review
org
Prevention and treatment of hyperphosphatemia
in chronic kidney disease
Marc G. Vervloet1 and Adriana J. van Ballegooijen1,2
1
Department of Nephrology, Amsterdam Cardiovascular Sciences, VU University Medical Center, Amsterdam, the Netherlands; and
2
Department of Epidemiology and Biostatistics, Amsterdam Public Health Institute, VU University Medical Center, Amsterdam, the
Netherlands
Hyperphosphatemia has consistently been shown to be
associated with dismal outcome in a wide variety of
populations, particularly in chronic kidney disease (CKD).
Compelling evidence from basic and animal studies
elucidated a range of mechanisms by which phosphate
may exert its pathological effects and motivated
interventions to treat hyperphosphatemia. These
interventions consisted of dietary modifications and
phosphate binders. However, the beneficial effects of these
treatment methods on hard clinical outcomes have not
been convincingly demonstrated in prospective clinical
trials. In addition, exposure to high amounts of dietary
phosphate may exert untoward actions even in the absence
of overt hyperphosphatemia. Based on this concept, it has
been proposed that the same interventions used in CKD
patients with normal phosphate concentrations be used in
the presence of hyperphosphatemia to prevent rise of
phosphate concentration and as an early intervention for
cardiovascular risk. This review describes conceptual
models of phosphate toxicity, summarizes the evidence
base for treatment and prevention of hyperphosphatemia,
and identifies important knowledge gaps in the field.
Kidney International (2018) 93, 1060–1072; https://doi.org/10.1016/
j.kint.2017.11.036
KEYWORDS: chronic kidney disease; dietary phosphate; hyperphosphate-
mia; intestinal phosphate absorption; phosphate binders
Copyright ª 2018, International Society of Nephrology. Published by
Elsevier Inc. All rights reserved.
Correspondence: Marc Vervloet, Department of Nephrology, VU University
Medical Center, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands.
E-mail: m.vervloet@vumc.nl
Received 30 October 2017; revised 21 November 2017; accepted 27
November 2017; published online 23 March 2018
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www.kidney-international.
A
bnormal phosphate metabolism is one of the key
disturbances in chronic kidney disease (CKD). It is
now recognized that overt hyperphosphatemia occurs
rather late in the process of CKD progression, usually at stage
4 and onward.1 However, adaptive mechanisms, particularly
high concentrations of parathyroid hormone (PTH) and
fibroblast growth factor-23 (FGF23), antedate the develop-
ment of overt hyperphosphatemia, promoting kidney phos-
phate excretion.2 Because these adaptive mechanisms may be
directly involved in uremia-associated pathologies, it is diffi-
cult to untangle assumed phosphate toxicity from pathoge-
netic effects of these adaptive responses. Moreover, a
reduction of phosphate exposure by dietary intervention or
inhibition of intestinal phosphate absorption does not
normalize elevated concentrations of PTH and FGF23. Other
factors such as vitamin D deficiency, inflammation, and
autonomous overproduction of these hormones may explain
the limited effects of phosphate-targeted intervention on their
circulating levels.
Maintaining normal phosphate balance is of crucial
importance for many physiological processes including bone
mineralization. Phosphate homeostasis is determined by
modulation of intestinal uptake of dietary phosphate, renal
phosphate reabsorption of ultrafiltered phosphate, and the
shift of intracellular phosphate between extracellular and
bone storage pools (Figure 1).3,4 It is well established that
phosphate is one of the major factors in the maintenance of
bone health and that phosphate deficiency results in bone
pathology, as seen in patients with specific monogenic dis-
eases, leading to isolated renal phosphate wasting syndromes.5
Hyperphosphatemia per se usually is asymptomatic.
Morbidity associated with hyperphosphatemia is the conse-
quence of acquired structural or functional6 abnormalities,
including vascular calcification, which has been recently
summarized7 but is beyond the scope of the current review.
This is important because the justification for treating
hyperphosphatemia is based on the assumption that associ-
ated abnormalities are caused by abnormal phosphate ho-
meostasis. The second assumption is that a reduction in
phosphate concentration over time toward the normal range
is accompanied by a parallel decline in morbidities and death.
Comparable assumptions formed the base to restore hemo-
globin concentration in renal anemia to near normal levels by
epoetin, aiming to improve clinical outcome, but proved
untrue.8
Kidney International (2018) 93, 1060–1072
MG Vervloet and AJ van Ballegooijen: Managing phosphate in CKD
Phosphate balance
Total adult body stores
700 g, 85% in:
1200 mg/d
Absorption
(960 mg/d)
Secretion
(150 mg/d)
1350 mg/d
Fecal excretion
(400 mg/d)
Figure 1 | Phosphate homeostasis. Phosphate balance by phosphate intake, absorption, storage, and excretion. Used with permission
from Hruska KA, Mathew S, Lund R, Qiu P, Pratt R. Hyperphosphatemia of chronic kidney disease. Kidney Int. 2008;74:148–157. Copyright ª 2008
International Society of Nephrology.4
Epidemiological evidence in support of the role of phosphate
in clinical events
The assumptions described above are based on numerous
observational studies that generally reported on the risk for
mortality or cardiovascular disease of higher serum phosphate
concentrations across the entire spectrum of CKD, ranging
from normal or slightly decreased kidney function to dialysis-
dependent end-stage kidney disease. Large studies in non-CKD
populations, collectively encompassing over 39,000 subjects all
found an association between phosphate, even in the normal
range, and all-cause mortality,9,10 cardiovascular events,11 or
cardiovascular mortality.12 Also in patients with CKD, an as-
sociation between phosphate and adverse events exists. In an
analysis of 1203 patients, Eddington et al. found a stepwise
positive association of serum phosphate concentration and
mortality in CKD stages 3 and 4 but not stage 5.13 Voormolen
et al.,14 however, analyzing patients with stage 5 (nondialysis)
CKD did find an increased relative risk for mortality of 1.62 for
patients with an average eGFR of 13 (
5.4) ml/min per 1.73
m2 and serum phosphate concentration of 4.71 (
1.16)
mg/dl.14 Although an analysis of the Modification of Diet in
Renal Disease (MDRD) study (n ¼ 840) could not confirm this
association,15 the largest study to date, from the Veterans Af-
fairs Medical Centers (n ¼ 3490) by Kestenbaum et al.16 found
a linearly increasing mortality risk for patients with CKD,
above a threshold serum phosphate concentration of 3.5 mg/dl
(1.13 mmol/l).16 Finally, in patients undergoing dialysis,
numerous studies have consistently reported the independent
association between hyperphosphatemia and mortality risk.17–23
Phosphate pools or serum phosphate concentration?
Generally, hyperphosphatemia is considered indicative for
overall phosphate burden. However, routine clinical
Kidney International (2018) 93, 1060–1072
review
Absorption Resorption
(300 mg/d) (300 mg/d)
Blood <1%
Phosphate
pool
Urinary excretion
(800 mg/d)
observations demonstrate that this view is an over-
simplification, as hyperphosphatemia is widely prevalent in
CKD, even in individuals with low bone mass, in which the
tissue contains approximately 85% of total body phosphate.
In fact, phosphate resides in different compartments, of
which plasma and interstitial fluids represent very small
fractions (Figure 2).24 Among these compartments, a rather
rapid exchangeable pool must exist, which is responsible for
the rebound of serum phosphate after dialysis, which is both
rapid and high, reaching a 40% increase within 60 minutes
after its hemodialysis-induced nadir.25 This phosphate pool of
unknown residence, which is responsible for the rebound, can
probably be depleted by intensified hemodialysis therapy,
especially by extended duration dialysis schedules.26,27
Importantly, the magnitude of this phosphate pool is diffi-
cult to estimate, and therefore, no report has been able to
demonstrate an association between serum phosphate con-
centration and the amount of phosphate in this or other
phosphate reservoirs. The implication is that phosphate may
accumulate in CKD, initially without causing hyper-
phosphatemia. Remarkable observations for instance from
the Framingham offspring cohort, as described above, indi-
cate that serum phosphate even within the normal range is
associated with increased risk for cardiovascular events.9,11
This may be explained by the assumption that differences in
the amount of stored phosphate in pools is much larger than
suggested by corresponding serum concentrations. Based on
these observations, authors have speculated about the po-
tential of phosphate toxicity in the absence of overt hyper-
phosphatemia.24,28 It is possible that serum phosphate
concentration is just an unreliable reflection of phosphate
stores and that these stores are the true “phosphate culprit”
causing cardiovascular disease (Figure 3, left side). This
1061
review MG Vervloet and AJ van Ballegooijen: Managing phosphate in CKD

