Sepsis is a leading cause of acute kidney injury (AKI) in critically ill patients, with sepsis-associated AKI (S-AKI). This article summarises the current understanding and management principles of S-AKI, based on established guidelines and recent consensus updates.

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Pathophysiology: More Than Just Ischemia

The traditional understanding of AKI primarily centred on renal hypoperfusion and ischemic tubular necrosis. However, S-AKI is now recognised as a multifactorial syndrome, where hemodynamic alterations are only one part of a broader pathophysiological spectrum.

1. Systemic Inflammation and Cytokine Storm

Sepsis induces a dysregulated immune response, leading to elevated pro-inflammatory cytokines (e.g., TNF-α, IL-6). These molecules damage renal endothelial cells, promote leukocyte infiltration, and generate oxidative stress, all of which contribute to tubular dysfunction—even in the absence of ischemia [2].

2. Microcirculatory Dysfunction and Endothelial Injury

Despite normal or increased renal blood flow, microcirculatory flow becomes heterogeneous due to loss of autoregulation, endothelial glycocalyx degradation, and capillary leak. This leads to regional hypoxia, particularly in the outer medulla [2,5].

3. Mitochondrial Dysfunction and Apoptosis

Renal tubular cells rely heavily on mitochondrial ATP production. Sepsis disrupts mitochondrial homeostasis, reducing ATP levels and triggering apoptosis or necroptosis via cytochrome c and reactive oxygen species [3].

4. Lack of Histological Necrosis

Biopsies often reveal minimal necrosis despite profound kidney dysfunction. This suggests a primarily functional or metabolic rather than structural injury in early S-AKI. Early recognition is thus crucial, with biomarkers such as TIMP-2•IGFBP7 and NGAL offering potential for earlier intervention [3].

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Treatment Essentials: A Multi-Pronged Supportive Approach

The treatment of S-AKI revolves around early recognition, hemodynamic stabilisation, appropriate antimicrobial therapy, and supportive renal care. There is no specific pharmacologic therapy for S-AKI; hence, a bundle-based, supportive approach is key to preventing further renal insult and improving survival.

Fluid Management: A Tailored, Time-Sensitive Approach

Fluid therapy in S-AKI is a critical but complex intervention. Early aggressive fluid administration is often necessary for hemodynamic resuscitation, yet excessive or prolonged fluid therapy contributes to interstitial oedema, intra-abdominal hypertension, and venous congestion—all of which impair renal recovery. Therefore, fluid administration must be individualised, phase-appropriate, and guided by continuous reassessment.

1. The Importance of an Individualised Strategy

In S-AKI, the kidney is both a victim and modulator of systemic inflammation and hemodynamic instability. While fluid therapy may reverse hypoperfusion initially, sustained or excessive administration exacerbates renal interstitial oedema, delays recovery, and increases the risk of RRT. Several large trials (e.g., FACTT, SOAP, CLASSIC) have shown that cumulative fluid overload is associated with increased mortality and delayed renal recovery.

2. Early Resuscitation and Initial Volume Assessment

The Surviving Sepsis Campaign recommends an initial fluid bolus of 30 ml/kg of crystalloids within the first 3 hours in patients with sepsis-induced hypoperfusion. However, this should be adapted based on individual perfusion markers such as hypotension, rising lactate, oliguria, and signs of peripheral hypoperfusion. Capillary refill, mental status, skin mottling, and urine output should be assessed dynamically.

3. Dynamic Measures Over Static Indices

Fluid responsiveness should be assessed using dynamic tests such as passive leg raise (PLR), stroke volume variation (SVV), and pulse pressure variation (PPV). Bedside echocardiography is valuable to assess cardiac filling, contractility, and venous congestion. Static indices like CVP are no longer recommended for volume guidance.

4. Fluid Choice: Composition and Clinical Implications

Balanced crystalloids (e.g., Ringer’s Lactate, Plasma-Lyte) are the preferred choice due to their favourable acid-base profile. Large volumes of 0.9% normal saline increase the risk of hyperchloremic metabolic acidosis and renal vasoconstriction, contributing to AKI. Hydroxyethyl starch (HES) is contraindicated due to the increased risk of AKI and mortality. Albumin may be considered in patients with persistent hypotension despite crystalloids or in cirrhotic patients with SBP or HRS.

