REVIEW ARTICLE

Management of Hyperphosphatemia in
End-Stage Renal Disease: A New Paradigm
Anjay Rastogi, MD, PhD,* Nisha Bhatt, MD,† Sandro Rossetti, MD,† and
Judith Beto, PhD, RDN, FAND‡

Bone and mineral metabolism becomes dysregulated with progression of chronic kidney disease (CKD), and increasing levels of para-
thyroid hormone serve as an adaptive response to maintain normal phosphorus and calcium levels. In end-stage renal disease, this
response becomes maladaptive and high levels of phosphorus may occur. We summarize strategies to control hyperphosphatemia
based on a systematic literature review of clinical trial and real-world observational data on phosphorus control in hemodialysis patients
with CKD-mineral bone disorder (CKD-MBD). These studies suggest that current management options (diet and lifestyle changes; reg-
ular dialysis treatment; and use of phosphate binders, vitamin D, calcimimetics) have their own benefits and limitations with variable
clinical outcomes. A more integrated approach to phosphorus control in dialysis patients may be necessary, incorporating
measurement of multiple biomarkers of CKD-MBD pathophysiology (calcium, phosphorus, and parathyroid hormone) and correlation
between diet adjustments and CKD-MBD drugs, which may facilitate improved patient management.
Ó 2020 The Authors. Published by Elsevier Inc. on behalf of the National Kidney Foundation, Inc. This is an open access article under the
CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Introduction and length of life.2-5 High serum phosphorus levels have

H OMEOSTASIS IN CALCIUM and phosphorus

metabolism is maintained through interactions
between the kidney, gut, and bone mediated by multiple
hormones, including active/analog vitamin D, parathyroid
hormone (PTH), and fibroblast growth factor 23 (FGF-
23). As kidney function progressively declines to more
severe stages of chronic kidney disease (CKD) leading to
end-stage renal disease (ESRD) requiring dialysis, this
balance becomes increasingly dysregulated,1 and CKD-
mineral bone disorder (CKD-MBD) and secondary
hyperparathyroidism (SHPT) develop. In addition to
biochemical imbalances, CKD-MBD is associated with
parathyroid gland hyperplasia, vascular calcification, ure-
mic bone disorders with increased risk for fractures, bone
pain, and cardiovascular (CV) events, and has been linked
to poor health outcomes including diminished quality
*
†
David Geffen School of Medicine at UCLA, Los Angeles, California.
Division of Nephrology, Department of Medical Affairs, Amgen Inc., Thou-
sand Oaks, California.
‡
Division of Nephrology and Hypertension, Loyola University Chicago, May-
wood, Illinois.
N.B. is currently not employed by Amgen Inc.
Financial Disclosure: See Acknowledgment(s) on page XXX.
Address correspondence to Anjay Rastogi, MD, PhD, CORE Kidney Pro-
gram, Division of Nephrology, Department of Medicine, UCLA David Geffen
School of Medicine, 7-155 Factor Building, 10833 Le Conte Ave, Los Angeles,
CA 90095. E-mail: rastogiadmin@mednet.ucla.edu
Ó 2020 The Authors. Published by Elsevier Inc. on behalf of the National
Kidney Foundation, Inc. This is an open access article under the CC BY-NC-
ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
1051-2276
https://doi.org/10.1053/j.jrn.2020.02.003
also been associated with increased mortality risk in the
general population and CKD-MBD patients.6-10
Although the natural course of CKD results in elevated
PTH and serum phosphorus levels with low serum
calcium, current standard of care therapy results in the
typical patient presenting with elevated levels of all 3
parameters. An understanding of why control of
phosphorus is important in the context of dysregulated
mineral balance is essential in formulating a
comprehensive, patient-centric plan for treatment.
As a first-line approach, dietary phosphorus control
should account for both the total phosphorus content and
the bioavailability of phosphorus in organic versus inor-
ganic sources. Phosphorus can be further managed through
dialysis treatment and the use of drugs that include phos-
phate binders, active/analog vitamin D, and calcimimet-
ics.3,11 Renal replacement therapy with dialysis is needed
to compensate for loss of kidney function in advanced
CKD and can help to reduce the positive phosphorus bal-
ance. However, regular dialysis treatment and diet alone are
not sufficient to reduce phosphorus levels to within the
normal range in the majority of patients and additional
drug therapy is often needed. Accordingly, management
of phosphorus levels in patients receiving dialysis should
be achieved through an integrated approach involving die-
tary control and medical intervention when necessary.
Indeed, control of phosphorus should be viewed within
the total complexity of mineral balance and inter-
relationships/compensatory mechanisms involved with
disease progression, particularly the unique roles of the kid-
ney, gut, and bone contributing to serum phosphorus

