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Secondary Hyperparathyroidism
transplant patients. Our group showed that mean serum creatinine calcium-sensing and vitamin D receptors appears to decrease as the size
concentration rose significantly within three months of treatment with of the gland increases.
36,37
Recently, Rodriguez et al. observed an
cinacalcet.
20
Similarly, serum creatinine concentrations tended to increase of vitamin D receptor expression in parathyroid cells of rats
increase, albeit not significantly, from 116.1±8.7µmol/l at baseline to given the calcimimetic R-568.
38
As a result, a reduction in the size of the
127.6±11.1µmol/l during a 26-week course of cinacalcet in 10 renal parathyroid gland may be expected. This was supported by experiments
transplant patients reported by Serra et al.
21
In contrast, Srinivas et al. in rats and suggested a reduction of parathyroid gland weight.
39
treated 10 patients for three to 18 months and observed a slight Likewise, vascular calcification has been demonstrated to be virtually
reduction of the mean serum creatinine concentration from absent in five out of six nephrectomised rats with cinacalcet treatment.
40
152±14µmol/l to 144±12µmol/l during treatment.
23
More recently, we
It is unknown whether a reduction of parathyroid gland size is present
in humans or if reduced parathyroid gland activity persists beyond the
Whether the beneficial effect of
time for which the drug is prescribed. Our group observed increased
levels of the principal ligand of the vitamin D receptor 1.25-
cinacalcet persists in these patients
dihydroxyvitamin D after cessation of cinacalcet. Thus, a persistent
after withdrawal cannot be predicted
vitamin D receptor-mediated inhibition of iPTH synthesis could facilitate
withdrawal of cinacalcet. Following the discontinuation of cinacalcet,
on the basis of the various action
serum calcium increased slightly in most patients, but remained within
mechanisms of calcimimetics. the normal range. The presence of augmented 1.25-dihydroxyvitamin D
concentrations may lead to limited synthesis of iPTH post-
transcriptionally.
41
This effect may be potentiated by the
were able to demonstrate that renal function as measured by cystatin C complementary mechanism of transcriptional inhibition of PTH
significantly improved on cessation of cinacalcet.
31
Taken together, synthesis with the increased 1.25-dihydroxyvitamin D concentrations.
38
these observations suggest that changes in renal function with Furthermore, the absence of the type II agonist of the calcium-sensing
cinacalcet are functional and reversible, yet monitoring of renal function receptor contributed to the rise in serum calcium.
seems to be mandatory until further data clarify this issue. Given the
results discussed above, these observations do not appear to necessitate
withdrawal of the drug. However, the exact mechanism of the
After cinacalcet withdrawal at
cinacalcet-associated functional renal impairment is unknown. Changes
three months, mean serum calcium
in calcium concentrations have been considered in the regulation of
renal function (independent of iPTH) following surgical concentrations increased but
parathyroidectomy when Rostaing et al. observed a significant and
remained within the normal range in
persistent increase in serum creatinine levels in eight out of 34 renal
transplant patients. Lee et al. reported a steeper rise in serum creatinine
eight out of 10 patients.
in 22 renal transplant patients.
14,35
In all studies, drug tolerability was not
a major factor, and though a role was anticipated due to the hepatic
drug metabolism, no significant interactions with immunosuppressants Whether the beneficial effect of cinacalcet persists in these patients after
were reported. However, some cases raised concerns over the the withdrawal cannot be predicted on the basis of the various mechanisms
development of hypercalciuria during the use of cinacalcet.
32,34
of action calcimimetics. Three studies prospectively addressed the effects
of cinacalcet withdrawal on PTH, serum calcium and renal function.
22,29,31
Is Cinacalcet a Mandatory Life-long Therapy in Persistent The first study, by Leca et al., observed two patients with severe iPTH
Hyperparathyroidism? Effects of Therapy Cessation elevations that were reduced, but not normalised, during an eight- to 12-
Calcimimetics were shown to attenuate the progression of parathyroid month course of cinacalcet treatment.
22
On cessation of cinacalcet, loss
hyperplasia in rats.
18
Whether the inhibition of proliferation causes a of control of iPTH levels recurred. Serra et al. reported on a group of
patients prospectively treated for six months with cinacalcet to normalise
serum calcium levels.
29
A four-week cessation of active treatment led to
In all studies, drug tolerability was
iPTH levels returning to pre-treatment quantities and supporting the
not a major factor, and though a role theory that only uninterrupted therapy enables normal parathyroid
was anticipated due to the hepatic
function. Kruse et al. tested the effect of a one-year course of
treatment.
31
This was followed by a prospective study that withheld
drug metabolism, no significant
cinacalcet for three months. Serum calcium was well controlled in nine
interactions with immunosuppressants
out of 10 patients before cessation of therapy. After cinacalcet
withdrawal at three months, mean serum calcium concentrations
were reported.
increased but remained within the normal range in eight out of 10
patients. In the remaining two it increased, reaching 2.6mmol/l.
reduction in the size of the parathyroid glands in renal transplant
patients with persistent hyperparathyroidism awaits confirmation. Beyond the three-month prospective study protocol, the patient files
Parathyroid glands with a reduced size may be more susceptible to the were reviewed for data nine months after cessation of cinacalcet. Two
regulatory effect of calcium and vitamin D because the density of patients described as ‘insufficiently controlled’ during the study period
26 EUROPEAN RENAL DISEASE 2007
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