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Journal of Infusion Nursing
The Art and Science of Infusion Nursing
The Art and Science of Infusion Nursing
patient's level of kidney function and monitoring for
toxicities. Understanding mechanisms through which
the pharmacokinetics of medications are altered by kid-
ney disease, the common drug classes that require renal
drug dose adjustments, and the use of equations used to
estimate a patient's kidney function is necessary for
evaluating the need for renal drug dosing.
 PHARMACOKINETICS
 Pharmacokinetics, or how the body processes a medica-
tion, typically is described by the absorption, distribu-
tion, metabolism, and elimination of a medication. The
degree of absorption of a medication is provided in drug
references as the bioavailability. Bioavailability is the
percentage of a medication that reaches systemic circu-
lation without being altered. Medications given through
the IV route have 100% bioavailability. Medications
administered by other routes, including topically and
orally, typically have less than 100% bioavailability. For
instance, for topical lidocaine patches, absorption is
approximately 3%. 3 Alendronate, an oral bisphospho-
nate commonly prescribed for osteoporosis, has a bio-
availability of 0.6%. 3
 The distribution of a medication in the body is often
represented by the volume of distribution. The volume
of distribution is a hypothetical value calculated by
dividing the amount of a medication given by the con-
centration of the medication in the bloodstream. 4
Medications with large volumes of distribution move
out of the bloodstream and into tissue. Medications
with smaller volumes of distribution are retained in
higher concentrations in the bloodstream. For instance,
the volume of distribution of tigecycline is large at 7 to
9 L/kg, indicating that the drug largely distributes into
tissues. 5 In comparison, the volume of distribution of
gentamicin, a drug that distributes primarily into extra-
cellular fluid, is 0.2 to 0.3 L/kg. 3
 Metabolism describes how medications are broken
down or altered in the body. The liver is commonly
involved in metabolizing medications. However, other
organs, such as the kidneys, as well as enzymes located
in the bloodstream or tissues, may break down medica-
tions. The metabolites, or products formed through
metabolic pathways, may be inactive or have therapeu-
tic effects.
 Author Affiliation: University of Utah College of Pharmacy,
University of Utah Hospital, Salt Lake City, Utah.
 Heather A. Nyman, PharmD, BCPS, is an assistant clinical profes-
sor of pharmacotherapy at the University of Utah College of
Pharmacy and a clinical pharmacist in Adult Acute Internal
Medicine at the University of Utah Hospitals and Clinics in Salt
Lake City, Utah.
 The author has no conflicts of interest to disclose.
 Corresponding Author: Heather A. Nyman, PharmD, BCPS, assis-
tant professor, clinical, University of Utah College of Pharmacy, and
clinical pharmacist, University of Utah Hospital, 30 South 2000
East, Room 4769, Salt Lake City, UT 84112 ( heather.nyman@hsc.
utah.edu ).
 ABSTRACT
 In patients with diminished kidney function, the
pharmacokinetics of many medications are
altered. Alterations in absorption, distribution, and
metabolism are observed in addition to altered
elimination through the kidney. Classes of intrave-
nous medications in which dose modifications are
frequently required for patients with diminished
kidney function include antibiotics, some anticoag-
ulants, and chemotherapy agents. Failure to follow
renal dose adjustment recommendations can lead
to an increased risk of toxicity. Equations fre-
quently used to estimate kidney function for the
purpose of making renal dose adjustments include
the Cockcroft-Gault, Modification of Diet in Renal
Disease (MDRD), and Chronic Kidney Disease
Epidemiology Collaboration (CKD-EPI) equations.
