Renal Replacement Therapy in the ICU: Timing, Modality, and Myths - A Critical Review

Dr Neeraj Manikath , claude.ai

Abstract

Background: Acute kidney injury (AKI) affects 20-25% of critically ill patients, with 13-15% requiring renal replacement therapy (RRT). Despite decades of research, optimal timing and modality selection remain contentious, with recent landmark trials challenging traditional approaches.

Objective: To provide an evidence-based review of contemporary RRT practices in the ICU, examining timing strategies, modality selection, and addressing persistent misconceptions in critical care nephrology.

Methods: Comprehensive review of recent randomized controlled trials, meta-analyses, and clinical guidelines, with particular focus on STARRT-AKI and AKIKI trial series.

Results: Early initiation of RRT does not improve survival compared to standard care. Continuous renal replacement therapy (CRRT) offers hemodynamic advantages in unstable patients, while intermittent hemodialysis (IHD) provides efficient solute clearance. Regional citrate anticoagulation has emerged as the preferred anticoagulation strategy for CRRT.

Conclusions: RRT timing should be individualized based on absolute indications rather than AKI severity alone. Modality selection should consider patient hemodynamics, institutional resources, and clinical expertise. The "earlier is better" paradigm lacks robust evidence support.

Keywords: Acute kidney injury, renal replacement therapy, critical care, CRRT, timing, anticoagulation

Introduction

Acute kidney injury represents one of the most challenging complications in intensive care medicine, occurring in approximately 20-25% of critically ill patients and necessitating renal replacement therapy in 13-15% of cases¹. The intersection of renal dysfunction with multi-organ failure creates a complex clinical scenario where traditional nephrology principles must be adapted to the unique physiological derangements of critical illness.

The evolution of RRT in the ICU has been marked by technological advances, from the early days of peritoneal dialysis to sophisticated CRRT platforms capable of precise fluid and solute management. However, despite these technological leaps, fundamental questions regarding optimal timing and modality selection have persisted, leading to significant practice variation worldwide.

Recent landmark trials, particularly the STARRT-AKI and AKIKI series, have challenged long-held assumptions about early RRT initiation, forcing a reevaluation of traditional approaches. This review synthesizes current evidence while addressing persistent myths that continue to influence clinical practice.

The Physiology of AKI in Critical Illness

Pathophysiological Considerations

Critical illness-associated AKI differs fundamentally from chronic kidney disease in its rapid onset, potential reversibility, and integration with systemic inflammatory responses. The kidney's role extends beyond simple filtration to encompass acid-base regulation, electrolyte homeostasis, and fluid balance - functions that become critical in the hemodynamically unstable patient.

The concept of "renal reserve" becomes particularly relevant in the ICU setting. While healthy kidneys can compensate for significant nephron loss, the combination of sepsis, hypoperfusion, and nephrotoxic exposures creates a perfect storm for acute decompensation. Understanding this pathophysiology is crucial for timing decisions, as it highlights why traditional markers like creatinine may lag behind actual kidney injury.

The Uremic Milieu in Acute Settings

Unlike chronic uremia, acute uremic toxicity develops rapidly and may contribute to multi-organ dysfunction through inflammatory mediators, oxidative stress, and disrupted cellular metabolism. However, the clinical significance of uremic toxins in acute settings remains poorly defined, contributing to uncertainty around RRT initiation timing.

Evidence from Landmark Trials

The STARRT-AKI Revolution

The Standard versus Accelerated Initiation of Renal Replacement Therapy in Acute Kidney Injury (STARRT-AKI) trial represents a watershed moment in critical care nephrology². This multinational, randomized controlled trial of 3,019 patients with severe AKI challenged the prevailing wisdom that earlier RRT initiation improves outcomes.

Key Findings:

No significant difference in 90-day mortality between accelerated (12 hours) and standard strategy groups (32.9% vs 34.1%, P=0.38)
Higher rate of RRT-free survival in the standard strategy group
61.8% of standard strategy patients never received RRT
Similar rates of major adverse events between groups

These findings fundamentally challenged the "time is kidney" paradigm that had driven much of contemporary practice. The trial's strength lies not only in its size and international scope but also in its pragmatic design, reflecting real-world clinical decision-making.

