Medicines Q&As
Q&A 167.4
What factors need to be considered when dosing patients with
renal impairment?
Prepared by UK Medicines Information (UKMi) pharmacists for NHS healthcare professionals
Date prepared: 31st May 2011
Background
Many commonly used drugs or their metabolites are excreted by the kidney, and this has particular
significance for people with renal impairment (RI). Impaired renal function alters drug
pharmacokinetics, potentially changing drug efficacy and increasing the likelihood of unwanted
effects, including renal toxicity (1). There may also be pharmacodynamic changes (2). Drugs that are
most affected by RI are those that are normally substantially renally excreted (≥ 30%) (3) or have
active or toxic metabolites which are renally excreted (4).
Answer
General drug dosing guidance in renal impairment
Drugs, or their metabolites, that are mainly excreted by the kidney may have a prolonged half-life in
RI, and accumulation may occur, which can result in toxicity (3,5). Drug accumulation sufficient to be
of clinical concern occurs in patients with RI if ≥30% of the drug is eliminated unchanged in the urine
(3), and dose reduction needs to be considered, depending on the degree of RI and fraction of drug
excreted unchanged (6)
There are three approaches to altering drug maintenance doses in patients with RI (1,3,7):
i)
either the standard dose can be given but at extended intervals or
ii)
a reduced dose is given at the usual intervals or
iii)
a combination of reduced dose and extended interval
Drugs that require maintenance of a serum concentration over the dosing interval should be
administered at the usual intervals, but with reduced doses. Drugs for which specific peak serum
concentrations must be achieved will be dosed with the standard dose at extended intervals (8).
Drugs with a narrow therapeutic index (e.g. vancomycin, lithium) require the greatest care in use (4).
Careful monitoring of plasma levels and clinical response are needed, followed by dose adjustments,
if appropriate. The loading dose should normally be the same size as for a patient with unimpaired
renal function, when a rapid therapeutic response is needed, as it takes about five times the half-life
of a drug to reach steady state concentrations. As the plasma half-life of drugs excreted by the kidney
is prolonged in RI it can take many doses for the reduced dosage to achieve a therapeutic plasma
concentration (9). For example, the initial dose/s of a course of antibiotic should not be reduced
because otherwise it may take a long time to reach therapeutic levels (4). There may be some
exceptions, e.g. drugs with a narrow therapeutic index whose volume of distribution (Vd) may be
altered in chronic kidney disease (CKD) (8). Single doses are not thought to be dangerous as
accumulation is unlikely (4).
It is suggested that a drug with the following characteristics is chosen for prescribing in patients with
RI (2):
 Wide therapeutic index
 Does not need renal metabolism to the active form
 No or minimal nephrotoxicity
 Active drug or active metabolites not renally excreted
 Not highly protein bound
 Low adverse effect profile
 Action unaffected by altered tissue sensitivity
 Unaffected by fluid balance changes
 Able to reach site of action in high enough concentrations in the presence of RI (2)
From the NHS Evidence website www.evidence.nhs.uk
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Medicines Q&As
Most drugs will not meet all the above criteria but if a drug has a narrow therapeutic index with no
potential for monitoring, potential renal adverse effects, or serious dose-related adverse effects, an
alternative should be found.
Additionally,
 Use recommended dosage regimens for renal failure
 Use plasma concentration measurements to adjust dose wherever possible
 Monitor the patient carefully for evidence of clinical effectiveness and toxicity (2,5)
 Exercise caution in patients with severe hepatic dysfunction, which is usually accompanied by
some RI (hepato-renal syndrome)(6)
Pharmacokinetics
The absorption, distribution, metabolism and excretion of drugs can be affected by RI to varying
degrees (2, 4, 7). These will be discussed individually.
