The Differentiating of Sepsis-Associated and Sepsis-Induced Acute Kidney Injury in Intensive Care Unit Patients

Introduction: Acute kidney injury (AKI) is a severe and common complication in Intensive Care Unit (ICU) patients, commonly resulting from sepsis. It is associated with elevated mortality, chronic renal failure, and other long-term consequences. Sepsis-associated AKI (SA-AKI) and Sepsis-induced AKI (SI-AKI), a specific sub-phenotype, differ in their underlying pathophysiology. Objective: To examine the distinctions between SA-AKI and SI-AKI, focusing on their pathophysiology, biomarkers for detection, and associated prognoses in critically ill patients. This literature review examines the findings of randomized control trials (RCTs) or meta-analysis studies that learn about biochemical mediators and biomarkers for SA-AKI and SI-AKI, including NGAL, Kim-1, and others, as well as the prognostic impact of these conditions. The literature was gathered from Google Scholar and PubMed using the keywords Sepsis-Associated Acute Kidney Injury, Sepsis-Induced Acute Kidney Injury, Intensive Care Unit, and Sepsis and published within the last ten years (2018–2023). Articles unavailable in the full text were excluded. Review: SA-AKI and SI-AKI are distinct entities within the broader spectrum of sepsis and AKI. SI-AKI involves sepsis-induced direct kidney damage, which differentiates it from other forms of SA-AKI. Various biomarkers such as NGAL, Kim-1, and others are crucial for early detection and differentiation between these conditions. Patients with SA-AKI and SI-AKI usually have a bad outlook. They are more likely to die, be disabled for a long time, and need longer stays in the ICU and hospital than patients with sepsis or AKI alone. Figuring out the underlying pathophysiology and using the right biomarkers can help with early diagnosis and could lead to better outcomes for patients through targeted therapies. Summary: SA-AKI and SI-AKI represent critical complications in ICU patients with sepsis, leading to high mortality and long-term adverse outcomes. Differentiating between these conditions using biomarkers is essential for early detection and management. These patients have a worse prognosis than those with sepsis or AKI alone. This shows how important it is to keep researching and finding better ways to treat these serious complications in critically ill patients.

INTRODUCTION

Over half of the patients in intensive care units (ICUs) around the world experience Acute Kidney Injury (AKI), with sepsis being the most common underlying cause. Epidemiological studies indicate that AKI is associated not only with acute severe effects but also with significant long-term consequences. Although patients may recover from AKI, they remain at risk of developing recurrent kidney injuries¹,².

Sepsis-associated AKI can manifest in a variety of phenotypes and prognoses³. Patients with AKI and those meeting the consensus criteria for sepsis are considered to have Sepsis-Associated Acute Kidney Injury (SA-AKI). Meanwhile, Sepsis-Induced Acute Kidney Injury (SI-AKI) can be seen as a sub- phenotype of SA-AKI, where mechanisms induced by sepsis produce direct kidney damage¹. The prognosis for SA-AKI and SI- AKI events is worse compared to sepsis and AKI separately⁴. There are still a lot of questions that need to be answered about definitions, epidemiology, pathophysiology, how to diagnose, how to treat, and how extracorporeal and new therapies affect patients⁵.

SA-AKI is defined as AKI occurring within seven days of a sepsis diagnosis. It is further categorized into early SA-AKI, which develops within 48 hours of sepsis diagnosis, and late SA-AKI, which arises between 48 hours and seven days. The proposed seven-day window is based on the observation that AKI typically develops within a few days following the onset of sepsis. Beyond this period, AKI is generally considered less likely to be directly related to the initial sepsis event. The difference between early and late SA-AKI is important because late-stage AKI progression has worse clinical outcomes and a higher death rate than early-stage AKI. Phenotyping for focused assessment and management can be improved by distinguishing between the early and late phases of SA-AKI. Untreated or early sepsis patients are at a higher risk of experiencing SI-AKI, whereas those who get sepsis-related treatments are more prone to developing SA-AKI. Additional variables may also contribute to the development of AKI¹.

REVIEW

Pathogenesis

Sepsis is marked by an overproduction of many pro-inflammatory cytokines and is linked to malfunction in multiple organs. SI-AKI is distinguished by a fast rapid loss of kidney function, as indicated by elevated creatinine and Blood Urea Nitrogen (BUN) levels, as well as reduced Glomerular Filtration Rate (GFR) and urine production. Multiple factors can contribute to SI-AKI, such as systemic inflammation and immune system dysregulation, hemodynamic change, activation of the complement system, dysregulation of the renin-angiotensin- aldosterone system (RAAS), dysfunction of mitochondria, metabolic reprogramming, and dysfunction of the microcirculatory system. Various factors can indirectly contribute to SA- AKI, such as nephrotoxic drugs, hyperchloremia, and abdominal compartment syndrome¹,⁶.

Pathogen-Associated Molecular Patterns (PAMPs) and Damage-Associated Molecular Patterns (DAMPs) are released following the invasion of a pathogen. These patterns attach to groups of receptors known as pattern recognition receptors, with one example being Toll-Like Receptors (TLRs). Toll-like receptors (TLRs) are present on the plasma membrane of immune cells, endothelial cells, and tubular epithelial cells (TEC). The binding process results in the overproduction of pro-inflammatory cytokines such as IL-1β, IL-6, IL-8, IL-18, TNF-α, chemokines, and Reactive Oxygen Species (ROS), while also activating the complement system. Uncontrolled immune response and extensive inflammation play a crucial role in the development of septic AKI⁶,⁷.

Figure 1.The Clinical Progression and Outcome of Sepsis-Associated Acute Kidney Injury (SA-AKI)The exact timing of renal injury onset in sepsis is unclear. Patients who come with sepsis probably have AKI, and conversely, patients who come with AKI also definitely have sepsis. AKI may coexist with sepsis at the time of hospital admission;(a)or develop during treatment;(b)S-AKI may improve early in the first week after diagnosis and is linked to a favorable prognosis. AKI can develop within the first 7 days, leading to permanent damage and progressing to SA-AKI. During this period, patients may achieve full or partial recovery, but some may suffer ongoing injury without improvement. In the long term, this lack of recovery can lead to chronic kidney disease (CKD)

The Renal Blood Flow (RBF) is the sum of cardiac output and the effective circulatory volume. During the onset of sepsis, there is an initial rise in cardiac output, followed by a progressive decline as a result of septic damage. Multiple studies have discovered that RBF remains stable or may even be elevated during the early stages of septic AKI⁸. These findings suggest that renal hypoperfusion is not necessary for septic AKI to occur. Vasodilation is caused by endothelial dysfunction in the kidney blood vessels and the release of vasoactive substances like nitric oxide⁶,⁸,⁹,¹⁰. Multiple studies have shown that sepsis can present with microcirculatory changes even without macrocirculatory alterations¹¹. These findings suggest that changes in microvascular hemodynamics may contribute to the development of SI-AKI.

The renal blood vessels consist of renal arteries, glomerular microvasculature, and peritubular capillaries. Endothelial cells primarily regulate the homeostasis of RBF and microvascular permeability. Alterations in the interaction among endothelial cells result in heightened capillary permeability and leukocyte secretion. Prior research has shown that endothelial nitric oxide synthase (eNOS) levels drop in a septic model induced by Cecal Ligation and Puncture (CLP), and this enzyme plays a crucial role in vasodilation¹²).

Figure 2.Pathogenesis of Sepsis AKIThe release of PAMPs, like lipopolysaccharides, and DAMPs

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