Management of disturbances of calcium and phosphate metabolism in chronic renal insufficiency, with emphasis on the control of hyperphosphataemia

Francesco Locatelli1,, Jorge B. Cannata-Andía2, Tilman B. Drüeke3, Walter H. Hörl4, Denis Fouque5, Olof Heimburger6 and Eberhard Ritz7

1 Department of Nephrology and Dialysis, Azienda Ospedale di Lecco, Ospedale A. Manzoni, Lecco, Italy, 2 Bone and Mineral Research Unit, Instituto Reina Sofia de Investigación, Hospital Central de Asturias, Universidad de Oviedo, Oviedo, Spain, 3 Department of Nephrology and Inserm U507, Necker Hospital, Paris, France, 4 Division of Nephrology and Dialysis, Department of Medicine III, University of Vienna, Vienna, Austria, 5 Department of Nephrology, Hôpital Edouard Herriot, Lyon, France, 6 Division of Renal Medicine, Department of Clinical Science, Karolinska Institute, Huddinge University Hospital, Stockholm, Sweden and 7 Department of Nephrology, University of Heidelberg, Heidelberg, Germany

Abstract

Background. Disturbances of calcium-phosphate (Ca-P) metabolism in chronic renal insufficiency (CRI) play an important role not only in bone disease (renal osteodystrophy) but also in soft tissue calcification, with an increased risk of vascular calcification, arterial stiffness, and worsening of atherosclerosis.

Methods. Discussion in order to achieve a consensus on key points relating to pathogenesis, clinical assessment, and management of renal osteodystrophy in dialysis patients.

Results. Secondary hyperparathyroidism develops primarily as a consequence of reduced active vitamin D production by the kidneys and phosphate retention, with the development of hyperphosphataemia, hypocalcaemia, and increased parathyroid hormone (PTH) levels. The same factors over the long term cause parathyroid gland hyperplasia and autonomous PTH production (tertiary hyperparathyroidism). As hyperphosphataemia and increased CaxP product have been associated with increased mortality in dialysis patients, hyperparathyroidism should be prevented and managed, starting in the pre-dialysis period, by calcium/vitamin D supplementation. Hyperphosphataemia is usually treated by means of intestinal phosphate binders, but different types of binders have been used. The traditional aluminium-based phosphate binders are certainly effective, but have the drawback of side effects due to aluminium absorption (osteomalacia, encephalopathy, microcytic anaemia). Calcium-containing phosphate binders (calcium carbonate or calcium acetate) have mainly been used for the last 10–15 years. However, they aggravate metastatic calcification, particularly if they are taken together with vitamin D analogues and a high calcium dialysate concentration. New calcium- and aluminium-free phosphate binders have recently been developed and may be useful, particularly in patients with metastatic calcification and/or hypercalcaemic episodes, in order to reduce the phosphate burden in the absence of an additional calcium load. New vitamin D analogues and calcimimetic drugs are also being developed for PTH suppression, with the goal to minimize or even entirely avoid hypercalcaemia and/or hyperphosphataemia. A suitable dialysate calcium concentration is important and must take into consideration the medical therapy and the calcium balance on an individual patient basis. Surgical parathyroidectomy is the ultimate means of treating hypercalcaemic hyperparathyroidism, when medical therapy has failed.

Conclusion. Achieving an evidence-based consensus can give clinicians a useful tool for the treatment of disturbances of Ca-P metabolism in CRI: this has become an important objective in nephrological care, particularly as ageing and increased risk of atherosclerosis have become major issues in the dialysis population.

Keywords: atherosclerosis; calcimimetics; hyperparathyroidism; hyperphosphataemia; metastatic calcification; osteodystrophy phosphate binders; vitamin D analogues

Introduction

Disturbances of calcium-phosphate (Ca-P) and vitamin D metabolism in chronic renal insufficiency (CRI) play a key role in the development of secondary hyperparathyroidism. This not only causes bone disease (renal osteodystrophy), but also significantly contributes to the high cardiovascular mortality of such patients. Calcification of coronary plaques, cardiac valves, and myocardial tissue, as well as diffuse myocardial fibrosis, are common pathologic findings in uraemic hearts [13]. Moreover, hyperphosphataemia and an increased calciumxphosphate product have been directly linked to increased mortality in a large number of haemodialysis patients [4]. Similarly, increased mortality was also recently observed in patients with high parathyroid hormone (PTH) levels. The data clearly point to the paramount importance of adequately controlling hyperphosphataemia, ‘a silent killer of patients with renal failure’ [1].