Absorption and bioavailability
Absorption (proportion of drug absorbed from the gastrointestinal tract) and bioavailability (the
proportion of the administered dose which reaches the systemic circulation of the patient) can both be
affected in renally impaired patients. Absorption may be reduced due to a number of factors such as
nausea, vomiting or diarrhoea associated with uraemia and gut oedema. An increase in the gut pH
from increased gastric ammonia production in uraemia, or from co-administered drugs, reduces the
bioavailability of drugs requiring an acidic environment for absorption. The increase in pH may
increase the bioavailability of weakly acidic drugs (2).
Drug doses are not routinely altered to allow for these factors alone, but a change in dose or route of
administration may be considered if the desired therapeutic effect is not being achieved (2).
Distribution
The state of hydration of a patient will affect the volume of distribution (Vd) of water soluble drugs with
a small Vd e.g. aminoglycosides with a Vd of approximately 0.25L/kg (2, 8). For example, the Vd of
gentamicin will increase in patients with oedema or ascites; consequently dose adjustment may be
needed to achieve satisfactory plasma concentrations in extremely volume overloaded patients
(>110% of ‘dry’ weight’) (8). Another factor affecting Vd in patients with CKD is reduction in protein
binding(Pb), caused by decreased serum albumin concentrations, reduction in albumin affinity for
drugs and competition for binding sites from accumulated metabolites and endogenous substances.
This is clinically important for highly protein bound drugs (>80%) (2, 5, 8). Apparently low total plasma
concentrations of these drugs will still be therapeutic as the proportion of free, therefore active, drug
will be higher. An important example of this is phenytoin (2, 5, 8). Alterations in tissue binding may
also affect the Vd of a drug (2). For example, the Vd of digoxin is decreased in patients with severe
RI, probably due to a decreased in tissue binding(3,6). However changes to distribution (Pb and Vd)
are most likely to be a significant issue in renal replacement therapies (refer to Q&A 168.2 Whatfactors-need-to-be-considered-when-dosing-patients-on-renal-replacement-therapies/ )
Metabolism
Renal impairment affects the metabolism of drugs (5) e.g. reduction and hydrolysis are slower. This
may increase serum concentrations of the parent drug and consequent toxicity if the drug is
metabolised to inactive metabolites (2). Many drugs and/or their phase I metabolites are eliminated by
glucuronidation and the glucuronides are excreted by renal mechanisms. Therefore in patients with
RI, glucuronide conjugates will accumulate in the plasma. For some drugs, e.g. ketoprofen, the
systemic hydrolysis of the glucuronide will occur, leading to increased levels of the parent compound
(3,6). Many active or toxic metabolites depend on renal function for elimination; therefore they may
accumulate in RI, for example norpethidine following the administration of pethidine (2,10).
Norpethidine is a central nervous system stimulant but not an analgesic. Even in patients with mild RI,
such as elderly patients, this metabolite can reach sufficient concentrations to cause seizures. The
use of lower doses of pethidine may limit its efficacy, therefore alternative analgesics should be
considered(3). There is also clinical evidence that alterations in drug metabolism and transport occur
during acute and chronic renal failure (10,11). In patients with severe chronic RI the accumulation of
uraemic toxins affects the activity of cytochrome P 450 metabolic enzymes and of P-glycoprotein,
organic anion-transporting peptides and multidrug resistance-associated protein transporters in the
liver and gastro-intestinal tract (11). Examples of drugs affected include imipenem, meropenem and
From the NHS Evidence website www.evidence.nhs.uk
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Medicines Q&As
vancomycin (10). Studies have shown that non-renal clearance of these drugs is lower in patients
with acute RI and lowest in patients with chronic RI, compared with patients with normal renal function
(10). Careful monitoring of patients is therefore essential.
Excretion
The extent to which reduced renal function is important for the elimination of a drug depends on the
proportion of the administered drug or any active or toxic metabolites which are eliminated by the
kidney (2).
A small number of drugs (for example, carbamazepine, theophylline) are mainly excreted hepatically
without toxic metabolites. The effect of RI on their metabolism has not yet been fully studied, but
appears to be unaffected by RI in humans (10,11). They can therefore be safely used in RI.