Journal of Renal Nutrition, Vol -, No - (-), 2020: pp 1-14 1

2 RASTOGI ET AL

levels. The current review focuses on phosphorus manage-
ment in dialysis patients with CKD-MBD and SHPT, with
particular attention given to how progressive disturbances
in calcium, phosphorus, and PTH may be mitigated in
these patients.
Systematic Literature Review on
Phosphorus Control in Chronic Kidney
Disease-Mineral Bone Disorder
A systematic literature review of clinical trial, real-world,
and observational data specifically focused on phosphorus
control in CKD-MBD and SHPT was conducted.
Relevant studies published between 2013 and 2019 were
identified using the MEDLINE and Embase databases.
The following unique search terms were applied: ‘‘phos-
phorus’’ AND ‘‘phosphate’’ AND ‘‘phosphate binders’’
AND ‘‘secondary hyperparathyroidism’ AND ‘‘SHPT’’
AND ‘‘chronic kidney disease mineral bone disorder’’
AND ‘‘CKD-MBD.’’ Common search terms included the
following: chronic kidney disease (CKD); chronic kidney
disease mineral bone disorder (CKD-MBD); end-stage
renal disease (ESRD); secondary hyperparathyroidism
(SHPT); dialysis; hemodialysis; parathyroidectomy; Kidney
Disease: Improving Global Outcomes (KDIGO) guide-
lines; Kidney Disease Outcomes Quality Initiative
(KDOQI) guidelines; calcimimetic; SensiparÒ; ParsabivÒ;
etelcalcetide; cinacalcet; vitamin D; vitamin D sterols;
vitamin D analogues; vitamin D analogs; calcitriol;
1,25(OH)2D; dialysate; diet; nutrition; malnutrition; dieti-
tian; dietician; gastrointestinal; calcium; calcium sensing re-
ceptor (CASR, CAR); parathyroid hormone (PTH,
iPTH); additives; paricalcitol; bone (in association with
CKD); phosphate binder; sevelamer; calcium-based
binders; non-calcium-based binders; aluminum-based
binders; iron-based binders; and lanthanum.
Phosphorus and phosphate were cross-referenced sepa-
rately given the common lack of differentiation between
the contents of phosphate and phosphorus in the medical
literature (see Box 1).12,13
Case reports, reviews, preclinical studies and reports
describing peritoneal dialysis, and post-transplant patients
were excluded. A total of 132 articles were selected
(Fig. 1) and used to review current phosphorus manage-
ment approaches for CKD-MBD patients receiving
dialysis.
Pathophysiology of Hyperphosphatemia in
Chronic Kidney Disease-Mineral Bone
Disorder
Serum phosphorus balance is dependent on the contri-
bution of dietary phosphorus absorption in the intestine,
glomerular filtration, and tubular excretion and reabsorp-
tion in the kidney, and a balance between bone formation
and resorption. As part of the normal physiological process,
these mechanisms work in tandem to maintain serum phos-
phorous within a tight range (3.0-4.5 mg/dL in adults).
Renal adaptation to changes in dietary phosphate intake
is rapid, thus maintaining net phosphate balance. During
the early stages of kidney failure, decreased renal phos-
phorus excretion (with associated increases in serum phos-
phorus levels) coupled with reductions in the renal
synthesis of active vitamin D3 (with associated decreases
in vitamin D-mediated calcium uptake from the intestine)
results in elevated levels of serum phosphorus and lowered
levels of serum calcium. Hypocalcemia is the main trigger
of parathyroid gland PTH synthesis and release, which in

Box 1. Phosphorus or phosphate?

Phosphorus and phosphate are used interchangeably in the literature; however, there are important dif-
ferences in the meanings of these terms. Phosphorus is an essential mineral required by every cell in the
body for normal function.
 Physiological functions of phosphorus include the formation and repair of bones and teeth, muscle contraction,
nerve signaling, kidney function, maintaining a normal heartbeat, generation of Adenosine Triphosphate and
other high-energy bonds, and signal transduction for hormones, drugs, and other cellular effectors.

