Cardiovascular complications in secondary hyperparathyroidism – specific changes, prevention and treatment

Introduction

Secondary hyperparathyroidism (SHPT) is one of the most frequent complications in chronic kidney disease (CKD).

Numerous publications in the field of nephrology from recent years indicate that the frequency of incidence of chronic kidney disease (CKD) is high and growing sharply. An ’epidemic’ of chronic kidney disease (CKD) is even mentioned. On the basis of the research done by PolNef it has been found that albuminuria, being a sensitive indicator of renal insufficiency, occurs in as much as 15% of the Polish population (in the USA – 11%) [1]. Some experts in the topic do not agree with the point concerning ’chronic kidney disease (CKD) pestilience’ in reference to stages 1-4 of CKD, seeing the reasons of ’epidemic’ increase in morbidity rate in the improper system used for defining CKD [2]. That entails the necessity of searching for new parameters, for example assessment of serum creatinine concentration (Scr/Q), which would allow the development of a new definition, making the classification independent of such elements as age, sex, or race [3]. On the other hand, it is unanimously agreed, that incidence and morbidity increases, worldwide, of stage 5 of CKD (the so-called pestilience of the final phase of chronic kidney disease) [2]. At the end of 2008, in Poland there were 12,783 patients undergoing haemodialysis, and 997 undergoing peritoneal dialysis. At the end of 2009 the number of patients undergoing dialyses was 16,520. The number of patients on renal replacement therapy is ever on the increase. Also, the age structure of dialyzed patients change, with elderly people dominating. The leading group of patients are those for whom diabetes is the undergoing cause for terminal renal insufficiency. The above reflects the contemporary social structure, particularly in highly developed societies. It also marks the pestilience of civilization-related diseases, including diabetes, arterial hypertension, or obesity. Due to substantial improvement of nephrologic care, and development of dialysis techniques, our patients not only live longer, but also survive to the time when complications of CKD occur, including also the development of secondary hyperparathyroidism (SHPT). This short paper aims at recalling the rudiments of vascular pathology in SHPT, as well as prevention and conservative therapy.

Secondary hyperparathyroidism – mechanisms of pathology development

The assessment of CKD progression, which means allowing to select the group of patients who are at risk to suffer complications in the course of the disease, threatened with complications in its course, appears to be an extremely significant element of prevention and treatment. It allows, at an early stage, to recognize pathologies in the course of CKD, to slow down their development, and to prevent the development of complications. The binding definition distinguishes 5 stages of CKD (tab. 1). It is based upon the presence of ‘kidney injury’ and/or decreased value of the estimated glomerular filtration rate (eGFR) for at least 3 months [2].

Following the development of sodium-phosphate metabolism disturbances, it becomes obvious that qualification of the patient to adequate stage of CKD is important, as it compels undertake specific pro­phylaxis and treatment. It has been demonstrated that sodium-phosphate metabolism disturbances manifest as early as in stage 3 of CKD, while some latent deviations are noticeable even in stage 2 of CKD, that is when the patient, usually symptom-free, is not aware of having the disease or of developing any disturbances. The following appear, in that order: decreased concentration of vitamin D3, increased concentration of PTH, increased concentration of phosphates, as well as decrease calcium concentration in blood serum [5, 6].

Decrease of calcitriol (1,25-dihydroxycholecalciferol) concentration in kidneys, hyperphosphataemia, hypocalcaemia, as well as increased secretion of fibroblast growth factor 23 (FGF-23) are the main reasons leading – in case of patients with chronic renal insufficiency – to hyperparathyroidism and increased secretion of PTH [5, 7]. The role of those elements in the development of sodium-phosphate metabolism disturbances is worth noting here.

Calcium acts via calcium receptors (CaR) located on the surface of parathyroid glands, renal tubules, the alimentary tract, and bones. CaRs are most densely packed upon the surface of chief cells of parathyroid glands, which is the reason why parathyroid glands respond in a very short time to even very minute changes in calcaemia [8]. A reduction in calcium level is the strongest physiological stimulator for increase of PTH secretion. When the active renal parenchyma is lost, hypocalcaemia increases. It increases significantly when GFR drops below 40 ml/min. A reason behind hypocalcaemia is also the impairment of calcium absorption from the alimentary tract, low calcium content in diet, and excessive phosphate supplementation in diet, accompanying such deficiencies. Of importance is also the increasing bone resistance to PTH action, which limits the availability of calcium from bone reservoirs. In uraemia, in coexisting hyperparathyroidism, also a shift takes place of the so-called ‘set point’ for calcium. Thus, for the inhibition of PTH production higher concentrations of calcium ionized in extracellular space is required. The above changes result in constant disinhibition of parathyroid glands activity, with overproduction of PTH [7].

