mini review
org
Parathyroid hormone metabolism and signaling in
health and chronic kidney disease
Pieter Evenepoel1,4, Jordi Bover2,4 and Pablo Ureña Torres3,4
1
KU Leuven, Department of Immunology and Microbiology, Laboratory of Nephrology and University Hospitals Leuven, Department of
Nephrology and Renal Transplantation, B-3000 Leuven, Belgium; 2Fundació Puigvert, Department of Nephrology, IIB Sant Pau, RedinREn,
Barcelona, Catalonia, Spain; 3Ramsay-Générale de Santé, Clinique du Landy, Service de Néphrologie-Dialyse, Saint Ouen, France, INSERM
U1151-CNRS UMR8253 Université Paris Descartes, and Service des Explorations Fonctionnelles, Hôpital Necker-Enfants Malades, Paris,
France; and 4Board member of the ERA-EDTA CKD-MBD Working Group
Circulating parathyroid hormone (PTH) shows a complex
relationship with hard outcomes in subjects with chronic
kidney disease (CKD). Moreover, intervention studies
directly targeting PTH failed to yield unequivocal results.
Disturbed PTH metabolism, posttranslational modifications
of PTH, and end-organ hyporesponsiveness to PTH may
explain the poor performance of PTH as an outcome
biomarker and precise target of therapy in the setting of
CKD, at least in the gray middle target zone. PTH fragments
accumulate in CKD patients and may exert effects that are
distinct from, if not opposite to biointact (1-84)PTH.
Posttranslational modification of PTH and especially
oxidation may alter the interaction of PTH with its receptor.
Its clinical relevance, however, remains a matter of ongoing
debate. Less controversial is the issue of end-organ
hyporesponsiveness to PTH. This phenomenon, formally
referred to as PTH resistance, has long been recognized in
CKD, but factors and mechanisms contributing to it remain
poorly defined. Subsequent evidence identified
downregulation of the PTH receptor and competing
downstream signals as underlying pathophysiologic
mechanisms. End-organ hyporesponsiveness to PTH in
CKD, along with important analytical and biological
variability, renders defining the PTH target range in CKD
challenging. Although this may still be accomplished at the
population level, it may prove to be very difficult at the
individual level. This is a disillusioning thought in an era of
personalized medicine. Parallel to the search of a functional
and readily available assay quantifying PTH signaling tone
or sensitivity, additional biomarkers (or a panel of
biomarkers) should be formally evaluated.
Kidney International (2016) 90, 1184–1190; http://dx.doi.org/10.1016/
j.kint.2016.06.041
KEYWORDS: CKD; hyperparathyroidism; mineral metabolism; parathyroid
hormone
Copyright ª 2016, International Society of Nephrology. Published by
Elsevier Inc. All rights reserved.
Correspondence: P. Evenepoel, Dienst nefrologie, Universitair Ziekenhuis
Gasthuisberg, Herestraat 49, B-3000 Leuven, Belgium. E-mail:
Pieter.Evenepoel@uzleuven.be
Received 7 May 2016; revised 24 June 2016; accepted 27 June 2016;
published online 18 September 2016
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www.kidney-international.
C
hronic kidney disease (CKD)–mineral bone disorder is
a systemic disorder that describes the complex bone
and mineral abnormalities that occur in CKD. Sec-
ondary hyperparathyroidism (SHPT) is an integral compo-
nent of CKD–mineral bone disorder and, if left unchecked,
leads to a worsening of laboratory abnormalities, bone dis-
ease, and soft-tissue calcification.1 In recent years, insights
into the pathogenesis of SHPT have improved, and the ther-
apeutic armamentarium to tackle this condition has
expanded. However, the relationship between circulating
parathyroid hormone (PTH) concentration and outcomes
in CKD patients is complex and rather weak, unless at the
extremes. In this mini review, we discuss factors and mecha-
nisms underlying the disappointing performance of PTH as
an outcome biomarker and target of therapy in CKD and
therefore focus on the underappreciated role of end-organ
hyporesponsiveness to PTH.
PTH METABOLISM AND SIGNALING IN HEALTH
PTH metabolism
PTH is a single-chain hormone of 84 amino acids that is
mainly produced by chief cells of the parathyroid glands. PTH
is cleaved from pre-pro–PTH and thereafter stored in secre-
tory granules awaiting 1 of 2 fates: circadian and pulsatile
secretion or intracellular degradation. Synthesis and secretion
of PTH are tightly regulated by extracellular calcium (Ca2þ).
