Renal replacement therapy

Dr Peter Sherren
Specialist trainee
Anaesthesia and Intensive Care

Bringing excellence to life

Objectives

 RRT Indications
 Modes and principles
 Dosing
 Replacement solutions
 Anticoagulation
 Special Circumstances


 AKI / CKD vs ARF / CRF

 RIFLE

 Renal failure - is the cessation
of renal function with or without
changes in urine volumes.


Anaesthesia UK. Acute renal failure.
Renal replacement therapy on ITU


“Renal tubular cell injury after a toxic or ischaemic insult results in
sloughing of tubular debris and cells into the tubular lumen with
eventual obstruction of tubular flow, increased intra-tubular
pressure and back leak of glomerular filtrate out of the tubule
1
and into the interstitium and renal venous blood”


 Renal:
 Symptomatic Uraemia
 Nephrogenic Pulmonary Oedema
 Severe Hyperkalaemia
 Severe metabolic acidemia
 Relative Urea/Creatinine levels

 Non Renal:
 SIRS/sepsis
 Fluid balance
 Rhabdomyolsis *
 Overdose/Drug accumulation
 Renal protection pre/post contrast, CIN
 Temperature control
 Plasmapheresis/Exchange (immune complexes)
 Severe acute liver failure with molecular adsorbent
re-circulating system (MARS, PROMETHEUS) as
bridge to transplant


 Early or late initiation of RRT (UO and Urea)

 The answer to whether early initiation of RRT is
beneficial with regards to survival and/or renal
recovery is not clear. Why?

 2
Getting et al 1999 . Urea 15.2 vs 33.7 conferred
survival benefit.

 3 4
Ronco et al 2000 and Saudan et al 2006 both
dose/outcome studies suggested an early start.

 5
Liu et al 2006 observational PICARD study (Urea
27) suggested an early start

 6
Not all agree, Bouman et al 2002 RCT no benefit
in early initiation of RRT. CvvHF


Recommendation?

 Intermittent vs continuous

 CRRT is an extracorporeal blood purification therapy intended to substitute for impaired
renal function over an extended period of time and applied for or aimed at being applied for
24 hours a day.

 Patients with AKI as part of MODS are less likely to tolerate
 Fluid shifts
 CVS instabiltiy (hyovolaemia and hypotension)
 Secondary renal insult

 In MODS, CRRT is certainly better tolerated in terms of drop in CVP/CO/SVR/MAP 7-9.

 Likely benefits in for CRRT in SIRS/SEPSIS & cytokine clearance over IHD10.

 Many papers advocating the benefit of CRRT in patients with raised ICP 12-13.

 In terms of survival and renal recovery the benefit of either is still to be demonstrated in all
AKI requiring RRT. Recent Cochrane Database review 2007 demonstrated important
haemodynamic effects but little survival benefits11.

So is there a place for IRRT?

 Ultrafiltration - movement of fluid across a pressure gradient,
via hydrostatic forces.

 Convection - The movement of solutes with a water flow
or “Solvent drag”

 Diffusion - Movement of solute from an area
of high concentration to an area of low concentration via
osmosis across a semi-permeable membrane

 Adsorption -
 Surface adsorption where the molecules are too large
to permeate and migrate through the membrane;
however can adhere to the membrane

 Bulk adsorption within the whole membrane when
molecules can permeate it


100,000

}
•Albumin (55,000 - 60,000)
50,000
“large”
10,000 • Beta 2 Microglobulin (11,800) 2

}
5,000 • Inulin (5,200)
molecular
weight,
daltons 1,000 • Vitamin B12 (1,355) “middle”
500 • Aluminum/Desferoxamine Complex (700)

• Glucose (180)

}
• Uric Acid (168)
100 • Creatinine (113)

• Phosphate (80)
50 ••Sodium (35)
Urea (60) “small”
•• Phosphorus (31)
Potassium (23)
10
5
0


 Intermittent RRT
 HD most commonly
 Peritoneal dialysis

 CRRT
• SCUF - Slow Continuous Ultrafiltration
 Ultrafiltration - fluid removal
• CVVHF - Continuous Veno-Venous Hemofiltration
 Convection - Small, medium and some large size
molecules MW <30000 Daltons
• CVVHD - Continuous Veno-Venous Hemodialysis
 Diffusion - Small molecules <500 Daltons
• CVVHDF - Continuous Veno-Venous
Hemodiafiltration
 Diffusion and Convection- small and medium sized
molecules

 Niche techniques
 Plasmapheresis/exchange
 Haemoperfusion


 Method
 Peritoneal catheter
 Instil 1-2 litres dialysis fluid
under gravity

 Dialysis Fluid
 Similar composition to ECF
 Variable Tonicity
 Variable K+ and glucose
content

 Advantages
 Technically simple
 Safer than haemodialysis if:
 high risk of systemic
bleeding
 circulatory instability
 vascular access difficult
 Indicated in some cases of
pancreatitis

 Disadvantages
 Pain
 Bowel perforation
 Bleeding
 Infection/Peritonitis/SP/SEP
 Metabolic


 Requires AV shunt or Percutaneous catheter.