Hyperphosphataemia occurs when GFR drops below 50 ml/min. In the phase of extreme renal insufficiency (renal failure), it is diagnosed in 60-70% of patients. It is believed that this pathology is the primum movens of sodium-phosphate metabolism disturbances [7]. Phosphates, regardless the concentration of calcium and vitamin D, increase PTH secretion. They are both a substrate and a factor inducing calcification [9, 10]. No wonder, then, that hyperphosphataemia is referred to as the ‘silent killer’ of patients with CKD. Phosphates constitute a key factor responsible for the formation of metastatic calcifications, that is for deposition of minerals in soft tissues, with the, clinically, most serious calcifications within the cardiovascular system. The pathology affects vascular walls, the myocardium, as well as the heart valves [6, 7]. The risk of cardiovascular death in that population is 20-30 higher than in general population. It is assumed that cardiovascular pathologies are responsible for the death of half the patients undergoing dialyses. Coronary problems are mainly held responsible for that. The increase of phosphate concentration by every 1 mg/dl above the value of 6.5 mg/dl (2.1 mmol/l) results in enhancing the risk of cardiovascular death by 6% [7, 11].

As early as in stage II of CKD, gradual reduction of the concentration of D3 vitamin in active form takes place. That is preceded by the reduction of 25(OH)D3 concentration, which is a substrate for kidneys. A substantial reduction of 25(OH)D3 occurs only after the GFR drops below 29 ml/min/1.73 m2 [12]. In patients with severe renal insufficiency, the deficiency of 25(OH)D3 does not depend upon the age, sex, ethnic origin, body mass index (BMI), physical activity, supply of milk and vitamin D supplements [13]. The active form of vitamin D regulates the growth rate of parathyroid glands, it inhibits the synthesis and secretion of PTH [9]. As we know, the main sites for its synthesis are cells of renal tubules, provided with 1-α-hydroxylase. That enzyme is located in the mitochondrial membrane of cells of proximal renal tubules. Hydroxylation of carbon 25(OH)D3 in the 1-α position ensure full biological activity for the particle. The drop to the level of 1.25-dihydroxy vitamin D3 occurs, however, not only due to the reduction in the amount of active renal parenchyma, equipped with 1-α-hydroxylase, but also as a result of hypercalcaemia, hyper-phosphatemia, metabolic acidosis, the activity of uraemic toxins, or increase of concentration of the FGF-23 protein, from the phosphatonin group [7].

Secondary hyperparathyroidism belonging to the picture of chronic kidney diseases is one of its most frequent consequences. This basic endocrine pathology accompanies CKD from its early stages to the time of therapy by dialyses, and lasts even after kidney transplantation. In the latter case, one encounters the case of autonomy in the activity of parathyroids. Secondary hyperparathyroidism is a compensation mechanism, allowing to equipoise the phosphate balance, by reducing the phosphate reabsorption in the proximal tubule, from 80-95% to some 15% in advanced renal insufficiency [5, 7]. In the course of CKD, continuous hyperparathyroidism is connected with progressive proliferation of their cells, and contributes to their diffuse hyperplasia. A part of the cells is more spontaneous in proliferation, forming small noduli, which undergo encapsulation when growing. We then refer to nodular proliferation. In extreme forms, a single nodule may even occupy the entire gland. At the same time, in the tissue of the affected parathyroid glands, the density of receptors VDR and CaR is reduced. Too small number of receptors precludes stimulation of intracellular degradation of PTH, or reduced gene transcription for PTH by the, already reduced, concentration of calcium and vitamin D [7, 14-17].

Secondary hyperparathyroidism – risk factors for the progression of vascular complications

Secondary hyperparathyroidism is the cause of numerous complications. Pathologies of bones come to the foreground. They are followed, in terms of frequency, by vascular calcifications, as well as calcification of heart structures: the myocardium as well as native valves and biological prostheses of valves. They are currently present in 63–69% of patients who begin dialyses. In the dialyzed patients they are encountered in adult population and in children, although they are less frequent in the pediatric group [15].

It is suggested that the tempo of increase of vascular calcifications is higher in patients undergoing haemodialyses, in comparison with patients undergoing peritoneal dialyses. In patients undergoing extracorporeal dialyses, lower concentrations of fetuin A have been found, which substance is responsible for the inhibition of calcium phosphate precipitation [5, 11, 14]. Also the progression of vascular changes is faster in diabetic patients who begin haemodialyses. Not only SHPT contributes to the development of vascular complications, but also the direct influence of glucose upon the expression of such key mediators of calcification formation as: transcriptive factor Cbf-α-1 (core binding factor α-1), osteocalcin, osteopontin (OPN), bone morphogenetic protein 2 (BMP-2) or alkaline phosphatase, interleukin 1β (IL-1β), interleukin 6 (IL-6), collagen type I, or tumour necrosis factor α (TNF-α) [10, 19]. It is particularly important, as patients with diabetes mellitus comprise the most numerous group among the dialyzed patients, and that percentage is constantly on the increase. In accordance with the data from 2008, patients with diabetic nephropathy, in the renal insufficiency phase, account for 22.2% of all patients dialyzed in Poland. In the following year, 2009, the percentage amounted to 24.8%. Tables 2-4 comprise the collected risk factors, responsible for promoting vascular calcifications in patients with complete renal failure, who developed SHPT.

