Sepsis-Associated Acute Kidney Injury: Pathophysiology and Treatment Modalities

Abstract

Sepsis-associated acute kidney injury (S-AKI) is a critical complication that significantly contributes to the morbidity and mortality of sepsis patients. This narrative review explores the complex and multifactorial pathophysiology of S-AKI, which involves hemodynamic alterations, microcirculatory dysfunction, endothelial damage, inflammatory responses, oxidative stress, and direct tubular injury. Conventional perspectives linking S-AKI primarily to reduced renal blood flow are now being reconsidered, with growing insights highlighting the significance of microcirculatory dysfunction and endothelial activation as key contributors. The review also discusses the current diagnostic approaches for S-AKI, emphasizing the limitations of existing biomarkers and the need for earlier and more accurate detection methods. Standard treatment strategies focus on supportive care, including fluid management, vasopressor therapy, and renal replacement therapy. However, these approaches often fail to address the underlying mechanisms of S-AKI, resulting in persistently high mortality rates. Emerging therapies, including the use of antioxidants, anti-inflammatory agents, and stem cell-based treatments, offer the potential for improved outcomes. These innovative approaches aim to target the pathophysiological processes at the molecular level, offering hope for better management of S-AKI. The review highlights the need for ongoing research to further understand the mechanisms driving S-AKI and to develop more effective therapeutic strategies.

Keywords: cytokine storm; emerging therapies; endothelial activation; fluid management; inflammatory response; microcirculatory dysfunction; oxidative stress; renal replacement therapy; s-aki pathophysiology; sepsis-associated acute kidney injury.

Figure 1. A bacterial infection in intestinal tissue triggers an immune response mediated by macrophages, monocytes, and complement activation. This leads to vasodilation and the secretion of proinflammatory molecules such as TNF-α and IL-1.

TNF: tumor necrosis factor; IL: interleukin (Image credits: Arshpreet Kaur)

Figure 2. Proinflammatory cytokines induce vasodilation and extravasation of polymorphonuclear leukocytes and other cytokines, which target the infection. However, in the presence of a dysregulated immune response, these mechanisms can lead to a cytokine storm and a subsequent procoagulant state.

TNF: tumor necrosis factor; IFN-γ: interferon gamma; Th1: T-helper 1 cells (Image credits: Alisson Barbosa Silva)

Figure 3. The procoagulant state associated with sepsis can damage or obstruct blood vessels, compromising systemic and renal circulation. This reduction in glomerular filtration rate (GFR) results in elevated serum creatinine and blood urea nitrogen (BUN), presenting clinically as Acute Kidney Injury (AKI) linked to a dysregulated immune response.

TF: Tissue Factor; VIIa: Activated Factor VII; Ca²⁺: Calcium ions; PL: Phospholipids; FVIIIa: Activated Factor VIII; FVa: Activated Factor V; Xa: Activated Factor X; II: Prothrombin; IIa: Thrombin (activated Prothrombin); I: Fibrinogen; Ia: Fibrin (activated Fibrinogen); BUN: Blood Urea Nitrogen.   (Image credits: Pallavi Shekhawat)