Biomarker Enrichment in Sepsis-Associated Acute Kidney Injury: Finding High-Risk Patients in the Intensive Care Unit.

BACKGROUND: Sepsis-associated acute kidney injury (AKI) is a leading comorbidity in admissions to the intensive care unit. While a gold standard definition exists, it remains imperfect and does not allow for the timely identification of patients in the setting of critical illness. This review will discuss the use of biochemical and electronic biomarkers to allow for prognostic and predictive enrichment of patients with sepsis-associated AKI over and above the use of serum creatinine and urine output. SUMMARY: Current data suggest that several biomarkers are capable of identifying patients with sepsis at risk for the development of severe AKI and other associated morbidity. This review discusses these data and these biomarkers in the setting of sub-phenotyping and endotyping sepsis-associated AKI. While not all these tests are widely available and some require further validation, in the near future we anticipate several new tools to help nephrologists and other providers better care for patients with sepsis-associated AKI. KEY MESSAGES: Predictive and prognostic enrichment using both traditional biomarkers and novel biomarkers in the setting of sepsis can identify subsets of patients with either similar outcomes or similar pathophysiology, respectively. Novel biomarkers can identify kidney injury in patients without consensus definition AKI (e.g., changes in creatinine or urine output) and can predict other adverse outcomes (e.g., severe consensus definition AKI, inpatient mortality). Finally, emerging artificial intelligence and machine learning-derived risk models are able to predict sepsis-associated AKI in critically ill patients using advanced learning techniques and several laboratory and vital sign measurements.

Real-World Use of AKI Biomarkers: A Quality Improvement Project Using Urinary Tissue Inhibitor Metalloprotease-2 and Insulin-Like Growth Factor Binding Protein 7 ([TIMP-2]*[IGFBP7]).

INTRODUCTION: Novel urinary biomarkers, including tissue inhibitor metalloprotease-2 and insulin-like growth factor binding protein 7 ([TIMP-2]*[IGFBP7]), have been developed to identify patients at risk for acute kidney injury (AKI). We investigated the "real-world" clinical utility of [TIMP-2]*[IGFBP7] in preventing AKI. METHODS: We performed a before and after single-center quality improvement study of intensive care unit (ICU) patients at risk for severe (KDIGO stage 2 or 3) AKI. In the prospective cohort, ICU providers were allowed to order [TIMP-2]*[IGFBP7] for patients at their discretion, then offered AKI practice recommendations based on the results. Outcomes were compared to a historical cohort in which biomarker values were not reported to clinical teams. RESULTS: There was no difference in 7-day progression to severe AKI between the prospective (n = 116) and historical cohorts (n = 63) when [TIMP-2]*[IGFBP7] ≥0.3 (24 [28%] versus 8 [21%], p = 0.38) despite more stage 1 AKI at time of biomarker measurement in the prospective cohort (58 [67%] versus 9 [23%], p < 0.001). In the prospective cohort, patients with higher [TIMP-2]*[IGFBP7] values were more likely to receive a nephrology consult. Early consultation (within 24 h of biomarker measurement, n = 20) had a nonsignificant trend toward net negative volume balance (-1,787 mL [6,716 mL] versus + 4,974 mL [15,540 mL]) and more diuretic use (19 [95%] versus 8 [80%]) and was associated with less severe AKI (9 [45%] versus 10 [100%], p = 0.004) and inpatient dialysis (2 [10%] versus 7 [70%], p = 0.002) compared to delayed consultation (n = 10). CONCLUSIONS: Despite the prospective cohort having more preexisting stage 1 AKI, there were equal rates of progression to severe AKI in the prospective and historical cohorts. In the setting of [TIMP-2]*[IGFBP7] reporting, there were more nephrology consults in response to elevated biomarker levels. Early nephrology consultation resulted in improved volume balance and favorable outcomes compared to delayed consultation.

Fluid Overload and Mortality in Patients with Severe Acute Kidney Injury and Extracorporeal Membrane Oxygenation.

Background: Volume overload is increasingly being understood as an independent risk factor for increased mortality in the setting of AKI and critical illness, but little is known about its effect in the setting of extracorporeal membrane oxygenation (ECMO). We sought to evaluate the incidence of AKI and volume overload and their effect on all-cause mortality in adults after ECMO cannulation. Methods: We identified all adult patients who underwent ECMO cannulation at the University of Chicago between January 2015 and March 2017. We evaluated the incidence of KDIGO-defined AKI, RRT, and volume overload. Volume overload was defined as achieving a positive fluid balance of 10% above admission weight over the first 72 hours after ECMO cannulation. The primary outcome collected was 90 day all-cause mortality. Secondary outcomes included 30-day mortality, duration of ECMO and RRT therapy, length of stay, and dialysis independence at 90 days. Results: There were 98 eligible patients, 83 of whom developed AKI (85%); 48 (49%) required RRT and 19 (19%) developed volume overload at 72 hours. Patients with volume overload had increased risk of death at 90 days compared with those without volume overload (HR, 2.3; 95% CI, 1.3 to 4.2; P=0.004). Patients with AKI-D had increased risk of death at 90 days compared with those without AKI-D (HR, 2.2; 95% CI, 1.3 to 3.8; P=0.004). Volume overload remained an independent predictor of 90-day mortality when adjusting for RRT, APACHE score, weight (kg), diabetes, and heart failure (HR, 2.9; 95% CI, 1.4 to 6.0; P=0.003). Conclusions: Volume overload and AKI are common and have significant prognostic value in patients treated with ECMO. Initiating RRT may help to control the deleterious effects of volume overload and improve mortality.

Real-World Associations Between Renin-Angiotensin-Aldosterone System Inhibition Therapy, Hyperkalemia, and Outcomes: A Clinical and Scientific Call to Action.

See Article Linde et al.