Medicines Q&As
Q&A 168.5
What factors need to be considered when dosing patients on renal
replacement therapies?
Prepared by UK Medicines Information (UKMi) pharmacists for NHS healthcare professionals
Date prepared: January 2013
Background
Renal replacement therapy (RRT) is indicated when renal function is so poor that the kidneys are
barely operational. RRT is used in the management of acute renal failure to remove toxins, excess
fluid and to correct biochemical disturbances. It also forms part of ongoing regular care in patients
with stage 5 chronic kidney disease (CKD) where the glomerular filtration rate (GFR) is <15mL/min
(1, 2).
The main types of RRT in use are (2):
- haemodialysis (HD)
- haemodiafiltration (HDF)
- peritoneal dialysis (PD) [automated peritoneal dialysis (APD) and continuous
ambulatory peritoneal dialysis (CAPD)]
- continuous arteriovenous haemofiltration (CAVHF)/continuous venovenous
haemofiltration (CVVHF)]
- continuous arteriovenous haemodialysis (CAVHD)/continuous venovenous
haemodialysis(CVVHD)
- continuous arteriovenous haemodiafiltration (CAVHDF)/continuous venovenous
haemodiafiltration (CVVHDF)]
These methods all involve presenting blood to one side of a membrane and presenting a solution with
or without pressure to the other side. This encourages toxins to leave the patient’s blood and enter
the dialysis solution. The membrane can either be synthetic (as in HD) or natural (the patient’s
peritoneum in PD). HD/HDF is performed intermittently (e.g. three times a week). APD is a broad term
that is used to refer to all forms of PD employing a mechanical device to assist the delivery and
drainage of dialysate. APD can be continuous or intermittent (3) the others are all continuous
processes (1, 2).
HD, HDF and CAPD or APD are used in the management of chronic renal failure (CRF).
Haemofiltration, continuous arteriovenous/venovenous haemodialysis and continuous
arteriovenous/venovenous haemodiafiltration- collectively known as continuous renal replacement
therapies (CRRT) - are used in the treatment of patients with acute renal failure (1, 2).
Answer
The factors that need to be considered when dosing patients on RRT are: The drug being used
 Type of RRT
 Patient status
Drug factors
Drugs which are cleared by the kidneys are usually dialysed, and vice versa, although there are some
anomalies (1).
Factors affecting the removal of a drug from the blood by RRT include:
 Renal clearance as a proportion of total body clearance – if the renal clearance of a drug
is normally less than 25-30% of total body clearance, impaired renal function is unlikely to
have a clinically important effect on drug removal. Similarly, drug removal by RRT will have
little influence on total body clearance and dosing adjustments do not have to be considered.
However, drugs significantly eliminated by the kidney often undergo substantial removal
during RRT and dosing adjustments are frequently needed (4).
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Protein binding - highly protein bound drugs (>80%) are not generally removed by RRT.
However, if protein binding is approximately 50% or less, removal may be significant (5,6).
Volume of distribution (Vd) and water / lipid solubility – a large Vd reflects a drug that is
highly tissue bound and lipid soluble. Consequently only a small amount is present in the
plasma and available for clearance. As solutions used in RRT are aqueous, water-soluble
drugs are more easily removed. If the Vd of a drug is <1L/kg it will be cleared by RRT (6,7).
Drugs with a high Vd (>1L/kg) will be removed to a limited extent (6).CRRT may be more
effective in removing drugs with a high Vd because the equilibrium between the plasma and
tissue levels will be constantly changing (7).
Molecular weight (see below)
Presence of active and/or toxic metabolites – many drugs are metabolised to water
soluble metabolites, which are then renally excreted. These may be removed by RRT, but
often data are lacking on the amounts removed and the toxicity of the metabolites.
Timing of administration- For HD because the process is intermittent, drugs should be
given after the HD session, otherwise a proportion of the drug may be removed and its
duration of action reduced. It is preferable to adjust the timing of regular doses in patients
receiving HD, rather than adding extra doses, as suggested by some texts (7).
