Home About us Current issue Back issues Submission Instructions Advertise Contact Login   

Search Article 
  
Advanced search 
 
Saudi Journal of Kidney Diseases and Transplantation
Users online: 2589 Home Bookmark this page Print this page Email this page Small font sizeDefault font size Increase font size 
 

EDITORIAL Table of Contents   
Year : 1998  |  Volume : 9  |  Issue : 4  |  Page : 397-415
Osteodystrophy in Chronic Renal Failure Patients


Department of Nephrology and Hypertension, University of Antwerp, Belgium

Click here for correspondence address and email
 

How to cite this article:
D'Haese PC, Couttenye MM, De Broe ME. Osteodystrophy in Chronic Renal Failure Patients. Saudi J Kidney Dis Transpl 1998;9:397-415

How to cite this URL:
D'Haese PC, Couttenye MM, De Broe ME. Osteodystrophy in Chronic Renal Failure Patients. Saudi J Kidney Dis Transpl [serial online] 1998 [cited 2020 May 29];9:397-415. Available from: http://www.sjkdt.org/text.asp?1998/9/4/397/39098

   Introduction Top


In patients with chronic renal failure a number of events involved in mineral homeostasis are disturbed. When the renal function deteriorates to less than 50% of its normal capacity, the kidneys are no longer capable to fully excrete the daily phosphorus load. In addition there will be a decreased capacity to produce lα-hydroxylase; the enzyme responsible for the renal synthesis of the active form of vitamin D; i.e. calcitriol (lα, 25-(OH) 2 vitamin D3) which in turn leads to a decreased calcium absorption from the gut and ultimately the development of hypo­calcemia.

Both hypocalcemia and hyperphosphatemia stimulate parathormone (PTH) secretion. Over time there is also a characteristic increase in the calcium concentration required to suppress PTH secretion (shift in calcium 'set-point'). [1],[2] The net result of these changes is that the parathyroid glands become hypertrophied and hypersecretory. [3]

The changes in mineral metabolism due to renal failure inevitably lead to metabolic bone disease. Already in the early stages of renal impairment, histologic changes can be observed in the bone, so that by the time glomerular filtration rate (GFR) falls to 50% of normal, 50% of the patients exhibit abnormal bone histology. [4]

Renal osteodystrophy is a general term encompassing abroad spectrum of metabolic bone diseases. The state of secondary hyper­parathyroidism as described above, without interference of other metabolic factors, leads to a high turnover bone disease either expressed as a mild lesion without distortion of osteoid organization (lamellar osteoid) or the more pronounced form known as osteitis fibrosa in which the osteoblasts function in a more 'chaotic' way resulting in 'woven osteoid. In osteomalacia the effects of secondary hyperparathyroidism are overridden by other factors that induce a mineralization defect in combination with a low bone turnover. With the mixed bone lesion, which is considered a transitional state, characteristic features of both hyperparathyroidism and osteomalacia are concomitantly present. Finally, adynamic hone (disease), is a type of renal osteodystrophy, the prevalence of which within the dialysis population has grown rapidly during the last years. It is characterized by low bone formation, but in contrast to osteomalacia, in the absence of an increased osteoid volume. An overview of the histological qualification of the various types of renal osteodystrophy is presented in [Table - 1]. [5],[6],[7],[8],[9],[10]


   Phosphorus Retention Top


There is general agreement that phosphorus plays an important role in the pathogenesis of hyperparathyroidism. The mechanism by which this effect occurs is complex and to a certain extent controversial. It has been demonstrated that a rise in serum phosphorus can evoke an increase in PTH secretion [11] . Humans with normal renal function given an oral phosphorus load showed increases in serum phosphorus, decreases in ionized calcium and increased serum PTH. Whether this sequence of events also occurs in early renal failure has been questioned. Indeed, in these patients, despite relative hyperpara­thyroidism, low phosphorus levels are often observed due to a phosphaturic effect of increased PTH levels. [12] The role of phosphorus intake on the production rate of lα,25-(OH) 2 vitamin D 3 (lα-hydroxylase activity in the roximal tubule) is still controversial [13],[14],[15] . With further loss of renal function and its ensuing inappropriate phosphate excretion, phosphate levels undoubtedly increase. This hyperphosphatemia exerts a direct stimu­lating effect on the parathyroid glands as shown by Kilav et al. [16] It also stimulates PTH indirectly through a decreased lα-hydroxylase activity [13],[14] and physiochemical reduction of the calcemia via the calcium x phosphate solubility product. To what extent other mechanisms, such as an effect on phospholipid composition of the parathyroid cell membrane, calcium fluxes in the para­thyroid cell and/or regulations of calcium and/or calcitriol receptors on the parathyroid cell may influence the role of phosphorus in the PTH secretion is not yet fully understood. [17]


   1α,25-(OH) 2 Vitamin D 3 (Calcitriol) Deficiency Top


The kidney is the major site for the production of calcitriol. Here, this important metabolite of vitamin D is biosynthesized under the enzymatic l α-hydroxylase activity, localized in the proximal tubular epithelial cells.

As renal mass decreases with progression of renal failure and the GFR decreases to below 80 ml/min [18] , the ability to generate the active l α ,25-(OH) 2 vitamin D3 compound may also decrease whereas median concen­trations of inactive PTH will increase. Hence, relative (in incipient renal failure) or absolute (with more advanced loss of functional renal mass) deficiency of calcitriol are considered key events in the development of secondary hyperparathyroidism.

Calcitriol deficiency leads directly and indirectly to reduced parathyroid gland suppression and thus higher levels of PTH; directly through its genomic action on the parathyroid cell, and indirectly through reduced intestinal calcium absorption. Thus, a number of patients with reduced serum calcium levels, as may be seen at the onset of renal failure, may present with elevated serum PTH levels despite calcitriol levels within the normal range. Since serum PTH levels and calcitriol do not correlate.[19] the important triggering ability of calcitriol in the development of hyperparathyroidism is thought to be further determined by other underlying biological events yielding to a servocontrol mechanism. [20]

The issue of reduced vitamin D receptors (VDR) at the level of the parathyroid cell, as described before in renal failure patients [21] , remains controversial, at least as long as nodular transformation of the parathyroid gland with increasing duration of renal failure [3],[23] has not developed.[15] Concerning the possible involvement of the VDR gene polymorphisms in the pathogenesis of hyperparathyroidism and other bone lesions continuing controversial results have been reported. [24],[25],[26]


   Altered Parathyroid Function Top


At the transcriptional level, PTH mRNA is increased by lowering serum calcium concentration. [27] By virtue of their VDRs parathyroid cells also respond to increased calcitriol levels through a decreased PTH mRNA production; an effect that has been shown to override a possible simultaneous hypocalcemia induced stimulation. [27] Whether phosphorus either up-regulates or inhibits PTH mRNA synthesis is still a matter of debate. [16],[17],[18],[19],[20],[21],[22],[23],[24],[25],[26],[27],[28]

The secretion of PTH which occurs by exocytosis is controlled by the extracellular calcium concentration involving a recently cloned calcium sensing receptor; [29],[30] the calcium versus PTH relationship being sigmoidal. The cellular events underlying the calcium regulated PTH secretion are presented in [Figure - 1], Hypercalcemia activates the calcium receptor with subsequent production of inositol triphosphate which in turn raises the intracellular calcium concentration by a transient spike in the element's concentration derived from the endoplasmic reticulum, and a more sustained increase due to influx of calcium through voltage sensitive and insensitive channels. An increase in the diacylglycerol concentration leads to an increase in protein kinase C activity that will then inhibit PTH secretion. How hypo­calcemia leads to an increased secretion of PTH is less well documented but increased cAMP levels and protein-kinase-A have been implicated [31] [Figure - 1]. Evidence has been presented recently that similar mechanisms are at work in the regulation of the PTH gene transcription {synthesis) by extracellular calcium [33] Both in vitro [3] and in vivo [16] the secretion of PTH has also been shown to be influenced by the extracellular phosphate concentration, independent from serum calcium and vitamin D. With regard to parathyroid cell proliferation, stimulatory effects induced by hypocalcemia and hypovitaminosis D have been suggested'. Recent data also indicated a stimulatory effect of hyperphosphatemia on parathyroid gland hyperplasia. It remains to be shown however, whether phosphate regulates cell growth directly or indirectly. [24]

