The previously mentioned abnormalities will cause damage in target tissues. Skeleton and the cardiovascular system are the most importantly affected. Soft tissue calcifications and calciphylaxis are important complications, as they are clearly associated with increased morbimortality in CKD patients.

Valvular and vascular calcifications are not a passive process of calcium and phosphate deposition. The increase in phosphate and calcium, inflammation mediators and uraemia per se, among others, have been found to favour the active transformation of smooth muscle cells into chondro-osteogenic type cells. These cells produce collagen matrix that subsequently mineralizes leading to cardiovascular “ossification”. There are multiple systemic (such as fetuin A) and local (such as Matrix Gla Protein) inhibitors of calcification to counterbalance the accelerator effect of renal failure on vascular calcification. In fact, calcium and phosphate combine with calcification inhibitor proteins to form primary or secondary calciprotein nanoparticles which take part in these vascular calcification processes.21 Metabolic acidosis may slow the progression of calcifications22 while alkalosis (e.g., post-dialysis) may favour calcification. Cardiovascular calcifications progress rapidly in patients with CKD.

CKD is also a process of accelerated ageing that is multifactorial. As such, bone fragility is increased and it is associated with a high incidence of fractures (senile or postmenopausal osteoporosis). There is also muscle weakness and a propensity to falls. Arteriosclerotic disease itself may not be a direct consequence of CKD but it does coexist and becomes aggravated by it. Moreover, all these factors influence the damage of CKD on its target organs and therefore affects treatment and prognosis.

These harmful effects go beyond bone alterations. Hyperphosphataemia has been associated with an increase in intima-media thickness, vascular rigidity and calcification, myocardial hypertrophy and mortality.23,24 It induces inflammation, oxidative stress and endothelial dysfunction, and it favors CKD progression.23,24 Classically, PTH has been considered an uraemic toxin, and it has been associated to a number of systemic effects.5 More recently, vitamin D deficiency is also considered an important pathogenic factor in and beyond CKD; it is associated with alterations of immunoregulation, inflammatory response, regulation of cellular proliferation, insulin secretion and renin production, among others.25 Calcidiol also has a direct action on bone metabolism, and it is the local substrate for the generation of calcitriol.

In addition, the increase in FGF23 has been shown to directly induce left ventricular hypertrophy by acting through the FGFR426 and it also cause alteration of endothelium-dependent vasodilation. It is also associated with multiple systemic effects, including inflammation and calcium and sodium control,27 although the latter has been questioned.

The rise in FGF23 occurs at early stages of CKD, and it actually precedes the increase in PTH even when the serum phosphate concentration is normal. However, the earliest alteration appears to be the reduction of klotho in kidney causing resistance to the phosphaturic action of FGF23, and in its free circulating fraction. Klotho deficiency may be associated with premature ageing mechanisms, at least partially independent of FGF23.28

Bone produces molecules that are capable to act on other organs through specific receptors an modify different functions. Therefore, bone may be considered as a new endocrine organ not only due to the generation of FGF23 but also to other molecules, such as osteocalcin, or others that modify the Wnt- (sclerostin/Dkk1) and the osteoprotegerin/RANKL- signalling pathways. The abnormalities associated with mineral metabolism have been clearly shown in the population with CKD, mainly patients in dialysis. However, they have also been found in the general population. These mineral metabolism absnormalities are independent predictors of mortality, especially due to cardiovascular disease. This is based on findings from multiple epidemiological studies, meta-analyses, pre-specified secondary analyses from randomized clinical trials and post-hoc studies.24,28–36

Nevertheless, no definitive proof of causality exists because, among other reasons, the most relevant studies have been directly or indirectly affected by a lack of sufficient statistical power.37,38

Periodic determination of serum calcium and phosphate concentrations, together with PTH and alkaline phosphatase, is decisive for the therapeutic management of patients. Ideally, ionic calcium should be used, but there are processing and cost issues for their routine use. Total calcium should be adjusted for actual albumin (or plasma protein) levels, especially in cases of hypoalbuminemia or hypoproteinemia.

We should take into consideration that the accuracy of albumin-corrected calcium and ionized calcium is only weak, probably due to variations in albumin, pH, hemoconcentration and others, present in dialysis patients or with CKD.45,46 Correction formulas have even been developed that also take into account plasma phosphate in addition to albumin.47

It is also important to remember that extracellular calcium concentration does not always correlate with calcium balance (which can be positive or negative with normal plasma calcium). The same occurs with phosphate, so a normal plasma phosphate does not exclude the presence of systemic overload.

On the other hand, the isolated values of calcium and phosphate are not sufficient for the appropriate management of patients with CKD, since normal calcium and phosphate values are common, but at the expense of a SHPT, that could be even severe.

• -

  We consider that the monitoring intervals suggested by the KDIGO are reasonable; Ca and P should be measured every 6–12 months in CKD Stage 3; every 3–6 months in CKD Stage 4; every 1–3 months in CKD Stage 5, and in CKD Stage 5D monthly/bimonthly determination seems the most appropriate.

• -

  A closer monitorization may be necessary in patients under treatment with calcimimetics or with active vitamin D metabolites, especially during the period of dose adjustment.

• -

  In hemodialysis patients, blood samples should be obtained pre-dialysis in the middle of the week.

• -

  The calcium–phosphorus product provides information that may be useful, but only in dialysis patients and never separately assessing serum calcium and phosphorus values.

The level of circulating iPTH used to be measured with the no longer available Nichols Allegro kit (the normal range in the general population was 10–65 pg/mL). iPTH is now measured by immunoradiometry or immunochemiluminescence assays. PTH is the biochemical parameter (along with alkaline phosphatase) that best correlates with the histological lesions of SHPT, especially with osteoblastic activity. In fact, PTH better reflects actual parathyroid activity, and alkaline phosphatase the bone activity.

For this reason, the level of PTH is considered a good marker of underlying bone disease (at least the best readily available) in combination with total alkaline phosphatase or bone-specific alkaline phosphatase). Thus, considering the values of PTH and alkaline phosphatase may be enough to assess bone turnover and in most cases there is no need to perform a bone biopsy. This suggestion is especially relevant in these new guidelines in which an active treatment of the risk of fracture in patients with CKD is proposed (i.e. with antiresorptive agents). These should probably be avoided if adynamic bone disease is suspected (see below).

