Renal replacement therapy Indications

Indications, timing and patient selection for RRT

OVERVIEW

• Acute kidney injury (AKI) is common in critical illness, and severe AKI is associated with up to 60 % hospital mortality (Wierstra et al, 2016)
• Renal replacement therapy (RRT) may be provided by different modalities:
  • Continuous RRT (CRRT) is most commonly used in Australasian ICUs
  • Slow Low Efficiency Daily Dialysis (SLEDD) and Intermittent Haemodialysis (IHD) are important alternatives
  • Different modalities may be better suited to different patient groups and different RRT indications, however, there is a lack of high-level patient-centered evidence to guide choice of modality in the ICU setting
• The timing of RRT initiation in critical illness — early or late — also remains controversial

INDICATIONS

Usual indications for RRT can be “renal” or “non-renal” – these can be summarised using the UFAKE  mnemonic

Renal

• Uremia / azotaemia
  • uraemic encephalopathy
  • uraemic pericarditis
  • uraemic haemorrhage
  • consider if urea >30-35 mM (no strict cut-off)
• Fluid overload
  • oliguria resulting in clinically significant volume overload and respiratory distress, that is refractory to medical management
• Metabolic acidosis due to renal failure (e.g. pH <7.2) – retention of acids + hyperchloraemia (tubular dysfunction)
• Hyperkalaemia (>6.0) (concurrent with medical management)

Non-renal (E: extras = TNT)

• Toxins/ drugs
  • small, non-protein bound agents such as toxic alcohols, lithium, salicylate, theophylline, valproate
• Na+ 160mmol/L
• Temperature control hyperthermia
• Other controversial indications
  • Prevention of contrast nephropathy (no evidence!)
  • Sepsis — removal of cytokines by high volume haemofiltration (HVHF) remains controversial
  • Rhabdomyolysis (usually RRT is only used when renal impairment occurs)
  • MARS (“liver dialysis”)

TIMING

Starting RRT

• in general, RRT is started when one of the above indications is met
• However, the precise timing of initiation of RRT in critically ill patients is an area of controversy (see below)

Stopping RRT depends on multiples factors:

• resolution of the underlying cause
  • e.g. passing 30mL/hr of urine and CrCl >12-20mL/min
• able to be managed effectively using other therapies (e.g. frusemide for fluid balance)
• logistical considerations, such as:
  •  filter lifespan in CRRT
  • the timing of surgery
  • when IHD can be commenced in persistent renal failure

PATIENT SELECTION

In general, patients who are critically ill are more suited to CRRT and this is the modality most widely used for RRT in Australasian intensive care.

CRRT is usually more appropriate for patients with

• haemodynamically instability
• increased intracranial pressure
• severe volume overload (CRRT can remove >200-300mL/h)
• mechanical ventilation
• high protein turnover/ hypercatabolism
• high risk of osmotic dysequilibrium (e.g. severe uraemia due to delayed presentation of renal failure)

IHD is more suited for patients who require rapid removal of dialysable substances

• chronic end-stage renal failure (ESRF) (CRRT is less efficient and inconvenient)
• hyperkalaemia
• selected toxins

EARLY VERSUS DELAYED INITIATION OF RRT IN THE CRITICALLY ILL

The timing of RRT initiation in critically ill patients is controversial

• current evidence is conflicting
• many competing factors need to be considered

Rationale for early RRT

• Allows early removal of toxic substances with physiological consequences
  • these include
    • urea (causes encephalopathy, pericarditis and platelet dysfunction)
    • non-volatile acids (which cause acidosis)
    • drugs required for therapy that can have adverse effects when they accumulate
    • illness-specific agents, such as cytokines in sepsis, ammonia in severe liver dysfunction, intracellular substances released in rhabdomyolysis
  • harmful effects from these toxic substances are generally dose-dependent — there is no critical threshold for harm — so early removal may limit potential harm and risk of organ dysfunction
• In some conditions, the need for RRT may be inevitable regardless of the current level of renal dysfunction (e.g. massive bilateral kidney trauma)
• Limits the risks and complications of alternative medical therapies used for renal impairment, such as:
  • frusemide: ototoxicity
  • resonium: bowel obstruction and perforation
  • bicarbonate: hypernatraemia and hypercapnia
• RRT can simplify the management of critically ill patients with complex issues (e.g. combination of renal impairment, electrolyte derangement, fluid overload, hyperthermia, rhabdomyolysis in a patient with severe crush injury)