The issue of parathyroid cell apoptosis ah remains controversial. Whereas some groups were unable to find any evidence of prosrammed cell death, [34],[33] others reported various degrees of apoptosis [36],[37] Given the preset technical difficulties in demonstrating apoptosis particularly in slowly growing tissues, remains to be seen whether this is real c caused by technical artifacts, as recently demonstrated in both the myocardium [38] an the kidney. [39]

The PTH-induced alterations on the circulating calcium concentration are the results of the hormone's actions on various target organs In bone the cells of the osteoblastic lineage are the primary targets. Here, increased levels of PTH, together with other factors such as interleukin-1 (IL-1) and tumor necrosis factor a (TNF-α), will activate the remodeling cycle through actions on the layer of osteoblasts covering the bone surface. In addition, stimulated osteoblasts and other cells in the bone micro environment (i.e. marrow stromal cells) will produce various cytokines and growth factors; i.e. granulocyte macrophage colony-stimulating factor (GM-CSF), macrophage colony-stimulating factor (M­CSF), interleukin-6 (TL-6), interleukin-II (IL-II). These will, through cell-to-cell communication, stimulate the proliferation and differentiation of osteoclast precursor cells which after fusion to multinucleated osteoclasts will ultimately end-up in an increased bone resorption and release of calcium from the bone. [10],[40]

At low intermittent doses PTH has been shown to stimulate bone formation with an increased number of osteoblasts and higher alkaline phosphatase activity, a feature useful in the design of new therapies for osteoporosis. [41]

At the level of the kidney, the PTH inhibits phosphate re-absorption, increases fractional re-absorption of calcium, and stimulates the la-hydroxylase activity, which results in higher levels of active vitamin D.

New insight has also been gained, using refined knockout technology and in-vitro osteoblast culture models, in the major role played by parathyroid hormone related peptide (PTHrP) and the PTH/PTHrP receptor in bone development and its possible impli­cations in adult bone disorders such as renal osteodystrophy. [24] In addition to the stimulating effects of PTHrP on osteoblast activity, C-terminal fragments of this peptide have most recently been shown to exert anti-proliferative effects on osteoblasts as well, [42] and to inhibit bone resorption in vivo [43] .


   Other Factors Contributing to Renal Osteodystrophy Top


In addition to the systemic factors, a number of other substances may also play a role in the development of renal osteo­dystrophy. In patients with chronic renal failure accumulation of aluminium originating from inadequately treated water used to prepare the dialysis fluid or from the intake of aluminium-containing phosphate binding agents may exert a toxic effect on bone at three levels. Firstly, accumulation of the element at the calcified bone boundary may induce a mineralization defect. Whether this is due to a direct effect on the physicochemical process of hydroxyapatite formation or occurs indirectly by affecting osteoblast function [44],[45] is not yet fully understood. Secondly, as indicated by histomorphometric bone biopsy examination of aluminium­intoxicated patients, aluminium reduces the overall activity of the osteoblast which at the cellular level has been shown to be due to the transferrin-mediated anti-proliferative effect of the element on the osteoblast. To what extent aluminium also affects the proliferation/differentiation rate of osteoblast precursors remains to be established. [47]

Thirdly, it has recently been shown that the uptake of aluminium by transferrin­mediated endocytosis also suppresses the PTH secretion, not synthesis. [48] Whether the so-called aluminium-related bone disease will ultimately be expressed as osteomalacia, the mixed lesion or adynamic bone will depend on whether the effect of aluminum on mineralization, osteoblastic activity, or parathyroid gland function prevails. [5] It will also depend on the situation of the bone tissue at the onset of the intoxication.

Aside from aluminium, other (trace) elements, such as iron, silicon, zinc, lead, vanadium, sulphur and fluoride have also been associated with the development of bone lesions. [7],[49],[50],[51],[52],[53],[54]

At present their role in the development of particular types of renal osteodystrophy however, remains controversial. Recently, increased levels of strontium were observed in dialysis patients with osteomalacia. [55] Support for its role in the development of this bone disease was provided by an experimental study in which strontium administration to chronic renal failure rats resulted in the development of osteomalacic lesion. [56]

Clinical factors that may contribute to renal osteodystrophy include diabetes mellitus which, because of its concomitant deficiency of bone growth factors and lower PTH levels, is typically characterized by a low turn-over state. [57] Renal failure is associated with a state of gonadal dysfunction in both sexes and gonadal steroids are critical to bone remodeling through their potential effects on IL-1 and IL-6 production. Hence they have been considered a contributing factor to renal osteodystrophy. [58],[59] As lα,25­-(OH) 2 vitamin D 3 is deficient in renal failure and since i) this compound has been shown to induce a strong transcriptional up­regulation of the genes of osteocalcin and osteopontin [60] ii) these matrix proteins are secreted at the time of mineralization, their deficiency would be expected to affect matrix organization and mineralization. [10]

Metabolic acidosis is associated with a negative skeletal calcium balance, [61] which results from either the direct dissolution of bone [62] or the stimulation of cell-mediated bone resorption. [63] To what extent metabolic acidosis contributes to the development of renal osteodystrophy is not yet clearly understood. [64] Some evidence has been presented that at the cellular level, the acidotic state stimulates osteoclastic activity while osteoblastic activity is decreased. [62],[64],[65] Also, an additive effect of PTH and acidosis on osteoclastic bone resorption has been suggested. [66] Acidosis may also have an inhibitory effect on lα-hydroxylase activity, thereby contributing to a low calcitriol level. [67]


   The Spectrum of Renal Osteodystrophy Top


Renal osteodystrophy is a general term encompassing both high and low bone turnover forms of bone disease. Mild secondary hyperparathyroidism and osteitis fibrosa belong to the former group, while osteomalacia and adynamic bone disease belong to the low turn over group. In between these two groups, patients may present with a more or less normal histology or a mixed lesion showing the features of both hyperparathyroidism and osteomalacia.

Hyperparathyroid bone disease

As outlined above this disorder is caused by excessive levels of PTH and other activating factors on the skeleton. In hyperparathyroid bone disease, both formation and resorption of bone take place at an accelerated rate. As a result the number of osteoblasts and osteoclasts are increased. Hyperparathyroid bone disease can further be divided in the mild lesion with a high bone turnover but where the osteoid is properly laid down (lamellar) and mineralized, and osteitis fibrosa in which osteoblasts function in a more chaotic way resulting in the deposition of the so-called woven osteoid which is further characterized by the development of a typical marrow fibrosis consisting of fibrous tissue occupying the peritrabecular spaces. Although the mineralization rate is also increased it can not completely keep up with the increased osteoid deposition which will ultimately result in an increased amount of osteoid which mineralises poorly and consists of mechanically deficient woven bone resulting in fragile bone prone to fractures. [68]

Osteomalacia

In osteomalacia the effects of secondary hyperparathyroidism on bone are overridden by other factors that induce a mineralization defect and a low rate of bone turnover. This type of renal osteodystrophy is characterized by an excess of un-mineralized lamellar osteoid producing wide osteoid seams. The number of osteoblasts and osteoclasts are both reduced. Remaining osteoblasts however continue to produce osteoid, which does not get mineralized readily as assessed by tetracycline labeling. The total bone volume may vary whereas mineralized bone volume is always low [68] . Patients suffer from bone deformities, bone pain and fractures.

In end-stage renal failure patients, osteomalacia mostly results from aluminium exposure which is known to inhibit bone minerali­zation by a mechanism that, at the present, is still poorly understood. [5],[44],[45] In osteomalacic patients specific stains for aluminium [69],[70],[71] together with micro-analytical techniques [72] have demonstrated the element to be present at the osteoid calcified bone boundary. Aside from aluminium, other factors such as vitamin D deficiency and perhaps other (trace) elements such as strontium [56] may also play a role in the development of the disease.

