Introduction
(Article introduction authored by ICU Editorial Team)
Sepsis, a harmful response to infection, can lead to life-threatening organ dysfunction, with sepsis-associated acute kidney injury (SA-AKI) being the most common organ dysfunction and contributing to about 50% of all AKI in critically ill adults.
Despite advancements in understanding clinical risk factors, pathobiology, and treatment responses for SA-AKI, it remains a significant health burden.
This review explores current treatment standards and novel developments in the pathophysiology, diagnosis, outcome prediction, and management of SA-AKI. Sepsis-associated AKI, affecting up to 60% of sepsis patients, involves complex mechanisms such as inflammation, complement activation, mitochondrial dysfunction, and microcirculatory dysfunction.
The increased mortality risk associated with AKI in sepsis underscores the critical need for ongoing research to mitigate both short and long-term consequences.
From diagnosis to treatment of SA-AKI
In cases of suspected sepsis, lactate levels should be measured, and if elevated (>2 mmol/L), the measurement should be repeated, guiding resuscitation based on lactate levels.
Once sepsis is diagnosed, treatment should align with current sepsis guidelines. Before administering antibiotics, obtaining blood cultures is crucial.
In the presence of sepsis-induced hypoperfusion (lactate levels ≥2 mmol/L) or septic shock, initiate crystalloid fluid administration guided by dynamic parameters of fluid responsiveness.
Vasopressors, with norepinephrine recommended as the first-line choice, should be administered to maintain a mean arterial pressure (MAP) >65 mmHg and decrease serum lactate levels.
Dopamine is not advised in septic patients. This protocol ensures a systematic and evidence-based approach to managing sepsis and its complications.
The article also introduces a diagnostic and treatment algorithm for SA-AKI in adults, aligned with recent recommendations from the Acute Disease Quality Initiative group.
Early fluid administration is crucial in sepsis to support macro- and microcirculation. Guidelines recommend an initial 30 ml/kg of crystalloids, but fluid administration should be individualized and guided by fluid responsiveness to avoid volume overload.
The choice of fluid type, particularly 0.9% saline, has been debated, but recent studies suggest its safe use up to 4 L. All sepsis patients, especially those with comorbidities like chronic kidney disease, are considered at high risk for acute kidney injury (AKI).
Monitoring kidney function using serum creatinine and urine output is essential, but the KDIGO definition of AKI has limitations. Early detection of kidney damage is crucial, and combining damage and functional biomarkers may enhance sensitivity and specificity.
Biomarkers such as cystatin C, proenkephalin, TIMP2, IGFBP7, and plasma neutrophil gelatinase-associated lipocalin can aid in detecting AKI. Bedside Doppler ultrasound can assess renal perfusion, and the renal resistive index (RRI) may predict AKI. However, Doppler ultrasound may not discriminate patterns of renal recovery. Urinalysis and urine microscopy, especially evaluating cast elements and tubule epithelial cells, contribute to identifying sepsis-associated AKI. These tools collectively enhance early detection and monitoring of AKI in septic patients.
Patients at high risk for SA-AKI
For patients at high risk of acute kidney injury (AKI), KDIGO guidelines recommend implementing a care bundle of supportive measures. Although demonstrated to reduce AKI occurrence in surgical patients at risk, this effect has not been explicitly shown in sepsis patients. The suggested bundle for patients at high risk of AKI includes avoiding nephrotoxic agents, close monitoring of serum creatinine and urine output, avoiding hyperglycemia, considering alternatives to radiocontrast agents, and hemodynamic monitoring with optimization of volume status and hemodynamics. Implementation of these measures could potentially mitigate the risk of AKI in septic patients.
Patients with SA-AKI
Supportive measures outlined in the care bundle should be continued in patients with established acute kidney injury (AKI), although evidence supporting their positive influence on AKI course is lacking.
Diuretics are not recommended for the prevention or treatment of sepsis-associated AKI, as prophylactic use in high-risk patients has proven unsuccessful, and they do not attenuate AKI once established
However, their use in regulating fluid balance persists in critical illness.
The BICAR-ICU trial suggests potential benefits of intravenous sodium bicarbonate in severe metabolic acidaemia for critically ill patients with moderate–severe AKI.
However, caution is needed in interpreting the results, and the applicability to sepsis-associated AKI is not fully established.
Maintaining arterial blood pressure within an unknown target range in septic patients is important, with evidence suggesting a target MAP >85 mmHg in those with pre-existing hypertension may reduce serum creatinine increase and the need for renal replacement therapy.
Angiotensin II has shown potential benefits in vasodilatory shock with earlier discontinuation of RRT and lower 28-day mortality.
Timing and dosing of renal replacement therapy (RRT) in sepsis-associated AKI require careful consideration. Initiating RRT early does not show clear benefits, and a recommended delivery dose of 20–25 ml/kg/h is supported, with no additional benefits observed at higher doses or with high-volume hemofiltration.
In the setting of sepsis-associated AKI, continuous and intermittent RRT modalities demonstrate similar outcomes, but consideration for the patient’s hemodynamic stability is crucial, favoring continuous RRT for haemodynamically unstable patients.
Pathophysiology
SA-AKI results from complex interactions of various pathophysiologic mechanisms, including host susceptibility, sepsis-related effects, and the impact of sepsis-associated therapies.
Future trials addressing SA-AKI should consider this complexity, relying on biomarkers for patient selection.
Local Innate Immune Activation, Inflammation, and Complement Activation:
Early interactions of DAMPs/PAMPs with host PRRs induce immunity and complement activation, triggering systemic and local renal inflammatory responses. TLR4 engagement in tubular epithelial cells leads to oxidative stress. Microvascular dysfunction, oxidative stress, inflammatory amplification, intrarenal shunting, and tissue hypoxia contribute to SA-AKI.
RAAS Dysfunction:
Elevated renin levels in critically ill patients are associated with worse outcomes and refractory vasodilatory shock.
Inflammation-induced angiotensin-converting enzyme dysfunction leads to reduced angiotensin II, impacting vascular tone, fluid balance, and GFR.
Mitochondrial Dysfunction:
Sepsis induces mitochondrial injury in proximal tubules through oxidative damage, TLR4-mediated inflammation, and electron transport chain inhibition.
Mitochondrial impairment includes decreased mass, disrupted cristae, and variable swelling, affecting tubular and renal function.
Outcome Prediction:
Biomarkers, such as proenkephalin and TIMP2•IGFBP7, show promise in predicting patient-oriented outcomes, including AKI progression, need for RRT, and mortality.
Early identification using multiple biomarkers and advanced techniques like machine learning enhances risk stratification for SA-AKI and adverse outcomes in sepsis patients.
Conclusion
The pathophysiology of SA-AKI is very complex and still not fully understood. Currently, no specific therapy exists to prevent or treat this complex syndrome.
Management of SA-AKI involves early recognition and treatment of the underlying infection, fluid resuscitation, inotropic or vasopressor agents, diuretics, and potentially RRT. Prevention is key and includes early recognition and treatment of sepsis, avoidance of nephrotoxic agents, and appropriate dosing of medications.
Source: Alexander Zarbock, Jay L Koyner, Hernando Gomez, Peter Pickkers, Lui Forni, the Acute Disease Quality Initiative group , Sepsis-associated acute kidney injury—treatment standard, Nephrology Dialysis Transplantation, Volume 39, Issue 1, January 2024, Pages 26–35, https://doi.org/10.1093/ndt/gfad142
