Most patients with septic shock have AKI at the time of diagnosis [4, 16, 17]. In this population, the severity and course of AKI are correlated with mortality, early recovery of kidney function is associated with a better prognosis, and the progression of AKI is associated with a lower survival rate [17, 18]. Early identification of patients with different AKI courses might enable individualized management and also better stratification in clinical trials of kidney-targeted therapies. In the present study, we used an unsupervised clustering approach that combined kidney function variables and serial measurements of urine levels of an established kidney stress/damage biomarker. We identified three SA-AKI subphenotypes with different trajectories and short-term survival rates.
Subphenotype A (with a normal UO, a low SCr, a low urine [TIMP-2]*[IGFBP7] level, and a rapid improvement in kidney function) corresponds to a low likelihood of death or RRT initiation within the first seven days. Even though subphenotype B and subphenotype A had similar nonrenal SOFA scores, AKI was more severe and more persistent in subphenotype B patients; this led to higher RRT initiation rate. Subphenotype B patients might have been more susceptibility to the development of AKI – perhaps (at least in part) because of a higher baseline prevalence of conventional AKI risk factors (such as older age, underlying CKD, and previous exposure to renin–angiotensin system inhibitors [19–22]. One could assume that this population is very likely to need RRT; however, after adjustment for cofounding factors, the seven-day mortality rate for subphenotype B was not significantly greater than that for subphenotype A. Hence, subphenotype B constitutes a population of interest for test new kidney-targeting therapies in SA-AKI. However, the [TIMP-2]*[IGFBP7] variable did not distinguish this subphenotype from the others.
The small number of subphenotype C patients were characterized clinically by early-onset, severe oliguria but a relatively moderate elevation of SCr; this illustrates the limits of SCr-based estimations of AKI severity in patients receiving large amounts of intravenous fluids [23]. There is a well-characterized association between the magnitude and duration of oliguria on one hand and the progression of SA-AKI on the other [24, 25]. However, oliguria was also common in subphenotype B and, to a lesser extent, in subphenotype A (Supplemental Fig. 3); this finding suggests that oliguria was influenced by different disease mechanisms, such as hypotension and hypovolemia [26, 27]. The particularly high, sustained urine level of [TIMP-2]*[IGFBP7] distinguished subphenotype C from the other patients with oliguria. This elevated level might reflect very intense, prolonged kidney stress/damage as a result of more severe illness, especially as baseline risk factors for AKI were infrequent in this group. This hypothesis is also supported by recent data showing that patients presenting greater endothelial dysfunction and a more intense inflammatory response are less likely to recover from SA-AKI in the short term [28–30]. Subphenotype C had a significantly higher risk of early death (relative to phenotype A) and so could be categorized as “high risk”. Similarly, Molinari et al.’s ancillary analysis of the ProCESS study showed that with the same degree of AKI severity, a urine [TIMP-2]*[IGFBP7] level above the high-specificity cut-off of 2.0 (ng/mL)2/1000 was associated with a lower 30-day survival rate [31]. Our results suggest that a sustained, very high urine level of [TIMP-2]*[IGFBP7] is a potent warning sign of AKI progression and early death.
To the best of our knowledge, the present study is the first to have combined functional variables with a stress/damage biomarker in a clustering approach. The [TIMP-2]*[IGFBP7] level is the best-established AKI biomarker and was recently use to guide a therapeutic intervention for preventing AKI progression [32, 33]. Nevertheless, sepsis is a complex condition, and kidney-function-limited subphenotypes might not wholly reflect all the various patterns of organ dysfunction. Analyses of large databases (using much the same methods as in the present study) identified several sepsis subphenotypes, which differed with regard to the course of disease and the treatment response [34, 35].
Our study had several limitations. Firstly, it was an unplanned analysis of previously collected data. Secondly, our study population was relatively small, which might have limited the study’s statistical power. Thirdly, the fact that the study population presented AKI within 6 h of the diagnosis of septic shock (i.e. with the exclusion of those who developed AKI later than that) limits the generalizability of our results. Although a full description of change in kidney function was not available after day 3, most patients who recover from AKI do so within 3 days [36]. Lastly, TIMP-2 and IGFBP7 assays are not available in all hospitals, which limits the use of our clustering approach in routine clinical practice; however, the combination of kidney function variables with biomarker measurements could be used to stratify patients in clinical trials of kidney-targeted therapies.
In conclusion, we identified three distinct SA-AKI subphenotypes (with different short-term trajectory and survival rates) by combining conventional kidney function indicators with urine measurements of a cell-cycle arrest biomarker.
This approach might be useful for better stratifying patients in the early phases of septic shock but needs to be confirm in a larger, independent cohort.