Supplementary doses are only important for drugs with a low Vd and a narrow therapeutic
range (7). For CRRT and CAPD, since these are continuous processes, there is no need to
schedule doses around RRT sessions (1).
Therapeutic index - Most drugs have a broad therapeutic index, therefore a rigorous
adjustment of doses in patients undergoing RRT is unnecessary. However, for drugs with a
narrow therapeutic index e.g. aminoglycosides, dosage adjustment and where available,
serum drug level monitoring are essential (8).
Chronic administration versus single and loading doses – Single and loading doses do
not usually need to be altered in renal failure (9,10) even if the drug has a narrow therapeutic
index, because accumulation is unlikely (10). Initial doses of a course of a drug e.g. antibiotic,
that requires therapeutic levels quickly should not be reduced, as the time to reach
therapeutic levels may otherwise be prolonged. Maintenance doses and frequency will
depend on the extent of renal impairment and the drug being used (7, 10).
RRT factors
Dose adjustment for RRT is only necessary for drugs that require dose adjustment because of the
presence of renal failure. No RRT is as effective as the normal kidney – so doses used will never be
larger than those recommended in normal renal function (1). Removal by RRT only replaces
glomerular filtration. Some drugs also undergo renal tubular secretion or reabsorption (5,11) e.g.
fluconazole. Fluconazole undergoes substantial tubular reabsorption in the normal kidney, therefore in
a patient on CRRT the clearance may be even higher compared with normal kidney function, as the
drug is not reabsorbed (11).
 Blood, dialysate flow and ultrafiltration rates, replacement solution flow rate and
location (pre- or post- filter), chemistry and surface area of the membrane (1, 6). These
all affect drug clearance. Some membranes e.g. those made from polyacrylonitrile (PAN) may
adsorb significant amounts of drugs to their surface. However, adsorption is subject to
saturation, and the influence on drug removal will depend on the frequency of filter changes
(4, 5).
 Molecular weight (MW) Very large molecules are less likely to be removed than smaller
ones. Most drugs have a MW ≤ 500 Da, and very few are greater than 1500 Da (vancomycin
is 1448 Da). The type of membrane used has a major role to play in drug removal.
Membranes used in high-flux HD are made of biosynthetic material (e.g. polysulfone,
polyacrylonitrile) and have large pore-sizes (5,000 -20,000 Da), thus allowing the removal of
larger molecules (5, 6). The Renal Association guidelines recommend the use of high-flux HD
membranes (12). Membranes used in haemofiltration are even more permeable, allowing the
removal of molecules with a MW of up to 30, 000 Da (7). In haemofiltration, small, medium
and high MW solutes are removed by convection (see Table 1) and filtration
(“sieving”).Convection results in more rapid removal of molecules with a middle (500-15, 000
Da) or large (>15, 000 Da) MW compared with small molecules (2). In haemodiafiltration
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diffusion removes small molecules, whereas middle - and large - sized molecules are
removed by convection (2).
CAPD is less efficient at removing small solutes such as urea or creatinine (2).
Table 1. Definitions of terms used (2)
Diffusion
Convection
Ultrafiltration
The movement of solutes from fluid with a high to
a low concentration across a semi-permeable
membrane
The movement of solutes in fluid across a
membrane under pressure
The movement of fluid under pressure across a
semi-permeable membrane
Haemodialysis
In this procedure blood and dialysate flow in opposite directions separated by a semi-permeable
membrane. Excess fluid is removed by ultrafiltration (see Table 1) and waste products are removed
by diffusion. HD is an intermittent process – typically 3 four–hour sessions per week. The flow rate of
dialysate is fast (approximately 500mL/minute), enabling processing of big blood volumes.
Molecular size affects drug removal (see above). Increasing blood and solute flow rates increases
solute clearance. The composition of the dialysate will also affect the diffusion process. However the
efficiency of diffusion is reduced as flow rates increase, so this increase is not proportional to the
increase in flow rates (9).