84% 14%
Organic

1%

Inorganic, exchangable

Inorganic, non-exchangable

Figure 2 | Phosphate resides in different body compartments. Bone is the largest reservoir with small amounts in plasma and interstitial
fluid. Clinically the quantitative amount in each compartment is difficult to estimate except the blood compartment. It is unknown which
compartment contributes most to phosphate-related toxicity. Adapted with permission from Osuka S, Razzaque MS. Can features of phosphate
toxicity appear in normophosphatemia? J Bone Miner Metab. 2012;30:10–18.24 Copyright ª 2012 The Japanese Society for Bone and Mineral
Research and Springer.

hypothesis is supported by the observation in the third Na-
tional Health and Nutrition Examination Survey (NHANES)
cohort that observed that fasted phosphate concentrations,
which may better reflect phosphate stores, were associated
with mortality, while the higher non-fasted values were not.29
These valid, yet unproven, considerations form the evidence-
base to consider clinical interventions in the absence of
hyperphosphatemia, as discussed below.
Biochemical context of hyperphosphatemia
Phosphate toxicity at a given concentration may differ in
severity under different microenvironmental conditions
(Figure 3, right side). Changes in systemic and local pH, for
instance, modify transmembrane phosphate transport. In
acid–base physiology, it is well recognized that phosphate is a
relevant buffer in the extracellular fluid. In this regard, it is
noteworthy that trivalent phosphate (PO43 ) does not exist
under physiological conditions, nor does the element phos-
phorus (P) itself. At a pH of 7.4 the predominant phosphate
species are HPO42 and H2PO4. Because the pKa at body
temperature of this phosphate buffer is 6.8, approximately
80% of total phosphate consists of the bivalent version
HPO42–. This is of relevance for phosphate transport across
cellular membranes but is frequently neglected. Sodium-
phosphate cotransporters (NaPi) are specific for either
monovalent or divalent phosphate.30 Phosphate transport
into vascular smooth muscle cells (VSMC) across the inor-
ganic sodium phosphate co-transporter NaPi-III (SLC20

Treatment Limit phosphate Restore Multitarget

principle exposure normophosphatemia approach

Working Overloaded phosphate Hyperphosphatemia Complex phosphate

concept pools interactions

Calcium Inflammation
Klotho
deficiency pH

?
Endothelial cells

Vascular smooth muscle cells

Figure 3 | Pathways of phosphate toxicity. Conceptual models of phosphate toxicity: as an example, the effects of phosphate on vascular
smooth muscle cells are shown. As detailed in the text, exposure to phosphate, even with similar serum concentration, may induce pathology.
The therapeutic intervention, indicated on top, would be to limit phosphate exposure (left-sided scenario). Currently, observational clinical
studies are consistently demonstrating associations between overt hyperphosphatemia and dismal outcomes. The intervention, therefore,
that follows, as suggested for instance by the Kidney Disease: Improving Global Outcomes (KDIGO) guideline, is to treat hyperphosphatemia
(center scenario). Phosphate toxicity is importantly modified by other factors, like a-klotho status, pH, calcium concentration, inflammation, and
possibly others as well. Targeting phosphate toxicity would be to optimize these factors, besides controlling phosphate itself (right-sided
scenario).

