Download SW_QA167_6Dosing_in_renal_impairmentFINAL

Medicines Q&As
Q&A 167.6
What factors need to be considered when dosing patients with
renal impairment?
Prepared by UK Medicines Information (UKMi) pharmacists for NHS healthcare professionals
Before using this Q&A, read the disclaimer at www.ukmi.nhs.uk/activities/medicinesQAs/default.asp
Date prepared: 18th February 2016
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).
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 sufficient to be of clinical concern occurs in patients with RI if ≥30% of the drug
is eliminated unchanged in the urine or if the drug has active or toxic metabolites which are renally
excreted. Dose reduction needs to be considered, depending on the degree of RI and fraction of drug
excreted unchanged in order to avoid potential toxicity (3, 4, 5, 6). Single doses are not thought to be
dangerous as accumulation is unlikely (3). 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, if possible. In addition, caution should be exercised in patients with severe hepatic
dysfunction, which is usually accompanied by some RI ('hepato-renal syndrome')(3).
There are three approaches to altering drug maintenance doses in patients with RI, depending on the
desired goal of therapy (1,5,7):
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). In
general, the latter approach will achieve similar peak and trough concentrations and AUC to those in
patients with normal renal function (9).
Drugs with a narrow therapeutic index (e.g. vancomycin, lithium) require the greatest care in use (3).
Careful monitoring of plasma levels and clinical response are needed, followed by dose adjustments,
if appropriate.
When a rapid therapeutic response is needed, a loading dose may even be needed if one was not
routinely recommended for patients with normal renal function (9). The loading dose may be
calculated by the following formula: patient’s loading dose= usual loading dose x [(patient’s
VD)/(normal VD)](9).
The plasma half-life of drugs excreted by the kidney is prolonged in RI and it takes about five times
the half-life of a drug to reach steady state concentrations, therefore it can take many doses for the
reduced dosage to achieve a therapeutic plasma concentration(10). Consequently, the initial dose/s
of a course of a critical medicine e.g. an antibiotic should not be reduced because otherwise it may
take a long time to reach therapeutic levels.
Available through NICE Evidence Search at www.evidence.nhs.uk
1
Medicines Q&As
Pharmacokinetics
The absorption, distribution, metabolism and excretion of drugs can be affected by RI to varying
degrees (2, 3, 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). The effect of CKD on intestinal cytochrome P
450 metabolic enzymes and transporters may lead to an increase in bioavailability of orally
administered drugs, e.g. tacrolimus, in these patients (11).
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). In patients with
conditions such as sepsis, major burn injury etc., oedema formation and administration of IV fluids
leads to an increase in total body water thus increasing the VD of hydrophilic antimicrobials. Adequate
loading doses are therefore essential. In critically ill patients with associated acute kidney injury (AKI)
the loading dose of hydrophilic antimicrobials e.g. beta-lactams, aminoglycosides, may even need to
be increased by up to 25-50% (9,12). Conversely dehydration or muscle wasting may result in
unexpectedly high concentrations of drugs(13). 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%) (2,4,8).
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 (2,4 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 (5,6). However
changes to distribution (Pb and Vd) are most likely to be a significant issue in renal replacement
therapies (refer to Q&A168.7)
Metabolism
Renal impairment affects the metabolism of drugs (4) 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, systemic
hydrolysis of the glucuronide will occur, leading to increased levels of the parent compound ( 5,6).
Many studies have also shown reduced acetylation in patients with RI (11). 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 (2,14). 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 (5).
