Daily urinary creatinine predicts the weaning of renal replacement therapy in ICU acute kidney injury patients

Acute kidney injury (AKI) is a common condition in the intensive care unit (ICU). Approximately 5 % of ICU patients suffering from AKI require renal replacement therapy (RRT) [1]. Such patients have a hospital mortality rate of 45–70 % [1–6], and those surviving to hospital discharge continue to carry a high risk for long-term morbidity and mortality [7–10]. Several studies have shown that between 10 and 30 % of patients with AKI who required RRT will remain dialysis dependent at discharge [7–13]. Yet, renal function in AKI surviving patients requiring RRT ultimately recovers in the vast majority of case (more than 90 % of patients) [14]. However, performances of RRT may have untoward effects that contribute to the prolongation of renal failure or impede the ultimate recovery of renal function [15]. Indeed, RRT represents an independent and an added risk factor for mortality [16–18] as it exposes the patient to several complications like catheter-related infections or thrombosis, bleeding favored by anticoagulation, hemodynamic instability. The prolonged continuation of RRT could also be deleterious for renal recovery, particularly in cases of intradialytic hemodynamic instability, inducing renal ischemic lesions [19]. Renal biopsy in patients with prolonged AKI treated by hemodialysis showed regions of fresh tubular necrosis days-to-weeks after the initial insult [20]. RRT may also delay renal recovery possibly by purification of mediators and growth factors needful for the tubular repair [21]. Moreover, RRT may remove unpredictable amounts of antibiotics, amino acids and nutrients. Also, RRT represents a significant additional cost in the patient’s care. It is therefore a matter of concern to identify which factors present at the time of discontinuation may help physicians in predicting successful cessation of RRT [22]. To the best of our knowledge, a paucity of studies has been reported on RRT weaning during AKI [23–26]. Sepsis-related Organ Failure Assessment (SOFA) score [23, 26] and 2-h creatinine clearance [25] have been reported as a reliable predictive factors, but urine output remains the most consistent parameter significantly associated with the success of weaning [24]. This study was therefore undertaken to investigate and identify parameters, particularly 24-h urinary creatinine, present at the time of RRT weaning that would be associated with successful cessation of RRT during AKI.

This retrospective study was conducted, from January 2008 to December 2012, in two medical ICUs of the Montpellier University Hospital, France. It was approved by our local institutional review board (Ethic Committee of Montpellier; Comité de protection des personnes: CPP Sud Mediterranée 4) which waived informed consent from the patients or their relatives.

In this study, we found that almost half of surviving AKI patients treated with RRT had their treatment stopped at the first attempt. We found also that the capability of 24-h urine output to predict RRT weaning was significantly altered by the use of diuretics. In contrast, 24-h urinary creatinine appeared as a powerful marker of successful discontinuation of RRT even if patients received diuretics.

A large majority of ICU patients with AKI may recover sufficient kidney function to be independent of RRT. Indeed, all surviving patients we investigated herein recovered and were weaned from RRT even if several weaning attempts were necessary in some of them. Currently, practices of RRT weaning during AKI depend on every center policy and vary from a “wait and see” and a “go fast” attitudes. The “wait and see” attitude may prolong needlessly RRT and expose the patient to its hazardous effects without any benefits. Conversely a “go fast” attitude may lead to several unsuccessful attempts of weaning with the subsequent requirement of re-institution that is by itself harmful. Appropriate cessation of RRT is obviously critical regarding clinical and economic outcomes. There is, however, a paucity of data about how and when to stop RRT in critically ill patients with AKI, and identification of predictive factors of successful cessation of RRT is scarce. This lack of evidence contrasts with the field of mechanical ventilation, where many studies dealing with the process of weaning have been conducted [30]. We sought therefore to evaluate, in the present study, whether cessation of RRT can be early determined on the basis of clinical and routinely used parameters.