 Key words:  Cockcroft-Gault ,  dose adjustment ,
 kidney ,  kidney disease ,  medication ,  pharmacoki-
netics ,  renal
 Renal Dosing in High-Risk Populations
 Heather A.  Nyman ,  PharmD, BCPS
 DOI: 10.1097/NAN.0000000000000102
 A
n estimated 23 million Americans have
chronic kidney disease, and each year
many additional patients in acute settings
experience acute kidney injury. 1 , 2 Patients
with chronic or acute impairments in kid-
ney function are at risk of adverse outcomes if medica-
tion doses are not adjusted appropriately based on their
level of kidney function. In addition, some intravenous
(IV) medications can be toxic to the kidneys.
 Infusion nurses play a role in assessing the appropri-
ateness of the dosing of IV medications, based on a
Copyright (c) 2015 Infusion Nurses Society. Unauthorized reproduction of this article is prohibited.

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VOLUME 38  |  NUMBER 3  |  MAY/JUNE 2015
Copyright (c) 2015 Infusion Nurses Society 211
bound to albumin. In severe kidney disease, phenytoin
has decreased protein binding. 8 This leads to an increase
in the fraction of phenytoin not bound to proteins, and
a new equilibrium is established in the bloodstream
where free concentrations of phenytoin remain similar
but the total concentrations are decreased. Because total
phenytoin concentrations are often measured in clinical
practice and used to adjust the phenytoin dose, this
must be taken into account when interpreting total
serum phenytoin concentrations and making dose
adjustments in patients with severe kidney disease.
 Metabolism can be altered in patients with kidney
dysfunction. Alterations in hepatic metabolism in both
acute kidney injury and chronic kidney disease have
been demonstrated. 9 , 10 Research is under way to eluci-
date the mechanisms through which this occurs. The
kidneys also metabolize some medications. For these
medications, as kidney function declines, so generally
does the kidney's metabolic function.
 Diminished elimination of renally cleared medica-
tions requires dose adjustment to avoid toxicities associ-
ated with supratherapeutic drug concentrations. In
addition, elevated concentrations of active metabolites
can result in toxicity. Meperidine, midazolam, and mor-
phine are hepatically metabolized medications that have
renally eliminated active metabolites. Normeperidine,
an active metabolite of meperidine, can accumulate in
kidney dysfunction and cause anxiety, tremors, or sei-
zures. 3 Hydroxymidazolam, the active metabolite of
midazolam, can cause prolonged sedation in patients
with kidney failure. 3 Morphine-6-glucoronide, an active
metabolite of morphine, has been implicated in causing
central nervous system depression. 11-13
 CLASSES OF MEDICATIONS THAT
REQUIRE DOSE ADJUSTMENT IN
DIMINISHED KIDNEY FUNCTION
 Many medications require dose adjustment in patients
with kidney dysfunction. Broad classes of agents that
may require renal dose adjustment and are often given
via IV infusion are antibiotics, anticoagulants, and
chemotherapy agents.
 Antibiotics
 A majority of antibiotics require dose adjustment in
patients with kidney dysfunction. For this reason, it's
easier to think of the antibiotics that do not require dose
adjustment than it is to list the many antibiotics that do
( Table 1 ). For antibiotics that require dose adjustments
in kidney dysfunction, recommendations may be to
extend the dosing interval, reduce the dose, or both. For
example, with daptomycin, the recommendation is for
patients with a creatinine clearance (CrCl)  < 30 mL/min
 Elimination describes the methods through which the
medication and, often, metabolites are excreted from
the body. Common methods of elimination are in the
urine or bile.
 IMPACT OF KIDNEY
DYSFUNCTION ON
PHARMACOKINETICS OF
MEDICATIONS
 The impact of kidney dysfunction on the elimination of
medications excreted in the urine is the most widely
appreciated alteration in pharmacokinetics seen in kid-
ney disease. However, kidney dysfunction can also have
an impact on the absorption, distribution, and metabo-
lism of medications. Recently, investigators reviewed
data submitted to the US Food and Drug Administration
between 2003 and 2007 for new oral medications. 6
They found that of the medications that were eliminated
from the body through nonrenal pathways and had
pharmacokinetic data available in patients with kidney
disease, 57% had increased exposure in patients with
kidney dysfunction, and 26% had such significant
increase in exposure that dosage adjustments were rec-
ommended in kidney disease. This demonstrates that
the pharmacokinetics of medications not cleared by the
kidneys can be altered in patients with kidney disease.
