Pathophysiology and therapies of CKD-associated secondary hyperparathyroidism

ABSTRACT

Uremic secondary hyperparathyroidism (SHP) refers to the biochemical abnormalities that characterize CKD-MBD. However, historically parathyroid hormone (PTH) is identified as the key culprit hormone and the essential biomarker of secondary hyperparathyroidism. SHP represents the adaptive response to several mineral abnormalities that initiate and maintain increased PTH secretion through classical mineral derangements and more recently elucidated hormonal dysregulations. Among classic factors involved in the pathogenesis of SHP, phosphate, calcium, and calcitriol have a prominent role. The discovery of new pathogenetic factors involved in the development of SHP (and the eventual CKD-MBD) including fibroblast growth factor-23 (FGF23) and klotho provides new hypothesis and perspectives to our understanding of this complex metabolic disturbance. Recently more than serum phosphate a critical role in regulating FGF23 synthesis and the progression of CKD is ascribed to phosphate pool, reflected by production of glycerol-3-phosphate and the formation of excessive CPP-2. Finally, also skeletal resistance to PTH action, due to dysregulation of the Wnt–β-catenin system and intestinal dysbiosis, affecting the PTH actions on bone are causal factor of SHP. Identifying all the actors at play is mandatory to allow the most precise therapeutic prescription in the individual patient. This paper aims to review, in particular, the pathophysiology of SHP, which is essential to envisage the eventual therapeutic options for the associated MBD.

INTRODUCTION

CKD-MBD, a clinical entity described in 2006 [1], is characterized by a combination of the following: (i) abnormalities of calcium, phosphate, PTH, or vitamin D metabolism; (ii) abnormalities in bone turnover, mineralization, volume, or strength; and (iii) vascular and extra-skeletal calcifications [2, 3, 4]. The pathophysiology of CKD-MBD is complex, involves several organs (kidney, bone, intestine, and the vasculature), and is burdened by high mortality rates. Abnormal levels not only of serum calcium, phosphate, parathyroid hormone (PTH), and vitamin D metabolites, but also of alkaline phosphatase, fibroblast growth factor-23 (FGF23), alpha-klotho (klotho), and sclerostin, have all been identified as cardiovascular and/or global mortality risk factors in patients with CKD [5, 6, 7]. Historically, however, it was PTH that was identified as the key culprit hormone and the essential biomarker of secondary hyperparathyroidism (SHP). This paper aims to review, in particular, the pathophysiology of SHP, which is essential to envisage the eventual therapeutic options for the associated MBD.

Pathophysiology of uremic secondary hyperparathyroidism

PTH synthesis goes through three cleavage steps, from pre–pro-PTH (115 amino acids) to pro-PTH (90 amino acids) and finally to the active hormone (84 amino acids). These steps are realized in the parathyroid chief cells that contain secretory granules ready for blood release through exocytosis. Secretion occurs in few seconds in response to fluctuations of plasma concentrations of ionized calcium, while calcitriol, phosphate, and FGF23 are mainly necessary for parathyroid cells proliferation and PTH synthesis. SHP develops early in CKD and its prevalence increases as kidney function declines, ranging from 12% in patients with GFR >80 ml/min/1.73 m² to almost 60% in patients with GFR <60 ml/min/1.73 m² [8]. SHP represents the adaptive response to a series of mineral abnormalities that initiate and maintain increased PTH secretion through classical mineral derangements and more recently elucidated hormonal derangements (Table 1).

Table 1:

Classical and new pathogenetic mechanisms of secondary hyperparathyroidism.

Pathogenetic mechanisms of SHP
	Element	Pathological alteration	Induced by …	Therapy
Classical and always relevant	1,25(OH)2D	Reduction	● Reduced 1-alphahydroxylase activity ● Reduced native vitamin D	Native/active vitamin D
	PTH	Increase	● Low 1,25(OH)2D ● Hypocalcaemia ● Hyperphosphatemia	Calcimimetics VDR activators Phosphate binders
	Calcium	Reduction	● Low 1,25(OH)2D	Calcium intake
	Phosphate	Increase	● Reduced nephron number ● Dietary load	Phosphate binders, diet, calcimimetics
New and potentially relevant	FGF23	Increase	● Klotho reduction ● increased intratubular phosphate	Reduce phosphate load, calcimimetics
	Klotho	Reduction	● Reduced nephron number ● Increased intratubular phosphate	Reduce phosphate load, SGLT2i (?)
	CCP	Increase	• Reduced nephron number ● Increased intratubular phosphate	Reduce phosphate load
	Glycerol-3-phosphate	Increase	● increased phosphate pool ● Increased intratubular phosphate	Reduce phosphate load
	Intestinal microbiota	Dysbiosis	● Reduced SCFA-producing bacteria ● Increased SFB bacteria	Pre-/probiotics? New drugs