AKIKI Series Insights

The AKIKI (Artificial Kidney Initiation in Kidney Injury) trials provided complementary evidence supporting judicious RRT timing³,⁴:

AKIKI-1 (2016):

620 patients with severe AKI
Early vs. delayed strategy
No mortality benefit with early initiation
49% of delayed group never required RRT

AKIKI-2 (2021):

Focused on more restrictive delayed strategy
Confirmed safety of watchful waiting approach
Emphasized importance of careful patient selection

Meta-analytical Evidence

Recent meta-analyses have consistently supported the findings of individual trials⁵,⁶:

No survival benefit with early RRT initiation
Increased RRT exposure with early strategies
Potential for harm from unnecessary intervention

Clinical Pearls: Timing Strategies

Pearl 1: The "AEIOU" Mnemonic Revisited

Traditional absolute indications for RRT (Acidosis, Electrolyte abnormalities, Intoxications, Overload, Uremia) remain valid, but their application in critical care requires nuance:

Acidosis: pH < 7.15 despite maximal medical therapy
Electrolytes: Hyperkalemia > 6.5 mEq/L with ECG changes refractory to medical management
Intoxications: Dialyzable toxins with clinical deterioration
Overload: Fluid overload causing organ dysfunction unresponsive to diuretics
Uremia: Clinical uremic syndrome (rare in acute settings)

Pearl 2: The "Golden Hours" Fallacy

Unlike myocardial infarction or stroke, AKI does not have a defined therapeutic window where intervention within specific timeframes guarantees improved outcomes. The concept of "golden hours" for RRT initiation lacks evidence-based support and may lead to premature intervention.

Pearl 3: Fluid Balance as a Timing Indicator

Emerging evidence suggests that fluid balance may be more predictive of outcomes than traditional AKI staging. Patients with positive fluid balance > 20% of body weight at 72 hours show increased mortality, potentially indicating earlier RRT consideration for fluid management rather than uremic clearance⁷.

Modality Selection: Art and Science

Hemodynamic Considerations

The choice between continuous and intermittent modalities should be primarily driven by hemodynamic stability rather than arbitrary institutional preferences or convenience factors.

CRRT Advantages:

Superior hemodynamic tolerance
Better fluid removal control
Consistent solute clearance
Ideal for hemodynamically unstable patients

IHD Advantages:

Higher solute clearance rates
Shorter treatment times
Lower cost per treatment
Suitable for stable patients

Hybrid Approaches

Sustained low-efficiency dialysis (SLED) offers a compromise, providing extended treatment times with better hemodynamic tolerance than conventional IHD while maintaining higher clearance rates than CRRT. This modality deserves consideration in patients with moderate hemodynamic instability.

Anticoagulation Strategies: Practical Hacks

Hack 1: Regional Citrate Anticoagulation Protocol

For hemodynamically unstable patients requiring CRRT, regional citrate anticoagulation has emerged as the preferred strategy⁸:

Practical Implementation:

Target post-filter ionized calcium: 0.25-0.35 mmol/L
Systemic ionized calcium: 1.0-1.2 mmol/L
Monitor calcium ratio (systemic/post-filter) every 4-6 hours
Adjust citrate infusion based on post-filter calcium
Calcium replacement guided by systemic levels

Troubleshooting Citrate Accumulation:

Monitor total-to-ionized calcium ratio
Ratio > 2.5 suggests citrate accumulation
Reduce citrate infusion or discontinue if ratio > 3.0

Hack 2: No-Anticoagulation Strategy

In patients with severe bleeding risk or coagulopathy, CRRT without anticoagulation remains viable:

Optimization Strategies:

Use larger vascular access (12-14 Fr)
Maintain blood flow > 200 ml/min
Pre-dilution replacement fluid
Regular circuit inspection
Accept shorter filter life (12-24 hours)

Hack 3: Heparin Alternatives

For patients with heparin-induced thrombocytopenia or heparin resistance:

Argatroban Protocol:

Initial dose: 0.5-1.0 mcg/kg/min
Target aPTT: 45-60 seconds
Monitor for accumulation in liver dysfunction

Oysters: Debunking Persistent Myths

Oyster 1: "Early Dialysis Saves Lives"

The Myth: Initiating RRT at lower AKI stages (stage 2 vs stage 3) improves survival through prevention of uremic complications and better fluid management.

The Reality: The STARRT-AKI and AKIKI trials definitively demonstrate that early RRT initiation does not improve survival. In fact, premature RRT may expose patients to unnecessary risks including:

Catheter-related complications
Hemodynamic instability
Electrolyte disturbances
Delayed renal recovery

Clinical Implication: RRT timing should be based on absolute indications rather than AKI staging alone. The kidney's remarkable capacity for recovery should not be underestimated.

Oyster 2: "Higher Dose Dialysis is Always Better"

The Myth: Increasing dialysis dose beyond standard targets improves outcomes through enhanced toxin removal.