• -

  In dialysis patients, iPTH levels >450−500 pg/mL (or equivalent) are usually specific for high remodeling bone disease, specifically osteitis fibrosa or the mixed form and, virtually exclude low remodeling disease. In one study, the best PTH value to classify as high remodeling bone disease was iPTH levels >323 pg/mL (approximately 5X the upper limit of normal).48 Obviously, the values proposed by the 2009 and 2017 KDIGO guidelines (>9X upper limit of normal) increase specificity but at the expense of accepting other risks associated with high PTH levels.3,4

• -

  In dialysis patients, iPTH levels <100−120 pg/mL (or equivalent) are linked to low bone remodeling (adynamic form or, more rarely, osteomalacia) with a prediction value close to 90%. In one study, the best point of discrimination for low remodeling bone disease was iPTH levels <104 pg/mL (slightly less than 2X the upper limit of normal).48 Therefore, the intermediate levels of PTH2,4,49,50 have less specificity to predict the underlying bone pathology and do not necessarily correlate with worse or increased survival. It is important to take into consideration that PTH values should be avaluated according to the ongoing treatment devoted to control PTH.

Although it has not been established a direct correlation between PTH levels and cardiovascular injury, relatively higher or lower levels of PTH are associated with increased risk of mortality, especially cardiovascular. Older publications have described an association between elevated PTH levels and left ventricular hypertrophy.51 Thus, in dialysis patients, both levels below 150 pg/mL and above 300 pg/mL (approximately 2X–5X the upper limit of normal, targets of the KDOQI 2003 or SEN 2011 guidelines)1,50 have been associated, at a population level, with an increase in a mortality. In the COSMOS study,52 it was established that the PTH value associated with a minimal mortality in European patients was 398 pg/mL. In addition it is necessary to highlight that there is an agreement that low bone remodeling (i.e. PTH < 2X the low limit of normal) is also associated with vascular calcifications, fractures and mortality. In any case, mortality associated with elevated PTH is modulated by the level of P which is cause of the most severe hyperparathyroidism.

PTH levels should be measured every 6−12 months in CKD stages 3−4 depending on the baseline value and the degree of progression of CKD. Although treatment is not modified, it is convenient to know the rate of increase in PTH in order to implement measures not only in extreme cases but also with clear evolutionary increasing or decreasing trends. In stage 5 (including 5D) PTH should be measured every 3–6 months as recommended by the KDIGO guidelines.

A more frequent monitorization of PTH may be necessary in patients on treatment for hyperparathyroidism, especially during dose titration to analyze efficacy and side effects, as well as to evaluate the rate of change in PTH. It is important to highlight that rather than taking into consideration the individual values of calcium, phosphate or PTH, we should evaluate the combined change (trends) of these parameters rather than “isolated values”, which may be punctually discordant. It is also important to assess the changes in PTH, calcium and phosphorus in the context of the other CKD–MBD parameters (calcidiol, alkaline phosphatase, vascular calcification, etc.).

Currently, we have to face the problems derived from the lack of homogeneity of the different methods used for the measurement of iPTH. There are not good correlation coefficients between the different assays which makes it difficult to compare the laboratory results. The Spanish Society of Nephrology prepared a document aiming to clarify the interpretation of these different methods,53 including correction formulas to calculate iPTH (available in applications developed in Spain such as “Global Nephro Calculator”) with respect to the reference kit classically used (Allegro de Nichols) and from which almost all the information on PTH was originally obtained. It is important to note that these initial inter-method adjustment algorithms were established in patients with CKD 5D on hemodialysis, and therefore they should not be used in other CKD populations where the proportion of PTH fragments (cleared by the kidney) is different. Therefore, they are also not applicable to patients on peritoneal dialysis for whom different algorithms have been proposed.54

The determination of “whole” or “bio-PTH” with methods that quantify PTH 1–84 (biologically active PTH) with the interference of amino-PTH (PTH 1–84 phosphorylated at amino acid 14), as well as the calculation of the ratio between different PTH fragments,55 are not currently recommended in daily clinical practice. Likewise, the use of non-oxidized PTH measurements (iPTH — oxidized PTH) is not yet justified in daily clinical practice.55

It is recommended to measure the levels of 25(OH) D (calcidiol) to prevent and treat if necessary, the frequent insufficiency or deficiency of this prohormone in CKD patients. The levels of 25(OH) D reflect the vitamin D stores and may vary with the diet and the degree of sun exposure. Nevertheless, the optimal level of 25(OH) D and the level at which it is considered insufficient remain controversial both in the general population and in CKD patients.

According to the results of clinical trials conducted in the general population it can we concluded that levels below 20 ng/mL (50 nmol/L) are probably suboptimal for CKD patients. In these cases it is recommended the intake of native vitamin D supplements (especially cholecalciferol or ergocalciferol) as recommended for the general population. Values between 20 and 40−50 ng/mL should probably be the target in patients with CKD, although there is still much controversy in this regard.56,57

It is unknown the relative importance of the measurement of vitamin D with the different kits available on the market, as well as the clinical value of free vitamin D measurement.

Low serum levels of 25-OH-vitamin D have been associated with higher overall and cardiovascular mortality in patients with CKD (on dialysis or not ) and in the general population58; however, improved survival with native vitamin D supplementation has not been reported.59

Total alkaline phosphatase together with PTH are useful to assess bone turnover in patients without liver disease. The measurement of Bone alkaline phosphatase may have some advantages as compared with total alkaline phosphatase but these do not necessarily justify the additional cost. However, the measurement of both iPTH and bone alkaline phosphatase is prpobably the best approach correlating with bone turnover in CKD.60–62 It may be necessary to reconsider the use of alkaline phosphatase in patients with CKD, especially if it is being considered a proactive treatment for osteoporosis. The use of antiresorptive agents should probably be avoided in cases with a high suspicion of adynamic bone disease (low levels of PTH and alkaline phosphatase — i.e. bone alkaline phosphatase below the median reference limits60–63). In a multicenter study, the best cut-off point to discriminate low-turnover bone disease was bone alkaline phosphatase <33,1 U/L.48

Presently, alkaline phosphatase is associated with a positive linear increase in the risk of mortality (not as the U, J or inverted J shape observed in the relationship PTH-mortality), mainly in hemodialysis patients.64 It has also been described an independent association between of total alkaline phosphatase levels >120 IU/L and coronary calcification,65 mortality and other adverse effects.66 A high alkaline phosphatase activity reduces the serum concentration of pyrophosphate, an important inhibitor of vascular calcification. In hemodialysis there is an increase in alkaline phosphatase activity with the consequent reduction of serum pyrophosphate and an increased risk of vascular calcification.67–69 For this reason, alkaline phosphatase (and the related pyrophosphate) may be considered potential targets in the treatment of the CKD–MBD complex in the future.66,70,71

There is no evidence that monitorization of calcitriol is useful in the control of CKD patients. However, it can be used for research purposes or in the differential diagnosis of some cases of hypercalcaemia (sarcoidosis and other granulomatous diseases, lymphomas, etc.). In the presence of increased PTH levels, it is unknown what would be the normal or advisable values of calcitriol, but in advanced CKD calcitriol levels should be low; therefore, a “normal” level indicates pathology.