Classical mineral derangements: calcium, PTH, phosphate, and vitamin D

Calcium plays a major regulatory role on PTH [9]. Any minimal change in ionized calcium is perceived by the calcium sensing receptors (CaSR) expressed on the surface of the chief cells and modulates PTH secretion reciprocally [10]. In CKD, calcitriol deficiency decreases the expression of intestinal calcium transport proteins, such as calbindin and TRPV6, thus reducing calcium absorption [11]. In addition, calcium is less properly reabsorbed by the diseased renal tubules, even though hypocalciuria is present since early CKD stages. Further, chronic hypocalcaemia seems to play a pivotal role in the development of parathyroid gland hyperplasia through long-term reduction of CaSR signal transduction [12]. A downregulation of parathyroid CaSR expression in CKD renders parathyroid cells less sensitive to the inhibitory effect of ionized calcium such that higher concentrations are required to suppress PTH [13]. In early CKD inappropriate postprandial calciuria with transient hypocalcaemia may represent an additional mechanism of SHP [14]. Another cause of hypocalcaemia is skeletal resistance to PTH, which could play a role in the frequently reported adynamic bone disease of mild-to-moderate CKD patients that is ultimately overcome by increasingly severe parathyroid hyperfunction [15, 16, 17, 18]. Skeletal resistance to PTH, whose entire pathogenesis remains an unsettled issue, could be explained by, among others, the limitations intrinsic to the different PTH assay methods. Cavalier et al. recently emphasized how and why PTH values can differ significantly depending on the assay method employed and pointed to the need for an international standardization to reduce the discrepancies observed in clinical studies on PTH levels and bone histology [19].

The role of phosphate as a major determinant of SHP was evidenced by Slatopolsky et al. in an experimental model of chronic renal failure in which a low phosphate diet prevented serum phosphate and PTH increments in nephrectomized dogs [20]. At variance, a high phosphate diet, besides increasing serum phosphate and reducing serum calcium and calcitriol levels, resulted in very high PTH values. According to their hypothesis, high levels of PTH represented the price paid by the system (trade-off hypothesis) to restore serum levels of phosphate and calcium. In advanced stages of CKD, the adaptive response is insufficient and SHP becomes florid and associated with parathyroid gland hyperplasia [21, 22, 23]. We now know that in renal patients, dietary phosphate loads do not result in hyperphosphatemia in the early stages of CKD, since the proximal renal tubule, under the action of PTH (and the ‘novel’ FGF23, which is described later), decreases tubular phosphate reabsorption. PTH increments may be sufficient to correct hypocalcaemia by increasing bone resorption, renal tubular calcium reabsorption, and improving vitamin D hydroxylation. With a critical reduction of nephron number (CKD stages 3b to 5), the compensatory increase in PTH is inadequate and phosphate retention is noticeable due to some degree of PTH receptor resistance [24] or to inappropriately normal intestinal phosphate absorption despite reduced serum 1,25(OH)2D (calcitriol) concentrations [25]. In addition to indirect actions, mediated by calcium and calcitriol, phosphate directly stimulates the synthesis and secretion of PTH. Hyperphosphatemia seems to reduce the expression of CaSR in the parathyroid glands, thus rendering the glands less sensitive to the inhibitory action of calcium on PTH synthesis [26]. Phosphate directly affects PTH synthesis through a post-transcriptional action, which involves the binding of trans-activating proteins (trans-acting proteins or AUF1) to cis-domains located in the untranslated 3′ region of the PTH messenger RNA. In short, the increase in phosphate stabilizes PTH mRNA and promotes PTH synthesis [22, 27, 28]. Very recently, it has also been demonstrated that phosphate binds and inhibits the parathyroid CaSR, thus favouring PTH secretion [29].

Another factor involved in the development of parathyroid over function is the progressive reduction of calcitriol synthesis along with the decline of renal function. Generally, serum calcitriol starts to drop when GFR is <60 ml/min/1.73 m², but earlier reduction is possible [8]. Besides reduced renal mass, additional causes of reduced synthesis include: (i) insufficient natural vitamin D or cholecalciferol supply (80% of CKD patients have either insufficient or deficient 25OHD levels) [30]; (ii) direct inhibition of 1α-hydroxylase (CYP27B1) by hyperphosphatemia [31]; and (iii) downregulation of PTH receptor expression in the kidney and blunted PTH-mediated stimulation of calcitriol synthesis [15]. Low calcitriol promotes PTH secretion through indirect and direct actions. Indirect effects include lower intestinal calcium absorption and lower bone calcium release both favouring hypocalcaemia and the eventual PTH stimulation. Direct mechanisms include lower suppression of PTH synthesis by vitamin D receptors (VDR) in parathyroid glands [32] and lower induction of VDR expression in the parathyroid cells by calcitriol [33]. Lower VDR expression makes cells less sensitive to the inhibitory effect of calcitriol on PTH gene expression, amplifies the process, and favours hyperplasia, monoclonal cellular growth [10], transformation of chief to oxyphyl parathyroid cells [34], and nodule formation in the parathyroid glands [35, 36]. Finally, vitamin D response elements have been identified in the CaSR gene, providing upregulation of CaSR expression [37]. Therefore, calcitriol deficiency could lead to downregulation of CaSR expression and parathyroid hyperplasia.