There is also clinical evidence that alterations in hepatic drug metabolism and transport occur during
acute and chronic renal failure (14,15). In patients with severe chronic RI the accumulation of uraemic
toxins and inflammatory cytokines 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 (11,15). Drugs affected include imipenem,
meropenem, vancomycin(14), digoxin and erythromycin (11). For example, uraemic toxins inhibit
organic-anion-transporting polypeptide (OATP)-mediated uptake of erythromycin into hepatocytes,
which may be responsible for its reduced hepatic clearance in severe CKD (11). Studies have shown
Available through NICE Evidence Search at www.evidence.nhs.uk
2
Medicines Q&As
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 (14). Even drugs such as lidocaine
which is mostly metabolized by hepatic CYP1A2 and CYP3A4 have been reported to have reduced
clearance and prolonged half-life in patients with CKD, compared with control subjects (11). The
determination of specific drug-metabolising enzymes and transporters that are affected by RI is
complicated because of i) the interactions between them, ii) apparent differential effects in the
intestine and liver, iii) as yet incomplete understanding of the effect of uraemia on metabolism
mediators. This makes it difficult to translate pharmacokinetic data into clinically useful drug dosing
recommendations. Pharmacokinetic studies in patients with RI should be performed for all drugs,
even those primarily cleared by the liver(16). Careful monitoring of patients is therefore essential.
Excretion
The extent to which a reduction in glomerular filtration 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). For some drugs, e.g. methotrexate, reduction of renal excretion in
patients with advanced CKD is thought to occur also through a competitive inhibition of renal
transporter proteins by uraemic toxins (11). The excretion of several other drugs mainly eliminated in
the urine by active tubular secretion, is also reduced in RI e.g. sitagliptin and varenicline. Sitagliptin is
a substrate for human organic anion transporter-3 (hOAT-3), which may be involved in the renal
elimination of sitagliptin. However the clinical relevance of hOAT-3 in sitagliptin transport has not been
established(17).
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 (14,15). Monitoring of efficacy, blood levels or adverse
events is advisable however, in view of the emerging data on the effect of CKD on drug metabolism
(3,11). 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 (3).
Pharmacodynamics
Uraemia in RI can alter the clinical response to certain drugs (2,18) for example;
 Increased sensitivity to drugs acting on the central nervous system, due to increased
permeability of the blood-brain barrier(13)
 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).
 Reduced efficacy or increased toxicity of drugs such as warfarin or statins, independent of
changes in the pharmacokinetics of these drugs. Kidney disease is thought to alter the
physiological or pathological processes involved in the condition being treated (19).
Measuring renal function
Accurate measurement of renal function is essential in patients with RI so that drug dosages can be
adjusted accordingly. Because the production and excretion of creatinine decline with age, normal
serum creatinine values may not represent normal renal function in older patients (20).The normal
process of ageing involves the loss of nephrons and therefore it is reasonable to assume that all
elderly patients have some degree of renal impairment (21).
Current NICE guidance recommends the use of Chronic Kidney Disease Epidemiology Collaboration
(CKD-EPI) creatinine equation to estimate GFR or the use of equations incorporating an alternative
marker – cystatin C (22). However the estimation of glomerular filtration rate (eGFR) provided by the
Modification of Diet in Renal Disease trial (MDRD) has been the most widely used method of
estimating renal function (23).
Estimates of eGFR calculated using creatinine-based equations become less accurate as true GFR
increases (24), although the CKD-EPI equation is more accurate for values of GFR >60mL/min(26). In
individuals with reduced body size or muscle mass, e.g. frail, elderly, critically ill or patients with
Available through NICE Evidence Search at www.evidence.nhs.uk
3
Medicines Q&As
cancer or muscle wasting diseases the use of creatinine-based equations will lead to an
overestimation of the CrCl (21).
Neither equation should be used in pregnant patients, children under 18 years, marked catabolism or
rapidly changing renal function (10,21). Estimating CrCl from a serum creatinine level assumes that
renal function is stable over several days or more (21) 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.
Drug dosing calculations for patients with RI have traditionally been based on estimations of CrCl
using Cockcroft & Gault (C&G) (18) and the vast majority of published drug dosing information is
based on C&G estimation of CrCl (7).
