Abstract
OBJECTIVE:
To assess if loop diuretic challenge predicts the need for dialysis among critically ill patients with acute kidney injury (AKI) stage III.
PATIENTS AND METHODS:
Adult patients admitted to intensive care units between Jan 1, 2004, to Dec 31, 2016, were screened. AKI stage III was identified by an electronic surveillance tool and those who received loop diuretics of at least 1mg/kg intravenous bolus furosemide-equivalent were included. Urine output following loop diuretic challenge was modeled as a restricted cubic spline. We then compared the area under the curve for urine outputs at 2 hours and 6 hours after loop diuretic challenge to predict the need for dialysis within next 24 hours.
RESULTS:
Of 687 patients included in the study, those who received dialysis were younger and with higher SOFA scores on the day of loop diuretic challenge. Urine outputs at 2 hours and 6 hours were lower in patients who needed dialysis, but urine output by 6 hours was better in predicting dialysis initiation within 24 hours (AUC 0.71 vs. 0.67, p=.02). The sensitivity and specificity of 6-hour urine output cutoff ≤600ml to predict dialysis was 80.9% & 50.5% and ≤300cc was 64.2% & 68.2%.
CONCLUSIONS:
Among patients with stage III AKI, 6-hour urine output after the loop diuretic challenge had a modest discriminant capacity to identify dialysis initiation within the next 24 hours.
INTRODUCTION
Acute kidney injury (AKI) is common in critically ill patients and is independently associated with high mortality1–6. The direct relationship between AKI severity and death has been highlighted in the literature7. Stage III AKI, with the highest mortality, consists of a heterogeneous population that includes patients whose serum creatinine has increased by at least three times from the baseline, or has risen to at least 4mg/dL or more in the setting of an acute rise of at least 0.5mg/dL, or have urine output less than 0.3ml/kg/h for ≥24 hours, those who have anuria for ≥12 hours, and finally those who require acute dialysis. Thus stage III AKI represents patients with severe kidney injury who if not already on dialysis are at highest risk for requiring it.
Though dialysis is a life-saving therapy, controversy exists regarding the appropriate timing for dialysis initiation for patients with advanced acute kidney injury8, 9. Loop diuretics inhibit active chloride transport in the thick ascending limb of Henle which leads to natriuresis and increased urine output. The furosemide stress test, by assessing the proximal tubular cells ability to transport it to its site of action is able to predict the progression of acute kidney injury to higher stages10. More recently the response to loop diuretics has also been evaluated to predict progression to AKI after cardiac surgery11, predict progression of AKI when stratified according to biomarkers12 and to select the patients for early dialysis initiation13. However, the capability of a loop diuretic challenge test to predict the need for dialysis among those with AKI stage III has not been evaluated. As patients with stage III AKI are at risk for developing complications that could necessitate urgent dialysis, we designed this study to assess if the increase in urine output following the loop diuretic challenge can be utilized to predict the need for dialysis within 24 hours in patients with pre-dialysis stage III AKI.
MATERIALS AND METHODS:
Study Design and Study Population
In this retrospective study, we included patients ≥18 years old who were admitted or transferred to medical or general surgical ICUs at Mayo Clinic Hospital, Rochester, MN between Jan 1, 2004, to Dec 31, 2016. We used a validated electronic surveillance tool utilizing Acute Kidney Injury Network criteria to identify patients with stage III AKI14. We then identified patients who received the loop diuretic challenge, defined as at least 1 mg/kg intravenous (IV) bolus furosemide or its equivalent dose of IV bumetanide (1 mg IV bumetanide : 40 mg IV furosemide) after the diagnosis of stage III AKI. We excluded patients who had already received dialysis during hospitalization prior to the loop diuretic challenge and those with end-stage renal disease, solid organ transplants, bone marrow transplants, absence of research authorization, lack of a urinary catheter (due to difficulty in assessing urine output otherwise) or those who died within 24 hours of loop diuretic challenge. The study was approved by Institutional Review Board at the Mayo Clinic with an informed consent waiver for patients with the Minnesota Research Authorization, as it posed only minimal risk to human subjects.