More recent developments in the pathogenesis of SHP: FGF23, klotho, sclerostin, etc.

A striking novelty in the pathogenesis of SHP was the discovery of the FGF23–klotho hormonal system, which not only regulates phosphate, vitamin D, and PTH metabolism, but also has systemic effects. Directly or indirectly, through its co-receptor alpha-klotho, FGF23 inhibits phosphate transport in renal tubular cells, suppresses the activity of 1α-hydroxylase (which converts 25-hydroxyvitamin D to calcitriol), stimulates 24-hydroxylase (which converts calcitriol to inactive metabolites) and inhibits PTH secretion [38]. FGF23 increased production by osteocytes, possibly stimulated by phosphate load in early CKD, seems to precede or coincide with the decrease in the circulating concentration of calcitriol or with any increase in PTH, which would help facing serum phosphate increments. Notably, unlike PTH, FGF23 inhibits renal calcitriol production [21, 39]. The pathophysiological stimuli that cause increased FGF23 production by bone tissue in CKD are under investigation. One possibility is that the initial disturbance is a decrease in renal klotho expression, leading to renal FGF23 resistance and a subsequent increase in skeletal FGF23 synthesis [40]. However, evidence indicates that elevated FGF23 production in CKD is not solely due to reduced renal klotho levels. Notably, FGF23 levels appear to rise before klotho levels reduction in renal tubules. In the early stages of CKD, increased FGF23 is associated with reduced serum phosphate levels due to enhanced phosphaturia, suggesting functional FGF23 activity in the tubules, secondary to the presence of klotho [41]. Interestingly, not all patients with CKD exhibit an increase in FGF23 during the early stages of the disease, indicating that declining renal function alone is insufficient to stimulate FGF23 synthesis. A significant observation is that FGF23 levels increase before any detectable serum phosphate increment, raising the question of what triggers bone to increase FGF23 production in CKD. Relevant studies show that the body possesses phosphate buffering systems that maintain serum phosphate levels within narrow limits to prevent intravascular precipitation of phosphate and calcium [42]. This system, defined as calciprotein particles (CPP), consists of particles formed by calcium, phosphate, and fetuin-A that chelate circulating phosphate. There are different forms of CPP, with primary forms (CPP-1) measuring 9 nm and larger secondary CPP (CPP-2, 100 nm) that appear when the CPP-1 buffering system is saturated. Research by Akiyama highlights that while CPP-1 can directly activate FGF23 production at the bone level to regulate phosphate balance [43], CPP-2 plays a role in the development of inflammation and vascular damage [44]. In CKD patients, despite normal serum phosphate levels, there is an increase in CPP, particularly CPP-2 [45, 46]. Furthermore, some studies suggest that the increase in CPP in CKD correlates with the mortality risk in this population [47]. Collectively, these data indicate that in the early stages of CKD, serum phosphate levels do not change, but the total phosphate pool (CPP-1 and CPP-2) increases through an adaptive mechanism that leads to increased secretion of FGF23 to maintain an adequate phosphate pool. When this system becomes insufficient and leads to the formation of excessive CPP-2, which contributes to inflammatory and vascular damage in CKD, the buffering systems becomes maladaptive even before serum phosphate levels increments.

Another significant aspect is the recent evidence that the kidney may directly regulate bone FGF23 synthesis. The rise in FGF23 results from an imbalance between renal mass (i.e. the number of nephrons) and phosphate load. As the nephron count decreases, phosphate load per nephron increases. A recent experimental study [48] elucidates the potential role of this intratubular phosphaturia in regulating bone FGF23 production. The reduction in nephron number and the corresponding increase in phosphate load per nephron results in increased phosphate transit through the proximal tubular cells of the segment 1, mediated by type II sodium-phosphate co-transporters. The heightened intracellular phosphate load elevates the renal production of glycerol-3-phosphate, whose serum increments stimulate bone FGF23 synthesis. This points to a direct regulation of bone FGF23 synthesis by the kidney when tubular cells are metabolically stimulated by phosphate load [49]. Additionally, the increased production of FGF23 leads to the downregulation of tubular phosphate transporters, resulting in elevated phosphate concentration in segment 3 of the renal tubule. The study by Shiizaki et al. demonstrates that increased phosphate load in the S3 segment, on reaching critical thresholds, can cause the precipitation of intratubular calcium-phosphate particles. In a murine model, these particles were able to activate Toll-like receptor 4, triggering intracellular NF-κB and p38 signalling pathways, which induce inflammation, reduce renal klotho expression, and contribute to CKD progression [50]. These studies underscore the critical role of intratubular phosphate concentration in regulating bone FGF23 synthesis and the progression of CKD. Figure 1 shows an update on the role of phosphate in the development of SHP.

