Clin Exp Nephrol (2017) 21 (Suppl 1):S37–S45
DOI 10.1007/s10157-016-1369-2
REVIEW ARTICLE
Management of secondary hyperparathyroidism: how and why?
Hirotaka Komaba1,2 • Takatoshi Kakuta1,3 • Masafumi Fukagawa1
Received: 22 November 2016 / Accepted: 29 November 2016 / Published online: 2 January 2017
Ó Japanese Society of Nephrology 2016
Abstract Secondary hyperparathyroidism (SHPT) is a
common complication in chronic kidney disease. Cur-
rently, various treatment options are available, including
vitamin D receptor activators, cinacalcet hydrochloride,
and parathyroidectomy. These treatment options have
contributed to the successful control of SHPT, and recent
clinical studies have provided evidence suggesting that
effective treatment of SHPT leads to improved survival.
Although bone disease is the most widely recognized
consequence of SHPT and remains a major target for
treatment of SHPT, there is increasing evidence that
parathyroid hormone (PTH) and fibroblast growth factor 23
(FGF23), both of which are markedly elevated in SHPT,
have multiple adverse effects on extraskeletal tissues.
These actions may lead to the pathological development of
left ventricular hypertrophy, renal anemia, immune dys-
function, inflammation, wasting, muscle atrophy, and urate
accumulation. Given that treatment of SHPT leads to
decreases in both PTH and FGF23, these data provide an
additional rationale for treating SHPT. However, definitive
evidence is still lacking, and future research should focus
on whether treatment of SHPT prevents the adverse effects
of PTH and FGF23.
& Hirotaka Komaba
hkomaba@tokai-u.jp
1
Division of Nephrology, Endocrinology and Metabolism,
Tokai University School of Medicine, 143 Shimo-Kasuya,
Isehara 259-1193, Japan
2
The Institute of Medical Sciences, Tokai University, Isehara,
Japan
3
Division of Nephrology, Endocrinology and Metabolism,
Tokai University Hachioji Hospital, Hachioji, Japan
Keywords Chronic kidney disease
Fibroblast growth
factor 23
Parathyroid hormone
Secondary
hyperparathyroidism
Introduction
Secondary hyperparathyroidism (SHPT) is a common
complication in chronic kidney disease (CKD) that is
characterized by excessive synthesis of parathyroid hor-
mone (PTH) and parathyroid hyperplasia [1]. Hyperphos-
phatemia, decreased 1,25-dihydroxyvitamin D, and the
resultant slight decrease in serum calcium have been con-
sidered to be the main contributors to the pathogenesis of
SHPT [2]. In addition, recent investigations have identified
fibroblast growth factor 23 (FGF23), a bone-derived
phosphaturic hormone [3], as another important factor in
this pathogenesis. The current concept is that increased
FGF23, which presumably occurs to maintain a neutral
phosphate balance, results in decreases in the renal pro-
duction of 1,25-dihydroxyvitamin D and thereby leads to
increased PTH secretion [4, 5]. FGF23 is also known to
inhibit PTH secretion [6], but this effect is less pronounced
in end-stage renal disease (ESRD) because of the down-
regulation of the Klotho-FGF receptor 1 complex in the
parathyroid gland [7, 8].
Because uncontrolled SHPT potentially affects patient
outcomes, several national and international clinical prac-
tice guidelines recommend that PTH levels be kept within
specific ranges [9, 10]. Until several years ago, vitamin D
receptor activators (VDRAs) had been the mainstay of
treatment for SHPT [11]. However, their clinical utility has
been limited, because VDRAs enhance the intestinal
absorption of calcium and phosphorus, and the parathyroid
response to VDRAs is substantially decreased in advanced
123
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SHPT [12]. Cinacalcet hydrochloride, a new option for the
therapeutic control of SHPT, allosterically modulates the
parathyroid calcium-sensing receptor (CaSR) and increases
its sensitivity to extracellular calcium [13]. Despite
advances in medical therapy for SHPT, surgical parathy-
roidectomy (PTx) remains the definitive therapy for
refractory SHPT, which drastically decreases PTH levels
and ameliorates symptoms related to severe SHPT [14].
Although high-turnover bone disease has been the most
widely recognized consequence of SHPT [15], observa-
tional studies have demonstrated that elevations in PTH
levels are associated with an increased risk of mortality and
cardiovascular outcomes [16–18]. Furthermore, PTH has
been regarded as a uremic toxin, thus potentially also
explaining the poor health-related quality of life of this
population. Although the detailed mechanisms of these
actions have been unclear, recent research has provided
convincing evidence of direct and indirect involvements of
PTH and FGF23 in these pathological processes.
In this review, we outline current and future treatments
for SHPT and discuss clinical and experimental evidences
on the consequences of uncontrolled SHPT, with a partic-
ular focus on the novel pathogenic roles of PTH and
FGF23.
Current and future treatment of SHPT
VDRAs
The complex pathophysiology of SHPT offers several
options for the treatment of this disorder. Hyperphos-
phatemia plays an important role in the pathogenesis of
SHPT, and dietary phosphorus restriction or treatment with
oral phosphate binders inhibits PTH secretion in mild-to-
moderate CKD [19, 20]. Importantly, a series of experi-
mental studies have shown that high phosphate directly
stimulates PTH secretion [21, 22]. However, management
of hyperphosphatemia alone is typically not effective in
decreasing PTH levels in patients with ESRD. Thus,
treatment with VDRAs has long been the main strategy for
the management of SHPT [11].
Calcitriol, the first synthetic physiological VDRA,
effectively decreases serum PTH levels in patients with
CKD [23]. This agent inhibits PTH mRNA synthesis,
thereby decreasing the production of PTH. This effect is
mainly mediated by binding of calcitriol to its specific
receptor, VDR, and subsequent regulation of gene tran-
scription via vitamin D response elements within the pro-
moter regions of genes. In addition to its inhibitory effect
on PTH synthesis, calcitriol also enhances intestinal cal-
cium resorption and thereby exacerbates hypercalcemia,
particularly when it is used in conjunction with calcium-
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Clin Exp Nephrol (2017) 21 (Suppl 1):S37–S45
based phosphate binders. The increased occurrence of
hypercalcemia limits the clinical utility of calcitriol,
because hypercalcemia promotes vascular calcification
[24], thus potentially leading to cardiovascular events.
The newer selective VDRAs, such as paricalcitol (19-
nor-1,25-dihydroxyvitamin D2) [25] and maxacalcitol (22-
oxa-1,25-dihydroxyvitamin D3) [26], may be preferable for
control of biochemical outcomes, because they have more
modest effects on serum calcium levels. However, even
these selective VDRAs can cause hypercalcemia. Further-
more, clinical studies have demonstrated that VDRAs are
not effective in suppressing PTH secretion in patients with
enlarged parathyroid glands [12], presumably because of
decreased expression of the CaSR and vitamin D receptor
(VDR) in the parathyroid gland [27, 28]. Thus, VDRAs
have been effective in patients with mild-to-moderate
SHPT, but it has been challenging to control PTH levels
with these agents in patients with more advanced SHPT.
Calcimimetics
Cinacalcet hydrochloride is the most recent option for the
treatment of SHPT. A large number of trials have shown
that treatment with cinacalcet effectively reduces PTH
levels while simultaneously reducing serum calcium and
phosphate levels in patients with moderate-to-severe SHPT
[13]. Subsequent studies have documented that the use of
cinacalcet in combination with low doses of vitamin D
analogs provides a better control of SHPT while adequately
maintaining acceptable levels of calcium and phosphorus
[29]. Notably, cinacalcet is effective even in patients with
marked parathyroid hyperplasia [30], thus suggesting that it
may serve as an alternative to PTx for treatment of severe
SHPT. It is also noteworthy that treatment with cinacalcet
induces a reduction in parathyroid gland volume even in
glands with marked hyperplasia [30]. However, whether
such a morphological change results in the long-term
controllability requires further investigation.
After market introduction of cinacalcet, two observa-
tional studies from the US [31] and Europe [32] evaluated
the effectiveness of cinacalcet in the real-world clinical
setting. These studies have demonstrated significant
reductions in serum calcium, phosphorus, and PTH levels
after cinacalcet treatment, but the magnitude of these
effects was smaller than that in clinical trials, presumably
because of modest, slow dose titration. In contrast to these
observations in the US and Europe, the rate of PTx has
been found to dramatically decrease after introduction of
cinacalcet according to the recent survey in Japan [33]. The
Dialysis Outcomes and Practice Patterns Study (DOPPS)
has also demonstrated a marked reduction in PTx rate and
better control of PTH in Japan compared with other
countries after introduction of cinacalcet [34].
Clin Exp Nephrol (2017) 21 (Suppl 1):S37–S45 S39

