What are the findings of the Acute Kidney Injury (AKI) trials, including AKIKI (Acute Kidney Injury - Kidney Injury), AKIKI 2, ELAIN, and IDEAL ICU (Intensive Care Unit) regarding Renal Replacement Therapy (RRT) initiation in critically ill patients?

Overview of Major RRT Timing Trials in Critically Ill AKI Patients

AKIKI Trial (2016)

The AKIKI trial demonstrated that a delayed RRT initiation strategy is safe and reduces unnecessary dialysis exposure without increasing mortality. 1

Study Design and Population

• Multicenter French RCT enrolling 620 critically ill patients with KDIGO stage 3 AKI requiring vasopressors or mechanical ventilation 1
• Patients were randomized to either immediate RRT initiation ("early" strategy) or a "delayed" strategy where RRT was withheld unless specific severity criteria developed 1

Delayed Strategy Criteria

The delayed group initiated RRT only when one or more of the following occurred 1:

• Oliguria/anuria persisting >72 hours after randomization
• Blood urea nitrogen >40 mmol/L (approximately 112 mg/dL)
• Serum potassium >6 mmol/L or >5.5 mmol/L despite medical treatment
• Arterial pH <7.15 with metabolic acidosis
• Acute pulmonary edema with severe hypoxemia despite diuretics

Key Findings

• No mortality difference: 60-day mortality was similar between early (48.5%) and delayed (49.7%) strategies 1
• 49% of delayed-strategy patients never required RRT, avoiding unnecessary dialysis exposure 1
• Patients in the delayed group who eventually required RRT had similar outcomes to the early group 1

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ELAIN Trial (2016)

The ELAIN trial showed that early RRT initiation reduced 90-day mortality by 15.4% compared to delayed initiation, directly contradicting AKIKI's findings. 2

Study Design and Population

• Single-center German RCT of 231 critically ill patients with KDIGO stage 2 AKI and elevated plasma NGAL >150 ng/mL 2
• Early strategy: RRT initiated within 8 hours of reaching KDIGO stage 2 2
• Delayed strategy: RRT initiated within 12 hours of progressing to KDIGO stage 3 or when urgent indications developed 2

Critical Differences from AKIKI

• Earlier intervention point: ELAIN initiated RRT at KDIGO stage 2 (less severe AKI) versus AKIKI's stage 3 2
• Biomarker-guided: Required elevated NGAL levels suggesting higher risk of progression 2
• Median time to RRT: 6 hours (early) vs 25.5 hours (delayed) - much shorter delay than AKIKI 2

Key Findings

• 90-day mortality: 39.3% (early) vs 54.7% (delayed), absolute risk reduction of 15.4% (P=0.03) 2
• Better renal recovery: 53.6% in early group vs 38.7% in delayed group recovered kidney function by day 90 2
• Shorter RRT duration: 9 days (early) vs 25 days (delayed) 2
• Shorter hospital stay: 51 days (early) vs 82 days (delayed) 2

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AKIKI 2 Trial (Implied from Secondary Analyses)

AKIKI 2 explored whether an even more delayed strategy (beyond standard AKIKI criteria) could further reduce RRT exposure without harming patients. 3

Personalized Risk Stratification

• Secondary analysis of pooled AKIKI and IDEAL-ICU data identified heterogeneous treatment effects based on predicted risk of requiring RRT within 48 hours 3
• Patients at intermediate-high risk of RRT initiation benefited from early strategy with 14% absolute mortality reduction (95% CI: -27% to -1%) 3
• Patients at intermediate-low risk showed potential harm from early RRT with 8% absolute mortality increase (95% CI: -5% to 21%), though not statistically significant 3

Clinical Implication

This analysis suggests that one-size-fits-all timing strategies may be suboptimal, and the decision should account for individual patient's likelihood of kidney recovery versus progression 3

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IDEAL-ICU Trial (Referenced in Secondary Analyses)

IDEAL-ICU was a French multicenter trial similar to AKIKI that also compared early versus delayed RRT strategies. 3

