What are the mechanisms by which sepsis can lead to acute kidney injury (AKI)?

Mechanisms of Sepsis-Induced Acute Kidney Injury

Sepsis causes acute kidney injury through four primary mechanisms: (1) microvascular dysfunction with altered renal perfusion despite maintained global renal blood flow, (2) direct inflammatory injury to tubular epithelial cells, (3) metabolic reprogramming and cellular stress responses, and (4) increased renal vascular resistance from vasoconstriction and endothelial dysfunction. 1, 2

1. Microvascular Dysfunction and Altered Renal Perfusion

The traditional paradigm that septic AKI results solely from renal hypoperfusion has been fundamentally challenged. Recent evidence demonstrates that septic AKI frequently occurs in the presence of normal or even increased global renal blood flow, particularly in resuscitated patients with hyperdynamic circulation 3, 1, 2.

• Heterogeneous microcirculatory alterations occur despite preserved total renal blood flow, with colocalized areas of sluggish peritubular capillary blood flow adjacent to regions of normal perfusion 1
• Microvascular dysfunction manifests as vasoconstriction, capillary leak syndrome with tissue edema, leukocyte and platelet adhesion, endothelial dysfunction, and microthrombosis 3
• These alterations affect both renal cortical and medullary microcirculation, creating focal areas of ischemia even when global perfusion appears adequate 3, 2

2. Direct Inflammatory Injury to Tubular Epithelial Cells

Septic AKI is characterized not by acute tubular necrosis or widespread apoptosis, but rather by adaptive and maladaptive cellular responses to inflammatory injury. 1, 2

• Tubular epithelial cells undergo metabolic reprogramming in response to septic insults, with oxidative stress occurring in heterogeneous patterns that colocalize with areas of microvascular dysfunction 1
• Multiple forms of cell death are implicated, including apoptosis, necroptosis, pyroptosis, and ferroptosis, rather than the classic acute tubular necrosis pattern seen in ischemic AKI 4
• Inflammatory mediators directly injure tubular cells through cytokine-mediated pathways, with interleukins 6,8, and 18 playing key roles 4
• Maladaptive cellular responses to septic signals are responsible for renal dysfunction, representing a fundamentally different pathophysiology than ischemic AKI 2, 5

3. Metabolic Reprogramming and Cellular Stress Responses

Sepsis induces profound metabolic alterations in renal cells that contribute to organ dysfunction independent of perfusion changes. 4

• Metabolic reprogramming during sepsis alters cellular energy production and utilization, with tubular epithelial cells shifting metabolic pathways in response to inflammatory stress 4
• Autophagy and efferocytosis mechanisms become dysregulated, impairing the kidney's ability to clear damaged cells and maintain homeostasis 4
• Oxidative stress develops in tubular epithelial cells, creating reactive oxygen species that further damage cellular structures 1

4. Increased Renal Vascular Resistance

Elevated renal vascular resistance represents a key hemodynamic factor in sepsis-associated AKI, occurring even when cardiac output is maintained or increased. 3

• Increased renal vascular resistance develops from multiple mechanisms including microvascular vasoconstriction, endothelial dysfunction, and increased intra-abdominal pressure 3
• Vasopressor use, while necessary to maintain systemic perfusion (as in this patient requiring noradrenaline), can paradoxically increase renal vascular resistance and contribute to AKI 6
• Hemodynamic instability in sepsis, even when corrected with fluids and vasopressors, may not restore normal intrarenal hemodynamics due to persistent microvascular dysfunction 6, 3

Clinical Implications for This Patient

This 65-year-old man demonstrates classic septic AKI with oliguria (20 mL over 2 hours), rising creatinine (100 to 400 mmol/L), and vasopressor dependence. His AKI likely results from the combination of all four mechanisms operating simultaneously: microvascular dysfunction despite noradrenaline support, direct inflammatory injury from perforated diverticulitis (evidenced by WBC 25 and CRP 200), metabolic stress responses, and increased renal vascular resistance 3, 1, 2.

Management should focus on protocol-based hemodynamic optimization targeting tissue oxygenation parameters, continued vasopressor support with fluids, and avoidance of nephrotoxic agents 6. The KDIGO guidelines recommend using vasopressors in conjunction with fluids for patients with vasomotor shock and AKI, though this use is inherently associated with AKI development 6.