Currently available phosphate binders are flawed by marked side effects, due to intestinal absorption and retention in the body. Aluminium compounds have been shown to be toxic in the long term, as aluminium can be absorbed by the gut and cause encephalopathy, adynamic bone disease, and microcytic anaemia [5]. Calcium-containing compounds often have to be used in high doses, leading to hypercalcaemia and an increased risk of metastatic calcification, especially in patients also on vitamin D therapy. This issue is currently being given more emphasis than in the past, because of the observation of ‘significant, rapidly increasing coronary artery calcification in adults with end-stage renal disease’ [2]. Therefore, research has been directed towards the development of new, non-absorbable calcium- and aluminium-free phosphate binders, new vitamin D analogues, and calcimimetics.

Despite increasingly successful medical therapy, surgical parathyroidectomy (PTx) is still required in a non-negligible proportion of patients on maintenance dialysis. A recent evaluation of patients starting renal replacement treatment (RRT) between 1983 and 1996 in the Lombardy Registry of Dialysis and Transplantation (RLDT) has shown that the mean annual incidence of first PTx was 5.28 per 1000 patient years, and that the incidence increased with time on RRT (3.3 per 1000 patient years in patients on RRT for less than 5 years vs 11.6 in those treated for 5–10 years and 30 in those treated for more than 10 years) [6]. Interestingly, during a follow-up of 7 years, the proportion of patients who underwent PTx and were admitted to RRT between 1990 and 1992 was not different from that of the patients admitted to RRT between 1983 and 1985.

All of these issues will be presented and discussed in depth in this report, focusing in particular on the management of hyperphosphataemia and providing a final consensus on key points.

Hyperparathyroidism in CRI: pathogenesis and prevention

Secondary hyperparathyroidism develops in CRI as a consequence of disturbances of calcium, phosphorus, and vitamin D metabolism. In addition to these well-acknowledged factors, other systemic and local factors may influence PTH synthesis, release, or peripheral activity, further contributing to hyperparathyroidism.

Role of calcium and calcium-sensing receptor
The main factor involved in the regulation of PTH secretion is the concentration of ionized calcium in the extracellular fluid. A very important feature of the parathyroid gland is its sensitivity to small changes in serum calcium concentration [7]. A reduction in extracellular calcium concentration leads immediately, within seconds, to an increase in PTH secretion. Subsequently (hours and days), it stimulates an increase in PTH synthesis. Finally (weeks to months), it enhances parathyroid cell proliferation. Plasma calcium modulates PTH via a change in PTH-mRNA stability and influences the amount of hormone secretion and the degree of hormone degradation within the parathyroid gland [8].

Parathyroid cells have a calcium-sensing receptor (CaR) that recognizes not only extracellular calcium but also other divalent, trivalent, and polyvalent cations [9]. Regulation of CaR expression has major physiological and pathological implications. Recent studies suggest that this receptor is not regulated by extracellular calcium. In contrast, 1,25(OH)2D3 and phosphorus may be implicated in its regulation, although this issue still remains controversial [8]. There is agreement on the fact that hyperplastic parathyroid glands display less sensitivity to calcium than normal tissue [10]. Furthermore, it is important to stress that under physiological conditions, PTH is not completely suppressed during hypercalcaemia, and a basal rate of hormone secretion persists. This basal rate of PTH also occurs in hyperplastic glands, although at a higher level due to a greater gland mass.