Due to its highly reactive nature, phosphorus is bound to oxygen as phosphate in all biological systems.
 Organic phosphates form the structural components of cells and are distributed in the skeleton (85%), teeth
(0.4%), soft tissue (14%), blood (0.3%), and extravascular fluid (0.3%). Inorganic phosphates exist as phosphate
ions (85%), bound to protein (10%) or complexed with calcium, magnesium, or sodium (5%).12
 It is the amount of phosphate in the blood that is measured with a serum phosphorus/phosphate test.
 Because the mass of phosphate (H2PO4) is 3 times greater than the mass of phosphorus, a recommended daily
intake of phosphorus of 1,000 mg is equivalent to 3,000 mg phosphate.13
 PHOSPHORUS CONTROL IN CHRONIC KIDNEY DISEASE
Figure 1. Flow chart of literature selection for systematic
literature review. Overall, 1,901 potential abstracts were
identified. Preclinical studies (N 5 169), case reports
(N 5 19), and review articles (N 5 332) were omitted. Studies
were also excluded if study subjects had primary or tertiary
hyperparathyroidism, hyperthyroidism due to calcium-
sensing receptor mutations, parathyroid carcinoma or malig-
nancy, were not on dialysis, or had chronic kidney disease
stage 4 or lower (N 5 685). Finally, all non-English
(N 5 135) and duplicate manuscripts were discounted, and
a total of 132 manuscripts met our inclusion criteria and
were evaluated.
turn increases calcium release from bone and renal phos-
phate excretion.3 FGF-23, secreted by cells in the bone
in response to rising phosphorus, acts to increase excretion
of phosphorus by the kidney, but has an inhibitory effect on
active vitamin D synthesis, further exacerbating distur-
bances in bone and mineral metabolism. Together, these
compensatory actions are an adaptive response to maintain
the physiology of mineral homeostasis within normal levels.
With CKD progression, phosphorus handling by the in-
testine, kidney, and bone becomes increasingly dysregu-
lated, and the adaptive response becomes maladaptive. As
the loss of renal function becomes more severe, vitamin
D levels become clinically deficient and renal phosphorus
excretion is increasingly impaired, with exacerbation of
the phosphorus and calcium imbalances and elevations in
PTH levels, leading eventually to SHPT.4 Elevated PTH
levels in SHPT increase bone turnover and resorption,
which releases phosphorus, reduces the phosphorus reser-
voir capacity of the skeleton, and contributes to fracture
3
Figure 2. A simplified overview of disordered mineral meta-
bolism in CKD-MBD. The decline in kidney function with dis-
ease progression leads to increased retention of
phosphorus. Patients with CKD-MBD have impaired renal
synthesis of active vitamin D, essential for GI calcium absorp-
tion. Decreased GI absorption of calcium can lead to hypo-
calcemia, which signals the parathyroid glands to secrete
PTH. High PTH then triggers increased reabsorption of cal-
cium (an adaptive response to rebalance low calcium) and
phosphorus from bone. This maladaptive response, over
time, drives progression of CKD-MBD. CKD-MBD, chronic
kidney disease-mineral bone disorder; GI, gastrointestinal;
PTH, parathyroid hormone; Vit D, active vitamin D.
and bone pain in patients with CKD-MBD.1,5 Eventually,
regardless of the levels of PTH and FGF-23, the kidney
can no longer excrete sufficient phosphorus to maintain
homeostasis, resulting in hyperphosphatemia (Fig. 2).14
Excessive retention of phosphate in the body can cause a
wide range of conditions, such as vascular calcification,
impaired bone mineralization, and dysregulated cell
signaling and cell death.15 Although less than 5% of people
with normal kidney function or those in CKD stages 1 and
2 exhibit hyperphosphatemia, the prevalence increases in
CKD stage 3b (estimated glomerular filtration rate
[eGFR] # 44 mL/minute/1.73 m2) and becomes incre-
mentally higher in stages 4 (eGFR 15-29 mL/minute/
1.73 m2) (20%) and 5 (eGFR , 15 mL/minute/
1.73 m2) (40%).14 By the time a patient receives dialysis,
they are highly likely to be hyperphosphatemic.
Several studies have demonstrated associations between
disturbances in mineral metabolism and adverse CV and
mortality outcomes in CKD patients, particularly in cases
of elevated serum phosphorous levels.16 In a meta-analysis
of cohort studies (N 5 25,546 non-dialysis–dependent
CKD patients), every 1 mg/dL increase in serum phospho-
rous was shown to be associated with increased risk of both
kidney failure (hazard ratio 5 1.36) and mortality (hazard
ratio 5 1.20).17 A systematic review of 47 cohort studies
(N 5 327,644 CKD patients) linked higher serum phos-
phorous levels with mortality and observed that the risk
of death increased by 18% for every 1 mg/dL increase in
serum phosphorous.18 Although there is some evidence
4 RASTOGI ET AL
linking elevated serum phosphorous with adverse out-
comes in CKD patients, high-quality clinical evidence sup-
porting an ideal target range is lacking. The ongoing
pragmatic, multicenter Pragmatic Trial of Higher vs Lower
Serum Phosphate Targets in Patients Undergoing Hemodi-
alysis trial (NCT04095039) aims to assess the optimal
serum phosphorous range and compares all-cause hospital-
ization and mortality rates between patients assigned to the
experimental Hi arm (phosphorus $ 6.5 mg/dL) or stan-
dard of care Lo arm (phosphorus , 5.5 mg/dL).19
Chronic Kidney Disease-Mineral Bone
Disorder: Guidelines and Current Clinical
Practice
The recent 2017 update to the Kidney Disease: Improving
Global Outcomes (KDIGO) guideline emphasizes the
complexity of CKD-MBD and recommends that treatment
be based on serial assessments of phosphate, calcium, and
iPTH, considered together. The guideline also states that
decisions pertaining to phosphate-lowering therapy should
be based on progressively elevated serum phosphate—that
dietary phosphate intake should be limited—and the dose
of calcium-based phosphate binders restricted. When
making dietary recommendations, the phosphate source
(e.g., animal, vegetable, additives) should be considered.
The updated guidelines also focus on treating CKD patients
with hyperphosphatemia and lowering elevated serum
phosphorous levels toward the normal range.20
Conventional drug therapy approaches toward CKD-
MBD management involve the progressive stepwise addi-
tion of additional therapies as kidney disease advances.
With this traditional approach, dietary intervention is rec-
ommended first; if this approach does not control CKD-
MBD, phosphate binders are added followed by active/
analog vitamin D, and calcimimetics are used as a final resort
Box 2. Novel Paradigm for Hyperphosphatemia Management in CKD-MBD
in difficult-to-treat cases when goal laboratory values are
not achieved. However, based on the updated KDIGO
2017 guideline recommendations that all 3 key laboratory
values (calcium, phosphorus, and PTH) be addressed simul-
taneously (goal range listed below), as well as current
thinking that calcimimetics may be used with first-line
drug treatment and dietary modification, we discuss an in-
tegrated approach to CKD-MBD treatment in the
following sections.
Chronic Kidney Disease-Mineral Bone
Disorder Management: An Integrated
Approach
The 3 cornerstone approaches that collectively work to
control the 3 key laboratory values in CKD-MBD include
dietary and lifestyle modification, dialysis, and drug treat-
ment with phosphate binders, active/analog vitamin D,
and/or calcimimetics.1,3,21 These are referred to as the
3Ds of hyperphosphatemia management: diet, dialysis,
and drugs (Box 2).
The following sections focus on the three 3D treatment
options in greater detail. These treatment options have unique
benefits and limitations and, therefore, should not be viewed
singularly in isolation but collectively as part of a holistic
approach to improve mineral markers in CKD patients.
Dietary Control of Phosphorus Intake
Dietary awareness and control, by limiting phosphorus
absorption in the gut, are central to management of hyper-
phosphatemia in patients receiving maintenance dialysis
because phosphorus intake can limit the amount of phos-
phorus available for absorption in the gut. However, foods
high in phosphorus are plentiful in the normal diet (e.g.,
meats and fish, nuts, whole grains, legumes, cheese) and
contain many important nutrients. Thus, avoiding
 PHOSPHORUS CONTROL IN CHRONIC KIDNEY DISEASE 5

Box 3. Hidden sources of phosphorus

There can be surprisingly high levels of phosphorus in foods traditionally considered low in phosphorus,
as well as in common medications, due to the use of phosphate additives. These difficult-to-measure
forms of ingested phosphorus are thus termed ‘‘hidden’’ sources.

