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Theoretical Aspects of Renal Replacement Therapy

# OBJECTIVES & QUESTIONS

• CORE PRINCIPLES
• THERAPY MODALITIES
• CIRCUITS

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Introduction

### What is renal replacement therapy?

• Renal replacement therapy (RRT) describes techniques used to purify the blood and achieve the solute and fluid homeostasis usually produced by the kidney
• Continuous renal replacement therapy (CRRT) describes treatments which are applied for prolonged periods at a time (usually >24 hours)

### How can modes of renal replacement be classified?

Modality of Fluid and Solute Removal
• Hemofiltration
• Haemodialysis
• Hemodiafiltration
Continuous vs. Intermittent Modality
• Intermittent:
• Intermittent haemodialysis (IHD)
• Slow low-efficiency dialysis (SLED)
• Extended daily dialysis (EDD)
• Continuous:
• Continuous venovenous hemofiltration (CVVH)
• Continuous venovenous haemodialysis (CVVHD)
• Continuous venovenous hemodiafiltration (CVVHDF)
• Slow continuous ultrafiltration
• Peritoneal dialysis (PD)
• Arteriovenous
• Venovenous - requires an external pump

Mechanisms

# Definition

The transport of solute across a semi-permeable membrane, down a concentration gradient
The passage of fluid across a semi-permeable membrane due to a hydrostatic pressure
The transport of a solute across a semi-permeable membrane along with solvent (by "solvent drag")

### What are the characteristics of molecules cleared by RRT?

• Small volume of distribution (<1L/kg)
• Low degree of protein-binding
• High water solubility
• Low molecular weight:
• Only smaller molecules (up to 500 Da) are cleared by hemodialysis
• Up to a maximum 40 kDa can be cleared by hemofiltration
• Low endogenous clearance (<4 ml/min/kg)
• Extraction ratio exceeding endogenous elimination

### What factors influence the clearance of a substance from plasma?

• Membrane properties:
• Surface area of membrane
• Hydraulic permeability
• Pore size
• Charge
• Pressure gradients: hydrostatic, colloid, osmotic
• Solute properties: size, charge, concentration

Modality Principles

# Mechanisms

• Clearance of solutes via diffusion down a concentration gradient
• A counter-current flow of a solution containing various electrolytes on the opposite side of membrane to blood allows diffusion to occur
• No fluid is added to the filtrate after diffusion
• Rate of solute clearance determined by:
• Concentration gradient between plasma and dialysate
• Particle size, ionic charge and protein binding
• Membrane pores, thickness and surface area
• Clearance of solutes via convection driven by hydrostatic pressure
• Filtrate removal is balanced by the addition of a solution to maintain volume
• Does not significantly change the concentration of serum electrolytes and waste products unless a replacement fluid is infused into the blood, effectively diluting out those solutes the physician wishes to remove
• Rate of filtrate and solute removal determined by:
• Blood flow
• Membrane coefficient (pore size/permeability)
• Clearance of solute via convection and diffusion
• Countercurrent dialysate is used in addition to hydrostatic pressure
• Fluid replacement is required to maintain plasma volumes

# Size

<500 Da
500 - 60,000 Da
Albumin is 66 kDa (Not a middle molecule!)
Variable

# Examples

• Urea
• Creatinine
• Potassium
• Oxalate
• Uric acid
• Interleukins
• Cytokines
• B2 -microglobulin
• ANP
• TNF
• Light chains
• Homocysteine
• Hippuric acid
• Phenol

# Removal

• Better cleared by diffusion (Haemodialysis)
• Rate of clearance increased by:
• Increasing speed of dialysis fluid flow
• Better cleared by convection (Hemofiltration)
• Dialysis clearance increased by:
• Increased dialysis time
• Increased membrane pore size
• Increased membrane surface area
• Difficult to remove via RRT
• Clearance improved by:
• Increased time and flow
• Absorbent technology
• Albumin dialysis

Modality Choice

# Other Specific Clinical Considerations

• Hemofiltration is better at removing middle molecules
• Hemodialysis better at removing small molecules
• CRRT causes less rapid fluid shifts and is the preferred option if there is any degree of cardiovascular instability
• CRRT may be associated with better cerebral perfusion in patients with an acute brain injury or fulminant hepatic failure
• CRRT is more labour intensive and more expensive than IHD
• Availability of equipment may dictate the form of RRT.
• It is wise to use a form of RRT that is familiar to all the staff involved
• Convective modes of RRT may be beneficial if the patient has septic shock
• CRRT can aid feeding regimes by improving fluid management