The function of most crucial protein substances, which take part in the maintenance of calcium-phosphate homeostasis has been presented above:

  1. High PTH or profound decline of PTH (< 150 ng/ml) – with the absence of PTH or too low concentration of PTH, adynamic bone disease (ABD) may occur. Low bone turnover intensifies calcium binding in extraosseous structures, thus calcium ions become a substrate of metastatic calcifications. It should be pointed out that this kind of osteodystrophy is most conducive to metastatic calcifications, and is most resistant to treatment. High values of PTH, in turn, are connected with development of SHPT and all the complications listed in table 3 [6, 20].

  2. Fetuin A – the strongest inhibitor of crystallization of calcium phosphate deposits. It is to be a substance with multidirectional activity: anti-inflammatory, anti-sclerotic, inhibiting pathological calcification. It is an inhibitor of smooth muscle cell (SMC) apoptosis. It intensifies the phagocytosis of apoptotic corpuscles by SMC, which allows to remove the potential nuclei of calcification from vessel walls. In in vitro studies, the addition of fetuin A to the environment, in which matrix vesicles are present, causing significant reduction of their calcification. Low concentrations of fetuin A are observed in patients undergoing dialyses, in particular haemo-dialyses [6, 10, 11].

  3. Matrix Gla protein (MGP) binds large quantities of calcium ions. Its activation depends upon vitamin K. In case of administering warfarin or acenocoumarol its function can be eliminated, which promotes the process of vascular calcification [6].

  4. Bone morphogenic protein (BMP-7) inhibits osseous transformation of SMC. Through the activation of metabolism and mineralization of skeleton it stimulates bones for increased uptake of Ca and P, thus for removal of calcification substrate from the circulatory system [6].

  5. Osteopontin (OPN) – acid phosphoprotein, being an inhibitor of bio-apatite crystal growth – the basic and most crucial phase for phosphates. It is also an activator of osteoclast function [11].

  6. Osteoprotegerin (OPG) is a protein substances influencing the differentiation and maturing of osteoclasts. It inhibits be binding with RANKL (receptor activator of Nf-kB ligand), before it is joined with the receptor proper for it. Its effect is reduced bone resorption [6, 11].

  7. Bone morphogenic protein 2a (BMP-2a) its expression intensifies under the influence of increased phosphataemia. It is antagonistic for BMP7 [6].

  8. Fibroblast growth factor 23 (FGF-23) is a polipeptide hormone playing an important role in inducing and maintaining of SHPT in patients with renal insufficiency. Physiologically, it occurs in low concentrations (about 50 pg/ml). A positive correlation has been found between the concentrations of that phosphatonine, and the concentration of phosphorus, calcium, and SHPT in the serum of patients undergoing dialyses. The concentration of FGF-23 in the serum increases in the serum with the loss of kidney filtration function, to counteract phosphate retention [21]. It has phosphaturic activity, in connection with its co-factor, Klotho protein. The connection with Klotho protein allows for phosphorylation of FGF-23, which provides the ability to block the Na-Pi co-transporters of proximal tubule epithelium with microvilli. Chronic excessive expression of FGF-23 results also in suppression of 1.25-dihydroxyvitamin D synthesis, via reduced activity of 1-α hydroxylase, as well as increases the PTH concentration in blood. It may also act in a mechanism, which is independent from Klotho protein, inducing cardiomyocyte hypertrophia. Increased FGF-23 is a predictor of cardiovascular incidents [22, 23].

  9. Klotho protein is a co-factor of interactions between FGF-23 and its receptor. They can be found mainly in the distal tubule and parathyroid glands. Animals deprived of Klotho protein suffer from severe hypercalcaemia and/or hyperphosphatemia. They are also characterized by increased concentration of 1.25-dihydroxyvitamin D, as Klotho protein causes dis-inhibition of the activity renal 1-α hydroxylase. Its result is a severe calcification of vessels, soft tissues, osteoporosis, and premature ageing [10, 22].

