MANAGING CHRONIC KIDNEY DISEASE CLINICAL REVIEW

Considerations and controversies in managing chronic

kidney disease: An update

Lalita Prasad-Reddy, Pharm.D.,

M.S., BCPS, BCACP, CDE, Chicago
State University, Chicago, IL, and Rush
University Medical Center, Chicago, IL.
Diana Isaacs, Pharm.D., BCPS, BC-
ADM, CDE, Cleveland Clinic Diabetes
Center, Cleveland, OH.
Alexander Kantorovich, Pharm.D.,
BCPS, Chicago State University College
of Pharmacy, Chicago, IL, and Advocate
Christ Medical Center, Oak Lawn, IL.
Purpose. Current considerations and controversies surrounding the man-
agement of chronic kidney disease (CKD) are reviewed.
Summary. Patients diagnosed with CKD require a unique clinical ap-
proach to prevent medication toxicities and ensure appropriate manage-
ment of disease-progressing comorbidities, and they require attention to
commonly occurring complications that may affect disease control and
impact quality of life, including anemia and CKD–bone–mineral disorder
(CKD-BMD). Many CKD-related comorbidities put patients at increased
cardiovascular risk, including diabetes, hypertension, and hyperlipidemia.
Although there are clinical guidelines to help clinicians manage CKD and
its related complications and comorbidities, there are many clinical con-
troversies surrounding optimal treatment. Recent literature and clinical
studies bring into question multiple controversies regarding the optimal
management approach to the patient living with CKD, including the ap-
propriateness of iron and erythropoiesis-stimulating agents (ESAs) for the
treatment of anemia and vitamin D supplementation for the prevention of
CKD-BMD. While available guidelines can provide clinicians with guidance
regarding the appropriate management of the patient with CKD, they of-
ten differ dramatically in the optimal approach to the management of co-
morbidities and complications. For a patient with CKD, the pharmacist has
an important role to ensure optimal outcomes, by appropriately managing
comorbid conditions and optimizing drug dosing.

Conclusion. Multiple controversies regarding the optimal management

of patients with CKD, including the appropriateness of iron and ESAs for
treatment of anemia and vitamin D supplementation for the prevention of
CKD-BMD. Available guidelines differ dramatically in the optimal approach
to the management of comorbidities and complications.

Keywords: chronic kidney disease, cinacalcet, erythropoietin, hyperten-

sion, phosphate binders, vitamin D

Am J Health-Syst Pharm. 2017; 74:795-810

In the United States, chronic kid-

Address correspondence to Dr. Prasad-
Reddy (lprasad@csu.edu).
Copyright © 2017, American Society of
Health-System Pharmacists, Inc. All rights
reserved. 1079-2082/17/0601-0795.
DOI 10.2146/ajhp160559
ney disease (CKD) remains the
eighth leading cause of death. With
new cases of diabetes mellitus and
hypertension—the two primary eti-
ologies of CKD—growing at alarming
rates, the number of diagnoses of CKD
continues to grow.1,2 An estimated
20% of the population has CKD at
various stages of severity, and more
than 100,000 individuals progress to
end-stage renal disease (ESRD) each
year.2 Individuals with CKD have an
increased risk of morbidity and mor-
tality, regardless of disease stage3 and
of CKD-related complications that
may affect quality of life. Therefore,
careful attention to disease-specific
considerations is important. Patients
with CKD also have disease-related
complications that often make dis-
ease management more challenging
and can affect quality of life, including
anemia, bone disorders, and metabol-
ic abnormalities. Caring for patients
with CKD can be complex and chal-