Despite this, advice on adjustment of drug doses in RI in the BNF is now expressed in terms of eGFR,
rather than CrCl, for most drugs (10). Although the two measures of renal function are not
interchangeable, the BNF advises that 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 (10). The national Kidney Disease Education Program in the USA has
also endorsed the use of eGFR for drug dosing in renal disease (25,26).
However, 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 (10).
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) (10).
Failure to correct to absolute, non-normalised 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 1.73m2 this will underestimate GFR and will potentially result in drug under-dosing (7,18).
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
drug dosages (10).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 (18).
In general, ideal body weight (IBW) should be used when calculating C&G particularly in oedematous
patients and patients with ascites. For obese patients IBW can be used, but some experts have
suggested that an adjustment factor of 40% be applied to the patient’s excess weight over their ideal
weight i.e. adjusted body weight = [IBW + (0.4x ABW-IBW)] where ABW is actual body weight
(21,27).Clinical judgement is needed, e.g. if a patient's excess weight is due to high muscle mass not
excess body fat, actual body weight should be used. Some experts have proposed the use of CrCl
range for drug dosing purposes, with the lower boundary defined by using IBW in the CG equation
and the upper boundary by using TBW(28). Where an accurate GFR is deemed necessary e.g. in
chemotherapy dosing, an isotope GFR determination should be performed (7).
There is evidence that in elderly patients with CKD the use of the MDRD equation to calculate eGFR
instead of an estimated CrCl overestimates GFR and leads to the calculation of higher than
recommended doses of drugs such as enoxaparin, gentamicin, digoxin, amantadine, gabapentin,
NOACs and ramipril in up to 50% of these patients(29,30,31,32). For example, a general-practice
based study in over 4100 patients with atrial fibrillation has shown that using MDRD instead of C&G to
calculate eligibility and dose of dabigatran or rivaroxaban would have led to up to 15% of patients
aged ≥ 80 being incorrectly judged eligible or receiving too high a dose of dabigatran. The
corresponding figure for all patients taking rivaroxaban was 13.5% (33).
Available through NICE Evidence Search at www.evidence.nhs.uk
4
Medicines Q&As
The situation may be further complicated by the use of alternative equations to estimate GFR such as
the CKD-EPI equation or the use of equations incorporating cystatin-C (22,34).
In a study comparing 3 equations for estimating GFR in patients undergoing percutaneous coronary
intervention (PCI), there was considerable discrepancy in the classification of patients into stages of
CKD. The equations used were C&G, CKD-EPI and MDRD. Equation choice affected drug-dosing
recommendations for antiplatelet and antithrombotic agents, with the formulas agreeing for only 34%
of patients with a GFR of <30mL/min/1.73m2 (as estimated by at least one equation). The authors
comment that the eGFR equation selected to determine drug dosing in the clinic ideally would be
identical to the equation used in the drug’s original pharmacokinetic study; although many
pharmacokinetic studies have used the C&G equation there is no standard approach (35). For new
drugs most studies are designed and performed by the manufacturer therefore the manufacturer's
dosage in RI recommendations should be followed. A study comparing secondary sources of
prescribing information for patients with RI found a considerable degree of variability amongst the
definitions and recommendations in four different standard sources (36,37).
It is also worth noting that historically, there has been substantial variability in serum creatinine values
reported by different clinical laboratory creatinine measurement methods. Consequently, the results of
pharmacokinetic studies on which this dosing information was based, were dependent upon the
particular method for measuring serum creatinine used in a given study (9,26). However it is not
possible or practical to repeat all the studies using a standardised creatinine measurement method.
The estimated GFR based on current standardised creatinine assays is likely to lead to different
dosage recommendations from those intended by the original study, even if the same estimating
equation is used, because of the change in analytical methodology (9,21).
In addition the level of RI is often defined differently among the pharmacokinetic studies and each
category (‘mild’, ‘moderate’, ‘severe’) often encompasses a broad range of kidney function. The drug
dosage adjustment recommendations that use broad ranges of kidney function may not be optimal for
all patients whose kidney function lies within the specified range, especially for drugs that have a
narrow therapeutic index (9).