The Reality: The ATN and RENAL trials established that intensive RRT (higher doses) does not improve outcomes⁹,¹⁰. Current evidence supports:

CRRT effluent flow rate: 20-25 ml/kg/hr
IHD: Kt/V 1.2-1.4 per session

Clinical Implication: Standard dosing is appropriate for most patients. Higher doses may increase complications without benefit.

Oyster 3: "CRRT is Always Superior for ICU Patients"

The Myth: Continuous modalities are inherently superior for all critically ill patients.

The Reality: Modality selection should be individualized. While CRRT offers hemodynamic advantages, IHD may be appropriate for:

Hemodynamically stable patients
Need for rapid toxin removal
Limited CRRT resources
Mobilization requirements

Clinical Implication: Choose modality based on patient-specific factors rather than blanket institutional preferences.

Practical Implementation Framework

Decision Algorithm for RRT Initiation

Assess Absolute Indications:
- Life-threatening hyperkalemia
- Severe metabolic acidosis
- Dialyzable intoxication
- Fluid overload with organ dysfunction
- Clinical uremic syndrome
If No Absolute Indications Present:
- Continue optimal medical management
- Monitor fluid balance closely
- Reassess q4-6 hours
- Consider nephrology consultation
Patient Factors Favoring Earlier Consideration:
- Oliguria < 0.3 ml/kg/hr × 24 hours
- Rapid AKI progression
- Multiple organ dysfunction
- Limited diuretic responsiveness

Quality Metrics

Institutions should track key performance indicators:

RRT-free survival rates
Time from indication to initiation
Circuit survival times
Catheter-related complications
Renal recovery rates

Future Directions and Emerging Technologies

Biomarker-Guided Therapy

Novel AKI biomarkers may enhance timing decisions:

NGAL (Neutrophil Gelatinase-Associated Lipocalin)
KIM-1 (Kidney Injury Molecule-1)
[TIMP-2]×[IGFBP7] (NephroCheck)

These biomarkers may identify patients at highest risk for progression, potentially refining timing strategies beyond traditional markers.

Artificial Intelligence and Machine Learning

AI-driven platforms are being developed to:

Predict AKI progression
Optimize RRT timing
Personalize treatment protocols
Reduce practice variation

Wearable RRT Devices

Miniaturized, wearable RRT systems represent the future of acute dialysis, potentially allowing earlier mobilization and improved patient comfort while maintaining therapeutic efficacy.

Conclusions and Clinical Recommendations

The landscape of RRT in critical care has been fundamentally transformed by recent high-quality evidence. The paradigm shift from "earlier is better" to "watchful waiting with readiness to act" represents a maturation of the field, emphasizing individualized care over protocol-driven approaches.

Key Recommendations:

Timing: Base RRT initiation on absolute indications rather than AKI staging alone. The majority of patients with severe AKI can be managed conservatively with careful monitoring.
Modality Selection: Choose based on hemodynamic stability, with CRRT preferred for unstable patients and IHD acceptable for stable patients.
Anticoagulation: Regional citrate anticoagulation should be the first-line strategy for CRRT, with no-anticoagulation approaches viable in high bleeding risk patients.
Dose: Standard dosing (20-25 ml/kg/hr for CRRT, Kt/V 1.2-1.4 for IHD) is appropriate for most patients.
Quality Improvement: Institutions should implement standardized protocols while maintaining flexibility for individual patient needs.

The future of RRT in critical care lies not in more aggressive intervention, but in smarter, more precise application of available technologies guided by robust evidence and clinical judgment.

Continuing Medical Education Questions

Based on the STARRT-AKI trial, what is the appropriate timing for RRT initiation in severe AKI?
- A) Within 6 hours of AKI diagnosis
- B) When absolute indications are present
- C) At AKI stage 2
- D) When creatinine doubles
What is the preferred anticoagulation strategy for CRRT in hemodynamically unstable patients?
- A) Unfractionated heparin
- B) Regional citrate anticoagulation
- C) No anticoagulation
- D) Argatroban
Which factor is MOST important in modality selection?
- A) Patient age
- B) Hemodynamic stability
- C) AKI stage
- D) Institutional preference

Answers: 1-B, 2-B, 3-B

References

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Gaudry S, Hajage D, Martin-Lefevre L, et al. Comparison of two delayed strategies for renal replacement therapy initiation for severe acute kidney injury (AKIKI 2): a multicentre, open-label, randomised, controlled trial. Lancet. 2021;397(10281):1293-1300.
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Conflict of Interest: None declared Funding: None

Saturday, September 13, 2025