To explore the reasons for these differences, we ana- pretreatment PTH levels (Fig. 1d). Notably, serum calcium
lyzed data from our historical cohort study of 2292 main- levels before cinacalcet administration were relatively
tenance hemodialysis patients in Japan. During the increased in patients with mild SHPT (intact PTH
observational period from December 2008 to December \300 pg/ml), thus possibly indicating one reason for the
2011, the percentage of patients receiving cinacalcet decision to start cinacalcet in these patients. These data
increased progressively, whereas the mean dose remained highlight the actual practice patterns of cinacalcet pre-
stable. Most patients received one 25-mg tablet daily scription in Japan and suggest that the successful man-
(Fig. 1a). At the time immediately before cinacalcet agement of SHPT in Japan can be attributed to early
administration, median intact PTH was 286 pg/ml (in- initiation of low-dose cinacalcet for mild-to-moderate
terquartile range 207–385 pg/ml), and only 15% of patients SHPT.
met indication criteria for PTx in Japan (intact PTH As described above, cinacalcet is effective even in
C500 pg/ml) (Fig. 1b). After the initiation of cinacalcet patients with severe SHPT, but appropriate dose increases
treatment, median intact PTH levels decreased to approx- are required to achieve effective control of SHPT. How-
imately 160–180 pg/ml (Fig. 1c). Cinacalcet also led to a ever, aggressive dose increases are occasionally difficult
reduction in serum calcium levels regardless of mainly because of the gastrointestinal adverse effects, such