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 CLINICAL REVIEW
lenging; therefore, maximizing the
therapeutic efficacy of medications,
minimizing toxicities, and limiting
disease progression are essential. This
article reviews controversies in the
treatment of CKD, including manage-
ment of common comorbidities.
Background of current
guidelines for CKD
management
An interprofessional approach
is often used to successfully man-
age CKD. In addition to the knowl-
edge and skills of each team member,
guidelines are available to help di-
rect care. Kidney Disease: Improving
Global Outcomes (KDIGO) is a global
organization dedicated to developing
and implementing evidence-based
clinical practice guidelines in kidney
disease. The KDIGO guidelines are
composed of 9 installments published
between 2008 and 2013.4 In addition,
the National Kidney Foundation Kid-
ney Disease Outcomes Quality Initia-
tive (KDOQI) provides clinicians with
guidance for patients with all stages
of CKD and related complications.
Specific installments of the KDOQI
were published over a span of a de-
cade, from 2002 to 2012.5 A number of
commentaries are available from the
National Kidney Foundation on each
specific segment of the KDIGO guide-
lines, as most were published after
the issuance of KDOQI clinical state-
ments. Although both organizations
provide clinical guidance on the diag-
nosis, evaluation, common comorbid
conditions, associated CKD compli-
cations, and disease management,
KDIGO guidelines have largely super-
seded KDOQI guidelines, as newer
evidence has emerged on the optimal
treatment of anemia, hypertension,
and bone–mineral disorder (BMD) in
patients with CKD. The guidelines also
include staging information based on
glomerular filtration rate (GFR) and
albuminuria, which can be found in
Table 1.6 Staging of CKD is useful be-
cause it identifies patients who have
a higher risk of disease progression
and disease complications. As a result,
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MANAGING CHRONIC KIDNEY DISEASE
KEY POINTS
• The pharmacist has a pivotal
role in the management of pa-
tients with chronic kidney dis-
ease (CKD), including patient
education; management of
clinical interventions to optimize
blood pressure, glucose, and
cholesterol management to
slow progression of CKD; and
prevention of CKD-related clini-
cal manifestations.
• Anemia, one of the most com-
mon and troubling complica-
tions of CKD, requires a multi-
modal approach to treatment to
improve outcomes in patients.
• CKD–bone-mineral disorder
is a complex disorder with a
multitude of factors contributing
to a diverse clinical presenta-
tion, and practitioners should
be aware of optimal treatment
approaches to prevent the
clinical consequences of renal
osteodystrophy.
management of patients is individual-
ized based on CKD stage to avoid fur-
ther patient deterioration.
Diabetes mellitus
Diabetes is the leading cause of
CKD, and the prevalence of diabetes
in patients with CKD and the general
population continues to increase.1,2
Over time, hyperglycemia results in
vascular target organ damage, includ-
ing diabetic kidney disease (DKD). The
initial manifestation of DKD is persis-
tent albuminuria in patients with type
1 diabetes; albuminuria is a marker
for DKD in patients with type 2 diabe-
tes.7 Intensive treatment of hypergly-
cemia prevents an increased urinary
albumin-to-creatinine ratio (UACR)
(defined as 30–299 mg/g) and reduces
progression to persistent and severely
increased albuminuria (UACR of ≥300
| NUMBER 11 | JUNE 1, 2017
mg/g).7,8 Glucose goals for patients
with diabetes and CKD are generally
the same as those for patients with di-
abetes without CKD, with the Ameri-
can Diabetes Association, KDOQI, and
KDIGO recommending a glycosylated
hemoglobin (HbA1c) goal value of <7%
for most patients.7-9 These organiza-
tions advocate a patient-centered
approach, adjusting the HbA1c goal
for patient-specific factors. Because
many patients with CKD have multi-
ple comorbidities and are predisposed
to polypharmacy, a higher HbA1c goal
value may be justified to minimize ad-
verse effects and mitigate the dangers
of hypoglycemia.7
However, HbA1c may not be an
accurate marker in patients with ad-
vanced CKD due to multiple con-
founding factors. Of note, HbA1c value
is influenced by the lifespan of red
blood cells (RBCs). The normal life-
span of an RBC is 120 days, but this
may be reduced by 20–50% in pa-
tients with advanced CKD, especially
in those receiving hemodialysis.10 Ad-
vanced CKD, especially cases that re-
quire dialysis, contribute a falsely low
HbA1c value. Patients with CKD are
also prone to iron deficiency anemia,
which can cause a falsely high HbA1c
value, which usually decreases after
iron treatment. If the patient’s HbA1c
value does not correlate well with
blood glucose concentration readings,
glycated albumin may be a more use-
ful measurement.10 The glycated albu-
min value provides an average range of
glucose control from the previous 2–3
weeks. Although the glycated albumin
value provides a snapshot of glucose
control over a shorter time frame than
the average 3-months provided by the
HbA1c value, the glycated albumin val-
ue may be more useful since it is not
affected by RBC turnover or albumin
concentrations.10 Strong correlations
between blood glucose and glycated
albumin values have been observed
in patients with stages 4 and 5 CKD,
including those on dialysis. However,
there is no clear consensus on the op-
timal concentration of glycated albu-
min, and there is a lack of standardiza-
 MANAGING CHRONIC KIDNEY DISEASE
tion on how to interpret the numbers
in terms of glycemic control.10
Overall, the lowering of blood glu-
cose levels is associated with delaying
the onset and progression of urinary
albumin excretion, GFR decline, and
the need for dialysis.7,8 Although low-
ering blood glucose levels prevents the
progression of albuminuria—a car-
diovascular risk factor—a reduction
in albuminuria through blood glucose
lowering has not been directly linked
to improved cardiovascular outcomes
in clinical trials.8 In addition to lower-
ing blood glucose levels, guidelines
suggest the use of an angiotensin-
converting enzyme inhibitor (ACEI) or
angiotensin-receptor blocker (ARB) in
normotensive patients with diabetes
and albuminuria to prevent further
kidney damage.7,8 In patients with
type 1 diabetes and an elevated UACR
(30–299 mg/g), ACEIs have been
shown to reduce progression to per-
sistent albuminuria (≥300 mg/g) and
prevent further decline of estimated
GFR (eGFR).11,12 The use of an ARB ver-
sus placebo resulted in a 16–20% risk
reduction in worsening serum cre-
atinine, the development of ESRD, or
death from any cause in patients with
type 2 diabetes.11,12 However, there is
no strong evidence for the use of these
agents in normotensive patients with-
out albuminuria; therefore, use in this
population is not recommended.
Some evidence suggests that
achieving strict glycemic control may
actually increase cardiovascular events
and all-cause mortality in patients
with CKD.13 The risks of severe hypo-
glycemia and death increase with de-
clining kidney function.1 One reason
for this increase is that the half-life
of insulin is prolonged as renal func-
tion declines.11 An analysis of the Ac-
tion to Control Cardiovascular Risk in
Diabetes (ACCORD) trial compared
outcomes between patients with (n =
3,636) and without (n = 6,506) CKD.14
Risk for the primary outcome, the
composite of the first occurrence of
nonfatal myocardial infarction, non-
fatal stroke, or cardiovascular death,
was significantly higher in patients
Table 1. Staging of Chronic Kidney Disease by GFR and Albuminuriaa
Variable
GFR (mL/min/1.73 m2)
≥90
60–89
45–59
30–44
15–29
<15 or dialysis
Albumin excretion rate (mg/24
hr) or albumin:creatinine ratio
(mg/g)
<30
30–299
≥300
GFR = glomerular filtration rate.
a
with CKD (hazard ratio [HR], 1.87; 95%
confidence interval [CI], 1.65–2.11).
Intensive blood glucose lowering
(HbA1c goal of <6%; mean HbA1c, 6.7%)
in patients with CKD was associated
with a 31% higher risk for all-cause
mortality (p = 0.01) when compared
with standard blood glucose control
(HbA1c goal of 7–7.9%; mean HbA1c,
7.5%).
The first-line agent for blood glu-
cose lowering in patients with type 2
diabetes is metformin due to its prov-
en safety and efficacy.7 Previously, the
Food and Drug Administration (FDA)
advised that metformin should not be
used in patients with a serum creati-
nine concentration exceeding 1.4 mg/
dL (in women) or 1.5 mg/dL (in men)
due to the theoretical risk of lactic aci-
dosis. In reality, rates of metformin-
associated lactic acidosis are extreme-
ly low.1 In April 2016, after reviewing
the literature on actual cases of lactic
acidosis, FDA required label changes
to remove this contraindication and
allow for the expanded use of metfor-
min in patients with impaired renal
function.15 KDIGO guidelines suggest
reducing the metformin dose to 1,000
mg/day when the eGFR is less than 45
AM J HEALTH-SYST PHARM |
CLINICAL REVIEW
Category Description
G1 Normal or high
G2 Mildly decreased
G3a Mildly to moderately decreased
G3b Moderately to severely
decreased
G4 Severely decreased
G5 Kidney failure
A1 Normal to mildly increased
A2 Moderately increased
A3 Severely increased
mL/min/1.73 m2 and discontinuing
metformin when the eGFR is less than
30 mL/min/1.73 m2.1
Sulfonylureas and meglitinides
also may predispose patients to hy-
poglycemia since the drugs’ activ-
ity is prolonged with reduced kidney
function.8 If a sulfonylurea is used,
glipizide is preferred due to its short
half-life and lack of active metabolites.
Thiazolidinediones are metabolized
by the liver and can be used safely in
patients with CKD, though patients
must be cautious of possible fluid re-
tention. The dipeptidyl peptididase-4
inhibitors, glucagon-like pepetide-1
receptor agonists, and α-glucosidase
inhibitors are other second-line
agents that can be used, but many
have renal thresholds requiring dose
reductions or cessation beyond a cer-
tain eGFR.8 Sodium–glucose cotrans-
porter 2 inhibitors, also second-line
agents, prevent renal sodium and glu-
cose reabsorption from the proximal
renal tubules. Due to their mechanism
of action, these agents should not be
used in patients with an eGFR of <45
mL/min/1.73 m2 because they lose ef-
fectiveness in this setting.16,17 Insulin
may be the safest choice for patients
VOLUME 74 | NUMBER 11 | JUNE 1, 2017 797
 CLINICAL REVIEW
with severe CKD. Although there are
no dose adjustments recommended
for the use of insulin in this popula-
tion, there is a higher risk of hypo-
glycemia due to reduced renal clear-
ance; as a result, all CKD patients with
diabetes require careful monitoring of
blood glucose levels with gradual in-
sulin dose adjustments.7,8
Hypertension
Hypertension remains the second
most common etiology of CKD, and
CKD itself can lead to hypertension. In
addition, hypertension is a cardiovas-
cular risk factor and associated with an
increased risk of ESRD.18 Patients with
CKD generally have a more difficult
time achieving blood pressure con-
trol and often need multiple agents
to reach blood pressure targets.9 His-
torically, the blood pressure goal for
