Four hour creatinine clearance is better than plasma creatinine for monitoring renal function in critically ill patients

Acute kidney injury (AKI) is common in critically ill patients and is frequently fatal [1–5]. Although defined as an abrupt decrease in glomerular filtration rate (GFR) [6, 7] there are no real time measures of GFR to enable timely diagnosis. In practice, diagnosis depends on observing an increase in plasma creatinine (pCr); according to creatinine kinetics, this may not become apparent until 24 to 72 hours after a decrease in GFR [8]. This temporal disconnect between changed GFR and pCr is readily observable, particularly where there is a clearly defined time of injury, such as cardiopulmonary bypass surgery. The relationship is less clearly demonstrated following multiple or continuing injury and after vigorous resuscitation. The relationship between change in GFR and change in plasma creatinine has not been investigated in critically ill patients at high risk of AKI. In contrast, numerous urinary and plasma biomarkers of kidney injury are under investigation, and are usually assessed by their ability to predict an increase in creatinine [9, 10]. Although, many biomarkers show promise as predictors of change in renal function, of dialysis need and of mortality, their primary biological role is to mark the presence of renal injury. With the exception of plasma cystatin C, these biomarkers are not markers of function.

Creatinine clearance (CCl) is an easy to estimate GFR in the intensive care unit, since most patients are catheterised and have frequent measurements of pCr. In patients with normal creatinine a low CCl may be an early indicator of AKI [11]. Several studies have shown that short duration (1 to 4 h) CCl measures are feasible in the critically ill [11–14]. Several of these evaluated CCl by comparing short duration clearance with 24-h clearance [12–14]. While validating the brief clearance technique, these studies did not evaluate the use of brief CCl in the detection of AKI.

Evaluation of 4-h CCl was a planned component of the two-centre Early intervention in Acute Renal Failure (EARLYARF) randomised controlled trial of high dose erythropoietin for the prevention of AKI in the ICU [15]. We hypothesised that CCl would give more timely and accurate information on renal function than pCr. We compared these metrics in the diagnosis of AKI and AKI severity and as predictors of the need for dialysis and mortality. We also compared these metrics with urine output. Finally, we compared serial measurements of CCl with serial measurements of pCr.

The study was approved by the multiregional ethics committee of New Zealand (MEC/050020029) and registered under the Australian New Zealand Clinical Trials Registry (ACTRN012606000032550 [16]). Screening on entry to the ICU was by presumptive consent, followed by written consent from the patient or family.

The measurement of a brief CCl, relative to a known baseline value (or when unknown, relative to a calculated CG baseline value), provided earlier diagnostic and prognostic information, compared with change in pCr alone. AKI on entry to the ICU was identified in one third of patients not identified by pCr. After admission to the ICU, these patients were identified earlier than those identified by ΔpCr, consistent with the delay in pCr equilibration suggested by creatinine kinetics. ΔCCl also identified a cohort of patients, the (ΔpCr_AKI and ΔCCl_No-AKI) group, with normal renal clearance but with an increased pCr, consistent with recovering renal function after an earlier loss of GFR. This mistiming between CCl measurement and steady state pCr potentially explains the poor correlation (r² = 0.18) observed. The probability of death or dialysis was more closely associated with the ΔCCl RIFLE severity grade than with ΔpCr severity grade. Serial measurements of CCl provided a diagnosis of AKI and of improving renal function earlier than serial measurements of pCr and also identified patients at risk of dialysis.

A low on-entry CCl was associated with poor outcome, including death. In contrast, neither UO nor pCr predicted death. The moderate AUCs indicate that CCl is not a useful stand-alone predictor of death. When added to a risk prediction model for AKI in patients with low on-entry pCr (< 1.24 mg/dl), CCl greatly improved the model. A sub-threshold CCl predicted the development of AKI and was associated with severity of AKI when AKI was determined using the on-entry creatinine as baseline. The combination of a normal pCr (< 1.24 mg/dl) and low CCl (< 48.6 ml/min) had a moderately high predictive value (0.88) for the early detection of AKI.

Patients with a low CCl and increased pCr need additional information to distinguish on-entry AKI from chronic kidney disease (CKD) in the absence of a pre-admission baseline creatinine. The presence or absence of oliguria alone in this group was not sufficient to distinguish patients with CKD from those with AKI (data not shown). Underlying CKD causes the relative increase in pCr to be lower, potentially delaying diagnosis of AKI if a relative change in creatinine is used for diagnosis [24]. An absolute rise in creatinine allows diagnosis to be independent of the underlying function [24]. However, for early diagnosis, injury biomarkers not associated with CKD are needed to identify on-entry AKI from CKD without AKI. Unfortunately, amongst the injury markers we measured in this cohort (with time course of sufficient duration to be increased when pCr was increased) biomarker performance depended on baseline renal function [10] which makes interpretation difficult when the patient has CKD. Only 22% of patients (n = 16) with an initial one third decrease in CCl subsequently developed a 50% increase in pCr as predicted by the creatinine kinetic model. Serial measurements were needed to identify patients with only a transient decrease in CCl. Some of the false positives in this group reflected a high initial CCl, suggesting caution when interpreting a decrease in CCl if the initial CCl baseline is high (> 140 ml/min).