# Peritoneal Dialysis

• Efficient and intensive technique
• Allows for down-time for interventions
• Can be performed overnight
• Staff required for a shorter time
• Lower costs
• Provides better haemodynamic stability
• Efficient solute removal and electrolyte balance with continuous removal
• Round-the-clock maintenance of volume status
• Nutrition and medication given while volume status maintained
• User-friendly machines
• Better haemodynamic stability than haemodialysis
• No need for anticoagulation

• May cause haemodynamic instability with rapid fluid removal
• Relative need for anticoagulation
• Potential for disequilibrium
• Need for expensive machinery
• Need for personnel
• Patient immobilisation
• Need for prolonged anticoagulation
• Nursing staff intensive
• Expensive machinery
• Risk of hypothermia
• Slow correction of volume and electrolyte disorders
• Many nurses unfamiliar with methods
• Risks of leaks and peritoneal infection

# Requirement

• Venous access
• Anticoagulation
• Skilled staff
• Expensive equipment
• Round the clock skilled nursing staff
• Venous access
• Anticoagulation
• Complex equipment
• Peritoneal catheter
• Sterile peritoneal solutions
• Trained staff

### Which modality is better for critically unwell patients?

• There is no evidence that the use of either continuous or intermittent therapies have a survival benefit in critical illness
• Continuous modalities have been Several benefits have been proposed from the use of continuous modalities:
• Improved haemodynamic stability and lower rates of therapy-induced hypotension – due to slower and more predictable rates of fluid removal and solute flux
• Increased clearance with continuous modes to aid with the resolution of uraemia and electrolyte imbalance
• Better tolerated in patients with raised intracranial pressure or hepatic encephalopathy due to less rapid shift in solute concentration and preservation of cerebral perfusion
• Better clearance of inflammatory mediators
• Given this international guidance favours the use of continuous therapies in critical illness
• KDIGO guidance recommends continuous therapies in ‘haemodynamically unstable patients’ or those with ‘raised ICP, brain injury or other forms of brain oedema.’
• Surviving sepsis guidance recommends continuous therapies in ‘haemodynamically unstable septic patients

Specialist Modalities

### What is SCUF?

• Provision ultrafiltration to remove excess fluid – mainly at the end of a dialysis session
• It is useful solely for fluid removal and does not alter the patient’s biochemistry

### What are hybrid therapies?

• Hybrid therapies refer to a collective of recently developed therapies which includes:
• SLED / EDD – Slow Low-Efficiency Daily Dialysis / Extended Daily Dialysis
• SCD – Sustained Continuous Dialysis
• Most therapies delivered via conventional dialysis machines over a more extended period than usual IHD
• Hybrid therapies benefit from being intermittent, but also are associated with
less haemodynamic and osmotic disturbance than intermittent HD, and good solute control

### What is SLED?

• SLED is an intermittent therapy typically delivered over 6-12 hours
• It typically uses lower blood and dialysate flow rates using conventional dialysis machines
• The advantaged of SLED are:
• Improved haemodynamic stability
• High solute clearance
• Removes the need for expensive CRRT machines and customized solutions
• Allows for diagnostic and therapeutic procedures

Circuit Anatomy & Performance

### How do the circuits differ for each modality of continuous RRT?

Haemodialysis
Haemofiltration
Haemodiafiltration
SCUF

Dose & Efficacy

# Net Ultrafiltrate Rate

Blood Flow Rate
Ultrafiltrate Rate
Dialysate Flow Rate
Effluent Rate
(Dose)
Substitution Fluid Rate
Net Ultrafiltrate Rate
Qb
Quf
Qd
Qef
Qs
Qnet
• The rate of blood flow from the patient towards the filter
• Blood flow rates are typically slower than in intermittent dialysis, ranging from 150-200mL/min
• The rate at which ultrafiltrate is produced by hydrostatic pressure across the membrane during convective therapies
• It is influenced by the blood flow rate and the filtration fraction
• The flow rate of dialysis fluid in dialytic therapies
• Standard flow rates range from 8-50 mL/min
• The effluent flow rate is the equivalent to ultrafiltration rate Quf in continuous haemofiltration, Qd in continuous haemodialysis, and both Quf & Qd in continuous hemodiafiltration
• It is analogous to the ‘dose’ in continuous therapies
• Dosing is weight-based and is typically prescribed at a dose ranging from 20 mL/kg/hr to 35 mL/kg/hr
• Techniques in which produce a volume of ultrafiltrate require replacement of this fluid with a substitute fluid to prevent significant loss of volume.
• The rate of substitution fluid describes the rate at which this replacement fluid is added to the plasma
• Represents the overall rate of fluid removal
• It is the difference between the total effluent removed (Qef) minus the volume of replacement therapy
• The fluid removal rate can be tailored by the machine to meet the total removal goal of the patient