Figure 1:

Novel pathogenic mechanisms of secondary hyperparathyroidism. In CKD, nephron loss results in elevated serum phosphate (Pi) pool and increased phosphate concentration in the remaining nephrons (PiU). Serum phosphate load promotes the formation of type 1 and type 2 CPPs, which stimulate the production of FGF23. Elevated phosphate levels within individual nephrons increase glycerol-3-phosphate production (G3-P) and decrease tubular expression of klotho, both enhancing FGF23 synthesis. Upregulation of FG23 suppresses renal production of calcitriol, resulting in hypocalcaemia and increased PTH secretion. Further, FGF23 increases intratubular phosphate concentrations while simultaneously lowering systemic serum phosphate pools. The sustained elevation of serum phosphate directly stimulates PTH synthesis.

Further recent discoveries are shedding light on the controversial actions of PTH on bone. We know that PTH either stimulates bone production or resorption depending on whether its secretion is intermittent or continuous. This apparent paradox could be explained by recently discovered cofactors. A study by Pacifici et al. demonstrated that in germ-free murine models (grown in a germ-free environment or treated with broad-spectrum antibiotics), intermittently administered PTH failed to promote bone mass growth. This anabolic inactivity of intermittent PTH on bone was associated with a deficit in butyrate, a short-chain fatty acid (SCFA) that regulates osteoblast and osteoclast metabolism [51]. Notably, the administration of butyrate in these models restored the anabolic capacity of intermittent PTH on bone [51]. The same research group investigated the role of the microbiota in the bone catabolic action of continuously infused PTH. Using a murine model colonized with segmented filamentous bacteria (SFB, Gram-positive commensal bacteria that induce the differentiation of Th17 cells), they found that SFB are necessary for the bone catabolic action of continuous PTH [52]. These findings are relevant to CKD because CKD patients are known to have intestinal dysbiosis, which reduces the presence of SCFA-producing bacteria and favours the colonization of SFB. This creates an imbalanced gut microbiota that promotes the catabolic action of PTH on bone, counteracting potential anabolic effects [53].

Another possible explanation of skeletal hyporesponsiveness to the action of PTH might come from a dysregulation of the Wnt–β-catenin system, which is a stimulator of osteoblasts proliferation and activity, inhibited by sclerostin and counteracted by PTH. In CKD, circulating levels of sclerostin increase early thus blunting osteoblast activity and leading to a low bone turnover, which with CKD progression could be overcome only by higher PTH elevations up to eventual production of high turnover bone [54].

Finally, two other aspects cannot be disregarded. In healthy adults, the main type of cells producing PTH are pale and basophilic (chief or principal cells), while large eosinophilic oxyphil cells are less represented and have unclear functions. Hyperplasia of the parathyroid glands is first manifested by an increase in the number of active secretory cells within the glands, mainly the chief cells. These principal cells, stimulated by hypocalcaemia and the uremic environment, transform into oxyphil cells, which are characterized by an increase in the number of mitochondria, which is a determining element in their trans-differentiation into oxyphil cells as shown by the single cell sequencing recent studies [34, 55]. Of note, these two cell types respond differently to usual therapies, for example, calcimimetics such as cinacalcet promote the trans-dedifferentiation of main cells into oxyphils cells whereas this phenomenon is not observed with calcitriol [34]. Second, there is now scientific evidence that variations in serum PTH concentrations may be linked to common genetic polymorphisms, which are located near genes involved with vitamin D metabolism, renal type 2a sodium-phosphate co-transporter, claudin 14, and calcium metabolism [56].

As a whole, the number of possible pathogenetic factors involved in the development of SHP (and the eventual CKD-MBD) is increasing and provides new hypotheses and perspectives for our understanding of this complex metabolic disturbance, while also suggesting novel therapeutic possibilities.

Clinical and diagnostic features of SHP in CKD

Clinically, even advanced SHP is most often asymptomatic. Clinical manifestations are generally due to bone disease (osteitis fibrosa and fractures) and the consequences of hypercalcaemia and hyperphosphataemia [57]. Only severe disease can cause mechanical bone pain, arthralgias, proximal myalgias, and an erosive enthesopathy that put the patient at risk of tendon rupture, and finally favour the occurrence of fractures, even after minor trauma. Also, systemic features including asthenia, pruritus, pancreatitis, hypertension, cardiac failure, and erythropoietin-resistant anaemia may occur later. The deposition of calcium in tissues could lead to red eye syndrome, cutaneous, and vascular calcification and pseudogout due to intra-articular deposition of radio-opaque crystals of calcium pyrophosphate dehydrate. An infrequent but dramatic consequence of SHP is the calciphylaxis syndrome in which we can observe cutaneous and vascular calcifications [58]. It is the result of arteriolar calcification evolving in skin necrosis and gangrene and may be fatal. Pathogenesis of calciphylaxis is very complex, however, post  hoc analysis of the EVOLVE trial in haemodialysis patients showed that improving PTH control, through cinacalcet administration, allowed a significant decrease in the incidence of calcific uremic arteriolopathy as compared to placebo [59].