Vascular complications of secondary hyperparathyroidism – histology

It is believed that vessels suffer most from phosphate-calcium disturbances. Vascular calcinations are present in 63-69% of patients who start dialyses [11]. Vascular pathologies in the course of SHPT involving chronic kidney disease may, practically, apply to any vascular bed. Lesions are usually dispersed and occur on many levels. Clinical consequences of vessel calcification depend upon their extent and severity, as well as on which organs have been affected by the pathology. For example, coronary vessels calcification correlated positively with the number of atherosclerotic plaques, increasing the risk of myocardial infarction, as is co­n­nected with greater risk of vascular wall de-lamination after angioplasty [11]. High concentrations of PTH per se impair the activity and damage the structure of the cardiac muscle, by intensification of intra-parenchymal fibrosis in the cardiac muscle, as well as destruction of fine coronary vessels of the myocardium [24]. The consequence of that is the enhanced cardiovascular risk, as well as increased mortality among patients.

Development of metastatic calcifications in vessels is connected with changes in smooth muscle cells (SMC) which, influenced by many stimuli, may undergo reverse differentiation towards osteoblast like cells. That process is promoted not only by a high level of phosphates in the intra- and extracellular space, but also by hyperglycaemia. The effect depends upon the time of exposure and glucose concentration. Smooth muscle cells thus changed deposit the mineral material identical with what is found in the osseous tissue. They synthesize extracellular matrix, rich in collagen, which undergoes secondary mineralization. Calcification contain: amorphous calcium phosphate, phosphate in the form of hydroxyapatite, as well as calcium-magnesium phosphate [6, 11]. It has been demonstrated that before nodullar calcification of vascular smooth muscles occurs, their apoptosis takes place, which intensifies the calcification. The apoptotic corpuscles, products of in vitro culture, isolated from the culture of vascular smooth muscles, have the abi­lity to accumulate calcium in crystalline form, and to initiate the calcification process, constituting sites for e-nucleation for calcium phosphate deposits [11]. Not only SMC may be subject of de-differentiation towards osteoblasts. This applies also to macrophages, activated in inflammatory processes, in the area of atherosclerotic plaque or pericytes [6]. The assessment of the degree of vessel calcification is possible thanks to the calcification score or calcium scoring (CaSc). The classification of risk groups, depending upon the CaSc values, proposed by Rumberger et al. from Mayo Clinic (Rochester, MN, USA) has been presented in table 5 [6]. This applies to the assessment of coronary risk, depending on the value of CaSc.

In patients with extreme renal insufficiency the distribution of calcifications is different, in comparison with the population without CKD. Ectopic mineralization affects the tunica intima and tunica media in patients with CKD. One can encounter there the, frequent in general population atherosclerotic process, usually affecting the tunica intima of the vessel, first of all the atherosclerotic plaque (intimal calcification), as well as medial calcification (mediasclerosis), also referred to as tunica media sclerosis of the Möckenberg type or calciphylaxis. In uraemia both types of lesions coexist, however, the se­cond type of vascular pathology is characteristic for CKD, in particular for diabetes-related kidney diseases. The consequence of the coexistence of both types of calcifications in patients with CKD is the, unheard-of in other populations, stiffness of arteries, increased pressure and pulse rate, decreased flow through vessels in the diastolic phase, reduced coronary reserve, and hypertrophy of the left ventricle [6, 11, 25].

Lesions of atherosclerotic type are encountered first of all within the tunica intima of the vessel. They are accompanied by areas of necrosis. The dying cells are highly permeable for calcium and phosphorus ions. When the intracellular concentrations of those ions are higher than their solubility product, crystallization occurs. Initially dispersed points of deposition of calcium-phosphate compounds join, developing huge, non-uniform crystals, distribute in various points, which accompany the necrotic parts of atherosclerotic lesion. Then, gradually, in a significant part of calcified blood vessels or heart valves, the bone transformation starts, including formation of bone marrow, cartilage, as well as mature trabecular structures bones. It is a well-ordered process, with the participation mechanisms similar to those playing their role in bone formation [11].

The other type of vascular calcification is the calcification of the tunica media of blood vessels, also known as tunica media sclerosis of the Möckenberg type. Such type of pathologies are found independent of calcification of the tunica intima. Linear calcifications occur along the elastic membrane, where the extracellular substance rich in elastin and collagen, accumulates in excess. The more advanced the lesion, the more vessels of the tunica media are affected. In final stages, the tunica media of vessels is filled, with peripherally located rings, made of mineral substances. In that location, total ossification of the sites affected with lesion may also occur [10, 11].