Previous studies have reported the association of the success of an interruption of RRT with age [23], previous renal function [24, 25], the prior length of RRT, the SOFA score at ICU admission [23, 26] and its decrease from admission to the day of attempt [23]. None of these parameters have been found determinant in the success of weaning in our study. Blood parameters including serum urea and creatinine and their kinetic were also helpless to guide the weaning of RRT in our population. Urine output was reported to be the most important predictor of successful discontinuation of RRT. In the trial by Bouman et al. [31], continuous RRT was discontinued when the urine output returned to and was stable at more than 60 ml/h, but there were no data about the optimal rate of urine output predicting the success of weaning. Wu et al. [23] evaluated retrospectively 94 patients weaned from IHDF for 5 or more days, of which 64 were free from RRT for ≥30 days. 24-h diuresis was at 1435 ± 1172 versus 598 ± 700 ml in the success and the re-dialysis groups, respectively, but diuretics were used in 36 % of patients of both groups. Oliguria (100 ml in 8 h) was independently associated with re-initiation of RRT [23]. The BEST Kidney investigators [24] found that urine output of >400 ml/day without diuretics had the best operative characteristics with a Se, Sp, PPV and NPV of 0.47, 0.81, 0.81 and 0.77, respectively. However, diuretics administration negatively affected its predictive ability. They concluded that patients with more than 400 ml/day of urine without diuretics or more than 2300 ml/day with diuretics have more than 80 % of chance to successful discontinuation of RRT. Recently, an urine output >8.5 ml/kg/24 h was also found to predict IHDF weaning [32]. In our study, at the day of attempt, 24-h urine output failed to predict the success of weaning (2300 vs 1900 ml/24 h, p = 0.052) but a high proportion of our patients, more than 75 %, received furosemide. We observed, however, that furosemide induced a significantly higher diuresis in the success group. Indeed, recent studies reported a significantly higher urine output in case of successful discontinuation of RRT even if diuretics were used [25, 26]. Nevertheless, the usefulness of diuresis to guide RRT weaning is clearly reduced since diuretics often may be necessary to correct or avoid a fluid overload [33]. We sought then to determine predictive factors that would be independent of diuretics like urinary creatinine and urea. Urea and creatinine collected in urine during 24-h were significantly higher at the day of attempt of RRT weaning and the following 2 days (with a gradual increase) in the success group. By multivariate analysis, 24-h creatininuria was the most powerful predictor of success of weaning. A level ≥5.2 mmol/24 h had a Sp, Se, NPV and PPV of 75, 88, 82 and 84 %, respectively. Differences of creatinine urinary level observed between the two groups should not be related to muscle mass, as they were independent of patient’s age and weight. Also, these differences may not be explained by differences of urea or creatinine generation rate since ratios of urinary levels to generation rates were significantly higher in the success group. Of note, clearance of creatinine (and urea) was significantly higher in the S₊ group, as reported by Fröhlich et al. [25]. In a recent study, Aniort and colleagues [32] sought also to identify predictive factors of intermittent hemodialysis weaning by investigating retrospectively 67 AKI patients. They found that daily urinary urea was the best weaning marker with an optimal threshold >1.35 mmol/kg/24 h (AUC 0.96, 95 % CI 0.93–0.99) as compared to 24-h urine output. In the contrary of our findings, they did not observe any differences in urinary creatinine between weaned and unweaned patients. However, almost 1/3 of their patients (22/67) have a baseline GFR < 30 ml/mn and expectedly 26/67 patients did not recovered renal function. Our population included exclusively patients with a baseline GFR ≥ 60 ml/mn explaining, at least for a part, these discordant results.

RRT modalities (continuous or intermittent) may affect renal recovery and dialysis dependence, but their effects remain a matter of debate. A systematic review of the literature including mainly observational studies concluded that patients who received intermittent RRT had a significant increased risk of dialysis dependency as compared to those who received continuous RRT [34]. We observed indeed a higher proportion of continuous therapies with a higher weight decrease in the success group. However, differences were not significant and our RRT strategy was based on hemodynamic precluding any conclusions from our study. It is noteworthy that two recent studies failed to demonstrate any impact of RRT modalities on renal recovery [35, 36].

Patients who require RRT for AKI have a mortality exceeding 60 %, but most patients that recover function enough to be free from RRT survive to hospital discharge [37]. In the study of BEST Kidney investigators [24], patients whose CRRT was successfully stopped had better outcome than those who needed to be re-treated (mortality: 28.5 vs 42.7 %, p = <0.0001, respectively). In our study, the patients who were weaned from RRT after a second or more attempt had a significantly higher length of RRT and of ICU stay as compared to patients successfully weaned. Moreover, we observed that 4/28 patients of the failed group deceased 3 months later and none in the success group. Whether failure of discontinuation of RRT is just a marker of severity of disease or is harmful by itself remains questioned [38].

This study has several limitations. First, it was a retrospective and bi-center cohort study. Second, the weaning of RRT was not based on standardized criteria but decided by the attending physician who obviously followed general rules. Third, daily urinary creatinine requires 24-h urine collection, a procedure routinely performed with accuracy in ICUs. The measurement of urinary creatinine in a shorter time period or as spot urine concentration would be more easily feasible but may induce less accuracy. Nevertheless, the use of urinary creatinine as a marker of RRT cessation should be internally and externally validated to be used in routine practice. Last, we defined the attempt of weaning as a discontinuation of RRT during 72 h and estimated a success if discontinuation lasted more than 15 days. Various definitions have been used including an interruption of RRT during at least 5 days [23], but we thought that this duration may be too short regarding the severity of our patients. Also, considering RRT weaned after 7 days of interruption, as chosen by others [24, 25] has revealed insufficient. In the BEST Kidney cohort, for example, 15 patients considered as RRT-free were re-treated by CRRT before discharged from the ICU [24]. Indeed, Wu et al. [23] observed that an average of 10.1 ± 6.1 days lasted before re-dialysis if the attempt of weaning RRT failed.

In summary, the usefulness of 24-h urine output to predict the success of RRT weaning in AKI patients treated by diuretics may be significantly altered. Our study showed that 24-h urinary creatinine, in spite of diuretic use, is an independent and performing predictive factor of successful RRT weaning. A 24-h urinary creatinine ≥5.2 mmol indicates that RRT will be successfully stopped in 84 % of cases. Larger and prospective studies are needed to confirm our observations and to test a strategy of RRT weaning based on urine output, urinary creatinine and urea, and severity scores.