The optimum frequency for monitoring loss of GFR remains to be determined, and near real-time measurements of GFR are possible [8]. In this study, CCl was measured on entry to the ICU and then 12 hourly. Since urine output is measured hourly in most ICUs, the frequency of CCl measurements could easily be increased with more frequent plasma and urine creatinine sampling. CCl would then have the potential to provide earlier information on worsening of AKI severity and to facilitate interpretation of changes in pCr. For example, while a modest increase in pCr suggests progression of severity, for example, from RIFLE stage R to stage I, renal function may remain unchanged. An unchanged CCl would demonstrate that the apparent progression represented a prior, rather than a continuing decrease in GFR. Detection of a true decline in renal function requires demonstration of incremental loss of GFR, which may be detected by serial CCl measurements but not initially by serial pCr measurement. CCl may also be preferable to pCr for other clinical purposes, such as calculation of dose for renal-excretion drugs [25], or for triaging patients in trials in AKI, aiming to intervene after a decrease in GFR but prior to creatinine increase, so-called secondary prevention [26].

Alone, the urine output criterion for diagnosis of AKI was not a reliable alternative to CCl. Consistent with these findings, Prowle et al. recently demonstrated that most episodes (94%) of oliguria were not associated with AKI (RIFLE I by the creatinine- change criterion) the next day [27]. As discussed, there are many modifiers of urine output in critically ill patients, including the administration of fluids and diuretics, and impaired ability for urinary concentration in some patients with CKD.

The search for new biomarkers of AKI has aimed to identify injury that leads to significant loss of GFR, as an alternative to waiting for GFR-induced change in pCr. Nevertheless, most biomarker studies have relied on change in creatinine, the surrogate for change in GFR, on the assumption that pCr changes follow a simple creatinine kinetic model [28]. This was the assumption behind the RIFLE definition of equating a percentage increase in pCr with a percentage decrease in GFR [6, 18]. Although the AKIN removed change in GFR from the RIFLE, we have argued that the principal of measuring a change in GFR should be retained as the gold standard in the definition of AKI [29]. While awaiting a commercially available real-time measure of GFR, we postulate that serial CCl may allow identification of the specific phase of injury in AKI [26]. Brief CCl could also help determine whether a particular injury biomarker was increased before or after a decrease in GFR, which may also facilitate appropriate intervention. In a recent AKI biomarker study, the difference between the estimated baseline and 12-h CCl within 48 h of ICU admission was used to define patients with AKI [30]. This enabled the study to assess the effectiveness of a combination of pCr and urinary gamma-glutamyltranspeptidase in AKI detection. This suggests that change in CCl may be independently useful as a selection criterion for early intervention.

A low CCl (in our study < 48.6 ml/min) on entry to the ICU indicates that individuals are at high risk of AKI. We suggest this should lead to the appropriate management recommended by the Kidney Disease: Improving Global Outcomes (KDIGO) consortium (see Figure 4 in [31]). This comprises: discontinuation of nephrotoxic agents, maintenance of perfusion pressure and volume status, further haemodynamic monitoring, continued monitoring of serum creatinine and urine output, avoidance of hyperglycaemia and contrast procedures, and additional diagnostic workups. In addition, we recommend further CCl monitoring. As a research tool, where available, measurement of biomarkers of kidney injury could assist in establishing the diagnosis of AKI [32, 33]. In contrast, if CCl on entry to the ICU is normal in the presence of an increased pCr, patients may be stratified to lower risk. At this stage, we would recommend at least one more 4-h CCl to confirm normal clearance. Clearly, biomarkers of acute kidney injury could be helpful here too, if available. Clearly all patients who appear to have had a short episode of AKI prior to entry to ICU should have nephrology follow up after discharge to check for progression to CKD.

In a high-risk clinical setting, short duration CCl measurement is useful for patients with a known baseline creatinine for whom a CG estimation of baseline CCl can be made or when pCr is low. In this setting, low CCl suggests an acute loss of renal function and will influence drug dosing, initiate avoidance of known nephrotoxins, and trigger early nephrology consultation. Regular additional CCl would monitor recovery. Further, larger studies are required to determine the optimum frequency and duration of CCl measurement.

When pCr is increased in a patient with normal baseline values, 4-hourly CCl can distinguish resolving and ongoing renal impairment.

CCl may be useful in clinical trials by identifying patients soon after loss of renal function and before pCr is elevated, or by excluding patients when renal function is impaired.