Cinacalcet dose (mg/day) Cinacalcet prescription (%)

A 25 150 B 50
Indication for PTx
n = 2,281 Cinacalcet dose (mg/day)
Cinacalcet prescription (%)

Intact PTH >500 pg/ml

125

Number of patients
20 40

100
15 30
75
10 20
50

5 10
25

0 0 0

Intact PTH (pg/ml)

Time period

C 450 D
10.5 intact PTH <300 pg/ml (n = 140)
Mean serum calcium (mg/dl)
Median intact PTH (pg/ml)

400 n = 259 intact PTH >300 pg/ml (n = 119)

350 10.0
300
250
9.5
200
150
100 9.0

50
0 8.5
0 3 6 9 12 15 18 21 24 27 30 33 36 0 3 6 9 12
Months Months

Fig. 1 Prescription pattern of cinacalcet hydrochloride in Japan. criteria for PTx in Japan (intact PTH C500 pg/ml). c Median
a Cinacalcet use and dosage between December 2008 and December (interquartile range) intact PTH levels during cinacalcet treatment.
2011. Of the 2292 patients in the entire cohort, we excluded 11 After initiation of cinacalcet treatment, median intact PTH levels
patients with missing data on cinacalcet prescription. The percentage decreased to approximately 160–180 pg/ml. d Mean (±SD) serum
of patients receiving cinacalcet increased progressively, whereas the calcium levels during cinacalcet treatment. Cinacalcet led to a
mean dose remained stable, and most patients received one 25-mg reduction in serum calcium levels regardless of pretreatment PTH
tablet daily. b Distribution of intact PTH levels before cinacalcet levels. Serum calcium levels before cinacalcet treatment were
administration. Cinacalcet was mainly prescribed for patients with relatively increased in patients with mild SHPT
mild-to-moderate SHPT. Only 15% of patients met the indication

