In this prospective study, it was shown that for ICU patients with complex causes of AKI, urine output in combination with uNGAL was a better predictor of renal function recovery than either applied as a single parameter. Relative to the cessation of CRRT, the best predictions, 92% (continued dialysis dependency) and 93% (renal recovery), were obtained with uNGAL at 6 hours after cessation combined with the cumulated urine output for 24 hours prior to cessation. The main implication of this is that although uNGAL as a single parameter was not shown to be diagnostically superior to urine output, it did add to the predictive ability of the latter. Additionally, uNGAL enabled the prediction of renal function recovery as soon as 6 hours after CRRT cessation, as opposed to 12–24 hours for urine output as a single parameter. As such, this study may be taken as a proof of concept that uNGAL is a significant paraclinical parameter with regard to the evaluation of renal recovery and continued dialysis dependency in ICU patients.
We arbitrarily chose a “positive” test outcome to associate with continued renal failure (and dialysis dependency), but the cut-offs for uNGAL 6 hours and UOC24pre (Table 4) can easily be applied as predictors of renal recovery as well.
Being able to predict the state of recovery or non-recovery in ICU dialysis patients as early as 6 hours after CRRT discontinuation has several potential benefits. In addition to the benefit of reducing the time a given patient is without obligatory dialysis, there may also be an economic benefit by avoiding unnecessarily replacement of the dialysis filter.
The procedure in the ICU from which the patients in this study were recruited is that only patients who are ready to be discharged may be transferred from CRRT to haemodialysis. It follows that to initiate haemodialysis, the patient must have infection/inflammatory control and no longer require vasopressor or respiratory support. In this situation, the laboratory parameters indicating inflammation, including uNGAL, are expected to be low. From Table 2 this difference between patients in whom haemodialysis was initiated and patients in whom CRRT was re-initiated is particular evident for UOC24pre, UOC24post and partly for uNGAL at 24 hours. If, in theory, it was possible to identify patients in need of haemodialysis at a point before CRRT cessation, the NPV of the combined uNGAL at 6 hours/OUC24pre test in our setting would be 100%, as 1 out of 14 patients with a negative test became permanently haemodialysis dependent (Table 4).
To date, only a very few studies have examined the ability of uNGAL ability to predict renal function recovery after dialysis in critically ill patients. In the study by Yang et al. , 102 patients were enrolled, and 8 biomarkers, including uNGAL, were analysed at 24 hours after the discontinuation of dialysis. At 60 days after discontinuation, renal recovery was defined as a serum creatinine level < 0.5 mg/dl (84.2 µmol/L). The ability of uNGAL to predict renal recovery at this time point was poor, with an AUC of 50% . However, Yang et al.’s  main purpose for measuring uNGAL was not, as in this study, the determination of the immediate need to restart dialysis but prognosticate lasting damage to the kidney. Another study [Biological Markers of Recovery for the Kidney (BioMark)] by Srisawat et al.  also indicated the ability of uNGAL to predict more lasting kidney damage. Finally, a study from 2019 by Stads et al.  included 92 patients and tested 7 variables, including uNGAL 2 days after the discontinuation of dialysis. Renal recovery was defined as freedom from dialysis 7 days after discontinuation. Urine NGAL was not significantly (p = 0.025) associated with renal recovery. However, it should be considered whether this study has clinical relevance. It is likely that, at 2 days after discontinuation, the physician already had a very good inclination of the need for dialysis.
There are several limitations of our study. The major limitation was the small number of included patients. This has 2 implications. With a limited number of patients in the different subgroups of recovery and non-recovery, the cut-off limits for uNGAL at 6 hours and UOC24pre become less certain, since the range of values of either inevitably will contain gaps rather than representing an unbroken continuum. With regard to the cut-off values representing the best NPV of the combined parameters, uNGAL at 1,650 µg/L and UOC24pre at 210 mL were flanked by values of 1,327 µg/L and 1,863 µg/L and by 195 and 228 mL, respectively. The true cut-off values for the two parameters may therefore in reality lie close to one of their flanking values at either end. The other uncertainty arising from the limited number of patients is the confidence in the calculated NPV and PPV values given in Table 4. For example, the NPV at 93% is based on the ratio of 13/14 patients and will thus – based on the binomial distribution – have a 90% one-sided lower confidence limit at 75%. In conclusion, a larger study with more included patients is needed to confirm the findings of this study.
Second, a number of urine samples were missed for a multitude of reasons. The impact of this was mitigated by extrapolating 14 out of 51 values for uNGAL at 6 hours from uNGAL at either 0 hours or 12 hours using linear regression. Despite solid statistically significant correlations between uNGAL values at 6 hours with those at 0 hours and at 12 hours, this is clearly a source of uncertainty with regard to the values of uNGAL at 6 hours that were interpolated. Finally, concerning urine sampling, when the patient’s urine flow is low, there is a risk of NGAL concentration in the very small volume of urine in the catheter, which could lead to falsely elevated uNGAL values. This is probably the main reason uNGAL at 0 hours (the time of CRRT discontinuation) turned out to be a worse predictor of renal recovery than uNGAL at 6 hours. Perhaps this outcome would have been different if we had used diuretics while the patients were on CRRT.
The main strength of the study is that it focused on the main clinical issue, i.e., the turning point at which the physician acts and discontinues CRRT. How soon can the physician obtain a reliable estimate of whether the patient has regained renal function or whether dialysis has to be reinitiated? The study showed that the use of two variables, uNGAL and urine output, had greater clinical usefulness than the use of either variable as a single test. The generalizability of the study results appears to be quite good, especially because the included AKI patients were selected very broadly. However, the results should be used with care in ICUs in which furosemide is given routinely while the patients are on dialysis.