Mixed uremic osteodystrophy

In this type of renal osteodystrophy characteristic features of both hyperpara­thyroidism and osteomalacia are present. In the mixed lesion a predominant pathogenic cause is lacking. It is caused primarily by hyperparathyroidism and defective minerali­zation with or without decreased bone formation; features that may co-exist in varying degrees. Marrow fibrosis is present together with increased amounts of osteoid, which can either be of the lamellar or woven type. [68]

Adynamic bone disease

Adynamic bone is characterized by hypo­cellular bone surfaces with decreases in both osteoblastic surfaces and numbers. Osteoclast surfaces may be decreased or normal. [3] The reduced amount or even absence of osteoid together with a decrease in trabecular bone volume are two key aspects of this disorder and in this respect differs from osteomalacia; the other low turnover form of renal osteo­dystrophy.

Neither the exact pathogenesis nor the clinical implications of this type of renal osteodystrophy are at present well understood. Adynamic bone disease has primarily been associated with aluminium intoxication. In contrast to its deleterious effect on bone mineralization as noted in osteomalacia, in the case of adynamic bone disease aluminium is suggested to act at the level of either the osteoblast by reducing its cellular activity and/or proliferation [46],[74],[75],[76] or by suppressing PTH secretion by the parathyroid gland; [48],[77] actions which are thought to be transferring-mediated. [46],[48] The discrepant observation of a growing number of patients with adynamic bone disease concomitantly with a drastic reduction in the exposure to aluminium implies, however, that other pathogenic factors must be active. Here, besides to diabetes mellitus [78] a role has also been attributed to over treat­ment with calcium and vitamin D. Also age, time on dialysis, CAPD and male gender [79],[80],[81],[82],[83] have been reported to hold an increased risk for the development of adynamic bone disease.

Although in dialysis patients with adynamic bone disease serum PTH levels are reduced for the degree of renal failure, the levels are still above the upper normal limit compared to subjects with normal renal function [79] . This suggests that the production of one or more suppressors of bone formation must be increased or that promoters of bone formation must be decreased. [10] Here, a potential role for interleukin-II, interleukin­IV and endothelin, respectively inhibiting bone formation, [84] bone resorption [85] and osteoclast function [73] has been put forward. As osteogenic protein-1 (also called bone morphogenic protein-7) is produced by renal tubular cells [86] and is considered a potent osteoblast growth factor, [87] its deficiency may also contribute to the development of adynamic bone disease in end-stage renal failure. [10] It has been suggested that calcitriol might also lead to a relative resistance of bone on the remodeling effect of PTH. [88] Therefore, its seems that calcitriol may lead to the development of adynamic bone not only by suppressing PTH secretion but also by rendering the bone unresponsive to the effect of PTH. [89],[90] Recently, the provocative hypothesis based on experimental evidence [91],[92] has been put forward stating that by the relative iron depletion noted in the current dialysis population secondary to the intro­duction of erythropoietin, there will be an increase in: (i) number of binding sites for aluminium on transferrin, (ii) the affinity of transferrin for aluminium and (iii) the number of transferrin receptors. This in turn will increase the cellular uptake of the aluminium-transferrin complex via endocytosis [46],[48] making transferrin receptor expressing tissues, such as the parathyroid gland and osteoblast, prone to the deleterious effects of aluminium even when present at relatively low concentrations.

It has been a matter of controversy whether adynamic bone disease represents a clinically relevant disease or is merely a histological diagnosis with no clinical consequences. As low bone turnover implies a failure of the normal homeostatic mechanisms responding to biomechanical stresses in bone, one may reasonably assume that in individuals with adynamic bone, the healing of microfractures and the renewal of areas of bone that have become unstable would be impaired and that this would lead to clinical symptoms [89] , Literature data also point to an increased fracture rate in comparison to that seen in the general population and increased mortality rate as compared with that among patients with other forms of renal osteodystrophy. [93]


   Renal Osteodystrophy: An Evolving Disorder Top


As renal osteodystrophy has a dynamic nature as demonstrated in studies involving serial bone biopsies, [73] one would expect, decreasing prevalence of low turnover bone disease with the withdrawal of aluminium containing phosphate binding agents and the diminished exposure to aluminium containing dialysis fluids. However, whereas concomi­tantly with the decreasing proportion of patients with stainable aluminium, the incidence of osteomalacia indeed decreased [82],[94] a growing number of patients with adynamic bone disease (up to 61% of the dialysis population) has repeatedly been reported. [80],[82],[83],[94],[95] Adynamic bone not only emerges at the expense of osteomalacia, but also goes along with a decreasing prevalence of hyperparathyroid bone disease. [80],[82],[96] The exact physiopathological mechanisms behind a dynamic bone disease are not yet clearly understood and thus reason(s) for its increasing prevalence remain largely unknown. As already outlined in this paper, epidemio­logical and experimental studies have put forward a number of factors contributing to the development of the disorder. Further studies are needed however, to unravel the pathogenetic mechanisms underlying their potential role.


   Diagnosis and Treatment of Renal Osteodystrophy Top


Invasive versus non-invasive diagnosis of renal osteodystrophy

Histological, histomorphometric and in some cases histochemical examination of a bone biopsy must still be considered the gold standard for diagnosis of renal osteodys­trophy. Here classification of the various types of renal bone disease in general is based on the quantification of osteoid deposition, bone formation rate, the presence of marrow fibrosis and histochemical staining of aluminium at the osteoid calcified bone biopsy. Iron deposition, however, has to be excluded beforehand, since it may interfere with aluminium staining [97],[98],[99] Nevertheless, standard clinical practice in diagnosing renal osteodystrophy has evolved away from taking a bone biopsy as it requires invasive procedures. In recent years various non­invasive alternatives making use of bio­chemical indices of bone formation as well as bone resorption [Table - 2] have been evaluated which are essentially all equally and fairly well correlated with histological parameters of bone turn-over. [95],[100],[101],[102] These degrees of correlation do not imply, however, that they are useful to make a diagnosis of renal osteodystrophy. Therefore, evaluation and validation of the diagnostic performance of these biochemical markers in terms of sensitivity, specificity and positive and negative predictive values, as was done recently for bone alkaline phosphatase, osteocalcin and PTH in the diagnosis of aluminum bone disease, [79],[95] remains a challenge for the clinical nephrologists. [24],[102],[103],[104]

Recently, a strategy for the diagnosis and differentiation between aluminium overload/ increased risk for toxicity/aluminium-related bone disease based on baseline serum aluminium values in combination with a low-dose desferrioxamine test and serum PTH measurement has been established. [105]

Aside from biochemical markers, some studies also focused on the diagnostic value of instrumental techniques such as dual X-ray absorptiometry (DEXA) for measurement of the bone mineral density (BMD), hand X­rays by radiographic analysis or ultrasono­graphy for parathyroid imaging. [106],[107],[108] Although these techniques may to a certain extent provide some useful information, their diagnostic values in renal osteodystrophy remains questionable and in general do not add much to the information provided by biochemical markers of bone turnover. Much research needs to be done applying these techniques to end-stage renal disease patients if they are ever to be clinically useful in the renal osteodystrophy population.

Treatment of renal osteodystrophy

The mainstays of the prevention and treatment of renal osteodystrophy continue to be phosphate restriction/binding and calcium supplementation. [109] Phosphate control should start with a low phosphate diet. As it is impractical to reduce the daily phosphorus intake to below 8OOmg/day [1] a phosphate binder, either calcium carbonate or calcium acetate taken with each meal in proportion to its phosphate content is usually also required.

