Analysis of the kinetics of the parathyroid hormone, and of associated patient outcomes, in a cohort of haemodialysis patients

SHPT is normally observed in patients with CKD stage 4 to 5, resulting from a prolonged decrease in serum levels of calcium and vitamin D (1,25(OH)₂D₃) or an increase in serum phosphate level. SHPT in this clinical population has been associated to an increase in PTH gene expression, synthesis, and secretion, and to a proliferation of parathyroid cells in chronic cases [20]. More recently, the role of Klotho deficiency, resistance of parathyroid cells to fibroblast growth factor (FGF)-23 action, due to a decrease of fibroblast growth factor receptor 1 expression [21], and a decrease of serum 1,25(OH)₂D₃ due to the excess FGF-23 synthesis, have been postulated to influence SHPT in patients with end-stage CKD [22].

Tertiary hyperparathyroidism, with an increase of the set-point calcium-PTH and frequent hypercalcemia, represents the response of the autonomous function of one or more parathyroid glands to long-standing SHPT [23]. The consequences of prolonged SHPT include bone disease, previously known as osteitis fibrosa, with an increased risk for radiological demineralization [24], fractures [25] and brown tumors [26], as well as an increased risk for cardiovascular calcification [5] and mortality [2].

In a recent metaanalysis of HD patients, Natoli et al. reported that only a high serum PTH level was associated with mortality [27]. Using the Fresenius US database, Block et al. reported an increased rate of mortality only among patients with a serum PTH level >600 pg/mL in an adjusted model, whereas in an unadjusted model, only low PTH levels were associated with a higher rate of mortality [11]. The same findings were confirmed for patients with CKD not on dialysis by Kovesdy et al. [7] and Nakai et al. in Japan [28]. The mechanism of PTH toxicity is poorly understood. However, an elevated calcium x phosphorus (Ca x P) product associated with tertiary HPT and a high serum PTH level, associated with high serum FGF-23level, have been associated with a risk for progression of cardiovascular calcification [5, 29].

In patients with CKD and in those on HD in particular, both low and high serum PTH levels have been associated with a higher rate of mortality [30]. Twenty years ago, Fournier et al. reported that a persistently low PTH state could result from aluminum intoxication, older age, diabetes, and excessive calcium and vitamin D use, as well as being frequently observed in patients undergoing peritoneal dialysis [31, 32]. The toxicity of a serum level of PTH that is within normal range, and even judged to be too low in HD patients, is probably related to an underlying condition, such as hypo phosphatemia and poor nutrition [33]. Over the last century, the excessive use of calcium and vitamin D to treat hyperphosphatemia and prevent SHPT has led to iatrogenic ABD, with the resulting hypercalcemia increasing the risk of extraosseous calcifications and mortality [8, 34]. Based on the data in the Taiwan HD registry, Lin et al. found that a low serum PTH level increased the risk of mortality usually when associated with hypercalcemia [35]. Today, in industrialized countries, non-calcium phosphate binders and higher serum PTH targets are used to prevent an excessive calcium load and hypercalcemia and, therefore, iatrogenic ABD is infrequently reported [4].

In addition to iatrogenic causes of low serum PTH, Fukagawa et al. suggested that a low serum PTH level may reflect a malnutrition status, which would explain the poor prognosis of these patients [36]. In HD patients, Mehrotra et al. reported an inverse relationship between age and serum levels of PTH [37], with a further association between low serum albumin levels and low PTH level in a Japanese cohort of HD patients [38]. The malnutrition-inflammation syndrome was associated with low PTH levels and poor outcomes [10, 39]. In their study of 748 HD patients, Dukkipati et al. also reported that low PTH (<150 mg/mL) was associated with protein energy wasting and inflammation. They further reported that a PTH level between 100 and 150 pg/mL to be associated with a greater survival compared to other PTH levels [40].

The effect of inflammation of PTH levels was described by Bologa et al. who reported that, in vitro, PTH secretion is suppressed by IL-6 [41], with IL-1ß inhibiting PTH secretion in parathyroid tissue slices [42], with IL-1 specific receptors upregulating the calcium-sensing receptor mRNA. Therefore, the KDIGO experts recommend maintaining serum PTH levels in a large range, from to 2–9 times the upper limit of the assay in HD patients to lower the risk of severe osteitis fibrosa and ABD [2] and to favor survival, based on the U-shape survival curve associated with serum PTH level. Hence, it is advisable to treat SHPT in HD patients in order to prevent health complications related to SHPT and improve survival, but without surpassing target levels due to the risk of ABD and related hypercalcemia.