Throughout the progression of kidney disease, it may be observed a decrease in the excretory capacity of calcium or phosphorus. It has been suggested that serial determinations of calciuria would make it possible to monitor potential calcium overload in patients with CKD. Also the previously mentioned FEP or maximum tubular reabsorption of phosphorus (TmP) (Normal FEP = 10%–20%) can be early markers of phosphorus overload.

However, in order to achieve a phosphate balance, phosphate intake should be maintained relative to the reduced glomerular filtration, requiring an increase in the FEP. The increase in FEP is accomplished by a reduction of the tubular absorption of phosphate which is accomplished by the action of an increased production of phosphatonins, mainly FGF-23 and others (FGF-7, secreted frizzled related protein 4, etc.) and PTH. These hormones modulate the expression of sodium-phosphate transporters (NaPi-IIa, NaPi-IIc, and PiT-2 type III) on the apical membrane of proximal tubule cells. However, the FEP may be increased up to a maximum limit (approximately 50%–55% in patients without proximal tubulopathies) which means that, given a certain phosphorus load, a critical reduction in glomerular filtration cannot cope with excretion, resulting in positive phosphorus balance with hyperphosphatemia.

Patients with advanced CKD receiving diuretics seem to have higher serum phosphate concentrations, perhaps because diuretics interfere with the maximal capacity to excrete phosphate.72 Urinary excretion of phosphate greater than 40 mg mL/min/1.73 m2 of GFR (i.e., more than 400 mg of urinary excretion of phosphate in patients with a GFR of 10 mL/min/1.73 m2 or 800 mg in patients with a GFR of 20 mL/min/1.73 m2) have been shown to be associated to hyperphosphatemia.73 It has also been suggested that for patients with a GFR lower than 25 or 15 mL/min/1.73 m2, a phosphaturia lower than 800 mg/day or 600 mg/day respectively, would be reasonable targets.7 It is noteworthy that the total amount of P ingested does not always correlate well with daily phosphaturia; this is explained by the different bioavailability (intestinal absorption) of the different sources of P, thus intestinal absorption of P from vegetal proteins is less than that from animal proteins. The ratio phosphorus/urea nitrogen in urine (UUN) may reflect the amount of P absorbed relative to the protein intake.74 Finally, we note that proteinuria appears to independently increase phosphorus retention.75

This phosphatonin plays an important role in the pathophysiology of mineral disorders and SHPT in CKD; in fact, the increase in FGF23 precedes the elevation in PTH. High FGF23 is associated with poor survival of CKD patients, and it is an early marker of phosphorus overload and severity of SHPT.32,34,76,77 FGF23 is mainly produced by osteocytes and new sources of FGF23 are being described, such as its production by cardiac cells. It is known that in addition to phosphate, FGF23 is also regulated by Ca, iron, sodium, among others, and that FGF23 has effects beyond the cardiovascular system (infection, inflammation…).78 However, its measurement in the clinical setting is still not recommended except for the diagnosis of some specific pathologies. There are kits commercially available for the measurement of the intact FGF-23 molecule and for the C-terminal fragments.79 There are also automated methods for measuring FGF23 that are still not widely used.

It is a molecule of extreme interest since it acts as a co-receptor of FGF23R1, the specific receptor for FGF23. There is a circulating form of klotho with independent actions that have been closely related to healthy aging.9 There is not a widely accepted standardized method for the measurement of klotho, and there is now a significant ongoing research on klotho.

They are associated with propensity of vascular calcification and its methodology and clinical value are still a subject under debate.80

Certain markers of bone remodeling, such as osteocalcin, free serum pyridolines, propeptides, and the C-terminal telopeptide of collagen, show good correlations with bone histology but do not improve the predictive power of PTH and/or alkaline phosphatase, and therefore its systematic use is not justified.60,63 The only bone derived molecules that do not accumulate in CKD are alkaline phosphatase, intact P1NP (bone formation marker) and tartrate-resistant acid phosphatase 5b (resorptive marker) because these molecules undergo hepatic clearance.60,81 The interest of their measurement could be reassessed with the appearance of the new guidelines for the treatment of osteoporosis in CKD.63

The bone biopsy is the “gold standard” for making a diagnosis and for a better understanding of the disease process. The predictive value achieved by biochemical parameters have made bone biopsy an exceptional indication, although currently its indication is being revitalized.98

The recommendations proposed by the SEN, and by KDIGO (3.50) have shown to be of limited help in decision-making. Notions previously defined as “unexplained” or “inconclusive biochemical parameters” are of little help in making the decision to biopsy; aluminum-induced bone disease has virtually disappeared with dialysis water treatment. And presently, the indication of biopsy before the use of antiresorptive agents is currently questioned.4,91

Therefore, despite its definite diagnostic value, the indication for bone biopsy must be individualized in the context of clinical cases where its diagnostic value is relevant for making therapeutic or prognostic decisions, as well as for research, with the intention to prove that there are therapeutic measures that can be applied to other patients.

To be take into consideration:

• a)

  Clinical manifestations: pathological fractures and/or persistent bone pain (especially exhibited in cases of osteomalacia), radiological changes not explained by ROD or biochemical changes that are not compatible with the pattern of ROD. All these circumstances may lead to investigate another bone disease of metabolic origin.

These may be examples:

• -

  High remodeling: a) Oxalosis: severe radiological images of osteitis fibrosa, without overt increase in PTH. Genetic diagnosis should be performed before the bone biopsy, but it may not be conclusive. b) Paget’s disease, depending on its presentation.

• -

  Low remodeling: a) Rickets/osteomalacia. b) Chronic hypophosphatemia without specific clinical manifestations, and with inconclusive genetic study.

• a)

  Non-iatrogenic persistent hypercalcemia of uncertain etiology, with suppressed PTH and a potential systemic disease pending diagnosis.