Role of phosphorus
It has been demonstrated clearly that phosphorus retention plays an important role in the pathogenesis of secondary hyperparathyroidism [7,8,1012]. Several mechanisms are involved. Phosphorus induces hypocalcaemia and decreases plasma 1,25-(OH)2D3 levels by reducing the activity of the renal enzyme 25-hydroxyvitamin D-1 {alpha} hydroxylase. Recent studies demonstrated that phosphorus also stimulates PTH-mRNA synthesis independent of changes in serum calcium and 1,25(OH)2D3 [11,12]. All of these mechanisms are closely related to each other. In addition, phosphorus also increases parathyroid cell proliferation directly [13].

In vitro studies have demonstrated that high phosphorus levels increase PTH synthesis at the post-transcriptional level. The parathyroid cells respond to changes in serum phosphorus concentration at the level of gene expression by the same mechanism as that described for calcium; that is by influencing PTH-mRNA stability. Low phosphorus decreases, whereas high phosphorus increases PTH-mRNA stability through a change in the activity of the cytosolic protein AUF-1 which binds specifically to the PTH-mRNA 3'-UTR and determines its stability [14].

Role of vitamin D
In CRI, a decreased number of vitamin D receptors (VDR) and resistance to the action of vitamin D are of great importance in the pathogenesis of secondary hyperparathyroidism [10]. This phenomenon is far more marked in the nodular than in the diffuse forms of parathyroid hyperplasia [15]. In CRI, VDR are down regulated. The mechanism seems to be post-transcriptional [12]. As a result, the low serum 1,25(OH)2D3 level and parathyroid VDR number lead to a stimulation of PTH gene expression. In addition, the heterologous regulation of the CaR expression probably involves also 1,25(OH)2D3 and phosphorus. Thus, vitamin D deficiency and phosphorus retention may reduce CaR-mRNA. There is also evidence that 1,25(OH)2D3 can regulate parathyroid cell proliferation directly [16].

Other factors
In addition to calcium, phosphorus, and vitamin D other systemic and local factors are involved in the regulation of parathyroid gland function and PTH peripheral activity. Amongst them, the best known are aluminium, metabolic acidosis, oestrogens, and catecholamines [9,10,17,18]. In addition, it must also be mentioned that a poor peripheral PTH action can be due to target cell resistance, secondary to PTH-receptor down-regulation and post-receptor resistance [10].

Parathyroid gland stimulation and enlargement: an overview
In the regulation of parathyroid gland activity, one can distinguish three different steps. For the acute release of PTH, serum calcium is the only known regulatory factor. For the medium and long-term synthesis of PTH, calcium, phosphorus, and vitamin D are all involved. Vitamin D acts at the transcriptional level, whereas both calcium and phosphorus operate at the post-transcription level. Finally, for the long-term effect involving parathyroid cell hyperplasia—and hence parathyroid gland enlargement—hypocalcaemia, hyperphosphataemia, and low 1,25-(OH)2D3 are effective stimuli. Parathyroid cell proliferation is initially polyclonal, but later on it may be complicated by monoclonal or multiclonal proliferation, which is characteristic of severe and autonomous forms of hyperparathyroidism [10]. The majority of parathyroid glands removed surgically from uraemic patients with severe forms of secondary hyperparathyroidism are nodular, with a reduction in VDR and CaR expression, indicating a reduced capacity to respond to therapy.

The need for early management of secondary hyperparathyroidism
The fact that the above-mentioned disturbances are poorly reversible in the long-term emphasises the need for early management of secondary uraemic hyperparathyroidism, starting with careful control of all the factors involved in the pre-dialytic period. An adequate diet, avoiding excessive ingestion of phosphorus, should be prescribed when creatinine clearance falls to around 30–40 ml/min [19]. Patients should be instructed about phosphorus and protein content of current foods. They need to learn the way to maintain their individual preferences, keeping an adequate nutritional intake. Good personalized dietary advice is important for the prevention and management of secondary hyperparathyroidism.

Clinical consequences and management of hyperphosphataemia and increased CaxP product

CaxP product
The control of hyperphosphataemia in advanced CRI is of utmost importance for three main reasons, as already mentioned above: (i) hyperphosphataemia contributes to the pathogenesis of secondary hyperparathyroidism and its skeletal expression, osteitis fibrosa [7,8,1012]; (ii) it promotes, together with calcium and vitamin D, the formation and deposition of calcium-phosphate crystals in soft tissues, in particular in the vessel wall, in heart valves, and in peri-articular regions [1,2]; and (iii) there is a direct, independent association between the degree of hyperphosphataemia and cardiovascular morbidity and mortality in dialysis patients [2,20].