Available treatments for SHPT include the use of native vitamin D [43], oral calcium [44], high DCC [19], calcitriol and analogs [45], and cinacalcet [46], as well as surgical PTX [47]. In a randomized controlled study evaluating the relative effectiveness of using calcium salt and non-calcium phosphate binders in the treatment of SHPT, outcomes were frequently worse for patients receiving calcium salts due to an inadequate calcium load, resulting in higher calcemia and more frequent episodes of hypercalcemia and extraosseous calcification [48]. By comparison, observational studies have described the use of oral calcium to be associated with better outcomes when prescribed adequately [49, 50]. The outcomes associated with the use of DCC are difficult to evaluate as few centers adjust DDC to levels of calcemia and bone turnover markers in patient-specific ways as we do in our center [19]. However, an observational study in a French regional cohort of HD patients identified no deleterious effects of high DCC (1.75 mmol/L) when prescribed for patients with hypo- or normo-calcemia [51].

A large observational study based in the United States (US) identified the use of calcitriol, and of its analogs, as being effective in lowering the risk of mortality in HD patients [52], as we previously reported in our regional cohort [53]. Randomized trials did not provide evidence of a survival advantage with the use of cinacalcet therapies, compared to high doses of calcitriol, or of its analogs [54]. In secondary analyzes of the data from this trial, cinacalcet therapies were associated with a lower incidence of fractures [55] and calciphylaxis [56]. The long-term prognosis of cinacalcet therapies, compared to PTX, has yet to be evaluated. In our study, we reported better outcomes among patients in the MPD group than among those in the NPD and SPD groups who were using calcium therapy (DCC and oral calcium), cinacalcet and alfacalcidol. When calcium, vitamin D or cinacalcet are used to lower serum levels of PTH, it is not possible to differentiate the impact of these therapies on survival from the impact of changes in serum levels of vitamin D or the Ca x P product on survival.

Low PTH levels after surgical PTX has been reported to improve outcomes in a US-based study of HD patients [57]. However, Konstantidinis et al. recently reported that only a few patients meeting the biological criteria for PTX actually accepted the surgery in the US, even if the PTX allowed achieving biological KDOQI targets of PTH [58]. In Japan, the survival rate after PTX has been reported to be very good, with an early mortality rate of only 0.15 % [59]. In our study, patients who underwent surgical PTX had excellent mid-term outcomes; however, the majority of these patients underwent kidney transplantation by the end of the study period and, therefore, the longer term survival could not be evaluated.

In a French observational study, using the KDIGO biological target of PTH level, Merle et al. reported that a decrease in serum PTH level after one year, including both changes from normal to low levels and from high-to-low levels, was associated with a higher rate of cardiovascular-related mortality [16]. Among factors associated with a higher risk of mortality, Merle et al. identified a high serum CRP level and a high DCC (1.75 mmol/L). Of importance is their finding that mortality risk increased when high DCC and a low albumin level were associated with a PTH decrease; high DDC was not associated with an increased rate of mortality among patients in whom PTH level remained in the low range. However, Merle et al.’s study was based only on biannual PTH sampling, and information on acute comorbid conditions or changes in therapeutic intervention was not available between sampling periods. Moreover, high DCC was prescribed in their study based on usual care rather than being individualized based on PTH values. We consider that using the KDIGO target level (i.e., low-normal-high level classification) to study PTH variations may be questionable as a small variation in PTH level could be associated with a change in target zone classification. In the COSMOS study of 4500 European HD patients evaluated at 6-month intervals, Fernandez-Martin et al. reported that a serum PTH decrease was not associated with an increased rate of mortality when baseline PTH levels were within the KDIGO range of normal (168 – 674 pg/mL), with the risk of mortality significantly increasing among patient with a baseline PTH level <168 pg/mL [15]. Again, no data on acute comorbid conditions or change in therapeutic intervention was provided. We hypothesize that a decrease in PTH among patients in the low level KDIGO range would reflect an acute comorbid condition, rather than a medical decision on treatment, which would explain the finding of a higher rate of mortality. In their large US-based cohort study of HD patients, Streja et al. reported that an increased in serum PTH level from <150 pg/mL to 150–300 pg/mL was associated with a lower risk of mortality [60]. Once again, this was an observational study with no information on the underlying cause of variation in PTH level provided.

The fact that we conducted a monocentric study with a small number of patients limits the generalization of our results. However, the treatment using a strategy that has been homogenous for 20 years, as well as using monthly serum PTH sampling, allowed us to identify factors associated with variation in serum PTH levels.