all patients with CKD was less than
130/80 mm Hg.19 However, KDIGO
updated the goal in 2012 to less than
140/90 mm Hg in patients without
albuminuria, and the Eighth Joint Na-
tional Committee–appointed panel
has endorsed the updated KDIGO
2012 target of <140/90 mm Hg.9,19,20
The blood pressure goal increased be-
cause there was a lack of randomized,
controlled trials supporting the lower
goal, which had been based mostly
on observational studies. Lower goals
(<120/80 mm Hg) have demonstrated
benefits in CKD progression but have
led to worsening cardiovascular out-
comes. The exception is that KDIGO
and KDOQI continue to recommend
a blood pressure goal of <130/80 mm
Hg in patients with albuminuria based
on improved kidney outcomes in this
population.9
A systematic review of random-
ized controlled trials was conducted
to determine optimal blood pressure
control on cardiovascular outcomes in
patients with CKD.21 It included three
landmark trials totaling 2,272 partici-
pants. The results of the trials did not
show that a blood pressure goal of
<130/80 mm Hg improved outcomes
compared with a goal of <140/90 mm
Hg. The exception was for patients
798 AM J HEALTH-SYST PHARM | VOLUME 74
MANAGING CHRONIC KIDNEY DISEASE
with albuminuria (urine albumin con-
centration of >300 to 1,000 mg/day).
Participants in the more-intensive-
control group required more anti-
hypertensive medications and had
slightly higher rates of adverse effects.
The reduction in cardiovascular out-
comes supports the lower blood pres-
sure goal in patients with albumin-
uria, though more clinical trial data
are needed, as the number of CKD
patients included in these trials was
relatively small.
The release of the Systolic Blood
Pressure Intervention Trial (SPRINT)
may further affect future hypertension
guidelines and bring the ideal blood
pressure goal again into question.22
In this trial, 9,361 participants were
randomly assigned to a systolic blood
pressure goal of <140 mm Hg (stan-
dard) versus a systolic blood pressure
goal of <120 mm Hg (intensive). The
trial was stopped early after a median
follow-up of 3.26 years, because the
primary outcome including myocar-
dial infarction, other acute coronary
syndromes, stroke, heart failure, or
death from cardiovascular causes was
25% lower in the intensive group.
While this provides support for a low-
er goal and may influence future hy-
pertension guidelines, its application
in CKD is not fully known since pa-
tients with proteinuria or an eGFR of
<20 mL/min/1.73 m2 were excluded.
Preferred agents for treating hy-
pertension in patients with CKD
and albuminuria include ACEIs
and ARBs. These agents work on
the renin–angiotensin–aldosterone sys-
tem (RAAS) and cause vasodilation of
the efferent glomerular arterioles, re-
sulting in decreased intraglomerular
pressure and reduced urine albumin
excretion.9 KDIGO guidelines do not
recommend any specific antihyper-
tensive in patients with CKD without
albuminuria.9 ACEIs and ARBs are
generally considered equally effec-
tive, though ARBs pose a lesser risk
of dry cough.9 When using ACEIs or
ARBs, it is important to monitor se-
rum creatinine and potassium lev-
els.20 Serum creatinine levels often
| NUMBER 11 | JUNE 1, 2017
increase after the initiation of therapy,
with an increase of up to 30% consid-
ered clinically acceptable. ACEIs and
ARBs should be avoided in individu-
als with bilateral renal artery stenosis
and used cautiously in patients with
fluid depletion.9 ACEIs and ARBs also
present the risk of angioedema. In 7
head-to-head trials, this risk was 2.2
times higher with ACEIs versus ARBs.
A meta-analysis that included 74,857
patients treated with an ACEI revealed
a 0.3% rate of angioedema. The ARB
group included 35,479 patients with a
0.11% rate of angioedema compared
with 0.07% with placebo.23
Patients with CKD often require 2
or more agents to control hyperten-
sion.9,20 There has been much discus-
sion of combining ACEIs and ARBs to
slow the progression of CKD. Further,
smaller clinical trials found a reduc-
tion in albuminuria with this combina-
tion. The Ongoing Telmisartan Alone
and in combination with Ramipril
Global Endpoint Trial (ONTARGET)
was a randomized controlled trial
comparing the ARB telmisartan in
combination with the ACEI ramipril
to telmisartan or ramipril alone.24
The trial included 25,620 patients
and found no differences in cardio-
vascular endpoints among treatment
groups. However, there were higher
rates of adverse effects, including hy-
potension, syncope, hyperkalemia,
and renal dysfunction, in the group
receiving combination therapy.20 Al-
though the total number of patients
with CKD in the trial was small, the
combination of telmisartan and
ramipril is not recommended at this
time due to the overall lack of proven
benefit and concerns about hyperka-
lemia and renal dysfunction in CKD
patients. A better approach is to use
the maximum tolerated dose of either
an ACEI or ARB.9,24
The direct renin inhibitors also af-
fect the RAAS and reduce plasma re-
nin activity; however, when combined
with an ACEI or ARB, higher rates of
hyperkalemia and hypotension have
been observed. Therefore, FDA advis-
es against this combination, and there
 MANAGING CHRONIC KIDNEY DISEASE
is limited evidence to support the use
of direct renin inhibitors in CKD.9
ACEIs or ARBs can be combined
safely and effectively with other first-
line antihypertensives, including di-
uretics and calcium channel blockers,
for the treatment of essential hyper-
tension. Clinicians must be cognizant,
however, that thiazide diuretics lose
effectiveness in patients with stage
4 or 5 CKD, for whom a loop diuretic
may be substituted. Loop diuretics
are especially effective if there is con-
comitant edema.9 ACEIs or ARBs can
also be combined with β-blockers, es-
pecially in patients who have strong
indications for their use, such as heart
failure.20 Other second-line agents in-
cluding α-blockers, vasodilators, and
centrally acting α-agonists may need
to be added for resistant hyperten-
sion.9,20 Aldosterone antagonists may
have some benefit on urine albumin
excretion but can potentiate the risk of
hyperkalemia, especially when com-
bined with ACEIs or ARBs. This risk
is further increased when the eGFR
is low; therefore, they should be used
very cautiously in patients with CKD
and are contraindicated when the
eGFR is less than 30 mL/min.9
Hyperlipidemia
Lipid abnormalities are common
in patients with CKD, though the type
of abnormalities often vary depend-
ing on category of CKD.25 The goal of
treatment is to reduce the occurrence
of atherosclerosis and cardiovascular
events. However, evidence that treat-
ing hyperlipidemia improves renal
outcomes is lacking.26 KDIGO and
KDOQI guidelines recommend treat-
ing most patients with CKD over age
50 years with a statin or statin in com-
bination with ezetimibe, with the ex-
ception of those on dialysis.8,26 Statins
are also recommended for patients
under age 50 years who have known
coronary disease, diabetes, stroke, or a
10-year cardiovascular risk of >10%.26
This is slightly different than the
2013 American College of Cardiology/
America Heart Association treatment
of blood cholesterol guideline, which
does not specify treatment for CKD
but recommends a statin as first-
line for individuals age 40–75 years
with a cardiovascular risk exceeding
7.5%.27
A meta-analysis including 80 ran-
domized trials and 51,099 participants
with CKD compared the effects of
statins versus placebo or no treatment.
The investigators concluded that
there was moderate- to high-quality
evidence that statins significantly re-
duced all-cause mortality (relative risk
[RR], 0.81; 95% CI, 0.74–0.88), cardio-
vascular mortality (RR, 0.78; 95% CI,
0.68–0.89), and cardiovascular events
(RR, 0.76; 95% CI, 0.73–0.80) in pa-
tients with CKD not on dialysis. Statins
had little to no effect on mortality and
cardiovascular events for patients re-
ceiving dialysis.28
The Study of Heart and Renal Pro-
tection (SHARP) trial was a double-
blind randomized trial that included
9,270 patients with CKD.29 Of those,
3,023 were on dialysis. Patients were
randomly assigned to simvastatin
20 mg plus ezetimibe 10 mg daily
versus matching placebo. The pri-
mary outcome was first major ath-
erosclerotic event. The group treated
with simvastatin–ezetimibe had a
17% reduction in major atheroscle-
rotic events (11.3%) versus placebo
(13.4%) over a median follow-up time
of 4.9 years. There were fewer events
in patients on dialysis who received
simvastatin–ezetimibe than in pa-
tients receiving placebo; however, the
subgroup analysis did not reach sta-
tistical significance.29 When a patient’s
eGFR is less than 30 mL/min/1.73 m2,
it is thought that cardiovascular risk is
caused by vascular stiffness and calci-
fication, structural heart disease, and
sympathetic overactivity. Due to mal-
nutrition, these patients often have
low or normal levels of low-density-
lipoprotein (LDL) cholesterol, and
LDL cholesterol–lowering therapy
may not be as effective in dialysis
patients.29 Therefore, it is not recom-
mended to initiate statins in dialysis
patients, though guidelines suggest
the option to continue statin therapy
AM J HEALTH-SYST PHARM | VOLUME 74
CLINICAL REVIEW
in patients initiated on them before
they started dialysis.25,26
Patients with CKD are often at
higher risk of adverse effects due to
polypharmacy and reduced renal
clearance. Guidelines recommend try-
ing to achieve target doses of statins
used during clinical trials,26 which are
usually of moderate or high inten-
sity.27 However, dose reductions are
often needed in patients with CKD
due to adverse effects such as my-
opathy. Combining statins with ezeti-
mibe may reduce adverse effects, but
ezetimibe monotherapy is not recom-
mended due to a lack of evidence on
cardiovascular outcomes when used
without a concurrent statin. It is also
not recommended to combine statins
with fibrates due to an increased risk
of myopathy and rhabdomyolysis.26,27
There is less evidence to support
other cholesterol-lowering medica-
tions (e.g., niacin, bile acid seques-
trants) in patients with CKD, though
fish oil may be added to a statin or to
the combination of statin and ezeti-
mibe if hypertriglyceridemia is pres-
ent. Renal dosing adjustments are not
required in patients with CKD.27 Table
2 includes treatment goals, preferred
agents, and dose adjustments for the
treatment of diabetes, hypertension,
and hyperlipidemia in patients with
CKD.1,7,8,20,27
Anemia in CKD
Anemia is one of the most common
and troubling complications of CKD.
It is twice as common in patients with
CKD compared with those without
CKD, and the prevalence of anemia
rises as a patient’s disease progresses
(8.4% at stage 1 to 53.4% at stage 5).30
Anemia, as a manifestation of CKD,
leads to higher rates of morbidity and
mortality as well as increased health-
care costs.30
The World Health Organization
(WHO) defines anemia as a blood he-
moglobin concentration of <13 g/dL
in men and postmenopausal women
and of <12 g/dL in women of child-
bearing age.31 KDIGO guidelines mir-
ror the WHO definition of anemia for
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AM J HEALTH-SYST PHARM |