Fluid Type	Recommendation	Notes
Balanced Crystalloids	✅ Preferred	Mimic plasma, better acid-base profile, safer for kidneys
Normal Saline	⚠️ Cautious Use	Risk of acidosis and renal vasoconstriction
Synthetic Colloids	❌ Avoid	Nephrotoxic and increases mortality
Albumin	❓ Selected Use	Consider in hypoalbuminemia, cirrhosis, or shock
Gelatins/Dextrans	❌ Not Recommended	Limited benefit; risk of hypersensitivity and coagulopathy

5. Integration With the ROSE Model: Phase-Based Strategy

The ROSE model (Resuscitation, Optimisation, Stabilisation, Evacuation) provides a framework for fluid management across illness phases:

• Resuscitation (0–6 h): Rapid fluid bolus to restore perfusion (30 ml/kg), guided by hemodynamics
• Optimisation (6–24 h): Dynamic testing to fine-tune perfusion; stop fluid if no further responsiveness
• Stabilisation (24–72 h): Aim for zero balance; avoid "fluid creep" from maintenance and nutrition
• Evacuation (>72 h): Actively remove excess fluid (diuretics or CRRT) in cases of overload or pulmonary oedema

This approach aligns fluid therapy with evolving patient needs, minimising renal and systemic complications.

6. Monitoring and Clinical Targets

Close monitoring is essential to guide therapy and prevent harm:

• Urine output: Target >0.5 ml/kg/h
• Lactate clearance: Marker of perfusion adequacy
• Bedside ultrasound: IVC diameter, B-lines, renal perfusion
• Cumulative balance: Aim to avoid >10% positive fluid balance

7. Summary and Clinical Implications

Fluid management in S-AKI must be dynamic, physiology-driven, and phase-specific. Aggressive early resuscitation should give way to careful titration, followed by timely de-resuscitation. Avoidance of fluid overload and judicious fluid selection are key to renal recovery and improved patient outcomes.

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2. Vasopressor Therapy: Restoring and Maintaining Organ Perfusion

Septic shock often persists despite adequate fluid resuscitation, necessitating vasopressor support to maintain perfusion pressure and prevent multi-organ dysfunction. In patients with S-AKI, careful titration of vasopressors is critical to restore renal perfusion without exacerbating ischemic injury.

1. First-Line Agent: Norepinephrine

Norepinephrine is the preferred first-line vasopressor in septic shock. It primarily stimulates α1-adrenergic receptors, causing vasoconstriction and increasing systemic vascular resistance, thereby raising mean arterial pressure (MAP) without significantly increasing heart rate. The target MAP is typically ≥ 65 mmHg. In patients with chronic hypertension, a higher target may be appropriate to ensure adequate renal perfusion.

2. Adjunctive Vasopressors: Vasopressin and Epinephrine

If the target MAP is not achieved with norepinephrine alone, vasopressin (up to 0.03 U/min) may be added as a second-line agent. Vasopressin works via V1 receptors and has a synergistic effect, often allowing a reduction in norepinephrine dose. Epinephrine is considered in refractory cases but may increase lactate levels and carry a higher risk of arrhythmias.

3. Role of Dopamine and Other Agents

Dopamine is no longer recommended in most septic patients due to its unpredictable effects, higher risk of tachyarrhythmias, and no clear renal benefit. Phenylephrine is avoided unless there's a specific contraindication to norepinephrine (e.g., atrial fibrillation with rapid ventricular response).

4. Individualised MAP Targets and Monitoring

MAP goals should be individualised. While 65 mmHg is a general threshold, some patients (e.g., elderly or hypertensive individuals) may require higher MAPs for adequate renal perfusion. Conversely, excessive vasopressor use to achieve arbitrary targets can reduce renal perfusion via excessive vasoconstriction.

Monitoring involves continuous blood pressure, urine output, serum lactate, and serial creatinine levels. Bedside Doppler and renal ultrasound may help assess renal perfusion.

5. Timing and Integration with Fluid Strategy

Vasopressors should be initiated after adequate fluid resuscitation, or concurrently if hypotension is life-threatening. Early initiation in the presence of persistent hypotension helps prevent prolonged hypoperfusion and reduces time to hemodynamic stability.