Rationale for delayed RRT

• 50% of patients randomised to the “delayed RRT” arm of the AKIKI trial never required RRT with no difference in survival or length-of-stay in ICU or in hospital
• Safety
  • reduced exposure to the complications of:
    • renal replacement therapy (e.g. exposure to an extracorporeal circuit, errors of adverse effects related to anticoagulation, fluid and electrolyte management)
    • vascath insertion (e.g. vessel injury and bleeding, CLABSI (infection), and air embolism)
• Logistics
  • RRT is relatively expensive, compared to the relatively inexpensive alternative medical therapies for managing renal impairment and its complications
  • requires necessary equipment, skilled staff and monitoring
  • increased workload for patient care
• Pathophysiology
  • In general, RRT is only a supportive measure, not a curative therapy for acute kidney  injury or its underlying cause
  • RRT may contribute to delayed renal recovery (e.g. hypotension due to fluid removal, exposure to an extracorporeal circuit) (see here)
  • RRT may remove beneficial substances (e.g. endogenous mediators, therapeutic drugs)

Evidence

• Systematic review (Wierstra et al, 2016)
  • Earlier meta-analyses suggested that “early” RRT improves survival in critical illness, however, no survival benefit was seen in the subgroup of higher quality trials (RCTs)
  • Systematic review of 36  studies (7 RCTs, 10 prospective cohorts, and 19 retrospective cohorts)
  • n = 1042 patients from 9 studies were considered to be of high quality and were included for quantitative analysis
    • No survival advantage was found with “early” RRT (OR 0.665; 95 % CI 0.384–1.153, p = 0.146)
    • No survival difference in subgroup analysis of reason for ICU admission (surgical/medical) or definition of “early” (time/biochemical)
    • No significant differences were observed in ICU or hospital LOS
  • Conclusion
    • no difference in survival or ICU/ hospital LOS with early or late RRT
    • AKIKI and ELAIN trials were published after this systematic review
• AKIKI trial (Gaudry et al, 2006)
  • multi-center RCT (31 French ICUs)
  • n =620 critically ill adults with stage 3 AKI, as per the KDIGO criteria
  • Intervention: immediate RRT (early RRT)
  • Comparison: RRT initiation only when medically necessary (severe hyperkalemia, metabolic acidosis, pulmonary oedema, or a blood urea nitrogen level greater than 112 mg/dL, or oliguria for more than 72 hours) (late RRT)
  • Outcomes:
    • no difference in the primary outcome of 60-day mortality (48.5% vs 49.7% p-value of 0.79)
    • no difference in secondary outcomes
      • mortality at 30-days
      • ICU length-of-stay
      • long-term dialysis dependence
      • ventilator-free days
      • vasopressor-free days
    • There were differences in:
      • the proportion of patients that actually received RRT (98% in early RRT group versus 51% in the late RRT)
      • how early patients experienced adequate urine production (defined as 1000 mL of urine in a 24-hour period without the help of diuretics) (earlier in the late RRT group)
      • the rate of catheter-related bloodstream infections (10% in early RRT vs 5% in late RRT)
  • Commentary and criticisms
    • The type of RRT used was at the discretion of the treating physician and only 45% received CRRT, which is at odds with standard Australasian ICU practice
    • Most of the patients in the late RRT group (68%) were dialysed because of either oliguria for > 72 hours, or a BUN greater than 112 mg/dL
    • the majority were medical patients (80%, e.g. sepsis)
    • Fragility index = “-18”
    • the outcome is consistent with the pre-existing literature (see systematic review by Wierstra et al, 2016)
• ELAIN trial (Zarbock et al, 2016)
  •  single-center RCT from Germany
  • n = 231 critically ill adults with stage 2 AKI
  • Intervention: immediate RRT (early RRT)
  • Comparison: RRT initiation only when stage 3 KDIGO criteria were met
  • Outcomes:
    • improved primary outcome of 90-day mortality in the early RRT group (39.3% versus 54.7%)
    • secondary outcomes
      • These favoured early RRT:
        • duration of mechanical ventilation (median of 125.5h vs 181.0h).
        • number of patients who still required RRT at 60-days (15.9% vs 23.7%)
      • there was no difference in the recovery of renal function at 90-days (88.2% vs 85.2%) (secondary outcome)
  • Commentary and criticisms
    • all patients received CVVHDF and were only transferred to IHD or SLEDD if RRT was required for more than 7 days
    • the majority were surgical patients (47% were cardiac surgery)
    • median time difference to initiation of dialysis between the immediate and delayed groups was 25.5 hours
    • Fragility index = 3
    • given the small trial size and that prior studies (see systematic review by Wierstra et al, 2016) the large mortality difference seen is this trial is unlikely to be true
• STARRT-AKI
  • This is a large pragmatic international multi-center RCT, including ICUs in Australasia,  that is currently in progress comparing early versus delayed RRT
• IDEAL-ICU
  • Another French multi-center RCT is also in progress comparing early versus late RRT in the critically ill