Variables
Variables of interest including both demographic and clinical variables were retrieved from electronic health records using the integrated Multidisciplinary Epidemiology and Translational Research in Intensive Care Laboratory DataMart15, 16. These variables included baseline creatinine, baseline urine flow rate, Sequential Organ Failure Assessment (SOFA) score on the day of loop diuretic challenge, highest serum potassium and lowest serum bicarbonate on the day of loop diuretic challenge, Charlson comorbidity index and hourly urine output for up to 6 hours after the loop diuretic challenge. For those with measured serum creatinine within 6 months prior to the admission, baseline creatinine was calculated as the median of all measured values. Values within last 7 days prior to admission were excluded. For individuals without available measured serum creatinine prior to admission, it was back-calculated by using MDRD formula with estimated GFR of 60 ml/min/1.73 m2. The baseline urine flow rate was defined as the average urine output within 6 hours before the loop diuretic challenge.
Outcomes
The primary outcome of interest was the need for acute dialysis within 24 hours of loop diuretic challenge. The secondary outcome was the need for acute dialysis within 72 hours after the loop diuretic challenge.
Statistical Analysis
We used t-test and Wilcoxon rank-sum test as appropriate to compare differences in baseline variables. As the 2 hour urine output after loop diuretic challenge has been shown to have the best performance for the prediction of AKI stage I and II progression10 and 6 hour urine output has been shown to have the best ability for prediction of delayed graft function in patients with kidney transplant17, we compared the area under the curve (AUC) of the receiver operating characteristic of both 2 hour and 6 hour urine outputs to predict the need for dialysis within next 24 hours and 72 hours. Due to the nonlinear relationship between post loop diuretic challenge urine output and need for acute dialysis, we used restricted cubic spline transformations of the post loop diuretic challenge urine output for the analyses. We also assessed the sensitivity and specificity of different urine output cutoffs at 6 hours after the loop diuretic challenge to predict the need for acute dialysis in next 24 hours. Finally, we fit a multivariable regression model to assess how the AUC to predict the initiation of acute dialysis in next 24 hours changes with addition of the covariates that were decided a-priori to be clinically important in assessing the need for acute dialysis. The covariates included baseline serum creatinine, baseline urine flow rate, age, sex, race, SOFA score on the day of loop diuretic challenge, mechanical ventilation use, highest serum potassium and lowest serum bicarbonate on the day of loop diuretic challenge and Charlson comorbidity index. We used DeLong test to compare AUCs. We used Stata 14.2 (StataCorp, College Station, TX) for all analyses.
RESULTS
We included 687 patients with stage III AKI who received a loop diuretic challenge. Of those, 23.6% (162) were dialyzed within 24 hours of receiving the loop diuretic challenge. The patients who received dialysis within 24 hours of the loop diuretic challenge were younger (63.9 ± 14.5 vs. 67.6 ± 15.6 years, p=.008), had lower Charlson comorbidity indices (4.9±2.4 vs. 5.8±2.7, p<.001) and higher SOFA scores (10.4±3.9 vs. 8.2±3.4, p<.001) on the day of the loop diuretic challenge (Table 1). The median [interquartile range (IQR)] baseline urine output was lower in patients who underwent dialysis within 24 hours of loop diuretic challenge (10.1[3.9–18.8] vs. 20.7[7.5–46.3] ml/hour; p<.001). As shown in Table 1, there were no clinically significant differences in the baseline creatinine, baseline serum albumin level, highest serum potassium on the day of the loop diuretic challenge or the lowest serum bicarbonate on the day of the loop diuretic challenge between the two groups.