A specific form of pathology calcification of tunica media in arteries with small diameter. Its occurrence is connected with the process called calcific uremic arteriolopathy (CUA). This rare pathology occurs in a modest percentage (4%) of patients undergoing haemodialyses, in particular when they are additionally administered courarin derlivatives. Those lesions may be vast indeed. In 87% they are located on the skin of legs and buttocks [11, 20, 26]. They are characterized by calcification of tunica media in small arteries, with or without endovascular fibrosis and extracellular calcification. This is accompanied by intravascular clots. All that leads to painful ischaemia and necrosis of peripheral tissues supplied by those vessels [11, 27]. Unfortunately, the course has very poor prognosis, particularly when septic complications. It is reported that in case of CUA the mortality rate reaches 60-80% [26]. Treatment of calcific uremic arteriolopathy is long-term (3-18 weeks). Its failure rate is really substantial. Surgical treatment is the basis for therapy. It is complemented with intensification of dialyses (7 days a week, 4 hours each day), with reduced calcium concentration in the dialysing fluid. It is recommended to use treatment with hyperbaric oxygen (2.5 ATM, 90 min a day) or oxygen therapy, through oxygen mask (10-15 l/min). It is recommended to leave off calcium preparations, which bind phosphates and vitamin D. They are replaced by Cinacalcet (Mimpara) (30-60 mg/24 h), with mainteinance of iPTH > 40 pg/ml and Sewelamer (dose 800-1600 mg/24 h). It is recommended to leave off preparations of warfarin and iron. To remove the iron accumulated in lesions, sodium thiosulphate is administered (12.5-25 g three times a day, intravenously). Prophylaxis and antibiotic treatment complete the therapy [20].

Secondary hyperparathyroidism – prevention and treatment

The most important element in the management of patients with SHPT, and thus exposed to the above mentioned pathologies is early prevention, to be followed only later by treatment of the lesions that formed. The more so that the treatment is long term, as a rule, and the failure rate may be high. That is why so much stress is put on screening diagnostic examinations and preventive actions. As regards prevention, the safest and most effective management is early correction of calcium-phosphate metabolism in chronic kidney disease. It is connected with early referral to a nephrologist. In case of diabetic nephropathy, patients are referred when eGFR < 60 ml/min/1.73 m2, whereas in case of other non-diabetic nephropathies, when eGFR < 30 ml/min/1.73 m2.

Diagnostic in the course of CKD and SHPT is to be based upon controlling the parameters of calcium-phosphate metabolism. Biochemical examinations comprise the assessment of: calcium, phosphates, alkaline phosphatase, PTH (assessment of 1-84 PTH molecule using third generation tests), vitamin D (25-hydroxyvitamin D or possibly 1.25-dihydroxyvitamin D). In stages I and II of CKD calcium and phosphates are assessed once a year. In stage III, as above, with additional assessment of PTH concentration once a year. Stage IV requires assessment of the above parameters once every quarter of a year. In renal insufficiency calcium and phosphates are assessed every month, PTH every 3 months. Also the assessment of vitamin D and alkaline phosphatase is considered. In prevention, strict control of phosphatemia and avoidance of hypercalcaemia is possible, by cutting down the presence of phosphates in diet to 800-1000 mg/d, which may be achieved by restricting proteins (1 g of protein is responsible for supplying 12-16 mg of phosphorus). It should be remembered that total dose of calcium per 24 hours is 2 g, when converted into elementary calcium (including calcium preparations which bind phosphates) [5, 6, 17]. The aims of preventive and treatment measures in stage V of chronic kidney disease (CKD) are presented in table 6.

According to de Francisco [29] the treatment aims in SHPT are: maintenance of proper levels of calcium and phosphorus concentration in blood serum, inhibition of PTH secretion and maintenance of correct metabolism of bones, inhibition of parathyroid gland hypertrophy, inhibition of the development and progress of calcification of vessels and soft tissues. Those aims are achieved via offsetting the imbalance in calcium-phosphate metabolism, correcting the active vitamin D deficiency, direct action on those cells of parathyroid gland, which secrete PTH, by means of conservative treatment and procedures [5].

Vitamin D deficiency is referred to when the concentration of 25-hydroxycholecalcipherol drops below 30 mg/ml [5]. Most often, it is stage III of CKD [4, 9]. One should, then, begin the administration of exogenous preparations of vitamin D. Treatment with preparations of vitamin D requires special supervision, regarding especially the control of calcium and phosphate level, as well as assessment of PTH and the level of vitamin D. That should be arranged on individual basis. The patients who do not undergo dialyses may be administered cholecalcipherol in the dose of 600-800 IU/day. Dialyzed patients, on the other hand, should receive active preparations of vitamin D, in the form of calcitriol, alphacalcidol (1-α derivative) or, better still, analogues of vitamin D, such as doxercalcipherol and paricalcitol. The administration of those medicines, in particular of analogs of vitamin D, may have a beneficial influence – probably in a mechanism which is independent of direct influences upon the regulation of calcium-phosphate metabolism [5]. Those other effects are the so-called pleiotropic action of vitamin D, manifested during the activation of its receptors (VDR). The effects also include reduction of cell proliferation, regulation of inflammatory processes as well as immune response, influence upon the metabolism of lipids, protection of kardiomyocytes, cells of smooth muscular coat, and vascular endothelium. The consequence of that should be reduced incidence of cardio-vascular complications and improved survival of the dialyzed patients [16]. In experimental conditions, a significantly lower calcium content in vascular walls in patients treated with paricalcitol, an analog of vitamin D [10]. One should keep in mind the possible induction of hypercalcaemia, in the course w treatment with vitamin D preparations. That threat is less acute when analogs of vitamin D are used. An absolute contraindication for the application of preparations of vitamin D is hypercalcaemia (Ca > 10.2 mg/dl; 2.55 mmol/l), particularly when it co-exists with hyperphosphatemia [17].