For these reasons clinical judgement should be used alongside any estimates derived from equations
(21).
Acute Kidney Injury
Patients with acute kidney injury (AKI) will often develop multiorgan dysfunction syndrome or
multisystem organ failure. When dosing patients with AKI, these and other factors - rapidly fluctuating
levels of renal function, changes in volume status and the effects of renal replacement therapy (RRT)
- need to be considered in addition to those discussed above(9). Dosage adjustment should be
guided by clinical judgement and monitoring, in addition to published guidance which may be based
on older studies in CKD patients or patients on RRT. Refer to Q&A168.7. Volume status will affect the
size of the loading dose of water-soluble antimicrobials (see above under 'Distribution'). For
subsequent doses, the dose or dose interval is adjusted according to whether the antimicrobial effect
is concentration- or time- dependent or both concentration- and time-dependent (12,38) (please refer
to Blot et al. (12), Keller et al. (38) and Fissell (39) for a discussion of the pharmacodynamics and
pharmacokinetics of antimicrobials in RI, AKI and renal replacement therapy[RRT]).
Summary


The absorption, distribution, metabolism and excretion of drugs can be affected by renal
impairment (RI) to varying degrees. Generally, changes in drug absorption and bioavailability
are unlikely to be a clinically significant problem for most drugs, but the effect of CKD on
intestinal cytochrome P 450 metabolic enzymes and transporters may lead to an increase in
bioavailability of some orally administered drugs in patients with RI. Changes to drug
distribution (protein binding and Vd) are more likely to be an issue in 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. Renal excretion of a drug is
dependent on GFR and when renal function is impaired, clearance of the drug is decreased
Available through NICE Evidence Search at www.evidence.nhs.uk
5
Medicines Q&As











and the plasma half-life prolonged. The excretion of some drugs that are mainly eliminated in
the urine by active tubular secretion is also reduced in RI. 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.
Single doses are not thought to need adjustment as accumulation is unlikely.
Use plasma concentration measurements to adjust dose wherever possible and monitor the
patient carefully for evidence of clinical effectiveness and toxicity of drugs
The vast majority of published drug dosing in RI information is based on Cockcroft & Gault
(C&G) estimation of creatinine clearance (CrCl). However it has been replaced in clinical
practice by the Modification of Diet in Renal Disease trial (MDRD) and the Chronic Kidney
Disease Epidemiology Collaboration (CKD-EPI) equations for estimating GFR
Although these equations are not interchangeable, the British National Formulary advises
that for most drugs and for most patients (over 18 years and of average build and height)
dosage adjustment based on the eGFR is acceptable
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)(10). If using
C&G for these patients it may be necessary to base the calculation on ideal body weight or
adjusted body weight.
Where an accurate GFR is considered necessary e.g. in chemotherapy dosing, an isotope
GFR determination should be performed.
Published data on drug dosage adjustment in RI include mainly case reports and
pharmacokinetic studies in small numbers of subjects. They are also subject to variability in
serum creatinine assays performed by different clinical laboratory creatinine measurement
methods.
The eGFR equation selected to determine drug dosing in practice ideally would be identical to
the equation used in the drug’s original pharmacokinetic study. But although many
pharmacokinetic studies have used the C&G equation there is no standard approach. The
manufacturer's SPC will often provide guidance on dosing in RI, especially for new drugs.
When dosing patients with AKI – multisystem organ failure, rapidly fluctuating levels of renal
function, changes in volume status and the effects of renal replacement therapy (RRT) - need
to be considered in addition to those factors discussed above
Clinical judgement should be used alongside any estimates derived from equations.
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
latest BNF, BNF for children, SPC and specialist sources of information (40).