 Food additives, including pH regulators, stabilizers, and flavor/color enhancers, may contribute up to one-third
of dietary phosphorus. Dietary phosphorus in the form of food additives has roughly doubled from 1990 to 2005,
and approximately 50% of foods in US supermarkets have phosphorus-containing additives.23,24
 Poor labeling of phosphorus content. Food labels contain little information on phosphorus content, and
when present, there is a discrepancy between the listed value and the level of phosphorus measured in a given
food sample.25
 Phosphorus in medications. More than 10% of drug formulations contain phosphorus, which can significantly
contribute to the daily phosphorus intake in patients taking multiple medications simultaneously.26,27 Common
medications high in phosphorus include:
1. Paroxetine (antidepressant)
2. Amlodipine (calcium channel blocker)
3. Lisinopril (antihypertensive)
4. Sitagliptin (antidiabetic)

phosphorus-rich foods can be difficult for patients with
CKD, and malnutrition is an important concern in this
already nutritionally compromised patient population.
Moreover, healthier diets can be more inconvenient and
expensive compared to inexpensive fast food that can be
very high in additive phosphorus. The phosphorus burden
of what we eat depends upon multiple factors including the
food source (animal- vs. plant-derived), presence of phos-
phate additives, and method of food preparation,22 which
can all impact the bioavailability of phosphorus. This is
further complicated by other hidden sources of phosphorus
in foods and medications (see Box 3).23-27
In the United States, the recommended daily allowance
of phosphorus for adults is 900 mg/day. In a typical diet, the
phosphorus content is generally proportional to the
amount of protein, and the 3 main sources of phosphorus
are proteins, dairy products, and cereals and grains. The
highest concentrations of naturally occurring phosphorus
are found in cereal grains (120-360 mg/100 g), cheese
(220-700 mg/100 g), egg yolk (586 mg/100 g), legumes
(300-590 mg/100 g), and fish and meat (170-290 mg/
100 g). Phosphorus is higher in processed foods compared
with fresh foods,28 which makes it difficult to obtain an ac-
curate measure of dietary phosphorus intake. Moreover,
food labels provide little information on phosphorus
content.25 Inorganic phosphates, such as phosphoric acid,
polyphosphates, and pyrophosphates, are commonly used
as food additives or preservatives in processed meats
(e.g., chicken nuggets, hotdogs), cheese spreads, sauces
and dressings, bakery products, soft drinks, and red wine;
such additives can increase the phosphorus intake by up
to 1 g/day.29 Proteins with phosphorus-containing addi-
tives provide approximately twice the phosphorus per
gram of protein compared with fresh foods.28
The crude amount of phosphorus in foods does not
reflect true phosphorus exposure because of variability in
phosphorus bioavailability, or the proportion of phos-
phorus digested and taken up systemically by the body.