 Oral absorption may be altered in chronic kidney
disease for a variety of reasons. Delayed gastric empty-
ing is frequently encountered in patients with kidney
disease; this does not affect the total amount of a drug
absorbed, but it may delay the time to achieve peak
drug concentrations. Altered gastric pH, drug interac-
tions (particularly the result of drug adsorption to phos-
phate binders), and bowel edema associated with vol-
ume overload states may decrease absorption of some
oral medications. In addition, decreased gut activity of
some metabolic enzymes has been described and may
lead to increased absorption of other medications. 7
 Distribution of drugs may also be altered in chronic
kidney disease as the result of changes in protein and
tissue binding, as well as changes in total body water.
Acidic medications are primarily bound to albumin in
the bloodstream. In general, acidic drugs have decreased
protein binding in advanced kidney disease. This can
result in increased concentrations of free drug and
therefore increased distribution out of the bloodstream.
Potential causes for decreased protein binding of acidic
drugs include uremic toxins competing for binding sites
on albumin, conformational changes in albumin in kid-
ney failure that affects protein binding, and low albu-
min levels that are commonly seen in patients with
kidney disease. 8
 Phenytoin is the classic example of a drug with
altered protein binding in kidney disease. It is highly
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Journal of Infusion Nursing
fluconazole, an antifungal agent. Another antifungal
agent, amphotericin B, does not require renal dose
adjustment but can cause direct toxicity to the kidney.
For this reason, routine monitoring of kidney function
during amphotericin B therapy is recommended. In addi-
tion, acyclovir and foscarnet may cause nephrotoxicity
through deposition of crystals in the kidney. Maintaining
adequate hydration during therapy with these agents
and monitoring kidney function are recommended.
 Anticoagulants
 Anticoagulants that require dose adjustment for reduced
kidney function include the low-molecular-weight hep-
arins (eg, enoxaparin), glycoprotein IIb/IIIa agents used
with non-ST segment elevation myocardial infarction
(NSTEMI) or around percutaneous coronary interven-
tions (eg, tirofiban and eptifibatide), and some of the
IV-direct thrombin inhibitors (eg, bivalirudin and lepir-
udin), which can be used in patients with heparin-
induced thrombocytopenia. Fondaparinux use is con-
traindicated when CrCl is  < 30 mL/min. 3 Notably,
heparin and argatroban do not require renal dose
adjustment. 3
 Anticoagulants are considered high-risk drugs
because of their potential to cause severe bleeding if
dosed too high. Studies have found that when glycopro-
tein IIb/IIIa inhibitors in NSTEMI are not appropriately
dose-reduced for kidney dysfunction, there is an associ-
ated increased risk of bleeding. 16 , 17 Therefore, confirm-
ing that anticoagulants are dosed appropriately in
patients with kidney dysfunction is critical. Monitoring
the appropriate coagulation parameter during therapy
with anticoagulants is also important. For instance, an
anti-Xa level can be monitored to verify that doses of
low-molecular-weight heparins are appropriate, and
activated partial thromboplastin time (aPTT) is fol-
lowed to adjust dosing of the direct thrombin inhibitors.