Besides calcium and phosphate, laboratory markers of SHP include serum levels of PTH, vitamin D, and bone turnover markers (total and bone-specific alkaline phosphatases, osteocalcin, and type I collagen metabolites) [30, 60]. Serum phosphate and calcium are significantly deranged only in later CKD stages [8]. Serum 25OHD levels are almost invariably reduced in renal patients [30], [8], while calcitriol levels steadily decrease along with GFR reduction. Evaluation of hydroxylases efficiency can be sought through metabolites ratio, such as, e.g. 1.25/25 D ratio [61] or 24,25D/25 D ratio [62]. FGF23, which drops early in CKD [63] is currently not recognized as an early marker of ensuing SHP possibly because available assays still lack international standardization and sufficient reliability for routine application [64]. Total or bone-specific alkaline phosphatase have been recently proposed as reliable indicators of bone turnover, and are possibly better than PTH [65]. As for PTH, the third-generation assay allows better comparison among different commercial assays but a definitive standardization of the assay is claimed [66]. The best available marker of bone resorption in renal failure is tartrate resistant acidic phosphatase 5b, while firm reliability of collagen metabolites indicative of bone synthesis (procollagen type I N-terminal peptide) and resorption (C-terminal telopeptide of collagen type I) is hampered by blood retention along with GFR reduction [60].

Diagnosis of SHP-related bone disease requires X-ray examination showing subperiosteal bone resorption, which is particularly well expressed at the radial border of the second phalanges of the second and third fingers [67]. Resorption of the distal phalanges indicates severe SHP and can lead to distal osteolysis translating clinically into a digital pseudo-hippocratism. Subchondral bone resorption causes widening of pubic symphysis and sacroiliac and acromion-clavicular joint spaces. In the axial skeleton, bone resorption and formation frequently coexist leading to a salt and pepper appearance of the skull and the so-called rugger jersey vertebrae in which condensed endplates contrast with low density of the central parts. In severe cases, bone condensation can result in a rare pseudo-Pagetic aspect, which, in contrast to true Paget's disease, involves the whole axial skeleton. Brown tumours due to SHP should be differentiated from amyloid erosions, which always involve articular areas. These radiologic signs are typical of severe SHP.

As for bone mineral density (BMD), this does not provide exact information about bone turnover or architecture, which are adversely affected in CKD patients with SHP. However, DXA is widely available and is the clinical standard to measure BMD indicative of bone mass or quantity, but not quality. DXA is also an important tool for diagnosing osteoporosis in CKD 4–5D [68]. In addition, DXA predicts fractures in CKD [69] and a very low BMD is an indicator of bone fragility and should prompt a rapid correction of SHP [70, 71]. BMD reductions are detectable earlier than X-ray signs throughout the course of CKD and SHP.

Bone biopsy should not be considered a mandatory step in the evaluation of bone health. However, it represents the diagnostic gold standard and may be performed in complex cases: to exclude a bone mineralization defect, to confirm suspicions of low bone turnover, or to rule out atypical bone pathology, as these are likely to require different therapeutic approaches. Bone scan demonstrates an increased uptake of ⁹⁹technetium pyrophosphate or bisphosphonate in the axial skeleton resulting from increased bone turnover and so it is for ¹⁸F-sodium fluoride positron emission tomography (18F-NaF-PET) [72]. In CKD, the use of ¹⁸F-fluoride activity correlates strongly with turnover [72].

Finally, we know that SHP favours intima and media vascular calcifications in patients with end stage renal disease. Diagnosis of vascular calcifications and their progression in CKD patients require electron-beam computed tomography and/or multiple slices computed tomography, which are not universally available and are costly. More simple evaluation of vascular calcifications can be obtained by radiograms of the pelvis, hands, thigh, lateral lumbar spine, and ultrasonography of the common carotid artery. Using these simple methods a distinction between arterial intima and media calcifications may be obtained [73]. Of note 18F-NaF-PET also identifies sites of active vascular calcification [74], and may detect early vascular lesions before arterial wall calcifications are visualized by CT. But we have to underline that low PTH and hypoparathyroidism also favour calcifications [75] thus suggesting that normal parathyroid function is required not only for the maintenance of optimal bone structure, but also to contrast soft tissue calcifications. Given the high morbidity and the limited efficacy of therapy in advanced stages, SHP should be controlled early in the course of CKD.