Hypercalcemia not only reduces overall PTH secretion but
also favors release of PTH fragments, whereas hypocalcemia
stimulates overall PTH secretion and favors (1-84)PTH
release. After secretion, (1-84)PTH and its fragments are
further metabolized in the kidney and liver.2 The half-life of
C-terminal PTH fragments is much longer than the half-life
of (1-84)PTH, being 2 to 4 minutes. Thus, circulating PTH
is a heterogeneous mixture of full-length hormone and
fragments, with (7-84)PTH accounting for as much as 50% of
overall PTH.3
Increasingly specific PTH assays have been developed over
the years. Second-generation assays are currently the most
widely implemented. They use a capture antibody that binds
near the N-terminus and a second solid phase–coupled
antibody that binds to the C-terminus. Differences in anti-
body specificities and affinities of the assays translate in
differing recovery of (1-84)PTH and differing cross-reactivity
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P Evenepoel et al.: PTH hyporesponsiveness in CKG
with (7-84)PTH and other fragments. This may explain,
together with the lack of an agreed-on common standard
(calibrator), the large variability that exists among commer-
cially available second-generation PTH assays.4 The third-
generation assay uses the same capture antibody, but the
detection antibody is more specific for the first 4 amino acids
of PTH, thereby avoiding cross-reactivity with the N-terminal
truncated PTH fragments. PTH shows homology with PTH-
related peptide (PTHrP), the molecule responsible for most
humoral hypercalcemia of malignancies; however, PTHrP
does not cross-react with PTH in those PTH assays.
PTH signaling
PTH and PTHrP exert their multiple actions by binding to
PTH/PTHrP type 1 receptor (PTH1R). PTH1R is highly
expressed in bone and kidney, but also at lower levels in the
vasculature and in other tissues at various times throughout
development. PTH1R is a 7-transmembrane, G protein–
coupled receptor linked to heterotrimeric G proteins Gs and
Gq. The activation of PTHR1 by PTH signals through several
intracellular pathways, including protein kinase A and protein
kinase C, although a preference for certain pathways is
apparent in each organ and function, which depends on the
presence or the absence of the sodium-dependent hydrogen
exchanger regulatory factor-1.3 Termination of PTH1R
signaling is achieved through negative feedback of PTH
secretion in response to restoration of Ca2þ levels or by a
desensitization-internalization process of the receptor.3,5
In addition to PTH1R, a second G protein–coupled PTH
receptor, PTH2R, has been identified. The PTH2R normally
responds to tuberoinfundibular peptide 39, but is inhibited by
PTH and does not interact with PTHrP. PTH2R is expressed
in various tissues, but its function is still poorly understood.
Finally, a receptor has been characterized in osteoblasts
and osteocytes with specificity for the C-terminal region of
PTH (C-PTHR).6,7 Although much remains to be learned
about the C-PTH/C-PTHR system, available evidence in-
dicates that it seems to act antagonistically to the PTH/
PTH1R system. A major effect of C-PTHR activation could be
the suppression of osteocytic osteolysis.
Classic target organs of PTH
Bone. PTH plays an important role in maintaining Ca2þ
homeostasis and in bone remodeling. PTH pulses and sus-
tained PTH elevations promote calcium release from the bone
using various mechanisms with markedly different kinetics.
PTH-mediated Ca2þ release from a rapid skeletal exchange-
able pool and osteocytic osteolysis are thought to underlie the
acute (minute-hours) response to hypocalcemia. The slow
response, which takes several days, is driven by bone cells
involved in the remodeling process.
