Why do kidneys fail during sepsis?

Why Kidneys Fail During Sepsis

Kidneys fail during sepsis primarily due to a complex interplay of hemodynamic alterations, microcirculatory dysfunction, and inflammatory responses that lead to adaptive responses in tubular epithelial cells rather than simple hypoperfusion.

Pathophysiological Mechanisms

Hemodynamic Alterations

• Splanchnic and systemic vasodilation causes effective arterial underfilling, triggering compensatory vasoconstrictor system activation (renin-angiotensin-aldosterone and sympathetic nervous systems) 1
• This leads to kidney vasoconstriction that initially conserves sodium and water but eventually reduces kidney blood flow to levels that impair glomerular filtration rate (GFR)
• Contrary to traditional belief, sepsis-induced AKI can occur even with normal or increased renal blood flow in resuscitated septic patients 2

Microcirculatory Dysfunction

• Alterations in renal microcirculation occur despite normal or increased global renal blood flow 2
• Key microvascular changes include:
  • Vasoconstriction
  • Capillary leak syndrome with tissue edema
  • Leukocyte and platelet adhesion with endothelial dysfunction
  • Microthrombosis
• Increased renal vascular resistance (RVR) is a critical hemodynamic factor in sepsis-associated AKI 2

Inflammatory Response

• Bacterial products and cytokines have vasodilatory properties that worsen splanchnic and systemic vasodilation 1
• These inflammatory mediators directly alter kidney peritubular microcirculation
• They can directly damage kidney tissue and cause oxidative stress 1
• Oxidative stress affects cellular metabolism and induces apoptosis

Cellular Adaptive Responses

• Recent evidence suggests that adaptive responses of tubular epithelial cells to injurious signals are responsible for renal dysfunction 3
• These maladaptive cellular responses include metabolic reprogramming and dysregulated inflammatory responses 4
• The recognition of pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) by proximal tubular epithelial cells triggers mitochondria-mediated metabolic downregulation 1
• This leads to reprioritization of cell functions to favor survival processes at the expense of normal tubular function

Clinical Implications and Management

Definition and Diagnosis

• Sepsis-associated AKI (SA-AKI) is best defined as AKI occurring within 7 days of sepsis onset 4
• AKI is diagnosed according to Kidney Disease Improving Global Outcomes (KDIGO) criteria
• Novel biomarkers can be used for prediction of duration and recovery of AKI (Grade C, weak recommendation) 1

Fluid Management

• Appropriate fluid resuscitation and maintenance of blood pressure are crucial to prevent further kidney damage 5
• Balanced crystalloid solutions (e.g., Ringer's Lactate, Plasmalyte) are preferred over 0.9% NaCl to reduce risk of hyperchloremic acidosis 6
• Avoid hydroxyethyl starch solutions due to increased risk of worsening renal function 6
• For initial management, use isotonic crystalloids with an initial bolus of 500 mL, followed by reassessment 6

Renal Replacement Therapy

• Either continuous or intermittent renal replacement therapy (RRT) can be used in patients with sepsis and acute kidney injury (weak recommendation, moderate quality of evidence) 1
• Continuous therapies are suggested for managing fluid balance in hemodynamically unstable septic patients (weak recommendation, very low quality of evidence) 1
• RRT should not be used solely for increases in creatinine or oliguria without other definitive indications for dialysis 1

Special Considerations

Cardiac Comorbidity

• In patients with pre-existing cardiac dysfunction or sepsis-induced cardiomyopathy, fluid management must be carefully tailored to prevent pulmonary edema 7
• Monitoring for signs of fluid overload (jugular venous distention, crackles on lung examination, worsening oxygenation) is essential 6

Biomarkers for Prognosis

• Several biomarkers show promise for predicting AKI progression and recovery:
  • Plasma NGAL has shown predictive value for kidney recovery (AUROC = 0.74) 1
  • Proenkephalin-A levels are significantly lower in patients who recover kidney function within 48 hours 1
  • Urinary C-C motif chemokine ligand 14 is predictive of persistent AKI 1

Prevention Strategies

• Early identification of patients at risk of AKI is crucial for timely intervention 4
• Limit further insults to the kidney by:
  • Avoiding nephrotoxic medications
  • Maintaining adequate perfusion pressure
  • Treating the underlying sepsis promptly
• Monitor fluid status carefully to prevent both hypovolemia and fluid overload

By understanding these complex mechanisms, clinicians can better approach the management of sepsis-induced AKI with targeted interventions that address the underlying pathophysiology rather than simply focusing on renal perfusion.