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MG Vervloet and AJ van Ballegooijen: Managing phosphate in CKD
subfamily member Pit-1) is considered to be among the
earliest triggers in the development of arterial wall calcifica-
tion.31 Interestingly, Pit-1 transports only monovalent phos-
phate (H2PO4).30 At a given systemic serum concentration
of phosphate, the local tissue pH dictates the availability of
this phosphate species to enter VSMC, as the ratio of
monovalent over bivalent phosphate changes with pH,
meaning that more substrate for Pit-1 becomes available at
lower pH. In advanced stages of CKD, acidosis is preva-
lent,32,33 and the lower pH may directly promote phosphate
transport into VSMCs. However, because the systemic pH is
generally maintained in the normal range, the local pH of the
arterial vessel wall is likely to be more important than sys-
temic acidemia. Hypermetabolism or inflammation in the
vessel wall increases local CO2 production,34 comparable to
the Bohr effect on hemoglobin. Moreover, VSMCs can
regulate local pH at the micro-level and increase acidity in its
proximity.35
Besides pH, other conditions also influence local phosphate
toxicity. In vitro studies have clearly shown that a-klotho in-
hibits phosphate entrance into VSMCs in a concentration-
dependent manner.36 Therefore phosphate toxicity may be
more pronounced in settings of a-klotho deficiency such as
CKD. This was recently confirmed in a mouse CKD model
with a-klotho deficiency, which demonstrated that restoring
a-klotho by delivery through adeno-associated viral vector
attenuated aortic calcification.37 In support of this concept,
upregulation of endogenous a-klotho by treatment with an
activator of peroxisome proliferator-activated receptor-g
(PPAR-g), a nuclear factor that upregulates a-klotho, led to an
inhibition of VSMC calcification in vitro.38 These studies
indicated that phosphate-induced vascular pathology may
differ depending on the a-klotho status.
A final example of the relevance of the biochemical context
in which phosphate may or may not exert toxic effects on the
vasculature is the modifying role of calcium.39 Higher con-
centration of systemic or local calcium (from VSMC
apoptosis or matrix vesicles) may act synergistically with
phosphate to induce and propagate vascular calcification.40
Some proximal aspects of the process of vascular calcifica-
tion are dependent on concentration of calcium even at high
concentrations of phosphate.41,42 Apart from phenotypic
changes induced by entrance of phosphate into VSMSs,
spontaneously formed calcium-phosphate crystals, if the
concentration of the minerals exceed their saturation product,
may induce part of the pathological effects on VSMCs as
well.43 Because inhibition of this crystal formation, and not
lowering phosphate concentration per se, has protective
properties against soft tissue calcification as shown in
experimental studies,44 it is conceivable that targeting calci-
fication propensity (a novel circulating biomarker for calci-
fication)45 or specific features of calciprotein particles,46 is a
more effective approach than solely focusing on phosphate
concentrations.
None of the above-mentioned aspects of potential mech-
anisms of phosphate-related pathology and subsequent
Kidney International (2018) 93, 1060–1072
review
morbidity have been thoroughly studied in clinical trials.
Despite decades of research dedicated to controlling phos-
phate overload in CKD, it is disappointing to conclude that an
unequivocal proof of benefit of phosphate lowering strategies
is still lacking. As outlined previously, the paradigm of
exclusively targeting hyperphosphatemia may have to change
to target phosphate-induced toxicity, an approach that en-
compasses more than just restricting phosphate exposure by
diet or phosphate binders. With these considerations in mind,
a balanced view of potential benefits and harms of current
dietary and pharmacological interventions for phosphate
exposure in CKD is presented as either a preventive measure
or a treatment modality for established hyperphosphatemia.
Dietary phosphate restriction in absence of
hyperphosphatemia
Phosphate balance studies. The first phosphate restriction
studies were conducted in animals decades ago. Multiple
animal models (rat, dog, and cat) demonstrated a dose-
response relationship between diets with increasing phos-
phate content and renal toxicity, as reflected by renal tubular
necrosis, nephrocalcinosis, inflammation, and albuminuria,
or by the development of hyperparathyroidism.47–51 In sub-
totally nephrectomized animal models, restriction of phos-
phate intake can prevent proteinuria, kidney calcification,
proximal tubular injury, and premature death.52–55 These
studies demonstrated a direct relationship between phosphate
load per nephron, kidney calcification, and proximal tubular
injury.
Human metabolic studies performed decades ago indicate
that high intake of phosphate additives could lead to a posi-
tive phosphate balance.56,57 It is, however, still unclear what
the clinical implication of this positive balance will be, and if
ultimately a novel steady state will be reached, for instance,
through an increase of FGF23 and PTH synthesis, both of
which promote phosphaturia.58 Clearly, more long-term
phosphate balance studies are needed to understand phos-
phate balance at different amounts of intake and different
dietary sources of phosphate at various stages of CKD, as
outlined below.
Human phosphate intake studies and patient outcomes
Observational studies that examined the relationship between
phosphate intake and health outcomes showed mixed results,
depending on kidney function.59–61 In the general population
without kidney disease, phosphate intake $1400 mg/d as
estimated based on dietary recall, was prospectively associated
with all-cause mortality.59 In a large multiethnic study, higher
phosphate intake was associated with greater left ventricular
mass.62
In stage 3 CKD patients,60 phosphate intake (based on
24-hour dietary recall) was not associated with premature
death, whereas in hemodialysis patients,61 phosphate intake
(based on food frequency questionnaire) was strongly
associated with premature death. Results from the hemo-
dialysis study were consistent when examining individual
1063
review
foods and food groups of soda and fast food consumption
as phosphate sources. Importantly, the correlation between
phosphate intake and serum phosphate concentration was
very weak (r ¼ 0.1), and no association persisted after
multivariate adjustment. A possible explanation for the
divergent results between CKD and end-stage renal disease
(ESRD) patients may be that CKD patients lowered their
total protein-derived energy intake over time. In addition,
these patients still possess the possibility of excreting
phosphate, thereby preventing the development of hyper-
phosphatemia and possibly remaining in phosphate balance
for a longer period of time.63 For all these intake studies, it
is important to note that phosphate-containing food addi-
tives were not taken into account, and therefore these
results may be an underestimation of true exposure to
exogenous phosphate.
Few small, human intervention studies investigated the
effect of phosphate interventions by dietary modification on
vascular health.64,65 A high dietary phosphate load increased
serum phosphate concentration after 2 hours and significantly
decreased flow-mediated dilation.64 This suggests that post-
prandial high phosphate concentrations impair endothelial
function. Interestingly, in a recent cross-over study, 2 weeks’
exposure to high phosphate intake impaired flow-mediated
vasodilation (a clinical estimate of endothelial function) in
healthy volunteers but without increasing serum phosphate
concentration.65 However, there was no effect on pulse wave
velocity.
Urinary phosphate excretion
Counter-intuitively, in individuals with stable cardiovascular
disease with a mean estimated glomerular filtration rate (eGFR)
of 71 ml/min per m2, higher 24-hour urinary phosphate
excretion was associated with lower risk of cardiovascular
events and with a similarly improved trend for all-cause mor-
tality.66 These associations were attenuated but persisted after
adjusting for multiple factors that included age and eGFR. This
study also clearly showed the absence of an association between
phosphate intake and its serum concentration. In an observa-
tional analysis of the Modification of Diet in Renal Disease
(MDRD) trial examining the effect of baseline protein intake on
CKD progression, phosphate intake as estimated by urinary
phosphate excretion was not associated with the risk of pre-
mature death or incident ESRD in CKD patients without
hyperphosphatemia.67 However, it should be noted that
phosphate intake nowadays is much higher than it was 20 years
ago, and in this analysis, it was assumed that baseline phosphate
intake (prior to randomization and education in the Modifi-
cation of Diet in Renal Disease [MDRD] trial) remained
unchanged for many years.68 In conclusion, these data do not
support a relationship between high phosphate intake and
adverse outcomes in normophosphatemic patients with or
without moderate CKD. Further studies are needed to deter-
mine these effects in the setting of more advanced CKD and
especially in the setting of hyperphosphatemia.
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MG Vervloet and AJ van Ballegooijen: Managing phosphate in CKD
Protein source for phosphate
Human intervention studies focusing on the isolated effect of
phosphate intake when keeping protein intake constant are
scarce.69 The available evidence is focused on protein
restriction, as protein-rich foods are the main sources of
dietary phosphate intake. In a meta-analysis of 10 studies with
moderate to severe CKD with a study duration of >1 year,
lower protein intake reduced the risk of renal replacement
therapy or premature death by 32%.70 In addition to the
amount of protein, the source of phosphate may be equally
important. Most of the studies that compared animal protein
to plant-based protein found that plant-based protein was
favorable for kidney function preservation and albumin-
uria.71–73 A balance study compared the effect of phosphate
source (meat or vegetarian) in patients with CKD and found
lower phosphate and FGF23 concentrations for the vegetarian
diet.69 These studies provide insight into the relationship
between protein sources and CKD progression; however, it
remains unclear if the effect of plant-based protein is due to
differences in amino acid, dietary acid load, or phosphate
availability itself.
Intake of phosphate additives
Some human studies examined the role of phosphate ad-
ditives on outcomes (Table 1). In healthy premenopausal
women, the intake of phosphate-containing food additives
from processed cheese was cross-sectionally associated with
higher serum PTH concentrations.74 However, in the
Multi-Ethnic Study of Atherosclerosis (MESA) study, a
large multiethnic cohort, no association was found between
processed food intake and serum phosphate concentra-
tions.75 In another cross-sectional study in a middle-aged
population in Finland, a significant relationship was
observed between higher total phosphate intake and food
additive phosphate intake with higher carotid intima-media
thickness.76
Some short-term human experiments have been con-
ducted as well. A small cross-over diet study in young in-
dividuals with normal kidney function showed that high
phosphate additive intake resulted in elevated concentra-
tions of FGF23, osteopontin, and osteocalcin.58 In CKD
patients, a 3-week cross-over trial comparing commercially
available products with or without phosphate additives
showed a trend toward increased albuminuria but was not
significant.77 Collectively these studies demonstrate that a
diet high in phosphate additives induces changes in hor-
monal systems involved in phosphate metabolism and in-
termediate endpoints. Importantly, the mixed results
regarding the possible influence of serum phosphate
concentration on outcomes suggest that this laboratory
value does not reflect exposure to phosphate-containing
additives. More research is needed to study long-term
effects of these additives on patient-level endpoints,
in particular in CKD populations at highest risk for
phosphate toxicity.
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MG Vervloet and AJ van Ballegooijen: Managing phosphate in CKD review