Aluminium containing phosphate binders should be avoided by all means. However, they may be the only available alternative in hypercalcemic patients particularly those in whom vitamin D treatment is contra­indicated. Here, the concomitant intake of citrate (Shohl's solution, fruit juices..) should be avoided since this will increase gastrointestinal absorption of phosphate [111] . The use of magnesium salts in the presence of low magnesium dialysate may allow both the control of serum phosphate concen­trations and higher doses of calcitriol. They can also be used to reduce the required dose of aluminum phosphate binders. As magnesium inhibits mineralization, however, its use requires careful monitoring of serum magnesium concentrations. [113],[114]

Uremic patients may be in negative calcium balance because they often ingest 500 mg/day or less. Also, gut absorption of calcium may be reduced because of decreased serum calcitriol levels. In order to prevent or suppress over secretion of parathyroid hormone, serum calcium levels in end-stage renal failure patients need to be maintained at the upper limit of the normal range. Therefore, the calcium level in the dialysate should be between 6 and 7 mg/dl (1.5-1.75 mM) providing an influx of approximately 800 mg per treatment. [110] Lower calcium levels may exacerbate hypocalcemia and stimulate PTH secretion. As the positive calcium balance is usually greater in CAPD patients, the standard dialysis solution (1.75 mm) is usually adequate within this population. Lower calcium dialysate solution are useful to treat patients in whom hyper­calcemia develops because of supplemental calcium administration or vitamin D therapy Here the dialysate calcium concentration should be reduced to 5 mg/dl (1.25 mM) [10] The efficacy of oral calcium supplementation importantly depends on the timing of intake; calcium taken between meals is more a calcium supplement than a phosphate binder. [10]

Several studies have confirmed the potent inhibitory effect of calcitriol on PTH synthesis and secretion in dialysis patients by both raising serum calcium and inhibiting 1 parathyroid hormone gene transcription. [115],[116] Hence calcitriol and other vitamin D analogues (vitamin D, alfacalcidol, dihydro­tachysterol, calcifedol..) have been widely used to treat secondary hyperparathyroidism, as well as to correct deficient endogeneous production of lα,25-(OH) 2 Vitamin D3. These agents lessen bone pain and improve bone histological features. Since the effe­ctiveness of vitamin D preparations appear to be dependent on peak serum levels achieved, adequate dosing is essential and may obviate the need for surgical intervention of hyperparathyroidism with parathyroidectomy. Revised guidelines for calcitriol dosing according to the severity of hyperpara­thyroidism have recently been presented by Llach et al. Vitamin D preparations are contraindicated in hyperphosphatemic patients because they will further increase the calcium­phosphorus product. [110] Also the use of these compounds should be avoided in the presence of adynamic bone since, aside from their effect on parathyroid gland function, they are also known to decrease osteoblast proliferation. [118]

In patients with aluminium-related bone disease the first line of therapy should consist of withdrawing all sources of aluminium, including aluminium-containing phosphate binders and dialysate with high aluminium content. Although these measures will prevent exacerbation of the aluminium overload they will not remove the element from bone. Here, the use of desferioxamine is recommended. To reduce the risk for side effects associated with the use of this chelator [119],[120] desferrioxamine should be administered at doses as low as 5 mg/kg once weekly during the last hour of dialysis. [121],[122],[123] To ensure adequate removal of both the aluminium and iron desferrioxamine chelates (i.e. aluminoxamine and ferrioxamine) either high-flux polysulphone dialyzers or a charcoal hemoperfusion column should be used during the dialysis session following desferrioxamine administration. [124] Strategies for treatment of aluminium-related bone disease have recently been outlined [121],[122]

The treatment of renal osteodystrophy still poses substantial problems. Therefore, efforts are undertaken continuously to further optimize treatment modalities. Research has been directed towards the development of non-hypercalcemic drugs that are able to interfere with excessive PTH synthesis in the absence of major side effects. A novel class of drugs, the so-called 'calcimimetics' is now being developed. [125] These speci­fically act on the calcium receptor thereby suppressing PTH secretion without affecting plasma calcium or phosphorus levels. The ideal phosphate binder is still lacking, and various compounds are still being evaluated [126],[127] . To which extent bone growth factors such as insulin growth factor may play a role in the therapy of renal bone disease in the near future is still a matter of debate. [128]


   Renal Bone Disease in Hemodialysis versus CAPD Top


There are several differences between CAPD and haemodialysis, which can affect mineral homeostasis. Various studies have indicated that the dialysis modality has a major impact on bone turnover and the progression of uremic bone disease. It has repeatedly been shown that CAPD is an independent risk factor for the development of the adynamic form of renal bone disease.

This finding has been explained by;

i) the lower response of calcium turn over to the action of PTH

ii) the greater positive calcium balance in CAPD vs. haemodialysis providing a more effective suppression of PTH secretion

iii)the greater phosphate removal. [83],[129],[130],[131]

Bone mineral density studies (BMD) have suggested a better bone metabolism and preservation of cortical bone in patients treated by CAPD as opposed to those undergoing haemodialysis treatment; a phenomenon which, at least in part, might be explained by the higher residual renal function generally observed with the former treatment. [132],[133] Others however, have not been able to demonstrate any difference in BMD between CAPD and haemodialysis patients. [134] Histologic findings have provided some evidence for a better therapeutic improvement of metabolic bone disease in CAPD. [135]

In view of the fact that hyperphosphatemia can more easily be controlled in CAPD than by hemodialysis, CAPD patients require less aluminium containing phosphate binders, which together with the lower intradialytic transfer of aluminium put these patients at a lower risk for bone aluminium accumu­lation. [136] Nevertheless, even with the latter treatment modality, care should be taken when treating younger and smaller children, since this population is known to be at an increased risk for aluminium toxicity. [137],[138]


   Acknowledgments Top


The authors are grateful to Erik Snelders for expert desk editing and Dirk De Weerdt for his excellent drawing