Table 2. Treatment of Type 2 Diabetes, Hypertension, and Hyperlipidemia in CKD1,7,8,20,27,a

Condition and Therapeutic Goals
Type 2 diabetes
• HbA1c goal: ~7%, may be increased
due to risk of hypoglycemia
• FBG goal: 80–130 mg/dL
• Postprandial goal: <180 mg/dL
VOLUME 74
Preferred Agents
• Metformin as first-line therapy if eGFR
>45 mL/min
• Second-line agents include the
following, which do not require
renal dose adjustments: DPP4
Comments
• Reduce dose of metformin with eGFR <45 mL/min to 1,000 mg/day and stop when eGFR
<30 mL/min
• SGLT2 inhibitors are an option if eGFR >45 mL/min
• Greater risk of hypoglycemia with insulin and insulin secretagogue (sulfonylureas,
meglitinides) when renal function is impaired

inhibitors (linagliptin), GLP-1 RAs • Avoid α-glucosidase inhibitors when SCr is >2 mg/dL or CLcr is <25 mL/min
(dulaglutide, liraglutide, albiglutide),
TZDs (pioglitazone, rosiglitazone),
sulfonylureas (glipizide), insulin
| NUMBER 11

Hypertension
• BP goal: <140/90 mm Hg (general • ACEIs and ARBs preferred. • Lack of evidence to support ACEI–ARB combination
CKD) • ACEIs and ARBs can be combined • Thiazides ineffective when CLcr is <30 mL/min
• BP goal: <130/80 mm Hg (albuminuria) safely with other first-line agents
(thiazides, CCBs)
|