Table 1 | Phosphate additives and health outcomes

Study, year Study design Country Study population Exposure Outcome

Observational
Kemi et al.,74 Cross-sectional Finland N ¼ 147 healthy Intake phosphate-containing food High cheese consumption was
2009 premenopausal additives from processed cheese associated with higher serum
women aged 31–43 PTH: b 36.5 ng/l
years
Gutiérrez et al., Cross-sectional USA 2664 MESA participants, Processed food intake (processed Not associated with serum
2012 aged 62 years meat, soda, fast food) phosphate
Itkonen et al., Cross-sectional Finland N ¼ 546 middle-aged, no Intake of food additive phosphate Higher carotid intima-media
2013 CKD, aged 37–47 years thickness
40 mm P<0.05
highest versus lowest group
Interventional
Absence of hyperphosphatemia
Gutiérrez et al., 2 week feeding USA 10 healthy individuals, 1000 mg of phosphate per day with FGF23þ 23%
2015 trial normal kidney foods free of phosphorus Osteopontin þ10%
function additives, followed by a diet Osteocalcin þ 11%
containing identical food items;
Chang and 3 week cross-over USA N ¼ 31 adults with mean Higher versus lower phosphate Albuminuria: þ14.3%
Grams,29 2017 trial eGFR 45 ml/min per intake by the addition of FGF23: þ3.4%
1.73 m2 commercially available diet but not significant
beverages and breakfast bars
Presence of hyperphosphatemia
Sullivan et al.,80 3 months RCT USA 279 ESRD patients with - Intervention (n ¼ 145) received 0.6 (95% CI, 1.0 to 0.1)
2009 baseline phosphate education on avoiding foods with mg/dl phosphate favoring
>5.5 mg/dl phosphate additives when intervention
purchasing groceries or visiting Also intervention significantly
fast food restaurants. increased in reading
- Control participants (n ¼ 134) ingredient lists and nutrition
usual care. facts labels
De Fornasari 3 month RCT Brazil N ¼ 34 ESRD patients Intervention group (n ¼ 67): Intervention 2.2 mg/dl lower
et al., 2017 with baseline Individual orientation to replace phosphate versus 0.4
phosphate >5.5 mg/dl processed foods high in control group
phosphate additives with foods Intervention 70% reached the
of similar nutritional value phosphate target of #5.5
without these additives. mg/dl versus 18.5% in control
Control group (n ¼ 67) received group
nutritional orientation without
replacing foods
CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; ESRD, end-stage renal disease; FGF23, fibroblast growth factor-23; MESA, Multi-Ethnic Study of
Atherosclerosis study; PTH, parathyroid hormone; RCT, randomized control trial.