 
   References Top

1.Goodman WG, Beliii T, Gales B, Juppner H,Segre GV, Salusky IB. Calcium­regulated parathyroid hormone release in patients with mild or advanced secondary hyper-parathyroidism. Kidney Int 1995;48: 1553-8.  Back to cited text no. 1    
2.Schwarz P, Sorensen HA, Transbol I.Inter­relations between the calcium setpoints of Parfitt and Brown in primaryhyperpara­thyroidism: a sequential citrate and calcium clamp study. Eur J Clin Invest 1994;24:553-8.  Back to cited text no. 2    
3.Driieke TB. The pathogenesis of parathyroid gland hyperplasia in chronic renal failure. Kidney Int 1995;48:259-72.  Back to cited text no. 3    
4.Malluchc HH, Ritz E, Lange HP, et al.Bone histology in incipient and advanced renal failure. Kidney Int 1976;9:355-62.  Back to cited text no. 4    
5.Goodman WG, Duarte ME. Aluminium: effects on bone and role in the pathogenesis of renal osteodystrophy. Miner Electrolyte Metab 1991;17:221-32.  Back to cited text no. 5    
6.D'Haese PC Cabrera WE, Lamberts LV,et al.. Bone strontium levels are increased in dialysis patients with osteomalacia.Nephrol Dial Transplant 1996;11:42  Back to cited text no. 6    
7.Phelps KR, Vigorita VJ, Bansal M,Einhorn TA. Histochemical demonstration of iron but not aluminum in a case of dialysis­associated osteomalacia. Am JMed 1988;84:775-80.  Back to cited text no. 7    
8.Eastwood SB, Stamp TC, De Wardener HE,Bordier PJ, Arnaud CD. The effect of 25-hydroxy vitamin D 3 in the osteomalacia ofchronic renal failure. Clin Sci Mol Med 1977;52:499-508.  Back to cited text no. 8    
9.Jorgetti V, Soeiro NM. Mcndes V: et al. Aluminium-related osteo dystrophy anddesferrioxamine treatment: role of phosphorus. Nephrol Dial transplant 1994;9:668-74.  Back to cited text no. 9    
10.Hruska KA, Teitelbaum SL. Renal osteo­dystrophy. N Engl J Med 1995:333:166-74.  Back to cited text no. 10    
11.Reiss E, Canterbury JM; Bercovitz MA, Kaplan EL. The role of phosphate in this creation of parathyroid hormone in man. J Clin Invest I970;49:2146-9.  Back to cited text no. 11    
12.Martinez I, Saracho R, Montenegro J, Llach F. A deficit of calcitriol synthesis may not be the initial factor in the pathogenesis of secondary hyperparathyroidism. Nephrol Dial Transplant 1996;ll(suppl3): 22-8.  Back to cited text no. 12    
13.Portale AA, Halloran BP, Murphy MM, Morris RC Jr. Oral intake of phosphorus can determine the serum concentration of 1,25-dihydroxy-vitamin D by determining its production rate in humans. J Clin Invest 1986;77:7-12.  Back to cited text no. 13    
14.Portale AA, Halloran BP, Morris RC Jr. Physiologic regulation of the serum concentration of 1,25-dihydroxyvitamin D by phosphorus in normal men. J Clin Invest 1989:83:1494-9.  Back to cited text no. 14    
15.Ritz E, Matthias S, Stefanski A. Genesisof disturbed vitamin D metabolism in renal failure. Nephrol Dial Transplant 1995; 10(suppl4):3-10.  Back to cited text no. 15    
16.Kilav R, Silver J, Naveh-Many T. Parathyroid hormone gene expression inhypophosphatemic rats. J Clin Invest 1995;96:327-33.  Back to cited text no. 16    
17.Slatopolsky E, Dclmez JA. Pathogenesis ofsecondary hyperparathyroidism. Am J Kidney Dis 1994;23;229-36.  Back to cited text no. 17    
18.Wilson L, Felsenfcld A, Drezner MK, Llach F. Altered divalent ion metabolism in early renal failure; role of 1.25 (0H)2D. Kidney Int 1985;27:565-73.  Back to cited text no. 18    
19.Reichel H, Szabo A, Uhl J, et al. Intermittent versus continuous administration of 1,25-dihydroxy-vitamin D 3 inexperimental renal hyperparathyroidism. Kidney Int 1993;44:1259-65.  Back to cited text no. 19    
20.Ritz E, Seidel A, Rarmsch H, Szabo A, Bouillon R. Attenuated rise of 1,25(OH) 2 vitamin D 3 in response to parathyroid hormone in patients with incipient renal failure. Nephron 1991;57:314-8.  Back to cited text no. 20    
21.Korkor AB. Reduced binding of (3H)1,25­dihydroxyvitamin D 3 in the parathyroid­glands of patients with renal failure. NEngl J Med l987;316:1573-7.  Back to cited text no. 21    
22.Szabo A, Merke J, Thomasset M, Ritz E. No decrease of 1,25{OH) 2 D 3 receptors andduodenal calbindin-D9k in uraemic rats. Eur J Clin Invest 1991;21:521-6.  Back to cited text no. 22    
23.Mendes V, Jorgetti V; Nemeth J, et al. Secondary hyperparathyroidism in chronic hemodialysis patients: a clinicopathological study. Proc Eur Dial Transplant Assoc 1983;20:731-8.  Back to cited text no. 23    
24.Driieke TB. Silver J. Mineral metabolism. Curr Opin Nephrol Hypertens 1997;6:305-7.  Back to cited text no. 24    
25.Carling T, Kindmark A, Hellman P, Holmberg L, Akerstrom G, Rastad. Vitamin D receptor alleles b, a and T: riskfactors for sporadic primary hyperparathyroidism (HPT) but not HPT of uremiaor MEN 1. Biochem Biophys Res Commun 1997; 231:329-32.  Back to cited text no. 25    
26.Fernandez E, Fibla J, Betriu A, Piulats JM, Al mirall J, Montoliu J. Association between vitamin D receptor gene polymorphism andrelative hypopara­thyroidism in patientswith chronic renal failure. J Am Soc Nephrol l997;8:1546-52.  Back to cited text no. 26    
27.Naveh-Many T, Fricdlaender MM, Mayer H, Silver J. Calcium regulates parathyroid hormone messenger ribonucleic acid (mRNA), but not calcitonin mRNA in vivo in the rat. Dominant role of 1, 25­dihydroxy-vitaminD. Endocrinology 1989; 125: 275-80.  Back to cited text no. 27    
28.Hernandez D, Concepcion MT. Rodriguez M, Salido E, Torres A. High phosphorus diet increases prepro PTH mRNA independent of calcium and calcitriol in normal rats. Kidney Int 1996;50:1872-8.  Back to cited text no. 28    
29.Riccardi D, Lee WS Lee K, Segre GV, Brown EM, Hebert SC. Localization of theextracellular Ca(2+) -sensing receptor andPTH/PTHrP receptor in rat kidney. Am J Physiol 1996;271:F951-6.  Back to cited text no. 29    
30.Gogusev J, Duchambon P, Hory B, et al. Depressed expression of calcium receptor in parathyroid gland tissue of patients with hyperparathyroidism. Kidney Int 1997;51: 328-36.  Back to cited text no. 30    
31.Silver J. Regulation of parathyroid hormone synthesis and secretion, hi: Coe FL and Favus MJ (eds). Disorders of bone and mineral metabolism. New York, Raven Press 1992;83-106.  Back to cited text no. 31    
32.Moallem E: Silver J, Naveh-Many T. Regulation of parathyroid hormone messenger RNA levels by protein kinase A and C in bovine parathyroid cells. J Bone Miner Res 1995;10:447-52.  Back to cited text no. 32    
33.Nielsen PK, Feldt-Rasrnussen U, Olgaard K. A direct effect in vitro of phosphate on PTH release from bovine parathyroid tissue slices but not from dispersed paratliyroid cells. Nephrol Dial Transplant 1996;ll: 1762-8.  Back to cited text no. 33    
34.Naveh-Many T, Rahaminov R, Livni N,Silver J. Parathyroid cell proliferation in normal and chronic renal failure rats. The effects of calcium, phosphate, and vitamin D. J Clin Invest 1995;96:1786-93.  Back to cited text no. 34    
35.Wang Q, Palnitkar S, Parfitt AM. Parathyroidcell proliferation in the rat: effect of age and of phosphate administration and recovery. Endocrinology 1996;137:4558-62.  Back to cited text no. 35    
36.Wang W, Johansson H, Kvasnicka T. Farnebo LO, Grimelms L. Detection ofapoptotic cells and expression of Ki-67 antigen, Bcl-2, p53 oncoproteins in human parathyroid adenoma. APMIS 1996;104: 789-96.  Back to cited text no. 36    