It is well-known that there are several ways to achieve adequate control of hyperphosphataemia in CRI patients. They include dietary management in terms of low protein intake, the prescription of various phosphorus-binding drugs and an intensification of the dialysis procedure. Each of these methods, in addition to the expected favourable consequences of better control of plasma phosphate, has drawbacks in the form of side effects, which should always be taken into account.

The side effects which may result from severe, uncontrolled protein and phosphorus restriction should not be underestimated, especially in the stage of advanced renal failure with its progressively worsening appetite: a severe reduction in protein intake, most often in association with insufficient calorie intake, actually contributes to malnutrition in a number of patients, or further aggravates it in those who are already malnourished [21]. On the other hand, compliance with dietary restriction is not easily achieved in most patients in the long run, as it involves major changes in lifestyle.

That is the reason why CRI patients often need oral phosphate binders together with meals, in order to reduce intestinal phosphate absorption.

When prescribing phosphorus binders, it is important to emphasize that they should be administered as closely as possible with meals—preferably after rather than before meals, in order to avoid negative effects on the appetite. The dose of phosphorus binder needs to be adapted to the phosphorus content of the meals. Generally speaking, throughout the day only two meals (sometimes one) contain enough phosphorus to justify the use of phosphate binders. However, many nephrologists still prescribe phosphorus binders in three equal doses distributed throughout the day without any need [22].

Among the different phosphate binders available for the control of hyperphosphataemia, the well-known aluminium-containing binders are highly efficient. However, there is the danger of aluminium intoxication with microcytic anaemia, osteomalacia, and encephalopathy as the most frequent clinical manifestations. Whether such drugs should still be prescribed at all, in cases of otherwise uncontrollable hyperphosphataemia, remains a matter of debate [23,24]. Probably short courses of aluminium-containing phosphate binders can be safely given to achieve control of hyperphosphataemia, followed by the use of different binders.

Orally administered calcium-containing salts occupy the first place to date as phosphate-binding drugs, the two most popular preparations being calcium carbonate and calcium acetate [2529]. Both compounds should be taken during or at the end of meals to bind dietary phosphate. They can also be taken between meals to correct hypocalcaemia, when serum phosphorus is normal. Either drug has been prescribed in doses up to 10 or even 15 g/day. However, whether a total daily amount of 6 g, in two or three divided doses, should be exceeded is currently subject to intensive discussion. In fact, the price to pay for phosphate binding by calcium salts is that large amounts of unbound calcium are absorbed and potentially deposited in soft tissues, especially if plasma phosphate remains elevated, via an increased CaxP product. In accordance with this, a direct association has recently been found between the prescribed dose of oral calcium carbonate and arterial wall stiffness, the latter being related to a calculated vascular calcium score [30]. Moreover, in the study by Goodman et al. [2] it was found that young dialysis patients with coronary artery calcifications, as demonstrated by electron-beam CT, had been ingesting twice as much calcium-containing phosphate binder than those without calcium deposits. The risk of inducing extra-skeletal calcifications is further enhanced by the administration of vitamin D [31]. Therefore, caution should be used in administering calcium-containing phosphate binders together with active vitamin D derivatives.

The prescription of calcium citrate to uraemic patients should be avoided, especially in case of the concomitant administration of aluminium-containing compounds. Calcium citrate favours intestinal aluminium absorption, and hence aluminium intoxication [32].