Diet therapy in the presence of hyperphosphatemia
The recent Kidney Disease: Improving Global Outcomes
(KDIGO) guideline on the CKD-associated bone and mineral
disorder (CKD-MBD) suggests in patients with CKD stages 3
to 5 that dietary phosphate intake be limited for the treat-
ment of hyperphosphatemia, combined with other treat-
ments.78 Few studies have investigated the effect on
hyperphosphatemia of diet and phosphate additive replace-
ment.79–81 In a 6-month trial among dialysis patients in
Spain, which compared intensive dietary intervention with
usual dietary recommendations, phosphate intake was
significantly lower in the experimental group.81 The achieved
serum phosphate concentration was 0.93 mg/dl (0.3 mmol/l)
lower in the experimental group, and the prevalence of
hyperphosphatemia (>5.5 mg/dl; 1.8 mmol/l) declined
markedly more than in the control group (49% vs. 82%,
respectively).
Two randomized trials have investigated the effect of
replacing foods high in phosphate additives with food without
additives and found significant reductions in serum
phosphate concentrations and prevalence of hyper-
phosphatemia.79,80 In ESRD patients, education to avoid
phosphate additive-rich foods, compared to usual diets, also
resulted in modest improvements in hyperphosphatemia.80
Moreover, the intervention group participants read ingre-
dient lists and nutrition fact labels more often, although they
failed to achieve better food knowledge.
Another recent trial indicated that replacing phosphate-
containing food additives with food without additives
impressively reduced hyperphosphatemia in ESRD patients
from an average of 7.2 mg/dl (2.3 mmol/l) to 5.0 mg/dl (1.6
mmol/l).79 Long-term studies of the association between high
phosphate intake, especially in the form of highly absorbable
food additive phosphate and health outcomes are needed.
Treatment in CKD populations
The KDIGO guideline for CKD-MBD recommend that, in
patients with CKD stage 5, phosphate intake should not
exceed 1000 mg per day.78 Although this suggestion is made
in the guideline, it is mainly based on expert opinion.

