Fluid balance and urine volume are independent predictors of mortality in acute kidney injury

We performed a secondary analysis of data from 601 patients enrolled in a prospective multicenter ICU cohort study of adult patients (age ≥18 years) admitted to 10 ICUs from September 2009 to April 2010 (NEFROlogia e Cura INTensiva (NEFROINT) Study), designed to describe the epidemiology of AKI in Italian ICUs [28]. Detailed methods of data collection have been previously described [29]. Collected data included demographics, anthropometrics, admission diagnosis, comorbidities, daily vital signs and laboratory data to calculate automatically the Acute Physiology and Chronic Health Evaluation II (APACHE II) [30], the Simplified Acute Physiology Score II (SAPS II) [31] and the Sequential Organ Failure Assessment (SOFA) [32] scores. RRT details and mortality were also reported. Furthermore, 24-hour urine output, worst 6-hour and worst 12-hour urine output, fluid balance and use of diuretics were recorded daily. Furosemide was the only diuretic used in all the centers. Fluid balance was calculated daily as the difference between fluid intake and fluid output. Fluid output included all body fluids, including urine and, if applicable, dialysis ultrafiltrate. This study was approved by the ethics committee of St. Bortolo Hospital, Vicenza, Italy. Because of the anonymous and non-interventional nature of the study, the ethics committees of the participating study centers (see list below) waived the need for informed consent.

AKI was defined according to the renal SOFA score as a creatinine >3.5 mg/dL or a urine output <500 mL/day, as used by the Sepsis Occurrence in Acutely Ill Patients (SOAP) study investigators [20]. Patients who received RRT were assigned a renal SOFA score of 4, regardless of the serum creatinine or urine output. AKI was considered 'early' if it occurred in the first two days of ICU admission and 'late' if it occurred more than two days after ICU admission [20]. Oliguria was defined as a urine output of less than 500 mL/day. Mean fluid balance (MFB) and mean urine volume (MUV) were calculated as the arithmetic mean of the daily values during the patient's ICU stay. The SOFA score was expressed in two ways: total score and the score without the renal component (non-renal SOFA). For sensitivity analysis, we also defined AKI using the Risk, Injury, Failure, Loss of kidney function and End-stage kidney disease (RIFLE) consensus [33].

Continuous variables were expressed as both mean ± SD and as median (IQR) and compared between any two groups (for example, AKI versus non-AKI, survivors versus non-survivors, early versus late AKI and so on), using the t-test or Mann-Whitney U test, as appropriate. Normality of distribution was evaluated by visual inspection of histograms and by the Kolmogorov Smirnov test. Categorical variables are expressed as number of cases and proportion and compared with the Mantel-Haenszel Chi-square test or the Fisher exact test.

To evaluate the influence of MFB and MUV on the survival time of AKI patients, exploratory univariate analysis for several variables was first performed to identify possible confounders associated with 28-day mortality. A multivariable Cox regression analysis was then performed using a forward stepwise selection method, criteria for entry 0.05 and for removal 0.10. The assumption of proportional hazards was checked graphically using log(-log(survival probability)) plots and was found appropriate. Variables considered for multivariable analysis were age, gender, co-morbid disease, sepsis, non-renal SOFA, and MFB, as were used in a previous study [20], with the addition of MUV and diuretic use. Age, sepsis and diuretic use were all significant on univariate analysis. APACHE II, SAPS II, and total and non-renal SOFA scores were also significant on univariate analysis, but the strongest association with mortality was seen with non-renal SOFA, and this was used in all multivariable models. We tested for collinearity among all variables. From the Cox model, hazard ratio (HR) and 95% CIs were generated. We also performed a number of sensitivity analyses. First, since MFB and MUV were found to be collinear, we repeated the analysis using an interaction term MFB*MUV. Second, we also expressed urine output as the presence of oliguria anytime during the ICU stay and the duration of oliguria (defined as the proportion of ICU days complicated by oliguria) as an alternate representation of urine volume in the models. Third, diuretic use was also expressed as duration of diuretic use (defined by the proportion of ICU days in which diuretics were used). The 28-day survival by timing of AKI, oliguria and diuretic use were additionally evaluated graphically using the Kaplan-Meier product limit survival plot. All statistical analysis was performed using the SPSS 19.0 (SPSS Inc, Chicago, IL, USA) software package, with a two-sided P value <0.05 considered as statistically significant.

Of the 601 patients enrolled in the NEFROINT study [28], 25 were excluded because of the presence of end-stage renal disease on chronic RRT and three other patients were excluded because of incomplete data on fluid balance and urine output, leaving 573 patients for analysis. Characteristics of the entire cohort are shown in Additional file 1, Table S1. The mean age was 63.0 ± 17.3 years and 59.5% were men. All-cause 28-day mortality was 21.8% and mean ICU length of stay was 10.1 ± 12.0 days. Of these patients, 132 (23%) developed AKI.