Table 1:
Baseline Characteristics
| Characteristics | Not dialyzed within 24 hours of loop diuretic challenge (N=525) | Dialyzed within 24 hours of loop diuretic challenge (N=162) | p value | |
|---|---|---|---|---|
| Age | 67.6 ± 15.6 | 63.9 ± 14.5 | .008 | |
| Sex (Male) (%) | 49.1 | 56.2 | .1 | |
| Charlson’s Score | 5.8±2.7 | 4.9±2.4 | <.001 | |
| SOFA score* | 8.3±3.4 | 10.4±3.9 | <.001 | |
| Highest serum potassium*(meq/L) | 4.5±0.8 | 4.8±0.9 | <.001 | |
| Lowest serum bicarbonate* (mmol/L) | 19.3±4.9 | 18.4±4.8 | .06 | |
| Baseline average urine output (ml) | 20.7 (7.5–46.3) | 10.1(3.9–18.8) | <.001 | |
| Baseline serum albumin (mg/dL) | 2.9±0.6 | 2.9±0.6 | .8 | |
| Baseline serum creatinine (mg/dL) | 1.0 (0.8–1.3) | 0.9 (0.7–1.2) | .05 | |
| Baseline estimated glomerular filtration rate (ml/min) | 59 (47–94) | 69(50–99) | .04 | |
| Serum creatinine* (mg/dL) | 3.5 (2.5–4.5) | 4.1 (3.0–5.3) | <.001 | |
| Blood Urea Nitrogen* (mg/dL) | 59 (41–78) | 63 (45–84) | .04 | |
| Serum pH* | 7.35±0.08 | 7.32±0.11 | .007 | |
| Race | Caucasian | 87.8 | 88.8 | .9 |
| African American | 1.9 | 2.5 | ||
| Asian | 1.1 | 1.2 | ||
| Others | 3.1 | 1.9 | ||
| Unknown | 6.1 | 5.6 | ||
| Mechanical Ventilation Use | 52.2 | 52.3 | .1 | |
On the day of the loop diuretic challenge
Characteristics of the Loop Diuretic Challenge
Only 17 patients received intravenous bumetanide (4 patients started dialysis within 24 hours) while remaining patients received iv furosemide for the loop diuretic challenge. The mean dose of furosemide was 1.99±0.85 mg/kg and that for bumetanide was 0.04±0.01mg/kg. The median [IQR] time from diagnosis of AKI-III to loop diuretic challenge was shorter among patients who received dialysis within 24 hours (7.9[2.3–16.3] vs. 12.9[4.6–29.1] hours; p<.001]. The median [IQR] urine output within the next 2 hours after the furosemide diuretic challenge was significantly lower in patients who started dialysis within 24 hours of the challenge (48[12–136] vs. 138[42–338] ml; p<.001). Similarly, the patients starting dialysis within 24 hours of the loop diuretic challenge had a lower total 6-hour urine output after the challenge (210[62–466] vs. 616[200–1396] ml; p<.001). In comparison with 2-hour urine output, the 6-hour urine output however had better discriminant capacity in predicting the initiation of acute dialysis within 24 hours after the loop diuretic challenge as evidenced by the better AUC value (0.67 [95% CI: 0.62–0.71] vs. 0.71 [95% CI: 0.67–0.75], respectively; p=.02) (Fig 1). The discriminant capacity of the baseline urine output to predict the initiation of acute dialysis within next 24 hours was similar to the total 2 hour urine output after the loop diuretic challenge (AUC 0.66 [95% CI: 0.61–0.70] vs. 0.67 [95% CI: 0.62–0.71]; p=0.84), but was lower than that for 6 hour urine output (AUC 0.66 [95% CI: 0.61–0.70] vs. 0.71[95% CI: 0.67–0.75]; p=0.02). Similarly the 6-hour urine output had a better discriminant capacity than the 2-hour urine output in predicting the need for dialysis within both 48 and 72 hours (0.71 [95% CI: 0.67–0.75] vs 0.67 [95% CI: 0.63–0.71]; p=.01 at 48 hours and 0.71 [95% CI: 0.67–0.75] vs 0.66 [95% CI: 0.62–0.70]; p=.005 at 72 hours). Finally there was a significant improvement in the discriminant capacity of the model to identify the outcome of dialysis initiation within 24 hours of the loop diuretic challenge when it was adjusted for variables that may impact the decision to dialyze (0.79 [95% CI: 0.74–0.83] vs 0.71 [95% CI: 0.67–0.75]; p<.001).