Kidney International (2018) 93, 1060–1072 1065

review
Lowering phosphate intake in a diet is challenging. It re-
quires intensive patient education to understand the
complexity of dietary labels and avoid malnutrition.82 A
systematic review among CKD patients indicates an average
reduction of 0.72 mg/dl serum phosphate after any educa-
tional intervention, whereas the reduction was more pro-
nounced in interventions for $4 months.83,84 This suggests
that appropriate dietary counseling can help to keep phos-
phate concentrations within the recommended range and can
assist in management and treatment strategies for CKD.
Food composition tables usually do not take into account
food additives.85 Because phosphate additive intake varies
between 10% and 50% of total intake, specific attention in
dietary counseling should be paid to foods high in phosphate
additives.
Phosphate binder therapy is expected to remove on
average no more than approximately 200 to 300 mg of
phosphate per day,86 which motivates the potential of dietary
counseling to reduce phosphate intake by a greater amount.
Growing evidence shows that a reduction in ultraprocessed
foods with a high content of phosphate additives is related to
better phosphate management79,80 and health outcomes.87
Control of dietary phosphate requires a specific set of skills
and knowledge by trained dieticians. It should be tailored to
each individual’s preference, family situation, availability of
foods, purchase, and food preparation to efficiently integrate
dietary phosphate control into daily life of CKD management.
How to reduce phosphate intake?
Almost all foods contain phosphate, but greater amounts are
found in animal products such as meat, fish, eggs, and dairy.
Nuts, seeds, and many vegetables are also rich in phosphate. A
regular Western diet provides between 1000 and 1500 mg/d.88
Most phosphate is absorbed in the proximal intestine, pre-
dominantly in the jejunum. The absorbed phosphate enters
the extracellular fluid pool and moves into and out of bone
tissue.
In addition, phosphate is commonly used as an additive
for preservation or thickening of foods. For example, 1 can of
cola contains 65 mg of phosphate, equivalent to 20 grams of
cooked chicken filet,89 which contributes to a high phosphate
load. Furthermore, products like enhanced meat, flavored
water, and frozen meals with high phosphate content fill our
grocery shelves rapidly. Also, the bioavailability of phosphate
additives (industrial phosphate; e.g., phosphoric acid, poly-
phosphates) is higher than phosphate from natural sources.
The bioavailability of phosphate from natural sources is
approximately 60% to 80%, with lowest bioavailability for
legumes at 40%, whereas soda and salad dressings approach
100% bioavailability.90,91 Phosphate additives contribute 10%
to 50% of total phosphate intake in Western diets.92
Furthermore, net phosphate absorption varies depending on
overall intake, food source, and matrix, the relative amounts
of dietary calcium, phosphate, and vitamin D sterols, and bile
acid concentration,69,93 thus a large variety of factors deter-
mine daily phosphate load.
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MG Vervloet and AJ van Ballegooijen: Managing phosphate in CKD
The food preparation technique also influences phosphate
content. Boiling reduces phosphate content due to deminer-
alization of food, as the minerals move from the food into the
boiling water.94 Reported phosphate reductions by boiling
vary between 35% and 50%.95 All these details can be useful
for dietary counseling aimed to lower the phosphate load
from the diet.
Inorganic phosphate is also added to medications and is
another, generally unrecognized source of phosphate expo-
sure. In a Canadian hemodialysis population, 11% of pre-
scribed medication contained a phosphate salt with a median
phosphate burden of 111 mg per day.96 With a median daily
pill burden of 19, prescription medication can substantially
contribute to the daily phosphate load in dialysis patients.97
Moreover, phosphate is usually added to multivitamin sup-
plements with estimations between 20 and 150 mg per sup-
plement. The use of a multivitamin supplement will further
contribute to a higher dietary phosphate load.
Recommendations for future research
 Perform phosphate balance studies keeping protein intake
constant at different stages of CKD, initially to test feasi-
bility followed by studies on clinical outcomes.
 Update phosphate additives content in food composition
database.
 Conduct randomized controlled dietary trial interventions
among CKD patients to inform evidence-based recom-
mendations. These studies should have sufficient follow-up
and clinically relevant endpoints (Table 1).
Pharmacological interventions to prevent
hyperphosphatemia
It is difficult to establish when an intervention should be
considered as a "preventive" or as a "therapeutic" measure, as
hyperphosphatemia is not a disease. Moreover, serum phos-
phate exhibits circadian fluctuations not only physiologically
but also in patients with CKD. For the remainder of this re-
view, interventions for phosphate homeostasis with normal or
slightly increased serum phosphate concentrations will be
considered as preventive and in the setting of overt hyper-
phosphatemia as therapeutic. Clinically, the decision to apply
preventive measures is essentially confined to predialysis
CKD.1
Change in the KDIGO guideline on CKD-MBD
One of the key changes of the recently updated KDIGO
guideline for CKD-MBD (guideline 4.1.2) is that it no longer
suggests maintaining phosphate concentrations within the
normal range.78 This change was largely based on a trial by
Block et al.,98 which showed a discrepancy between the effect
of phosphate binders on serum phosphate concentration,
which indeed was slightly lowered, and intermediate end-
points (serum FGF23 and coronary artery calcification
[CAC]) which were unchanged or even worsened.98 In that
study, different phosphate binders were used, but the sample
size of subgroups was too small to evaluate differences
Kidney International (2018) 93, 1060–1072
MG Vervloet and AJ van Ballegooijen: Managing phosphate in CKD
between individual phosphate binders.99 The baseline phos-
phate concentration in that study was 1.36 mmol/l (4.2 mg/
dl); therefore that study could be considered a proof of
concept trial of pharmacotherapy to prevent the development
of hyperphosphatemia. Because that trial fulfilled predefined
criteria to be included in the KDIGO update and, importantly
also included a placebo, its impact on this section of the
guideline was substantial. The question arises whether that
study disqualifies future attempts to prevent phosphate-
induced pathology in the absence of hyperphosphatemia.
The 3 conceptual models of phosphate toxicity (Figure 2),
consisting of concentrations of phosphate, the phosphate
pool, and phosphate in a complex system, could be examined
separately. Interestingly, in the trial by Block et al.,98 all
binders used (calcium-containing binders, lanthanum, and
sevelamer) had comparable effect on lowering phosphate
concentration and 24-hour urine phosphate excretion.
However, phosphate concentrations were measured under
nonfasted conditions, and the impact of the different in-
terventions on the total phosphate pool is difficult to esti-
mate. The 24-hour phosphate excretion, which declined for
all phosphate binders, is probably a better reflection of
gastrointestinal uptake during steady state than a parameter of
total phosphate content.
Are calcium-based phosphate binders unsafe
in predialysis CKD?
The decline of 24-hour urinary phosphate excretion in the
calcium-containing binder group in the above-mentioned
study by Block et al.98 contradicts findings from a meticu-
lously performed balance study in CKD patients with a mean
eGFR of 36 ml/min per m2.63 In that short-term study, no
change in excretion of phosphate was accomplished in
response to 1.5 g of calcium carbonate per day; however, in
the study by Block et al.98, patients with similar degrees of
CKD received 5.9 g of calcium acetate per day. The progres-
sion of CAC in the calcium carbonate group in the trial by
Block et al.98 has been suggested to be the consequence of
calcium loading.100 Notably, the noncalcium-containing
phosphate binders did not lower CAC progression
compared to placebo, and the statistical significance of the
differences between individual treatment subgroups could not
be evaluated due to insufficient sample size.99 In addition,
patients without coronary calcification at baseline did not
develop calcification regardless of treatment allocation.98
Different findings emerged from the head-to-head trial by
Russo et al.101, where the use of calcium-containing binders
(2 g of calcium carbonate daily) in CKD patients with base-
