Limiting Acute Kidney Injury Progression In Sepsis: Study Protocol and Trial Simulation

Abstract

Objectives: To describe study design considerations and to simulate a trial of biomarker-guided sepsis management aimed to reduce acute kidney injury (acute kidney injury). Tissue inhibitor of metalloproteinases-2 and insulin-like growth factor-binding protein 7, urinary biomarkers of cell-cycle arrest, and indicators of kidney stress can detect acute kidney injury before clinical manifestations. We sought to determine the event rates for acute kidney injury as a function of serial measurements of urinary (tissue inhibitor of metalloproteinases-2)•(insulin-like growth factor-binding protein 7) in patients at risk of sepsis-associated acute kidney injury, so that an escalating series of kidney-sparing sepsis bundles based on international guidelines could be applied.

Design: We described the study protocol of "Limiting acute kidney injury Progression In Sepsis," a phase 4, multicenter, adaptive, randomized controlled trial. We performed simulations to estimate the rates for the trial's primary endpoint using patient-level data from two previous studies (Sapphire and Protocolized Care for Early Septic Shock).

Setting: Academic and community ICUs.

Patients: Critically ill patients with sepsis or septic shock, without evidence of stage 2/3 acute kidney injury at enrollment.

Interventions: None.

Measurements and main results: Our primary endpoint is progression of two or more stages of acute kidney injury, death, or dialysis within 72 hours after enrollment. In the Sapphire simulation, 45 of 203 patients (22%) with sepsis met the endpoint. In Protocolized Care for Early Septic Shock, 144 of 607 patients (24%) with septic shock met the endpoint. In both simulations, (tissue inhibitor of metalloproteinases-2)•(insulin-like growth factor-binding protein 7) patterns, suggested by Limiting acute kidney injury Progression In Sepsis protocol, stratified the risk for the endpoint from 6% (three negative tests) to 41% (for patients eligible for the highest level of kidney-sparing sepsis bundle) in Sapphire, and 14% (two negative tests) to 46% (for the highest level of kidney-sparing sepsis bundle) in Protocolized Care for Early Septic Shock.

Conclusions: Findings of our Limiting acute kidney injury Progression In Sepsis trial simulation confirmed that (tissue inhibitor of metalloproteinases-2)•(insulin-like growth factor-binding protein 7) could identify patients with different rates of progression to moderate/severe acute kidney injury, death, or dialysis in 72 hours. The Limiting acute kidney injury Progression In Sepsis protocol algorithm is therefore feasible in terms of identifying suitably high-risk individuals for kidney-sparing sepsis bundle.

Trial registration: ClinicalTrials.gov NCT04434209.

Figure 1.

Protocol treatment algorithm. The figure shows the protocol treatment algorithm. After every [TIMP-2]•[IGFBP7] test, the patients are allocated to a different level of treatment (standard of care [SOC], L1, L2, and L3) according to the [TIMP-2]•[IGFBP7] value (e.g., ≤ 0.3, 0.3–1.0, or ≥ 1.0; < 1.0 or ≥ 1.0 [ng/mL]²/1,000). The first [TIMP-2]•[IGFBP7] draw will be performed at 6–9 hr from sepsis diagnosis, the second one after 6–9 hr from the first one (around 12–18 hr from sepsis diagnosis), whereas the third one after 12–15 hr from the second one (around 24–33 hr from sepsis diagnosis). The red circled numbers represent special rules applied to that specific protocol hub. The rules are as follows: ① If the patient’s [TIMP-2]•[IGFBP7] results remain in the same category range, but the quantitative score increases or remains the same, the next higher kidney-sparing sepsis bundle (KSSB) level will be instituted. ② If the third [TIMP-2]•[IGFBP7] quantitative score increases or remains the same as the second [TIMP-2]•[IGFBP7] test, then the next higher KSSB level will be instituted. If the third [TIMP-2]•[IGFBP7] test quantitative score is lower than the second [TIMP-2]•[IGFBP7] test, then the patient’s care will remain at the KSSB level assigned after the second test. ③ If the patient’s second [TIMP-2]•[IGFBP7] result is greater than or equal to 1 but shows a decline by 50% or more, then the patient’s care will remain at KSSB Level 2. If the patient’s third [TIMP-2]•[IGFBP7] result remains greater than or equal to 1 but shows a decline by 50% or more in comparison with the second [TIMP-2]•[IGFBP7] value, then the patient’s care will remain at KSSB Level 2. IGFBP7 = insulin-like growth factor-binding protein 7, L = level of the kidney-sparing sepsis bundle, NC = NephroCheck, [TIMP-2]•[IGFBP7], TIMP-2 = tissue inhibitor of metalloproteinases-2.

Figure 2.

Protocol simulation in Sapphire study. The figure shows the protocol algorithm simulated in Sapphire study cohort. These patients did not receive these levels of kidney-sparing sepsis bundle, but these interventions would have been recommended based on the biomarker results. In each box, it is shown the total number of patients in this level of treatment, whereas in the round brackets, it is shown the percentage of these patients that reach the primary endpoint. The first [TIMP-2]•[IGFBP7] test was performed at enrollment, the second 12 hr later, and the third 24 after enrollment. Since time of enrollment varied among patients, but for most of them, it was when the patient was already admitted in the ICU and/or completed the first resuscitative treatments, for the purposes of our trial simulation, these timepoints will represent 6, 18, and 30 hr from sepsis diagnosis and start of the treatment. If any [TIMP-2]•[IGFBP7] result was missing or unavailable, we applied the last of the general rules planned also for Limiting acute kidney injury Progression In Sepsis trial: the subject will remain at the current treatment level and use the appropriate decision rules according to the next test in the algorithm (see Supplemental Digital Content, chapter “Study Interventions,” paragraph “General Rules,” http://links.lww.com/CCM/G472). For the rules of the red circled numbers, see legend of Figure 1. AKI = acute kidney injury, IGFBP7 = insulin-like growth factor-binding protein 7, L = level of the kidney-sparing sepsis bundle, NC = NephroCheck, [TIMP-2]•[IGFBP7], SOC = standard of care, TIMP-2 = tissue inhibitor of metalloproteinases-2.

Figure 3.

Protocol simulation in Protocolized Care for Early Septic Shock (ProCESS) trial. The figure shows the protocol algorithm simulated in ProCESS. These patients did not receive these levels of kidney-sparing sepsis bundle, but these interventions would have been recommended based on the biomarker results. In each box, it is shown the total number of patients in this level of treatment, whereas in the round brackets, it is shown the percentage of these patients that reach the primary endpoint. The first[TIMP-2]•[IGFBP7] test was performed at 6 hr from enrollment/sepsis diagnosis, whereas the second at 24 hr from enrollment/sepsis diagnosis. For the rules of the red circled numbers, see legend of Figure 1. ^aIn ProCESS, the dialysis endpoint was evaluated at 48 hr from enrollment instead of 72 hr. AKI = acute kidney injury, IGFBP7 = insulin-like growth factor-binding protein 7, KDIGO = Kidney Disease: Improving Global Outcomes, L = level of the kidney-sparing sepsis bundle, NC = NephroCheck, [TIMP-2]•[IGFBP7], SOC = standard of care, TIMP-2 = tissue inhibitor of metalloproteinases-2.