Dialysis

Dialysis is the separation of particles in a liquid based on their ability to pass through a membrane.

Indications

Failure of normal renal functions, i.e.:

• Acid
• Electrolyte derangement
  Particularly hyperkalaemia.
• Intoxications
• Overload
• Uraemia

Physical Mechanisms

Fluid and electrolytes can be removed by four different mechanisms:

• Diffusion
  Diffusion is the spontaneous movement of substances from a higher concentration to a lower concentration, where rate of movement is proportional to the concentration gradient (as per Fick's Law).

• Ultrafiltration
  Movement of water, as determined by Starling's Forces.
  • When a solvent passes through a membrane, the process is called osmosis. The frictional forces between solutes and water molecules will pull dissolved substances along, a process known as bulk flow or solvent drag.

Implementation

• Haemodialysis
  Uses diffusion.
  • Blood is pumped through an extracorporeal circuit that contains a dialyser.
  • Dialysate flow is countercurrent, which maximises the gradient for diffusion.
  • Solutes move across a membrane between blood and dialysate, as per Fick's Law:
    • Concentration gradient between blood and dialysate
      • Flow rate of blood and dialysate
    • Solubility of the solute
      • Mass
      • Charge
      • Protein binding
    • Dialysis membrane permeability
      • Thickness
      • Porosity
      • Surface area

• Haemofiltration
  Uses ultrafiltration.
  • Both a positive hydrostatic pressure in blood and a negative hydrostatic pressure in dialysate is generated, causing ultrafiltration and removal of solutes via solvent drag.
  • Elimination via bulk flow is independent of solute concentration gradients across the membrane.
  • Transport is dependent on Starling Forces:
    • The transmembrane pressure generated
      This is a function of:
      • Blood flow to the membrane
        Determines hydrostatic pressure.
      • Oncotic pressure gradient
    • Porosity of the membrane
  • Additionally, a high filtration fraction will cause excessive haemoconcentration, and clotting of the filter
  • The filtered fluid (ultrafiltrate) is discarded, and replaced with another fluid depending on the desired fluid balance.

Differences

• Renal Replacement Therapy (RTT) can be via:
  • Peritoneal dialysis (PD)
  • Intermittent haemodialysis (IHD)
    IHD causes greater cardiovascular instability compared to CRRT as the fluid and electrolyte shifts occur more rapidly.
  • Continuous Renal Replacement Therapy (CRRT)
    • Continuous Veno-Venous Haemofiltration (CVVH)
    • Continuous Veno-Venous Haemodiafiltration (CVVHDF)

Method chosen depends desired effect:

• Small molecules (<500 Da) and electrolytes can be removed by filtration or dialysis
• Medium-sized molecules (500-5000 Da) are best removed by filtration
• Low molecular weight proteins (5000-50000 Da) are removed by filtration
  This includes removal of inflammatory proteins, which may be beneficial in sepsis.
• Water is best removed by filtration

Pharmacokinetics of RRT

Pharmacokinetics are unpredictable, but are broadly affected by:

• Drug factors
  • Free drug in plasma
    Drugs with a small proportion of free drug in plasma are (unsurprisingly) poorly removed by RRT (but may be removed via plasmapheresis). These include:
    • Highly (> 80%) protein bound substances
      Examples included phenytoin, warfarin, and many antibiotics.
      • Not that this may not apply in overdose
        Once protein binding sites are saturated, both free drug fraction and efficacy of dialysis is increased.
    • Drugs with a V_D greater than 1L.kg^-1
  • Size/Molecular Weight
    • Small molecules (< 500 Da) are more easily cleared by diffusive methods of RTT
    • Molecules > 15kDa are poorly dialysed
      This includes proteins, heparins, and monoclonal antibodies.
  • Volume of distribution
    Drugs with high volumes of distribution are poorly dialysed, as removal of drug from plasma only removes a small proportion of total-body drug content.

• Dialysis factors
  • Dose/Flow rates
    Reduced flow rates will reduce clearance.
    • Conventional high-flux haemodialysis has more rapid clearance compared to lower-flux haemoperfusion or CRRT
  • Membrane permeability
  • Timing
    Drugs given between IHD or SLED sessions will not be cleared until the next session.s

• Patient factors
  • Residual renal function
    Patients residual GFR will also affect pharmacokinetics.

An Incomplete List of Drugs

References

1. Johnson CA, Simmons WD. Dialysis of Drugs. Nephrology Pharmacy Associates.