Various paracrine and endocrine signals participate in
bone remodeling, with PTH playing a central role. Direct
effects of PTH on osteoblasts and osteocytes and indirect
actions on osteoclasts promote both bone formation and
bone resorption. The final effect on bone mass, either
Kidney International (2016) 90, 1184–1190
mini review
anabolic or catabolic, appears to depend on the duration and
periodicity of PTH exposure. Bone resorption predominates
in response to continuous exposure to high circulating PTH
levels, whereas intermittent PTH administration leads to a net
increase in bone mass. Continuous, as compared with inter-
mittent, PTH exposure regulates in bone cells different sets of
genes or, alternatively, affects the same sets of genes in a
sustained versus transient manner, the first favoring bone
resorption and the second bone formation. PTH1R signaling
in osteoblasts and osteocytes can increase the receptor acti-
vator of nuclear factor-kB ligand/osteoprotegerin (RANKL/
OPG) ratio. The OPG-RANKL-RANK pathway appears to be
the main mediator of the catabolic actions of PTH. Moreover,
continuous exposure to PTH causes a sustained upregulation
of monocyte chemoattractant protein-1, another mediator of
bone resorption. The anabolic effect of PTH on bone,
conversely, seems to be mediated largely through canonical
Wnt signaling. PTH may increase Wnt signaling both directly
and indirectly (e.g., by repressing the osteocytic expression of
secreted Wnt antagonist sclerostin5) (Figure 1).
PTH also interacts with skeletal endocrine functions.8
Again, the dynamics of exposure seem to be of importance.
Whereas short-term (1-34)PTH infusion studies showed
suppressed circulating fibroblast growth factor 23 (FGF23)
levels, longer term infusion studies showed a delayed increase
in FGF23, most probably in response to the PTH-induced
increase in circulating calcitriol.9
Kidney. In the kidney, PTH stimulates Ca2þ reabsorption
in the distal convoluted tubule by activating specific ion
channels. It also increases urinary phosphate excretion mainly
by regulating sodium-phosphate cotransporters in the prox-
imal convolute tubule via both protein kinase A– and protein
kinase C–dependent pathways. It also indirectly enhances
intestinal Ca2þ and phosphate absorption by stimulating the
renal production of 1,25-dihydroxy-vitamin D3.3
Nonclassic target organs of PTH
PTH1R is expressed in various other tissues, including the
pancreas, bone marrow, and vasculature. PTH and PTHrP exert
acute vasodilatory actions through PTH1R activation in
vascular smooth muscle cells and reduce vascular oxidative
stress and procalcific and profibrotic signals that drive arte-
riosclerotic disease.10 These actions may be considered para-
doxical when viewed against the backdrop of the hypertension
and vascular disease arising in the setting of primary hyper-
parathyroidism. It is suggested that the vasculopathy of SHPT
may relate to an arterial desensitization to paracrine PTHrP/
PTH1R-dependent regulation of vascular tone and/or renal
hemodynamics in addition to direct toxic effects mediated by
high calcium and/or phosphate levels, often accompanying
SHPT. Thus strategies that selectively preserve the paracrine
PTHrP/PTH1R pathway are generally predicted to exert car-
diovascular benefits, with reduced calcification, restricted
neointimal formation, and appropriate regional tissue perfu-
sion in response to physiologic demands reflecting preservation
of healthy conduit artery structure and function.10 Diseases or
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mini review
Figure 1 | Parathyroid hormone (PTH) and bone metabolism. PTH elicits bone anabolic and catabolic effects by stimulating both bone
formation and, indirectly, bone resorption. PTH exerts its action by binding to the PTH type 1 receptor (PTH1R) mainly expressed on osteoblasts
and osteocytes. PTH may increase osteoanabolic Wnt signaling both directly and indirectly (e.g., by repressing the osteocytic expression of
secreted Wnt antagonist sclerostin). FZD, frizzled; LRP, low-density lipoprotein receptor; OPG, osteoprotegerin; PKA, protein kinase A; RANKL,
receptor activator of nuclear factor-kB (ligand).
interventions impeding paracrine PTHrP/PTH1R signaling,
conversely, may foster vascular disease.
The biological actions of PTH thus extend beyond main-
taining mineral and bone metabolism to include endocrine,
immunologic, and cardiovascular effects. Most recently,
PTHrP/PTH1R signaling has also been demonstrated to fos-
ter wasting and muscle atrophy.11 This further strengthens the
notion of PTH as an important uremic toxin.