In the prevention and treatment of hyperphosphatemia, phosphate-binding preparations are used. They are divided into preparations containing calcium and non-calcic ones (tab. 7). Applying calcium preparations, attention should be paid to the possibility of developing hyperckalcaemia (particularly when the dose of elementary calcium exceeds 6 g/d). An alternative for calcium preparations and the non-calcic compounds, which bind phosphates. The preferred medicine, in particular in the case of concurring hyperphosphataemia and hypercalcemia, as well as the phosphate-calcium product exceeding 55 mg2/dl2, is sevelamer. Its daily dose is between 800 and 1600 mg/d. Sevelamer, by binding phosphates, reduces the frequency of calcifications in coronary vessels and aorta [17]. The drug also has hypolipemic activity (it reduces the level of total cholesterol, LDL cholesterol, apolipoprotein B, it increases the level of HDL cholesterol fraction), it has influence upon the level of CRP and B2-microglobulin [6]. It appears in two forms: hydrochloride and sevelamer carbonate. It is believed that the carbonate offers a better therapeutic option, as ¾ unlike the hydrochloride, it does nor aggravate the existing acidosis, it does not simulate catabolism, nor does it enhance the bone turnover [10]. Unfortunately, the use of sevelamer in everyday practice is limited due to its steep price.

Another group of drugs, the so-called calcimimetic drugs directly affects cells of parathyroids. They are allosteric activators of calcium receptor in parathyroid glands. Those drugs block the secretion of PTH through antagonistic influence upon calcium receptor (CaR) at the surface of parathyroid glands. Calcimimetic drugs sensitize CaR to calcium. The indication for their use is SHPT in dialyzed patients with PTH concentration exceeding 300 pg/ml and total calcium concentration above 8.4 mg/dl. In earlier stages of CKD that drugs are not recommended, due to increased risk of hypocalcaemia, accompanying its use [5]. Calcimimetic drugs are also recommended in case of ineffective surgical treatment of SHPT, as well as in situations, where such surgical treatment cannot be applied, due to too high risk of operation, inconvenient location of the affected parathyroid glands, lack of possibility of their identification, or lack of consent of the patient for surgical treatment [30]. At present, the only available calcimimetic drug is cinacalcet (Mimpara). Dose selection is difficult and should be made for each individual separately. The initial dose is usually 30 mg/day. The dose is to be increased every 2-4 weeks, until a dose is reached which allows to achieve the desired concentration of PTH [1]. The drug is not recommended for children. The treatment with calcimimetics is referred to as temporary para­thyreoidectomy. The pathology recurs after the adminis­tration of the drug is discontinued, thus the necessity of maintaining the therapy until the end of patient’s life. Unfortunately, no explicit proofs exist as to enhanced survival or reduction of cardio-vascular complications in patients with SHPT, treated with that drug [5].

In future, one may expect introduction of new medicines in SHPT therapy and complications of that disease, such medicines as for example recombined fetuin A, BMP-7 or treatment with denosumabem – human recombined monoclonal antibody anti-RANKL [6].

In advanced SHPT, as there are no possibilities to provide effective conservative treatment, surgery is necessary. The initial stage is the localization of glandular tissue. Great difficulty in intraoperative diagnosis of those glands is connected with their varying number, size, co­lour, and location. That is why localization before surgery is needed, based upon numerous diagnostic techniques. The leading role in diagnostics is played by radioisotope examinations, computer tomography, nuclear magnetic resonance, or ultrasonographic examinations. The final and decisive way of identifying them is microscopic exa­mination [31]. Table 8 presents a review of available techniques for localization of parathyroid glands.

Surgical treatment of SHPT is applied only in severe cases of SHPT, resistant to pharmacotherapy (concentration of PTH > 800 pg/ml; 88 pmol/l ), with concurrent hypercalcaemia and/or hyperphosphatemia and/or high phosphate-calcium product, as well as incidence of extra-skeletal calcifications, pruritus, and myopathy. Parathyreoidectomy is performed in some 4% of patients dialyzed in Poland. It should be kept in mind that total parathyreoidectomy threatens with the occurrence of adynamic form of renal osteodystrophy [30].

