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7.6.2025

Michal Pazderník

“Timing of renal replacement therapy in ICU patients“

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AKI and Acute cardiovascular diseases

Estimated incidence rates depend on classification criteria (KDIGO, RIFLE, AKIN) => range from 25 - 47%

Large scale meta-analysis (more than 3.5 million patients)

Incidence of AKI in AHF - 36% (95% CI: 32-35%, P<0.001)

AHF patients who developed AKI had a higher risk of death than non‐AKI patients (RR, 3.65; 95% CI: 3.04–4.3)

AKI is an independent predictor of mortality in Cardiogenic Shock Registries (FRENSHOCK, CZECH-SHOCK) and in general ICU population

Jentzer JC, Bihorac A, Brusca SB, et al. Contemporary Management of Severe Acute Kidney Injury and Refractory Cardiorenal Syndrome: JACC Council Perspectives. J Am Coll Cardiol. 2020 Sep 1;76(9):1084-1101.

Singh S, Kanwar A, Sundaragiri PR, et al. Acute Kidney Injury in Cardiogenic Shock: An Updated Narrative Review. J Cardiovasc Dev Dis. 2021 Jul 28;8(8):88.

Ru SC, Lv SB, Li ZJ. Incidence, mortality, and predictors of acute kidney injury in patients with heart failure: a systematic review. ESC Heart Fail. 2023 Dec;10(6):3237-3249.

Hoste EA, Bagshaw SM, Bellomo R, et al. Epidemiology of acute kidney injury in critically ill patients: the multinational AKI-EPI study. Intensive Care Med. 2015 Aug;41(8):1411-23.

Pazdernik M, Ostadal P, Seiner J, et al. Clinical characteristics, management and predictors of mortality: results from national prospective cardiogenic shock registry (CZECH-SHOCK). Eur Heart J Acute Cardiovasc Care. 2025 Feb 28:zuaf034.

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Early RRT definition

Varies between trials:

Time from ICU admission:

Starting RRT within 6 hours of the diagnosis of KDIGO stage 3 - AKIKI trial
Starting RRT within 8 hours of fulfilling KDIGO stage 2 criteria – ELAIN trial

Plasma NGAL level: >150 ng/ml

Starting RRT within 12 hours after documentation of acute kidney injury – IDEAL- ICU trial

RIFLE criteria

Zarbock A, Kellum JA, Schmidt C, et al. Effect of Early vs Delayed Initiation of Renal Replacement Therapy on Mortality in Critically Ill Patients With Acute Kidney Injury: The ELAIN Randomized Clinical Trial. JAMA. 016 May 24-31;315(20):2190-9.

Gaudry S, Hajage D, Schortgen F, et al. Initiation Strategies for Renal-Replacement Therapy in the Intensive Care Unit. N Engl J Med. 2016 Jul 14;375(2):122-33.

Barbar SD, Clere-Jehl R, Bourredjem A, IDEAL-ICU Trial Investigators and the CRICS TRIGGERSEP Network. Timing of Renal-Replacement Therapy in Patients with Acute Kidney Injury and Sepsis. N Engl J Med. 2018 Oct 11;379(15):1431-1442.

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Pathophysiology of AKI in ACVD patients

Decrease in blood flow and end-organ hypoperfusion

Systemic and venous congestion (renal vein congestion - neurohormonal feedback - tubular cell injury => cardio-renal syndrome)

Mechanical circulatory support (loss of pulsatile flow, shear stress, hemolysis)

Contrast induced nephropathy (PCI, CTA,…)

Singh S, Kanwar A, Sundaragiri PR, et al. Acute Kidney Injury in Cardiogenic Shock: An Updated Narrative Review. J Cardiovasc Dev Dis. 2021 Jul 28;8(8):88.

Zarbock A, Kellum JA, Schmidt C, et al. Effect of Early vs Delayed Initiation of Renal Replacement Therapy on Mortality in Critically Ill Patients With Acute Kidney Injury: The ELAIN Randomized Clinical Trial. JAMA.

Gaudry S, Hajage D, Schortgen F, et al. Initiation Strategies for Renal-Replacement Therapy in the Intensive Care Unit. N Engl J Med. 2016 Jul 14;375(2):122-33.

Barbar SD, Clere-Jehl R, Bourredjem A, IDEAL-ICU Trial Investigators and the CRICS TRIGGERSEP Network. Timing of Renal-Replacement Therapy in Patients with Acute Kidney Injury and Sepsis. N Engl J Med. 2018 Oct 11;379(15):1431-1442.

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When to initiate early RRT?

Severe hyperkalemia

Emergency RRT for K⁺ >6.5 mmol/l if unresponsive to medical therapy
No RTCs exist defining exact hyperkalemia thresholds for RR

Uremia and its complications (encephalopathy, pericarditis, etc.)