Hyperlipidemia
JUNE 1, 2017

• No specific lipid targets
• Reduce morbidity and mortality
from atherosclerosis
• Statin or statin–ezetimibe combination;
fish oil for high triglycerides
• Lack of evidence to use
pharmacotherapy in dialysis patients
• If possible, prescribe statin doses used in clinical trials (moderate or high intensity)
• May need to reduce dose as renal function declines to avoid adverse effects
• Statin dosing recommendations for severe renal impairment:
• Atorvastatin: no dose adjustments
• Fluvastatin: no dose adjustments, doses >40 mg daily not studied
• Lovastatin: CLcr of <30 mL/min: use with caution and carefully consider doses >20

MANAGING CHRONIC KIDNEY DISEASE

mg/day
• Pitavastatin: CLcr of 15–60 mL/min (not receiving hemodialysis): initial: 1 mg once
daily; maximum: 2 mg once daily
ESRD: Initial: 1 mg once daily; maximum: 2 mg once daily
• Pravastatin: severe impairment: initial: 10 mg once daily
• Rosuvastatin: CLcr of <30 mL/min: initial: 5 mg once daily; maximum: 10 mg/day
• Simvastatin: CLcr of <30 mL/min: initial: 5 mg daily with close monitoring
a
CKD = chronic kidney disease, HbA1c = glycosylated hemoglobin, FBG = fasting blood glucose, eGFR = estimated glomerular filtration rate, DPP4 = dipeptidyl peptidase-4, GLP-1 RA = glucagon-like
pepetide-1 receptor agonist, TZD = thiazolidinedione, SGLT2 = sodium–glucose cotransporter 2, SCr = serum creatinine, CLcr = creatinine clearance, BP = blood pressure, ACEI = angiotensin-converting
enzyme inhibitor, ARB = angiotensin receptor blocker, CCB = calcium channel blocker, ESRD = end-stage renal disease.
 MANAGING CHRONIC KIDNEY DISEASE
patients with CKD.4 As anemia is such
an important marker in CKD patients,
hemoglobin monitoring through
routine venipuncture should be per-
formed at least annually in all patients
with CKD and more frequently in later
stages of the disease.4,5 A diagnosis of
CKD-induced anemia is made when
the hemoglobin concentration mea-
sures below the specified cutoffs and
only after a full anemia evaluation to
exclude other causes of anemia such
as folate or vitamin B12 deficiency, oc-
cult bleeding, or iron deficiency has
occurred. In addition to hemoglobin
levels, other monitoring should in-
clude serum iron, total iron-binding
capacity to calculate transferrin satu-
ration, ferritin, vitamin B12, folate, a
complete blood count, RBC indices,
and reticulocyte count.31 Monitoring
of circulating erythropoietin levels
has not proven useful in patients with
renal disease; therefore, such moni-
toring should not be performed.31,32
Reticulocyte counts, whose monitor-
ing is important in patients with sus-
pected CKD-induced anemia, should
be interpreted cautiously, as low val-
ues are present in patients not only
with CKD but other chronic diseases
and illnesses. When all other causes
of anemia are excluded including iron
deficiency and hematologic abnor-
malities, anemia secondary to CKD
can be diagnosed.
Anemia in CKD often presents as
a low hemoglobin concentration
with a normal mean corpuscular
volume (normocytic) with hypo-
proliferative properties. 32 Patients
with CKD-induced anemia will often
have iron deficiency, though it is not
uncommon to have normal iron and
transferrin saturation percentages
before CKD diagnosis.32
The pathogenesis of CKD-induced
anemia is multifactorial, involving
multiple organ systems, physical
blood loss, and deficiencies in he-
moglobin building blocks, such as
iron.31,32 The largest contributor to
anemia in CKD is likely erythropoietin
deficiency. Erythropoietin, a hormone
produced primarily in the kidneys,
acts on erythroid progenitor cells to
increase RBC production, leading to
augmentation of oxygen delivery.33
The production of erythropoietin
declines as GFR decreases and CKD
progresses, predisposing patients to
higher rates of anemia as their disease
progresses.31
Iron deficiency is common in CKD
patients. A true deficiency of iron can
be present or functional deficiency
can occur, in which patients cannot
use intrinsic iron stores for erythro-
poiesis. Patients with functional iron
deficiency often have low transferrin
saturation values, correlating to lower
concentrations of transportable iron,
with high ferritin levels signifying ad-
equate iron stores. The assessment of
ferritin, however, must be done cau-
tiously, as it also functions as an acute-
phase reactant. Blood loss contributes
significantly to anemia, especially in
patients on hemodialysis. Blood loss is
common secondary to frequent blood
draws, sequestration of blood in he-
modialysis circuits, and altered plate-
let functioning due to uremia. Uremia
has also been shown to directly reduce
erythropoiesis.34
Other factors contributing to ane-
mia in CKD include shortened RBC
lifespans, inflammation, and elevated
hepcidin concentrations. Hepcidin, a
Table 3. Comparison of Iron Agents
Agent Availability
I.V. formulation
Ferric carboxymaltose Prescription
Ferric gluconate Prescription
Ferumoxytol Prescription
Iron dextran Prescription
Iron sucrose Prescription
Oral formulation
Ferrous fumarate Nonprescription
Ferrous gluconate Nonprescription
Ferrous sulfate Nonprescription
Polysaccharide iron Nonprescription
AM J HEALTH-SYST PHARM | VOLUME 74
CLINICAL REVIEW
hormone produced in the liver, regu-
lates gastrointestinal iron absorp-
tion as well as iron recycling. In CKD,
hepcidin levels become elevated in
response to reduced renal clearance.34
When elevated, iron absorption and
recycling are inhibited, leading to
reductions in erythropoiesis.31,32 Al-
though there are no pharmacologic
agents currently approved in the
United States targeting the excess of
hepcidin in patients with CKD, hep-
cidin antagonists are being developed
and studied and may become a facet
of CKD-induced anemia treatment in
the future.
Management of anemia in CKD is
often bimodal, consisting of iron re-
placement, exogenous erythropoiesis-
stimulating agent (ESA) administra-
tion, or both.4 Currently, multiple oral
and i.v. iron formulations are available
(Table 3). Oral iron is efficacious, safe,
easy to administer, and less expensive
than i.v. formulations but causes ad-
verse gastrointestinal effects and re-
quires administration twice or thrice
daily.4 Further, oral iron formulations
interact with multiple drugs. These
interactions include reduced iron ab-
sorption with tetracycline antibiotics
as well as agents that reduce gastric
pH (e.g., proton pump inhibitors)
and agents to which iron binds and
Elemental Test Dose
Iron Content Required?
50 mg/mL No
12.5 mg/mL No
30 mg/mL No
50 mg/mL Yes
20 mg/mL No
33% No
12% No
20% No
100% No
| NUMBER 11 | JUNE 1, 2017 801
 CLINICAL REVIEW
thereby reduces their absorption (e.g.,
fluoroquinolones, levothyroxine, le-
vodopa).4 Staggering the timing of ad-
ministration of such drugs is one way
to avoid these interactions; however,
multiple medication administration
times may become burdensome and
reduce patient adherence to already-
complex CKD medication regimens.
Clinical studies have shed light
on the efficacy of oral iron in raising
hemoglobin levels.35,36 Although oral
iron increases hemoglobin levels, the
time to increase these values is much
longer compared with i.v. formula-
tions.36 In contrast to i.v. formula-
tions, oral iron has not been shown
to reduce the need for transfusions;
however, the use of i.v. formulations
increases the patient’s risk of infec-
tion.37 In a meta-analysis comparing
oral and i.v. iron supplementation in
both hemodialysis-dependent and
nonhemodialysis-dependent patients
with CKD, a significant increase in he-
moglobin concentration was observed
in hemodialysis patients using i.v. iron
(mean increase of 0.83 g/dL).38 There
was also a significant benefit found
in the nonhemodialysis-dependent
CKD population, but its clinical sig-
nificance is likely negligible due to the
resulting small increase in hemoglo-
bin concentration (mean increase of
0.31 g/dL). One of the main reasons
for the benefit observed with i.v. iron
in hemodialysis-dependent patients
was due to the bypass of hepcidin in
the gastrointestinal tract, making the
full dose of iron bioavailable. As a re-
sult of this meta-analysis as well as
other clinical trials, KDIGO guidelines
recommend oral iron as an option for
nonhemodialysis-dependent patients
with CKD, including those receiving
peritoneal dialysis; for patients receiv-
ing hemodialysis, the recommenda-
tion to use i.v. iron is strong.4 Prac-
titioners should attempt to use oral
iron in nonhemodialysis patients with
CKD for the first-line treatment of iron
deficiency, but in situations where oral
therapy is not tolerated, drug interac-
tions lead to burdensome medication
administration times, or anemia is
802 AM J HEALTH-SYST PHARM | VOLUME 74
MANAGING CHRONIC KIDNEY DISEASE
very severe, i.v. iron can be considered
as a first-line treatment. Other consid-
erations for i.v. iron use should include
the risk of infection, i.v. access, previ-
ous response to oral or i.v. iron ther-
apy, adverse effects of prior treatment
with iron, patient adherence, and cost.
The risk factors for infection with i.v.
iron in hemodialysis-dependent pa-
tients include higher serum ferritin
levels, use of iron sucrose, and main-
tenance dosing (discussed below).39
These risk factors need to be further
refined, as conflicting studies have
been published examining their util-
ity. It is important to note that the rate
of infection with i.v. iron, though con-
cerning, is low. Other adverse effects
of i.v. iron therapy are more likely to
manifest, such as flushing, hypoten-
sion, and iron overload.
Another area of controversy re-
garding the use of iron in patients with
CKD is administration technique.
Maintenance (iron administered at
set intervals) versus repletion (iron
administered only when iron levels
are low) strategies have been used in
clinical practice, but no guidance ex-
ists regarding which administration
technique is preferred, as no ran-
domized clinical trials have directly
compared the two strategies.4,5 The
results of a retrospective study sug-
gests maintenance iron supplemen-
tation may result in fewer infections
when compared with repletion dos-
ing, particularly among patients with
a dialysis catheter.40 It is likely too early
to completely abandon the repletion
dosing technique, but further pro-
spective studies should be conducted
to assess whether this strategy should
be avoided.
The use of exogenous ESAs in con-
junction with iron has changed the
management of CKD-induced ane-
mia since the introduction of these
agents in the early 1990s. Two agents
are predominantly used, epoetin alfa
and darbepoetin, with differences
exhibited in pharmacokinetic and
pharmacodynamic profiles, half-lives,
and erythropoietin receptor–binding
capabilities.31,41,42 These agents have
| NUMBER 11 | JUNE 1, 2017
similar adverse-effect profiles and
boxed warnings, including increased
risk of thromboembolic complica-
tions, uncontrolled hypertension, and
shortened overall survival in cancer
patients, leading to a risk evaluation
and mitigation strategy for use in that
patient population.41,42
One of the largest clinical con-
troversies surrounding ESA use in
CKD-induced anemia was target he-
moglobin levels. Studies have shed
light on target hemoglobin values and
changed clinical practice, but guide-
lines have not yet been updated to
reflect the results of these studies.4,5
ESAs are utilized only when other
causes of anemia have been excluded,
the risks (e.g., stroke, hypertension,
vascular access loss) and benefits (e.g.,
decreased need for transfusions, im-
provement in anemia-related symp-
toms) are carefully weighed against
each other, and the patient exhibits
specific hemoglobin concentrations.
The Normal Hematocrit Study
(NHS), a randomized, prospective,
open-label trial, compared the attain-
ment of hemoglobin concentration
targets of 10 g/dL (low hemoglobin
group) or 14 g/dL (normal hemoglo-
bin group) in hemodialysis patients
with coexisting heart failure or coro-
nary artery disease.43 The composite
primary endpoint of all-cause mortal-
ity or first nonfatal myocardial infarc-
tion was investigated. The study was
stopped early due to safety concerns
seen in the normal hemoglobin group.
Although the primary endpoint was
not significant in this interim analy-
sis (RR, 1.3; 95% CI, 0.9–1.9), a 7% in-
crease in mortality rate in the normal
hemoglobin group was observed. The
final trial results revealed a significant
difference in the primary endpoint
in patients assigned to the normal
hemoglobin group (RR, 1.28; 95% CI,
1.06–1.56).44
The Correction of Anemia with
Epoetin Alfa in Chronic Kidney Dis-
ease (CHOIR) study, which was set up
similarly to the NHS, compared non-
dialysis-dependent patients with CKD
not previously treated with ESAs who
 MANAGING CHRONIC KIDNEY DISEASE
were randomized to receive epoetin
alfa treatment adjusted hemoglobin
goals of 11.3 or 13.5 g/dL.45 The primary
endpoint was the composite of death,
myocardial infarction, hospitalization
for congestive heart failure (without re-
nal replacement therapy), and stroke.
There was a significant increase in risk
of a major cardiovascular event to those
in the group with the higher hemoglo-
bin target (HR, 1.34; 95% CI, 1.03–1.74;
p = 0.03), and no benefits were seen in
quality of life. There was also a signifi-
cantly higher risk of congestive heart
failure found in the group with the
higher hemoglobin goal (11.2% versus
7.4%, p = 0.02).45
The Trial of Darbepoetin Alfa in
Type 2 Diabetes and Chronic Kidney
Disease (TREAT) was a randomized,
double-blind, placebo-controlled trial
that enrolled nondialysis-dependent
CKD patients with type 2 diabetes
and baseline hemoglobin concentra-
tions of ≤11 g/dL.46 The primary ef-
ficacy outcome was the time to the
composite of death from any cause,
nonfatal myocardial infarction, con-
gestive heart failure, stroke, or hos-
pitalization for myocardial ischemia.
The darbepoetin group received treat-
ment to reach a target hemoglobin
concentration of 13 g/dL, while pa-
tients in the placebo group received
rescue darbepoetin alfa only when
their hemoglobin concentration
dropped below 9 g/dL. Once the he-
moglobin concentration reached 9.0
g/dL, darbepoetin was stopped and
placebo reinitiated. The trial found no
significant difference between groups
in the primary efficacy endpoint. The
darbepoetin group had lower rates of
transfusions but significantly more
strokes and only modest improve-
ments in patient-reported fatigue.46
The composite of these three
landmark trials in addition to obser-
vational studies evaluating hemo-
globin goals led FDA to issue a drug
safety communication on the use of
ESAs and hemoglobin concentration
goals in 2011.47 Currently, FDA recom-
mendations include initiation of ESA
treatment in dialysis patients only
when the hemoglobin concentration
drops below 10 g/dL and reduction
of ESA dosage or discontinuation of
therapy if hemoglobin concentration
approaches 11 g/dL. For nondialysis-
dependent patients, FDA recom-
mends initiating ESA treatment when
the hemoglobin concentration drops
below 10 g/dL, keeping in mind 2 ad-
ditional considerations.47 The first
consideration is that the rate of hemo-
globin concentration decline without
ESA use will likely lead to a transfu-
sion. Transfusions in patients with
CKD should be avoided, as some pa-
tients will progress to transplantation
and previous exposure to transfusions
could potentially increase the risk of
rejection.47 Second, the symptoms
associated with the anemia must be