Ultimately, kidney transplantation is the only me­thod of choice in the treatment of chronic uraemia and its complications, including SHPT. Kidney transplantation may be treated as a method which inhibits the process of soft tissue calcification [6].

It should be mentioned that in case vascular complications occur, the patients from that group may be offered a full range of endovascular diagnostics and treatment, as well as procedures in vascular surgery. Such patients gain significant advantage of such therapy. A certain inconve­nience regarding the above treatment lies in the dispersed and multi-level type of vascular lesions. It should be repeated, however, that without metabolic compensation, the effectiveness of that treatment is very limited, and is connected with high frequency of pathology recurrence. Providing an overview of the above treatment methods is beyond the framework of this short study.

In the end, it is worth mentioning again, that the spectrum of SHPT is wide indeed. The treatment efficiency may be limited significantly, that is why the main focus of our efforts should be aimed at early and effective prophylaxis, which provides chances to avoid them. Thus, it allows to enhance the quality of life of that specific group of patients with chronic kidney insufficiency, as well as to lower the costs of treatment significantly. The problem become ever more grave, as both in Poland and worldwide the number of patients on kidney replacement therapy is on the increase. Thus, ever more often in our practice as doctors we will face such challenges.

References

  1. Rutkowski P (2008) Komentarz do: An epidemic of chronic kidney disease: fact or fiction. Nefrol Nadciś Tęt; 5: 43-45.

  2. Glassoch RJ, Winearls Ch (2008) An epidemic of chronic kidney disease: fact or fiction. Nephrol Dial Transplant, 23: 1117-1121.

  3. Pottel H, Hoste L, Martens F (2010) New insight in glomerular filtration rate formulas and chronic kidney disease classification. Clin Chim Acta, 411: 1341-1347.

  4. Książek A, Rutkowski B (red) (2004) Nefrologia. Czelej Sp. z o.o., Lublin; 186-187.

  5. Nowicki M (2009) Diagnostyka i leczenie wtórnej nadczynności przytarczyc. Forum Nefrol, 2: 222-226.

  6. Stompór T (2006) Zwapnienie ściany naczyniowej u chorych na mocznicę: znaczenie czynników genetycznych i nabytych. W: Więcek A, Kokot F (red) Postępy w nefrologii i nadciśnieniu tętniczym. Medycyna Praktyczna, Kraków; t. 5: 52-68.

  7. Chudek J (2002) Patofizjologia i leczenie wtórnej nadczynności przytarczyc. W: Więcek A, Kokot F (red) Postępy w nefrologii i nadciśnieniu tętniczym. Medycyna Praktyczna, Kraków; t. III: 173-182.

  8. Nowak Z, Wańkowicz Z (2008) Rola receptora wapniowego w stanach fizjologii i patologii. W: Więcek A, Kokot F (red) Postępy w nefrologii i nadciśnieniu tętniczym. Medycyna Praktyczna, Kraków; t. 7: 23-30.

  9. Slatopolsky E, Dusso A (2002) Control of uremic bone disease: role of vitaminum D analogs. Kindey Int; 61 (supl 80): 143-148.

  10. Stompór T (2008) Zwapnienia pozakostne w mocznicy: postępy w patogenezie, rozpoznawaniu i leczeniu. W: Więcek A, Kokot F (red) Postępy w nefrologii i nadciśnieniu tętniczym. Medycyna Praktyczna, Kraków; t. 7: 113-119.

  11. Speer MY, Giachelli CM (2004) Cardiovascular pathology; regulation of cardiovascular calcyfication. Cariovasc Pathol; 13: 63-70.

  12. Remuzzi A (2007) Vitamin D, insulin resistance, and renal disease. Kidney Int; 71: 96-98.

  13. Chochol M, Scragg R (2007) 25-hydroxyvitamin D, insulin resistance, and kidney function in the third national health and nutrition examination survey. Kidney Int; 71: 134-139.

  14. Handy G , Hruska K (2006) New insight into mineral and skeletal regulation by active forms of vitamin D. Kidney Int; 69: 218-223.

  15. Fukagawa M, Nakanishi S (2006) Basic and clinical aspects of parathyroid hyperplasia in chronic kidney disease. Kidney Int; 70: 3-7.

  16. Matuszkiewicz-Rowińska J, Kulicki P (2012) Selektywni agoniści receptora dla witaminy D w leczeniu wtórnej nadczynności przytarczycy. Nefrol Dial Pol; 16: 175-177.

  17. Myśliwiec M (2008) Postępy w leczeniu wtórnej nadczynności przytarczyc (WNP) u chorych z przewlekłą niewydolnością nerek. W: Więcek A, Kokot F (red) Postępy w nefrologii i nadciśnieniu tętniczym. Medycyna Praktyczna, Kraków; t. VII: 99-101.