123
S40
as nausea and vomiting. In this regard, the introduction of a
new calcimimetic etelcalcetide [35] is a promising option,
because the intravenous route of administration for this
agent is associated with lower luminal gastrointestinal
exposure. Indeed, a recent phase 3 trial has demonstrated
that intravenous administration of etelcalcetide for patients
with moderate-to-severe SHPT results in a marked reduc-
tion in PTH levels, with a low incidence of gastrointestinal
adverse effects [36]. Future studies should directly com-
pare cinacalcet and etelcalcetide in terms of effectiveness,
adverse effects, long-term outcomes, and cost. These data
would be important to determine the adequate target pop-
ulation for these two agents.
PTx
When medical treatment fails or is not tolerated because
of adverse effects in patients with severe SHPT, surgical
PTx is the final therapeutic option [14]. The number of
PTx was dramatically decreased after the introduction of
cinacalcet in Japan [33], but some patients require PTx
even in the era of cinacalcet. For patients who refuse or
cannot tolerate surgical PTx, percutaneous ethanol
injection therapy (PEIT) [37] and percutaneous vitamin
D injection therapy (PDIT) [38] have occasionally been
performed in Japan. However, these interventions have
not been performed as often since the introduction of
cinacalcet.
After successful PTx, circulating PTH levels drastically
decreases, which is followed by progressive reductions in
serum calcium and phosphorus. This condition is known as
hungry bone syndrome and is characterized by massive
deposition of calcium and phosphate in the bone, which
occurs as a result of a transient increase in bone formation
and sustained decrease in bone resorption [39]. To prevent
overt hypocalcemia, calcium administration and calcitriol
treatment are usually required for several weeks after PTx.
There are two major surgical procedures for PTx: total
PTx with or without autotransplantation and subtotal PTx.
No definitive evidence exists in favor of one over the other,
but total PTx with autotransplantation may be preferable in
patients who will require long-term hemodialysis after
surgery [14]. Total PTx without autotransplantation should
be prohibited in patients who have a better chance of
receiving kidney transplantation because of the risks of
iatrogenic hypoparathyroidism and hypocalcemia after
kidney transplantation.
For preoperative localization, cervical ultrasonography
should be routinely performed, and 99mTc-sestamibi
scintigraphy and computed tomography may preferably be
added. It should be acknowledged that the parathyroid gland
may be located ectopically, owing to the complex develop-
ment during embryogenesis, and unresected parathyroid
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Clin Exp Nephrol (2017) 21 (Suppl 1):S37–S45
tissue at initial surgery may cause persistent or recurrent
SHPT [40].
Consequences of SHPT: a rationale for treatment
Effect on bone metabolism
The most widely recognized concern related to SHPT is
high-turnover bone disease [15], which is also referred to
as osteitis fibrosa. PTH binds to the PTH/PTHrP receptor
on osteoblasts and thereby indirectly stimulates osteoclast
formation and the rate of bone remodeling. Thus, sustained
release of excess amounts of PTH into the circulation by
enlarged parathyroid glands leads to high-turnover bone
disease. Most importantly, high-turnover bone disease can
lead to increased bone fragility, thus explaining the bone
pain and increased fracture risk associated with severe
SHPT. The association between PTH levels and fracture
risk has been inconsistent among studies, but the DOPPS
has demonstrated that intact PTH levels above 900 pg/ml
are independently associated with an elevated risk of new
fracture [41].
The skeletal consequences of SHPT can be more fully
understood by focusing on the effects of PTH-lowering
treatment on bone metabolism. PTx is the definitive ther-
apy for uncontrolled SHPT and improves high-turnover
bone disease. As described above, PTx transiently leads to
increased bone formation, thus causing uncoupling of bone
formation and bone resorption and consequently increased
bone uptake of serum calcium and phosphate (hungry bone
syndrome). In accordance with the rapid accumulation of
calcium and phosphate by the skeleton, several observa-
tional studies have consistently demonstrated an increase in
bone mineral density after PTx [42]. The effect of PTx on
fracture risk has been evaluated in one observational study
from the United States Renal Database System (USRDS)
[43]. This study has found decreased long-term risk for
fractures among patients who underwent PTx compared
with matched controls. Adynamic bone disease associated
with very low PTH levels has been a concern associated
with PTx, because this condition may lead to decreased
bone strength. However, the USRDS study has demon-
strated that the association of PTx with lower risk of
fracture was stronger among patients who undergo total
versus subtotal PTx. This finding supports the benefit of
total PTx in terms of bone health and raises the question of
whether very low PTH actually leads to increased bone
fragility.
The effects of PTH-lowering treatment on bone metabo-
lism have also been evaluated in the Bone Histomorphom-
etry Assessment for Dialysis Patients with Secondary
Hyperparathyroidism of End-Stage Renal Disease
Clin Exp Nephrol (2017) 21 (Suppl 1):S37–S45
(BONAFIDE) study, a single-arm trial which has evaluated
the effect of cinacalcet on bone histology in patients with