weighed against the adverse effects
associated with ESAs.47 The current
recommendations do not address at
what concentration below 10 g/dL to
initiate ESA therapy or whether to tar-
get a hemoglobin concentration of 10
g/dL or between 10 and 11 g/dL.
Not only does overall hemoglobin
concentration need to be considered
when initiating an ESA, but the rate
of rise in hemoglobin must also be a
consideration. The package inserts of
both ESAs indicate that if the hemo-
globin concentration rises more than
1 g/dL in any 2-week period, the ESA
dose should be reduced by 25%, as
increased rates of cardiovascular ad-
verse events were found in patients
with steeper rises in hemoglobin lev-
els.41,42 Consequently, if the hemoglo-
bin concentration does not increase
by at least 1 g/dL over a 4-week period,
the ESA dose should be increased by
25%. In patients with dose increases
exceeding a total of 300 units/kg/week
of epoetin or 1.5 mg/kg/week of dar-
bepoetin, ESA hyporesponsiveness
should be considered.48 Up to 10%
of patients exhibit ESA hyporespon-
siveness, which can lead to further
increases in morbidity, mortality, and
healthcare costs. The most common
reason for ESA hyporesponsiveness is
iron deficiency.48 Thus, it is important
in ESA-treated patients to maintain
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CLINICAL REVIEW
transferrin saturation at >20% and
a serum ferritin concentration of at
least 200 ng/mL if on hemodialysis or
100 ng/mL if on peritoneal dialysis or
not receiving any dialysis treatment.5
Iron values should be monitored at
least every 3 months in patients with
adequate iron stores. The frequency of
monitoring is shortened to every 1 or 2
months in patients who are just start-
ing ESA therapy, in patients whose
ESA dose has been adjusted, or those
who have been administered iron to
assess repletion.5
Complications of CKD-BMD
Perhaps the most complex clinical
manifestations of CKD are the bone
dyscrasias that result from the inter-
play of alterations in serum phospho-
rus, vitamin D, calcium, and parathy-
roid hormone (PTH). The kidneys are
major regulators in bone homeostasis,
and the term CKD-BMD highlights
the alterations in serum markers that
predispose patients to fracture risk
and increase the potential for vascular
calcification.3 Because the pathogen-
esis of CKD-BMD is complex, prac-
titioners should be aware of when
to screen patients for complications
as well as appropriate target ranges,
monitoring values, and available
treatment options. Current guidelines
recommend monitoring serum PTH,
vitamin D, calcium, and phosphorous
values once the GFR drops below 60
mL/min/1.73 m2, as the clinical con-
sequences of CKD-BMD, which in-
clude adynamic bone disease, osteitis
cytisis fibrosa, and osteomalacia, can
be prevented with appropriate and
timely management.3
Pathogenesis of CKD-BMD.
To gain an appreciation of the avail-
able treatments for CKD-BMD, an
understanding of the pathogenesis
of disease progression that results
in bone dyscrasias is necessary. As
kidney function deteriorates, altera-
tions in the normal homeostasis of
phosphate, vitamin D, calcium, PTH,
and fibroblast growth factor 23 (FGF-
23) result in a clinical cascade caus-
ing bone turnover. The main etiology
| NUMBER 11 | JUNE 1, 2017 803
 CLINICAL REVIEW
of CKD-BMD is increased levels of
PTH, which result in secondary hy-
perparathyroidism related to altera-
tions in the other aforementioned
biomarkers. PTH levels rise early in
the course of CKD and continue to
increase as the disease progresses.49
Typically, the first metabolic abnor-
mality that stimulates PTH secretion
is hyperphosphatemia. When the
GFR drops below 60 mL/min/1.73
m2, the kidneys’ ability to excrete
phosphorus is compromised, and
high serum levels of phosphorus
prevail. The subsequent hyperphos-
phatemia results in a compensatory
increase in the stimulation of PTH,
a direct inhibitory effect on 1-α-
hydroxylase, the enzyme responsible
for activating vitamin D and reduc-
ing serum calcium concentrations.50
Furthermore, in patients with hy-
perphosphatemia, a novel biomarker
(FGF-23) has recently been elucidated
as a contributing factor to the progres-
sion of CKD.51 Evidence suggests that
in patients with CKD, increased levels
of FGF-23 serve as an independent
risk factor for the progression of CKD
and cardiovascular disease and po-
tentially for cardiovascular calcifica-
tion.52-54 In terms of the pathogenesis
of CKD-BMD, FGF-23 is released by
osteocytes and suppresses the 1-α-
hydroxylase enzyme, reducing overall
vitamin D activation and contributing
to the pathogenesis of bone turner.51
The parathyroid gland carries the
calcium-sensing receptor, a receptor
that is receptive to changes in serum
calcium concentrations.55 Sensing the
deficiency in calcium levels, the para-
thyroid gland releases PTH, which
ultimately results in calcium release
from the bony structures, compro-
mising overall bone structure and
integrity, all of which predispose pa-
tients to abnormalities in bone turn-
over and fracture. In addition to these
skeletal abnormalities, alterations in
serum markers such as calcium and
phosphorus can serve as a catalyst to
increase vascular calcification.3 In pa-
tients with CKD, vascular calcification
has been associated with an increased
804 AM J HEALTH-SYST PHARM | VOLUME 74
MANAGING CHRONIC KIDNEY DISEASE
overall risk of cardiovascular events
and mortality.3,56
Hyperphosphatemia. Hyperphos-
phatemia is associated with a com-
pensatory increase in PTH and direct
reduction in 1-α-hydroxylase activity,
which leads to CKD-BMD, and can
also increase the risk of cardiovascu-
lar disease, morbidity, and all-cause
mortality in patients with CKD.57,58
Furthermore, hyperphosphatemia re-
mains the main stimulus for the de-
velopment of vascular calcification,
even more than does hypercalcemia57;
thus, maintaining phosphorous levels
within a normal range must be a pri-
ority. Three treatment modalities can
be utilized to control phosphorous
concentrations in patients with CKD.
These include dietary restriction, the
use of phosphate binders to limit di-
etary absorption of phosphorus, and,
in extreme cases of hyperphosphate-
mia or in those patients with stage 5
CKD, dialysis.3,57 For many patients, a
combination approach of dietary re-
striction and phosphate binders can
effectively manage phosphate levels.
KDIGO guidelines state that phos-
phorous levels should be maintained
within a normal range in patients with
stage 3 or 4 CKD and within a near-
normal range for patients with stage
5 CKD.3 The less-prescriptive recom-
mendations from KDIGO, in contrast
to previous guidelines, are primarily
due to a lack of data that associate a
specific level of phosphorus to im-
proved patient outcomes. Nonethe-
less, phosphorous concentrations
should be monitored in all patients
beginning at stage 3 CKD to prevent
complications.3,59
Treatment of hyperphosphate-
mia. A nonpharmacologic approach
for the management of hyperphos-
phatemia is restriction of dietary
sources of phosphorus. This can be
challenging, as dietary restriction may
result in an overall reduction in pro-
tein calories and weight loss, which
can increase the risk of mortality in
patients with CKD.58 Therefore, pa-
tients should be counseled to limit
their intake of dietary sources of phos-
| NUMBER 11 | JUNE 1, 2017
phorous that are not nutrient dense
in nature, including processed foods,
beer, and sodas.58 Other sources of di-
etary phosphorus include dairy prod-
ucts and meats, but restricting intake
is often a challenge in the typical West-
ern diet. KDIGO guidelines note that
dietary restriction of phosphorus is
often not sufficient to maintain levels
within a normal range in patients with
CKD, especially stage 5 CKD, but can
be used as an adjunct therapy to phos-
phate binders.3
A variety of phosphate binders are
available for use, and little data exist
to suggest that one class is superior in
effectiveness over another in reduc-
ing phosphorous concentrations.3,59,60
A challenge to the use of phosphate
binders is that little evidence supports
the effects of phosphate binders on
overall outcomes (e.g., cardiovascu-
lar mortality), and their use is largely
guided by clinical practice.59,61 There-
fore, agent selection is often guided
by cost, calcium concentrations, drug
interactions, and comorbid conditions.
Regardless of the agent, all binders are
limited by their dosing, as they must be
taken with each meal to work effective-
ly.60 Phosphate binders comprise 50% of
the pill burden for dialysis-dependent
patients; thus, strict adherence to these
agents can be challenging.62
The optimal phosphate binder
would have a low pill burden, effec-
tively decrease phosphorous concen-
trations, avoid drug–drug interac-
tions, and minimize adverse effects
such as gastrointestinal intolerances.
Unfortunately, an optimal agent does
not exist. A variety of agents are avail-
able, and KDIGO guidelines do not
prefer one agent over another, with the
exception of aluminum hydroxide.3 Al-
though an effective binder, accumula-
tion of aluminum can result in osteo-
malacia, adverse neurologic effects,
and adynamic bone disease; thus, its
use should be avoided when possible.3
The exception, however, is that alumi-
num does exhibit phosphate-binding
effects without the presence of food,
so it can be used as an option in pa-
tients who are not taking anything
 MANAGING CHRONIC KIDNEY DISEASE
orally. When used, treatment duration
should be limited.3,59,63 Often, the first
phosphate binder administered is a
calcium-containing agent, presum-
ably due to its efficacy in binding
phosphorus, low cost, and wide avail-
ability. However, the use of calcium-
containing agents, such as calcium
acetate and calcium carbonate, is lim-
ited by their adverse gastrointestinal
effects, drug–drug interactions, and,
most importantly, tendency to in-
crease overall calcium concentrations,
predisposing patients to vascular cal-
cification.3,60 Thus, practitioners must
be vigilant in ensuring normal se-
rum calcium–phosphorous products
by ensuring a calcium–phosphorous
product is <55 mg2/dL2.3 If serum calci-
um concentrations are increasing, the
dose of the calcium-containing agent
should be reduced or an alternative
should be used instead.3
Agents such as lanthanum and
sevelamer provide new options for the
management of hyperphosphatemia
in patients with hypercalcemia and ad-
verse gastrointestinal effects.60 These
agents also may decrease overall mor-
tality in patients with CKD59,60 by re-
ducing cardiovascular risk, though the
likelihood of this reduction requires
further examination.3 Sevelamer ex-
erts its action by exchanging an ion for
phosphate, depending on the formu-
lation, while lanthanum forms insol-
uble complexes with phosphate that
are then passed through the gastro-
intestinal tract.3,60 Sevelamer also has
beneficial effects on the lipid profile,60
which may be promising, as patients
with CKD have an increased base-
line cardiovascular risk. The potential
mechanism through which sevelamer
lowers the lipid profile is the exhibi-
tion of an overall antiinflammatory
effect.64 Overall, both agents appear
to be well tolerated. In clinical trials,
adverse gastrointestinal effects were
most common, though occurred to
a lesser degree when compared with
calcium-containing agents. However,
hypercalcemia occurred to a lesser
extent.3 New agents that are non-
calcium containing may also improve
cardiovascular outcomes, yet that re-
mains to be examined further.3
In the past few years, new iron-
based phosphate binders have been
introduced to the U.S. market. These
iron-based agents form complexes
with phosphorous in the gastroin-
testinal lumen, allowing for disposi-
tion in the feces.65 In 2013, sucroferric
oxyhydroxide was approved for the
management of hyperphosphatemia
in patients with CKD on dialysis.60,66
A clinical conundrum exists regard-
ing whether to use these agents in
patients with CKD, as iron overload
remains one of the potential leading
toxicities of these agents and vigilant
monitoring of iron indices is neces-
sary.61 Conversely, in patients with
CKD, iron-deficiency anemia occurs
as a common comorbidity, so the use
of iron-based phosphate binders may
reduce the need for supplementation
in some patients, though the absorp-
tion would be limited when compared
with other conventional iron supple-
mentation modalities.67 These hy-
potheses need to be examined further
in clinical trials and practice. None-
theless, in clinical trials, these agents
have shown promise when compared
with other currently marketed prod-
ucts. In a randomized double-blind
study, sucroferric oxyhydroxide was
compared with sevelamer carbonate
in dialysis patients with hyperphos-
phatemia.68 After 12 weeks, sucrofer-
ric oxyhydroxide and sevelamer both
reduced phosphorous concentrations,
and sucroferric oxyhydroxide met the
criteria for noninferiority when com-
pared with sevelamer, whose effects
lasted until week 24. To achieve this
serum reduction, a mean of 3 tablets
per day was necessary for sucroferric
oxyhydroxide, while patients treated
with sevelamer received a mean of 8
tablets daily. Greater adherence was
observed with sucroferric oxyhydrox-
ide, as it had a lower pill burden. Be-
cause phosphate binders are such a
major component of the pill burden
for patients with CKD, sucroferric
oxyhydroxide may help to maximize
adherence.
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CLINICAL REVIEW
In a randomized double-blind
study, ferric citrate, the other commer-
cially available iron-based phosphate
binder, was compared with sevelamer
in 200 patients with CKD who were
receiving hemodialysis.69 The primary
outcome of the study was the mean
change in serum phosphate concen-
tration from baseline to 12 weeks. At
the end of the study, patients who
received ferric citrate experienced a
mean reduction of 2.53 mg/dL in se-
rum phosphate concentration, while
those who received sevelamer (varying
doses) experienced a mean reduction
in serum phosphate concentration of
2.40 mg/dL, meeting the criteria of
noninferiority of ferric citrate when
compared with sevelamer. In addi-
tion, iron indices, such as transferrin,
ferritin, and hemoglobin levels, in-
creased with the iron product without
causing iron overload, further sup-
porting the use of iron-based binders
for the management of hyperphos-
phatemia.69 Clinical considerations
for the various phosphate binders are
outlined in Table 4.3,59,60
Vitamin D deficiency. Vitamin
D deficiency is common in the gen-
eral population and even more preva-
lent in patients with CKD.70 The most
prominent role of vitamin D is the
facilitation of calcium absorption to
assist in bone homeostasis through
PTH regulation. In patients with CKD,
a reduction of active vitamin D results
in decreased intestinal calcium ab-
sorption and a compensatory increase
in PTH, further augmenting the risk
for CKD-BMD.3 Beyond this integral
role in bone homeostasis, vitamin D
has also demonstrated the potential
to mitigate cardiovascular disease via
suppression of the renin–angiotensin
system, a reduction in albuminuria,
and an overall improvement in car-
diac function. Other potential ben-
efits of vitamin D include improved
immune regulation, reduced overall
infection risk, and assistance in lipid
metabolism.71
Supplemental vitamin D repre-
sents both vitamin D2 (ergocalciferol),
which is primarily synthesized by ul-
| NUMBER 11 | JUNE 1, 2017 805
 CLINICAL REVIEW MANAGING CHRONIC KIDNEY DISEASE