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Antibiotic Management in Sepsis-Associated Acute Kidney Injury (S-AKI)

Timely initiation of empiric antibiotic therapy is a core tenet of sepsis management. However, in the setting of S-AKI, antimicrobial stewardship becomes particularly complex due to altered pharmacokinetics, dynamic renal function, and increased risk of nephrotoxicity. The goal is to ensure adequate early antibiotic exposure to improve survival while minimising the risk of drug-induced worsening of renal injury.

Initiation: Early, Appropriate, and Empiric

Time-to-antibiotic is an independent predictor of mortality in sepsis. Broad-spectrum antibiotics must be administered within the first hour of sepsis recognition, including in AKI patients [1].

Empiric regimens should consider local antibiogram data and the likely source of infection. In AKI patients, beta-lactams (e.g., meropenem, piperacillin–tazobactam) are often first-line, with careful renal dose adjustment.

Do not delay initiation for fear of nephrotoxicity in the acute phase—early control of infection outweighs theoretical renal risks.

Pharmacokinetic Alterations in AKI and Sepsis

Sepsis and AKI both significantly alter antibiotic pharmacokinetics:

1. Expanded volume of distribution (Vd): Due to capillary leak and fluid resuscitation, especially for hydrophilic drugs (e.g., beta-lactams, aminoglycosides), leading to subtherapeutic plasma levels.
2. Reduced renal clearance: In AKI, excretion of renally eliminated antibiotics is diminished, increasing the risk of accumulation.
3. Augmented renal clearance (ARC): Some critically ill patients, especially early in sepsis, can paradoxically exhibit high GFR (>130 ml/min/1.73 m²), leading to underdosing unless accounted for [2].

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Dosing Principles in S-AKI

Loading Dose: Should generally be the same as in patients with normal renal function, even in oliguria/anuria, to rapidly achieve therapeutic concentrations, especially for time-dependent antibiotics (e.g., beta-lactams).

1. Maintenance Dose: Adjust based on eGFR, serum creatinine trends, or measured creatinine clearance. Be cautious—serum creatinine may be misleading in early AKI.
2. Renal Replacement Therapy: Dosing should consider RRT modality (CRRT vs. IHD), flow rates, filter type, and drug characteristics (molecular weight, protein binding, Vd).

CRRT increases the clearance of many antibiotics, often necessitating higher doses than in non-dialysis AKI. Frequent re-evaluation is required due to dynamic clinical status.

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Specific Antibiotic Considerations

1. Vancomycin: Nephrotoxic at high trough levels; use TDM targeting AUC/MIC 400–600 rather than trough alone. Avoid in combination with other nephrotoxins if possible. Dose cautiously in AKI and adjust for CRRT clearance.
2. Aminoglycosides (e.g., amikacin, gentamicin): Concentration-dependent bactericidal activity; however, nephrotoxicity is well-established. Use once-daily dosing, short courses, and monitor peaks and troughs.
3. Piperacillin–Tazobactam + Vancomycin: A high-risk combination for nephrotoxicity—use with extreme caution. Recent meta-analyses suggest additive risk compared to vancomycin alone or vancomycin + cefepime [3].
4. Colistin: Considered in MDR infections but carries substantial nephrotoxic risk. Prefer colistimethate sodium over polymyxins, and adjust dosing rigorously based on renal function.

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Therapeutic Drug Monitoring (TDM)

1. Vancomycin: TDM is standard. In AKI or CRRT, use AUC-guided dosing, not just trough levels.
2. Aminoglycosides: Mandatory TDM due to narrow therapeutic index.
3. Beta-lactams: Though not routinely monitored, evidence supports the use of prolonged or continuous infusions to maximise time above MIC (T>MIC), especially in sepsis with increased Vd [2].

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De-escalation and Duration

1. De-escalation: After culture results and clinical stabilisation, narrow the antibiotic spectrum to reduce resistance pressure and limit nephrotoxic exposure.
2. Shorter duration (e.g., 7 days) is now preferred for most infections if there is good source control and clinical response. This is especially important in AKI patients.

Antibiotic	Renal Dosing	Nephrotoxicity	Monitoring Notes
Meropenem / Piptazo	Full LD, adjust MD by GFR/CRRT	Low	Prolonged infusion improves T>MIC
Vancomycin	Adjust per AUC/MIC or trough	Moderate–High	TDM is essential; avoid with Piptazo combo
Amikacin / Gentamicin	Once-daily; avoid if possible	High	Peak/trough TDM; limit duration
Colistin	Renal adjustment mandatory	Very High	Narrow index; avoid unless MDR organism
Linezolid	No adjustment in AKI	Low	Monitor for cytopenias in prolonged use

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Clinical Pearls

1. Do not delay antibiotic initiation in AKI. Dose appropriately and monitor closely.
2. Use loading doses in all septic patients, including those on dialysis.
3. Consider CRRT-related clearance in drug dosing—underdosing can lead to treatment failure.
4. Avoid nephrotoxic combinations if alternatives are available.