RENAL REPLACEMENT THERAPY IN TOXICOLOGY

Renal replacement therapy is clinically useful for enhanced elimination of selected toxic agents

• The RRT mode (IHD versus CRRT) and duration is important and the optimal choice varies depending on the agent
• At present, there is a lack of high-level evidence guiding the use of RRT in toxicology
• Existing evidence has been critically appraised and expert consensus guidelines have been created by the EXTRIP workgroup

Table from Kellum et al (2016):

References and Links

Journal articles and textbooks

• Bagshaw SM, Lamontagne F, Joannidis M, Wald R. When to start renal replacement therapy in critically ill patients with acute kidney injury: comment on AKIKI and ELAIN. Critical care. 2016; 20(1):245. [pubmed]
• Gaudry S,Hajage D, Schortgen F, et al. Initiation strategies for renal-replacement therapy in the intensive care unit. N Engl J Med. 2016; 375(2):122-33. [pubmed]
• Kellum,JA, Bellomo R, Ronco C. Continuous Renal Replacement Therapy. Oxford University Press, 2016. [Google books]
• Ghannoum M, Nolin TD, Lavergne V, et al. Blood purification in toxicology: nephrology’s ugly duckling. Advances in chronic kidney disease. 2011; 18(3):160-6. [pubmed] [article]
• Wald  R, Adhikari  NK, Smith  OM,  et al; Canadian Critical Care Trials Group.  Comparison of standard and accelerated initiation of renal replacement therapy in acute kidney injury. Kidney Int. 2015;88(4):897-904. [pubmed]
• Wierstra BT, Kadri S, Alomar S, et al. The impact of “early” versus “late” initiation of renal replacement therapy in critical care patients with acute kidney injury: a systematic review and evidence synthesis. Critical care. 2016; 20(1):122. [pubmed]
• 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. 2016;315(20):2190-9. [pubmed]

FOAM and web resources

• CC Nerd — The Case of the Afflicted Kidney by Rory Spiegel (2016)
• EXTRIP workgroup
• The Bottom Line — ELAIN trial (2016)
• The Bottom Line — AKIKI trial (2016)
• The Bottom Line — Editorial: Early vs Late Renal Replacement Therapy (2016)