• b)

  Possible exposure to metals with a potential effect on the skeleton (aluminum, heavy metals, etc.).

• c)

  Studies with relevant designs oriented to diagnosis and therapy, such as the study of the potential effect of drugs on bone damage of metabolic origin (anti-resorptive drugs, bone anabolic agents…). As mentioned before, it is reasonable to perform a bone biopsy in patients with 3a-5D CKD if knowledge of the type of ROD may impact the therapeutic decisions.4,99

However, current guidelines consider that the absence of a bone biopsy should not limit the prescription of antiresorptive treatment in a patient at high risk of fracture.4,91

In the different studies performed in the general population, there were patients included that had impaired renal function and it has been observed in post-hoc analysis, that patients with reduced renal function had an improvement in BMD and a reduction in the risk of fractures, regardless of the degree of renal dysfunction.4,181 Thus, these benefits have been described with the use of with alendronate, risendronate, (and also with the selective estrogen receptor modulator, raloxifene) in patients women with osteoporosis with CKD stages 1–4 (with apparently normal creatinine or <1.6 mg/dL), with no known prior diagnosis of CKD, and with normal values of calcium, phosphorus, PTH, and alkaline phosphatase.4,181

Likewise, in the few published studies of dialysis patients, improvement in BMD has also been observed, especially when the patients had elevated PTH.182 However, it must be taken into account that, according to the data sheet, bisphosphonates are not recommended due to lack of experience for creatinine clearance <35–30 mL/min, although they have been used successfully in patients affected by calciphylaxis.182 Contrary to what might have been expected, it has not been clearly demonstrated that bisphosphonates cause adynamic bone disease.4,63

Although there have been very few negative effects of bisphosphonates on the kidney, if given intravenously it is important to lengthen the infusion time, reduce the dose by half and limit the exposure time (i.e. two years) to avoid side effects. Cases of tubular necrosis, interstitial nephritis, and focal glomerulosclerosis with nephrotic syndrome have been described. Oral administration does not appear to alter renal function.

Special mention deserves osteonecrosis of the jaw, which has been related in recent years to treatment with antiresorptive agents, although its incidence is very low. This lesion is defined as the presence of one or several ulcerated lesions with bone exposure in the upper jaw and/or mandible of a duration of more than eight weeks. It is rare to observe these lesions in patients on oral bisphosphonates. Risk factors for the development of osteonecrosis include the administration of intravenous bisphosphonates for a long period of time, neoplasms, chemotherapy, radiotherapy, high doses of steroids, alcohol and/or tobacco abuse, and especially local factors such as periodontal disease, tooth extraction, and maxillofacial surgery. This is why good oral hygiene and temporary suspension of these drugs are recommended in the event that these treatments are required, after assessing the risk/benefit (suspension only if the risk of fracture is relatively low). Atypical femoral (diaphyseal) fracture has also been described in very few cases. It is possible that the benefits of reducing a high risk of fracture and associated mortality justify the low risk of these very rare complications.

Denosumab is a humanized monoclonal antibody with high affinity and specificity against the receptor activator of nuclear factor kappa B (RANKL) that is administered subcutaneously every 6 months. By inhibiting the proliferation and activity of osteoclasts, denosumab decreases bone resorption and consequently increases BMD and therefore the risk of fractures are reduced.183 It is not eliminated by the kidney, which may be an advantage in patients with CKD since it does not require dose correction. However, it may cause severe hypocalcaemia with transient worsening of SHPT, especially in patients with CKD. Rebound bone loss has been described after discontinuation of denosumab.184

Although there is no conclusive evidence, both antiresorptive agents (bisphosphonates, denosumab) could exacerbate adynamic bone disease, or simply not be effective. It reasonable to stop the treatment with bisphosphonates during a period of time; this strategy should not be used with denosumab since a recent post hoc analysis has shown that the benefits of denosumab are rapidly lost and the risk of fractures is increased.185 The use of “sequential therapies” with these agents would be indicated. There is increasing experience of its prolonged use in patients with persistent high risk of fracture or with corticosteroid-induced osteoporosis.186–188

Regarding the risk of osteonecrosis of the jaw and atypical femoral fracture, the same principles mentioned with bisphosphonates could be applied.

Teriparatide is a fragment of human PTH including the first 34 amino acids of N-terminal molecule. This PTH fragment interacts with the type 1 PTH receptor, which is located primarily on osteoblasts and renal tubular cells. Intermittent teriparatide therapy increases the number of osteoblasts and subsequent augments bone formation. This anabolic effect is mediated by a decrease in osteoblast apoptosis and an increased activation of osteoblasts and pre-osteoblasts. It could have an indication in ABD, but its use is limited to two years due to the risk of osteosarcoma.189

Measurement of calcidiol levels is suggested in patients with CKD from stage 3 or in patients who, for whatever reason, are diagnosed with SHPT. Vitamin D deficiency or insufficiency should be corrected following the strategies recommended in the general population.110 It is considered that the recommended level should be >20 ng/mL to cover the daily needs of 97.5% of the population or 30 ng/mL to avoid increased levels of PTHi.110,193

Exact doses are not well defined. Clinical trials in the general population have used doses of 300–800 IU/day, considering a maximum of 4000 IU/day.110

In Spain we do not have a pharmacopoeia for vitamin D2 (ergocalciferol) except in multivitamin preparations. However, we have vitamin D3 (cholecalciferol) in the form of drops (in bottles of 10 mL = 20,000 IU/bottle = 2000 U/mL = 30 drops; 1 drop = 67 IU) or even in single-dose vials of 25,000 IU (to usually administer monthly –830 IU/day– or every 15 days). Although the dosage must be individualized, in general cholecalciferol doses of less than 600–800 IU/day (i.e. 9–12 drops) are usually ineffective. There are also several preparations that contain 200–800 IU of vitamin D3 + various amounts of calcium. It is recommended to be cautious with the use of these associations, especially in patients with vascular calcifications or at risk of developing vascular calcifications.

Calcifediol is easier to use is (ampoules or capsules of 0.266 mg = 266 µg = 16,000 IU of 25-(OH) vitamin D) generally administered monthly and exceptionally every two weeks, with closer control and during short periods. There is also a presentation in drops, in bottles of 10 and 20 mL, where 1 drop = 240 IU. Attention should be paid in obese patients as it is a fat-soluble vitamin.