 Chemotherapy
 Cisplatin, carboplatin, capecitabine, methotrexate,
oxaliplatin, and etoposide are commonly used antineo-
plastics that require dose adjustment in patients with
kidney function impairment. 3 , 18 Dose reductions of
vinorelbine, docetaxel, cyclophosphamide, and irinote-
can have been recommended in patients with CrCl  < 10
mL/min or in those requiring hemodialysis. 18
 Other Medications
 Other medications that may be administered by IV infu-
sion and require renal dose adjustments include raniti-
dine, famotidine, cimetidine, and metoclopramide; all
are agents commonly used to treat gastrointestinal
conditions. Bisphosphonates are not recommended or
to reduce the dosing frequency from dosing once a day
to dosing every 48 hours. 14 In contrast, with ceftaroline,
the dosing recommendation is to maintain the every-12-
hours dosing frequency as kidney function declines but
to reduce the dose given if the CrCl is 50 mL/min or
less. 15 Levofloxacin is a medication with which both the
dose and frequency may need to be adjusted. The rec-
ommended dosing of levofloxacin to treat community-
acquired pneumonia is 500 mg IV once a day in a
patient with CrCl  >= 50 mL/min. For patients receiving
hemodialysis, the recommended dose of levofloxacin to
treat pneumonia is 500 mg IV times 1 dose followed by
250 mg IV every 48 hours. 3 For antibiotics with renal
dose adjustments, evaluating kidney function before
drug initiation is necessary to ensure that dosing is
appropriate for the patient's level of kidney function.
 Many antibiotics also have the potential to cause
acute kidney injury through either direct toxicity to the
kidney (eg, aminoglycosides and colistin) or through
rare, idiosyncratic adverse events such as acute intersti-
tial nephritis, which can be seen with a wide range of
antibiotics. Monitoring serum creatinine (SCr) levels
during prolonged therapy with these types of agents is
recommended to detect toxicity to the kidney.
 Some antivirals and antifungal agents also require
renal dose adjustments. IV antivirals that require dose
adjustments are acyclovir, foscarnet, and ganciclovir.
Renal dose adjustments are recommended for
 TABLE 1
 Intravenous Antibiotics
That Do Not Require
Renal Dose
Adjustment
-  Azithromycin
-  Ceftriaxone
-  Clindamycin
-  Cloxacillin
-  Doxycycline
-  Erythromycin
-  Linezolid
-  Metronidazole
-  Moxifloxacin
-  Nafcillin
-  Oxacillin
-  Quinupristin/dalfopristin
-  Rifampin
-  Tigecycline
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VOLUME 38  |  NUMBER 3  |  MAY/JUNE 2015
Copyright (c) 2015 Infusion Nurses Society 213
 The MDRD and CKD-EPI equations provide esti-
mates of glomerular filtration. These equations were
developed to assist in diagnosing and classifying kidney
disease. The primary difference in the performance of
the equations is that the CKD-EPI equation is more
accurate than the MDRD equation at glomerular filtra-
tion rates (GFRs) greater than 60 mL/min/1.73 m 2 . 25
The majority of laboratories follow the recommenda-
tions from kidney organizations to report an estimated
GFR whenever a SCr is ordered in adults to facilitate
recognition of chronic kidney disease. 23 , 27
 Because MDRD- or CKD-EPI-estimated GFR values
are readily available to many clinicians, it would be
convenient to use the equations for drug dosing. If these
equations are used, however, important issues to con-
sider are the limited data evaluating the impact of using
them for drug dosing, the difference in units between
the MDRD and CKD-EPI equations and most drug dos-
ing recommendations, and the limited data on the accu-
racy of the MDRD and CKD-EPI equations in the
elderly. 27
 The MDRD and CKD-EPI equations provide esti-
mates of kidney function in units of milliliters per min-
ute per 1.73 m 2 . This provides an estimate of kidney
function normalized to an average body surface area of
1.73 m 2 . These are units that are most convenient for
diagnosing and staging kidney disease. Most drug dos-
ing recommendations, however, are provided in units of
milliliters per minute. It is recommended that if using
the MDRD or CKD-EPI equations for drug dosing, that