 Removal of solutes by diffusion (mainly small
sized molecules) via conc gradient. Access
 Ultrafiltration, via hydrostatic gradient. Very
effectively (1-2L/HR) Return
 High blood flow rates required (350-400ml/min
+)

 Semi permeable membrane is used for selected
diffusion. Dialysate is used to create a
concentration gradient across a semi permeable
membrane.

 Need dialysate flow +/- countercurrent. The
counter-current flow increases solute removal by S
maintaining gradient along filter (flow rate 15-
45ml/min, 1-3L/Hr)

 No replacement fluid

 Minimal Adsorption Effluent
 AKI without sepsis or CVS instability.


 Advantages to waste
 Rapid correction of volume overload
 Better solute clearance than
PD/CRRT Dialysate Out Blood In
 Intermittent hence mobility (from patient)

 Disadvantages
 Specialist nurses, water tanks etc
 Vascular access complications
 Anticoagulation Dialysate In Blood Out
 CVS instability
 NO medium/large molecule (to patient)
clearance.

LOW CONC HIGH CONC


 Primary therapeutic goal:
 Safe management of fluid
removal Blood In
 UF rate ranges up to 2 L/Hr via (from patient)
hydrostatic forces.
 No dialysate Fluid Volume
Reduction
 No replacement fluids
 Large fluid removal via
ultrafiltration Blood Out
 Minimal solute clearance
to waste (to patient)

LOW PRESS HIGH PRESS


Access
 Primary therapeutic goal:
 Convective solute removal Return
 Management of intravascular
volume (pressure gradient)
 Blood Flow rate = 10 - 180 ml/min,
newer machines 300ml/min.
 UF rate ranges 6 - 50 L/24 h (> 500
Replacement
ml/h) GFR 10-20%.
 Replacement solution can help to
drive convection
 Removal of small and medium sized
molecules
 No dialysate
Effluent


 Advantages
 Better at removal of middle sized MW
molecules >500-1000 daltons
 Use for Cytokine adsorption and CVS
instability in intractable septic shock10,16 to waste Blood In
 Accurate control of ultrafiltered
volume (from patient)Repl.
 CAVH self-regulating
 CVVH requires no arterial access Solution

 Disadvantages
 Complex equipment
 Worse clearance/diffusion of small MW Blood Out
solutes. NA/K/Ur/Creat
 CAVH blood-pressure dependent
 Access site complications (esp CAVH) (to patient)

LOW PRESS HIGH PRESS


 Primary therapeutic goal: Access
 Solute removal by diffusion and
convection
Return
 Management of intravascular Dialysate
volume
 Blood Flow rate = 10 - 180ml/min, again
newer machines capable of 300ml/min
 Combines CVVH and CVVHD therapies
 UF rate ranges 12 - 24 L/24h (> 500
Replacement
ml/h)
 Dialysate Flow rate = 15 - 45 ml/min (~1
- 3 L/h). Countercurrent flow
 Uses both dialysate (1 L/h) and
replacement fluid (500 ml/h+)

Effluent


to waste
 Advantages Blood In
 Better clearance of small solutes
(from patient)
over HF, K/Na/Ur/Creat
 Less limited by poor access and Dialysate
hypotension Solution Repl.
 Benefits in ARF & MOF4 Solution
 Small/medium/large molecule
removal to a degree
Blood Out
 Disadvantages
 Not as efficient adsorption and (to patient)
middle molecular clearance
 Solute and drug clearance less
LOW
predictable HIGH PRESS
 Fluid balance complicated PRESS
 Complicated equipment LOW HIGH CONC
 Clotted filter may be disguised CONC


 Studies in patients with end stage kidney disease (ESKD) requiring IHD
have led to well defined targets for what constitutes adequate clearance17

 In AKI the dosing/clearance/filtrations rates are not nearly so clear.

 IHD fractional clearance Kt/V well used.

 In post filter dilution CvvHF Ultrafiltration volume acts as a surrogate for
clearance in the critically ill16.

 Ultrafiltration volume in ml/kg/hr represents the filtered fraction of
patient’s blood.