Study Characteristics

• Enrolled 488 patients with severe AKI 3
• Used similar delayed strategy criteria as AKIKI 3
• Data were pooled with AKIKI for secondary analyses examining treatment effect heterogeneity 3

Combined AKIKI/IDEAL-ICU Findings

• When analyzed together (1,107 patients total), evidence emerged for heterogeneous treatment effects across risk strata 3
• The benefit or harm of early RRT depends on the patient's baseline risk of needing dialysis - those most likely to need it anyway may benefit from earlier initiation 3

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STARRT-AKI Trial (2020)

The STARRT-AKI mega-trial definitively showed that accelerated RRT provides no mortality benefit and increases adverse events, strongly supporting delayed initiation strategies. 4

Study Design and Scale

• Largest RRT timing trial to date: 3,019 patients across multiple countries 4
• Accelerated strategy: RRT within 12 hours of meeting eligibility criteria 4
• Standard strategy: RRT discouraged unless conventional indications developed or AKI persisted >72 hours 4

Definitive Results

• No mortality difference: 90-day mortality was 43.9% (accelerated) vs 43.7% (standard), relative risk 1.00 (95% CI: 0.93-1.09, P=0.92) 4
• 96.8% of accelerated-strategy patients received RRT vs only 61.8% of standard-strategy patients - meaning 38% avoided unnecessary dialysis 4
• Increased dialysis dependence: Among 90-day survivors, 10.4% in accelerated group remained dialysis-dependent vs 6.0% in standard group (RR 1.74,95% CI: 1.24-2.43) 4
• More adverse events: 23.0% in accelerated group vs 16.5% in standard group (P<0.001), including hypotension and infections 4

Reconciling STARRT-AKI with ELAIN

The contradiction between STARRT-AKI and ELAIN likely reflects 2, 4:

• Single-center vs multicenter: ELAIN's single-center design may have introduced selection bias
• Sample size: STARRT-AKI's 3,019 patients vs ELAIN's 231 provides far more statistical power
• Biomarker selection: ELAIN's NGAL-based enrichment may have identified a specific high-risk subgroup

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Modality Comparison: CRRT vs Intermittent HD

A secondary analysis of AKIKI and IDEAL-ICU found that CRRT as first modality offered no survival advantage over intermittent hemodialysis and may actually be associated with worse outcomes in less severely ill patients. 5

Key Findings

• Among 543 patients receiving early RRT, 60-day mortality was higher with CRRT (54.4%) vs IHD (46.5%), weighted HR 1.26 (95% CI: 1.01-1.60) 5
• In patients with SOFA scores 3-10 (less severe illness), CRRT was associated with significantly worse survival compared to IHD (weighted HR 1.82,95% CI: 1.01-3.28) 5
• No evidence of survival difference in more severely ill patients 5

Clinical Caveat

CRRT should be reserved for hemodynamically unstable patients requiring vasopressor support, not used routinely for all ICU patients with AKI. 6, 7, 5

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Current Guideline Recommendations

KDIGO and other major societies now recommend delayed/standard RRT initiation over early/preemptive initiation in the absence of life-threatening complications. 8, 6

Absolute Indications for Immediate RRT 8, 6, 7:

• Refractory hyperkalemia with ECG changes
• Severe metabolic acidosis (pH <7.15) unresponsive to medical management
• Acute pulmonary edema causing respiratory compromise despite diuretics
• Uremic complications (encephalopathy, pericarditis, bleeding)
• Severe symptomatic dysnatremia resistant to medical management

Monitoring Strategy for Delayed Approach 6:

• Close monitoring after reaching KDIGO stage 2 or 3 AKI
• Consider broader clinical context and trends rather than single laboratory thresholds
• Assess fluid status, electrolytes, acid-base balance, and urine output trends
• Urine output is the most robust predictor of successful RRT discontinuation (sensitivity 66.2%, specificity 73.6%) 8

Common Pitfall to Avoid

Do not reflexively initiate RRT based solely on elevated creatinine or BUN values in the absence of urgent indications - this approach exposes patients to unnecessary dialysis, increased adverse events, and potential dialysis dependence without mortality benefit 6, 4