these estimates be converted to units of milliliters per
minute for patients who have a body surface area sig-
nificantly different from the average value of
1.73 m 2 . 25   Table 2 provides the equation to do this. The
convenience of using these automatically reported val-
ues for drug dosing is partially offset by the added step
are contraindicated in patients with a CrCl  < 30 to
35 mL/min. 19 IV-administered bisphosphonates (eg,
pamidronate, zoledronic acid, ibandronate) rarely have
been associated with acute kidney injury. 20 For these
reasons, checking an SCr before bisphosphonate drug
infusion is recommended. 3
 EQUATIONS USED FOR RENAL
DOSE ADJUSTMENTS OF
MEDICATIONS
 As discussed, determining a patient's kidney function is
necessary to renally dose many IV medications and to
monitor for nephrotoxicity during therapy with some
medications. Three equations are commonly used in
clinical practice to estimate kidney function in adults:
the Cockcroft-Gault (CG); Modification of Diet in
Renal Disease, or MDRD; and Chronic Kidney Disease
Epidemiology Collaboration, CKD-EPI equations. 21-23
The Schwartz equation is used for pediatric patients. 24
 All of the equations commonly used in clinical prac-
tice to estimate a patient's kidney function are based on
the SCr. Creatinine in the bloodstream comes from the
metabolism of creatine in muscle and dietary meat
intake. It typically is released into the bloodstream at a
relatively constant rate. It is cleared exclusively by the
kidneys and is easily measured in blood, making it a
convenient marker to use to estimate kidney function.
However, creatinine production is directly influenced
by an individual patient's muscle mass and dietary pro-
tein intake. 25 Patient-specific factors that influence a
patient's SCr that are accounted for in the estimating
equations include age and gender and, in the CKD-EPI
and MDRD equations, race. 25 Other patient-specific
conditions that affect muscle mass, and therefore creati-
nine generation, that are not accounted for in these
equations include conditions such as amputation, para-
plegia or quadriplegia, vegan diet, or muscle-wasting
disease. 25
 The CG equation has been used for decades. Most
drug dose-adjustment recommendations are based on
CrCl, the estimate that is provided by the CG equation.
There is a lack of consensus regarding what weight to
use when calculating a CG CrCl in obese patients. Using
total body weight can result in a gross overestimate of
an obese patient's kidney function. For this reason,
many clinicians use ideal body weight, adjusted body
weight, or lean body weight rather than total body
weight. As demonstrated in the example in  Figure 1 , the
weight used in the CG equation for obese patients has a
dramatic impact on the calculated estimate of kidney
function. Based on the data available, it appears at this
time that the lean body weight provides the most accu-
rate estimate of the CrCl for obese patients with a BMI
 > 40. 26
 FIGURE 1  Clinical scenario: impact of weight used in Cockcroft-Gault
equation on estimation of kidney function.  Abbreviations: SCr, serum
creatinine; eCrCl, estimated creatinine clearance using the Cockcroft-
Gault equation . Units: weight in kilograms. Adjusted body weight (kg)  =
ideal body weight  + 0.4  x (actual body weight   ideal body weight);
lean body weight for males (kg)  = (9270  x total weight)/(6680  + 216  +
body mass index) where body mass index is in units of kilograms per
meter squared; lean body weight for females (kg)  = (9270  x total body
weight) / (8780  + 244  + body mass index), where body mass index is in
units of kilograms per meter squared; ideal body weight for males (kg)
 = 50 kg  + 2.3 kg for each inch over 5 feet; ideal body weight for
females (kg)  = 45.5 kg  + 2.3 kg for each inch over 5 feet.
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Copyright (c) 2015 Infusion Nurses Society
Journal of Infusion Nursing
risks of potentially under- or overdosing, and the toxic-
ity and characteristics of the drug in question.
 In addition, there are patient populations in which all
creatinine-based equations, including the CG, MDRD,
and CKD-EPI, would not be expected to perform well.
