1. Renal Replacement Therapies in Critical Care
Dr. Andrew Ferguson
Consultant in Intensive Care Medicine & Anaesthesia
Craigavon Area Hospital, United Kingdom

2. Where are we - too many questions?
What therapy should we use?
When should we start it?
What are we trying to achieve?
How much therapy is enough?
When do we stop/switch?
Can we improve outcomes?
Does the literature help us?

3. Overview Impact of Acute Kidney Injury in the ICU
Dose-outcome relationships & IRRT v CRRT
Mechanisms of solute clearance
Therapies in brief
IRRT, CRRT & Hybrid therapies e.g. SLEDD
Solute clearance with IRRT v CRRT v SLEDD
Extracorporeal blood purification in sepsis
Putting it together – making a rational choice

4. AKI classification systems 1: RIFLE

5. AKI classification systems 2: AKIN
Stage
Creatinine criteria
Urine output criteria 1
x baseline (or rise > 26.4 mmol/L)
< 0.5 ml/kg/hour for > 6 hours 2
>2 - 3 x baseline
< 0.5 ml/kg/hour for > 12 hours 3
> 3 x baseline (or > 354 mmol/L with acute rise > 44 mmol/L)
< 0.3 ml/kg/hour for 24 hours or anuria for 12 hours
Patients receiving RRT are Stage 3 regardless of creatinine or urine output

6. Acute Kidney Injury in the ICU
AKIis common: 3-35%* of admissions
AKI is associated with increased mortality
“Minor” rises in Cr associated with worse outcome
AKI developing after ICU admission (late) is associated with worse outcome than AKI at admission (APACHE underestimates ROD)
AKI requiring RRT occurs in about 4-5% of ICU admissions and is associated with worst mortality risk **
* Brivet, FG et al. Crit Care Med 1996; 24:
** Metnitz, PG et al. Crit Care Med 2002; 30:

7. Mortality by AKI Severity (1)
Clermont, G et al. Kidney International 2002; 62:

8. Mortality by AKI Severity (2)
Bagshaw, S et al. Am J Kidney Dis 2006; 48:

9. RRT for Acute Renal Failure
There is some evidence for a relationship between higher therapy dose and better outcome, at least up to a point
This is true for IHD* and for CVVH**
There is no definitive evidence for superiority of one therapy over another, and wide practice variation exists***
Accepted indications for RTT vary
No definitive evidence on timing of RRT
*Schiffl, H et al. NEJM 2002; 346: ** Ronco, C et al. Lancet 2000; 355: 26-30
*** Uchino, S. Curr Opin Crit Care 2006; 12:

10. Therapy Dose in IRRT p = 0.01 p = 0.001
Schiffl, H et al. NEJM 2002; 346:

11. Therapy Dose in CVVH 45 ml/kg/hr 35 ml/kg/hr 25 ml/kg/hr
Ronco, C et al. Lancet 2000; 355: 26-30

12. Outcome with IRRT vs CRRT (1)
Trial quality low: many non-randomized
Therapy dosing variable
Illness severity variable or details missing
Small numbers
Uncontrolled technique, membrane
Definitive trial would require 660 patients in each arm!
Unvalidated instrument for sensitivity analysis
“there is insufficient evidence to establish whether CRRT is associated with improved survival in critically ill patients with ARF when compared with IRRT”
Kellum, J et al. Intensive Care Med 2002; 28: 29-37

13. Outcome with IRRT vs CRRT (2)
No mortality difference between therapies
No renal recovery difference between therapies
Unselected patient populations
Majority of studies were unpublished
Tonelli, M et al. Am J Kidney Dis 2002; 40:

14. Outcome with IRRT vs CRRT (3)
Vinsonneau, S et al. Lancet 2006; 368:

15. Proposed Indications for RRT
Oliguria < 200ml/12 hours
Anuria < 50 ml/12 hours
Hyperkalaemia > 6.5 mmol/L
Severe acidaemia pH < 7.0
Uraemia > 30 mmol/L
Uraemic complications
Dysnatraemias > 155 or < 120 mmol/L
Hyper/(hypo)thermia
Drug overdose with dialysable drug
Lameire, N et al. Lancet 2005; 365:

16. Implications of the available data
AKI is not an innocent bystander in ICU
We must ensure adequate dosing of RRT
Choice of RRT mode may not be critical
Septic AKI may be a different beast
We must strive to avert acute kidney injury

17. The Ideal Renal Replacement Therapy
Allows control of intra/extravascular volume
Corrects acid-base disturbances
Corrects uraemia & effectively clears “toxins”
Promotes renal recovery
Improves survival
Is free of complications
Clears drugs effectively (?)