Figure 3. Bioavailability of phosphorus in relation to dietary source. Bioavailability of phosphorus (% of phosphorus absorbed
from the gastrointestinal tract into the circulation) is dependent upon the dietary source29-32 with greatest bioavailability from
inorganic additives present in common foods such as drinks (sodas), processed foods (fast food), and canned foods. The
amount of phosphorus absorbed from animal sources can be as high as phosphorus from inorganic additives, whereas that
from plant sources is the lowest.
6 RASTOGI ET AL
The bioavailability of phosphorus is dependent upon the
food source and generally increases from plant to animal
to inorganic sources (Fig. 3).30-33 Despite the high
phosphorus content of plant-derived foods, mammals
lack the enzyme phytase, which is required to degrade
this form of phosphorus, leading to limited gastrointestinal
(GI) absorption and low bioavailability.34,35 In contrast,
phosphorus in meat is easily hydrolyzed and absorbed,
and close to 100% may be absorbed from foods containing
additives. Phosphorus absorption is linear over quite a large
range; hence, the amount and bioavailability of ingested
phosphorus is crucial. However, there is a lack of
evidence-based information on true phosphorus absorp-
tion, which can be difficult to measure in human feeding
studies and can be affected by the presence of other minerals
in the intestine such as vitamin D.30 Thus, the complexity
of oral intake makes it challenging to estimate true phos-
phorous ingestion in relation to absorption.
It is estimated that 30% of patients receiving dialysis
take at least 1 medication containing phosphorus, and
the median phosphorus burden from prescribed medica-
tions can be more than 100 mg/day.3,27 This source of
phosphorus is clinically significant for patients with
advanced CKD, given that more than 25% of these pa-
tients are prescribed .25 tablets per day for a range of
conditions.36 CV and central nervous system drugs ac-
count for approximately 90% of phosphorus-containing
medications.27 Examples of drugs taken by ESRD pa-
tients that contain phosphorus are central nervous system
medications such as paroxetine (111.5 mg phosphate per
40 mg tablet), codeine, and oxycodone; CV medications
including amlodipine (120 mg phosphate per 10 mg
tablet) and lisinopril (32.6 mg phosphate per 10 mg
tablet); and the diabetic drug sitagliptin (110 mg phos-
phate per 100 mg tablet).27,37,38 However, the level of
phosphorus can vary between different formulations of
the same drug, which underscores the difficulty in con-
trolling medicinal phosphorus intake.39
Patients should be encouraged to consume foods with
the least amount of inorganic phosphate, low
phosphorus-to-protein ratios, and adequate protein con-
tent.40 Care should be taken in maintenance dialysis pa-
tients to avoid concomitant reductions in dietary
protein41 because a low-protein diet can lead to hypoalbu-
minemia, protein energy wasting, and uremic malnutri-
tion, which are associated with increased mortality.42-46
In contrast, dialysis patients with higher protein intake
usually have higher serum albumin, higher body mass,
and better survival.41,47-50 However, with a
recommended daily protein intake of 1-1.2 g/kg/day for
patients receiving dialysis, it is extremely difficult to keep
phosphorus levels below 900 mg/day; assuming a
phosphorus-to-protein ratio of 14, the phosphorus intake
with food is approximately 1,340 mg/day for an 80 kg pa-
tient.51 Furthermore, considering that foods containing
phosphate additives have a phosphorus content almost
70% greater than foods without additives,52 tight control
of dietary phosphorus intake is a critical yet challenging
aspect of providing care to CKD patients receiving dialysis.
Choosing meats and poultry without breading, marinades,
or sauces can limit phosphorus intake, and seafood is an
excellent source of low fat protein, with lower phosphorus
content than red meat. Additional strategies to encourage
protein but limit phosphorus intake include the use of dairy
substitutes and egg white in cooking and baking, as the yolk
contains the majority of the phosphorus in eggs. Patient
awareness and adaptation is an on-going conversation.
Dialytic Removal of Phosphorus
In the United States, more than 120,000 individuals with
ESRD initiate renal replacement therapy annually, with the
prevalent dialysis population, as of 2016, exceeding
725,000 patients.53 Although a range of dialysis modalities
are accessible to patients with ESRD, almost 90% of patients
undergoing maintenance dialysis use conventional in-
center hemodialysis. Additionally, home dialysis modalities,
including both peritoneal dialysis and home hemodialysis,
represent available alternatives to conventional in-center
hemodialysis for patients with ESRD.54 However, conven-
tional dialysis treatment removes only a fraction of absorbed
phosphorus. A dietary phosphorus consumption of
1,000 mg/day with a 70% GI absorption rate provides an
approximate weekly phosphorus burden of 5,000 mg,
which is inadequately managed by conventional hemodial-
ysis strategies alone. Standard hemodialysis (4 hours) re-
moves, on average, 700-900 mg of phosphorus,
amounting to a weekly phosphorus removal of 2,100-
2,700 mg with a conventional thrice weekly hemodialysis
regimen and a large phosphorus deficit.55
Alternative strategies targeting phosphorus kinetics to
increase dialytic phosphorus removal, including frequency,
duration, and timing of dialysis, have been investigated.55-58
Although phosphorus is classified as a small molecule, it
behaves like a middle molecule and is negatively charged,
thus leading to reduced dialytic clearance compared with
small, water-soluble molecules.59 Serum phosphorus levels
plateau during the later parts of a dialysis session, suggesting
that extending weekly dialysis time or increasing dialysis
frequency to 5 or 6 times per week may represent attractive
alternative treatment schedules for additional phosphorus
removal. Improved phosphorus removal and reductions in
phosphate binder dose have been reported in patients
receiving more frequent dialysis at shorter treatment dura-
tions.56,58 To date, the greatest cause for optimism has been
provided by frequent nocturnal dialysis, totaling more than
30 weekly dialysis hours.57,60 Data from randomized
controlled trials showed that nocturnal hemodialysis was
significantly more effective at lowering serum phosphorus
than conventional hemodialysis. Phosphorus levels were
reduced from 5.5 6 1.5 to 4.4 6 1.7 mg/dL, and phosphate
 PHOSPHORUS CONTROL IN CHRONIC KIDNEY DISEASE
Table 1. A Comparison of Phosphorus Removal Between Dialysis Modalities
Modality Frequency
Conventional HD 334h
Extended HD 335h
Short daily HD 633h
Nocturnal daily HD 6 3 6-8 h
CAPD 24.0 h*
APD, CCPD 18.5 6 7.3 h*
APD, automated PD; CAPD, continuous ambulatory PD; CCPD, continuous cycling PD; HD, hemodialysis; PD, peritoneal dialysis.
*Dwell time.
binder medication dose was reduced or completely discon-
tinued in 73% of patients (the protocol for nocturnal dial-
ysis required in the addition of phosphate to the dialysate
bath as needed to prevent hypophosphatemia).57 In addi-
tion, encouraging evidence in favor of longer/more
frequent hemodialysis sessions for improved phosphorous
control is available from the Frequent Hemodialysis
Network Daily and Nocturnal trials. In patients receiving
nocturnal dialysis, assignment to more frequent sessions
(6 times/week) was associated with a relative decrease of
1.24 mg/dL in mean serum phosphorous compared to
assignment to less frequent sessions (3 times/week) at
month 12 (end of study). In addition, while none of the pa-
tients assigned to more frequent dialysis had serum phos-
phorous .8 mg/dL, serum phosphorous was .8 mg/dL
in 18% of those assigned to less frequent dialysis sessions
at the end of the study. Among all patients receiving
nocturnal dialysis, 42% required the addition of phosphorus
into the dialysate to prevent hypophosphatemia. In the
Daily trial, assignment to frequent hemodialysis (6 times/
week) was associated with a relative decrease of 0.46 mg/
dL in mean serum phosphorus levels compared to assign-
ment to less frequent sessions (3 times/week). Similar to re-
sults from the Nocturnal trial, only 1% of the participants
assigned to more frequent dialysis in the Daily trial had
serum phosphorous .8 mg/dL at the end of study,
compared to 9.6% in the less frequent arm.61 A comparison
of the extent of phosphorus removal with different dialysis
modalities is provided in Table 1.
Despite these advances in dialysis technology, adequate
dialytic phosphorus removal is an unmet need, and more
than 25% of dialysis patients still have serum phosphorus
levels above the target range.62 Thus, in addition to regular
dialysis, phosphorus-lowering strategies should include di-
etary management to limit intake of foods or beverages rich
in phosphorus, phosphate binders to decrease intestinal ab-
sorption, and active/analog vitamin D and calcimimetics to
decrease phosphorus indirectly by decreasing PTH-
induced bone resorption and release of phosphorus from
bone.
Drug Therapy
Phosphate Binders
The current guidance for phosphorus management is to
lower serum levels toward the normal range, partly with
7
Phosphorus Removal (mg/wk) Reference
1,572 6 366 104
3,400 6 647 105
2,452 6 720 56
8,000 6 2,800 106
2,790 6 1,022 107
2,739 6 1,042 107
phosphorus-lowering treatment consisting of phosphate
binders.1,3 Because treatment decisions should be based
upon progressively or persistently elevated serum phos-
phorus,3 this section focuses on the use of phosphate-
binding agents to manage serum phosphorus in patients
with stage 5 CKD on dialysis. Of note, no phosphate binder
has been approved by the Food and Drug administration
for use in nondialysis CKD patients.
Phosphate binders are designed to be taken with meals to
reduce the amount of phosphorus available for absorption
in the GI tract. There are quite a few phosphate binders
currently approved by the Food and Drug administration
and available on the market, and they can all lower phos-
phorus absorption from the GI tract to variable extents.
However, each type has advantages and disadvantages
related to the mechanism of binding, cost, pill burden,
efficacy, adverse effects, degree of systemic absorption,
and effects on other targets63-67 (Table 2). It is important
to understand that phosphate binders only limit the amount
of phosphorus absorbed in the gut; these agents have little to
no effect on controlling phosphorus that has entered the
circulation following release from the bones. As such, phos-
phate binders will not be sufficient to bring phosphorus
within range in patients with very high levels of phosphorus
secondary to uncontrolled hyperparathyroidism where the
bones can significantly contribute to the high levels of
phosphorus; rather, phosphate binders should be used in
combination with diet and calcimimetics to control phos-
phorus from all sources. Active/analog vitamin D may be
best avoided until the phosphorus level is better controlled,
as this can increase phosphorus absorption from the gut.
Aluminum hydroxide, the first phosphate binder used on
mass scale, has a high ionic binding affinity, low pill burden,
and is relatively inexpensive; however, the potential for
serious toxicity limits it to short-term use as rescue ther-
apy.62,68 Calcium-based binders, which are some of the
most commonly used binders and available as generic/
over-the-counter formulations (e.g., calcium carbonate),
can improve hypocalcemia but also can contribute to
increased calcium loading (hypercalcemia), a risk factor
for CV calcification and mortality.62 Iron-based agents
(e.g., ferric citrate) can improve anemia but can result in
iron overload and associated toxicity68,70; an exception is
sucroferric oxyhydroxide, a newer agent with minimal
8 RASTOGI ET AL