Concerns about the possibility of tissue calcification have prompted research towards new calcium- and aluminium-free phosphate binders. Sevelamer hydrochloride (RenaGel) has recently been marketed in the USA, Canada, Israel, and several European countries. RenaGel is a non-absorbable calcium- and aluminium-free polymer that is intended to be taken orally in divided doses with meals. It has proved to be well-tolerated and effective in lowering hyperphosphataemia and controlling high PTH levels in haemodialysis patients [3338]. It can be effectively and safely used in combination with calcium supplementation and vitamin D for enhanced suppression of PTH [39]. Finally, its favourable effects on lipid profile (reduced total and LDL-cholesterol, unaffected HDL-cholesterol) may provide further benefit by decreasing the cardiovascular risk related to dyslipidaemia [37,40]. A recent case-control study by Collins et al. [41] in haemodialysis patients matched for age, gender, race, and diabetic status showed that, even after correction for co-morbidity factors, the hospitalization risk was lower in patients treated with RenaGel than in control patients, for a mean follow-up of 17 months. However, given the high cost of long-term therapy with RenaGel, precise indications have still to be developed as to when RenaGel and/or a calcium-containing phosphate binder should be used.

Another calcium- and aluminium-free phosphate binder currently under investigation is lanthanum carbonate [42]. However, concerns have been expressed as to the potential intestinal absorption of lanthanum, a rare earth element with an atomic number of 57 and atomic weight of 139, with possible long-term accumulation in tissues, as has been observed for aluminium.

Intensification of the dialysis procedure leads to a better control of hyperphosphataemia [43]. As a result of the slow equilibration of phosphorus between different body compartments, longer dialysis time or in particular more frequent dialysis sessions are more efficient for phosphorus removal than increased blood flow or dialyser clearance. If longer dialysis is combined with more frequent dialysis as in the recently described daily (nocturnal) method [44], this can even lead to over-depletion of easily removed low-molecular weight substances, such as phosphorus. Thus, attention must actually be paid not to inducing hypophosphataemia with such highly efficient methods.

Whatever the dialysis procedure chosen, attention should always be paid to ensure dialysis adequacy as the first-line measure to achieve control of hyperphosphataemia. Similarly, when hyperphosphataemia is present, nephrologists should first verify that an adequate dialysis dose is delivered.

Management of disturbed calcium metabolism
As PTH begins to increase slightly in the early phases of CRI [17], calcium supplements and/or vitamin D supplementation are advisable. For calcium supplementation, given the recent attention to the risk of vascular calcifications due to oral calcium overload [2], it is advisable not to exceed 1–2 g of elemental calcium/day. For vitamin D supplementation, the first step should be to make sure that the patients have normal levels of 25(OH)2D3 (around 40–50 pmol/l), either spontaneously or through supplementation of native vitamin D. If necessary, low doses of 1{alpha}(OH)D3 or 1,25(OH)2D3 (0.1–0.2 µg/day) can be prescribed. The goal is that patients reach advanced renal failure with mildly elevated PTH levels, that is 125–250 pg/ml by Nichols assay, in the absence of severe parathyroid gland enlargement.

Vitamin D analogues
An absolute or relative deficiency of 1,25(OH)2D3 plays a key role in the genesis of secondary hyperparathyroidism. Therapy with active vitamin D (1,25[OH]2D3 [calcitriol]) or analogues, with or without calcium supplements, has become a major tool to correct hypocalcaemia and suppress PTH levels. In fact, the acute administration of calcitriol to achieve high peak plasma levels causes a prolonged suppression of pre-pro-PTH-mRNA in the parathyroid cell [45]. Vitamin D and analogues can be administered either per os or by the i.v. route. Experimental data have indicated that stimulation of parathyroid gland function is more effectively suppressed when the same total dose of 1,25(OH)2D3 is given by intermittent bolus administration rather than by continuous infusion [46]. Therefore, studies were designed to assess the efficacy of intermittent administration of vitamin D, either per os or i.v.

A 12-week trial of intermittent (twice weekly) vs continuous (daily) oral administration of calcitriol in dialysis patients showed that 11 of 21 (52.4%) patients in the intermittent group and 18 of 24 (75.0%) patients in the continuous calcitriol group had reached the treatment goal, i.e. a plasma PTH <=10 pmol/l in the absence of hypercalcaemia and hyperphosphataemia [47].