Monitoring of efficacy, blood levels or adverse events is prudent however (4). The effects of a number
of drugs are measured by direct physiological response. These drugs can be used, with caution (i.e.
lower starting doses), in renally impaired patients. Indeed many of the drugs used to manage renal
failure (e.g. calcitriol, phosphate binders) are titrated according to response (4).
Pharmacodynamics
Uraemia in RI can alter the clinical response to certain drugs (2,12) for example;
 Increased sensitivity to drugs acting on the central nervous system
 Increased risk of hyperkalaemia with drugs such as potassium-sparing diuretics
 Increased risk of gastrointestinal bleeding or oedema with non-steroidal anti-inflammatory
drugs (NSAID).
Measuring renal function
Accurate measurement of renal function is essential in patients with RI so that drug dosages can be
adjusted accordingly. The estimation of glomerular filtration rate (eGFR) provided by the Modification
of Diet in Renal Disease trial (MDRD) is now the most widely used method of estimating renal
function (13). It is calculated using serum creatinine concentration, age, sex and ethnic origin (14)
which is different from the traditional Cockcroft and Gault (C&G) estimation of creatinine clearance
(CrCl). Drug dosing calculations for patients with RI have traditionally been based on estimations of
CrCl using C&G (14) and the vast majority of published drug dosing information is based on C&G
estimation of CrCl (7).
Advice on adjustment of drug doses in RI in the BNF is now expressed in terms of eGFR, rather than
CrCl, for most drugs (9). Although the two measures of renal function are not interchangeable, in
practice, for most drugs and for most patients (over 18 years) of average build and height, eGFR
(MDRD ‘formula’) can be used to determine dosage adjustments in place of CrCl (9). When
calculating renal function, MDRD eGFR normalised estimates largely correlate with C&G estimates for
CKD stages 3-5 (15), except for patients at extremes of body weight (9,1215). The MDRD formula is
not validated for use in children under 18 years (9). The BNF advises that for potentially toxic drugs
with a narrow therapeutic index, CrCl (calculated from the C&G formula) should be used to adjust
drug dosages in addition to plasma-drug concentration and clinical response (9).
Neither the C&G equation nor the MDRD equation give reliable estimates in patients with normal or
mildly impaired renal function. The MDRD equation can underestimate normal renal function by as
much as 30% when compared with gold standard methods (isotopic measurement of GFR)(15).
The eGFR calculated by the MDRD equation is normalised to a standard body surface area (BSA) of
1.73m2.Therefore there is a potential for under- or over- dosing patients at extremes of body weight.
In order to calculate the correct dose the normalised eGFR should be converted to the patient’s
absolute GFR using the following formula: GFR ABSOLUTE = (eGFR x BSA ACTUAL/1.73) (9). This is
particularly important for drugs with a narrow therapeutic index. Failure to correct to absolute, nonnormalised GFR in patients with a BSA smaller than 1.73m 2 will overestimate GFR and potentially
result in drug overdosing. Conversely, in patients with a BSA greater than 1.73m 2 this will
underestimate GFR and will potentially result in drug under-dosing (7,12).
The BNF advises that in patients at both extremes of weight (BMI of less than 18.5 kg/m2 or greater
than 30 kg/m2) the absolute GFR or CrCl (calculated from the C&G formula) should be used to adjust
From the NHS Evidence website www.evidence.nhs.uk
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Medicines Q&As
drug dosages (9).When using the C&G equation to calculate CrCl it is important to note that it uses
body weight as a marker of muscle mass (creatinine being a breakdown product of muscle).
Therefore in obese or extremely underweight patients there is also potential for over- or underestimation of CrCl. Guidance is available on when to use actual or ideal body weight in these
circumstances (12,15). Furthermore, estimating CrCl from a serum creatinine level assumes that renal
function is stable, and that the serum creatinine level is fairly constant. With rapidly changing renal
function the serum creatinine levels will no longer reflect the true creatinine clearance rate (15).
