MULTIMODAL APPROACH IN THE DIAGNOSIS OF SEPTIC AKI

Acute Kidney Injury, Critical Illness, Renal Resistive Index, Sepsis

Renal Resistive Index (RRI), Cell Cycle Arrest Biomarkers, Intensive Care Units, Sepsis, Sepsis-Associated AKI

In recent studies, it has been reported that the renal resistance index is effective in detecting sepsis-related acute renal failure (SA-AKI) in the early period. Similarly, urinary biomarkers \[TIMP-2\]\*\[IGFBP-7\], released in response to tubular epithelial cell stress, have been reported to indicate the presence of acute renal injury (AKI) early on, before functional loss occurs (increased creatinine). This observational study aims to evaluate the renal resistance index and urinary biomarker variation in patients diagnosed with sepsis and to investigate their usefulness in the early detection of renal dysfunction that may develop after sepsis.

Purpose and Rationale: Sepsis is a life-threatening condition caused by a dysregulated host response to infection and remains a major cause of morbidity and mortality in intensive care units. Acute kidney injury (AKI) is one of the most frequent complications of sepsis and is associated with prolonged ICU and hospital stay, increased healthcare costs, and higher mortality. Early detection of renal dysfunction in septic patients is therefore crucial to improve clinical outcomes. The diagnosis of AKI in clinical practice is mainly based on changes in serum creatinine and urine output according to KDIGO (Kidney Disease: Improving Global Outcomes) criteria. However, serum creatinine reflects functional loss of the kidney and may increase only after significant renal injury has already occurred, which may delay the diagnosis of AKI. Recently, several physiological and biochemical markers have been investigated for earlier detection of AKI. The renal resistive index (RRI), obtained by Doppler ultrasonography of intrarenal arteries, reflects renal vascular resistance and changes in renal hemodynamics. Previous studies suggest that RRI may increase before conventional markers of kidney injury become abnormal and may help identify patients at risk of AKI during the early phase of critical illness. In addition, urinary biomarkers reflecting tubular cellular stress have been proposed as early indicators of kidney injury. Tissue inhibitor of metalloproteinases-2 (TIMP-2) and insulin-like growth factor binding protein-7 (IGFBP-7) are released by renal tubular epithelial cells during cellular stress and cell cycle arrest. The combined urinary biomarker product \[TIMP-2\]•\[IGFBP-7\] has been shown to identify patients at risk for AKI before increases in serum creatinine occur. This observational study aims to evaluate changes in renal resistive index and urinary biomarkers (\[TIMP-2\]\*\[IGFBP-7\]) in patients with sepsis and to investigate their potential role in the early detection of sepsis-associated acute kidney injury. Design: Prospective, single-center, observational cohort study with consecutive patient enrollment over an estimated period of approximately 12-month period (or until the target sample size is reached) following ethics committee approval and study registration. Anticipated sample: 120-130 (It has been increased to prevent potential data loss.) Participants - Eligibility: Inclusion: Patients receiving treatment in intensive care, ≥18 years of age, diagnosed with sepsis, able to undergo RRI, and who have obtained informed consent from their legally authorized representative (or the patient). Exclusion: End-stage renal disease (chronic RRT or eGFR \<15 ml/min/1.73 m²), kidney transplant, renal artery stenosis, technical/anatomical contraindications to RRI, poor echogenicity (for RRI imaging), pregnancy. Procedures and Timing: Renal resistance index (RRI) will be measured by Doppler ultrasonography immediately after sepsis diagnosis (T0, baseline, first measurement), 24 hours later (T24, second measurement), and 48 hours later (T48, third measurement). RRI measurements will be taken from the interlobar arteries of both kidneys, and at least three RRI Doppler waveforms will be recorded for each kidney. Urinary biomarker levels of \[TIMP-2\]•\[IGFBP-7\] will be measured immediately after the diagnosis of sepsis (T0) and at 24 hours after sepsis diagnosis (T24). Renal function tests and electrolyte levels will be recorded at the time of admission to the intensive care unit (T0), and 24 hours (T24), 48 hours (T48), and 72 hours (T72) after sepsis diagnosis (every 24 hours for 72 hours). Outcomes: Primary: Whether sepsis-related acute renal failure (SA-AKI) develops in patients diagnosed with sepsis, and the effect of RRI and urinary \[TIMP-2\]•\[IGFBP-7\] biomarkers in predicting the development of SA-AKI. Secondary: need for RRT up to 1 week after sepsis diagnosis, SA-AKI onset timing, ICU length of stay, and hospital length of stay. Analysis: Descriptives and appropriate group comparisons (AKI+ vs AKI-). Primary model: Logistic regression → AKI (yes/no) \ RRI\_T0 (continuous and prespecified ≥0.70 threshold) + \[TIMP-2\]·\[IGFBP-7\] + covariates (age, eGFR, SOFA, vasopressors, nephrotoxins/contrast, fluid balance). Safety and Privacy: Ultrasound and urine sampling are not risky; the study does not direct clinical treatment.

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