Table 2. Comparison of Common Phosphate Binding Oral Agents in Chronic Kidney Disease
Phosphate Binder Pros Cons References

Calcium-based: calcium  Increases calcium and can  Hypercalcemia and/or 62,63,72

acetate calcium correct hypocalcemia positive calcium balance

carbonate calcium citrate  Low cost  Cardiovascular calcification
 Moderate pill burden
Sevelamer-based:  No systemic absorption  Adverse GI effects 62,64-66,72,77,101

sevelamer  Potentially less vascular  High pill burden

carbonate sevelamer
hydrochloride
Iron-based: sucroferric
calcification (calcium-free)  High cost
 Lowers LDL cholesterol  Binds fat-soluble vitamins
 Improvement in metabolic  Metabolic acidosis with the
acidosis with hydrochloride variant
carbonate variant
 Lower pill burden  High cost 67,71,73,74

oxyhydroxide  Minimal systemic absorption,

Iron-based: ferric citrate
no iron overload
 Greater efficacy
 Increased GI motility which
might be beneficial in
constipated and PD patients
 Noninferior to sevelamer,  Systemic absorption with 66,71,73

well tolerated, beneficial potential for iron overload

effect on renal anemia
Lanthanum carbonate  Twice as potent as calcium  High cost 62,72,73

and sevelamer  Systemic absorption and

potential tissue deposition/toxicity
 GI intolerance, nausea
 Difficult to chew
GI, gastrointestinal; LDL, low-density lipoprotein; PD, peritoneal dialysis.

systemic absorption and no evidence of iron accumulation
in a phase 3 clinical study.71-74 Sucroferric oxyhydroxide
also tends to have a favorable side effect profile on the GI
system and is one of the most efficacious binders
currently on the market. Resin-based ion exchange binders
(e.g., sevelamer) have no systemic absorption, can lower
cholesterol, and have beneficial effects on vascular calcifica-
tion.75,76 However, sevelamer can have adverse GI effects
with a high pill burden and binds to fat-soluble vitamins,
thereby reducing its bioavailability.62,72,77 Lanthanum car-
bonate, another non-calcium-based binder, has high
phosphate-binding affinity, low pill burden, and works
over a wide range of pH with no negative effects on
bone; however, it is expensive, can produce adverse GI ef-
fects, and has uncertain long-term effects on the liver and
nervous tissues because of systemic absorption and is diffi-
cult to chew.62,72,73 To optimize use, doses of phosphate
binders may be titrated up or down or removed from the
treatment plan based on serial serum phosphorus levels
and timing of meals. Examples of real-world questions
regarding the use of phosphate binders in CKD patients
are listed in Box 4.73,78,79
Vitamin D
Abnormal vitamin D metabolism plays a key role in the
development of SHPT.80-83 Low levels of vitamin D are
common in patients with CKD due to poor nutrition,
limited sun exposure, and reduced ability of the kidney to
convert vitamin D into its biologically active form.84
Thus, active/analog vitamin D is administered as standard
of care, with either oral or intravenous dosing, to CKD-
MBD patients to increase calcium and decrease PTH.
Different forms of vitamin D, including calcitriol, parical-
citol, and doxercalciferol, are generally equally effective at
decreasing PTH, with similar safety profiles, but can lead
to hypercalcemia and hyperphosphatemia.85-89 An
overview of natural and synthetic forms of vitamin D is
provided in Box 5.80,82,83,85,86
Vitamin D regulates PTH directly by binding to the
vitamin D receptor in the parathyroid gland to suppress
synthesis of PTH and indirectly by increasing calcium ab-
sorption from the gut, which in turn regulates PTH stored
in the parathyroid glands. As a result, active/analog vitamin
D can correct hypocalcemia when present,21,90 but can also
increase absorption of phosphorus from the gut and release
of phosphorus from bone, leading to increased serum phos-
phorus. Thus, serum levels of calcium, phosphorus, and
PTH must be monitored with active/analog vitamin D
treatment, as increases in calcium and phosphorus above
their normal ranges can result in hypercalcemia and hyper-
phosphatemia and thereby limit the dose and frequency of
drug administration.6-9,21
 PHOSPHORUS CONTROL IN CHRONIC KIDNEY DISEASE 9