Management of uremic secondary hyperparathyroidism

Targeting PTH

Serum PTH levels in renal patients are generally regarded as indicators of the severity of SHP, however, they are also associated with a U-shaped curve with cardiovascular mortality [76]. In addition, due to skeletal resistance, greater than normal serum levels of PTH are required for normal bone turnover. Accordingly, the first recommended target in dialysis patients has been between 150 and 300 pg/ml [77], a range later changed into between two and nine times the upper limit of ‘local’ normality [3]. This wider PTH target range was chosen to account for the significant inter-assay and intraindividual variability of PTH measurements, the association of this range with the lowest mortality risk, and the demonstration that normal bone turnover was not accurately predicted by the narrower PTH target values. Importantly, we do not have a specific target for non-dialysis patients whose optimal PTH levels remain unsettled. To personalize treatment of CKD-MBD it is better to avoid either excessive suppression or insufficient SHP control. It is thus reasonable to guide the temporal trends of PTH and aiming at values a little bit higher than normal but susceptible to suppression with available drugs [78].

Drugs to target these PTH levels mainly aim to normalize serum calcium and phosphate and to stimulate VDR and CaSR.

Targeting calcium

KDIGO guidelines suggest to maintain calcaemia within the normal range (2.10–2.50 mmol/l) but preferably close to the lower limits of normality because this has been associated with better life expectancy compared to the upper limits (which are associated with increased vascular calcifications) [4]. This is strikingly different from older strategies aiming at hypercalcaemia with oral calcium supplements to suppress PTH and reduce hyperphosphatemia given the phosphate binding properties of these supplements. This strategy has changed with the increased awareness of the risk of vascular calcifications [4]. However, given that intestinal calcium absorption is low in CKD, a negative calcium balance is possible, with detrimental effects on bone mineralization and the risk of fractures in the long term. To maintain a neutral calcium balance in adults with CKD, the CKD-MBD and the European Renal Nutrition working groups recently suggested the rough estimation of calcium balance in the individual patient pointing to a total calcium intake from diet and medications of 800–1000 mg/day and not exceeding 1500 mg/day [79]. In dialysis patients, the use of a dialysate calcium concentration between 1.25 and 1.50 mmol/l is suggested. In thecase of hypocalcaemia, calcium salts, vitamin D derivatives, and dialysate calcium can be adjusted taking into account a patient's daily calcium intake, age, physical activity, serum PTH concentration, and the estimated degree of bone turnover [80].

Targeting phosphate

Serum phosphate should be kept within the normal range in CKD patients [4], first by avoiding dietary loads. Oral phosphate binders that reduce the availability of phosphate for intestinal absorption are the most frequently employed drugs. Historical aluminium-containing binders are used only as a rescue therapy given the potential toxicity [4]. Calcium salts form poorly absorbed complexes with dietary phosphate in the intestine, but the unbound fraction is absorbed with the risk of hypercalcaemia. In particular, calcium carbonate provides bicarbonate, which may be useful against metabolic acidosis. Calcium-free phosphate binders are the preferentially used drugs. Sevelamer hydrochloride, which is as effective as calcium carbonate but with lower risk of hypercalcaemia and cardiovascular calcification, can reduce LDL cholesterol and is associated with better cardiovascular outcomes and survival [81]. Sevelamer carbonate has been introduced subsequently in an attempt to increase serum bicarbonate. Lanthanum carbonate (LaCa) is an alternative with similar efficacy in reducing hyperphosphataemia. Of note, LaCa accumulates in liver lysosomes and is excreted with the bile without apparent toxicity in the short and medium terms. LaCa does not cross the blood–brain barrier nor accumulates in the central nervous system or in the skeleton [82, 83], however, surveillance is still licit. Further chelating drugs are iron based and include sucroferric oxyhydroxide and ferric citrate [84, 85] with potentially positive effects on iron balance (Table 2).

Table 2:

Phosphate binders: clinical and pharmacologic characteristics.

Binder	Formulation (type, mg)	P bound (mg)	Maximum daily dose (mg)	Maximum P bound (mg/day)	Extra P effects	Side effects(a)/risks
Sucroferric oxyhydroxide	Pill, 500	130	3000	780	Possible increase in iron absorption	Diarrhoea, darkening of stools
LaCa	Pill or powder, 1000	135	3000	405		Diarrhoea, nausea, vomiting
Sevelamer hydrocloride	Powder, 2400	63	7200	189	Possible LDL cholesterol reduction	Diarrhoea, nausea, dyspepsia, vomiting, metabolic acidosis (children)
Sevelamer carbonate	Pill, 800	21	7200	189	Possible LDL cholesterol reduction	Diarrhoea, nausea, dyspepsia, vomiting
Calcium carbonate	Pill, 500	56	2000	222		Risk of positive calcium balance
Calcium carbonate	Pill, 1000	111	2000	222		Risk of positive calcium balance
Aluminium—Magnesium hydroxide	Pill, 400	46				Risk of aluminium toxicity
Aluminium—Magnesium hydroxide	Spoon, 548	63				Risk of aluminium toxicity
Ferric citrate	Pill, 500	??	3000	??	Ameliorating anaemia	Risk of iron toxicity Diarrhoea, darkening of stools, nausea, constipation