AKI patients were older, more likely to be diabetic and to have sepsis or a cardiovascular diagnosis at ICU admission and higher illness severity scores than non-AKI [see Additional file 1, Table S1]. MFB was higher (0.7 ± 1.2 versus 0.5 ± 1.1 L/day; P = 0.008) and MUV was lower (1.8 ± 1.1 versus 2.6 ± 1.3 L/day; P <0.001) in the AKI group. Diuretics were used more commonly on AKI patients and for a larger proportion of ICU days (Table 1). Mortality was higher among AKI patients (50% versus 13.4%; P <0.001) and ICU stay was longer.

AKI patient characteristics according to outcome are shown in Table 2. Non-surviving AKI patients were older, had higher illness severity scores and were more likely to be septic. The MFB was higher (1.3 ± 1.2 versus 0.2 ± 0.7 L/day; P <0.001) and the MUV was lower (1.3 ± 0.9 versus 2.3 ± 1.0 L/day; P <0.001) among non-survivors. Oliguria was also more common in non-survivors (83.3% versus 54.5%; P = 0.001) and persisted for a larger proportion of the ICU stay (35.5 ± 34.5% versus 13.6 ± 21.9%; P <0.001).

Early AKI was present in 83 patients (62.9% of the AKI group) and was associated with higher illness severity scores, lower MUV (1.6 ± 1.1 versus 2.2 ± 0.9 L/day; P <0.001), a larger proportion of days of oliguria (32.3% versus 11.5%, P <0.001) and fewer RRT-free days, but a shorter ICU stay than late AKI [see Additional file 1, Table S2]. The MFB, the proportion of days with diuretics and the mortality were not different between the groups.

As expected, oliguric patients had a higher MFB (0.9 ± 1.3 versus 0.4 ± 1.0 L/day; P <0.001), tended to receive diuretics more often (73.6% versus 62.7%; P = 0.06), had higher mortality (60.4% versus 14.4%; P <0.001) and longer ICU stay (15.5 ± 15.8 versus 9.3 ± 10.9; P <0.001) than non-oliguric patients.

In general, non-survivor AKI patients had significantly higher MFB compared to survivors (Figure 1). When analyzing the subgroups separately by AKI timing, the presence of oliguria and the use of diuretics, the same results were observed. The MUV was significantly lower among non-survivors overall, and in most of the subgroups, except in non-oliguric patients. Figure 2 demonstrates the pattern of cumulative fluid balance among survivors and non-survivors in the first seven days in the ICU. Non-survivors consistently had higher mean cumulative fluid balance throughout the ICU stay and the magnitude of the difference between the groups increased with each additional day.

The 28-day survival was significantly better among non-oliguric patients (Figure 3; P <0.044) and in patients treated with diuretics (Figure 4; P = 0.001). The 28-day survival was similar between early and late AKI (not shown, P = 0.16 on log rank test).

On multivariate Cox regression analysis (Table 3), both MFB and MUV were independent predictors of 28-day mortality (MFB, adjusted HR 1.67, 95%CI 1.33 to 2.09 per L/day; P <0.001 and MUV, adjusted HR 0.47, 95%CI 0.33 to 0.67 per L/day; P <0.001, Model 1). Interestingly, the use of diuretics appeared to be associated with a lower risk of death in both unadjusted and adjusted analysis (adjusted HR 0.25, 95%CI 0.12 to 0.52; P <0.001). Collinearity was observed between MFB and MUV, and we performed a second model including the interaction between the two (MFB*MUV). In this model, the interaction term was significant; the effect of MFB was somewhat attenuated, while the effect of MUV was accentuated. Of interest, higher non-renal SOFA scores were significantly associated with increased mortality on univariate analysis (HR 1.18, 95CI% 1.10 to 1.27; P <0.001), but this was no longer significant on multivariable analysis (HR 1.04, 95CI% 0.96 to 1.14; P = 0.35).

In terms of sensitivity analyses [see Additional file 1, Table S3], qualitatively similar results were seen when MUV was alternatively expressed as presence of oliguria (adjusted HR 1.86, 95%CI 1.50 to 2.32 for MFB, and adjusted HR 1.35, 95%CI 0.67 to 2.71 for oliguria) or duration of oliguria (adjusted HR 1.72, 95%CI 1.37 to 2.15 for MFB, and adjusted HR 1.01, 95%CI 1.003 to 1.02 for %ICU days with oliguria), and when diuretic usage was expressed as duration of diuretics (adjusted HR 1.73, 95%CI 1.38 to 2.18 for MFB and adjusted HR 0.99, 95%CI 0.98 to 0.99 for %ICU days on diuretics). Furthermore, results were also similar when AKI was defined using RIFLE criteria (n = 378 AKI patients; crude mortality 28.8%). The adjusted HR for MFB was 1.51, 95%CI 1.31 to 1.74 L/day; P <0.001 and for MUV was 0.48, 95%CI 0.38 to 0.62 L/day; P <0.001 in this sensitivity analysis (Table 4).