Box 4. Common questions on the use of phosphate binders in patients with CKD-MBD

1. Can phosphate binders be taken without food?

 In accordance with prescriber information, all binders should be taken shortly before or with meals to achieve
maximal efficacy and avoid unwanted effects.73 When taken in an empty stomach or hours after eating, there is
an increased risk of hypercalcemia with calcium-based binders and nausea or vomiting with lanthanum
carbonate.
 Effectiveness of phosphate binding is dependent upon the GI transit time of food. Binders are most effective
when food is present in the stomach and small intestine, where most phosphorus is absorbed.78,79
2. Why would a dose be missed?
 It is important to understand how often and why doses are missed and whether behavioral changes could be
adopted to maintain adherence, e.g., Are special pill boxes with a more attractive design or shape needed?
 Additional medications may not be effective if adherence is low.
3. If a dose is missed, should it be skipped until the next meal?
 Common practice is to take the missed dose as soon as possible, unless it is close to the next scheduled dose.
However, extra doses are not recommended and will not ‘‘make up’’ for the missed dose.
4. Should chewable tablets, such as over-the-counter calcium carbonate, be chewed or swallowed
whole?
 Swallowing tablets whole could lead to a reduced effect. Chewing into pieces allows the binder to reach more
sites in the esophagus and intestine to bind phosphorus. An exception is sucroferric oxyhydroxide, which can
be broken into smaller pieces and swallowed as it dissolves quite easily in the GI system.
5. Should phosphate binder use be personalized?
 Physicians, dieticians, and the healthcare team should educate the patient on how he/she can adjust the dose of
phosphate binders depending on dietary phosphorus load. This is very similar to how the insulin dose is
managed in diabetic patients. However, the patient will need to have some basic understanding of the phos-
phorus load in the meal.

Box 5. Vitamin D compounds

Nutritional vitamin D is ingested with the diet or in supplements and must undergo hydroxylation in the liver and
kidney to become active.82,83

 Non-nutritional vitamin D can be synthesized in the skin from exposure to sunlight.

Active vitamin D and vitamin D analogs are functionally active and effectively lower PTH levels. Active forms
directly activate the nuclear vitamin D receptor, and analogs may be designed with modifications to confer an
improved side effect profile or differential nonclassical effects compared with natural forms.83

 Calcitriol: Synthetic calcitriol was introduced in the 1970s and effectively reduces PTH; however, dose-
dependent development of hypercalcemia and hyperphosphatemia prompted the development of calcitriol
analogs.85,86
 Paricalcitol is an analog with a wider therapeutic window but similar efficacy and safety as calcitriol.77,78
 Doxercalciferol is an analog of vitamin D2 and undergoes hydroxylation in the liver to become active, without
involvement of the kidney.80
10 RASTOGI ET AL

Figure 4. The key players in hyperphosphatemia in CKD-MBD: kidney, gut, and bone. Hyperphosphatemia (high serum phos-
phorus) in CKD-MBD results from disordered mineral metabolism that is regulated by the kidney, gut, and bone, thereby neces-
sitating a multifaceted, integrative approach to treatment. Treatments that alter the contribution or sources of high phosphorus
from each of these target organs/tissues have unique advantages and inherent limitations. For instance, phosphate binders only
reduce phosphorus absorption in the gut but will not impact phosphorus released from bone. CKD-MBD, chronic kidney
disease-mineral bone disorder; GI, gastrointestinal; PTH, parathyroid hormone; SHPT, secondary hyperparathyroidism.