  18. Al-Aly Z, Qazi R (2007) Changes in serum 25-hydroxyvitamin D and plasma intact PTH levels following treatment with ergocalciferol in patients with CKD. Am J Kidney; 50: 59-68.

  19. Andress D (2006) Vitamin D in chronic kidney disease: a systemic role for selective vitamin D receptor activation. Kidney Int; 69: 33-43.

  20. Myśliwiec M (2012) Zwapnienia naczyń w CKD – co nowego w patogenezie i leczeniu. W: Więcek A, Kokot F (red) Postępy w nefrologii i nadciśnieniu tętniczym. Medycyna Praktyczna, Kraków; t. XI: 55-60

  21. Ritz E (2003) FGF-23 – nowy hormon fosfaturyczny. W: Więcek A, Kokot F (red) Postępy w nefrologii i nadciśnieniu tętniczym. Medycyna Praktyczna, Kraków; t IV: 35-40.

  22. Kokot F, Franek E (2008) Czynnik wzrostowy fibroblastów (FGF-23) i białko Klotho – ważne ogniwa regulacji osi kostno-nerkowej. W: Więcek A, Kokot F (red) Postępy w nefrologii i nadciśnieniu tętniczym. Medycyna Praktyczna, Kraków; t. VII: 71-76.

  23. Hruska K, Mathew S (2011) The roles of the skeleton and phosphorus in the CKD mineral bone disorder. Adv Chronic Kidney Dis; 18: 98-104.

  24. Schmitt CP, Odenwald T, Ritz E (2006) Calcium, calcium regulatory hormones, and calcimimetics; impact on cardiovascular mortality. J Am Soc Nephrol; 17: 78-80.

  25. Cardus A, Parisi E (2006) 1.25-dihydroxyvitamin D3 stimulates vascular smooth muscle cell proliferation trough a VEGF – mediated pathway. Kidney Int; 69: 1377-1384.

  26. Arseculeratne G, Evans AT, Morley SM (2006) Calciphylaxis – a topical overview. J Eur Acad Dermatol Venereol; 20: 493-502.

  27. Muscat M., Brincat M, Degaetano J, Vassallo J, Calleja-Agius J (2013) An usual site for calciphylaxis: a case report. Gynecol Endocrinol; 29: 91-92.

  28. National Kidney Foundation (2003) K/DOQI clinical practice guidelines for bone metabolism and disease in chronic kidney disease. Am J Kidney Dis; 41: 1-201.

  29. De Francisco AL (2006) Medical therapy of secondary hyperparathyreoidism in chronic kidney disease. Expert Opin Pharmacoter; 7: 2215-2224.

  30. Całka A, Napora M, Januszko-Giergielewicz B (2009) Nadczynność przytarczyc leczona kalcymimetykiem – opis przypadku. Forum Nefrol; 2: 241-245.

  31. Podwiński A (2004) Przed i śródoperacyjna lokalizacja gruczołów w nadczynności przytarczyc. W: Więcek A, Kokot F (red) Postępy w nefrologii i nadciśnieniu tętniczym. Medycyna Praktyczna, Kraków; t. III: 183-186.

  32. Bednarczuk T, Chudziński W, Kobylecka M, Królicki L, Bar-Andziak E (2009) Endokrynologia. Postępy. Zagadki kliniczne. Pytania do ekspertów. Medycyna Praktyczna; 2: 52-60.

  33. Carlier T, Oudoux A, Mirallie E (2008) 99mTc-MIBI pinhole SPECT in primary hyperparathyroidism: comparison with conventional SPECT, planar scintigraphy and ultrasonography. Eur J Nucl Med Mol Imaging; 35: 637-643.

  34. Linhartova M, Mitas L, Stary K (2012) The value of intraoperative ultrasonography in paratyroid surgery. Rozhl Chir; 91: 614-619.

  35. Szmit-Domagalska J, Petriczko E, Chrupek M et al (2009) Pierwotna nadczynność przytarczyc u 15-letniego chłopca. Endokrynol Pediatr; 4: 87-94.

  36. Pino R, Pantoja H, Gonzalez P (2005) Usefulness of computed tomography and magnetic resonance in the preoperative diagnosis for hyperparathyroidism. An Otorrinolaringol Ibero Am; 32: 491-498.

  37. Aschenbach R, Tuda S, Lamster E (2012) Dynamic magnetic resonance angiography for localization of hyperfunctioning parathyroid glands in the reoperative neck. Eur J Radiol; 8: 3371-3377.

  38. Ogilvie CM, Brown P, Matson M (2006) Selective parathyroid venous sampling in patient with complicated hyperparathyoidism. Eur J Endocrinol; 155: 813-821.

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