The potency of calcifediol (µg to µg) appears to be about 5 times that of cholecalciferol194 and its half-life is longer. The administration of calcifediol on a monthly basis (exceptionally every 15 day), with the aforementioned controls of the levels of calcidiol, creatinine, calcium and phosphorus, is a convenient alternative to adjust the nutritional intake in patients with CKD or osteoporosis.195 For patients with CKD stages 3–4 with SHPH and vitamin D deficiency, a formulation with extended/prolonged release of calcifediol has already been marketed in some countries.196

Between 15–20 mg/kg/day of calcium m in the diet would be sufficient to ensure the coverage of this element. The recommended daily amount in the general population varies according to age and sex between 1000 and 1300 mg/day.110 It is not known whether these amounts should be limited in patients with vascular calcifications.

There is a limited information about the use of antiresorptive agents in patients with early CKD stage. This could consider paradoxical, especially if it is considered that this type of patients have a higher risk of fractures than the general population. However, in patients with CKD stages 1–2 with osteoporosis and/or high risk of fracture it is currently recommended, according to the WHO criteria, the same management as in the general population.4

Protein restriction will seek to avoid phosphorus intake and hyperfiltration, but with adequate monitoring to avoid malnutrition. The patient will easily tolerate the change if he had already adapted to the diet from the previous stages.

Some authors only limit products with disproportionate phosphorus content compared to protein content (abuse of dairy products, sodas and especially products prepared with additives), since many patients spontaneously lose appetite for protein as kidney disease progresses.

The levels of 25(OH)D3 will continue to be monitored to ensure that they are normal with the administration of cholecalciferol or calcifediol in its various forms if it is required.110

With this degree of renal function and dietary intervention, it is not difficult to maintain normal serum phosphate levels, at least until advanced CKD stage 3b. If this is not the case, phosphate binders may be started, although calcium binders should be used with caution in patients with vascular calcifications.

In case of progressive and significant increase in iPTH levels, the suggested initial dose of calcitriol is 0.25 µg 2–3 times a week or every 48 h, and the dose of α-calcidiol is 0.25 µg every 24–48 h.197 These doses should be adjusted according to regular biochemical controls without trying to normalize PTH levels for the adaptive reasons explained above. It may be advisable to give it at night because it is followed by an 8-h fast and thus has less effect on intestinal absorption of calcium.

The suggested dose of paricalcitol in this stage is 1 mcg 2−3 times a week or every 48 h depending on the iPTH levels. This dose should be adjusted according to the results of periodic biochemical controls. Conversion to paricalcitol typically follows a relationship of 1 mcg paricalcitol ≈ 0.25 mcg calcitriol ≈ 0.50 α-calcidiol.

In patients with CKD 3a–3b with PTH in the normal range and with osteoporosis and/or high risk of fracture according to WHO criteria, the treatment suggested is as in the general population.4,198 The indication of bisphosphonates or denosumab should be carefully weighed in cases with suspected EOA. In patients with CKD 3a onwards (3a-5D) with biochemical abnormalities of the CKD–MBD complex and decreased BMD and/or fragility fractures, it is suggested that the decision about treatment options should be made taking into account the magnitude and reversibility of the biochemical abnormalities and the progression of CKD, considering the possibility (not mandatory) of a bone biopsy.4,91,198

Protein restriction will be slightly more important (maximum 0.8 g/kg of weight/day) but only if adequate nutrition can be ensured.

The levels of 25(OH)D3 will continue to be monitored to ensure they are normal with the administration of cholecalciferol or calcifediol in its various forms if required.

With this reduction in kidney function, it becomes somewhat difficult to maintain normal phosphate levels despite dietary restriction. In the event of a progressive and persistent increase in phosphorus above normal levels, measures of phosphate restriction should be increased and/or a higher dose of binders should be used with meals, which, if they contain calcium, should not be exceeded in any case the 1000 mg/day. In any case, we must remember that the KDIGO 2017 guidelines4 suggest restricting the doses of calcium-based binders in adults from CKD stage 3a, having increased the degree of evidence as compared to previous guidelines, despite the limitations in the data sheets for lanthanum carbonate and sevelamer carbonate. Interestingly, and accepted in the data sheet, aluminum hydroxide could be used (if available) for a short period, administering it only in meals whose phosphorus content justifies it. There is experience about the effectiveness use of oxyhydroxide sucroferric before starting dialysis.

At this stage, depending on PTH levels, the recommended initial dose of calcitriol is 0.25–0.50 mcg every 24–48 h. These doses should be adjusted to the results obtained with regular biochemical controls. The more reduced effect of paricalcitol on calcium and phosphorus absorption, as well as its potentially lesser effect on cardiovascular calcifications, may make its use recommendable in this stage, especially trying to avoid high doses of calcitriol or α-calcidol.

The suggested starting dose of paricalcitol at this stage is 1 mcg every 24–48 h. This dose should be adjusted based on periodic biochemical controls.

As previously mentioned, in patients with CKD 3a and above (3a-5D) with biochemical abnormalities of the CKD–MBD complex and decreased BMD and/or fragility fractures, it is suggested that treatment options take into account the magnitude and reversibility of biochemical abnormalities and progression of CKD, considering the possibility (not mandatory ) of a bone biopsy. If treatment with antiresorptive agents is considered due to the existence of a high risk of fracture in patients with creatinine clearance <30 mL/min and with adequate control of the biochemical values of CKD–MBD, the possibility of treatment with antiresorptive drugs such as denosumab could be considered even though they are eliminated by the kidneys. But of course, following the warnings mentioned above.111,199 The use of bisphosphonates is not strictly contraindicated, but they are not recommended since the experience is insufficient.

Protein restriction should be maintained, taking care not to compromise adequate nutrition.

The serum Calcidiol values will continue to be monitored, to ensure that they are greater than 20 ng/mL with cholecalciferol or calcifediol.

With this degree of renal function the administration of phosphate binders with meals are usually required to maintain normal phosphate levels. The guideline is the same as in the previous stage, but doses are usually higher. It is advised a greater restriction of calcium binders.

In this stage, the recommended doses are the same as in the previous stage, although they may be modified depending on calcemia, phosphataemia and serum PTH values. The suggested initial dose of paricalcitol in this stage is 1 µg every 24 h if the iPTH is less than 500 pg/mL and increase to 1−2 µg every 24 h if the iPTH is above 500 pg/mL, the dose should be modified depending on calcemia and phosphatemia.

