Acute Kidney Injury in Sepsis: Pathophysiology and Management
Pathophysiology
Sepsis-associated AKI is not primarily driven by renal hypoperfusion as traditionally believed, but rather by microcirculatory dysfunction, inflammatory cascade activation, and endothelial damage, even when systemic renal blood flow remains normal or increased. 1, 2
Core Mechanisms
Microcirculatory dysfunction occurs through leukocyte and platelet activation with micro-thrombi formation, creating dissociation between renal blood flow and kidney function 1, 3
Inflammatory cascade activation involves complex immunologic mechanisms leading to endothelial damage and tubular cell injury without diffuse acute tubular necrosis on biopsy 1, 4
Metabolic reprogramming and oxidative stress contribute to tubular cell dysfunction, representing functional rather than structural injury in early phases 5, 3
Deranged coagulation pathways interact with inflammatory responses to cause epithelial tubular cell injury and dysfunction 1
Maladaptive fibrotic responses begin early and may progress to chronic kidney disease even in survivors 1
Emerging Understanding
Septic AKI represents biologically distinct subphenotypes with different inflammatory/endothelial profiles, short-term renal recovery rates, and 90-day mortality 6
Two AKI subphenotypes show differential treatment responses, with subphenotype 1 demonstrating potential survival benefit from low-dose vasopressin 6
Immediate Resuscitation (First 3 Hours)
Administer at least 30 mL/kg of isotonic crystalloid within 3 hours of sepsis recognition and start broad-spectrum antibiotics within 1 hour. 7
Fluid Selection
Use balanced crystalloids (lactated Ringer's or Plasma-Lyte) rather than normal saline to avoid hyperchloremic metabolic acidosis 7
Avoid colloids entirely—they increase AKI risk without improving outcomes 7
Never use starch-containing fluids—strong evidence demonstrates nephrotoxicity and decreased renal function 5
Critical Pitfall
Never withhold or delay antibiotics due to nephrotoxicity concerns—treating sepsis takes absolute priority over renal considerations 7
Never reduce loading doses of antibiotics due to renal dysfunction, as this leads to subtherapeutic levels and treatment failure 7
Hemodynamic Management
Use norepinephrine as first-line vasopressor targeting MAP ≥65 mmHg if hypotension persists despite adequate fluid resuscitation. 7
Vasopressor Strategy
Norepinephrine is the dominant agent with the strongest evidence base for septic AKI 5
Vasopressin may have a role as adjunctive therapy, particularly in specific AKI subphenotypes 6, 5
Avoid dopamine as first-line agent—it is associated with increased mortality and arrhythmias in septic shock and is ineffective for AKI prevention 7, 5
Hemodynamic Targets
Maintain MAP ≥65 mmHg consistently through protocol-based optimization targeting tissue oxygenation parameters 8, 7
Recognize that vasopressor use, while necessary for systemic perfusion, can paradoxically increase renal vascular resistance 8
Loop Diuretic Management
Do not use loop diuretics to prevent or treat AKI in sepsis, except when managing established volume overload after hemodynamic stabilization. 8
Evidence-Based Restrictions
Randomized trials and meta-analyses show furosemide does not prevent AKI and may increase mortality in septic patients 8
In hemodynamically unstable sepsis, loop diuretics precipitate volume depletion, hypotension, and further renal hypoperfusion 8
KDIGO Grade 1B recommendation (strong, moderate-quality evidence) against using loop diuretics for AKI prevention 8
Limited Indication
Use only in hemodynamically stable patients with confirmed fluid overload (pulmonary edema, peripheral edema, positive fluid balance) 8
Observational data suggest higher furosemide doses may reduce mortality in AKI patients with volume overload, while cumulative positive fluid balance correlates with higher mortality 8
Renal Replacement Therapy Decision-Making
Initiate RRT only for definitive indications: refractory volume overload despite diuretics, severe metabolic acidosis, or life-threatening hyperkalemia—not based on creatinine level or AKI stage alone. 7
RRT Timing and Modality
No clear guidelines exist on optimal timing for RRT initiation; decisions must be individualized, though early initiation in rapidly developing oliguric AKI should not be delayed 6
Intermittent hemodialysis (IHD) and continuous RRT (CRRT) are equivalent in mortality outcomes for septic AKI patients 6
In hemodynamically unstable patients, CRRT may facilitate fluid balance control, though evidence for superior hemodynamic tolerance is limited 6
Intensive RRT dosing does not improve outcomes—standard-dose RRT is recommended over high-intensity regimens 6
Escalation Algorithm
| Clinical Situation | Action |
|---|---|
| Persistent volume overload despite adequate loop diuretics | Initiate CRRT [8] |
| Hemodynamically unstable requiring fluid removal | Use CRRT as preferred modality [8] |
| Stable patient with standard indications | Either IHD or CRRT acceptable [6] |
Supportive Management
Metabolic Control
Target blood glucose 110-149 mg/dL using protocolized insulin therapy 7
Provide 20-30 kcal/kg/day total energy intake 7
Protein Administration
0.8-1.0 g/kg/day in non-catabolic AKI without dialysis 7
1.0-1.5 g/kg/day in patients on RRT 7
Up to 1.7 g/kg/day in hypercatabolic patients on CRRT 7
Nephrotoxin Avoidance
Avoid nephrotoxic agents systematically while balancing against the need for appropriate antimicrobial therapy 8
Adjust maintenance doses (not loading doses) of renally cleared antibiotics based on kidney function 7
Management of Persistent AKI
When AKI persists beyond 48 hours, reassess the underlying etiology for multifactorial causes including ongoing sepsis, unrecognized nephrotoxins, or obstruction. 6, 7
Diagnostic Reassessment
Perform urine sediment analysis to evaluate for active cellular injury patterns 6, 7
Assess proteinuria to identify glomerular involvement 6
Obtain renal ultrasound to exclude obstruction 7
Consider nephrology consultation if etiology remains unclear or subspecialist care is needed 6
Functional Assessment Limitations
eGFR equations (MDRD, CKD-EPI) are not accurate in AKI because they require steady-state creatinine 6
Timed urine creatinine clearance is the best available estimate for persistent AKI in steady state, though it overestimates GFR 6
Prognostic Implications
Persistence of AKI and stuttering recovery patterns are linked to increased morbidity and 90-day mortality 6
Even single episodes of septic AKI increase subsequent risk of chronic kidney disease 5
The combination of acute renal failure and sepsis carries 70% mortality 6
Special Considerations and Pitfalls
Context-Specific Cautions
In malaria-induced AKI, avoid overzealous fluid resuscitation as it may worsen acute lung injury 7
In neutropenic patients, the combination of renal failure and sepsis has particularly high mortality requiring aggressive early intervention 6