NDT Plus 2008 1(Supplement 3):iii9-iii13; doi:10.1093/ndtplus/sfn080
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Clinical significance of parathyroid intervention on CKD-MBD management
Hiroaki Ogata1,
Masahide Mizobuchi1,2,
Fumihiko Koiwa3,
Eriko Kinugasa1 and
Tadao Akizawa2
1 Department of Internal Medicine, Showa University Northern Yokohama Hospital, Yokohama
2 Department of Nephrology, Showa University School of Medicine, Tokyo
3 Division of Nephrology, Department of Internal Medicine, Showa University Fujigaoka Hospital, Yokohama, Japan
Correspondence: Hiroaki Ogata, Department of Internal Medicine, Showa University Northern Yokohama Hospital, Chigasaki-chuo 35-1, Tsuzuki, Yokohama 224-8503, Japan. Tel: +81-45-949-7000; Fax: +81-45-949-7927; E-mail: ogatah{at}med.showa-u.ac.jp
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Abstract
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Recently published ‘Guidelines for the management of secondary
hyperparathyroidism in chronic dialysis patients’ by the
Japanese Society for Dialysis Therapy advocate that percutaneous
ethanol injection into enlarged glands, which has been considered
as the only alternative to parathyroidectomy (PTx), should be
indicated in patients with a single enlarged parathyroid gland
(estimated volume >500 mm
3, or estimated major axis >10
mm), and that PTx should be recommended in patients with multiple
enlarged glands. Cinacalcet cannot achieve optimal control of
chronic kidney disease–mineral bone disorder in all patients,
and parathyroid intervention will be required in a considerable
number of patients with refractory secondary hyperparathyroidism.
Received for publication March 8, 2008. Accepted for publication March 10, 2008.
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Clinical significance of CKD-MBD
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Chronic kidney disease (CKD) is inevitably associated with various
disruptions in bone mineral metabolism, including abnormalities
in the concentrations of serum calcium (Ca), phosphate (P) and
parathyroid hormone (PTH), as well as 1,25(OH)
2 dihydroxy-vitamin
D
3 deficiency, as the residual kidney function declines [
1,2].
It has become evident that various bone mineral disorders associated
with CKD (CKD-MBD) are also associated with the development
of cardiovascular disease. Therefore, recently published guidelines,
namely ‘the Kidney Disease Outcomes Quality Initiative
(K/DOQI) clinical guidelines for bone metabolism and disease
in CKD’ [
3] and ‘Guidelines for the management of
secondary hyperparathyroidism in chronic dialysis patients’
[
4,5] by the Japanese Society for Dialysis Therapy (JSDT), have
set stringent targets for the concentrations of serum Ca and
P (Table
1). Nationwide surveys, which are carried out annually,
have demonstrated that poor Ca and P management, as well as
abnormal PTH concentration, are associated with high morbidity
and mortality in Japanese patients on haemodialysis [
6,7]. Observational
studies have also shown that hyperphosphataemia, hypercalcaemia
and increased Ca
x P product are more strongly associated with
high cardiovascular morbidity and mortality than elevated PTH
level [
8,9]. The JSDT guidelines recommend the management of
P and Ca concentrations prior to controlling the PTH concentration
in patients with secondary hyperparathyroidism (SHPT). However,
SHPT is highly prevalent in long-term dialysis patients, and
excess PTH has been demonstrated to be one of the uraemic toxins
[
1,
8–12]. A markedly high PTH concentration is implicated
in various complications, including hypertension, abnormal lipid
metabolism, glucose intolerance, erythropoietin-resistant anaemia
and abnormal cardiovascular remodelling in uraemia [
1,
8–12].
In fact, parathyroidectomy (PTx) has been shown to ameliorate
these abnormalities in patients with severe SHPT. In addition,
PTx was reported to reduce the fracture risk and long-term mortality
rate in dialysis patients [
13,14]. Calcimimetics treatment,
which can be considered as a pharmacological parathyroid ablation,
has been demonstrated to improve cardiac and renal remodelling
in uraemic rats [
12,
15]. Thus, it is of clinical importance
to control the serum PTH concentration, as well as the serum
P and Ca concentrations in uraemic patients.