Peritoneal Dialysis
In PD a solution is infused into the peritoneal cavity, where the patient’s peritoneum acts as a semipermeable membrane. Diffusion and convection of solutes occurs between capillary blood and the
dialysis solution in the peritoneal cavity, and osmosis removes excess fluid (2).
Factors affecting drug removal include:
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Composition of the dialysate
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Pathology of the peritoneum – peritonitis increases the permeability of the membrane
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Volume and exchange rate of dialysate in the peritoneum
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Molecular weight of drug (see above)
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Osmotic concentration gradient between plasma and dialysate i.e. glucose concentration of
the dialysis bag (7).
Haemofiltration and Haemodiafiltration
Factors affecting drug removal include: Dialysate flow rate
 Blood flow rate
 Ultrafiltration rate
 Type of membrane used - filters differ with regard to membrane composition, surface area,
electrostatic charge, permeability to water and solutes (7,13)
 Composition of dialysis fluid
 Administration of pre- or post-dilution replacement solutions
RRT technologies and practices have evolved significantly in recent years. In most cases, these have
resulted in greater drug clearances. Pharmacokinetic studies that formed the basis for many of the
drug dosing recommendations used today were performed in the 1980s and 1990s using RRT
techniques such as CAVHF. This achieves a lower drug clearance than current methods of
continuous RRT which use higher flow rates and more efficient filters (6,14). These studies varied in
design, using different haemofilters, blood and dialysate flow rates and ultrafiltration rates; and drug
clearance was calculated by various methods. Dosing recommendations based on this older data
may result in underdosing of drugs e.g. antibiotics, resulting in therapeutic failure and the emergence
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of resistant organisms (6, 14). Advice on drug dosage in CRRT from the literature should therefore be
applied cautiously to individual patients.
- Haemofiltration
The ultrafiltration rate determines the clearance of a drug during CRRT. In continuous venovenous
haemofiltration (CVVHF) a pump is used to propel blood around the extra-corporeal circuit, so higher
ultrafiltration rates can be achieved. In continuous arteriovenous haemofiltration (CAVHF), filtration is
maintained by the patient’s arterial pressure, as blood is supplied from an artery and feeds back to a
vein.
CAVHF/CVVHF is a continuous, slow process using a highly permeable membrane with larger pores
than in HD. Water and solutes (including drugs) are removed from the blood as it flows past the
membrane, (see “Molecular Weight” above). CAVHF is no longer routinely used in the UK.
- Haemodiafiltration
This process is a combination of haemodialysis and haemofiltration (simultaneous diffusion,
ultrafiltration and convection). This gives clearance of small, middle and large molecules. Blood is
withdrawn as for haemodialysis and passes through a high-flux dialyser. This has the ability to
remove large volumes of extracellular fluid and molecules up to 30,000 Da (2).
If there are no specific guidelines on how to dose a drug in a particular RRT system the patient can be
dosed in accordance with the theoretical glomerular filtration rate (GFR) achieved by that particular
mode of RRT. It is important to know the type of RRT and membrane used as clearances will vary (7),
as outlined above.
Table 2. Dosing schedule in different types of RRT (7, 15)
Renal replacement therapy
Dosing schedule
Intermittent HDF2
Typical theoretical GFR
achieved during therapy
(ml/min)
150-200 during dialysis (0-10
between dialysis periods)
See notes
CAPD (4 exchanges daily)
5-10
As for GFR < 10ml/min
CAVHF3
0-15
As for GFR 10-20 ml/min
CVVHF3
15-25
As for GFR 10-20 ml/min
CAVHDF
20
As for GFR 10-20 ml/min
CVVHDF4
30-40
See notes
Intermittent HD1
As for GFR <10 ml/min
See notes
i) If a drug is likely to be removed by HD it should be given after the procedure and not before (7).
ii) HDF removes drugs more efficiently than HD, although there is limited information in this area (15).