PTH METABOLISM AND SIGNALING IN CKD
Although data from the CRIC (Chronic Renal Insufficiency
Cohort) study pointed out that PTH concentrations start to
increase once the estimated glomerular filtration rate drops
below 45 ml/min per 1.73 m2, more recent data from a Swiss
population–based cohort study show a steady increase of PTH
concentrations paralleling the estimated glomerular filtration
rate decline and already being significant at an estimated
glomerular filtration rate of 126 ml/min per 1.73 m2.12 In
patients with advanced CKD, SHPT is an almost universal
complication. Both enhanced PTH synthesis and secretion
and increased parathyroid gland mass contribute to the high
circulating PTH levels in CKD. The pathogenesis of SHPT is
complex, involving multiple closely interacting factors. These
include Ca2þ, phosphate, calcitriol, FGF23, Klotho, and
uremic toxins. In addition, normal inhibitory feedback
mechanisms become deficient in CKD due to downregulation
of the parathyroid Ca2þ-sensing, vitamin D, and FGF23/
Klotho receptors. End-organ hyporesponsiveness to the
action of PTH may also contribute to the exacerbation of
SHPT in CKD because higher and higher levels of PTH are
progressively needed to maintain Ca2þ homeostasis.
Despite CKD patients generally present with serum PTH
levels that are many times higher than those of patients with
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P Evenepoel et al.: PTH hyporesponsiveness in CKG
primary hyperparathyroidism, bone and renal phenotypes
markedly differ. Indeed, patients with primary hyperpara-
thyroidism show high-normal calcitriol levels, hyper-
calciuria, and high bone turnover. To the contrary, these
features are not universally present in CKD patients with
SHPT. Thus, high circulating PTH levels in CKD are not
necessarily paralleled by increased PTH signaling or at least
PTH signaling is attenuated. Disturbed PTH metabolism,
posttranslational modifications, and end-organ hypores-
ponsiveness to PTH probably contribute to the complex
relationship between circulating PTH and outcomes in CKD
(Figure 2).
Disturbed PTH metabolism in CKD
PTH metabolism is disturbed in CKD,2,13 which results in a
marked prolongation of the half-life of C-terminal PTH
fragments. Clinical data show a proportional increase in C-
terminal PTH fragments versus biointact PTH during the
progression of CKD. Mounting evidence indicates that
C-terminal PTH fragments, by binding to the PTH1R or C-
PTHR, exert biological effects that are distinct if not opposite
of (1-84)PTH.9
Posttranslational PTH modification in CKD
Proteins in the human body, in both health and disease, are
exposed to chemical reactions capable of altering their
structural and functional properties. Substantial carbamyla-
tion or glycation of key proteins (including albumin, eryth-
ropoietin, low-density lipoprotein, and collagen) has been
reported in CKD.14 Although glycation and carbamylation of
PTH have so far not been reported, recent evidence indicates
that PTH may be oxidized to a variable extent in patients with
CKD.15 Oxidized PTH loses its biological activity as it fails to
Kidney International (2016) 90, 1184–1190
P Evenepoel et al.: PTH hyporesponsiveness in CKG mini review

(–)
(–)

(–)

cAMP

Figure 2 | Impact of chronic kidney disease (CKD) on parathyroid hormone (PTH) metabolism and signaling. CKD has an impact on many
aspects of PTH metabolism and signaling: (i) increased synthesis and secretion, parathyroid cell proliferation, and vitamin D receptor (VDR) and
calcium-sensing receptor (CaSR) downregulation; (ii) accumulation of C-terminal PTH fragments; (iii) posttranslational modification of PTH; (iv)
competitive inhibition between (1-84)PTH and its fragments; (v) PTH type 1 receptor (PTH1R) downregulation; (vi) PTH1R dysfunction; (vii)
inhibitory or competing downstream signals. cAMP: cyclic adenosine monophosphate; FGF23, fibroblast growth factor 23; FGFR1, fibroblast
growth factor receptor 1; LPS, lipopolysaccharide; PhosR, phosphate-sensing receptor.

bind its receptor. Oxidation of methionine residue 8 seems
especially crucial in generating conformational changes in
the secondary structure of PTH. A high-resolution liquid
chromatography and/or mass spectrometry method was
developed (so-called fourth-generation assay) to reliably
quantify oxidized PTH in serum samples.15 Although of in-
terest, confirmatory studies are warranted because PTH
oxidation could also occur as an ex vivo artifact.