The increase in serum phosphate levels is one of the main problems presented by CKD patients on dialysis. Avoiding hyperphosphataemia has two purposes: one, to achieve an adequate control of bone-mineral metabolism, mainly to avoid the development, progression and complications of SHPT, and the other objective is to reduce cardiovascular risk and the high rate of morbidity and mortality in these patients. The independent association between hyperphosphatemia and mortality has been demonstrated by retrospective analysis of several large databases. More recently, the COSMOS study has shown a significant reduction in the risk of mortality associated with decreases in serum phosphorus.52 Therefore, maintaining serum phosphorus within normal limits (i.e. <4.5 mg/dL), with reasonable therapeutic measures is a priority. The COSMOS study showed that the lowest mortality is observed with a serum phosphorus level of 4.4 mg/dL (range 3.6–5.2); in another study, the “Dialysis Outcomes and Practice patterns Study “(DOPPS), the survival improved in those patients with a low number of serum phosphate above 4.5 mg/dL during a period of 6 months.200 Likewise, the area under the curve of the serum phosphorus concentration of the patients (with serial measurements, as recommended by the KDIGO) was also a better predictor of cardiovascular death than the most recent serum phosphorus level.200 Additionally, those types of patients with phosphorus levels greater than 5 mg/dL were associated with a higher rate of mortality and hospitalization, regardless of whether the serum levels of calcium and PTH are high, normal, or low.201

In this case, the treatment of hyperphosphatemia is based on three fundamental pillars:

• a)

  Restriction of dietary intake of foods with a high content of phosphorus without compromising the necessary protein intake.

• b)

  Modifications of the characteristics and dialysis scheme to optimize the elimination of this solute.

• c)

  Administration of phosphorus binders.

• d)

  In most cases it is required combination of these three therapeutics alternatives.

In hemodialysis, protein–energy requirements must be higher than those recommended for the general population, given the catabolic condition and the disease itself. Understandably, protein–energy requirements are also higher than those recommended in patients with CKD who are not yet on dialysis.

The priority must be to guarantee an adequate caloric, protein and mineral support. The price to pay for a presumably adequate diet should never be insufficient nutrition. Common sense sets the standards for a balanced diet. Four meals daily, balanced in carbohydrates, fats and proteins. A recent meta-analysis shows that diet (and 20−30 min per month of therapy by a dietitian) may reduce phosphorus levels without compromising nutritional status, but the evidence is low and probably this therapy will be useless if it is not maintained.202

It is considered that the optimal protein intake should be 1–1.2 g/kg/day (of which 50% should be of high biological value, that is, animal proteins), and the caloric intake should be 30–35 kcal/kg/day (35 for younger and 30 for older than 65 years). In peritoneal dialysis, the recommendation is even higher (1.2–1.3 g/kg/day).

Less restriction of dietary protein may result in an increases in phosphorus intake. Therefore, the price to pay to ensure enough protein intake may be the need for higher doses of phosphate binders.

The ideal duration of the dialysis session is a highly controversial topic. Currently it is considered that the duration of dialysis should be individualized according to the requirements of each patient. Although there is no absolute evidence that there is an independent effect of dialysis time on phosphorus control, except for patients with high residual renal function. In general terms, an increase in dialysis time and/or frequency improves solute removal.

• -

  The duration of the dialysis session may be decisive in the elimination of small solutes, mainly located in the space intracellular, as is the case with phosphorus.

• -

  There are not controlled and randomized prospective studies that confirm definitively that an increase in the time of dialysis has a positive effect on control of hyperphosphatemia. However, most published studies describe that increasing the duration of the hemodialysis session and/or nocturnal intermittent a hemodialysis have beneficial effect on phosphorus removal.203

• -

  Another alternative is to Increase the frequency of hemodialysis sessions. Again, there are no adequate studies to assess the effect of an increase in the frequency of dialysis on phosphorus clearance. Most of these the studies are observational, with a limited number of selected patients, followed by a short time period.

• -

  Currently, to achieve a significant reduction in phosphorus levels there is a tendency to increase frequency and time of hemodialysis with schedules of 2.5−3.0 h 5–6 times a week.204,205 The increase in time and frequency, can be an effective procedure for the treatment of refractory hyperphosphatemia. With long nocturnal dialysis daily (5–6 sessions of 6−10 h duration per week) there is a marked decrease in phosphorus levels, which allows a reduction in the doses of phosphate binders. Even it may be necessary to add phosphate to the dialysis bath, despite having realyze that the patients had increased the daily intake of phosphorus.205

• -

  Techniques with high convective transport can be considered a therapeutic alternative for hyperphosphatemia. As compared with low flow membranes, the high flow membranes have a greater phosphorous removal capacity. However, currently there is no clear evidence of the potentials advantage of the new membranes or hemodiafiltration regarding the phosphorus clearance.

As already mentioned, most hemodialysis patients have a positive phosphorus balance, so they will require additional treatment with intestinal phosphate binders to prevent hyperphosphatemia. The potential limitations of calcium binders (associated or not with magnesium) and aluminum hydroxide are the same as in previous stages; it is suggested the restriction of calcium binders in adults and it is recommended avoiding the use of aluminum binders (in addition to avoiding contamination of dialysis fluid with aluminum).4 There is extensive experience with both sevelamer and lanthanum carbonate and less with oxyhydroxide sucroferric, although with encouraging results with the latter due to the low number of tablets needed to control serum phosphorus. A new recent clinical trial shows how strict control (versus 5.0–6.0 mg/dL) of plasma phosphorus with lanthanum carbonate or oxyhydroxide Sucroferric could delay the progression of coronary calcification in these patients,206 while in another trial whose objective was to maintain plasma phosphorus between 3.5–6.0 mg/dL, no differences were observed in cardiovascular events between lanthanum carbonate and calcium.207

Currently, as a general recommendation on calcium levels, it is considered that the objective is to avoid hypercalcaemia (usually >9.5 mg/dL). A European study in dialysis patients52 showed that the lowest mortality was observed in patients with calcium levels between 7.9–9.5 mg/dL.

It is important to avoid the association of high calcium with low PTH levels, as well as the association of high calcium and phosphorus levels, combinations that have been related to increased mortality or the presence of vascular calcifications. A certain degree of asymptomatic hypocalcemia induced by calcimimetics is considered tolerable and could even be beneficial. In addition, with a relatively low calcium, FGF23 decreases, as long as P is controlled.208

The proportional increase in calcium with the increase in protein recommendations varies depending on the amount of dairy products. As a guideline, a diet of 1–1.2 gr/kg/day of protein already contains between 550 and 950 mg of calcium.