The RDH gives guidance on dosing in HDF for some drugs where published information is available
(15)
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iii) The Renal Drug Handbook does not give specific guidelines for CAVHF/CVVHF, but comments
that dosing schedules will be similar to CAVHD/CVVHD even though the drug clearance capacity of
CAVHF/CVVHF will be lower (15).
iv) Certain drugs e.g. antibiotics may undergo removal to a considerable degree by CVVHDF (2, 15)
In practice patients on renal units on all forms of CRRT are dosed as if they have a GFR of about 1020ml/min i.e. as for moderate RF (1, 15). The Renal Drug Handbook gives guidance on dosing in
CVVHDF for some drugs where published information is available (15).
Patient factors

Condition being treated
In many situations it is important not to underdose the patient, e.g. in the treatment of severe
infections, there is a risk of sub-therapeutic antibiotic plasma levels.

Residual renal function
Some patients may have residual renal function, which will contribute to drug excretion. This has to be
accounted for in adjusting the dose. The kidneys play a greater role in drug elimination; as kidney
function improves, the percentage of drug eliminated by RRT declines (6)
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Pharmacokinetic changes induced by renal failure
- Protein binding
Protein binding values derived from studies in healthy volunteers do not apply in critically ill patients,
therefore predictions of drug removal based on protein-binding estimates from healthy subjects will
result in inaccurate predictions of drug clearance by continuous RRT (6) Critically ill patients with ARF
often have low albumin values, which may result in an increase the unbound fraction of many drugs,
e.g. phenytoin (4).
- Volume of distribution
In critically ill patients with ARF the Vd may differ from values obtained in healthy volunteers or may
show greater inter- and intra- individual variation e.g. the Vd of aminoglycosides increases by
approximately 25% in such patients (4, Volume of distribution will increase for water soluble drugs in
patients with oedema or ascites and decrease in patients with muscle wasting or volume depletion
(9).
Summary
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There are a number of factors that need to be considered when dosing patients on RRT.
Consider the drug, the patient and the type of RRT.
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Alteration of drug dosage is only necessary if renal clearance exceeds 25% of total body
clearance
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Drugs which are cleared by the kidneys are usually dialysed, and vice versa, although there are
some anomalies

Dose adjustment for RRT is only necessary for drugs that require dose adjustment because of
the presence of renal failure. No RRT is as effective as the normal kidney – so doses used will never
be larger than those recommended in normal renal function

Pharmacokinetic studies that formed the basis for many of the drug dosing recommendations
used today were performed in the 1980s and 1990s using less efficient techniques of RRT than those
employed currently. These studies varied in design, used different haemofilters, blood, dialysate and
ultrafiltration rate and calculated drug clearance by different methods. Advice on drug dosage in
CRRT from the literature should therefore be applied cautiously to individual patients. Dosing
recommendations based on this older data may result in underdosing of drugs e.g. antibiotics

In patients on HD, dose after the dialysis session otherwise a proportion of the drug may be
removed during the HD session and its duration of action reduced. For CRRT and CAPD, since these
are continuous processes, there is no need to schedule doses around RRT sessions

For toxic drugs, and for drugs with a narrow therapeutic index, drug monitoring with
measurements of plasma concentrations, where available, and monitoring of the patient for
therapeutic response and adverse effects, are essential
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Limitations
A detailed discussion of the main types of RRT is beyond the scope of this review. There are other
techniques of RRT in use, such as slow continuous ultrafiltration (SCUF), slow extended daily dialysis
(SLEDD), which are not discussed here. Please see Q&A 167.4 for what factors need to be
considered when dosing patients with renal impairment.
Disclaimer
 Medicines Q&As are intended for healthcare professionals and reflect UK practice.
 Each Q&A relates only to the clinical scenario described.
 Q&As are believed to accurately reflect the medical literature at the time of writing.
 The authors of Medicines Q&As are not responsible for the content of external websites and
links are made available solely to indicate their potential usefulness to users of NeLM. You must
use your judgement to determine the accuracy and relevance of the information they contain.
 See www.ukmi.nhs.uk/activities/medicinesQAs/default.asp for full disclaimer.