### What determines the clearance in CRRT?

• Clearance describes the volume of blood that is cleared of a substance per unit of time
• The determinant of clearance in CRRT depends upon the mechanisms that are being utilised
• In continuous haemofiltration:
• A volume of ultrafiltrate is produced following the passage of the pressurised plasma over the membrane
• Clearance is of a solute determined by the:
• Rate at which ultrafiltrate is produced (Quf)
• Sieving coefficient of the filter membranes (determined by the ratio of solute concentrations in the ultrafiltrate)
• Most small molecules have a sieving coefficient of 1, meaning they pass freely through the membrane (though this is less true of middle molecules)
• Therefore, the clearance is analogous to the ultrafiltrate production rate (Quf)
• In continuous haemodialysis:
• The concentration gradient across the membrane determines clearance
•  The gradient is affected by the dialysate flow rate (Qd) and the blood flow rate (Qb)
• Qd is much slower than Qb, and the dialysate becomes fully saturated.
• Therefore, the dialysate rate (Qd) becomes the rate-limiting factor for solute removal and is analogous to clearance
• Overall consequently, clearance is equivalent to the combination of the ultrafiltration rate (Quf) and dialysate (Qd), which is termed the effluent rate (Qef)
• This is often discussed in terms of the ‘dose’ of a continuous replacement therapy which is given

### How is the effluent rate determined?

• In ultrafiltration, the effluent rate is determined by the flow of plasma into the membrane and the fraction of this which is filtered out as effluent (known as the filtration fraction)
• To maintain a constant effluent rate:
• At low blood flows a large filtration fraction is required
• At high flows, a small filtration fraction can be used
• The renal replacement circuits have inbuilt algorithms to deliver a desired effluent flow rate based upon the blood flow from the patient

### What effect do changes in the blood flow rate have?

• Normal filter blood flows range between 50-200mL/min
• Choosing the appropriate flow is a trade-off between the advantages and disadvantages of high and low flows:

# Low Blood Flows

• A lower filtration fraction required thus reducing the risk of filter clotting
• Easier to match ultrafiltration rates and therefore fluid removal targets
• Reduced haemodynamic instability
• Reduced risk of filter related complications
• Lower suction pressures needed to achieve flow rates

• Increased risk of haemodynamic instability
• Increased risk of hypothermia or haemolysis
• Increased risk of filter clotting due to high filtration fractions
• More challenging to meet fluid removal targets
• Increased risk of filter clotting due to high filtration fractions
• More challenging to meet fluid removal targets

### What effect do changes in the filtration fraction have?

• The filtration fraction is a measure of haemoconcentration in the filter
• It is defined by the ratio between volume removed by convection per volume of plasma flow
• If the ratio is too high, the filter tends to clot – more concentrated blood is ‘stickier’ and more likely to coagulate
• Generally aiming to keep the filtration ratio below 25-30% will prevent clotting in the filter.

Membranes

# Material

• The rate of blood flow from the patient towards the filter
• Blood flow rates are typically slower than in intermittent dialysis, ranging from 150-200mL/min
• The rate at which ultrafiltrate is produced by hydrostatic pressure across the membrane during convective therapies
• It is influenced by the blood flow rate and the filtration fraction
• The flow rate of dialysis fluid in dialytic therapies
• Standard flow rates range from 8-50 mL/min
• The effluent flow rate is the equivalent to ultrafiltration rate Quf in continuous haemofiltration, Qd in continuous haemodialysis, and both Quf & Qd in continuous hemodiafiltration
• It is analogous to the ‘dose’ in continuous therapies
• Dosing is weight-based and is typically prescribed at a dose ranging from 20 mL/kg/hr to 35 mL/kg/hr
• Techniques in which produce a volume of ultrafiltrate require replacement of this fluid with a substitute fluid to prevent significant loss of volume.
• The rate of substitution fluid describes the rate at which this replacement fluid is added to the plasma
• Represents the overall rate of fluid removal
• It is the difference between the total effluent removed (Qef) minus the volume of replacement therapy
• The fluid removal rate can be tailored by the machine to meet the total removal goal of the patient

### Which membranes are used in CRRT?

• There is no conclusive evidence that any specific membranes improve the outcome
• In practice, most filters used for CRRT are:
• Synthetic, high-flux membranes
• Surface area of 0.6–1.2m2
• Pore size allowing the passage of molecules up to 50,000 Daltons

# Author

The Guidewire
Trainee in ICM & Anaesthesia

# Reviewer

The Guidewire
Trainee in ICM & Anaesthesia