histological evidence of high-turnover bone disease [44].
This study has demonstrated that long-term treatment with
cinacalcet diminishes the elevated bone formation rate,
lowers biochemical markers of high-turnover bone disease,
and generally improves bone histology. Recently, the effect
of cinacalcet on fracture risk has been evaluated by a sub-
analysis of the Evaluation of Cinacalcet Hydrochloride
Therapy to Lower Cardiovascular Events (EVOLVE) trial, a
randomized controlled trial designed to assess the effect of
cinacalcet on clinical outcomes [45]. This study has not
found a significant effect of cinacalcet in the primary
intention-to-treat analysis, but the prespecified lag-censoring
analysis, which took into account the crossover effect
(dropout and drop-in), exhibited a significant reduction in the
risk of fracture in the cinacalcet group. Collectively, these
clinical trial data further confirm the view that inadequately
high PTH is a direct cause of high-turnover bone disease in
patients with SHPT.
Several studies have also demonstrated that treatment
with VDRAs leads to an improvement in osteitis fibrosa
associated with SHPT [46]. However, all these studies were
performed in the 1980s and 1990s, and the effects of
VDRAs on the risk of fracture have not been adequately
evaluated. VDRAs may have direct effects on bone meta-
bolism that is independent of their effect on PTH secretion,
but the clinical significance of this independent skeletal
effect in patients with SHPT remains unclear.
Effect on mortality
Elevations in serum PTH levels are associated with
increased risks of mortality and cardiovascular events
[16–18]. Thus, SHPT is regarded as one of the prominent
risk factors for death and cardiovascular events among
patients undergoing hemodialysis. Indeed, recent evidence
from our group [47] and others [48–50] suggests that PTx
for treatment of uncontrolled SHPT leads to improved
survival. Although all these data are from observational
studies, the survival benefit associated with PTx is inde-
pendent of patient characteristics and is consistent across
different countries, thus supporting the validity of these
findings. In addition, the results of the EVOLVE trial also
suggest that treatment for SHPT is beneficial in terms of
cardiovascular outcomes [51]. Although the primary anal-
ysis has not demonstrated a significant effect, the pre-
specified lag-censoring analysis has demonstrated a
significant reduction in the risk of the death or cardiovas-
cular outcomes in patients administered cinacalcet.
There are several mechanisms through which uncon-
trolled SHPT may lead to poor survival. The first possi-
bility is that the high risk of fracture associated with high-
S41
turnover bone disease causes increased mortality. A recent
study from the DOPPS has demonstrated high rates of
death and hospitalization after bone fracture in hemodial-
ysis patients [52]. Given that elevated PTH is a risk factor
for fracture [41], it is possible that uncontrolled SHPT may
lead to increased mortality through fracture and its related
adverse events, such as prolonged immobilization, malnu-
trition, and infection.
The second major possibility is that elevated PTH may
cause impaired control of serum calcium and phosphorus
and thereby accelerate the progression of vascular calcifi-
cation. Until recently, the use of VDRAs has received
attention as a potential cause of disturbed mineral meta-
bolism [11], but recent investigations suggest that high-
turnover bone disease associated with SHPT also con-
tributes this condition through excess bone resorption rel-
ative to the rate of bone formation [53]. This hypothesis is
supported by a recent observational study demonstrating
that higher serum PTH levels are associated with an
increased risk of developing hypercalcemia and hyper-
phosphatemia [54]. In addition, clinical studies have
demonstrated that the treatment of SHPT using either
cinacalcet [13, 29, 30] or PTx [47] leads to sustained
reductions in serum calcium and phosphate. A more recent
study has also demonstrated that a single-dose injection of
the novel calcimimetic etelcalcetide reverses the increase
in serum calcium and attenuates the increase in serum
phosphate during the interdialytic period [35]. These data
highlight the importance of controlling parathyroid func-
tion and bone turnover as a means to improve bone strength
and to attenuate the progression of vascular calcification.
Non-traditional effects
High-turnover bone disease and vascular calcification are
likely to be the main mechanisms through which high PTH
leads to adverse outcomes, but this does not preclude other
possibilities. One of the possible mechanisms linking high
PTH and poor outcomes is wasting and muscle atrophy. A
large number of patients with ESRD exhibit signs of
wasting, which is characterized by increased energy
expenditure and loss of adipose and muscle mass. Obser-
vational studies have suggested the possible involvement
of SHPT in the pathogenesis of wasting [55] and muscle
weakness [56], but the detailed mechanisms remain
unclear. Recently, Kir et al. have found that PTH and PTH-
related protein (PTHrP), which share the same receptor, are
important mediators of the loss of adipose tissue and
muscle mass in cancer and CKD [57]. Their previous work
on cancer cachexia has shown that tumor-derived PTHrP
induces wasting through driving the expression of genes
involved in thermogenesis in adipose tissues [58]. In their
follow-up study, the investigators found that 5/6
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S42 Clin Exp Nephrol (2017) 21 (Suppl 1):S37–S45