Urea >35-40 mmol/L

Severe metabolic acidosis

IF acidosis persists despite bicarbonate, urgent RRT is required (<7.15)

Intoxication with dialysable toxins

Ethylene glycol, salicylates, methanol, barbiturates, lithium, dabigatran, etc.

Significant fluid overload

ELAIN trial: Early RRT reduced mortality in patients with PaO2/FiO2 < 300 mmHg + fluid balance > 10% of body weight
Other trials excluded these patients

Jaber S, Paugam C, Futier E, et al. Sodium bicarbonate therapy for patients with severe metabolic acidaemia in the intensive care unit (BICAR-ICU): a multicentre, open-label, randomised controlled, phase 3 trial. Lancet. 2018 Jul 7;392(10141):31-40.

Zarbock A, Kellum JA, Schmidt C, Effect of Early vs Delayed Initiation of Renal Replacement Therapy on Mortality in Critically Ill Patients With Acute Kidney Injury: The ELAIN Randomized Clinical Trial. JAMA. 2016 May 24-31;315(20):2190-9.

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What are possible advantages of early RRT?

1. Hemodynamic Stability & Fluid Balance

Reduction of Venous Congestion

• AKI + volume overload → ↑ right atrial/venous pressures → myocardial stress, ↓ oxygen delivery

• CRRT → controlled fluid removal → ↓ congestion without hypotension

Interruption of Cardiorenal Syndrome

• Type 1 CRS → heart failure → AKI → fluid overload → worsening cardiac & renal function

• CRRT → breaks cycle → prevents further decline

2. Metabolic Stabilization

Correction of Electrolyte Imbalances

• Hyperkalemia → risk of malignant arrhythmias

• Other electrolytes (Na, P, Ca)→ Stabilizes cardiac & cellular function

Management of Metabolic Acidemia

• Acidemia → ↓ myocardial contractility, vasodilation, catecholamine resistance/insensitivity

Toxin Clearance

• Uremic toxins → cardiac dysfunction, immune suppression, coagulopathy

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What are possible advantages of early RRT?

3. Inflammatory & Neurohormonal Modulation

Cytokine & Inflammatory Mediator Removal

• AKI → systemic inflammation → vasomotor dysfunction, myocardial depression

Neurohormonal Regulation

• RAAS & Sympathetic Activation → vasoconstriction, Na retention, K shifts

4. Prevention of multiorgan dysfunction

� Pulmonary Consequences

• Fluid overload → ↑ pulmonary capillary wedge pressure → pulmonary edema, hypoxia

Hepatic & Splanchnic Congestion

• Venous congestion → hepatic congestion leading to impaired function, coagulopathy, intestinal edema

Cerebral Edema & Neurological Impact

• Fluid overload + metabolic derangements → ↑ ICP, encephalopathy

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Landmark trials

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AKIKI trial

Early (immediately in KDIGO 3; n = 311) or delayed (> 72 hours oliguria/anuria or urgent indications; n = 308) initiation of RRT.

NEJM, 2016

No increase in mortality in delayed group
50% of delayed group never needed dialysis

� 💡 Message: Many ICU patients recover kidney function without dialysis, avoiding unnecessary intervention

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STARRT-AKI trial

Early (within 12 hours of diagnosis in KDIGO 2-3; n = 1465) or delayed (persistent AKI>72 hours or life threatening complications; n = 1462) initiation of RRT.

No difference in 90-day mortality
Higher dialysis dependence in early-start group�

💡 Message: No survival benefit, but higher long-term risks

NEJM, 2020

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IDEAL-ICU trial

Early (within 12h of RIFLE-F) or delayed (delayed up to 48h or if urgent indications) strategies

. No mortality difference

. caveat: Only septic shock patients

. stopped early due to futility

NEJM, 2018

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Delayed strategy (KDIGO 3 with oliguria >72 hours or urea 40-50 mmol/L) or more delayed strategy (urea >50 mmol/l or hyperkalemia, acidosis, pulmonary edema)

no difference in RRT-free days = primary outcome
death at 60-days (HR 1.65, 95%, CI 1.09-2.50, p=0.018) in more delayed group = secondary outcome

AKIKI 2 TRIAL

Lancet, 2021

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Zarbock A, Kellum JA, Schmidt C, Effect of Early vs Delayed Initiation of Renal Replacement Therapy on Mortality in Critically Ill Patients With Acute Kidney Injury: The ELAIN Randomized Clinical Trial. JAMA. 2016 May 24-31;315(20):2190-9.

Early RRT (≤8h after KDIGO stage 2) vs. Delayed RRT (< 12 hours of progression to KDIGO 3, or in urgent indications).

90-Day Mortality:�Early: 39.3%. Delayed: 54.7%. HR: 0.66 (P = .03). Absolute reduction: -15.4%.

Renal Recovery by Day 90:�Early: 53.6%. Delayed: 38.7%. OR: 0.55 (P = .02). Improvement: +14.9%.

Duration of RRT:�Early: Median 9 days. Delayed: Median 25 days. HR: 0.69 (P = .04).