The total intake of elemental calcium per day should not exceed 1000 milligrams, including both dietary calcium and that included in phosphorus binders or ion exchange resins.

Adjustments in the calcium concentration in the dialysis fluid can contribute to optimizing the calcium balance in these patients. There is no consensus on what should be the calcium content in the dialysis fluid. Values of 1.25 mM (2.5 mEq/L; 5 mg/dL) have been associated with a negative calcium balance and a tendency to increase the PTH. In addition, with 1.25 mM there could be a worse hemodynamic tolerance to ultrafiltration, which is enhanced if the magnesium content is not adequate. Higher levels of calcium such as 1.75 mM (3.5 mEq/L; 7 mg/dL), reduce the secretion of PTH but produce a positive calcium balance and should be reserved only for severe symptomatic hypocalcemia or cases of hungry bone syndrome post-parathyroidectomy.

Following the 2017 KDIGO,4 we insist that hypercalcemia must be avoided and a persistent increase in calcium in the dialysis fluid does not seem advisable patients with to calcimetic-induced hypocalcemia. Furthermore, it is important the control of P in the presence of hypocalcemia. In addition, in patients with low PTH, a Ca 1.25 mmol/L (even 1 mmol/L) in the dialysis fluid with may be indicated to stimulate PTH secretion and prevent adynamic bone disease (ABD). But, it should be taken into consideration that low concentrations of Ca Calcium in the bath may predispose to arrhythmias and hemodynamic instability.

If possible, the calcium content in the dialysis fluid should be individualized according to the characteristics of each patient and the evolution of PTH.209

Taking into account all the factors mentioned, the recommended concentration that is generally best suited to the needs in situations of normocalcaemia and controlled PTH is 1.5 mmol/L (3 mEq/L; 6 mg/dL). One proof of the lack of consensus is that the KDIGO guidelines4 have not reached the same conclusion and suggest the use of fluid in the bath between 1.25 and 1.50 mmol/L (2.5−3 mEq/L). The calcium balance according to the dialysis fluid in patients with hypocalcaemia secondary to the use of calcimimetics is still unknown. All these considerations are applicable to peritoneal dialysis, where the use of fluids with a high calcium content is very common and frequently erroneous in patients who already have a greater probability of suffering from ABD and a longer exposure time to ABD.210,211

It is suggested that initial goal is to maintain the serum PTH values in the range of 150−300 pg/mL (approximately 2–5 times the upper limits of normality) corrected for the kit used as the initial target for iPTH. Concentrations of PTH outside this range have been associated with increased morbidity and mortality in hemodialysis patients.212–214 It is especially advised to avoid values below 100−120 and above 500–600 pg/mL as It was already mentioned in the previous guides. These latter values approximately coincide with the values considered as “extreme risk” expressed in the KDIGO guidelines (avoid values <2X and >9X in relation to the upper limits of normality of the kit used for measuring PTHi) (3.4). The recent COSMOS study establishes a PTH of 398 pg/mL as the point of greatest survival of the population.52 For this reason, we mention an initial therapeutic objective of PTH between 2X–5X–7X the upper limit of normality for the kit used.

The working group considers that establishing values <2X and >9X of the upper limits of normal for the kit used as the only adequate quality control margin as suggested by the KDIGO is possibly inappropriate, since it would inevitably result in that a significant number of patients would fall outside these ranges due to the Gaussian distribution of the populations. Establishing a narrower therapeutic goal as suggested (“aim” initially at 2X–5X), would ensure that a greater number of patients would be in the safety margin away from the extremes of risk. Accepting such wide margins208 can also have not only negative impacts on bone quality, but also favor the progression of parathyroid hyperplasia, decrease the efficacy of therapeutic strategies209 and also make it difficult to control calcemia and phosphatemia.215 Something similar occurs with the increase in PTH before the start of dialysis, since this value predicts uncontrolled SHPT at 12 months of dialysis despite the use of more drugs to reduce PTH secretion 160. The margin suggested by the KDIGO is based on epidemiological studies that associate these extreme values of iPTH with greater specificity for the diagnosis of high or low bone turnover disease, or others that associate these values with higher mortality.214

To maintain patients in this range of PTH, it is important to have an appropriate control of the serum calcium, phosphorus, and probably calcidiol levels, since the pre-dialysis period208; if having achieved this objective, the PTH is significantly elevated or it is increasing progressively (assess increasing trends even within the range between 2X–9X), the use of active metabolites of vitamin D, calcimimetics or a combination of both is suggested to reduce PTH. It should be kept in mind that relatively low PTH levels are associated with increased mortality regardless of the values of calcium and phosphorus (low, normal, or high).201 However, it is possible that this association is not be due to the decrease in PTH, but to the underlying disease or other associated factors such as age, diabetes, malnutrition, inflammatory state, etc.63,216

Although the EVOLVE study was not significant in its primary endpoint (cardiovascular outcome),38 most members of KDIGO 2017 and SEN were reluctant to exclude potential benefits of cinacalcet in patients with CKD 5D based on a series of nominally significant results in pre-specified secondary analyses and post-hoc studies.166,170,171,217,218 However, it is not considered that there is yet enough evidence to prioritize any anti-parathyroid agent219 and that all are acceptable as first-line treatment in dialysis patients.4

Also, it is considered reasonable to base initial therapy on calcium and phosphorus levels,216 as well as other aspects of CKD–MBD (e.g., vascular calcification), and that the dose of phosphate binders be adjusted so that treatments to control PTH do not compromise calcium and phosphorus levels.

There are suggestions that indicate that at this stage it is also necessary to maintain adequate levels of calcidiol.221,222 This could be useful for the control of SHPT, but especially for other pleiotropic, auto- or paracrine effects of vitamin D.