nephrectomized mice developed cachexia associated with
adipose browning and wasting. They further generated
mice with fat cell-specific deletion of the PTH/PTHrP
receptor and demonstrated that these mice are resistant to
adipose browning and skeletal muscle atrophy after
nephrectomy [57]. These data provide an additional
explanation as to why wasting is common in dialysis
patients with SHPT and why treatment of SHPT leads to
improvement of this condition.
PTH may also be involved in the pathogenesis of renal
anemia. There are several possibilities explaining the
relationship between SHPT and anemia: [1] severe SHPT
may induce marrow fibrosis (osteitis fibrosa), thus limiting
the space for red marrow and reducing the number of
erythroid precursors; [2] PTH may directly inhibit bone
marrow erythropoiesis; [3] PTH may exacerbate the
already reduced endogenous erythropoietin production; and
[4] PTH may increase the fragility of red blood cells and
thereby reduce their life span [59]. Although the relative
importance of these potential mechanisms remains unclear,
the pathogenic role of PTH in renal anemia has also been
supported by clinical observations on patients receiving
SHPT treatment. Several observational studies have
demonstrated an improvement of renal anemia after PTx in
patients with severe SHPT [60]. Furthermore, a recent
study has demonstrated that cinacalcet is associated with
improved management of anemia in hemodialysis patients
with SHPT [61]. These data support the view that SHPT is
one of the contributors to renal anemia and provides an
additional rationale for managing SHPT.
Another possible extraskeletal consequence of SHPT is
related to the function of PTH as an immunologic media-
tor. Neutrophils and lymphocytes express the PTH/PTHrP
receptor, and elevated PTH levels may play a pathogenic
role in immune dysfunction [62]. Indeed, PTx reverses the
immunologic defect in patients with severe SHPT [63]. We
have also recently found that PTx is associated with
decreased mortality from infectious diseases [47]. How-
ever, in vitro evaluations for the effects of PTH on immune
system have demonstrated inconsistent results [62].
Because infectious disease is one of the major causes of
death in dialysis patients and can be attributed to altered
host defenses, further studies should be undertaken to fully
elucidate the functional role of PTH in immune system.