Moriniere et al. [48] showed that intermittent i.v. administration of 1{alpha}(OH)D3 (alfacalcidol) to haemodialysis patients improved significantly severe hyperparathyroidism without hyperphosphataemia and hypercalcaemia, if oral calcium carbonate and low dialysate calcium were used. Cannella et al. [49] demonstrated that long-term therapy with high-dose i.v. calcitriol pulses in regular haemodialysis patients with proven hyperparathyroid bone disease was able to consistently decrease circulating iPTH towards levels which were comparable with those of subjects with mild or no hyperparathyroid bone disease, and also to decrease the functional mass of parathyroid glands.

A study by Bacchini et al. [50] compared the efficacy, side effects and costs of ‘pulse oral’ vs i.v. calcitriol therapy, finding that intermittent intensive calcitriol therapy, regardless of the route of administration, was effective in suppressing PTH in mild to moderate hyperparathyroidism. In contrast, intermittent calcitriol therapy had a limited ability to achieve sustained serum PTH reductions in haemodialysis patients with severe hyperparathyroidism. The incidence of hypercalcaemic crises was 24% in pulse oral calcitriol-treated patients and 14% in i.v. calcitriol-treated haemodialysis patients, despite lowering calcium dialysate concentration.

In conclusion, clinical trials concerning the comparative efficacy of intermittent, either i.v. or per os, vs continuous administration of active vitamin D have been inconclusive as to what is the best route of administration for the drug, probably because of the inhomogeneity of the studies and the relatively low number of patients studied. This is reflected in the variability of clinical practice patterns regarding the administration of vitamin D and analogues. However, all of these studies showed, to a greater or lesser extent, that hypercalcaemia and hyperphosphataemia are concerns to be taken into account when administering therapy with vitamin D and analogues.

Experimental and clinical studies were, therefore, performed with a number of novel vitamin D analogues, with the intention of suppressing circulating PTH levels without affecting calcaemia and phosphataemia, including maxicalcitol (22-oxacalcitriol), falecalcitriol (26,27-hexa-fluorocalcitriol), paricalcitol (19-nor-1,25-dihydroxyvitamin D2), and doxercalciferol (1{alpha}-hydroxyvitamin D2). However, none of these new compounds were shown to have entirely lost the capacity to induce an increase in plasma calcium or phosphate, and none was superior to calcitriol or alfacalcidol in the long run [51]. Marked hypercalcaemia and hyperphosphataemia require the withdrawal of vitamin D sterols in end-stage renal disease with secondary hyperparathyroidism. In such cases, calcium- and aluminium-free phosphate binders and calcimimetics (see below) may be the first treatment of choice.

Another issue of great interest is whether or not calcitriol administration induces regression of parathyroid gland hyperplasia in renal patients, beyond suppressing PTH. This remains a subject of debate. Notwithstanding the positive findings reported by Cannella et al. [49] in dialysis patients, in rats Jara et al. [52] found no evidence of apoptosis in hyperplastic parathyroid glands in response to high-dose calcitriol combined with marked hypercalcaemia.

Role of dialysis
Calcium mass balance studies showed that in a patient with a normal serum calcium before haemodialysis, dialysate calcium concentrations of 1.25, 1.5, and 1.75 mM result, respectively, in a negative, zero, and a positive calcium balance [53]. Low dialysate calcium concentration (1.25 mM) worsens secondary hyperparathyroidism [54]. Haemodialysis with a high calcium dialysate (1.75 M) impairs left ventricular relaxation, when compared with treatment with a lower calcium dialysate (1.25 or 1.5 mM) [55].

The choice of dialysate calcium concentration must take into consideration medical therapy. For patients receiving calcium supplementation via phosphate binders and/or vitamin D treatment, it is better to use a relatively low dialysate calcium concentration (for instance 1.5 mM) to avoid a positive calcium balance. However, one should be cautious with very low calcium dialysate concentrations such as 1.25 mM, as this can result in a negative calcium balance and stimulate PTH, particularly if patients are not compliant with prescribed calcium/vitamin D supplements.

A recent survey carried out in Spanish dialysis centres demonstrated that the most widely used dialysate calcium concentration was 1.25 mM (44%). This group of patients, who were receiving no more vitamin D supplements than those dialysed with 1.5 or 1.75 mM dialysate calcium concentration, showed significantly higher serum PTH levels [56].

