| Abstract|| |
The extent of aluminum related bone disease was evaluated in 41 patients on regular maintenance hemodialysis in two dialysis centers in Riyadh, Saudi Arabia. There were 22 males and 19 females aged 20 to 70 years (mean 35.5+11.2 years). Thirty eight of the patients were on aluminum based oral phosphate binders. Investigations performed included serum calcium, magnesium, aluminum and parathormone and radiological investigations including skeletal survey and dual photon absorptiometry. All the patients underwent bone biopsy and the biopsy material was subjected to morphometric studies, including staining for aluminum deposits. The patients were divided into two groups: group 1, (16 patients, 39%) with negative aluminum staining in the bone biopsy tissue, and group 2, (25 patients, 61%) with positive aluminum staining. Bone pain and its distribution as well as fractures were similarly prevalent in both groups. The levels of aluminum in the blood was significantly higher in group 2 (32.9 + 20.2 vs 17.9 + 11.2 ug/L P<0.05), though it was lower than the lowest accepted toxic level (40 ig/L). There was no significant difference between the two groups in the biochemical or hormonal data, frequency of abnormal radiological signs and pattern of bone histology. Our study indicates that increased aluminum deposition in the bone is prevalent in patients on maintenance hemodialysis using aluminum based phosphate binders, but adynamic bone disease is not prevalent. Further studies may be needed on a larger scale to assess the magnitude of the problem.
Keywords: Renal osteodystrophy, Aluminum, Hemodialysis, Bone biopsy.
|How to cite this article:|
Souqiyyeh MZ, Huraib SO, Aswad S, Shaheen FA, Al-Swailem AR. Is Aluminum Related Bone Disease Common in Hemodialysis Units Using Aluminum Based Phosphate Binders?. Saudi J Kidney Dis Transpl 1995;6:22-7
|How to cite this URL:|
Souqiyyeh MZ, Huraib SO, Aswad S, Shaheen FA, Al-Swailem AR. Is Aluminum Related Bone Disease Common in Hemodialysis Units Using Aluminum Based Phosphate Binders?. Saudi J Kidney Dis Transpl [serial online] 1995 [cited 2022 Jan 20];6:22-7. Available from: https://www.sjkdt.org/text.asp?1995/6/1/22/40894
| Introduction|| |
Bone disease is an invariable accompaniment of chronic kidney diseases associated with a significant reduction in glomerular filtration rate ,, . With the prolongation of lives of patients managed by hemodialysis (HD) renal bone disease has become a major problem  .
The pathogenesis of renal osteodystrophy is attributed to many factors including parathyroid hormone , , vitamin D deficiency , toxins such as aluminum ,,, , iron  and heparin  . A new form of osteomalacia, which does not respond to vitamin D, has been described in HD patients and is becoming a major problem in many centers. This entity (low turnover osteomalacia or adynamic bone disease) has been found to be related to aluminum toxicity , .
We used in this study, the biochemical and hormonal data, and radiological investigations including dual photon absorptiometry in patients on maintenance HD and correlated them with bone histology to evaluate the prevalence of aluminum toxicity in these patients, and the capability of the non-invasive investigations to predict the bone pathology.
| Subjects and Methods|| |
Forty-one patients on chronic HD (22 males, 19 females) in two dialysis centers in Riyadh, Saudi Arabia were selected from a larger dialysis population of 309 patients. The patients were selected on the basis of giving consent to undergo bone biopsy and also fulfilled the following criteria: age more than 18 years, not bedridden, not pregnant, and patients who had not undergone oopherectomy. The patients signed an informed consent form before entering the study. The demographic data are summarized in [Table - 1]. All the patients were on HD with acetate containing dialysate. Aluminum concentration in the treated water was 0.001 (µg/L (acceptable level is up to 0.01 µg/L).
The patients were on aluminum hydroxide 1500 ± 500 mg/day (38 patients), calcium carbonate 1500 ± 500 mg/day (3 patients) and/or 1 hydroxy vitamin D3 1.0 ± 0.5 mg (18 patients). None of the patients were on a combination of both calcium carbonate and aluminum hydroxide.
Biochemical parameters including serum calcium, magnesium, phosphate, alkaline phosphatase, and bicarbonate were studied in all the 41 patients. Measurements were made using automated discrete analyzer (American paralled R). The values of serum calcium were corrected for serum albumin levels by the formula described by Kleeman and co-workers  . All the samples reported in this study were the mean value of three consecutive monthly pre-dialysis measurements. The parathyroid hormone radioimmunoassay was analyzed by the Endocrine
Research Laboratory at King Khalid University Hospital in Riyadh using Amsham Kits (C-terminal), and the assay of serum aluminum was analyzed in Bioscientia Laboratories, Mannes, West Germany.
