DISCUSSION
It is well known that EC, like the BT described in our case, start
primarily with the super saturation of plasmatic calcium and phosphorus.
DP could precipitate this abnormality, because without an efficient
phosphate-binding therapy, all patients undergoing PD have the trend of
remarkable positive phosphorus balance unless they have severely
malnourished status [13]. Phosphate transfer across the peritoneal
membrane is almost exclusively diffusive and can be improved by
increasing the number of CAPD cycles and dialysis solution dwelling time
[14]. Additionally, there is an additional risk factor associated
with calcium phosphate binders’ therapy, contributing to developing LBT
because they can provoke positive calcium balance that could result in
over-suppression of PTH [13,15].
In our case, it was clear that CKD-BMD began within PTH values expected
based on KDIGO goals, using the prescribed calcimimetics. However, the
PTH over-suppression did not recover despite more than six months after
suppressing the hormone curbing, turning to a different biochemical
pattern suggestive of LBT. The whole therapeutic arsenal available to
control secondary hyperparathyroidism includes oral calcium and vitamin
D analogues, high calcium concentrations in the dialysate,
calcimimetics, and hypoparathyroidism induced by parathyroidectomy, all
of which have largely contributed to increasing prevalence of ABD.
[13,16].
Even though there are complex mechanisms for explaining ABD appearance,
there are two important aspects that must be borne in mind. Firstly,
over-treatment of secondary hyperparathyroidism without appropriate
follow-up could be a key reason that justifies the increase in ABD
diagnoses, and secondly, there is probably a real need to redefine the
PTH target values. In this sense, LBT should be considered when PTH is
below150 pg/ml in patients with advanced CKD, with a sensitivity and
specificity of the PTH cut-off point for diagnosis of 68.6% and 61.2%
respectively at said hormone levels [16, 17]. However, the target
range of PTH levels proposed for CKD patients in dialysis [6] is not
a guarantee of normal bone turnover, as we saw in our case.Pereira et al. analysed 49 patients with CKD on PD with bone
biopsy, finding ABD as a frequent pattern (42.9%) in patients with PTH
within the recommended plasmatic range [6]; ABD was found in 59% of
cases, and the median PTH in patients with adynamic bone was 312
(60–631) pg/mL [7].
Identifying the possible reasons for LBT is a decisive step in guiding
therapeutic strategies, because of the fact that ABD management is
usually multitargeted, including a change of dialysis therapy,
hypercalcemia and hyperphosphatemia avoidance, using calcium-free
phosphate binders, all of which are fully recommended even for normal
calcemic and hypercalcaemic patients.
In the best-case scenario, calcium balance should be maintained neutral,
with no net flux of calcium from the bones to the extracellular fluid,
thus, in theory, with a dialysate calcium concentration of 2.5 mEq/L, no
net flow of calcium should occur [18]. The 2007 CKD-MBD guidelines
suggest the use of a calcium concentration in the dialysate between 2.5
mEq/L and 3.0 mEq/L. Nevertheless, a recent kinetic modelling study in
HD patients [19] depicted that a dialysate calcium concentration
less than 2.5 mEq/L would be necessary to prevent long-term calcium
accumulation in a significant proportion of patients, and that calcium
can also be removed during ultrafiltration. Normal subjects and CKD
patients using 800 mg calcium diet had slightly negative to neutral
calcium balance results, whereas taking 1500 mg of calcium in addition
to regular diet intake from calcium carbonate daily sources would result
in a positive calcium balance in subjects with stage 3 and 4 CKD who are
already consuming a calcium-adequate diet [20].
Spasovski et al . demonstrated that there were changes in
parameters for reflecting higher bone turnover in patients treated with
dialysate calcium of 2.5 mEq/l, probably by prevention of a positive
calcium balance and enabling sustained stimulation of PTH secretion,
allowing LBT prevention [21], meanwhile Sethi et al developed
measures to show an increased bone turnover in patients receiving 2.5
mEq/l of dialysate calcium, most likely resulting from inhibition to a
positive calcium balance and continuously stimulating PTH secretion
[22].
Moreover, the use of sevelamer has been studied and it is fully capable
of achieving better control of phosphemia without concomitant use of
elemental calcium. In addition, in experimental studies in murines,
using sevelamer within diet besides normalising the serum phosphorus,
surprisingly a reversion of the CKD-induced trabecular osteopenia was
found, increasing osteoblast surfaces in the metaphyseal trabeculae of
the tibia and femur, and also had reinforced osteoid surfaces and more
importantly, the bone formation rates [23]. Subsequently,Ferreira et al. evaluated patients with bone biopsies at the
beginning and end of a one-year-period with sevelamer hydrochloride or
calcium carbonate, the group in sevelamer treatment resulted in no
statistically significant changes in bone turnover or mineralisation
compared with calcium carbonate, yet bone formation rate was higher and
trabecular architecture improved only with sevelamer [24,25].
The former measures were implemented in our patient, including
adjustments in dialysis time, achieving better control of the
calcium-phosphorus balance, according to our requirement, as shown in
table 1.
EC type BT is a well-known complication of CKD that appears on average
at approximately 3.5 years after dialysis onset; its incidence increases
with a longer renal-replacement period. Nevertheless, in our patient the
tumour appeared after a short time in PD, which draws attention to the
fact that the disappearance of EC was achieved after just three months
of using the STS, which was significantly faster than expected.
In addition, going deeper with STS, it is a well-known drug, having
until now weak but growing evidence built in the last decade, mainly in
the management of calciphylaxis over many years [26]. Despite this,
a number of mechanisms have been proposed, primarily involving
complexation with calcium ions or dissolution of calcium deposits, both
of which were recently rebutted by O’Neill and Hardcastle [27], proposing a more relevant antioxidant action that targets
inflammation and intimal hyperplasia based on the fact that thiosulfate
can be oxidised to sulphate, yet, there being no robust evidence, so it
remains in use due to its availability, tolerance, and safety.
Moreover, only a few case reports and some small-case-series have
demonstrated real efficacy in the treatment of BT [28-31], with the
aggregate that usually results being partial, perhaps due to the use of
low doses of STS at the beginning of the therapy. In our case, we
started with a full dose, maintaining the same continuously, without
interruptions, because it was well-tolerated, and the x-ray images
promptly demonstrated a substantial size reduction of the tumour. Herein
we believe that this therapeutic behaviour guaranteed more rapid
regression of the lesions, needing as little as a three-month-period of
treatment to almost disappear. Indeed, the patient was without lesions
after more than one year of follow-up after treatment completion.
Finally, it is important to remark that CKD-MBD patterns changed over
time, and the diagnosis of ABD is increasing, which makes it necessary
to redefine PTH cut-off points, mainly in PD. Likewise, close monitoring
of biochemical parameters that guide variations in turnover is
necessary, with prevention of possible risk factors related to LBT.
Conflict of interest: The authors declare no competing
interests and no financial support.