Calcimimetics
Type II calcimimetics are able to reduce serum PTH and ionized calcium in dialysis patients with secondary hyperparathyroidism. Potential indications are all patients with hyperparathyroidism, in particular those who respond to high-dose calcitriol therapy with an adequate decrease of serum PTH level, but who experience an increase of calciumxphosphorus product at the same time. In the experimental animal, calcimimetics not only cause a decrease in circulating PTH, but also suppress parathyroid cell proliferation [57]. Moreover, these compounds are able to halt or even reverse osteitis fibrosa in uraemic rats [58]. The additional administration of active vitamin D compounds may be necessary to overcome intestinal malabsorption of calcium and to maintain normocalcaemia.

Indications for PTx
Indications for PTx include the following, as recently summarized [59]: therapy-resistant hypercalcaemia and hyperphosphataemia in the presence of high circulating PTH levels; biomechanical problems (e.g. fractures, avulsion of the quadriceps tendon); and calciphylaxis (absolute indication).

The modalities of PTx in CRI patients with secondary hyperparathyroidism include subtotal PTx, total PTx with auto-transplantation, and total PTx without auto-transplantation. Subtotal PTx is performed by reducing one gland to approximately 100–300 mg and removing all other glands. If total PT with auto-transplantation is performed, several pieces of non-nodular portions of the parathyroid glands are grafted either into the muscles of the non-fistula-bearing forearm, the sternocleidomastoid muscle; the pre-sternal subcutaneous tissue, the subcutaneous fat of the forearm, or the abdominal fat.

Subtotal PTx or total PTx with auto-transplantation is performed to avoid hypoparathyroidism and the need for long-term supplementation of calcium and vitamin D analogues, in particular after renal transplantation. A recurrence rate, however, between 0 and 80% has been reported for both procedures. In addition, over-productive auto-transplanted parathyroid tissue may be difficult to resect due to invasive growth.

Total PTx without auto-transplantation is the procedure of choice in hyperparathyroid patients with fulminant metastatic calcinosis. However, adynamic bone disease may develop after this procedure. Alcohol injection into the parathyroid gland, as an alternative procedure to PTx, was proposed by Giangrande et al. [60], and has become highly popular in Japan [61].

After succesful PTx, the decrease in PTH is usually accompanied by hypocalcaemia. Severe post-operative hypocalcaemia should be treated by i.v. calcium (for instance, 20 mg/h), complemented by oral calcium supplementation (up to 12 g/day). Oral calcium salts should be taken between meals to avoid precipitation of calcium and phosphate in the intestine. Hypophosphataemic patients may occasionally require phosphate supplementation. Administration of active vitamin D compounds (e.g. calcitriol up to 6 µg/day) stimulates the intestinal transport of calcium and phosphate.

Pathogenesis, clinical implications, and management of low bone turnover disease

Low bone turnover is characterized by a reduced capacity to produce and mineralize bone [17]. In patients with CRI, two main histological forms of the disease have been described, namely osteomalacia and adynamic bone disease.

To date, the majority of patients with low bone turnover are free of symptoms, with the exception of patients having the aluminium-induced form of this disorder, in whom a high incidence of bone pain, hypercalcaemia, and bone fractures has been observed. It remains a matter of debate whether moderate aluminium-induced or non-aluminium-induced forms of low bone turnover will become a problem in the long-term. Patients with low bone turnover (in the presence or absence of aluminium overload) show a reduced ability to handle an exogenous calcium load, and have a more sustained hypercalcaemia after i.v. calcium infusion [62]. This limitation in handling and buffering calcium loads may imply a higher risk of extra-osseous calcifications.

The prevalence of the two forms of low bone turnover disease has changed in recent years, with an increase in the non-aluminium-induced forms, and a decrease in the aluminium-induced ones. These changes seem to be due to several factors. The most important ones are the decreased exposure to aluminium, the type of patients put on dialysis (more diabetics and older patients), and the excessive use of calcium supplements and vitamin D metabolites. Other less important factors may be low levels of sexual and thyroid hormones, and other emerging, but less studied, factors such as cytokines, gene polymorphisms, and changes in the expression of growth factors and receptors involved in bone metabolism.