The radiological studies performed included x-rays of skull, lumbosacral spine, chest, pelvis and both hands. All the x-rays were read by an experienced radiologist at King Khalid University Hospital in Riyadh. The radiological signs looked for were; subcortical erosions, osteopenia, osteosclerosis, osteomalacia (by the presence of looser zones), calcification of soft tissues, and pathological fractures.
The bone mineral density was studied using the dual photon absorptiometry machine (Lunar Radiation Corporation, Madison WI, USA). The results of the measurements were compared with international curves of age and sex-matched normal subjects. The patients were classified accordingly into high, low, normal or borderline.
Forty-one bone biopsies were obtained from the right, iliac spine. Prior to each bone biopsy, oral tetracycline 500 mg twice/day was given on days one, two, 13 and 14. The bone biopsy specimen was obtained on day 18. A 3-mm gauge needle (Vilaghy-Zellerman needle) was used to get the biopsy from the iliac crest, three cm posterior to the anterior superior iliac spine. Two pieces, each about one cm in length were obtained from each patient. The biopsy specimens were fixed in 70% ethyl alcohol. Undecalcified bone sections were prepared and stained at the laboratory of Professor Meunier at the University of Lyon, France according to the method described by Meunier  and Schencker, et al  .
The following parameters were measured in every biopsy specimen: trabecular bone volume, cortical thickness, spongybone volume and surfaces, ratios of bone absorption surfaces, and calcification rate. All the measurements were corrected for age and sex. Aurine tricarboxylic acid (Aluminon) was used to demonstrate aluminum deposits as described by Buchanan, et al  , and Maloney, et al  . Aluminum deposition was considered a sign of toxicity ,,, . A scale of 0-4 pluses was given to indicate the intensity of staining. The higher the scale, the more severe was the toxicity. The patients were divided into two groups: group 1 with no staining of the biopsy tissue for aluminum deposits, and group 2 with staining of variable intensity. Demographic data of the two groups are shown in [Table - 2].
The data compared between the two groups included the etiology of the kidney disease, symptoms of the patient, medications administered, biochemical data, dual photon xrays and biopsy diagnosis. Group 1 contained one diabetic patient, and three who had renal transplantation before, while the rest of the patients in this group had ESRD of unknown etiology. All the patients in group 2 had ESRD of unknown etiology.
| Statistical Methods|| |
The data were studied by Student's "t" test to compare the means ± standard deviations. Chisquare test was used, where appropriate.
| Results|| |
Both groups had similar prevalence and distribution of bone pain as well as prevalence of fractures. There was no difference in the frequency of intake of aluminum hydroxide, calcium carbonate, or vitamin D supplements between the two groups.
Comparison of the biochemical parameters showed significantly higher level of aluminum neither group exceeded the lowest accepted in the blood of patients in group 2, though toxic level (40 fig/L) in plasma , . The levels of serum phosphate, calcium, parathormone, and alkaline phosphatase were not different between the two groups [Table - 3].
Analysis of the x-ray surveys between the two groups did not show any difference in the frequency of occurrence of the radiological signs of renal osteodystrophy [Table - 4]. The comparison of dual photon absorptiometry findings between the two groups also did not show any significant differences. [Table - 5].
Analysis of bone histology showed no significant differences in the frequency of occurrence of osteomalacia and mineralization defects between the two groups. Also, there was no difference in the frequency of pure hyperparathyroidism or mixed types in the groups [Table - 6]. The patients in group 2 had demonstrable aluminum deposits in the bone of intensity + 'or + + .
| Discussion|| |
We evaluated the magnitude of clinical, biochemical, radiological, and histological aspects of aluminum related bone disease in chronic HD patients and tried to determine the non-invasive parameters which could help in evaluating this problem.
Aluminum toxicity in dialysis patients is associated with several clinico-pathological conditions including dialysis dementia , , osteomalacia , , adynamic bone disease , , and microcytic anemia , . There are many reports which show dissociation between the blood and tissue levels of aluminum, as also the blood levels of aluminum and the clinical manifestations of toxicity , .
In our study, the clinical manifestations of aluminum related bone disease were not different between the two groups, a finding similar to what was reported elsewhere ,,, . There was no statistically significant difference in the mean corpuscular volume of red blood cells between the two groups, a finding different from previous studies , . The group which had positive aluminum staining in the bone had more patients with low MCV than the group with the negative staining, but the results did not reach the statistical significance. Perhaps, this was due to the mild degree of toxicity seen in our study grump. We found a high prevalence of aluminum deposition in the bone of the dialysis patients (61%), which is comparable to other reports ,, . None of the non-invasive investigations including the hormonal, radiological and dual photon absorptiometry data could predict the pathology of the bone. The same conclusion was reported before about some of these investigations , .