 Remember that HDF incorporates diafiltration plus ultrafiltration to give
total filtration.

 Recent studies have described dose of CRRT in terms of ml/kg/h of
ultrafiltrate production.

 Ronco et al 20003 used this approach (ml/kg/hr) to demonstrate survival
benefits of 35 over 20ml/kg/hr.

 Kellum et al 200718 pooled 4 recent dose/outcome to demonstrate very large
effect on survival in favour of an augmented dose.

 Landmark multicentre RCT in America (AKI study19) and Australasia (RENAL
study20) showed that a high renal dosing regime in RRT conferred no benefit.

 The ideal dose for CRRT is not known or universally agreed upon; however 35
ml/kg/h of ultrafiltrate production is recommended as a minimum for CVVH
(post-dilution) and CVVHDF16.

 Maybe room for Short term High volume isovolaemic haemofiltration (STHVH)
doses of up to 100ml/kg/min or ~8-9L/Hr exchange for severe SIRS/sepsis 10,18.


 Cellulose
 Low flux
 Poor at removing middle MW
molecules
 Used in end ESRF.
 Cause more complement and
leukocyte activation16
 Leukocyte retention in the lungs,
renal parenchyma and other
organs, thus resulting in further
organ damage.
 Not desirable in the critically ill
patient.


 Synthetic
 Polysulphone (PS), Polyamide (PA), Polyacrylonitrile (PAN),
Polymethyl methacrylate (PMMA).
 High flux membranes.
 Flux being a measure of ultrafiltration capacity and based on the
membrane ultrafiltration coefficient.
 High flux membranes are highly water permeable.
 Allowing convective therapy and the removal of middle MW
molecules.
 Better biocompatibility, less complement/leucocyte activation
and end organ disfunction16.


 Adjusted based on pt. clinical need
 Help drive convective transport
 Administered pre or post filter
 Must contain:

 Sodium
 Calcium (except with citrate)
 Base (bicarbonate, lactate or citrate)
 May contain:
 Potassium
 Phosphate
 Magnesium


Contents
Lactasol Hemosol BO
mmol/L mmol/L

 Sodium 140 140
 Potassium 1 0
 Calcium 1.63 1.75
 Magnesium 0.75 0.5
 Chloride 100 109.5
 Lactate 45 3
 Glucose 10 -
 pH 5 – 6.5 7.4
 Bicarb - 32


 Patients with Liver dysfunction, profound hypoperfusion and pre-existing Lactic
acidaemia are at risk of lactate intolerance.

 Some studies have suggested better control of acidaemia with bicarbonate
solutions14 this has not universal though16

 Improved cardiovascular stability have also been reported14

 To date though use of either base has not demonstrated any survival or renal
outcome benefits14-16

 Conflicting views, as always! Bicarbonate in theory has some potential benefits
but currently no data to clearly advocate one or the other 16

 Indications for bicarbonate buffer16
 A rise of lactate of greater or equal to 5 mmol/L (from base-line) associated with a worsening
metabolic acidosis suggests lactate-intolerance.
 Severe pre-existing lactic acidosis pH <7.2 with associated lactate of ≥ 8 mmol/L.
 Severe liver dysfunction.


 Factors affecting filter life:
 Access, Anticoagulation, Pre/Post dilution,
Hyperlipidemia, Sepsis

 Pre-Dilution
 Increases filter life
 Increases convective transport
 Reduced solute clearance
 Some of delivered replacement fluid lost by
hemofiltration
 Lower anticoagulation requirements
 Higher UF required given loss of replacement fluid
through filter

 Post-Dilution
 No solute dilution, improved diffusion and solute
clearance
 Increased hemoconcentration
 Higher delivered dose of hemofiltration


 Heparin  Prostacyclin (PGI2)
 Intermittent bolus or continuous  Inhibits platelet aggregation
infusion
 Reduced risk of haemorrhage
 Disadvantages  Disadvantage
 Haemorrhage  vasodilation and hypotension
 Anti-thrombin III deficiency
 Thrombocytopaenia  Citrate
 Regional heparinisation  Complexes ionised calcium
 Ca infused in efferent limb
 Low molecular weight heparin
 Citrate metabolised Liver, renal and
 Less effect on platelet function skeletal muscle.
 Direct Thrombin Inhibitors  Some evidence for prolonged filter life
and less bleeding events22.
 r-Hirudin  Disadvantages
 Argatroban  Low Ca++, Low Mg++
 Hypotension and tetany
 Acidaemia in renal/hepatic impairment
as a result of reduced citrate
metabolism.