Where an accurate GFR is deemed necessary e.g. in chemotherapy dosing, an isotope GFR
determination should be performed (7,15).
Summary
The absorption, distribution, metabolism and excretion of drugs can be affected by renal impairment
(RI) to varying degrees (2, 4, 7). Generally, changes in drug absorption and bioavailability are unlikely
to be a clinically significant problem when considering drug dosing in patients with RI. Changes to
drug distribution (protein binding and Vd) are most likely to be an issue in renal replacement therapies
(refer to Q&A 168.5 What factors need to be considered when dosing patients on renal replacement
therapies?).
Drugs that are most affected by RI are those that are normally substantially renally excreted or have
active or toxic metabolites which are renally excreted (4). Renal excretion of a drug is dependent on
GFR and when renal function is impaired, clearance of the drug is decreased and the plasma half-life
prolonged. Therefore patients with RI who are given drugs that are mainly renally cleared will require
the dose or dose frequency to be adjusted. This is usually either by the standard dose being given at
extended intervals or a reduced dose given at the usual intervals (1, 7). Single doses are not thought
to need adjustment as accumulation is unlikely (4).
Before prescribing a drug to a patient with RI consider the following (2);
 Use drugs only when there is a definite indication
 Choose a drug that has no or minimal nephrotoxicity
 Use recommended dosage regimens for renal failure
 Use plasma concentration measurements to adjust dose wherever possible
 Monitor the patient carefully for evidence of clinical effectiveness and toxicity of drugs
The estimation of the GFR is the cornerstone of any alteration of a dose of a drug. (12, 15,16). The
vast majority of published drug dosing information is based on Cockcroft & Gault (C&G) estimation of
creatinine clearance (CrCl) (7). However the estimation of glomerular filtration rate (eGFR) provided
by the Modification of Diet in Renal Disease trial (MDRD) is now the most widely used method of
estimating renal function (13). Although the two measures of renal function are not interchangeable, in
practice, for most drugs and for most patients (over 18 years) of average build and height, eGFR
(MDRD ‘formula’) can be used to determine dosage adjustments in place of CrCl(9). The information
on dosage adjustment in the BNF is now expressed in terms of eGFR, rather than CrCl for most
drugs. However, dose regimens based on CrCl calculated by C&G should be used for potentially toxic
drugs with a narrow therapeutic index, together with monitoring of plasma-drug concentrations and
clinical response. The absolute GFR or CrCl calculated by the C&G formula should be used to adjust
drug dosages in patients at extremes of body weight (BMI <18.5kg/m2 or >30kg/m2)(9). If using C&G
for these patients it may be necessary to base the calculation on ideal body weight (12,15). Where an
accurate GFR is considered necessary e.g. in chemotherapy dosing, an isotope GFR determination
should be performed (7,15).
It is worth noting that published data on drug dosage adjustment in RI are sparse and include mainly
case reports and pharmacokinetic studies in small numbers of subjects. For new drugs most studies
are designed and performed by the manufacturer. This was highlighted by a study comparing
secondary sources of prescribing information for patients with RI. The study found a considerable
degree of variability amongst the definitions and recommendations in four different standard sources.
(17, 18).
Limitations
This Q&A discusses general principles of drug dosage adjustment in adults. For information on dose
adjustment of specific drugs or information on drug dosage adjustment in children, please consult the
From the NHS Evidence website www.evidence.nhs.uk
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Medicines Q&As
latest BNF, BNF for children, SPC and Renal Drug Handbook and other specialist texts or sources of
information.
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References
(1) Consumers Association. The patient, the drug and the kidney. Drug and Therapeutics Bulletin
2006; 44 (12): 89-95.
(2) 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. 127-137.