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) Sexton J. Drug use and dosing in the renally impaired adult. Pharmaceutical Journal 2003; 271:
744-746.
(4) 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
(5) Brater DC. Drug dosing in patients with impaired renal function. Clin Pharmacol Ther 2009; 86:
483-9
(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. 4th Edition 2014. Radcliffe Publishing Ltd.
Available through NICE Evidence Search at www.evidence.nhs.uk
6
Medicines Q&As
p. xiii – xvi
(8) Churchwell MD, Mueller BA. Selected pharmacokinetic issues in patients with chronic kidney
disease. Blood Purif 2007;25: 133-38
(9) Matzke GR et al. Drug dosing consideration in patients with acute and chronic kidney disease – a
clinical update from Kidney Disease: Improving Global Outcomes (KDIGO). Kidney International
2011; 80: 1122-37
(10) Joint Formulary Committee. British National Formulary. November 2015. London: BMJ Group
and Pharmaceutical Press; 2015, Prescribing in renal impairment.
http://www.evidence.nhs.uk/formulary/bnf/current Accessed 03/12/15
(11) Naud J et al. Current understanding of drug disposition in kidney disease. J Clin Pharmacol
2012;52: 10S-22S
(12) Blot SI et al. The effect of pathophysiology on pharmacokinetics in the critically ill patient –
concepts appraised by the example of antimicrobial agents. Adv. Drug Delivery Rev 2014; 77: 3-11
(13) Wills S, Badiani A, Power J. Southampton Medicines Advice Service. Medicines Learning Portal.
Clinical topics. Medicines and the kidney. Last updated: Sunday, July 12, 2015. Accessed via:
http://www.medicineslearningportal.org/2015/07/medicines-and-kidneys.html on 02.12.15.
(14) Vilay AM et al. Clinical review: Drug metabolism and nonrenal clearance in acute kidney injury.
Critical Care 2008; 2008;12:235
(15) Nolin T. Altered nonrenal drug clearance in ESRD. Curr Opin Nephrol Hypertens 2008; 17:555-9
(16) Lalande L et al. Consequences of renal failure on non-renal clearance of drugs. Clin
Pharmacokin 2014 53: 521-32
(17) MSD Summary of Product Characteristics JANUVIA 25mg, 50mg, 100mg film-coated
tablets. DORT 28th January 2016 . Accessed via
http://www.medicines.org.uk/emc/medicine/19609/SPC/JANUVIA+25mg%2c+50mg%2c+10
0mg+film-coated+tablets/ on 18.2.16
(18) 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
(19) Nolin TD et al. Optimizing drug development and use in patients with kidney disease. J Clin
Pharmacol 2011;51: 628- 30
(20) Munar MY, Singh H. Drug dosing adjustments in patients with chronic kidney disease. Am Fam
Physician 2007;75:1487-96
(21) Wills S, Badiani A, Power J. Southampton Medicines Advice Service. Medicines Learning Portal.
Clinical topics. Assessing renal function. Last updated: Sunday, July 12, 2015. Accessed via:
http://www.medicineslearningportal.org/2015/07/assessing-renal-function.html on 02.12.15.
(22) National Institute for Health and Care Excellence. Clinical Guideline. Chronic kidney disease in
adults: assessment and management. 23 July 2014. CG182. Accessed via
http://www.nice.org.uk/guidance/cg182/ on 03.12.15
(23) UK e CKD Guide. Revised January 2009. Renal Association. Available at
http://www.renal.org/whatwedo/InformationResources/CKDeGUIDE.aspx accessed 18.2.16
(24) BMA and NHS Employers. Chronic kidney disease frequently asked questions January 2010.