These include patients with very large or very small
muscle mass; patients with severe malnutrition, obesity,
severe liver disease, skeletal muscle disease that alters
muscle mass, paraplegia, or quadriplegia; patients on a
strict vegetarian diet; those who are pregnant; or those
in whom the SCr is not stable. 25 Options for estimating
kidney function in these patients are primarily to obtain
a measured CrCl or make decisions about drug dosing
based on a careful assessment of the risks of under- or
overtreating in the particular clinical situation.
 Cystatin C-Based Equations to Estimate
Kidney Function
 Cystatin C is a protein produced by all nucleated cells
in the body. New equations to estimate kidney function
have been developed based on serum concentrations of
cystatin C. 23 Cystatin C-based estimates of kidney func-
tion have been found to better predict adverse clinical
outcomes than SCr-based estimates. 23 However, the role
of these equations in routine patient care and for drug
dosing has not been determined.
 CONCLUSION
 In patients with diminished kidney function, alterations
in absorption, distribution, and metabolism are observed
in addition to decreased excretion of renally eliminated
medications. Many medications require renal dose
adjustments to avoid supratherapeutic drug levels and
subsequent toxicities.
 Classes of IV-administered medications that may
require renal dose adjustment include antibiotics, chem-
otherapeutic agents, and anticoagulants. Making the
appropriate dose adjustment is critical for avoiding
under- and overtreatment. The CG equation historically
has been the equation most commonly used to calculate
an estimate of a patient's kidney function in order to
dose-adjust medications with recommended renal dose
adjustments.
 The MDRD and CKD-EPI equations are newer equa-
tions that were developed primarily to assist with diag-
nosing and staging kidney disease. Because of the ubiq-
uitous reporting of estimates of kidney function using
these equations, it's convenient to use them for drug
dosing. On the basis of the limited data currently avail-
able, this seems reasonable for many medications.
However, for medications with significant toxicities-
such as anticoagulants-and in patients with obesity or
for those who are elderly, where there are limited data
of converting the reported value to units of milliliters
per minute.
 There are limited data on the impact of using MDRD
and CKD-EPI equations for drug dosing. The largest
study to date compared the CG equation with the
MDRD equation for drug dosing. The study found that
CG-based drug dosing agreed with MDRD-based drug
dosing for 13 renally adjusted medications 88% to 89%
of the time, depending on the weight used in the CG
equation. 28 On the basis of these data, it may be reason-
able to use MDRD for drug dosing. Because the CKD-
EPI equation would be expected to perform similarly to
the MDRD equation at lower levels of kidney function
where drug dose adjustments are typically made, use of
the CKD-EPI equation may also be reasonable.
Important caveats for the use of these equations for
drug dosing, however, are that there are limited data on
the performance of the equations in elderly or obese
patients. 27 In these patients, using the CG equation may
be most appropriate.
 When using any kidney function estimating equation
to dose medications, it's important to consider that the
equations provide estimates only. In 1 study that high-
lights this concept, researchers found that the MDRD
equation provided an estimate of kidney function that
was   30% from a patient's actual GFR only 83% of
the time. 29 In the same study, the CG equation provided
an estimate of kidney function that was within 30% of
the measured GFR 69% of the time. 29 The limited preci-
sion of the estimating equations in individual patients
underscores the need to take into account the clinical
scenario in addition to the estimate of kidney function
when determining a drug-dosing regimen. Patient- and
situation-specific factors that may be considered when
determining if more or less aggressive therapy is war-
ranted include the severity of the patient's illness, the
 TABLE 2
 Equation for
Converting MDRD or
CKD-EPI Equations to
Units of Milliliters per
Minute for Use in
Drug Dosing 25
 eGFR (mL/min)  = eGFR (mL/min/1.73m 2 )  x body surface area
1.73 m2
 Abbreviations: MDRD, modification of diet in renal disease; CKD-EPI, Chronic
Kidney Disease Epidemiology Collaboration. Units: body surface area in meters
squared.
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VOLUME 38  |  NUMBER 3  |  MAY/JUNE 2015
Copyright (c) 2015 Infusion Nurses Society 215
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