Table 4. Clinical Characteristics of Commonly Used Phosphate Binders3,59-63,66-69

Agent Benefits Disadvantages Clinical Considerations
Calcium carbonate Nonprescription availability, Drug–drug interactions May increase risk of vascular
effective phosphate binder, possible, increased risk of calcification, appropriate
inexpensive hypercalcemia, adverse patient counseling necessary
gastrointestinal effects
Calcium acetate Effective phosphate binder, less Adverse gastrointestinal effects May increase risk of vascular
hypercalcemia vs. calcium calcification, though calcium
carbonate absorption may be decreased
vs. carbonate
Aluminum Very effective phosphate binder, Potential for accumulation, Should not be used in dialysis-
hydroxide nonprescription availability adverse gastrointestinal dependent patients
and neurologic effects,
osteomalacia
Sevelamer Less hypercalcemia vs. calcium- Prescription only, risk of acidosis Potential benefits on lipid profile,
containing binders, generally due to ion exchange, adverse may affect absorption of some
well tolerated gastrointestinal effects, costly vitamins
Lanthanum Generally well tolerated, less Prescription only, costly Potential concerns for
carbonate hypercalcemia vs. calcium- accumulation
containing binders
Sucroferric Novel phosphate binders, Prescription only, costly, may May reduce pill burden for
oxyhydroxide may reduce need for iron predispose patients to iron patients
and ferric citrate supplementation (theoretical) overload

traviolet radiation from the yeast er-
gosterol, and vitamin D3 (cholecalcif-
erol), which can be found naturally in
fish products and is synthesized by ul-
traviolet B radiation. To become phys-
iologically active, both sources require
hydroxylation in the liver, which con-
verts the inactive forms of the vita-
min into 25-hydroxyvitamin D. In
patients with normal kidney function,
25-hydroxyvitamin D is hydroxylated
in the kidneys by 1-α-hydroxylase into
vitamin D’s most biologically active
form, 1,25-dihydroxyvitamin D.72 In-
terestingly, total body stores of vita-
min D are better represented by eval-
uating levels of 25-hydroxyvitamin
D rather than the active 1,25-dihy-
droxyvitamin D, primarily due to its
longer half-life.72 In patients with
CKD, increased serum phosphate
concentrations and FGF-23 levels
decrease overall 1-α-hydroxylase ac-
tivity, thus limiting the conversion
of 25-hydroxyvitamin into the active
form of 1,25-dihydroxyvitamin D.3,72
In patients with CKD, supplementa-
tion with vitamin D is associated with
decreased PTH levels73 and may mini-
mize the potential for CKD-BMD, pro-
teinuria and glomerular damage, and
cardiovascular disease. However, ex-
isting guidelines highlight that though
biochemical parameters may change,
clinical outcomes data associated
with vitamin D supplementation are
lacking.3,59
Both KDIGO and KDOQI sup-
port the screening of patients with
CKD beginning at stage 3 for po-
tential vitamin D deficiency via the
25-hydroxyvitamin D assay.3,59 For in-
dividuals with stage 3–5 CKD and vi-
tamin D deficiency, vitamin D supple-
mentation approaches that are used
for the general public are supported.
The challenge, however, is that the
value used to determine vitamin D
deficiency is a matter of controversy,
partly due to a lack of consistency in
serum measurements. Current guide-
lines advocate defining vitamin D de-
ficiency as a serum 25-hydroxyvitamin
D concentration of <10–20 ng/mL
and vitamin D insufficiency at higher
concentrations (21–35 ng/mL).59 The
most recent recommendations for vi-
tamin D supplementation are to ini-
tiate ergocalciferol 50,000 IU orally,
to be dosed weekly or monthly based
on serum 25-hydroxyvitamin D levels
in patients with CKD, a strategy more
aggressive than seen with supplemen-
tation in the general population, as
more-aggressive treatment regimens
may be necessary for patients with
CKD.3,59
While the optimal range for PTH
remains unknown, KDIGO guide-
lines recommend that for patients
with stage 3–5 CKD and PTH levels
above the normal level for the as-
say in use, clinicians should examine
other potential factors contributing to
hyperparathyroidism, such as hyper-
phosphatemia, vitamin D deficiency,
or hypocalcemia. If abnormalities
are present, correction of these fac-
tors may return PTH levels to a nor-
mal range. For patients with stage 5
CKD who receive dialysis, PTH levels
should be maintained at 2–9 times
the upper limit of normal of the PTH
assay in use, primarily due to a lack
of data on clinical outcomes associ-
ated with specific target PTH levels.3,59
KDOQI supports KDIGO’s position in
the adjustment of modifiable factors
that may increase PTH levels in stage
3–5 CKD but suggests a wider refer-