Treatment with active metabolites (calcitriol or α-calcidiol, paricalcitol) may reduced PTH levels, but can often increase the serum phosphorus, calcium, and calcium × phosphorus product and require careful monitoring. In retrospective studies the administration of active metabolites have been associated with increased survival in dialysis patients despite the increase in FGF-23 levels. One possible explanation is the experimental demonstration that treatment with calcitriol, for example, attenuates the FGF-23/FGFR-4/calcineurin/NFAT signaling pathway responsible for the induction of left ventricular hypertrophy by FGF-23,26,223 or that the VDR activators, particularly paricalcitol, attenuate fibrosis heart disease, at least partially, by regulating microRNAs.224

Treatment with active metabolites of vitamin D should be minimized or discontinued if there is an elevation in serum calcium and/or phosphorus (see next paragraph) or if the PTH is less than 100–150 pg/mL (or approximately <2X the upper limit of normal for the kit used). It has been mentioned already that paricalcitol has less effect on the elevation of Ca, P and CaxP and, although it lowers PTH rapidly, this effect has a relative value since the decrease in PTH levels does not constitute a medical emergency. Some authors propose the possibility of activating VDRs with low doses of paricalcitol (i.e. 1 µg /week), even with low PTH levels,225,226 if native vitamin D is not used in these circumstances. All active metabolites of vitamin D can be administered orally or intravenously at doses that will depend on serum PTH levels, and as long as serum calcium and phosphorus levels are controlled (e.g. <9.5 mg/dL and <5 mg/dL, respectively). Occasionally, in some cases of severe SHPT, vitamin D derivatives can lower plasma phosphorus (reducing PTH may decrease bone release of “endogenous phosphorus” from bone), but in cases of manifest hyperphosphataemia, it would be preferable to start treatment with calcimimetics and associate vitamin D analogues if neccesary.

Calcimimetics should not be started in dialysis patients with a serum calcium concentration (corrected for albumin) below the lower limit of the normal range (<8.4 mg/dL). If the patient is already being treated with calcimimetics, the treatment can be continued if the clinical situation and patient’s safety allows it.

In these patients, the use of cinacalcet could be considered if there in PTH trend towards an increase, even if it has not reached 300 pg/mL, as long as calcaemia and/or phosphatemia are elevated.

The starting dose r starting dose recommended for adults is 30 mg once daily, which should be adjusted every 2–4 weeks but not to exceed the maximum dose of 180 mg once daily. In case of need to reduce the dose, the drug can be given every 48 h. Other intermediate doses are achieved with the administration of different schedules (e.g. 60 mg–30 mg every other day would correspond to a dosage of 45 mg/day).

A therapeutic alternative to cinacalcet for the control of hyperparathyroidism is treatment with intravenous etelcalcetide, which also ensures therapeutic compliance in non-adherent patients.175 The recommended starting dose of etelcalcetide is 5 mg, administered by bolus injection 3 times a week (coinciding with hemodialysis sessions, at the end of the session). Corrected serum calcium should be at or above the lower limit of the normal range prior to administration of the first dose, dose increase, or restart after dose interruption. It should not be administered more frequently than 3 times per week. The dose of etelcalcetide should be adjusted individually between 2.5 mg and 15 mg, according to PTH and calcium levels, and with increments of 2.5 mg or 5 mg not more frequently than every 4 weeks until a dose maximum of 15 mg 3 times per week to reach the target value of PTH.

Blood samples to assess PTH levels should be obtained at least 12 h after the last dose.

In the event of significant hypocalcaemia (i.e. <7.5 mg/dL), it is recommended to reduce the dose of calcimimetic and/or increase the dose of vitamin D derivatives if PTH levels are still elevated.

The calcium concentration in the dialysis bath should not be increased to correct hypocalcemia unless it is symptomatic.

It is possible that the association of vitamin D metabolites and calcimimetics could have additive and/or synergistic effect on the control of secondary hyperparathyroidism, perhaps due to the upregulation of the parathyroid cell receptors,19,20,227 or to present other beneficial effects (e.g. on vascular calcification).228 It has been observed that the use of calcimimetics has been associated with a decrease in the need for derivatives of vitamin D and vice versa. The combination of treatments may help not only to reduce doses but also biochemical or clinical side effects,88,220 just as it occurs in combined treatment of arterial hypertension or immunosuppression in kidney transplants.

The following graphs (Figs. 7–12) show an indicative algorithm for the management of biochemical alterations of bone-mineral metabolism in patients in stage 5D, based on serum levels of iPTH and phosphorus.

Fig. 7.

Algorithm for treatment in dialysis I.

(0.22MB).

Fig. 8.

Algorithm for treatment in dialysis II.

(0.23MB).

Fig. 9.

Algorithm for treatment in dialysis III.

(0.24MB).

Fig. 10.

Algorithm for treatment in dialysis IV.

(0.22MB).

Fig. 11.

Algorithm for treatment in dialysis V.

(0.22MB).

Fig. 12.

Algorithm for treatment in dialysis VI.

(0.18MB).

Persistent tertiary or SHPT is found in 15%–50% of patients after the first year after transplantation, and those with higher serum PTH and calcium values at the time of transplantation will show persistence of SHPT for a longer period of time.230,231

Presently, since the introduction of cinacalcet, the percentage of dialysis patients who access transplantation with controlled PTH has increased notably. Now the problem is to decide whether cinacalcet should be suspended in a specific patient at the time of transplantation.

The persistence of SHPT is a risk factor for:

• -

  Loss of bone mass and increased risk of fracture.231

• -

  Hypercalcemia. Its incidence varies greatly depending on the time elapsed since the transplantation. It has negative cardiovascular effects, and it has also been identified as one of the many factors responsible for renal graft failure in the medium term.232

• -

  Hypophosphatemia, probably also secondary to persistently elevated FGF-23 values.231,233

• -

  Impaired kidney function and the incidence of tubulo-interstitial calcifications.234

For the management of these abnormalities, it is advisable to wait and observe the evolution, maintaining a close control of the serum levels of calcium, phosphorus and PTH.

Regarding the treatment there are two alternatives:

• -

  Parathyroidectomy. It has been shown to be effective in controlling calcemia and improving BMD, although has been described a short-term deterioration in kidney function after parathyroidectomy.235 Considering the wide use of cinacalcet, we believe that parathyroidectomy could be reserved for patients who do not respond to calcimimetics, although in a recent randomized study subtotal parathyroidectomy was superior and more cost-effective than cinacalcet for calcium control if the duration of treatment with cinacalcet had to be prolonged for more than 14 months.236

• -

  Calcimimetics (cinacalcet). It has been shown to be effective in correcting hypercalcemia and hypophosphatemia secondary to persistent hyperparathyroidism. No negative effect on renal function or interaction with immunosuppressants (calcineurin inhibitors or m-TOR inhibitors) has been described.237–240 In addition, calcimimetics could have a beneficial effect on BMD,240 although further studies must be performed to confirm this beneficial effect.

In patients with calcemia >10.5 mg/dL and iPTH >100 pg/mL, the most advisable strategy would be to start treatment with cinacalcet 30 mg/day and modify the dose depending on the response.