PTH hyporesponsiveness in CKD
The bone and renal responses to the action of PTH are
progressively impaired in CKD, a condition commonly
referred to as PTH resistance. We consider the term hypo-
responsiveness more appropriate because the response to
PTH is blunted, but not absent. Other conditions associated
with PTH hyporesponsiveness include aging, black race, and
diabetes. The concept of PTH hyporesponsiveness in CKD is
not novel but remains underappreciated in the nephrology
community. Its pathogenesis, moreover, is complex and only
partly understood. Multiple factors are involved including
phosphate loading, calcitriol deficiency, oxidative stress,
aluminum overload, magnesium deficiency, accumulation of
PTH fragments, and uremic toxins,16 inducing deficiencies in
trophic factors, excesses of growth inhibitors, or receptor or
postreceptor defects. Recent evidence points to decreased
PTH1R expression and function and competing downstream
signals in addition to local environmental factors as
contributing mechanisms.

Kidney International (2016) 90, 1184–1190 1187

mini review
PTH1R downregulation. Renal failure in rodents is asso-
ciated with a decreased expression of PTH1R (at least at the
mRNA level) in various tissues and on cells, including
bone17–19 and renal tubular cells.20 Human data are less
consistent, with some investigators demonstrating decreased
expression21 and others reporting increased expression22 of
PTH1R in uremic conditions. This apparent discrepancy
remains to be explained. Both analytical issues and case mix
may be involved. Although the mechanisms responsible for
the (putative) desensitization or downregulation of PTH1R in
CKD remain poorly defined, several lines of evidence impli-
cated C-terminal PTH fragments and cellular oxidative stress.
PTH fragments. PTH fragments may suppress PTH
signaling by promoting PTH1R downregulation in both bone
and kidney cells.23 Additionally, PTH fragments may oppose
PTH signaling by both acting as competitive inhibitors of
bioactive PTH and activating the C-PTHR.7 (7-84)PTH is
suggested to be a component of a feedback mechanism at the
level of the parathyroid gland, bone, or both.9,24 According to
this reasoning, increased bioactive PTH may, in addition to
increasing bone turnover, foster the secretion of (7-84)PTH
by the parathyroid gland, which in turn limits the actions of
the bioactive molecule on bone.
Cellular oxidative stress. A diminished calcemic response to
the infusion of bioactive PTH and/or downregulation of the
skeletal and renal PTH1R has been observed in para-
thyroidectomized uremic rats and in uremic rats with PTH
levels maintained within the normal range.16 This indicates the
involvement of factors beyond PTH fragments in the patho-
genesis of PTH hyporesponsiveness in uremia.25 Subsequent
experimental studies pointed to a circulating factor,26 most
likely uremic toxins triggering cellular oxidative stress, such as
indoxyl sulfate and inflammatory bioactive lipids (e.g., ox-
LDL), as the most likely culprit.27,28 Increased oxidative
stress, a common condition in CKD, may thus be in the causal
pathway between CKD and PTH hyporesponsiveness.
Dysfunctional PTH1R. A recent study suggested that solu-
ble Klotho might interact with the PTH1R on renal tubular
cells and thereby prevent binding of bioactive PTH. As FGF23
increases the release of soluble Klotho, it may thus be
hypothesized that part of the effect of FGF23 in lowering
calcitriol is mediated by impairing PTH signaling.29
Competing downstream PTHR1 signals and local
environmental factors
The downstream effects of PTH may be offset by competing
and/or inhibitory paracrine and endocrine signals, mediated
by, for example, high sclerostin and osteoprotegerin, low bone
morphogenetic protein 7, and Klotho, in addition to local
environmental factors (e.g., acid base disturbances, inflam-
mation).30 Increased osteocytic sclerostin expression has
indeed been observed in early-stage CKD.31 Of note, circulating
osteoprotegerin and sclerostin levels are many times higher in
advanced CKD than counterparts with normal kidney func-
tion. To what extent circulating sclerostin levels reflect bone
expression and affect local signaling remains to be investigated.
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P Evenepoel et al.: PTH hyporesponsiveness in CKG
CLINICAL RELEVANCE OF PTH HYPORESPONSIVENESS
Linear (simple) associations have been reported between
circulating PTH levels and bone outcomes (bone turnover,
bone loss, fractures) in patients with primary hyperparathy-
roidism. Conversely, the association between circulating PTH
levels and outcomes in CKD patients is complex, often
reported as curvilinear and overall rather weak.32,33 CKD-
induced changes in PTH metabolism and signaling substan-
tially and distinctly affect the relationship between PTH and
hard outcomes (i.e., bone disease, vascular calcification, sur-
vival). PTH hyporesponsiveness is as much an integral
component of CKD mineral bone disorder as elevated
circulating PTH levels.