37.Zhang P, Gogusev J, Duchambon P, Sarfati E, Driieke T. Apoptosis in patients with primary (IO) or secondary (IIO) hyper­parathyroidism (HPTH). J Am Soc Ncphrol 1996;7: 1504 (Abstract).  Back to cited text no. 37    
38.Olivetti G, Abbi R, Quaini F, et al. Apoptosis in the failing human heart. N Engl J Med 1997;336:1131-41.  Back to cited text no. 38    
39.Zhu M. Apoptosis and re-epithelializationin the rat kidney after toxic injury. Ph.D - thesis, University of Antwerp, 1997.  Back to cited text no. 39    
40.Monier-Faugere MC, Malluche HH. Roleof cytokines in renal osteodystrophy. Curr Opin Nephrol Hypertens 1997;6:327-32.  Back to cited text no. 40    
41.Dempster DW, Cosman F, Parisien M,Shen V, Lindsay R. Anabolic actions of parathyroid hormone on bone. Endocr Rev 1993;14:690-709.  Back to cited text no. 41    
42.Valin A, Garcia-Ocana A, De-Miguel F, Sarasa JL. Esbrit P. Antiproliferative effect of the C-terminal fragments of parathyroid hormone-related protein, PTHrP-(107-l 11) and (107-139) on osteoblastic osteo-sarcoma cells. J Cell Physiol 1997;170: 209-15.  Back to cited text no. 42    
43.Cornish J, Callon KE, Nicholson GC, Reid IR. Parathyroid hormone-related protein­(107-139) inhibits bone resorption in vivo. Endocrinology 1997; 138:1299-304.  Back to cited text no. 43    
44.Sprague SM, Krieger NS, Bushinsky DA. Aluminium inhibits bone nodule formation and calcification in vitro. Am J Physiol 1993;264:F882-F90.  Back to cited text no. 44    
45.Bellows CG, Aubin JE, Heersche JN. Aluminium inhibits both initiation and progression of mineralization of osteoidnodules formed in differentiating ratcalvana cell cultures. J Bone Miner Res 1995;10:2011-6.  Back to cited text no. 45    
46.Kasai K, Hori MT, Goodman WG. Transfernn enhances the antiproliferative effect of aluminium on osteoblast-like cells. Am J Physiol 1991;260:E537-43.  Back to cited text no. 46    
47.Goodman WG. Pathophysioiogic mechanisms of aluminium toxicity: Aluminium-induced bone disease. In: De Broe ME, Coburn JW (eds.) Aluminium and renal failure. Dodrecht, Kluwer Acad Publ 1990,87-108.  Back to cited text no. 47    
48.Smans KA, D'Haese PC, Van Landeghem GF, et al. Transferrin-mediated uptake of aluminium by human parathyroid cells results in hypoparathyroidism. J Am SocNephrol 1998 (In Press).  Back to cited text no. 48    
49.Pounds JG, Long GL, Rosen JF. Cellularand molecular toxicity of lead in bone. Environ Health Perspect 1991;91:17­-32.  Back to cited text no. 49    
50.Barrio DA, Braziunas MD. Etchcverry SB, Cortizo AM. Maltol compexes of vanadium (IV) and (V) regulate in vitro alkaline phosphatase activity and osteoblast-like cell growth. J Trace Elem Med Biol 1997;ll:110-5.  Back to cited text no. 50    
51.Moonga BS. Dempster DW. Zinc is apotent inhibitor of osteoclastic boneresorption in vitro. J Bone Miner Res1995;10:453-7.  Back to cited text no. 51    
52.Strause L, Saltman P, Glowacki J. The effect of deficiencies of manganese and copper on osteo-induction and onresorption of bone particles in rats. Calcif Tissue Int l987;41:145-50.  Back to cited text no. 52    
53.Hott M, de PoJlak C, Modrowski D, Marie PJ. Short-term effects of organic silicon on trabecular bone in mature ovariectomized rats. Calcif Tissue Int 1993;53:174-9.  Back to cited text no. 53    
54.Turner CH, Owan I, Bnzcndine EJ: ZhangW, Wilson ME, Dunipace AJ. High fluoride intakes cause osteomalacia and diminished bone strength in rats with renal deficiency. Bone 1996;19:595-601.  Back to cited text no. 54    
55.D'Haese PC, Couttenye MM, LambertsLV, Goodman WG, De Broe ME. Increased strontium levels in bone ofdialysis patients with osteomalacia. J Am Soc Nephrol 1995;6:935.  Back to cited text no. 55    
56.Schrooten I, Cabrera W, DauweS, et al. Strontium causes osteomalacia in chronic renal failure in rats. Kidney Int 1998;54:448-56.  Back to cited text no. 56    
57.Vincenti F, Arnaud SB, Recker R, et al. Parathyroid and bone response of the diabetic patient to uremia. Kidney Int1984:25:677-82.  Back to cited text no. 57    
58.Lyhne N, Pedersen FB. Changes in bone mineral content during long-term CAPD. Indication of a sex-dependent bone mineral loss. Nephrol Dial Transplant1995;10:395-8.  Back to cited text no. 58    
59.Morii H, Okamoto T, Iba K, et al. Age related changes of renal osteodystrophy. Endocrinol Jpn 1979; 26:81-4.  Back to cited text no. 59    
60.Owen TA, Aronow MA; Barone LM, Bettencourt B, Stein GS, Lian JB. Pleiotropic effects of vitamin D on osteoblast gene expression are related to the proliferative and differentiated state of the bone cell phenotype: dependency upon basal levels of gene expression, duration of exposure, and bone matrix competency in normal rat osteoblast cultures. Endocrinology 1991;128:1496-504.  Back to cited text no. 60    
61.Lcmann I Jr. Litzow JR, Lennon El. Studies of the mechanism by which chronic metabolic acidos is augments urinary calcium excretion in man. J Clin Invest 1967;46:1318-28.  Back to cited text no. 61    
62.Bushinsky DA, Krieger NS, Geisser DI, Grossman EB, Coe FL. Effects of pH onbone calcium and proton fluxes in vitro. Am J Physiol 1983;245:F204-9.  Back to cited text no. 62    
63.Kraut JA, Mishler DR, Kurokawa K. Effect of colchicine and calcitonin oncalcemic response to metabolic acidosis. Kidney Int 1984:25:608-12.  Back to cited text no. 63    
64.Kraut JA, Mishler DR, Singer FR, Goodman WG. The effects of metabolic acidosis on bone formation and bone resorption in the rat. Kidney Int 1986;30:694-700.  Back to cited text no. 64    
65.Krieger NS, Sessler NE, Bushinsky DA. Acidosis inhibits osteoblastic and stimulates osteoclastic activity in vitro. Am J Physiol 1992;262:F442-47.  Back to cited text no. 65    
66.Bushinsky DA. Effects of parathyroid hormone on net proton flux from neonatalmouse calvariae. Am J Physiol 1987;252:F585-9.  Back to cited text no. 66    
67.Lefebvre A, de Vemejoul MC, Gueris J. et al. Optimal correction of acidosis changes progression of dialysis osteodystrophy. Kidney Int 1989;36:1112-8.  Back to cited text no. 67    
68.Malluche H, Faugere MC. Renal bone disease 1990: an unmet challenge for the nephrologist. Kidney Int 1990;38:193-211.  Back to cited text no. 68    
69.Faugere MC, Malluche HH. Stainablealuminum and not aluminum contentreflects histology in dialyzed patients. Kidney Int 1986;30: 717-22.  Back to cited text no. 69    
70.Cournot-Witmer G, Zingraff J, Plachot JJ, et al. Aluminum localization in bone from hemodialyzed patients: relationship to matrixmine realization. Kidney Int 1981:20: 375-8.  Back to cited text no. 70    
71.Visser WJ. Aluminium induced bone disease: Histology. In: De Broe ME, Coburn JW (eds.) Aluminium and renal failure. Dordrecht, Kluwer Acad Publ 1990;241-47.  Back to cited text no. 71    
72.Verbueken AH, Van de Vyver FL, Van Grieken RE et al. Ultra structural localization of aluminum m patients with dialysis-associated osteomalacia. Clin Chem l984;30:763-8.  Back to cited text no. 72    
73.Hruska KA. Renal osteodystrophy. Baillieres Clin Endocrinol Metab 1997;11: 165-94.  Back to cited text no. 73    