^aAdverse reactions with a frequency >10%

New attempts in the management of phosphate load in CKD are possible after the identification of specific transport proteins in the intestine. Nicotinamide adenine dinucleotide and triazole derivatives act as non-competitive inhibitors of intestinal phosphate transport [86], and could be added to intestinal sodium-phosphate co-transporter (NPT2b) inhibitors, but with the risk of side effects including platelet count reduction [87]. Since dietary phosphate restriction and phosphate binders increase the intestinal expression of NPT2b, excessive phosphate deprivation in the intestinal lumen may trigger absorption of the ion. A new compound, Tenapanor, increases transepithelial electrical resistance of the sodium/hydrogen exchanger isoform 3 (NHE3, encoded by SLC9A3) [88] and reduces intestinal absorption of phosphate by reducing the tight junction permeability to phosphate [88]. Since 40%–60% of the intestinal phosphate absorption occurs by this paracellular pathway when it is abundant in the diet, this drug could help preventing dietary linked hyperphosphatemia [89]. Overall, therapeutic approaches to hyperphosphatemia include (1): dietary phosphate intake restriction to 800–1000 mg/day, but being careful not to induce protein deficiency and malnutrition (2); quantity and quality of dialysis delivered (dialysis method, duration and frequency of the dialysis session, dialysis membrane surface, Kt/V, etc.) (3); withholding of drugs stimulating intestinal absorption (e.g. vitamin D and its derivatives) (4); and avoiding inter-compartment transfer of phosphate towards blood (e.g. increased bone resorption, adynamic osteopathy, metabolic acidosis, hyperglycaemia, etc.).

Targeting vitamin D (native or active vitamin D)

Low levels of 25OHD3 (insufficiency or deficiency), which favours osteomalacia in normal people, are described almost invariably in CKD patients [19] and are associated with poor survival in almost all studies [90, 91, 92]. Native vitamin D supplements (cholecalciferol) improve this biochemical deficit and may even increase serum 1,25OH2D in dialysis patients, suggesting a contribution of vitamin D depletion in the development of SHP. Indeed, the efficacy of native vitamin D administration on SHP control in CKD is challenged and burdened by the risk of hypercalcaemia [93]. Recently, in CKD stage G3–G4 patients, an extended release calcifediol (25OHD) formulation has been reported to increase 25OHD levels over 50 ng/ml, without increments in serum calcium and phosphate, but with increments of 1,25OH2D levels and reduction of PTH [94], which suggests that targets for vitamin D repletion could be higher in CKD if aiming for PTH control [95].

Active vitamin D derivatives such as alfacalcidol or calcitriol are indicated to threaten SHP. However, excessive doses increase the serum CaxP product favouring extra-skeletal calcification, and adynamic bone with low PTH levels [4]. Vitamin D analogues such as paricalcitol (19-nor-1α,25 (OH)₂D₂) can also be used to decrease PTH, but the lower prevalence of hypercalcaemia and adynamic bone remains unproved [96, 97]. KDIGO guidelines suggest correcting vitamin D deficiency and insufficiency using treatment strategies recommended for the general population. Using calcitriol and vitamin analogues in CKD-5D and in CKD G4–G5 non-dialysis is suggested in case of severe and progressive hyperparathyroidism. However, guidelines recommendations are based on studies targeting cardiovascular endpoints and not PTH control. Furthermore, in non-dialysis patients a safe upper cut-off for PTH levels is still unknown. Therefore, the indication to reserve active vitamin D analogues only for severe SHP might be exceedingly cautious [78].

Targeting CaSR (calcimimetics)

A new possibility in ameliorating the management of SHP has come from the production of drugs capable of activating the CaR on parathyroid glands. [98]. Cinacalcet HCl (Mimpara^®, given orally) and more recently etelcalcetide (Sensipar^® or Parsabiv^®, given intravenously) are approved for the management of SHP in dialysis patients. RCTs have shown that both cinacalcet and etelcalcetide allow reaching target PTH values in >50% of patients, compared with only 10% of control patients receiving optimal standard therapy [99, 100]. Both decrease not only serum PTH but also reduce serum calcium, phosphate, and FGF23. In case of hypocalcaemia, an increase in calcium and/or vitamin D and/or dialysate calcium concentration is possible [101]. Cinacalcet treatment has been associated with a lower incidence of parathyroidectomy (PTX) in haemodialysis patients [102]. Two ‘post  hoc’ analyses from the EVOLVE randomized clinical trial suggest that calcimimetic therapy may reduce the risk of heart failure, sudden death (−16%) and fractures (−16%–29%) compared to placebo [103, 104]. The BONAFIDE study showed that cinacalcet significantly reduced bone formation rate, osteoclasts and osteoblasts numbers, and improved bone histology in 53% of dialysis patients with SHP [105]. The most frequent side effects, with either drug and in addition to hypocalcaemia, are nausea and vomiting, which may improve in the long term [106, 107]. In real-life studies, ∼50% of dialysis patients still have PTH levels above the KDIGO target after 12 months of treatment [108, 109]. The intravenous injectable calcimimetic, etelcalcetide, appears to be 20% to 30% more effective than cinacalcet in controlling PTH in dialysis patients with SHP, with no difference in side effects [110, 111]. Apart from the possibility of non-compliance and intolerance, the severity of SHP appears to be a major factor determining the response to cinacalcet treatment, reinforcing the importance of treating SHP at the earlier stages [108].