 Principles
 Same equipment as haemofiltration
 Larger pores in filter
 To remove pathogenic material (IgG/M, paraproteins etc) in plasma
 Replace with equal volume of substitute
 HAS, FFP
 Often rebound antibody synthesis and may need immunosupression

 Indications
 Multiple Myeloma/Waldenström macroglobulinemia and hyperviscocity
syndrome (HVS)
 Poisoning
 SIRS in conjunction with HF, early days
 Acute Guillian-Barre syndrome
 TTP and HUS
 Goodpastures
 Meningococcal sepsis


 Techniques used for extracorporeal drug removal
 Haemodialyis
 Haemoperfusion
 Continuous haemofiltration
 Continuous haemodiafiltration

 Factors effecting clearance
 Molecular size (<500 daltons desirable)
 Steric hindrance
 Polarity
 Volume of distribution, Water/lipid solubility
 Protein binding, in particular in HD
 Rate of Endogenous clearance
 Rate of redistribution


Substances for which haemodialysis may be used
 Salicylates clearance doubled over UA
(seizures/coma/↓pH/AKI/absolute level/paeds)
 Lithium
 Alcohols:
- ethylene glycol, methanol, ethanol, isopropanol
 Theophylline HP better
 Metformin
 (Bromide)


 HPF was first used in toxicology in the 1960s for barbiturate poisoning
 Since these initial reports HPF has been attempted in the treatment of a number of other
poisonings
 A standard haemofiltration / haemodialysis pump can be used
 The only special equipment required is the perfusion column
 Blood is pumped (150 - 250 mL/min) through a column containing an adsorbent, usually
activated charcoal, coated with a biocompatible ultrathin membrane
 Characteristics of compound removed
 Adsorbed by charcoal
 Vd and endogenous clearance factors similar to previous
 Protein binding, water solubility & molecular size are not such limiting factors
as with haemodialysis as blood in direct contact with adsorbent
 NO prospective controlled studies looking at the effect of HPF on outcome in poisoned
patients


 Carbamazepine
 Theophyllines
 Causes significant and prolonged toxicity  Both acute & chronic theophylline
(T1/2 19-32 hrs) poisoning can cause significant
 Problem of enterohepatic recirculation morbidity and mortality

 Binds activated charcoal  Better clearance than MDAC

 MDAC vs HP have similar ↑ clearance  Applications in severe OD with
dysrrthmias and seizures
 iIeus often limits MDAC/whole bowel
irrigation
 Reserved for life threatening seizure,  Phenobarbitone
cardiotoxicity, impaired gut motility or  Both MDAC and HPF increase
phenobarbitone clearance, HP to a
deteriorating despite MDAC treatment.
greater extent
 life-threatening toxicity &
deterioration despite full supportive
care

 Others
 TCA, Digoxin, Paraquat, Na valporate


 A common ‘non-renal’ indication for CRRT is in the management of severe sepsis.

 It has been shown that many, if not all of the septic mediators can be removed by CVVHF16.

 Cytokines (IL 1/6/8, TNF, complement, bradykinins, beta-2 microglobulin).

 Due to the MW of inflammatory mediators it has been shown that CvvHF is particularly effective in
their clearance and adsorption16.

 Due to high generation rate, studies have concentrated on the use of ‘high dose’ or ‘high volume’
haemofiltration.

 High volume haemofiltration has also been used as ‘rescue therapy’ for patients with severe septic
shock unresponsive to other treatments, with encouraging results for cardiovascular
stability/outcomes3,10,21,23,24.

 Ultrafiltration doses as high as 40-85ml/kg/Hr were shown to improve 28 day mortality in septic
shock23,24.


Any Questions?


 Initiation of RRT should be started earlier rather than later particularly when -
 AKI is unlikely to be reverse early
 Patient had normal renal function prior to insult
 CRRT
 Appears to offers some benefits over IHD but no Grade A evidence.
 Generally agreed that it is better tolerated in the critically ill.
 Modality
 No clear benefits for one modality over another when addressing the diverse
group that is AKI
 However, there are encouraging results for the use of certain modalities in
specific subgroups (Septic shock ± AKI, ↑ICP, OD, Rhabdomyolysis, Pulmonary
oedema, Solute issues, Immunological conditions etc)
 Correct modality for the correct patient


 Dose
 No clear evidence on dosing and outcome benefit for all AKI
 However 35 ml/kg/h of ultrafiltrate production is recommended as a minimum for CVVH
(post-dilution) and CVVHDF
 Higher rates for Cytokine clearance and adsorption in unresponsive septic shock shows
some promise
 Pre-dilution CRRT reduces solute clearance and an increase of 15% for ultrafiltration
rates of 2 L/h and up to 40% for rates of 4.5L/h should be considered.
 Lactate-based replacement fluids are as effective as bicarbonate-based fluids except
in conditions where liver function is compromised but there is little evidence that
either kind of fluid has survival advantage.
 Synthetic membranes for CRRT
 UFH, LMWH and prostacylin are most commonly used, but Citrate may offer some
interest for the future.