74.Rodriguez M, Felsenfeld AJ, Llach F. Aluminum administration in the ratseparately affects the osteoblast and bone mineralization. J Bone Miner Res 1990; 5:59-67.  Back to cited text no. 74    
75.Kidder LS, Klein GL, Gundberg CM, Seitz PK, Rubin NH, Simmons DJ. Effects of aluminum on rat bone cell populations. Calcif Tissue Int 1993;53:357-61.  Back to cited text no. 75    
76.deVernejoul MC, Belenguer R, Halkidou H, Buisine A, Bielakoff J, Miravet L. Histo­morphometric evidence of deleterious Bone1985;6:15-20.  Back to cited text no. 76    
77.Morrisscy J, Rothstein M. Mayor G, Slatopolsky E. Suppression of parathyroid hormone secretion by aluminum. Kidney Int 1983;23:699-7O4.  Back to cited text no. 77    
78.Pei Y, Hercz G, Greenwood C, et al. Renal osteodystrophy in diabetic patients. Kidney Int 1993; 44:159-64.  Back to cited text no. 78    
79.Couttenye MM. A dynamic bones disease in dialysis patients. Diagnostic, epidemio­logical and pathophysiological aspects. Ph.D -Thesis. Antwerp 1997.  Back to cited text no. 79    
80.Sherrard DJ, Hercz G, Pei Y, et al. Thespectrum of bone disease in end-stage renal failure - an evolving disorder. Kidney Int 1993;43:436-42.  Back to cited text no. 80    
81.Fournier A, Moriniere P, Cohen Solal ME, et al. A dynamic bone disease in uremia: may it be idiopathic Is it an actual disease? Nephron 1991;58:1-12.  Back to cited text no. 81    
82.Malluche HH, Monier-Faugere MC. Risk of a dynamic bone disease in dialyzed patients. Kidney Int Suppl 1992;38:S62-7.  Back to cited text no. 82    
83.Couttenye MM, D'Haese PC, Deng JT, VanHoof VO, Verpooten GA, De Broe ME. High prevalence of a dynamic bone disease diagnosed by biochemical markers in a wide sample of the European CAPD population. Nephrol Dial Transplant 1997;12: 2144-50.  Back to cited text no. 83    
84.Hughes FJ, Howells GL. Interleukin-11 inhibits bone formation in vitro. Calcif Tissue Int 1993;53:362-4.  Back to cited text no. 84    
85.Watanabe K, Tanaka Y, Morimoto I, et al. Interleukin-4 as a potent inhibitor of bone resorption. Biochem Biophys Res Commun 1990-172:1035-41.  Back to cited text no. 85    
86.Paredes A, Piqueras Al, Briscoe DM, et al. Localization of osteogenic protein-1 (OP­1)mRNA and protein expression in kidney. J Am Soc Nephrol 1993;4:700 (Abstract).  Back to cited text no. 86    
87.Sweeney WE, Jones WK, Harris HW, Paredes A, Ozkaynak E, Ayner ED. Osteogenic protein-1 (OP-1) alters growth and differentiation in the developing metanephros. Pediatr Res 1994;35:A374.  Back to cited text no. 87    
88.Goodman WG, Ramirez JA, Belin TR, et al. Development of a dynamic bone in patients with secondary hyperparathyroidism after intermittent calcitriol therapy. Kidney Int 1994;46:1160-6.  Back to cited text no. 88    
89.Mucsi I, Hercz G. Adynamic bone disease: pathogenesis, diagnosis and clinical relevance. Curr Opin Nephrol Hypertens1997;6:356-61.  Back to cited text no. 89    
90.Gonzalez EA, Martin KJ. Coordinate regulation of PTH/PTHrP receptors by PTH and calcitriol in UMR106-01osteoblast-like cells. kidney Int 1996;50:63-70.  Back to cited text no. 90    
91.Smans KA, Van Landeghem FG, D'HaesePC, Couttenye MM, De Broe ME. Is there a link between erythropoietin therapy and a dynamic bone disease. Nephrol Dial Transplant 1996; U: 1248-9.  Back to cited text no. 91    
92.Van Landeghem GF, D'Haese PC, Lamberts LV, De Broe ME. Competition of iron and aluminium for transferrin: the molecular basis for aluminium deposition in iron-overloaded dialysis patients. Exp Nephrol 1997;5:239-45.  Back to cited text no. 92    
93.Hercz G, Sherrard DJ, Chan W, Pei Y. Aplastic osteodystrophy: follow-up after 5 years. J Am Soc Nephrol 1994;5:851.  Back to cited text no. 93    
94.Monier-Faugere MC, Malluche HH. Trends in renal osteodystrophy: a survey from 1983 to 1995 m a total of 2248 patients. Nephrol Dial Transplant 1996:11:111-20.  Back to cited text no. 94    
95.Couttenye MM, D'Haese PC, Van Hoof VO, et al. Low serum levels of alkalinephosphatase of bone origin: a good marker of a dynamic bone disease in hemodialysis patients. Nephrol Dial Transplant 1996;11:1065-72.  Back to cited text no. 95    
96.Torres A, Lorenzo V, Hernandez D, et al. Bone disease in pre-dialysis, hemodialysis. and CAPD patients: evidence of a better bone response to PTH. Kidney Int 1995; 47:1434-42.  Back to cited text no. 96    
97.Verbueken AH, van de Vyver FL, Visser Van WJ, Grieken RE, De Broe ME. Laser microprobe mass analysis (LAMMA) to verify the aluminum staining of bone. Stain Technol 1986;61:287-95.  Back to cited text no. 97    
98.Parfitt AM, Drezner MK, Gloneux FH, et al. Bone histomorphometry; standardization of nomenclature, symbols, and units. J Bone Miner Res 1996; 11:150-9.  Back to cited text no. 98    
99.Salusky IB, Coburn JW, Brill J: et al. Bone disease in pediatric patients undergoing dialysis with CAPD or CCPD. Kidney Int 1988;33:975-82.  Back to cited text no. 99    
100.Gerakis A, Hutchison AJ, Apostolou T, Freemont A J. Bill is A. Biochemical markers for non-invasive diagnosis of hyperparathyroid bone disease and a dynamic bone in patients on hemodialysis. Nephrol Dial Transplant 1996; 11:2430-8.  Back to cited text no. 100    
101.Salusky IB, Ramirez JA, Oppenheim W, Gales B. Segre GV, Goodman WG. Biochemical markers of renal osteodystrophy in pediatric patients undergoing CAPD/CCPD. Kidney Int 1994;45:253-8.  Back to cited text no. 101    
102.Fournier A, Oprisiu R, Said S, et al. Invasive versus non-invasive diagnosis of renal bone disease. Curr Opin Nephrol Hypertens 1997;6:333-48.  Back to cited text no. 102    
103.Ferreira A. Biochemical markers of bone turnover in the diagnosis of renal osteodystrophy: what do we have, what do we need? Nephrol Dial Transplant I998;13(Suppl3):29-32.  Back to cited text no. 103    
104.Schmidt-Gayk H, Driieke T, Ritz E. Noninvasive circulating indicators of bone metabolism in uraemic patients: can they replace bone biopsy? Nephrol Dial Transplant 1996; 11:415-8.  Back to cited text no. 104    
105.D'Haese PC, Couttenye MM, Goodman WG, et al. Use of the low-dose desferrioxaminetest to diagnose and differentiate between patients with aluminium-related bone disease, increased risk for aluminium-toxicity, or aluminium overload. Nephrol Dial Transplant 1995:10:1874-84.  Back to cited text no. 105    
106.Mazzaferro S, Coen G, Ballanti P, et al. Osteocalcin, PTH, alkaline phosphatase and hand X-ray scores as predictive indices of histomorphometric parameters in renal osteodystrophy. Nephron 1990;56:261-­6.107.  Back to cited text no. 106    
107.Fletcher S, Jones RG, Rayner HC, et al. Assessment of renal osteodystrophy in dialysis patients: use of bone alkaline phosphatase. bone mineral density and parathyroid ultrasound in comparison with bone histology. Nephron 1997;75:4I2-9.  Back to cited text no. 107    
108.Fukagawa M, Kitaoka M, Inazawa T, Kurokawa K. Imaging of the parathyroid in chronic renal failure: diagnosis and therapeutic aspects. Curr Opin Nephrol Hypertens 1997;6:349-55.  Back to cited text no. 108    
109.Andress Dl, Sherrard DJ. The osteodystrophy of chronic renal failure. In: Schrier RW: Gottschalk CW (eds) Diseases of the kidney. Boston, Little Brown 1993:3:2759-88.  Back to cited text no. 109    