We did not find a higher prevalence of osteomalacia in the group with positive aluminum staining in our study. Besides, the majority of the patients had pure hyperparathyroidism, which has been claimed before to protect against aluminum low turn over or adynamic bone disease, by preventing the deposition of aluminum in the mineralization front line , . We believe that our patients were noncompliant to the phosphate binders, diet or both, as noted by the uncontrolled serum biochemical and hormonal parameters, with the resultant increased prevalence of hyperparathyroidism in the bone pathology. Accordingly, we concur with other authors that osteomalacia, low turn over or adynamic bone disease may appear if a strict control of hyperparathyroidism with parathyroidectomy is attempted in patients with aluminum toxicity ,, . This makes the need for a bone biopsy to assess the presence of aluminum related bone disease mandatory especially, before parathyroidectomy is performed in dialysis patients. Nonetheless, there is a great difficulty in getting bone biopsies in daily practice, and the cost involved is sometimes prohibitive. Desferroxamine has been shown to displace the deposits of aluminum from the tissue and raise the plasma value to a level at which more patients with toxicity can be identified ,, . This is not only a diagnostic maneuver, but also a therapeutic one  .
We conclude that aluminum deposition is highly prevalent in patients using aluminum based phosphate binders but the aluminum related bone disease was not increased in frequency. This may be because of the uncontrolled hyperparathyroidism seen in our study group protecting the bone from the toxic effects of aluminum. Similar findings might exist in other centers as well. Also, the clinical presentation and the noninvasive investigations alone cannot predict the bone pathology.
Because aluminum is ubiquitous around us, there is a need to evaluate the extent of aluminum toxicity in dialysis patients, despite the recent decline in use of aluminum based phosphate binders. Also, since dialysis patients cannot clear the absorbed aluminum, we expect the problem of aluminum toxicity to continue and there may be a need for multicenter cross sectional* and prospective interventional studies, including desferoxa-mine test and bone biopsies in patients on chronic dialysis.
| Acknowledgment|| |
Thanks to Mr. M.A. Taher, Mr. Pedly F. Atienza and Mr. S. Mohammedali of SCOT for their valuable secretarial assistance in preparing the manuscript.
| References|| |
|1.||Malluche HH, Ritz E, Lange HP, et al. Bone histology in incipient and advanced renal failure. Kidney Int 1976;9:355-62. [PUBMED] |
|2.||Slatopolsky E, Rutherford WE, Hruska K, Martin K, Klahr S. How important is phosphate in the pathogenesis of renal osteodystrophy? Arch Intern Med 1978;13S:848-52. |
|3.||Coburn JW. Renal osteodystrophy. Kidney Int 1980;17:677-93. [PUBMED] |
|4.||Stanbury SW, Lumb GA. Pararthyroid function in chronic renal failure. A statistical survey of the plasma biochemistry in azotaemic renal osteodystrophy. Q J Med. 1966;35(137):l-23. |
|5.||Massry SG. Parathyroid hormone as uremic toxin. In: Massry SG, Blassock RD, ed. Text book of Nephrology. Williams and Wilkines, Baltimore, 1983;2:73. |
|6.||Cheung AK, Manolagas SC, Catherwood BD, et al. Determinants of serum 1,25 (OH)2 D levels in renal disease. Kidney Int 1983;24:104-9. [PUBMED] |
|7.||Voigts AL, Felsenfeld AJ, Llach F. The effect of calciferol and its metabolites on patients with chronic renal failure. 1. Calciferol, dihydrotechysterol, and calcifediol. Arch Intern Med 1983;143:960-3. |
|8.||Dunstan CR, Evans RA. Aluminum and renal bone disease in Australia. Kidney Int (Suppl) 1984;18:S65-9. |
|9.||Smith AJ, Faugere MC, Abreo K, Fanti P, Julian B, Malluche HH. Aluminum related bone disease in mild and advanced renal failure: evidence for high prevalence and morbidity and studies on etiology and diagnosis.Am J Nephroi 1986;6(4):275-83. |
|10.||Sherrard DJ. Aluminum and renal osteodystrophy. Semin Nephroi 1986;6(4Suppl 1):5-11. |
|11.||Malluche HH, Faugene MC. Aluminum-related bone disease. Blood Purif 1988;6:1-15. |
