One potential issue is the self-fulfilling nature of predicting a rise in creatinine, using creatinine. Interestingly, we found that baseline NGAL values—but not baseline creatinine values—predicted WRF in multivariable models. Regardless, the hypothesis that NGAL rises earlier than creatinine does not hold true in this AHF cohort, as illustrated by the estimated trajectories corrected for study treatment. There are several potential explanations for the lack of an early rise in plasma NGAL, and thus the poor prognostic accuracy for WRF in AHF. First, plasma NGAL—in contrast with urinary NGAL—may not be a particularly appropriate tubular marker; it is strongly related to glomerular filtration rate, as reflected by its correlation with GFR and creatinine, and also involved in iron scavenging and immune response, as indicated by the correlation with markers such as CRP and markers of anemia . Shrestha et al noted strong correlations between urinary NGAL and measures for natriuresis and response to diuretics, while plasma NGAL only correlated well with GFR, though both predicted WRF . Second, there are multiple mechanisms for WRF in AHF patients. For example, true AKI (resulting in tubular damage), with substantial and rapid loss of function and decreased urine output is probably not comparable to the kind of WRF studied extensively in AHF. In the clinical context of AHF, changes in renal function may be driven more by hemodynamic and neurohormonal (mal) adaptation and drug effects than the (hypoxic) kidney injury common in intensive care or post-surgical settings; Dupont et al. showed that despite a relatively high incidence of AKI, defined based on creatinine increases, tubular injury was relatively uncommon in a small, prospective study of 141 AHF patients . Third, in contrast with studies in post-surgical or post-intervention patients , the timing of renal injury is often unclear in AHF, and its pre-hospital course may vary significantly, and may include undetected WRF. Pre-admission worsening congestion and intensification of diuretic therapy may have already triggered progressive renal impairment in the patients in our study—all of whom had at least a brief history of heart failure. Fourth, there is ongoing debate regarding the best measure for renal function and injury; a definition of WRF, based on a more “pure” marker, such as cystatin C or measured GFR, may have yielded very different results.