Figure 1:
AUCs for total urine output at 2 hour and 6 hour after loop diuretic challenge to predict dialysis in next 24 hours
A total 6-hour urine output of ≤600 ml had a sensitivity of 80.9% and a specificity of 50.5% to predict the need for dialysis within 24 hours after the loop diuretic challenge. In comparison, a cutoff of ≤300 ml had a sensitivity of 64.2% and a specificity of 68.2% for the need for dialysis within 24 hours after the loop diuretic challenge. The sensitivity and specificity of various clinically relevant total 6-hour urine output cut-offs to predict the initiation of acute dialysis in next 24 hours are shown in Table 2.
Table 2:
Sensitivity and Specificity of 6 hour post loop diuretic challenge urine output cut offs
| 6 hour post loop diuretic challenge urine output cut offs | Sensitivity % | Specificity % |
|---|---|---|
| 1200 | 93.8 | 29.3 |
| 900 | 91.4 | 38.3 |
| 600 | 80.9 | 50.5 |
| 500 | 76.5 | 55.4 |
| 400 | 70.4 | 61.0 |
| 300 | 64.2 | 68.2 |
| 200 | 49.4 | 74.9 |
| 100 | 34.0 | 81.5 |
| 50 | 21.0 | 87.2 |
We also assessed the discriminant capacity of the 6-hour and 2-hour urine output to predict the need for dialysis within 24 hours among all patients including those who died within 24 hours of the loop diuretic challenge and found that the 6-hour urine output still performed better though the difference was not statistically significant (0.69 vs. 0.66, p=.11). Similarly the 6-hour urine output had a better discriminant capacity than the 2-hour urine output in predicting the need for dialysis during the hospitalization (AUC 0.68 [95% CI: 0.64–0.72] vs 0.65 [95% CI: 0.61–0.69]; p=.003) however it was similar in predicting mortality within 72 hours of loop diuretic challenge (AUC 0.60 [95% CI: 0.52–0.68] vs 0.60 [95% CI: 0.52–0.67], p=.91).
DISCUSSION:
In this study we assessed the ability of the urine output response to loop diuretic challenge to predict the need for dialysis within next 24 hours, among critically ill patients with stage III AKI. We demonstrated that the sum of six-hour urine output after the loop diuretic challenge had a modest discriminant capacity to predict dialysis initiation within the next 24 hours (AUC 0.71). This was higher than the AUC for baseline urine output to predict the need for dialysis by 24 hours suggesting that the 6 hour urine output after the loop diuretic challenge offers information in addition to the baseline urine output to assess for the initation of dialysis.
Due to the substantial protein binding of loop diuretics, rather than being filtered through the glomeruli these drugs are actively secreted by the probenecid-sensitive organic anion transporters in the proximal tubular cells. The loop diuretics then inhibit the sodium-potassium-chloride transporter on the luminal side of the thick ascending limb of the loop of Henle by competing for the chloride site on the transporter18, 19. This leads to the inhibition of sodium absorption leading to natriuresis and increased urine output.
In recent years there has been an increased interest in the use of loop diuretics as a test to assess proximal tubular cell injury (furosemide stress test) and predict the progression of AKI. In a pilot study of 77 patients with stage I and II AKI, Chawla et al. showed that the AUC for total urine output at 2 hours after the furosemide stress test to predict the progression to stage III AKI was 0.8710. In addition, they found that using <200ml as the cut-off of the total two-hour urine output for predicting AKI progression in these patients had a sensitivity of 87.1% and specificity of 84.1%. In a follow-up study, the 2-hour urine output after the furosemide stress test was shown to be superior to the individual urinary biomarkers in predicting progression from stage I and II AKI to stage III AKI20. More recently, the furosemide stress test has also been used in patients undergoing renal transplant to predict the development of delayed graft function, defined as the receipt of dialysis within seven days of renal transplantation17. The authors retrospectively studied 200 patients undergoing deceased donor kidney transplant that received 100 mg of furosemide intra-operatively and found that a total 6-hour urine output of fewer than 600 ml had an AUC of 0.85 in predicting delayed graft function. Though the details regarding the exact stage of AKI, terminal urine output or renal biopsies of the donors were not reported, the median of the terminal creatinine for donors in this study was 2 mg/dL likely suggesting early AKI (in comparison to stage III AKI). Thus these studies suggest that furosemide stress test has a very good discriminant capacity to predict the progression of early AKI.