References
1. Tutorial 8 – Drugs in Renal Disease in Emerson A. & Wills S. UKMi Training Workbook. Version 7,
2011.
2. Currie A, Dunleavy J. Renal replacement therapy. In: Ashley C, Morlidge C, editors. Introduction to
renal therapeutics. London: Pharmaceutical Press; 2008. p. 85-106.
3. Rabindranath KS et al. Automated vs continuous ambulatory peritoneal dialysis: a systematic
review of randomized controlled trials. Nephrol Dial Transplant 2007;22:2991-8
4. Bugge J, F. Pharmacokinetics and drug dosing adjustments during continuous venovenous
hemofiltration or hemodiafiltration in critically ill patients. Acta Anaesthesiol Scand 2001; 45: 929-34
5. Kuang D et al. Pharmacokinetics and antimicrobial dosing adjustment in critically ill patients during
continuous renal replacement therapy. Clin Nephrol 2007; 67: 267-84
6. Susla GM. The impact of continuous renal replacement therapy on drug therapy. Clin Pharmacol
Ther 2009; 86:562-5
7. Millsop A. Drug dosing in patients with renal impairment and during renal replacement therapy. In:
Ashley C, Morlidge C, editors. Introduction to renal therapeutics. London: Pharmaceutical Press;
2008. p. 127-37
8. Ashley C. Renal failure – options for renal replacement therapy. Hospital Pharmacist 2004; 11: 5461
9. Levy J et al. Oxford Handbook of Dialysis. 3rd ed. Oxford: Oxford University Press; 2009, p, 74,
596, 622
10. Sexton J. Drug use and dosing in the renally impaired adult. Pharm J 2003; 271: 744-46
11. Schetz M. Drug dosing in continuous renal replacement therapy: general rules. Curr Opinion Crit
Care 2007; 13:645-51
12. Mactier R et al. Clinical Practice Guidelines-Haemodialysis. Renal Association.
http://www.renal.org/Clinical/GuidelinesSection/Haemodialysis.aspx#intro accessed on 21.11.2012
13. Joy M, S et al. A primer on continuous renal replacement therapy for critically ill patients. Ann
Pharmacother 1998; 32: 362-73
14. Mueller BA, Smoyer WE. Challenges in developing evidence-based drug dosing guidelines for
adults and children receiving renal replacement therapy. Clin Pharmacol Ther 2009;86: 479-82
15. Ashley C, Currie A eds. The Renal Drug Handbook 3rd ed. Oxford: Radcliffe Publishing; 2009,
p.xiv-xvii
Quality Assurance
Prepared by
Richard Leung, South West Medicines information and Training, Bristol (based on earlier work by
Julia Kuczynska)
Date Prepared
January 2013
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Medicines Q&As
Checked by
Julia Kuczynska, South West Medicines Information and Training, Bristol
Date of check
18th January 2013
Search strategy
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Medline Exp *RENAL INSUFFICIENCY or “KIDNEY FAILURE” or “RENAL FAILURE” and
[exp*DRUG ADMINISTRATION SCHEDULE or exp *PHARMACOKINETICS] [Limit to:
Publication Year 2010 – current (2013)]
Embase [exp*KIDNEY FAILURE or exp *ACUTE KIDNEY FAILURE or exp *CHRONIC
KIDNEY FAILURE or “RENAL FAILURE” ] and [exp *DRUG ADMINISTRATION or exp
*PHARMACOKINETICS] [Limit to: Publication year 2010 – current (2013)]
National Electronic Library for Medicines (NeLM): Haemodialysis, OR Peritoneal Dialysis OR
Continuous ambulatory peritoneal dialysis
Internet search (Google; [hemodiafiltration OR hemodialysis OR hemofiltration] + drug dose
Renal dialysis guidelines OR Renal dialysis site: nhs.uk OR Renal replacement therapy
site:nhs.uk OR Renal replacement therapy in the intensive care unit
In-house renal database/ resources
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