110.Kaye M. Bone Disease. In: Daugirdas JY. Ing TS (eds) Handbook of dialysis. Boston, Little Brown 1994;503-21.  Back to cited text no. 110    
111.Molitoris BA, FromentDH Mackenzie TA, Huffer WH, Alfrey AC. Citrate: a major factor in the toxicity of orally administered aluminum compounds. Kidney Int 1989;36:949-53.  Back to cited text no. 111    
112.Ghazali A, Ben-Hamida F, Bouzernidj M, El-Esper N, Westcel PF, Fournier A. Management of hyperphosphatemia in patients with renal failure. Curr Opin Nephrol Hypertens 1993;2:566-79.  Back to cited text no. 112    
113.Navarro-Gonzalez JF. Magnesium in dialysis patients: Serum levels and clinical complications. Chn Nephrol 1998;49:373-­78.  Back to cited text no. 113    
114.Boskey AL, Posner AS. Effect of magnesium on lipid-induced calcification: an in vitro model for bone mineralization. Calcif Tissue Int 1980;32:139-43.  Back to cited text no. 114    
115.Llach F, Nikakhtar B. Current advances in the therapy of secondary hyperpara­thyroidism and osteitis fibrosa. Miner Electrolyt Metab 1991;17:250-5.  Back to cited text no. 115    
116.Ridgeway RD 3 MacGregor RR Opposite effects of 1,25 (OH) 2 D 3 on synthesis and release of PTH compared with secretory protein I. Am J Physiol 1988;254:E279-86.  Back to cited text no. 116    
117.Llach F, Dressier R, Lindberg JS, Norris KC. The treatment of renal osteodystrophy: Optimizing outcomes. Nephrol Exchange1997;7:2-16.  Back to cited text no. 117    
118.Goodman WG, Ramirez JA, Belin TR, et al. Development of a dynamic bone in patients with secondary hyperparathyroidism after intermittent calcitriol therapy. Kidney Int1994;46:1160-­6.  Back to cited text no. 118    
119.Van Cutsem J, Boelaert JR. Effects ofdefcroxamine, feroxamine and iron on experimental mucormycosis (zygomycosis). Kidney Int 1989;36:1061-8.  Back to cited text no. 119    
120.McCauley J, Sorkin MI. Exacerbation of aluminium encephalopathy after treatment with desferrioxamine. Nephrol Dial Transplant l989;4:110-4.  Back to cited text no. 120    
121.Barata JD, D'Haese PC, Pires C, Lamberts LV, Simoes J, De Broe ME. Low dose (5mg/kg) desferrioxamine treatment in acutely aluminium-intoxicated hemodialysis patients using two drug administration schedules. Nephrol Dial Transplant 1996; 11:125-32.  Back to cited text no. 121    
122.D'Haese PC, Couttenye MM, De Broe ME. Diagnosis and treatment of aluminiumbone disease. Nephrol Dial Transplant1996;1 L Suppl 3:74-9.  Back to cited text no. 122    
123.Verpooten GA, D'Haese PC, Boelaert JR, Becaus I, Lamberts LV, De Broe ME. Pharmacokinetics of aluminoxamine and ferrioxamine and dose finding of desferrioxamine in hemodialysis patients. Nephrol Dial Transplant 1992;7:931-8.  Back to cited text no. 123    
124.Vasilakakis DM, D'Haese PC, Lamberts LV, Lemoniatou E, Digenis PN, De Broe ME. Removal of aluminoxamine and ferrioxamine by charcoal hemoperfusion and hemodialysis. Kidney Int 1992;41: 1400-7.  Back to cited text no. 124    
125.Antonsen JE, Sherrard DJ. Andress DL. Acalcimimetic agent acutely suppresses parathyroid hormone levels in patients with chronic renal failure. Rapid Communi­cation. Kidney Int 1998;53:223-27.  Back to cited text no. 125    
126.Dewberry K, Fox JS, Stewart J, Murray JR, Hutchison. Lanthanum carbonate: a novelnon-calcium containing phosphate binder. J Am Soc Nephrol 1997;8: 560(Abstract).  Back to cited text no. 126    
127.Chertow GM; Burke SK, Lazarus JM, et al. Poly (allylamine hydrochloride] (Renagel):a noncalcemic phosphate binder for the treatment of hyperphosphatemia in chronicrenal failure. Am J Kidney Dis 1997;29:66-71.  Back to cited text no. 127    
128.Jehle PM, Jehle DR, Mohan S, Keller F. Renal osteodystrophy: new insights in pathophysiology and treatment modalities with special emphasis on the insulin-like growth factor system. Nephron 1998:79: 249-64.  Back to cited text no. 128    
129.Coburn JW. Mineral metabolism and renal bone disease: Effects of CAPD versus hemodialysis. Kidney Int 1993;40:S92-100.  Back to cited text no. 129    
130.BO. Kurz P, Tsobanelis T, Roth P, et al. Differences in calcium kinetic pattern between CAPD and HD patients. ClinNephroJ1995;44:255-61.  Back to cited text no. 130    
131.Owen TA, Axonow MA, Barone LM, Bettencourt B, Stein GS; Lian JB. Pleiotropic effects of vitamin D onosteoblast gene expression are related to the proliferative and differentiated state ofthe bone cell phenotype: dependency upon basal levels of gene expression, duration of exposure, and bone matrix competency in normal rat osteoblast cultures. Endocrinology 1991;128:1496­-504.  Back to cited text no. 131    
132.Mottet JJ, Horber FF, Casez JP, Descoeudres C, Jaeger P. Evidence for preservation of cortical bone mineral density in patients on continuous ambulatory peritoneal dialysis. J Bone Miner Res 1996;ll:96-104.  Back to cited text no. 132    
133.Pasadakis P, Hodis E, Manavis J, Mourvati E, Panagoutsos S, Vargemezis V. The identification of bone mineral density in CAPD in comparison with HD patients. Adv Perit Dial 1995;ll:247-53.  Back to cited text no. 133    
134.Gabay C, Ruedin P, Slosman D, Bonjour JP, Leski M, Rizzoli R. Bone mineral density in patients with end-stage renal failure. Am J Nephrol l993;13:115-23.  Back to cited text no. 134    
135.Shusterman NH, Wasserstein AG, Morrison G, Audet P, Fallon MD, Kaplan F. Controlled study of renal osteodystrophyin patients undergoing dialysis. Improved response to continuous ambulatory peritoneal dialysis compared with hemodialysis. Am J Med 1987;82: 1148-56.  Back to cited text no. 135    
136.Joffe P, Podenphant J, Heaf JG. Bone histology in CAPD patients: a comparison with hemodialysis and conservatively treated chronic uremics. Adv Perit Dial 1989;5:171-6.  Back to cited text no. 136    
137.Milliner DS, Malekzadeh M, Lieberman E, Coburn JW. Plasma aluminum levels m pediatric dialysis patients: comparison of hemodialysis and continuous ambulatory peritoneal dialysis. Mayo Clin Proc 1987;62:269-74  Back to cited text no. 137    
138.Roodhooft AM, van de Vyver FL, D'Haese PC, van Acker KJ, Visser WJ, de Broe ME. Aluminum accumulation in children on chronic dialysis: predictive value of serum aluminum levels and desferrioxamine infusion test. Clin Nephrol 1987;28:125-9.  Back to cited text no. 138    

Top
Correspondence Address:
Marc E De Broe
Department of Nephrology-Hypertension, University Hospital Antwerp, Wilrijkstraat 10, B-2650 Antwerp (Edegem)
Belgium
Login to access the Email id


Rights and Permissions


    Figures

  [Figure - 1]
 
 
    Tables

  [Table - 1], [Table - 2]



 

Top
 
 
    Similar in PUBMED
    Search Pubmed for
    Search in Google Scholar for
    Email Alert *
    Add to My List *
* Registration required (free)  
 


 
    Introduction
    Phosphorus Retention
    1α,25-(OH)<...
    Altered Parathyr...
    Other Factors Co...
    The Spectrum of ...
    Renal Osteodystr...
    Diagnosis and Tr...
    Renal Bone Disea...
    Acknowledgments
    References
    Article Figures
    Article Tables
 

 Article Access Statistics
    Viewed2946    
    Printed45    
    Emailed0    
    PDF Downloaded215    
    Comments [Add]    

Recommend this journal