806 AM J HEALTH-SYST PHARM | VOLUME 74 | NUMBER 11 | JUNE 1, 2017

 MANAGING CHRONIC KIDNEY DISEASE
ence range in dialysis patients that
corresponds to a PTH concentration
of 150–600 pg/mL.59 Treatment with
native vitamin D analogs should be
initiated in patients with stage 3–5
CKD with rising levels of PTH, de-
spite correction of other causative
abnormalities.3,59
The available vitamin D analogs
include calcitriol, paricalcitol, and
doxercalciferol. While calcitriol and
the other analogs result in reductions
in PTH levels, dose-limiting adverse
effects include hypercalcemia, hyper-
phosphatemia, and elevated calcium–
phosphorous product.3,59 Few studies
exist directly comparing the various vi-
tamin D analogs, so treatment choice
is based on formulary preferences,
dosing considerations, i.v. versus oral
administration preferences, and risk
of hypercalcemia.
In a double-blind, prospective,
controlled trial, 263 hemodialysis pa-
tients with elevated PTH levels were
randomized to receive either calcitriol
or paricalcitol for 12–32 weeks. Dose
adjustment for both agents occurred
until PTH levels were 50% of their
baseline level. In contrast to calcitri-
ol, patients who received paricalci-
tol achieved a 50% reduction in PTH
levels significantly faster than those
receiving calcitriol (p = 0.025). Fur-
thermore, paricalcitol was associated
with a higher percentage of patients
achieving their target PTH levels.
Adverse effects, which included hy-
percalcemia and increased calcium–
phosphorous product, occurred more
frequently with calcitriol (p = 0.008).
Although this study’s population in-
cluded only patients who were dialysis
dependent, it highlighted the com-
parative efficacy of paricalcitol with
calcitriol and the potential benefit of
reduced hypercalcemia with vitamin
D analog therapy.74
Because secondary hyperparathy-
roidism due to CKD is associated with
significant morbidity and mortality,
appropriate therapeutic intervention
is necessary to minimize the risk for
CKD-BMD.3 Due to conflicting data,
many practitioners may still question
the therapeutic effectiveness of vi-
tamin D in the management of bone
dyscrasias in patients with CKD.
Calcimimetics. Cinacalcet is a
potential therapeutic option for pa-
tients with stage 5 CKD who are dialy-
sis dependent and continue to have
elevated PTH levels despite conven-
tional treatments.3 The first agent in
a class of medications known as the
calcimimetics, cinacalcet exerts its
action by decreasing sensitivity at
the calcium receptor in the parathy-
roid gland.75 In contrast to vitamin
D analogs that increase calcium and
phosphorous levels, cinacalcet does
not stimulate intestinal absorption of
phosphorus and decreases serum cal-
cium levels.
Cinacalcet’s efficacy in decreasing
PTH levels was evaluated in a mul-
ticenter, double-blind, randomized
trial of 395 patients who were dialysis
dependent and had PTH concentra-
tions exceeding 300 pg/dL despite
conventional therapy for hyperpara-
thyroidism. Individuals were ran-
domized to receive either once-daily
cinacalcet, adjusted from 30 to 180
mg daily, or placebo in addition to
background medications, which con-
sisted of phosphate binders, vitamin
D supplementation, or both. Patients
were further stratified into classifica-
tion groups, depending on severity of
hyperparathyroidism (mild, moder-
ate, or severe). Dose adjustment of
cinacalcet occurred over 16 weeks,
followed by a 10-week trial efficacy
phase. At the conclusion of the trial, a
greater percentage of patients treated
with cinacalcet experienced a reduc-
tion of greater than 50% in PTH levels
compared with those who received
placebo (p < 0.001). Significantly
more patients who received calcimi-
metic therapy achieved their target
PTH levels (p < 0.0001). Cinacalcet
treatment was also associated with a
significant reduction in the calcium–
phosphorous product (p < 0.0001).
The most commonly reported ad-
verse effects with cinacalcet treat-
ment were nausea, vomiting, and
diarrhea, which were described as
AM J HEALTH-SYST PHARM | VOLUME 74
CLINICAL REVIEW
mild to moderate in nature. Hypocal-
cemia occurred in 5% of patients and
typically resolved once adjustments
were made to background therapies
and the cinacalcet dose. This study
demonstrated the beneficial effects
of cinacalcet on reducing PTH levels
without predisposing patients to ad-
verse effects.76
Palmer and colleagues77 complet-
ed a meta-analysis of 18 trials with
7,446 patients treated with cinacalcet
versus conventional treatment for hy-
perparathyroidism. Compared with
conventional treatment, cinacalcet
did not decrease all-cause mortality
(RR, 0.97; 95% CI, 0.89–1.05) or car-
diovascular mortality (RR, 0.67; 95%
CI, 0.16–2.87). It was, however, associ-
ated with a significant reduction in the
need for parathyroidectomy (RR, 0.49;
95% CI, 0.40–0.59). In this analysis,
cinacalcet was associated with hypo-
calcemia, nausea, and vomiting.
The EVOLVE study was a large
multicenter, prospective, randomized,
placebo-controlled trial designed to
evaluate cinacalcet’s ability to attenu-
ate cardiovascular disease in dialysis
patients with secondary hyperpara-
thyroidism.78 A previous study had
suggested that cinacalcet, through its
ability to decrease both phosphate and
calcium, reduced cardiac calcifica-
tion.79 A total of 3,883 adults receiving
dialysis with appropriate background
therapy (vitamin D supplementation,
phosphate binders, or both) were ran-
domized to receive placebo or cina-
calcet 30 mg, which could be adjusted
every 4 weeks during a 20-week phase
to a maximum dose of 180 mg daily.
The median study period was 21.2
months for individuals treated with
cinacalcet, while the median for the
placebo group was 17.5 months. At
the end of the study period, the pri-
mary composite endpoint of death,
myocardial infarction, hospitalization
for unstable angina, heart failure, or
a peripheral vascular event occurred
in 48.2% of the cinacalcet group and
49.2% of the placebo group (HR, 0.93;
95% CI, 0.85–1.02; p = 0.11), not reach-
ing statistical significance. In terms of
| NUMBER 11 | JUNE 1, 2017 807
 CLINICAL REVIEW
adverse effects, hypocalcemia and ad-
verse gastrointestinal effects occurred
significantly more frequently with
cinacalcet. Although previous studies
suggested a beneficial and attenuated
effect of cardiovascular disease in pa-
tients with CKD who were treated with
cinacalcet, the EVOLVE study—one of
the largest trials examining dialysis
patients—failed to show this benefit.
For patients who are candidates
for calcimimetic therapy, cinacalcet
should be initiated at a dose of 30 mg
daily and increased to a maximum
dose of 180 mg daily. Dose adjustment
should not occur more frequently
than every 2–4 weeks to minimize
adverse effects. Because of the po-
tential for treatment-associated hy-
pocalcemia, serum calcium levels
should be checked within 1 week after
treatment initiation or after any dose
adjustment and then monthly once
the goal dose has been achieved. If a
patient’s serum calcium concentra-
tion falls below 8.4 mg/dL, calcium-
containing phosphate binders or vita-
min D should be adjusted to increase
this level. If a patient’s serum calcium
concentration falls below 7.5 mg/dL,
consider withholding doses of cina-
calcet. Although the package insert
states that cinacalcet’s dose should be
adjusted to a goal PTH concentration
of 150–300 pg/dL75 (based on previ-
ous KDOQI guidelines), more-recent
KDIGO guidelines indicate that an op-
timal concentration of PTH to reduce
the risk of fracture is unknown.3
For patients who are refractory
to medical treatment or have elevat-
ed levels of phosphorus, calcium,
or vitamin D due to pharmacologic
management of hyperparathyroid-
ism, parathyroidectomy is an op-
tion. Although surgical management
generally results in a reduction of
biochemical parameters, questions
exist regarding the overall clinical
outcomes of this approach. No clini-
cal trials have evaluated the effects
of parathyroidectomy on mortality,
cardiovascular disease, or quality of
life, though some retrospective trials
have shown promising results. Para-
808 AM J HEALTH-SYST PHARM | VOLUME 74
MANAGING CHRONIC KIDNEY DISEASE
thyroidectomy may be a viable op-
tion to reduce PTH levels in patients
resistant to medical management.3
Pharmacist’s role in the
management of CKD
The management of patients with
CKD requires a multidisciplinary ap-
proach to ensure the safe use of medi-
cations and prevention of disease
progression. Pharmacists have the
knowledge and expertise to help these
patients by performing prospective
drug utilization review, delivering pa-
tient education, and providing coun-
seling on lifestyle modifications. The
role of the pharmacist in the manage-
ment of CKD is likely to expand in the
future, with many already providing
disease management for common co-
morbid conditions and complications
through diabetes, hypertension, hy-
perlipidemia, and anemia clinics. Be-
cause adherence can be challenging
with complex CKD-management regi-
mens, the pharmacist has an instru-
mental role in conveying the impor-
tance of medication compliance and
adherence to patients. For patients who
progress to dialysis, the pharmacist has
a pivotal role in assisting them with the
appropriate medications that require
specific dialyzing considerations and
optimizing pharmacotherapy for po-
tential candidates for transplantation.
If possible, the patient should always
be included in the decision to continue
or discontinue a medication based on
risks and benefits.
Conclusion
Multiple controversies regarding
the optimal management of patients
with CKD, including the appropriate-
ness of iron and ESAs for treatment of
anemia and vitamin D supplementa-
tion for the prevention of CKD-BMD.
Available guidelines differ dramati-
cally in the optimal approach to the
management of comorbidities and
complications.
Disclosures
The authors have declared no potential
conflicts of interest.
| NUMBER 11 | JUNE 1, 2017
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