line mild hyperphosphatemia (4.5 mg/dl, 1.45 mmol/l) did
not induce more progression of CAC scores than no binder
use at all. Furthermore, sevelamer administration, studied in
the same trial, did significantly attenuate calcification pro-
gression. Both binders induced a 16% reduction in 24-hour
urine phosphate excretion but had no effect on serum
phosphate concentration. Importantly, this study also noted
that, in the absence of baseline vascular calcification, no
Kidney International (2018) 93, 1060–1072
review
calcification developed after 24 months in either treatment
arm. The differences between the 2 studies may be ascribed to
differences in phosphate exposure as measured by 24-hour
urine excretion (higher in the trial by Block et al.98), differ-
ences in baseline serum phosphate concentrations (higher in
the trial by Russo et al.101), and differences in population size
and follow-up duration.
In the open-label trial by Di Iorio et al.,102 baseline serum
phosphate was slightly higher (4.8 mg/dl per 1.6 mmol/l) than
in the 2 studies addressed previously.102 In this study, seve-
lamer was compared to calcium carbonate and improved
survival after 3 years of follow-up. Remarkably, phosphate
concentration improved only in the sevelamer group,
complicating the interpretation of this trial, which could
imply either an advantage of sevelamer over calcium car-
bonate or unsuccessful phosphate control in the calcium
carbonate group. Another remarkable finding was that
adjusting for time-varying covariates, which included serum
levels of phosphate, C-reactive protein, and cholesterol, did
not mitigate the beneficial hazard ratio for sevelamer group.
This is surprising, because this argues against improved
phosphate concentration (and cholesterol and C-reactive
protein) as a mediating factor of the benefit of sevelamer.
Unfortunately, 24-hour phosphate excretion was not
measured in this trial.
When trying to reconcile these data in normophosphatemic
CKD, there is no proven benefit to patient-level outcomes of
any pharmacological intervention in phosphate homeostasis, at
least not for the currently available treatment options. How-
ever, some data, as discussed above, do suggest that, with in-
cremental baseline phosphate concentrations beyond the
upper limit of normal, benefits of intervention may outweigh
the possible harm inflicted by phosphate binders. Adverse ef-
fects must be taken into account, which could include more
rapid progression of established vascular calcification for
calcium-containing binders, a risk that appears to be absent if
there is no baseline calcification at all. Furthermore, all phos-
phate binders have the capacity to bind vitamin K (at least
in vitro), which is a key factor in calcification defense.103
Therefore, it may be imprudent to consider noncalcium-
containing as completely safe. This should draw attention to
the possibility that phosphate toxicity is dependent on the
microenvironment, as outlined in the previous introductory
paragraphs. This principle is generally neglected in clinical
medicine, which focuses on phosphate concentrations only.
Pharmacological interventions to treat hyperphosphatemia
Pharmacological treatment of hyperphosphatemia is widely
used, especially in patients undergoing dialysis and contrib-
utes largely to the total pill burden for these patients.104 Costs
related to phosphate binders have been estimated at $750
million US dollars globally.105 Despite the treatment burden
for patient and economical impact for society, definite proof
of benefit at the patient-level for this intervention is lacking,
because this has never been studied appropriately. Impor-
tantly, total number of pills in and amount of phosphate
1067
review
binders prescribed in particular are associated with
nonadherence.106
What is the evidence to treat hyperphosphatemia in CKD?
The aim of controlling hyperphosphatemia is to lower associ-
ated risks for hard outcomes, particularly in mortality and
cardiovascular disease. Initially, this was based on meticulous
observations of large cohorts of dialysis patients who demon-
strated independent associations between both cross-sectional
and time-varying concentrations of phosphate with survival, as
described previously.16,17,23,107 Growing epidemiological evi-
dence supports treatment of hyperphosphatemia because a
decline in phosphate concentration is also associated with
reduced mortality.108 The most recent key finding in support of
targeting hyperphosphatemia is that observational data have
demonstrated a survival benefit for use of phosphate binders
versus not using binders.109–111 Obviously phosphate binders
are prescribed more frequently to well-nourished patients, and
indeed when adjusting for nutritional status, the relationship
was attenuated, but the association between phosphate binders
use and survival benefit persisted.109 Probably the most
compelling epidemiological support in favor of using phos-
phate binders for hyperphosphatemia in dialysis patients comes
from the Accelerated Mortality on Renal Replacement
(ArMORR) cohort, which applied propensity score matching
for phosphate binder prescription (Figure 4).111 After 1 year,
treatment with phosphate binders was associated with a sig-
nificant survival advantage compared with no treatment in
incident hemodialysis patients, except for those with a baseline
serum phosphate concentration below 3.7 mg/dl (1.2 mmol/l).
Despite all epidemiological data supporting use of phos-
phate binder for hyperphosphatemia it must be kept in mind
that observational studies can never provide the level of evi-
dence of a properly conducted prospective randomized trial.
Available pharmacological treatments and how to select
Phosphate binders are labeled for treatment of hyper-
phosphatemia, but calcimimetics also lower phosphate con-
centrations, at least in the setting of secondary
hyperparathyroidism. In that condition, a large proportion of
circulating phosphate may be derived from bone instead of
from dietary sources.112–114 Intestinal phosphate uptake is
accomplished by either a concentration or electrochemical
gradient driving paracellular transport or active transcellular
transport across ion channels. Dietary phosphate restriction
and phosphate binders lower the intestinal luminal free phos-
phate concentration. Animals studies revealed that, in the
setting of low intestinal phosphate concentrations, an upre-
gulation of NaPi2b occurred to maintain phosphate uptake by
active transcellular transport.115 This also occurs following
treatment with active vitamin D compounds.116 Subsequent
animal studies confirmed that inhibiting this transporter pre-
vented the development of hyperphosphatemia.117 Also, clin-
ically the gastrointestinal phosphate transporter NaPi2b
inhibitors nicotinamide118,119 and niacin120,121 are promising
treatments. However, these compounds are currently not on
1068
MG Vervloet and AJ van Ballegooijen: Managing phosphate in CKD
100
95
Survival (%)
90
85
80
75
0 90 180 270 365
Days
Phosphorus binder No phosphorus binder
Figure 4 | Survival of treated and untreated patients in an overall
propensity score–matched cohort of hemodialysis. Data from the
prospective observational ArMORR study compared treated (n ¼
3186) and untreated (n ¼ 3186) patients matched by their baseline
serum phosphate levels and propensity score of receiving
phosphorus binders during the first 90 days. After 1 year, treatment
with phosphorus binders was associated with a significant survival
advantage compared with no treatment in incident hemodialysis
patients. Adapted with permission from Isakova T, Gutierrez OM,
Chang Y, et al. Phosphorus binders and survival on hemodialysis. J Am
Soc Nephrol. 2009;20:388–396.111 Copyright ª American Society of
Nephrology. ArMORR, Accelerated Mortality on Renal Replacement.
the market, have not been studied in endpoints other than
biochemical control of serum phosphate concentration, still
face safety issues, and are therefore beyond the scope of this
review. The agent tenapanor (Ardelyx, Fremont, CA) targets
intestinal sodium–hydrogen exchanger and also limits ab-
sorption of phosphate. A recent clinical trial confirmed its ef-
ficacy in controlling serum phosphate concentrations.122
Currently, phosphate binders are the mainstay of orally
acting phosphate-lowering treatment. It should be empha-
sized that all phosphate binders effectively lower phosphate.104
Therefore, treatment choices are generally based on assumed
effects on intermediate endpoints like progression of vascular
calcification and patient-reported tolerance, which includes
gastrointestinal complaints and pill burden. For a long time,
the assumed risk of calcium content of some binders (calcium
carbonate and calcium acetate) has dominated this discussion.