Calcimimetics Their differential effect on multiple mineral markers,

Calcimimetics activate the calcium-sensing receptor to specifically decreased release of phosphorus from bone, is
inhibit calcium-regulated PTH secretion, effectively a key differentiating characteristic of calcimimetics
mimicking or potentiating the effects of extracellular cal- compared with active/analog vitamin D, which stimulate
cium. By reducing PTH, calcimimetics also decrease GI absorption of calcium and phosphorus, and compared
bone resorption and thus decrease the contribution of with phosphate binders, which diminish the availability of
serum phosphorus from bone.91-93 The oral calcimimetic phosphorus in the gut. Additionally, calcimimetics offer
cinacalcet and intravenous calcimimetic etelcalcetide both minimal (cinacalcet) to no (etelcalcetide) pill burden. Etel-
effectively reduce PTH while simultaneously reducing calcetide shows some advantages over cinacalcet, including
the serum levels of calcium and phosphorus.69,91 a stronger efficacy profile, longer half-life, and intravenous
mode of administration.94,95 Potential limitations of calci-
mimetics include hypocalcemia and nausea/vomit-
ing.91,96,97 Improvement in GI tolerability of cinacalcet
Table 3. Effect of Various Classes of Drugs on Key CKD- can be achieved by administration with meals.98,99
MBD Biomarkers
Although some centers administer cinacalcet postdialysis
Class of Drugs Calcium Phosphorus PTH FGF-23 to improve compliance, there are little data to support
Phosphate binders –/[* Y Y [Y† this approach.
Active/analog [ [ Y [
vitamin D Benefits and Limitations of Different
Calcimimetics Y Y Y Y
Modalities in Controlling Phosphorus
CKD-MBD, chronic kidney disease-mineral bone disorder; FGF- Updated guidelines and clinical evidence do not support
23, fibroblast growth factor 23; PTH, parathyroid hormone. targeting high phosphorus alone.3 When administered with
Note: Size of the arrow does not necessarily correlate with the
magnitude of impact for patient. maintenance dialysis, a combination of dietary control,
*Calcium-based phosphate binders will increase serum calcium. phosphate binders, active/analog vitamin D, and calcimi-
†Depends on the phosphate binder used. metics (i.e., the 3Ds of phosphate management) can be
 PHOSPHORUS CONTROL IN CHRONIC KIDNEY DISEASE
used to holistically address hyperphosphatemia in CKD-
MBD. However, each approach has benefits and limitations
(Fig. 4). A diet low in phosphorus, particularly in added
sources of phosphorus, is a key component of phosphorus
control but is rarely sufficient on its own to achieve levels
within the recommended range. All phosphate binders
can reduce serum phosphorus; however, phosphate binders
do not target phosphorus released from bone. Data sup-
porting mortality benefits with phosphate binders alone
are equivocal, and beneficial effects on other hard outcomes
(CVendpoints, fracture incidence, or prevention of dialysis
therapy initiation) compared with placebo or comparator
phosphate binders are lacking.100,101 High pill burden
with phosphate binders has been associated with increases
in nonadherence that are associated with high serum phos-
phorus (.5.5 mg/dL) and PTH (.600 pg/mL).100,102
Another disadvantage is the increasingly high cost of non-
calcium-based phosphate binders100; the cost of treatment
with calcium-based binders is low, but there may be an
increased risk of vascular calcification, and hence morbidity
and mortality. Because elevated PTH is linked to sustained
hyperphosphatemia, calcimimetics offer the advantage of
controlling both SHPT and high phosphorus, compared
to active/analog vitamin D, which can increase phosphorus
absorption leading to hyperphosphatemia. This is critical
given that patients with PTH levels above 600 pg/mL
and adequate nutritional intake are 3-5 times more likely
to have hyperphosphatemia.103 In the setting of hyperphos-
phatemia secondary to uncontrolled hyperparathyroidism,
calcimimetics play a central role along with dietary modifi-
cation, dialysis, and phosphate binders. By decreasing bone
resorption, calcimimetics will decrease the phosphorus
coming from bones; active/analog vitamin D can poten-
tially worsen hyperphosphatemia in this setting. Thus, ap-
proaches aimed only at reducing phosphorus intake or
intestinal phosphorus absorption are unlikely to produce
a clinically significant effect for CKD-MBD patients with
dysregulated PTH, calcium, and phosphorus (Table 3).
Conclusion
Control of phosphorus is complex but important for the
overall health and well-being of CKD patients, and an un-
derstanding of why and how phosphorus should be
controlled is important for the entire healthcare team.
One in 3 patients is not getting below 5.5 mg/dL phos-
phorus, and 2 in 3 are not getting toward the normal phos-
phorus range, which are the recommendations from the
recent KDIGO guidelines. This indicates that it is time to
reassess the approach to phosphorus management in
ESRD patients. In the integrated approach, the 3Ds—
Diet, Dialysis, and Drugs—are used concurrently to
manage not just phosphorus but all 3 key CKD MBD lab-
oratory values (calcium, phosphorus, and PTH). The 3
main classes of CKD-MBD drugs, including phosphate
binders, active/analog vitamin D, and calcimimetics,
11
should be used together to target the goal range for
CKD-MBD laboratory values, and instead of the old step-
wise approach, calcimimetics may be used together with
other first-line agents (phosphate binders and vitamin D)
in the appropriate setting. These 3 classes of drugs should
be used synergistically for additive effects, thereby mini-
mizing adverse effects and improving outcomes. When
used in addition to regular dialysis treatment, dietary and
lifestyle modifications, phosphate binders, active/analog
vitamin D, and calcimimetics have benefits and limitations
with mixed clinical outcomes. The current treatment para-
digm consists of a multifaceted, integrative approach to
phosphorus control, which includes serial measurements
of calcium, phosphorus, and PTH and should be accompa-
nied by an understanding of relationships between these
markers, their absorption and release from gut and bone,
and fluctuations with disease progression and treatment.
When taken together, these factors should facilitate optimal
patient management.
Key Take-Aways
 The 3 key CKD-MBD laboratory values are calcium,
phosphorous, and PTH. Serial assessment and anal-
ysis of trends related to these key laboratory values
should be performed before any change to therapy
because of the differential impact a given treatment
might have on individual laboratory values.
 In addition to hyperphosphatemia, hypercalcemia
should be avoided.
 With the new paradigm to CKD-MBD manage-
ment, the goal is to make sure the interventions com-
plement one another rather than making conditions
worse. Calcimimetics may be used as first-line
treatment with other drugs in the right setting,
together with dietary modification and dialysis.
 The dietary source of phosphorus (animal- vs. plant-
derived) and hidden phosphorus in food additives
and medications can significantly impact the
bioavailability of phosphorus in the body.
 The contribution of bone to hyperphosphatemia in
the setting of uncontrolled hyperparathyroidism is
often under-appreciated and under-addressed.
Acknowledgments
The authors acknowledge Charles M. Henley, PhD and Jonathan
Plumb, PhD of Fishawack, whose work was funded by Amgen Inc.;
Kate Smigiel, PhD and William W. Stark, Jr, PhD (employees and stock-
holders, Amgen, Inc.) for their assistance with the writing of this manu-
script; and Christina Lopez, MBA and Anita Mkrttchyan of the CORE
Kidney Program for their assistance. The authors also acknowledge the
Shaffer Foundation for supporting the ESRD CORE Kidney Program
at UCLA.
Financial Disclosures: This study was funded by Amgen Inc. S.R. is an
employee and stockholder of Amgen Inc. N.B. was previously employed
and is a stockholder of Amgen Inc. J.B. is an employee of Loyola Univer-
sity Chicago, Maywood, IL. A.R. is an employee of UCLA, Los Angeles,
12 RASTOGI ET AL
CA. A.R. has research support/clinical trial funding from AstraZeneca,
Bayer, GlaxoSmithKline, Kadmon Corp., NIH, Omeros Inc., Pfizer,
Protalix Biotherapeutics Ltd, Reata Pharmaceuticals Inc., and Sanofi
S.A; serves as a consultant/advisory board member for AstraZeneca, Fre-
senius Medical Care, GlaxoSmithKline, Otsuka, Relypsa, Rockwell
Medical, Inc., and Sanofi S.A.; and has speaker’s bureau support from
Amgen Inc., Fresenius Medical Care, Genzyme/Sanofi, Otsuka, Relypsa
Inc., and AstraZeneca.
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