Hospital Stay:�Early: Median 51 days. Delayed: Median 82 days. HR: 0.34 (P < .001). Reduction: -37 days.

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ELAIN Trial weaknesses

Small sample

Single centered

Unblinded

Mainly postsurgical cohort

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9 RCTs with 1938 patients
Early RRT did not provide a survival benefit

But…

Early RRT group had significantly fewer MV days (-4 days)
AKI population with high plasma NGAL had favorable outcomes regarding early RRT

Need for personalized approach and risk stratification to identify patients who may benefit from early RRT

Chen JJ, Lee CC, Kuo G, et al. Comparison between watchful waiting strategy and early initiation of renal replacement therapy in the critically ill acute kidney injury population: an updated systematic review and meta-analysis. Ann Intensive Care. 2020 Mar 3;10(1):30.

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NGAL

Early Biomarker for AKI:

NGAL detected in plasma within 2 hours of AKI; peaks at 6 hours, lasts for ~5 days.
Elevated serum and urine NGAL levels observed 24 hours earlier than creatinine rise.

Mechanism of Action:

NGAL is synthesized in response to renal tubular damage (e.g., ischemic, nephrotoxic, septic injuries).

NGAL Sources:

Urine NGAL: Reflects proximal tubular damage or upregulated synthesis in distal nephron segments.
Serum NGAL: Multifactorial, linked to neutrophil activation, liver/lung synthesis, and reduced kidney clearance.

Clinical Utility:

NGAL indicates renal tubular damage and may outperform serum creatinine in early AKI detection and selection of patients who may profit from early RRT
No clear superiority of urine vs. plasma NGAL; choice depends on lab preference.

Limitations:

Accuracy reduced in systemic inflammation and diseases affecting multiple organs.

Romejko K, Markowska M, Niemczyk S. The Review of Current Knowledge on Neutrophil Gelatinase-Associated Lipocalin (NGAL). Int J Mol Sci. 2023 Jun 21;24(13):10470.

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Evaluated the effectiveness of neutrophil gelatinase-associated lipocalin (NGAL) levels in predicting acute kidney injury (AKI) necessitating renal replacement therapy (RRT)

18 studies (1,787 patients with AKI included)

NGAL was an effective predictor of RRT need in patients with AKI

Plasma vs Urine NGAL had comparable performance

Xu C, Lin S, Mao L, Li Z. Neutrophil gelatinase-associated lipocalin as predictor of acute kidney injury requiring renal replacement therapy: A systematic review and meta-analysis. Front Med (Lausanne). 2022 Sep 21;9:859318.

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Furosemide stress test

Furosemide Stress Test (FST)

Procedure:

• 1 mg/kg IV furosemide (1.5 mg/kg if loop diuretics were used in the prior 7 days) + fluid resuscitation

Criteria:

• FST-responsive: Urine output > 200 mL in 2 hours

• FST-nonresponsive: Urine output ≤ 200 mL in 2 hours

Results

• FST non-responders were 2.7x more likely to initiate CRRT (P=0,0001)

Zhang K, Zhang H, Zhao C, et al. The furosemide stress test predicts the timing of continuous renal replacement therapy initiation in critically ill patients with acute kidney injury: a double-blind prospective intervention cohort study. Eur J Med Res. 2023 Apr 5;28(1):149.

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Catheters in critically ill

Deep venous catheters are associated with high rates of complications on the ICU - 60.9/1000 catheter-days

Bleeding
Thrombosis
Infections

Calviño Günther, Int. Care Med, 2016

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Hypotension

Intermittent hemodialysis (IHD): Up to 20–30% of sessions can be complicated by intradialytic hypotension.
CRRT: Less likely than IHD, but still can cause hypotension — especially in critically ill, vasoplegic, or septic patients.

AKIKI Trial + STARRT-AKI => more hypotension in early group.

Mechanisms of Hypotension in Dialysis:

Rapid fluid removal (ultrafiltration) exceeding plasma refilling rate
Vasodilation due to citrate or regional anticoagulation
Hypoalbuminemia
Sepsis-related vasoplegia in ICU patients
Blunted compensatory sympathetic responses

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Dialysis therapy in ICU

💰 Mean daily cost of CVVHDF is ± $2,143.

ICU dialysis is resource-intensive (machines, staff, monitoring)
If delayed dialysis is safe, resources can be allocated efficiently
Avoiding unnecessary dialysis improves ICU management

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Key Messages

Early RRT does not consistently improve survival and may increase risks like hypotension, infections, bleeding or thrombosis.

Early RRT is effective in specific subgroups of patients (hyperkalemia, uremia, acidosis, hypervolemia, poisoning, diuretic resistance).

Many patients recover without dialysis (AKIKI trial).

Do not wait too long (AKIKI 2 trial).

Biomarkers (e.g., NGAL) and Furosemide Stress Test can help refine the timing of RRT.

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Thank you for your time!