Accessed via http://www.britishrenal.org/getattachment/CKD-Forum/Clinical-Managment/CKD-FAQs(DH-Jan-2010).pdf.aspx on 18.2.16
(25) Stevens LA et al. Comparison of drug dosing recommendations based on measured GFR and
kidney function estimating equations. Am J Kidney Dis 2009; 54: 33-42
(26) National Institute of Diabetes and Kidney and Digestive Diseases & National Kidney Disease
Education Program. CKD and drug dosing: information for providers. Revised April 2015.
http://www.nkdep.nih.gov/resources/CKD-drug-dosing.shtml#suggested-approach accessed on
16.2.16
(27) Drug Dosing in Obesity Reference Table. Accessed via
http://clincalc.com/Kinetics/ObesityDosing.aspx#AdjustedBW on 22.01.16
(28) Brown DL et al. Functional range of creatinine clearance for renal drug dosing; a practical
solution to the controversy of which weight to use in the Cockcroft-Gault equation. Ann Pharmacother
2013; 47: 1039-44
(29) Denetclaw TH et al. Dofetilide dose calculation errors in elderly associated with use of the
modification of diet in renal disease equation. Ann Pharmacother 2011; 45: e44
Available through NICE Evidence Search at www.evidence.nhs.uk
7
Medicines Q&As
(30) Gill J , Malyuk R , Djurdjev O et al. Use of GFR equations to adjust drug doses in an elderly multiethnic group-a cautionary tale. Nephrol Dial Transplant 2007; 22: 2894-99
(31) Hellden A et al. Development of a computerised decisions support system for renal risk drugs
targeting primary healthcare. BMJ Open 2015; 5: e006775
(32) Cabello-Muriel A et al. Influence of equation used to estimate the renal function in dosage
potentially nephrotoxic drug. Eur J Hosp Pharm 2015; 22:23-27
(33) MacCallum PK, Mathur R, Hull SA et al. Patient safety and estimation of renal function in patients
prescribed new oral anticoagulants for stroke prevention n atrial fibrillation; a cross-sectional study.
BMJ Open 2013;3:e003343. Doi:10.1136/bmjopen-2013-003343
(34) Lamb EJ, Stevens PE, Deeks JJ. What is the best glomerular filtration marker to identify people
with chronic kidney disease most likely to have poor outcomes? BMJ 2015;350:g7667 (Published 12
January 2015) Accessed via http://www.bmj.com/content/350/bmj.g7667 on 03.12.15
(35) Parsh J et al. choice of estimated glomerular filtration rate equation impacts drug-dosing
recommendations and risk stratification in patients with chronic kidney disease undergoing
percutaneous coronary interventions. J Am Coll Cardiol 2015; 65: 2714–23
(36) 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
(37) Mehta DK et al. Dose adjustment in renal impairment. Brit Med J 2005; 331: 291-4
(38) Keller F et al. Pharmacokinetic and pharmacodynamic considerations of antimicrobial drug
therapy in cancer patients with kidney dysfunction. World J Nephrol 2015; 4: 330-44
(39) Fissell WH. Antimicrobial dosing in acute renal replacement. Adv Chron Kidn Dis 2013; 20:85-93
(40) Rodieux F et al. Effect of kidney function on drug kinetics and dosing in neonates, infants, and
children. Clin Pharmacokinet (2015) 54:1183–1204
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
18th February 2016
Checked by
Trevor Beswick, Director, South West Medicines Information and Training
Date of check
30th March 2016
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 2013-2015]. Date of Search 03.12.15
 Medline : exp *RENAL INSUFFICIENCY + [exp *DRUG ADMINISTRATION SCHEDULE or
exp *PHARMACOKINETICS] [Limit to: Publication Year 2014-2015]. Date of search 02.10.15
and PubMed 04.12.15
 In-house drug dosing in renal failure database and resources 04.12.15
 Internet Search (Google; REVIEW and PHARMACOKINETICS and KIDNEY FAILURE)
04.12.15
 NHS Evidence(KIDNEY FAILURE and [PHARMACOKINETICS or DRUG
ADMINISTRATION]) 04.12.15
Available through NICE Evidence Search at www.evidence.nhs.uk
8