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4. Diuretics and Nephrotoxins

The use of diuretics in S-AKI should be strictly limited to managing fluid overload in patients with residual urine output. Loop diuretics such as furosemide may help achieve a negative fluid balance but have no role in preventing AKI or improving renal recovery. High doses without response may delay the initiation of renal replacement therapy (RRT) and worsen outcomes.

Avoid or minimise exposure to nephrotoxic agents, including:

• NSAIDs
• IV contrast (when avoidable or without preventive protocols)
• Aminoglycosides (use with TDM and shortest course)
• Vancomycin combinations, especially with piperacillin–tazobactam
• Amphotericin B (prefer liposomal formulations if essential)

Review all prescriptions daily with a focus on de-prescribing or switching to less nephrotoxic alternatives.

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Nutrition and Glycemic Control

Critically ill patients with S-AKI are at risk of catabolic stress and malnutrition. Guidelines recommend initiating early enteral nutrition within 24–48 hours of ICU admission once the patient is hemodynamically stable.

• Target protein intake: 1.3–1.5 g/kg/day (up to 2 g/kg/day in CRRT patients)
• Energy requirements: 20–25 kcal/kg/day initially, adjusted with indirect calorimetry if available
• Avoid parenteral nutrition unless the enteral route is contraindicated or insufficient after 5–7 days

For glycemic control, maintain blood glucose between 140–180 mg/dL using insulin infusion protocols. Avoid hypoglycemia (<70 mg/dL), which is independently associated with mortality in the ICU.

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Monitoring and Clinical Surveillance

Close, structured monitoring is essential for timely intervention and prevention of complications in S-AKI. Key parameters include:

• Hourly urine output: Primary indicator of renal perfusion; target >0.5 ml/kg/h
• Serum creatinine and urea: Serial trends are more informative than isolated values
• Daily fluid balance: Use weight-based assessment and fluid charts
• Electrolytes and acid-base status: Monitor for hyperkalemia, acidosis, and sodium abnormalities
• Hemodynamic parameters: Continuous MAP, lactate clearance, and capillary refill guide volume status

Bedside ultrasound, especially point-of-care assessments of IVC, cardiac function, and lung B-lines, offers real-time, non-invasive support for fluid and perfusion decisions.

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Long-Term Implications

While short-term management of sepsis-associated AKI focuses on hemodynamic stabilisation and renal support, the long-term renal consequences are increasingly recognised as a critical component of survivorship.

A significant proportion of patients with S-AKI do not achieve full renal recovery at hospital discharge. Studies show that up to one-third of survivors progress to chronic kidney disease (CKD) within 12 months, and a smaller subset may develop end-stage kidney disease (ESKD), particularly those with:

• Severe or prolonged AKI
• Oliguria or anuria during ICU stay
• Need for dialysis (especially prolonged RRT)
• Pre-existing CKD, diabetes, or hypertension

Even patients who appear to recover renal function based on serum creatinine may exhibit subclinical tubular damage, reduced nephron reserve, or structural scarring on follow-up.

Given this, post-discharge nephrology follow-up is essential, ideally within 30–90 days of discharge. Recommended elements of follow-up include:

• Renal function assessment (eGFR, creatinine, BUN)
• Urinalysis for proteinuria or hematuria
• Blood pressure monitoring and cardiovascular risk modification
• Medication review to avoid nephrotoxins
• Lifestyle counselling to reduce further renal insult

Importantly, S-AKI also increases the risk of hospital readmission, cardiovascular events, and long-term mortality, making multidisciplinary care—linking nephrology, primary care, and critical care follow-up—critical to improving outcomes.

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Disclaimer- The views and opinions expressed in this article are those of the author and do not necessarily reflect the official policy or position of M3 India.

About the author of this article: Dr Anagha Auradkar is working as an assistant professor of Nephrology at  Dr B.R. Ambedkar Medical College, Bangalore.