein catabolism (as evidenced by a worsened nitrogen balance), despite receiving a similar protein intake. Of note, the authors also found a significant association between ARC and increased protein intake (adjusted OR 2.06; 95% CI 1.09–3.91). Another study [68] concluded that patients with ARC presented a lower nitrogen balance and increased muscle loss despite receiving similar protein intake; patients with a higher protein intake had higher levels of CL_CR. Whether a renoprotective nutrition (e.g., low-protein diet) would improve patient outcomes by reducing glomerular pressure and thus ARC (while perhaps promoting sarcopenia and muscle wasting) is less clear and warrants further investigation.

Tubular secretion seems to play a part as well in patients displaying ARC. A single-center, retrospective study [69•] attempted to compare GFR measured with iohexol plasma clearance and CL_CR in critically ill patients with ARC. They concluded that half of the patients presenting ARC did not in fact have hyperfiltration and concluded that 6 h-CL_CR appears to overestimate renal function by taking into account basal tubular excretion of creatinine. In a recent case report [70•], the same mechanism was evidenced. These findings suggest that ARC is due not only to increased glomerular filtration but also increased tubular secretion, at least to some extent. This is of particular importance, since it may influence renal elimination for drugs subject to these mechanisms, namely, some antimicrobials (β-lactams [71, 72], antiviral drugs [72], vancomycin [73]).

Additionally, one must consider the exogenous factors that contribute to ARC which do not result from the body’s own response to stimuli, but rather from medical intervention, such as aggressive fluid administration, use of vasopressor drugs, and inotropes. One study by Dhondt et al. [74] concluded that fluid resuscitation contributed more to the development of ARC than previously thought, after inducing a sepsis-like state in piglets through the continuous infusion (CI) of LPS from E. coli, except for one sham pig that only received the same amount of fluid treatment (0.9% sodium chloride solution, 6 mL/kg/h), and demonstrating that both groups displayed an elevated GFR over the time course of the study.

There are other factors that have been put forward when attempting to explain the pathophysiology behind ARC, such as a possible link between renal function and TBI [75], with the identification of elevated circulating atrial natriuretic peptide levels, and a significant correlation between neuromonitoring data (intracranial pressure, cerebral perfusion pressure, and the cerebrovascular pressure reactivity index) and ARC-presenting patients [76]. However, further studies are needed in order to shed light on this matter. The various mechanisms involved in the occurrence of ARC are summarized in Fig. 1.

Several studies have been published evaluating the influence of ARC in pharmacokinetics (PK)/pharmacodynamics (PD) of antibiotics, not only with the newest antibiotics but also with some of the old antibiotics, showing that ARC has been recognized as an important factor for adjusting antibiotics’ doses. The three most reported antibiotics in recent years were vancomycin, meropenem, and piperacillin-tazobactam, which can be explained by the easy access to clinical data resulting from TDM. This is in accordance with current recommendations for routine TDM to be performed for aminoglycosides, β-lactam antibiotics, linezolid, teicoplanin, vancomycin, and voriconazole in critically ill patients [7].

Some of the published studies found in literature had the purpose of evaluating the association of ARC with subtherapeutic concentrations of antibiotics when using the standard dosage regimens, while others used population pharmacokinetic models and simulation to recommend dosage regimens for patients with ARC. Only few studies have explored the real impact of ARC on clinical outcomes, such as clinical cure, antimicrobial resistance, or mortality.

Although there is an increased interest in ARC, there are still many issues requiring standardization, accuracy, or clarification:

ARC is a well-recognized event with significant prevalence in the ICU around the world, with robust association with subtherapeutic levels of several antibiotics. However, there is still work to do on the correct identification of ARC patients through measured CL_CR, understanding better the pathophysiology behind ARC, defining conditions for dose adjustments of antibiotics, and establishing an association with clinical outcomes.