In the recently updated KDIGO guideline on CKD-MBD,
there is now a more general suggestion to limit calcium-
containing binders in all patients,78 whereas the previous
guideline specifically mentioned subpopulations in which to
restrict calcium-containing in its phosphate binder use, like
patients with known vascular calcification.123 This change was
essentially based on the INDEPENDENT (Reduce Cardio-
vascular Calcifications to Reduce QT Interval in Dialysis) trial
in hemodialysis patients.124 In that trial, incident hemodialysis
patients with a mean 65 years of age were randomized to
either calcium carbonate or sevelamer and were found to have
a reduction in cardiovascular mortality when allocated to the
sevelamer group. The study however had some drawbacks.
The patients were relatively young, were not stratified for
Kidney International (2018) 93, 1060–1072
MG Vervloet and AJ van Ballegooijen: Managing phosphate in CKD
baseline CAC scores, and phosphate control was better for
those treated with sevelamer. The sevelamer arm had a
remarkably favorable cardiovascular survival of 94% after 3
years’ follow-up (compared to 60% in the calcium carbonate
group), which suggests that a specific population was
recruited, and hence external validity might have been limited.
At baseline, those with increased QT intervals were excluded,
whereas especially patients with QT elongation may benefit
from higher calcium concentrations.125,126
Two recent meta-analyses that compared calcium-
containing binders with noncalcium-containing binders, usu-
ally sevelamer, observed a survival advantage for noncalcium-
containing binders.127,128 These meta-analyses, as acknowl-
edged by the authors, cannot improve the quality of the original
studies on which the pooled estimates are based. Several of these
studies, including the largest Dialysis Clinical Outcomes
Revisited (DCOR) trial129 used higher than recommended
doses of calcium containing binders and suffered from
methodical issues like high drop-out rates. The DCOR trial was
negative in regards to its primary endpoint, all-cause mortality
after 24 months. However, the study did suggest reduced
mortality for those in study longer than 24 months and those
older than 65 years of age. Remarkably the suggested differences
in mortality were driven by non-cardiovascular causes.
From the perspective of phosphate as crucial component in
a complex microenvironment (Figure 3), the Calcium Acetate
Renagel Evaluation-2 (CARE-2) trial is of renewed interest. In
that trial, hemodialysis patients with established vascular
calcification at baseline were randomized to either calcium
acetate of sevelamer, with statin therapy in both groups if
needed to maintain LDL-cholesterol levels below 70 mg/dl.130
No differences were found in the progression of CAC after 1
year. This study suggests that calcification progression associ-
ated with the use of calcium-containing binders is not due to
calcium loading but to a lack of control of LDL-cholesterol
compared to sevelamer. This interpretation has been criti-
cized because the baseline risk for progressive vascular calci-
fication in the CARE-2 was exceptionally high due to comorbid
conditions like high prevalence of smoking and diabetic ne-
phropathy.131 In that setting phosphate binder selection may
have no detectable impact on development of vascular calci-
fication. However, this does not undermine the concept that
the setting in which hyperphosphatemia occurs is of impor-
tance; in the CARE-2 study there might have been over-
representation of diabetic kidney disease and smoking as
accelerators of phosphate toxicity.
Taken together, several lines of evidence advocate against the
use of calcium containing binders. However, when used in
restricted dose, and adequate phosphate control is achieved,
which was recently shown to be feasible132 these cheap binders
may still have a place in the treatment of hyperphosphatemia.
Treatment target
Following the decision to treat hyperphosphatemia and
selecting the way to do so, clinicians face the question what
the treatment target should be. Unfortunately there are
Kidney International (2018) 93, 1060–1072
review
virtually no data or guidelines that provide guidance.78 The
previously discussed analysis of the Current Management of
Secondary Hyperparathyroidism: A Multicenter Observa-
tional Study (COSMOS) demonstrated a benefit of a mean
phosphate decline of 1 mg/dl (0.32 mmol/l) for those having
a baseline value above 5.2 mg/dl (1.7 mmol/l).108 However,
whether those with higher baseline values benefit from
greater reductions of phosphate concentrations, a clinically
relevant issue, was not studied. A recent pilot study investi-
gated the effect of an intensive phosphate goal versus a more
liberalized phosphate target in hemodialysis patients in
Canada for 26 weeks. Serum phosphate concentration in the
intensive group declined by 0.40 mmol/l compared with the
liberalized group. This study showed that it is feasible to
achieve and maintain a difference in serum phosphate con-
centrations by titrating calcium carbonate. Future studies,
that may follow-up on this pilot study, might fill the
knowledge gap of optimal phosphate targets.132
Recommendations for future research
As mentioned by many authors, the ideal trial would be to
compare the effect on hard outcomes of a phosphate-lowering
intervention with placebo in the setting of overt hyper-
phosphatemia. Given the compelling experimental and
consistent epidemiological evidence pointing to a causal role
of hyperphosphatemia in the occurrence of mainly cardio-
vascular disease and mortality, the reluctance to execute such
a trial is understandable. Nevertheless, some studies may
move the field forward.
 Investigate the impact of different phosphate targets on
patient-level outcomes, possibly combined with the use of
different phosphate lowering strategies, with sufficient
sample size and follow-up duration. Such a trial could
identify the optimal treatment target and the optimal
approach to achieve that.
 Study the effect of targeting fasting serum phosphate con-
centration, as a reflection of phosphate pools.
 Investigate the differences in outcome using multifactorial
interventions addressing phosphate-toxicity modifying
factors, compared to phosphate concentration only.
Conclusion
The current management paradigm for treating phosphate-
induced toxicity is now focused on overt hyperphosphatemia.
Both dietary interventions and phosphate binder therapy are
effective in lowering serum phosphate concentrations, urinary
phosphate excretion, or both. Presently there is no definite proof
of a beneficial effect of phosphate lowering on patient-level
outcome. Moreover both dietary intervention and phosphate
binder therapy may have side effects. Despite these limitations,
treating hyperphosphatemia in CKD appears still appropriate
but should be paralleled by ongoing research to further underpin
this approach and improve therapeutic strategies. Currently,
there is insufficient evidence to actively prevent the development
of hyperphosphatemia by either dietary or pharmacological
intervention, with a possible exception for restricting phosphate-
1069
review
containing additives in patients with CKD. Possible novel
directions in addressing phosphate-associated pathology are to
consider both phosphate concentrations and phosphate loading
simultaneously. Phosphate loading is difficult to estimate clini-
cally, but measuring phosphate concentration in the fasting state,
when equilibration with phosphate pools has occurred, may be a
step forward. Finally, phosphate as a component of different
factors that modify its potential toxic effect may lead to an in-
tegrated approach to phosphate-induced comorbidity that is not
only focused on its serum concentration. The novel paradigm for
treating phosphate-induced comorbidity may be a multifactorial
approach that not only targets phosphate concentrations but also
consists of maintaining or increasing a-klotho, possibly lowering
FGF23, and optimizing co-existing metabolic derangements
such as acidemia, overt hyperparathyroidism, hypercalcemia,
diabetes, and inflammation.
DISCLOSURES
MGV has received research grants from AbbVie, Amgen, FMC, Sanofi,
and Dutch Kidney Foundation; has received speakers fees from
Baxter, Amgen, BBraun, and VFMCRP; and has consulted for Amgen,
Medice, VFMCRP, Otsuka, and Astellas. MGV is member of ERA-EDTA
working group on CKD-MBD and KDIGO working group on CKD-MBD.
The current narrative review is not written on behalf of these working
groups. The other author has declared no competing interests.
ACKNOWLEDGMENTS
AJvB is supported by a Dr. Kolff junior postdoctoral grant from the
Dutch Kidney Foundation (16OKG02).
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