It is important to stress that the majority of dialysis patients have been exposed throughout the years to several changes in the management of CRI and renal osteodystrophy. Therefore, in several cases a sum of the above discussed factors may have sequentially influenced bone turnover and contributed to the emergence of conditions favouring an increased incidence of low bone turnover.

Prevention and management
A general rule in the prevention and treatment of low bone turnover is to avoid excessive PTH suppression and any source of exposure to aluminium. This requires an adequate choice of vitamin D metabolites, dialysate calcium concentration, and phosphate binders. All of these recommendations should be considered particularly carefully in diabetic patients, aged patients, and also in peritoneal dialysis patients. Generally speaking, apart from avoiding all the risk factors mentioned previously, there is little that can be done to increase bone turnover. In some specific circumstances, the dialysate calcium can be reduced for a limited period of time, aiming at an increment in PTH levels. However, it is not advisable to use this approach as a current strategy for all dialysis patients with low bone turnover [17].

It is important to exclude any aluminium participation in low bone turnover disease states. With some limitations (mainly false negative results), the basal serum aluminium level and/or a challenge with a single desferrioxamine infusion (DFO test) can be useful in the diagnosis of an aluminium overload. However, only a bone biopsy can definitely demonstrate the presence and participation of aluminium in the pathogenesis of low bone bone turnover disease [17]. If the diagnosis of aluminium overload is made, removal of aluminium is necessary. To optimize aluminium removal the following steps need to be taken. The first is to avoid further aluminium exposure, either orally or via the dialysate. This measure implies not using aluminium-containing phosphate binders and aiming at a final aluminium concentration in the dialysate less than 2 µg/l. The second step is to increase aluminium removal. It is important to remember that even in the best conditions, the total amount of aluminium removed through the dialysis procedure is low (in the order of some micrograms per session). To optimize aluminium removal, it is necessary to use a dialysate with low aluminium concentration (less than 2 µg/l). If necessary, two other measures can be added, namely the administration of a low dose or ‘micro dose’ of desferrioxamine, and the use of highly permeable membranes [63,64].

Low bone remodelling does not represent a single pathogenic entity. It rather represents a useful concept to group a common mode of response of the skeleton to different factors. The forms of low bone turnover disease induced by aluminium require active medical management, whereas other forms of low bone turnover disease require only individual preventive measurements in order to avoid unnecessary suppression of bone turnover.

Final accord

After intensive discussion, the panel reached a consensus on the following key points.

Acknowledgments

This report comes from the third ‘Accord Workshop’, which took place in Paris in December 2000. The Accord programme is an independent initiative supported by Membrana GmbH, seeking to bring about European consensus on important treatment and management issues in nephrology and dialysis, to help optimize clinical outcomes for patients (more information can be found at the Accord website: www.accord-online.com). Francesco Locatelli, as chairman of the Accord programme, wrote the Introduction and oversaw the consistency of the manuscript edition of the Accord workshop. Other sections were by the following participants. Jörge B. Cannata-Andía: Hyperparathyroidism in CRI: pathogenesis and prevention, Pathogenesis, clinical implications and management of low-bone turnover disease. Tilman B. Drüeke: Clinical consequences and management of hyperphosphataemia and increased calciumxphosphate product. Walter H. Hörl: Management of disturbed calcium metabolism: vitamin D analogues, role of dialysis, calcimimetics, indications of parathyroidectomy. Denis Fouque, Olof Heimburger, and Eberhard Ritz participated in the discussion, in the final accord, and revised the manuscript giving their suggestions. We would like to thank Thorsten Brandt, Helen Wright and Marco D'Amico for their help in editing the manuscript.

Notes

Correspondence and offprint requests to: Prof. Dr Francesco Locatelli, Department of Nephrology and Dialysis, Ospedale A. Manzoni, Via Dell'Eremo 11, I-23900 Lecco, Italy. Email: nefrologia{at}ospedale.lecco.it Back

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