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Limitation of conservative treatment and indication for parathyroid intervention
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Although clinical guidelines recommend the strict management
of CKD-MBD on the basis of clinical evidence, many patients
have not satisfied the guideline targets. A large observational
study showed that only 21% of the patients satisfied the K/DOQI
guidelines’ criteria for PTH concentration and 5% met
the combined targets for Ca, P, Ca
x P product and PTH under
conventional treatment [
16]. The parathyroid cells within nodular
hyperplastic lesions are more proliferative than those within
diffuse hyperplastic lesions, and express less vitamin D receptor
(VDR) and calcium sensing receptor (CaSR) [
17–19]. Consequently,
when at least one parathyroid gland progresses to nodular hyperplasia,
SHPT cannot be treated even with injectable calcitriol or its
analogues. Tominaga
et al. have reported that over 85% of resected
parathyroid glands from dialysis patients with severe SHPT had
nodular hyperplastic lesions pathologically when the glandular
weight was more than 500 mg [
20]. In fact, an enlarged parathyroid
gland, with an estimated volume of over 500 mm
3 or major axis
of >10 mm as determined by ultrasonography, might be predictive
of poor responsiveness to conventional medical treatment, even
by administration of intravenous active vitamin D analogues
[
4,
21,
22].
When SHPT does not respond to medical treatment, parathyroid intervention should be indicated. Parathyroid intervention can be divided into two major categories: PTx and percutaneous ethanol injection into enlarged parathyroid glands (PEIT) [1,3,4,12,23–25]. Parathyroid intervention is very effective in reducing the PTH level without increasing the Ca and P loads in patients with SHPT. It can be expected to markedly improve both P and Ca management, particularly when PTx is successfully performed in patients with severe SHPT [12,14,25–27]. PEIT has been carried out as a less invasive alternative to PTx for refractory SHPT [1,3,4,12,22–24,28,29]. PEIT, as well as PTx, reduces serum PTH levels rapidly when the enlarged PTG is adequately destroyed.
In addition, more recently, the direct injection of active vitamin D analogues has also been performed in Japan [1,4,12]. Repeated vitamin D injections into enlarged parathyroid glands were reported to be effective in suppressing PTH secretion without the risk of recurrent nerve paralysis, which is one of the complications associated with PEIT [4]. The induction of parathyroid cell apoptosis and upregulation of VDR expression by parathyroid cells upon exposure to extremely high vitamin D concentrations have been shown to be one of the mechanisms underlying the decrease in size of the parathyroid glands [30]. These results suggest that percutaneous direct injection therapy may be considered a powerful therapeutic tool for refractory SHPT.
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Parathyroid intervention in clinical guidelines for CKD-MBD
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Table
1 summarizes the target values for P, Ca and PTH and the
indication for parathyroid intervention in the K/DOQI and JSDT
clinical guidelines [
3–5]. The indication for parathyroid
intervention still remains to be confirmed since there are no
studies that define the absolute biochemical and clinical criteria
for parathyroid intervention. There is no distinct difference
in the indication for parathyroid intervention between the two
guidelines. The K/DOQI and JSDT guidelines propose an interim
indication for parathyroid intervention in patients refractory
to medical treatment with high iPTH levels (>800 in the K/DOQI
and >500 pg/mL in the JSDT), associated with hyperphosphataemia
or/and hypercalcaemia. Unlike with the K/DOQI guidelines, the
JSDT guidelines encourage parathyroid intervention in patients
refractory to medical treatment with SHPT-associated complications.
The indication for parathyroid intervention proposed by the
JSDT guidelines is categorized into three grades: absolute,
strongly recommended and considerable indication. Even if the
iPTH level does not exceed 500 pg/ mL but hyperphosphataemia
and/or hypercalcaemia are refractory to medical management,
parathyroid intervention is recommended in the JSDT guidelines
(Table
2). In addition, the JSDT guidelines propose parathyroid
intervention for patients with clinical manifestations associated
with refractory SHPT, including musculoskeletal symptoms, severe
pruritus, progressive osteopenia, ectopic calcification, erythropoietin-resistant
anaemia or dilated cardiomyopathy [
4]. Cardiovascular calcification
is associated with a higher risk of cardiovascular morbidity
and mortality in long-term dialysis patients and is considered
to be an important manifestation of CKD-MBD. When cardiovascular
calcification progressively accelerates, parathyroid intervention
should be considerable even in patients with mild-to-moderate
SHPT in accordance with the JSDT guidelines.
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Table 2 Indication for parathyroid intervention in dialysis patients with secondary hyperparathyroidism from the JSDT guidelines (modified from reference [4])
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As discussed previously, the volume of the parathyroid gland
is a useful maker for predicting the responsiveness to active
vitamin D therapy. When the volume of one of the parathyroid
glands exceeds 500 mm
3 or 10 mm in the major axis as determined
by ultrasonography, parathyroid intervention is also recommended
in the JSDT guidelines.