Regarding bone, not only the accumulation of PTH frag-
ments but also the multifactorial desensitization of the
PTH1R may explain why low-turnover bone disease is very
prevalent in contemporary CKD patients, although these
patients often demonstrate circulating PTH levels far above
the upper normal limit.30,34 Cohort studies clearly showed
that only at the extremes is PTH able to predict the bone-
turnover status with acceptable sensitivity/specificity.1
There is close interaction between bone and vasculature in
CKD, commonly referred to as the bone-vascular axis. Low-
turnover bone disease is closely associated with vascular dis-
ease, especially calcification. The underlying pathophysiologic
mechanisms are complex and incompletely understood. In a
recent cross-sectional study, peripheral artery disease was
found to be associated with significant reductions in the
skeletal anabolic response to PTH.35 Thus, PTH hypores-
ponsiveness may be the common soil for low-turnover bone
disease and vascular disease and might indeed explain the
coincidence of these diseases in CKD.
CONCLUSIONS AND FUTURE DIRECTIONS
Monitoring PTH is routine clinical practice in nephrology
care. Much has been inferred from increased PTH values,
both in terms of skeletal integrity and fractures and in terms
of clinical outcomes for patients. However, recent data from
epidemiologic and intervention studies questioned the val-
idity of PTH as a consistent outcome biomarker and target of
therapy in CKD. Altered PTH metabolism and PTH hypo-
responsiveness along with a high biological variability may
explain why a circulating PTH level, unless at the extremes,
performs poorly as biomarker.
Although defining an optimal PTH range may be chal-
lenging but accomplishable at the population level, this
might be a very difficult task at the patient level. This is a
disillusioning thought in an era of personalized medicine.
Some even hastily advocated that given its many limitations,
the time has come to abandon PTH as an outcome
biomarker and target of therapy in CKD.36 It should be
emphasized that no biomarker so far clearly proved to be
superior to PTH in predicting bone metabolism in CKD.
More research is needed. Meanwhile, more frequent PTH
testing, enabling PTH trends to be captured accurately, rather
than abandoning PTH monitoring should remain the motto.
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P Evenepoel et al.: PTH hyporesponsiveness in CKG
The striking increase in low bone turnover disease in patients
with end-stage renal disease in recent decades clearly points
to overtreatment of secondary hyperparathyroidism. Better
knowledge of the issue of PTH hyporesponsiveness may help
to turn the tide. Obviously, PTH levels less than 2 times the
upper normal limit should be avoided in patients with
advanced CKD.
Additional efforts are mandatory to improve diagnostics. A
functional and readily available assay quantifying PTH1R
signaling tone or sensitivity would be a great step forward.
Parallel to the development of such an assay, the performance
of more specific biomarkers (or a panel of biomarkers)
should be tested, if possible, against the gold standard (e.g., a
bone biopsy when evaluating bone integrity). An increasing
body of evidence points to (bone-specific) alkaline phos-
phatase as a promising adjunct to PTH. Because no
biomarker is free of limitations (renal clearance and meta-
bolism, high biological variability), bone biopsies may still be
needed in some conditions. Recent technical advances
reduced morbidity and may help to lower the threshold for
this diagnostic procedure, allowing a better understanding in
the future of the narrow link between circulating PTH con-
centration, PTH-hyporesponsiveness, and hard outcomes.
DISCLOSURE
All the authors declared no competing interests.
ACKNOWLEDGMENTS
PE has received speaker’s and advisory board honoraria from Amgen,
Shire, Sanofi-Genzyme, and Vifor-Fresenius and research grants from
Amgen, Sanofi-Genzyme, and Tecomedical. JB declares having
received speaker’s and/or advisory board honoraria from Abbvie,
Amgen, Sanofi-Genzyme, Shire, Vifor/Fresenius-Pharma, Medice, and
Chugai.
PUT has received speaker’s honoraria, clinical trial studies
honoraria, and advisory board honoraria from Amgen, Shire, Astellas,
Hemotech, and Vifor-Fresenius.
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