Renal replacement therapy

Bringing excellence to life

Dr Peter SherrenSpecialist trainee

Anaesthesia and Intensive Care


ObjectivesObjectives

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 and into the interstitium and renal venous blood”1


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?

Getting et al 19992. Urea 15.2 vs 33.7 conferred

survival benefit.

Ronco et al 20003 and Saudan et al 2006

4 both

dose/outcome studies suggested an early start.

Liu et al 20065 observational PICARD study (Urea 27)

suggested an early start

Not all agree, Bouman et al 20026 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/MAP7-9.

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

Many papers advocating the benefit of CRRT in patients with raised ICP12-13.

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 viaosmosis 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


• Beta 2 Microglobulin (11,800) 2

• Inulin (5,200)

• Vitamin B12 (1,355)

• Aluminum/Desferoxamine Complex (700)

• Glucose (180)

• Phosphate (80)

• Urea (60)

• Phosphorus (31)

• Sodium (35)

•Potassium (23)

100,000

50,000

10,0005,000

1,000

500

100

50

10

50

molecular weight, daltons

}

}}

“small”

“middle”

“large”

•Albumin (55,000 - 60,000)

• Creatinine (113)• Uric Acid (168)


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.

Ultrafiltration, via hydrostatic gradient. Very effectively (1-2L/HR)

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 maintaining gradient along filter (flow rate 15-45ml/min, 1-3L/Hr)

No replacement fluid

Minimal Adsorption

AKI without sepsis or CVS instability.

S

Access

Return

Effluent


Advantages Rapid correction of volume overload Better solute clearance than

PD/CRRT Intermittent hence mobility

Disadvantages Specialist nurses, water tanks etc Vascular access complications Anticoagulation CVS instability NO medium/large molecule

clearance.

Dialysate Out

Dialysate In

Blood In

Blood Out

to waste

(from patient)

(to patient)

HIGH CONCLOW CONC


Primary therapeutic goal:

Safe management of fluid removal

UF rate ranges up to 2 L/Hr via hydrostatic forces.

No dialysate

No replacement fluids

Large fluid removal via ultrafiltration

Minimal solute clearance

Blood In

Blood Out

to waste

(from patient)

(to patient)

HIGH PRESSLOW PRESS

Fluid VolumeReduction



Convective solute removal

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 ml/h) GFR 10-20%.

Replacement solution can help to drive convection

Removal of small and medium sized molecules

No dialysate

AccessAccess

ReturnReturn

EffluentEffluent

ReplacementReplacement


Advantages Better at removal of middle sized MW

molecules >500-1000 daltons Use for Cytokine adsorption and CVS

instability in intractable septic shock10,16

Accurate control of ultrafiltered volume

CAVH self-regulating CVVH requires no arterial access

Disadvantages Complex equipment Worse clearance/diffusion of small MW

solutes. NA/K/Ur/Creat CAVH blood-pressure dependent Access site complications (esp CAVH)

Blood In

Blood Out

to waste

(from patient)

(to patient)

HIGH PRESSLOW PRESS

Repl.Repl.SolutionSolution



Solute removal by diffusion and convection

Management of intravascular 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 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+)

Dialysate

AccessAccess

ReturnReturn

EffluentEffluent

ReplacementReplacement


Advantages Better clearance of small solutes

over HF, K/Na/Ur/Creat Less limited by poor access and

hypotension Benefits in ARF & MOF4

Small/medium/large molecule removal to a degree

Disadvantages Not as efficient adsorption and

middle molecular clearance Solute and drug clearance less

predictable Fluid balance complicated Complicated equipment Clotted filter may be disguised

Repl.Repl.SolutionSolution

DialysateDialysateSolutionSolution

Blood In

Blood Out

to waste

(from patient)

(to patient)

HIGH PRESSLOW PRESS

HIGH CONCLOW 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/sepsis10,18.


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 other16

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 Intermittent bolus or continuous

infusion Disadvantages

Haemorrhage Anti-thrombin III deficiency Thrombocytopaenia

Regional heparinisation

Low molecular weight heparin Less effect on platelet function

Direct Thrombin Inhibitors

r-Hirudin

Argatroban

Prostacyclin (PGI2)

Inhibits platelet aggregation Reduced risk of haemorrhage Disadvantage

vasodilation and hypotension

Citrate Complexes ionised calcium Ca infused in efferent limb Citrate metabolised Liver, renal and

skeletal muscle. Some evidence for prolonged filter life

and less bleeding events22. Disadvantages

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 Causes significant and prolonged toxicity

(T1/2 19-32 hrs)

Problem of enterohepatic recirculation

Binds activated charcoal

MDAC vs HP have similar clearance

iIeus often limits MDAC/whole bowel irrigation

Reserved for life threatening seizure, cardiotoxicity, impaired gut motility or deteriorating despite MDAC treatment.

Theophyllines Both acute & chronic theophylline

poisoning can cause significant morbidity and mortality

Better clearance than MDAC

Applications in severe OD with dysrrthmias and seizures

Phenobarbitone Both MDAC and HPF increase

phenobarbitone clearance, HP to a 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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