There is a distinct difference in terms of interventional procedure between the two guidelines. In the K/DOQI guidelines, PTx, including subtotal PTx and total PTx with autotransplantation, is primarily recommended as an> effective surgical intervention. In contrast, the JSDT guidelines recommend not only PTx, but also PEIT as the primary procedure of parathyroid intervention. The JSDT guidelines advocate that PEIT is expected to reduce iPTH effectively and to manage CKD-MBD for a long period in patients with no more than one enlarged parathyroid gland (>500 mm3) [4,24,28]. In patients with multiple suspected nodular hyperplastic glands, even if PEIT is performed for all targeted glands, the long-term clinical results are unfavourable [23,24,28,29,32]. In addition, the risk of complications, including haemorrhage, recurrent nerve palsy and adhesion to surrounding tissue, increases with the number of injections [24,28]. PTx should be considered in patients with more than two enlarged glands. In patients with calciphylaxis with elevated PTH levels, PTx should be strongly recommended because calciphylaxis is a very emergent complication in uraemic patients [3,4,31].
While PTx removes all parathyroid glands regardless of their size or histology, PEIT selectively destroys only the largest one. Thus, it is very important to control the growth of any residual parathyroid glands, which are presumably responsive to active vitamin D analogues, and to suppress PTH secretion with medical management, mainly by active vitamin D therapy, after successful PEIT [23,24,28,29]. Otherwise, other glands will consecutively become nodular hyperplastic.
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Parathyroid intervention in the cinacalcet era
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It is of considerable interest whether cinacalcet, which has
recently become clinically available in Japan, can sufficiently
suppress PTH secretion in patients with enlarged parathyroid
glands, which are presumably refractory to vitamin D. Cinacalcet
significantly reduces the PTH concentration in dialysis patients
with SHPT, and simultaneously has favourable effects on Ca and
P metabolism, presumably as a consequence of the reduced PTH-driven
Ca and P efflux from the bone [
33–35]. In fact, cinacalcet
has been demonstrated to improve the achievement ratio of the
target values stipulated in the K/DOQI guidelines as compared
with conventional treatment alone, active vitamin D analogues
and P binders in patients with SHPT [
36]. In Japanese haemodialysis
patients with SHPT (iPTH
300 pg/mL), cinacalcet also decreased
the serum PTH levels with favourable management of the serum
P and Ca levels [
37]. In addition, an analysis of the combined
results from four similarly designed randomized, double-blinded,
placebo-controlled clinical trials showed that cinacalcet treatment
significantly decreased the risks of PTx, fracture and cardiovascular
hospitalization [
38]. In particular, the relative risk of PTx
was much lower (93% reduction) with the cinacalcet treatment
(RR 0.07) than with a placebo. These results suggest that cinacalcet
makes it possible to manage SHPT in most patients without PTx.
However, a considerable number of patients could not meet the
targets of clinical guidelines for mineral bone parameters [
36],
especially those with nodular hyperplasia [
39]. In addition,
medical economic issues will be raised if the treatment with
cinacalcet becomes prolonged. It has been reported that cinacalcet
might be more cost-effective in patients who have high risk
of mortality or who expect to receive a kidney transplant soon.
On the other hand, PTx might be more cost-effective in patients
who have a considerable life expectancy [
40,41]. A new alternative
indication for PEIT may be examined in patients refractory to
active vitamin D therapy. If PEIT destroys enlarged parathyroid
glands completely or incompletely, it will be possible to reduce
not only the dosage of cinacalcet, but also the drug expenditure.
Because enlarged parathyroid glands, possibly nodular hyperplasia,
express less CaSR, these glands are hyporesponsive to cinacalcet.
Following selective PEIT for enlarged parathyroid glands, which
are responsible for resistance to medical treatment, cinacalcet
may be a more potent treatment for SHPT than active VD analogues.
The clinical application of PEIT for severe SHPT may be expanded
in combination with cinacalcet. Parathyroid intervention is
still a useful tool for managing SHPT in the cinacalcet era.
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Conclusion
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Parathyroid intervention is indispensable in order to achieve
optimal management of SHPT. In Japan, PEIT has become widely
used in the management of refractory SHPT as a less invasive
alternative to PTx, particularly in patients with a single enlarged
parathyroid gland. However, it still remains to be determined
whether PEIT, as well as PTx, can improve hard outcomes, including
hospitalization and mortality, over long periods. Further studies
are necessary to confirm if parathyroid intervention facilitates
better CKD-MBD management and leads to the improvement of clinical
outcomes in long-term dialysis patients.
Conflict of interest statement. None declared.
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Abstract
Clinical significance of CKD-MBD