Parathyroidectomy

The extreme resource to control SHP is PTX, which is indicated when SHP is refractory to medical management [4]. Before calcimimetics availability, PTX was mainly indicated in patients with a long history of dialysis [112, 113] after a 6–8-week trial of active vitamin D, refractory hypercalcaemia, and/or hyperphosphataemia, soft tissue calcifications, or calciphylaxis (when considered secondary to poor SHP control). Additional criteria were unexplained dilated myocardiopathy and very large parathyroid glands [10]. Recent surveys on PTX show that, compared to the 20th century, PTX rates were much lower in the first decade of the 21st century [114, 115] with a prevalence ranging from 3% to 7%. These differences may at least partially be explained by different medical treatment modalities between geographic regions, commercial introduction of calcimimetics, and different modes of data analysis.

Perspectives

According to the previously mentioned new discoveries in the pathogenesis of SHP, new therapeutic scenarios are possible.

• Targeting CPP: dietary phosphate and phosphate binder prescriptions could aim to target CPP levels [116] to improve SHP control and reduce CKD progression. In the study by Nakamura et al. [117], LaCa reduced serum CPP levels in haemodialysis patients, but these findings were not replicated in CKD stages 3–4 [118].

• Targeting proximal tubule phosphate (PTFp): lowering PTFp may reduce intratubular calcium-phosphate microcrystals formation and glycerol 3-phosphate production by renal tubular cells thus affecting renal damage and FGF23 synthesis. Thus, measuring the effects of available therapies on PTFp could become standard. Interestingly, and very recently, Sodium-glucose co-transporter 2 inhibitors (SGLT2i) have been shown to induce sodium-phosphate co-transporters activity as a result of the increased intratubular sodium concentration. The greater phosphate reabsorption in the S1 segment of the renal tubule lowers PTFp in the S3 segment [119]. Thus, a lower formation of intratubular calcium-phosphate microcrystals and a reduction of TLR4 activation is theoretically possible, which may partially explain the renal anti-inflammatory and antifibrotic effects of SGLT2 inhibitors [120]. Conversely, however, the increased phosphate reabsorption in the S1 segment may worsen a patient's phosphate balance, increase FGF23 and PTH levels, and worsen the SHP profile [121, 122].

• Targeting intestinal dysbiosis: therapeutic modifications of intestinal microbiota could theoretically change the final bone effect of PTH in CKD. Probiotics have been shown to improve gut microbiota and bone health in osteoporotic populations [123, 124, 125], but evidence in CKD is lacking.

• Targeting miRNA: targeting the miRNA:microRNA (miRNA) profile in parathyroid glands of experimental hyperparathyroidism and of parathyroidectomized dialysis patients suggests involvement in hyperparathyroidism. Also, miRNA-let-7 and miRNA-148 antagonism modified PTH secretion both in vitro and in vivo [27]. In addition, miRNA-129 negatively regulated proliferative signalling in the parathyroid glands of CKD mice [126]. These findings allow for the proposal of novel pathogenetic pathways with eventual therapeutic interventions.

All these new elements expand our understanding of the pathophysiology of mineral metabolism disorders in CKD. No clear evidence supporting their role is currently available but further research and therapeutic observations are warranted.

CONCLUSIONS

SHP appears as a complex metabolic derangement that develops along with renal insufficiency and involves many organs. The mechanisms involved in this dysregulation are numerous and their interactions very complex. Recently, we are discovering the contribution of previously unsuspected players responsible for the systemic impact of this disorder. Identifying all the actors at play is mandatory to allow the most precise therapeutic prescription in the individual patient.

FUNDING

This paper was published as part of a supplement financially supported by an educational grant from CSL Vifor.

DATA AVAILABILITY STATEMENT

Data sharing is not applicable to this article as no datasets were generated or analysed during the current study

CONFLICT OF INTEREST STATEMENT

S.M. declares he is board member of the Società Italiana Nefrologia; L.T. has nothing to disclose; M.C.S. declares receipt of honoraria from Kyowa Kirin International and travel support from Kyowa Kirin International, all unrelated to the submitted work; M.H.T. has nothing to disclose; M.P. has nothing to disclose; S.R. has nothing to disclose; P.U.T. declares receipt of honoraria from Amgen and Theradial, consulting fees from Astra Zeneka, GSK, and Medici, and travel support from Astra Zenaka, Hemotech, and Theradial, all unrelated to the submitted work