Fig. 2 Schematic
representation of adverse effects
of PTH and FGF23. Bone
Parathyroid hyperplasia Vascular calcification
disease and vascular
calcification are the major
consequences of SHPT, but
PTH and FGF23, both of which
are markedly elevated in SHPT, PTH
have multiple adverse effects on Ca
extraskeletal tissues. These
actions may lead to the Stimulates bone P
pathological development of left resorption
ventricular hypertrophy, renal High-turnover bone
anemia, immune dysfunction,
Stimulates
inflammation, wasting, muscle FGF23
FGF23 secretion
atrophy, and urate accumulation

Left ventricular hypertrophy

Renal anemia

Immune dysfunction

Inflammation

Wasting

Muscle atrophy

Urate accumulation

123
Clin Exp Nephrol (2017) 21 (Suppl 1):S37–S45
PTH may also play a role in the pathogenesis of left
ventricular hypertrophy (LVH). Experimental studies have
demonstrated that PTH exerts a direct hypertrophic effect
on cardiomyocytes [64, 65]. In accordance with these
findings, several observational studies have demonstrated
that progression of LVH was retarded or even reversed
after PTx for SHPT [66]. Notably, in the EVOLVE trial,
one of the strongest effects of cinacalcet on cardiovascular
outcomes was observed in heart failure [51]. It is possible
that the decreased risk of heart failure in the cinacalcet
group may be attributable to improvement of LVH through
suppression of PTH. Because LVH is an important mech-
anism of cardiovascular disease in CKD, the exact role of
PTH in this pathogenic condition should be investigated in
future research.
Finally, a recent work by Sugimoto et al. has demon-
strated that PTH suppresses intestinal and renal excretion
of urate through down-regulation of the urate exporter
ABCG2, thus indicating that SHPT contributes to the
development of hyperuricemia [67]. Although the impor-
tance of hyperuricemia in CKD and ESRD remains a
matter of debate [68, 69], the effect of PTH on urate
metabolism may in part explain the association between
uncontrolled SHPT and mortality.
FGF23-mediated adverse effects
The major target organs of FGF23 are the kidney and
parathyroid gland, but recent investigations have identified
diverse adverse effects of FGF23 on non-target organs in a
Klotho-independent manner [70]. Accumulating evidence
suggests causal roles for FGF23 in the pathological
development of LVH [71], and recent studies have also
demonstrated that FGF23 directly contributes to renal
anemia [72], immune dysfunction [73], and hepatic pro-
duction of inflammatory cytokines [74]. Interestingly, most
of these adverse effects of FGF23 have also been impli-
cated as consequences of SHPT. Because PTH is one of the
major drivers of FGF23 secretion [75], increased FGF23
may be another mechanism linking SHPT with LVH,
immune dysfunction, and renal anemia. Future research
should determine the relative importance of and possible
interactions between PTH and FGF23 in the pathogenesis
of these adverse events. A schematic representation of the
adverse effects of PTH and FGF23 is summarized in Fig. 2.
Conclusions
Recent advances in medications targeting both the VDR
and CaSR are revolutionizing the treatment of SHPT.
However, in this new era, there is a subset of patients who
have SHPT that cannot be controlled by available
S43
therapeutic agents. PTx will remain a powerful treatment
option for these patients. Accumulating evidence also
indicates multiple extraskeletal effects of PTH and FGF23,
thus potentially explaining the poor outcomes of patients
with uncontrolled SHPT. These data provide an additional
rationale for treating SHPT, but definitive evidence is
lacking. Further efforts should be made to determine
whether treatment of SHPT prevents the adverse effects of
PTH and FGF23.
Acknowledgements This supplement is supported by the Grants
from the Japanese Society for Kidney Bone Disease (JSKBD) and
from the Research Meeting on Kidney and Metabolic Bone Disease.
The authors thank the following investigators who participated in the
historical cohort study of maintenance hemodialysis patients: Dr.
Miho Hida, Dr. Takao Suga, Dr. Reika Tanaka, Dr. Kayoko Watan-
abe, Dr. Nobuyoshi Takagi, Dr. Hiroshi Kida, Dr. Mitsumine Fukui,
Dr. Tateki Kitaoka, Dr. Tetsuo Shirai, Dr. Mikako Nagaoka, Dr.
Tsuneyoshi Oh, Dr. Eiji Nakano, Dr. Takayuki Hashiguchi, Dr.
Hirofumi Ishii, Dr. Koichi Shimizu, Dr. Yasuji Sugano, Dr. Toru
Furuya, Dr. Naoto Ishida, Dr. Hiroyuki Ogura, Dr. Hiroaki Nakada,
Dr. Miho Enomoto, and Dr. Tetsuya Kashiwagi.
Compliance with ethical standards
Conflict of interest H.K. has received honoraria, consulting fees,
and/or Grant/research support from Bayer Yakuhin, Chugai Phar-
maceutical, and Kyowa Hakko Kirin. T.K. has received honoraria
from Chugai Pharmaceutical and Kyowa Hakko Kirin. M.F. has
received honoraria, consulting fees, and/or Grant/research support
from Bayer Yakuhin, Kyowa Hakko Kirin, and Torii Pharmaceutical.
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