(3) Brater DC. Drug dosing in patients with impaired renal function. Clin Pharmacol Ther 2009; 86:
483-9
(4) Sexton J. Drug use and dosing in the renally impaired adult. Pharmaceutical Journal 2003; 271:
744-746.
(5) Aronoff GR et al. Drug Prescribing in Renal Failure. Dosing Guidelines for Adults and Children.
5th ed. Philadelphia: American College of Physicians; 2007. p.1-10
(6) Verbeeck RK and Musuamba F. Pharmacokinetics and dosage adjustment in patients with renal
dysfunction. Eur J Clin Pharmacol 2009; 65:757-73
(7) Ashley C, Currie A. editors. Renal Drug Handbook. 3rd Edition 2009. Oxford Radcliffe Medical
Press Ltd p.xiv – xvii
(8) Churchwell MD, Mueller BA. Selected pharmacokinetic issues in patients with chronic kidney
disease. Blood Purif 2007;25: 133-38
(9) Joint Formulary Committee. British National Formulary. 61ed. London: British Medical Association
and Royal Pharmaceutical Society of Great Britain; 2011, Prescribing in renal impairment.
www.bnf.org Accessed 12th April 2011
(10) Vilay AM et al. Clinical review: Drug metabolism and nonrenal clearance in acute kidney injury.
Critical Care 2008; 2008;12:235
(11) Nolin T. Altered nonrenal drug clearance in ESRD. Curr Opin Nephrol Hypertens 2008; 17:555-9
(12) Brown C. Prescribing principles for patients with chronic kidney disease. Pharmacy in Practice
January/February 2008.p.23-27 http://www.pharmacyinpractice.com/past-issues/2008-volume-18issue-1/7-PIP-Therapeutic-options-Jan-Feb-08.pdf
(13) UK e CKD Guide. Revised January 2009. Renal Association. Available at
http://www.renal.org/whatwedo/InformationResources/CKDeGUIDE.aspx accessed 6th June 2011
(14) Sullivan L. In Focus Review New National Guidelines for Estimating Glomerular Filtration Rate
http://www.nelm.nhs.uk/en/NeLM-Area/News/487372/487589/487603/?query=GFR&rank=1
Accessed 18th December 2008
(15) Devaney A, Tomson C. Chronic kidney disease – new approaches to classification. Hospital
Pharmacist 2006; 13: 406-10
(16) Diagnosis and management of chronic kidney disease. Guideline 103. June 2008. Scottish
Intercollegiate Guidelines Network http://www.sign.ac.uk/pdf/sign103.pdf
(17) Vidal L et al. Systematic comparison of four sources of drug information regarding dose
adjustment of dose for renal function. Brit Med J 2005; 331: 263-6
(18) Mehta DK et al. Dose adjustment in renal impairment. Brit Med J 2005; 331: 291-4
From the NHS Evidence website www.evidence.nhs.uk
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Quality Assurance
Prepared by
Julia Kuczynska, South West Medicines Information and Training, Bristol, (based on earlier work by
Richard Cattell and Caroline Metters)
Date Prepared
10th May 2011
Checked by
Trevor Beswick, Director, South West Medicines Information and Training
Date of check
8th June 2011
Search strategy
 Embase: [exp *KIDNEY FAILURE or exp *ACUTE KIDNEY FAILURE or exp *CHRONIC
KIDNEY FAILURE ] and [exp *DRUG ADMINISTRATION or exp *PHARMACOKINETICS]
[Limit to: Publication Year 2008-20011]
 Medline : exp *RENAL INSUFFICIENCY + [exp *DRUG ADMINISTRATION SCHEDULE or
exp *PHARMACOKINETICS] [Limit to: Publication Year 2008-2011]
 In-house drug dosing in renal failure database and resources
 Internet Search (Google; REVIEW and PHARMACOKINETICS and KIDNEY FAILURE)
 Pharmline (KIDNEY FAILURE and [PHARMACOKINETICS or DRUG ADMINISTRATION])
From the NHS Evidence website www.evidence.nhs.uk
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