In comparison, patients with stage III AKI likely have a more severe acute insult to the kidneys thus placing them at the risk of needing dialysis. The usual indications for dialysis in AKI are medically refractory hyperkalemia, metabolic acidosis, volume overload or uremia. There is, however, no specific test to assess which patients with stage III AKI are at the highest risk of needing dialysis. The loop diuretic challenge has not been previously examined systematically in stage III AKI patients.
The AUC of the diuretic challenge for the dialysis requirement among those with AKI stage III is substantially lower when compared to the studies looking at the performance of the test to predict the progression of stage I & II AKI. As loop diuretics need functioning nephron, severe damage to the tubules during stage III AKI could also potentially lead to an attenuated response to diuretics and partly explain these results. Our results are likely also affected by the inherent complexity and at times subjectivity from both patients and providers in the decision to initiate dialysis. This is also suggested by the fact that when the model looking at the outcome of dialysis within 24 hours of loop diuretic challenge is adjusted for variables that may impact the decision to dialyze, the AUC of the model increased to 0.79.
To the best of our knowledge, this is the first study assessing the ability of urine output after the loop diuretic to predict the need for dialysis in critically ill patients with stage III AKI. Though we have used the robust electronic data system available at our institution, our study has several limitations. This is a single center retrospective study, and thus the results may not be generalizable to institutions with markedly different patient populations or practice patterns. Though we only included patients who received at least 1mg/kg IV furosemide bolus or equivalent, due to the retrospective nature of the study it is not possible to know the exact reasons for administering high dose diuretics to these patients. In addition, this dose may not have been adequate for patients with severely reduced glomerular filtration rate in the setting of stage III AKI; likewise, it is not known if the addition of a thiazide-type diuretic or hyperoncotic albumin solutions would influence the predictive ability of the loop diuretic challenge. Due to the retrospective nature of the study it was not possible for us to assess the patients’ volume status at the time of the loop diuretic challenge or whether there was a need for fluid boluses after the same, however, among patients who were already on vasopressors, there was no significant increase the in doses of the same (Data not shown). Finally, we do not have details about patient wishes for or against initiating dialysis which may have also impacted our results, nor the specific indication for initiation of dialysis and whether the loop diuretic challenge response may have influenced this decision.
CONCLUSION:
In conclusion, in this study, we showed that among critically ill patients with stage III AKI the total urine output at 6 hours after the loop diuretic challenge had a modest discriminant capacity to predict dialysis initiation within the next 24 hours. Though its predictive power seems better in earlier stages of AKI, loop diuretic challenge appears to be a useful adjunct to assess dialysis needs in patients with advanced AKI.
Table 3:
Sensitivity and Specificity of 2 hour post loop diuretic challenge urine output cut offs
| 2 hour post loop diuretic challenge urine output cut offs | Sensitivity % | Specificity % |
|---|---|---|
| 1200 | 98.8 | 2.8 |
| 900 | 98.8 | 6.2 |
| 600 | 98.8 | 13.5 |
| 500 | 96.9 | 16.2 |
| 400 | 95.1 | 21.5 |
| 300 | 91.4 | 28.0 |
| 200 | 83.3 | 39.0 |
| 100 | 67.9 | 57.0 |
| 50 | 51.9 | 72.6 |
ACKNOWLEDGEMENTS:
Financial Support
This publication was made possible by CTSA Grant Number UL1 TR002377 from the National Center for Advancing Translational Sciences (NCATS), a component of the National Institutes of Health (NIH). Its contents are solely the responsibility of the authors and do not necessarily represent the official view of NIH.
ABBREVIATIONS:
- AKI
Acute Kidney Injury
- IV
intravenous
- AUC
Area under the curve
Footnotes
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Conflicts of Interest:
The authors have disclosed no conflicts of interest
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