18. Solute Clearance - Diffusion
Small (< 500d) molecules cleared efficiently
Concentration gradient critical
Gradient achieved by countercurrent flow
Principal clearance mode of dialysis techniques

19. Solute Clearance – Ultrafiltration & Convection (Haemofiltration)
Water movement “drags” solute across membrane
At high UF rates (> 1L/hour) enough solute is dragged to produce significant clearance
Convective clearance dehydrates the blood passing through the filter
If filtration fraction > 30% there is high risk of filter clotting*
Also clears larger molecular weight substances (e.g. B12, TNF, inulin)
* In post-dilution haemofiltration

20. Major Renal Replacement Techniques
Intermittent
Hybrid
Continuous
IHD
Intermittent haemodialysis
SLEDD
Sustained (or slow) low efficiency daily dialysis
CVVH
Continuous veno-venous haemofiltration
IUF
Isolated Ultrafiltration
CVVHD
Continuous veno-venous haemodialysis
SLEDD-F
Sustained (or slow) low efficiency daily dialysis with filtration
CVVHDF
Continuous veno-venous haemodiafiltration
SCUF
Slow continuous ultrafiltration

21. Intermittent Therapies - PRO
(Relatively) Inexpensive
Flexible timing allows for mobility/transport
Rapid correction of fluid overload
Rapid removal of dialyzable drugs
Rapid correction of acidosis & electrolyte abnormality
Minimises anticoagulant exposure

22. Intermittent Therapies - CON
Hypotension 30-60%
Cerebral oedema
Limited therapy duration
Renal injury & ischaemia
Gut/coronary ischaemia

23. Intradialytic Hypotension: Risk Factors
LVH with diastolic dysfunction or LV systolic dysfunction / CHF
Valvular heart disease
Pericardial disease
Poor nutritional status / hypoalbuminaemia
Uraemic neuropathy or autonomic dysfunction
Severe anaemia
High volume ultrafiltration requirements
Predialysis SBP of <100 mm Hg
Age 65 years +
Pressor requirement

24. Managing Intra-dialytic Hypotension
Dialysate temperature modelling
Low temperature dialysate
Dialysate sodium profiling
Hypertonic Na at start decreasing to 135 by end
Prevents plasma volume decrease
Midodrine if not on pressors
UF profiling
Colloid/crystalloid boluses
Sertraline (longer term HD)
2005 National Kidney Foundation K/DOQI GUIDELINES

25. Continuous Therapies - PRO
Haemodynamic stability => ??? better renal recovery
Stable and predictable volume control
Stable and predictable control of chemistry
Stable intracranial pressure
Disease modification by cytokine removal (CVVH)?

26. Continuous Therapies - CON
Anticoagulation requirements
Higher potential for filter clotting
Expense – fluids etc.
Immobility & Transport issues
Increased bleeding risk
High heparin exposure

27. SCUF High flux membranes Up to 24 hrs per day Objective VOLUME control
Not suitable for solute clearance
Blood flow ml/min
UF rate 2-8 ml/min

28. CA/VVH Extended duration up to weeks High flux membranes
Mainly convective clearance
UF > volume control amount
Excess UF replaced
Replacement pre- or post-filter
Blood flow ml/min
UF rate ml/min

29. CA/VVHD Mid/high flux membranes Extended period up to weeks
Diffusive solute clearance
Countercurrent dialysate
UF for volume control
Blood flow ml/min
UF rate 1-8 ml/min
Dialysate flow ml/min

30. CVVHDF High flux membranes Extended period up to weeks
Diffusive & convective solute
clearance
Countercurrent dialysate
UF exceeds volume control
Replacement fluid as required
Blood flow ml/min
UF rate ml/min
Dialysate flow ml/min
Replacement ml/min

31. SLED(D) & SLED(D)-F : Hybrid therapy
Conventional dialysis equipment
Online dialysis fluid preparation
Excellent small molecule detoxification
Cardiovascular stability as good as CRRT
Reduced anticoagulation requirement
11 hrs SLED comparable to 23 hrs CVVH
Decreased costs compared to CRRT
Phosphate supplementation required
Fliser, T & Kielstein JT. Nature Clin Practice Neph 2006; 2: 32-39
Berbece, AN & Richardson, RMA. Kidney International 2006; 70:

32. Kinetic Modelling of Solute Clearance
CVVH (predilution)
Daily IHD
SLED
Urea TAC (mg/ml)
40.3
64.6
43.4
Urea EKR (ml/min)
33.8
21.1
31.3
Inulin TAC (mg/L)
25.4
55.5
99.4
Inulin EKR (ml/min)
11.8
5.4
3.0
b2 microglobulin TAC (mg/L)
9.4
24.2
b2 microglobulin EKR (ml/min)
18.2
7.0
4.2
TAC = time-averaged concentration (from area under concentration-time curve)
EKR = equivalent renal clearance
Inulin represents middle molecule and b2 microglobulin large molecule.
CVVH has marked effects on middle and large molecule clearance not seen with IHD/SLED
SLED and CVVH have equivalent small molecule clearance
Daily IHD has acceptable small molecule clearance
Liao, Z et al. Artificial Organs 2003; 27:

33. Uraemia Control
Liao, Z et al. Artificial Organs 2003; 27:

34. Large molecule clearance
Liao, Z et al. Artificial Organs 2003; 27:

35. Comparison of IHD and CVVH
John, S & Eckardt K-U. Seminars in Dialysis 2006; 19:

36. Beyond renal replacement… RRT as blood purification therapy

37. Extracorporeal Blood Purification Therapy (EBT)
Intermittent
Continuous
TPE
Therapeutic plasma exchange
HVHF
High volume haemofiltration
UHVHF
Ultra-high volume haemofiltration
PHVHF
Pulsed high volume haemofiltration
CPFA
Coupled plasma filtration and adsorption

38. Peak Concentration Hypothesis
Removes cytokines from blood compartment during pro-inflammatory phase of sepsis
Assumes blood cytokine level needs to fall
Assumes reduced “free” cytokine levels leads to decreased tissue effects and organ failure
Favours therapy such as HVHF, UHVHF, CPFA
But tissue/interstitial cytokine levels unknown
Ronco, C & Bellomo, R. Artificial Organs 2003; 27:

39. Threshold Immunomodulation Hypothesis
More dynamic view of cytokine system
Mediators and pro-mediators removed from blood to alter tissue cytokine levels but blood level does not need to fall
? pro-inflammatory processes halted when cytokines fall to “threshold” level
We don’t know when such a point is reached
Honore, PM & Matson, JR. Critical Care Medicine 2004; 32:

40. Mediator Delivery Hypothesis
HVHF with high incoming fluid volumes (3-6 L/hour) increases lymph flow times
“Drag” of mediators and cytokines with lymph
Pulls cytokines from tissues to blood for removal and tissue levels fall
High fluid exchange is key
Di Carlo, JV & Alexander, SR. Int J Artif Organs 2005; 28:

41. High Volume Hemofiltration
May reduce unbound fraction of cytokines
Removes
endothelin-I (causes early pulm hypertension in sepsis)
endogenous cannabinoids (vasoplegic in sepsis)
myodepressant factor
PAI-I so may eventually reduce DIC
Reduces post-sepsis immunoparalysis (CARS)
Reduces inflammatory cell apoptosis
Human trials probably using too low a dose (40 ml/kg/hour vs 100+ ml/kg/hour in animals)

42. CRRT, Haemodynamics & Outcome
114 unstable (pressors or MAP < 60) patients
55 stable (no pressors or MAP > 60) patients
Responders = 20% fall in NA requirement or 20% rise in MAP (without change in NA)
Overall responder mortality 30%, non-responder mortality 74.7% (p < 0.001)
In unstable patients responder mortality 30% vs non-responder mortality 87% (p < 0.001)
Haemodynamic improvement after 24 hours CRRT is a strong predictor of outcome
Herrera-Gutierrez, ME et al. ASAIO Journal 2006; 52:

43. Common Antibiotics and CRRT
These effects will be even more dramatic with HVHF
Honore, PM et al. Int J Artif Organs 2006; 29:

44. Towards Targeted Therapy?
Non-septic ARF
Septic ARF
Cathecholamine resistant septic shock
Daily IHD
Daily IHD?
HVHF ml/kg/hour
for 96 hours
Daily SLEDD
Daily SLEDD?
CVVHD/F ? dose
EBT
PHVHF ml/kg/hour
for 6-8 hours then CVVH > 35 ml/kg/hour
35ml/kg/hour
CVVH > 35ml/kg/hour
? ml/kg/hour
Cerebral oedema
Honore, PM et al. Int J Artif Organs 2006; 29:

45. “You should listen to your heart, and not the voices in your head”
Marge Simpson