1. Allen R. Nissenson (1998)Kidney International Vol. 53, Suppl. 66
2. Gettings LG et al. Outcome in post-traumatic acute renal failure when continuous therapy is
applied early vs late. Intensive Care Med 1999;25(8):805-813
3. Ronco C et al. Effects of different doses on continuous veno-venous haemofiltration on
outcomes of acute renal failure: a prospective randomised trial. Lancet 2000; 356(9223): 26-
30.
4. Saudan P et al. Adding dialysis dose to continuous haemofiltration increases survival in
patients with acute renal failure. Kidney Int 2006; 70(9): 1312-1317.
5. Liu KD et al. Timing of initiation of dialysis in critically ill patients with acute kidney injury.
Clin J Am Soc Nephrol 2006; 1(5): 915-919.
6. Bouman CS et al. Effects of early high volume continuous veno-venous haemofiltration on
survival and recovery of renal function in intensive care patients with acute renal failure:
prospective , randomised trial. Crit Care Med 2002: 30(10): 2205-2211.
7. Davenport A et al. Improved cardiovascular stability during continuous modes of renal
replacement therapy in critically ill patients with acute hepatic and renal failure. Crit Care Med
1993; 21(3): 328-338.


8. Augustine JJ et al. Randomised controlled trial comparing intermittent with continuous dialysis
in patients with ARF. Am J Kidney Dis 2004; 44(6): 1000-1007.
9. John S et al. Effects of continuous haemofiltration Vs intermittent haemodialysis on
haemodynamics and splanchnic regional perfusion in septic shock patients: A prospective
randomised clinical trial. Neprol Dial Transplant 2001; 16(2): 320-327
10. Patrick M et al. Prospective evaluation of short-term , high volume isovolemic hemofiltration on
the hemodynamic course and outcome in patients with intractable circulatory failure resulting
from septic shock. Crit Care Med 2000. Vol 28(11) 3581-3586
11. Cochrane Database Syst Rev. 2007 Jul 18;(3):CD003773
12. Davenport A et al. Changes in ICP during haemofiltration in oliguric patients with grade IV
hepatic encephalopathy. Nephron 1989; 53(2): 142-146
13. Ronco C et al. Brain density changes during renal replacement in critically ill patients with acute
renal failure: Continuous versus intermitent haemodialysis. J Nephrol 1999; 12(3): 173-178.
14. Barenbrock M et al. Effect of Bicarbonate and Lactate buffered replacement fluids on
cardiovascular outcome in CvvHF patients. Kidney Int 2000; 58 (4): 1751-1757.


15. Thomas AN et al. Comparison of bicabonate or lactate buffered haemofiltration fluid; use in critically ill
patients. Nephrol Dial Transplant 1997; 12 (6): 1212-1217.
16. Standards and Recommendations for the provision of renal replacement therpy on intensive care units in the
UK. Intensive Care Society standards and Safety. 01/2009.
17. http://www.kidney.org/Professionals/kdoqi/
18. Kellum JA. Renal replacement therapy in critically ill patients with acute renal failure: does a greater dose
improve survival? Nature Clin Pract Nephrol 2007; 3(3):128-129.
19. VA/NIH Acute Renal Failure Trial Network. Intensity of renal support in critically ill patients with acute kidney
injury. N Engl J Med 2008; 359(1):7-20.
20. The RENAL Replacement Study Investigators. Intensity of Continuous Renal-Replacement Therapy in Critically
Ill Patients. N Engl J Med 2009; 361 (17): 1627-38.
21. Ratanarat et al. Pulse high-volume haemofiltration for treatment of severe sepsis: effects on hemodynamics
and survival. Critical Care 2005, 9:R294-R302
22. Monchi M et al. Citrate vs. heparin for anticoagulation in continuous venovenous haemofiltration: a prospective
randomised study. Intensive Care Med 2004; 30(2):260-265.
23. Honore PM et al. Prospective evaluation of short-term, high volume isovolemic haemofiltration on the
haemodynamic course and outcome in patients with intractable circulatory failure resulting from septic shock.
Crit Care Med 2000; 28(11): 3581-3587.
24. Ratanarat R et al. Pulse high-volume haemofiltration in critically ill patients: A new approach to patients with
septic shock. Seminar Dial 2006,19(1):69-74.


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