|12.||Eschbach JW, Cook JD, Scribner BH, Finch CA. Iron balance in hemodialysis patients. Ann Intern Med. 1977;87(6):710-3. |
|13.||Faugere MC, Malluche HH. Stainable aluminum and not aluminum content reflects bone histology in dialyzed patients. Kidney Int 1986;30:717-22. [PUBMED] |
|14.||Cournot-Witner G, Zingraff J, Plachot JJ, et al. Aluminum localization in bone from hemodialyzed patients: relationship to matrix mineralization. Kidney Int 1981;2O:375-8. |
|15.||Kleeman CR, Massry SG, Coburn JW. The clinical physiology of calcium homeostasis, parathyroid hormone and oalcitonin 1. Calif Med 1971;114:16-43. [PUBMED] [FULLTEXT]|
|16.||Meunier PJ. Histomorphometry of the skeleton. In:Peck WA, (ed). Bone and Mineral Research Annual 1. Amsterdam: Excerpta Medica 1983;191-222. |
|17.||Schencker RK, Olah AJ, Hermann W. Preparation of calcified tissues for light microscopy. In: Dickson GR (ed). Methods of calcified tissues preparation. Amsterdam: El Sevier 1984;l-56. |
|18.||Buchanan MR, Ihle BU, Dunn CM. Hemodialysis related osteomalacia: a staining method to demonstrate aluminium. J Clin Pathol 1981;34:1352-4. [PUBMED] [FULLTEXT]|
|19.||Maloney NA, Ott SM, Alfrey AC, Miller NL, Coburn JW, Sherrard DJ. Histological quantitation of aluminum in iliac bone from patients with renal failure. J Lab Clin Med 1982;99;206-16. |
|20.||Alfrey AC, Legendre GR, Kaehny WD. The dialysis encephalopathy syndrome. Possible aluminum intoxication. N Engl J Med 1976;294:184-8. |
|21.||Parkinson IS, Ward MK, Kerr DN. Dialysis encephalopathy, bone disease and anemia: The aluminum intoxication syndrome during regular hemodialysis. J Clin Pathol 19S1;34:1285-94. |
|22.||Ihle B, Buchanan M, Stevens B, et al. Aluminum associated bone disease: clinico-pathologic correlation. Am J Kidney Dis 1982^2:255-63. [PUBMED] |
|23.||Ott SM, Maloney NA, Coburn JW, Alfrey AC,Sherrard DJ. The prevalence of bone aluminum deposition in renal osteodystrophy and its relationto the response to calcitriol therapy. N Engl J Med 1982;307:709-13. [PUBMED] |
|24.||Short AI, Winney RJ, Robson JS. Reversible microcytic hypochromic anaemia in dialysis patients due to aluminium intoxication. Proc Eur Dial Transplant Assoc 1980;17:226-33. [PUBMED] |
|25.||Tielemans C, Kalima L, Collart F, et al. Red blood cells indices and aluminium toxicity in hemodialysis patients. Proc Eur Dial Transplant Assoc Eur Ren Assoc 1985;21:395-8. [PUBMED] |
|26.||Broe ME, Van de Vyver FL, Bekaert AB, et al. Correlation of serum aluminum values with tissue aluminum concentration. Contrib Nephrol 1984;38:37-46. [PUBMED] |
|27.||McCarthy JT, Milliner DS, Kurtz SB, Johnson WJ, Moyer TP. Interpretation of serum aluminum values in dialysis patients. Am J Clin Pathol 1986;86(5):629-36. |
|28.||Finch Fl, Bengfeld M, Martin KF. Interrelationship between parathyroid hormone, 1,25-dihydroxy cholecalciferol and aluminum the pathogenesis of osteomalacia in the rat. (ed). Aluminum and iron overload in hemodialysis Mara E. DeBroe (ed). Hognefe and Huber Publishers Toronto 1988;16-19. |
|29.||Hodsman AB, Sherrard DJ, Wong EG, et al. Vitamin-D-resistant osteomalacia in hemodialysis patients lacking secondary hyperparathyroidism. Ann Intern Med 1981;94:629-37. [PUBMED] |
|30.||Coburn JW, Norris KC. Diagnosis of aluminum related bone disease and treatment of aluminum toxicity with deferoxamine. Semin Nephrol 1986;6(4 Suppl 1):12-21. |
|31.||Milliner DS, Nebeker HG, Ott SM, et al. Use of the deferoxamine infusion test in the diagnosis of aluminumrelated ostoedystrophy. Ann Intern Med 1984;101:775-9. [PUBMED] |
|32.||Nebeker HG, Andress DL, Milliner DS, et al. Indirect methods for the diagnosis of aluminum bone disease: plasma aluminum, the desferrioxa-mine infusion test, and serum iPTH. Kidney Int Suppl 1986;18:S96-9. [PUBMED] |
|33.||Andress DL, Nebeker HG, Ott SM, et al. Bone histologic response to deferoxamine in aluminum related bone disease. Kidney Int 1987;31:1344-50. [PUBMED] |
Muhammad Ziad Souqiyyeh
Saudi Center for Organ Transplantation, P.O. Box 27049, Riyadh 11417
[Table - 1], [Table - 2], [Table - 3], [Table - 4], [Table - 5], [Table - 6]